case study of childhood schizophrenia

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“One in a million”: A case of a very early onset schizophrenia

1 Assistant Professor of Psychiatry, Department of Psychiatry, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA

2 PGY4-Child and Adolescent Psychiatry Fellow, Department of Psychiatry, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA

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Daisy Vyas Shirk

DO, 875 Stoverdale Road, Hummelstown, Pennsylvania 17036,

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Article ID: 100083Z06DS2020

doi: 10.5348/100083Z06DS2020CR

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Introduction: Very early onset schizophrenia (VEOS), psychosis prior to age 13, is rare with an incidence of less than 0.04%. Its clinical presentation, course, and outcome differ from early onset (ages 13–18) and adult onset (ages 18 and up) schizophrenia. It is associated with poor response to treatment, poorer prognosis, and multiple hospitalizations. Early identification and intervention has shown to improve overall functioning.

Case Report: We present a case of a 12-year-old female with significant family history of psychosis, admitted due to physical and verbal aggression, sexual inappropriateness, destruction of property, response to internal stimuli, decline in functioning, and 10 month history of social isolation. She responded to risperidone treatment. The patient was discharged to partial hospitalization program but could not tolerate the group setting resulting in discharge to outpatient services. Psychosocial supports were put in place to help with environmental and family dynamics to improve outcome.

Conclusion: As per a recent study, one-third of children and adolescents with psychosis initially present with negative symptoms. It has also been reported that 30% of those with negative symptoms develop treatment failure with antipsychotics. Given these statistics and the treatment challenges of this case, it was imperative to provide additional psychosocial supports to the patients and families, to improve overall functioning and long-term prognosis.

Keywords: Compliance, Intellectual disability, Psychotic disorders, Psychosocial support systems

INTRODUCTION

Very early onset schizophrenia (VEOS), defined as onset of psychosis prior to age 13, is considered to be very rare [1] . It has been shown to differ in its clinical presentation, course, and outcome compared to early onset (between ages 13 and 18) and adult onset (ages 18 and up) schizophrenia. It is associated with poorer prognosis, worse overall functioning, and multiple hospitalizations [2] . Early childhood adversity and borderline intellectual functioning have also been shown to contribute to development of psychosis [3] , [4] , [5] . Early identification and intervention have been shown to reduce the morbidity of the illness and improve overall functioning. Here we present the case of a young girl with very early onset schizophrenia.

CASE REPORT

This is a case of a 12-year-old female child who was admitted in the inpatient child psychiatry unit due to physical and verbal aggression toward peers and staff, sexually inappropriate touching, destruction of property, attempting to run out into traffic, and responding to internal stimuli.

The patient was reportedly doing well until 10 months prior to her hospitalization, after which she exhibited school refusal and declining grades. The only trigger reported was school bullying. She was noted to become more verbally and physically aggressive toward peers and school staff, with daily outbursts, eloping from school, poor sleep, and social isolation. At home, she was observed to sit in the halls in the middle of the night, conversing with herself. She changed from a child who “used to love talking, playing board games, and card game with her cousins” into someone who “now sits by herself and does not say anything to them or do anything with them.” She was also found one time sitting on her porch eating leaves.

She was referred and underwent partial hospitalization. During that treatment, she was observed to be impulsive, hyperactive, withdrawn, had difficulty with peer interactions, appeared internally preoccupied, laughed inappropriately, talked to herself, sing, or would dance alone without music. She struggled with boundaries and attempted few times to choke staffs with their lanyards or with her hands. She destroyed property, made verbal threats toward staff and peers, and made sexually inappropriate comments and gestures. She was given a trial of lithium and risperidone. She did not tolerate lithium but responded to risperidone 1 mg daily. Upon discharge, there was no follow-up and patient ran out of medication. This led to a deterioration of behaviors resulting in inpatient treatment.

Patient’s developmental history and medical histories are unremarkable. Her family history is significant for schizophrenia in her father who reportedly went from being a straight A student, attending college on a full scholarship to dropping out of school, having multiple incarcerations and now has been institutionalized in a long-term psychiatric facility for the past 10 years. The patient’s mother also received inpatient treatment after patient’s birth and there was a threat of all three children being removed by Children and Youth Services (CYS). At the time of hospitalization, she lived with her mother, 9-year-old sister, and 3-year-old brother. Child protection services were involved at the time of admission due to concerns of a possible sexual abuse based on patient’s sexualized behaviors.

Mental status examination at the time of admission

The patient had fair grooming but was agitated and uncooperative during the interview. Her eye contact varied from fair to intense staring. She did not display any motor abnormalities including tics or tremors. She spoke loudly and often repeated the phrase, “I don’t give a f***” to many questions. She refused to describe her mood and her affect was bizarre and labile; though content was characteristic of paranoia and perseverations. She refused to answer questions related to perceptual disturbances, suicidality, and homicidality. Her orientation, memory, and knowledge could not be fully assessed. Her attention, insight, and judgment were impaired.

Admission diagnosis

Unspecified psychosis was not revealed due to a substance or known physiological condition.

Course of inpatient treatment

The patient was diagnosed with unspecified psychosis on admission. Workup ( Table 1 , Table 2 , Table 3 , Table 4 , Table 5 , Table 6 ) was done and the patient was restarted on risperidone for her aggression and hallucinations. On her first three days of hospitalization, she displayed aggressive, impulsive, and disruptive behaviors toward peers and staffs. Her risperidone was titrated up to 1.75 mg/day. Her aggression subsided and she was able to attend groups. However, she had difficulty engaging with others, often preferring to sit by herself and away from the crowd. She initially endorsed auditory and visual hallucinations where she saw shadows or gravesite with numbers. She would occasionally have difficulty distinguishing reality from fiction, often asking staff if they were real or part of her imagination. Early on in her treatment, the patient had several days when she reported “itching” on her chest stating that she was being stabbed by someone. Once that was resolved, she became preoccupied by her fingertips and would often be seen picking at the tips of her fingers. She struggled with being able to process information and was often mute or would repeat things that had been said to her or perseverate on a specific sentence. She displayed paranoia on the unit, often worrying that someone would come in and hurt her and at times feared that the staff would hurt her. Initially, she had trouble sleeping at night and would often stand in her doorway staring at staff for the majority of the night. She was allowed to sleep on a mattress in her doorway which seemed to help at times but not consistently. Later, she denied having hallucinations although she appeared internally preoccupied throughout the stay.

Neuropsychological assessment was completed which revealed that the patient’s IQ was likely in the borderline range (70–79). She had limited verbal comprehension and expression, relative weakness in verbal knowledge, fluid reasoning, set-shifting, visual-motor integration, phonemic and semantic fluency, and rote verbal memory. She also had significant deficits in executive functioning and negative and positive symptoms of psychosis.

Medical issues

Started on Vitamin D3 to correct for low Vitamin D.

Interventions at discharge

Due to the many challenges this patient presented and concerns about compliance with aftercare recommendations, she was referred to as many outpatient services as possible to help improve her prognosis. These services included partial hospitalization, involvement of children and youth services, case management services, family support in the form of patient’s paternal grandmother, referral for electroencephalogram (EEG) and magnetic resonance imaging (MRI) of brain and school involvement.

Partial hospital treatment

Upon arrival to partial hospitalization, patient’s behaviors had deteriorated due to non-compliance with medications for a week as a result of problem with insurance. She reported sporadic hallucinations, giggled by herself, displayed thought blocking, disorganized behaviors, made random, unrelated, bizarre statements, sometimes loudly and perseverated on them and was paranoid.

During her partial hospitalization, she was disruptive, made sexually inappropriate comments and became verbally and physically aggressive toward staff. As a result of these behaviors and her inability to tolerate the group setting of partial hospitalization, she had to be discharged to outpatient services. As was the case during her discharge from inpatient treatment, patient’s mother did not show up for her discharge and CYS had to find her.

When found, her mother once again claimed she was unaware of the discharge.

Follow-up in outpatient treatment

In the outpatient clinic, risperidone was titrated up to 1 mg orally twice a day, with a good response. Patient’s mother reported that the patient was doing well in school and seemed to be at her baseline after dose increase. During outpatient visits, the patient denied hallucinations, thought blocking was noted to improve, and the patient was answering questions and smiling appropriately most of the times.

Response latency and processing time remained slow but showed improved from previous visits. Family based mental health (FBMHS) services were recommended and started with in-home therapy 2–3 times a week. A case manager through CYS was recommended to support family in managing follow-up appointments.

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Very early onset psychosis, defined as psychosis before the age of 13, is an extremely rare occurrence with an incidence of less than 0.04% [1] , [6] . One-third of children and adolescents with psychosis initially present with negative symptoms and 30% of those who present with negative symptoms at baseline go on to develop treatment failure with antipsychotics. Confounding these statistics is that VEOS is often difficult to diagnose, especially in this case due to lack of reliable collateral information from family. Our patient presented with several risk factors including father’s diagnosis of schizophrenia requiring institutionalization for the past 10 years. There was also a strong suspicion of mental illness in patient’s mother. Environmentally, our patient had a history of trauma in the form of bullying at school and she lacked social supports and lack of follow-up with treatment recommendations.

Additionally, our patient had several premorbid symptoms such as social withdrawal, poverty of speech, and steady decline in social and academic performance over the course of her educational history. Freeman et al. [4] have reported that there is a direct correlation between lower intellectual functioning and development of psychosis due to alteration in the way stimuli and events are interpreted. Another study demonstrated a significant association with psychosis and auditory hallucinations “that remained significant after controlling for age, gender, current social class and ethnicity” [5] . Childhood adversity, as experienced by this patient, also increases the risk of psychosis. A review by Varese et al. [3] showed that exposure to all types of adversity (except parental death) was related to an increased risk of psychosis. Furthermore, a recent study of adolescents experiencing psychosis suggested early intervention by a specialist team may improve treatment outcomes in both positive and negative symptoms [7] . This may also hold true for VEOS. At presentation, our patient displayed the following negative symptoms of schizophrenia: blunted affect, emotional withdrawal, poor rapport, social isolation, poverty of speech, mutism, and psychomotor retardation.

Comorbidities for this patient included oppositional defiant behaviors, borderline intellectual functioning and trauma in the form of physical and emotional abuse by peers, and suspicion of possible sexual abuse given her sexual acting out behaviors.

Our patient provided several treatment challenges due to her mother’s mental state and inability to provide reliable collateral information, non-compliance with follow-up with patient’s outpatient services, and non-compliance with following medication recommendations. Additionally, the lack of sufficient services for young children with psychosis made aftercare recommendations challenging for the treatment team.

Given the many complications this patient presented, the treatment team focused on utilizing the resources that were available such as patient’s paternal grandmother’s increased involvement in her care. There was also collaboration of care with outside agencies such as Children and Youth Services, Case Management, and her school. These services provided support to her mother and made her accountable for complying with aftercare plans and recommendations.

One-third of children and adolescents with psychosis initially present with negative symptoms and 30% of those with negative symptoms, develop treatment failure with antipsychotics. Given these statistics and the treatment challenges of treating children with psychosis, it is imperative to provide additional psychosocial supports to the patients and families, to improve overall functioning and long-term prognosis. This case presents an excellent example of many challenges that are faced in treating early onset psychosis.

SUPPORTING INFORMATION

Daisy Vyas Shirk - Conception of the work, Design of the work, Acquisition of data, Analysis of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Meenal Pathak - Acquisition of data, Analysis of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Jasmin Gange Lagman - Acquisition of data, Analysis of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Khurram S Janjua - Acquisition of data, Analysis of data, Drafting the work, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

The corresponding author is the guarantor of submission.

Written informed consent was obtained from the patient for publication of this article.

All relevant data are within the paper and its Supporting Information files.

Authors declare no conflict of interest.

© 2020 Daisy Vyas Shirk et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.

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CASE REPORT article

Early-onset schizophrenia with predominantly negative symptoms: a case study of a drug-naive female patient treated with cariprazine.

• Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary

Schizophrenia is a chronic and severe mental disorder characterized by positive, negative, and cognitive symptoms. Negative symptoms are usually present from the prodromal phase; early diagnosis and management of negative symptoms is a major health concern since an insidious onset dominated by negative symptoms is associated with a worse outcome. Antipsychotic medications, which are effective for treating positive symptoms, are generally ineffective for treating negative or cognitive symptoms. We present a 23-year-old woman showing severe symptoms at her first visit to our department. The patient’s parents reported that their daughter had experienced several years of psychosocial decline and putative psychiatric symptoms, but no medical attention had been previously sought; as such, the diagnosis of schizophrenia with predominantly negative symptoms was very much delayed. Early onset of schizophrenia, longer duration of untreated psychosis, and severe negative symptoms, which have limited treatment options, suggested a poor prognosis. We initiated monotherapy with cariprazine, a novel antipsychotic that has recently been proven efficacious in treating schizophrenia with predominantly negative symptoms. This report describes a 52-week cariprazine treatment regimen and follows the patient’s impressive clinical improvement confirmed by PANSS and CGI scores, and psychological tests.

Schizophrenia is a severe, chronic, and heterogeneous mental disorder that often has debilitating long-term outcomes. Its lifetime prevalence rate is estimated to be approximately 1% worldwide in the adult population ( Lehman et al., 2010 ). Onset generally occurs in late adolescence or early adulthood, with an average age of 18 years for men and 25 years for women. 1 The term early-onset schizophrenia (EOS) is used to refer to patients who are diagnosed with the disorder before this age. EOS is a severe, frequently disabling, and chronic condition with a prevalence approaching 0.5% in those younger than 18 years ( Hafner and Van der Heiden, 1997 ).

Schizophrenia is accompanied by a distortion of personality that affects fundamental mental and social functions, making everyday life extremely difficult for patients. Clinical symptoms are often classified in three main domains: positive symptoms, such as hallucinations, delusions, suspiciousness/persecution; negative symptoms, such as emotional withdrawal, blunted affect, and passive social withdrawal; and cognitive symptoms, such as impaired perception, learning, thinking, and memorizing. EOS may be accompanied by greater symptom severity, premorbid developmental impairment, ‘soft’ neurological signs (eg, clumsiness, motor incoordination), and a higher rate of substance abuse ( Hsiao and McClellan, 2008 ; Clemmensen et al., 2012 ; Immonen et al., 2017 ). Accordingly, diagnosis of EOS is often difficult and frequently delayed since onset is more commonly insidious than acute, which makes it difficult to differentiate EOS from underlying cognitive deficits, premorbid functional impairment, or other abnormalities ( Russell, 1994 ; Bartlet, 2014 ). Given this common delay in recognition of the disorder, the duration of untreated psychosis is often very long, further contributing to a poor outcome ( Penttila et al., 2014 ).

Although various hypotheses have been developed, the etiopathogenesis of schizophrenia and EOS is not fully understood ( McGuffin, 2004 ; Klosterkotter et al., 2011 ). 2 Among the rising and falling neurochemical theories, the dopamine hypothesis has remained a primary hypothesis guiding the treatment of schizophrenia. There are four dopaminergic pathways in the human brain: the mesolimbic, the mesocortical, the tuberoinfundibular, and the nigrostriatal. Positive symptoms of schizophrenia are associated with the hyperdopaminergic state of D 2 receptors in the mesolimbic area, while negative and cognitive symptoms are believed to be related to the hypodopaminergic dysregulation of the prefrontal cortex ( Stahl, 2003 ).

Negative symptoms of schizophrenia, which affect up to 60% of patients with schizophrenia ( Rabinowitz et al., 2013 ), form a complex clinical constellation of symptoms that challenge both diagnosis and treatment. By definition, negative symptoms mean the absence of normal functions. Negative symptoms are classified by their etiology as primary negative symptoms, which are core features of the disease itself, and secondary negative symptoms, which are consequences of positive symptoms, antipsychotic treatment, depression or extrapyramidal side effects. Five constructs have been accepted by general consensus as key aspects of negative symptoms: blunted affect, alogia, anhedonia, asociality, and avolition ( Marder and Galderisi, 2017 ). Patients with predominant negative symptoms lose their motivation, cannot function at school or work, and their interpersonal relationships severely decay. Due to impaired daily functioning and social amotivation, they may need constant care.

Although early intervention is associated with improvement in negative symptoms ( Boonstra et al., 2012 ), this may be challenging since negative symptoms develop slowly and may be difficult to detect or differentiate from other clinical features ( Kirkpatrick et al., 2001 ; Galderisi et al., 2018 ). Moreover, a more insidious onset predicts poorer outcome and more severe negative symptoms ( Kao and Liu, 2010 ; Immonen et al., 2017 ; Murru and Carpiniello, 2018 ). Diagnosis of patients with predominantly negative symptoms (lacking manifest psychotic signs) is often delayed, resulting in a longer duration of untreated psychosis. The length of untreated psychosis is closely related to poorer functional outcome ( Perkins et al., 2005 ).

Negative symptoms have traditionally had minimal response to antipsychotic treatment. First-generation antipsychotics are effective in treating positive symptoms, but negative symptom improvement is only evident when symptoms are secondary to positive symptoms. It was initially hoped that second-generation antipsychotics would target both positive and negative symptoms, but efficacy data have been disappointing. This was a large meta-analysis where only four second-generation drugs (amisulpride, risperidone, olanzapine, and clozapine) resulted to be more efficacious than first-generation antipsychotics in the overall change of symptoms, including positive and negative symptoms. The other examined second-generation antipsychotics were only as efficacious as first-generation antipsychotic agents ( Leucht et al., 2009 ). These studies were mainly conducted in patients with general symptoms of schizophrenia, therefore a secondary effect on negative symptoms could not be ruled out. Therefore negative symptom improvement cannot be considered a core component of atypicality ( Veerman et al., 2017 ). Previous studies have demonstrated that no drug had a beneficial effect on negative symptoms when compared to another drug ( Arango et al., 2013 ; Millan et al., 2014 ; Fusar-Poli et al., 2015 ), meaning that head to head comparisons of different agents among each other did not result in superiority of one drug to another. The latest comparison ( Krause et al., 2018 ) evaluated all studies that have been performed in the negative symptom population so far, and has found that amisulpride claimed superiority only to placebo, olanzapine was superior to haloperidol, but only in a small trial (n = 35), and cariprazine outperformed risperidone in a large well-controlled trial.

Hence cariprazine emerged as an agent of particular interest in regard to negative symptoms. Cariprazine is a dopamine D 3 /D 2 receptor partial agonist and serotonin 5-HT 1A receptor partial agonist. It has been hypothesized that cariprazine is the only antipsychotic that can block D 3 receptors in the living brain, thereby exhibiting functions that are related to D 3 blockade (e.g., improvement of negative symptoms) ( Stahl, 2016 ). In that large clinical trial including 460 patients with predominant negative symptoms and stable positive symptoms of schizophrenia, cariprazine was significantly more effective than risperidone in improving negative symptoms and patient functioning ( Nemeth et al., 2017 ).

Case Description

The 23-year-old female patient visited the Institute of Rare Diseases at our university with her parents. They had suspected for a long time that something was wrong with their daughter, but this was the first time they had asked for medical help. The patient was quiet and restrained since she did not speak much, her parents told us her story instead. Initially, the patient had done very well in a bilingual secondary school and was socially active with friends and peers. At the age of 15 years, her academic performance started to deteriorate, with her first problems associated with difficulty learning languages and memorizing. Her school grades dropped, and her personality started to gradually change. She became increasingly irritated, and was verbally and physically hostile toward her classmates, resorting to hitting and kicking at times. She was required to repeat a school year and subsequently dropped out of school at the age of 18 because she was unable to complete her studies. During these years, her social activity greatly diminished. She lived at home with her parents, did not go out with friends, or participate in relationships. Most of the time she was silent and unsociable, but occasionally she had fits of laughter without reason. Once the patient told her mother that she could hear the thoughts of others and was probably hearing voices as well. Slowly, her impulse-control problems faded; however, restlessness of the legs was quite often present.

Our patient’s medical history was generally unremarkable. She lacked neurological or psychiatric signs. She had a tonsillectomy and adenotomy at age 7 years. Epilepsy was identified in the patient’s family history (father’s uncle). On physical examination, there were no signs of internal or neurological disease; body mass index was 21.5 (normal weight).

During the first psychiatric interview and examination, we found that our patient was alert and vigilant, but had trouble relating due to decreased integrity of consciousness. Her attention could be aroused or partially directed, and she had difficulty keeping a target idea. Autopsychic and allopsychic orientations were preserved. Longer thinking latencies and slowed movement responses were observed, sometimes with even cataleptic impressions. Cognitive functions, such as thinking, memory, and concept formation, were severely impaired, and we were unable to carry out some of our neurocognitive tests -such as the Addenbrooke’s Cognitive Examination ( Hsieh et al., 2013 ), the Toulouse-Pieron attention test (Kanizsa G1951), Bells test ( Gauthier et al., 1989 ) and the Trail Making Test- because of the patient’s denial of symptoms and refusal to cooperate.

She often looked aside and laughed frequently, suggesting the presence of perceptual disturbances, but she denied her symptoms when asked. In contrast to the periodic inappropriate laughing, apathy and anhedonia were markedly present. During the examination, the patient could not recall anything she would do or even think of with pleasure. According to the heteroanamnesis, she lost her interest in activities she used to like, did not go out with friends anymore, and showed no signs of joy or intimacy towards her family members either.

Along with the affective hyporesponsiveness, amotivation and a general psychomotor slowing were observed. Hypobulia, void perspectives, and lack of motivation were explored. Parental statements indicated that the patient’s social activity had continued to diminish, and her appearance and personal physical hygiene had deteriorated. When we initiated a conversation, the patient was negativistic and agitated. Her critical thinking ability was reduced, which led to inappropriate behavior (she, e.g., unexpectedly stood up and left the room while the examination was still ongoing). Considering her status, she was admitted to the clinic after her first visit.

After several differential diagnostic tests were performed (e.g., routine diagnostic laboratory parameters, immune serological analyses, electroencephalogram, magnetic resonance imaging, genetic testing), all the possible common and rare disorders, such as Huntington’s disease, Niemann Pick C disease, mitochondrial disorders, and autoimmune diseases, were ruled out.

At first contact, to differentiate the symptoms and severity of putative schizophrenia, we mapped the positive, negative, and general symptoms, as well as a clinical impression, using the Positive and Negative Syndrome Scale (PANSS), the Scale for Assessment of Negative Symptoms, and the Clinical Global Impressions-Severity (CGI-S) ( Groth-Marnat, 2009 ).

The patient had a very high PANSS total score, which corresponded to being considered “severely ill” or “among the most severely ill’ on the CGI-S ( Leucht et al., 2005 ). The PANSS score was derived dominantly from the negative items of the scale. Overall, her negative symptoms fulfilled criteria for predominantly negative symptoms, meaning that positive symptomatology was reduced, while negative symptoms were more explicit and dominated the clinical picture ( Riedel et al., 2005 ; Olie et al., 2006 ; Mucci et al., 2017 ). Baseline rating scale sores are presented in Table 1 .

Table 1 Summary of symptom scale scores at the time of admission to the hospital.

The diagnosis of EOS with predominantly negative symptoms was given and treatment with the antipsychotic agent cariprazine was initiated. The patient was hospitalized for 2 weeks following her arrival at the clinic. Cariprazine was started at the dose of 1.5 mg/day and titrated up to 4.5 mg/day over a 2-week period: the patient received 1.5 mg/day for the first 3 days, 3 mg/day from day 4 to day 12, and eventually 4.5 mg/day from day 13 onward. During these 2 weeks, which were spent in hospital, the patient’s explicit negative symptoms such as poverty of speech, psychomotor retardation, poor eye contact, and affective nonresponsiveness improved; however, delusions and hallucinatory perceptions did not fade significantly.

Two weeks after discharge, we saw the patient for her first outpatient visit. Significant clinical improvement was observed. The patient calmly cooperated during the examination, with no signs of agitation. She was oriented to time, place, and self, attention could be drawn and directed, and she was able to keep a target idea and change the subject. Although according to the family, perceptual disturbances were still present, laughing with no reason and looking aside were much less frequent, and restlessness of the legs had stopped; these symptoms were not observed during the examination. Psychomotoric negativism had improved greatly, the patient was more communicative, and she paid more attention to the activities of family members. The pace of speech was close to normal: the thinking latencies and slowed movement responses as observed at admission were not seen anymore. The patient had adequate reaction time to questions asked and could focus in the interview. Mild obstipation and somnolence in the evening were her main complaints. Apart from some tick-like eye closures, there was no pathological finding during physical and neurological examination. At this point, cariprazine was reduced to 3 mg per day.

At her second outpatient visit, which occurred 8 weeks after treatment initiation, further improvement was observed. According to her mother, the patient was more active and open at home. Neurological examination found that the alternating movements of her fingers were slightly slowed. Cariprazine 3 mg/day was continued with concomitant anticholinergic medication.

At the third outpatient visit, which occurred 16 weeks after the first contact, the patient’s overall symptoms, including cognitive functions, such as memory and abstract thinking, as well as functions in activities of daily living, had improved remarkably. She had started to participate in the family’s daily life, even taking responsibility for some household duties; further, she went to the hairdresser for the first time in years, a step forward from her previous state of self-neglect. She was probably still having auditory hallucinations, which she considered natural, and some extrapyramidal symptom (EPS)-like ruminating movements, like to-and-fro swinging of her trunk, were observed. She did not look aside any more and tics were no longer present. Compared with previous visits overall, she was very relaxed, retained eye contact, cooperated, and communicated adequately during the interview. She started to develop insight into her condition, and she told us that her “thoughts were not healthy.” At the last two visits, the synkinesis of the arms was reduced.

After 16 weeks of treatment, the patient’s PANSS Negative Subscale Score and PANSS factor score for negative symptoms (PANSS-FSNS) score were reduced by 44.44% and 41.31%, respectively. Recent studies have demonstrated that linking the percentage improvement of PANSS with CGI-S and -Improvement (CGI-I) scores shows that a 25–50% reduction of PANSS scores corresponds to clinically meaningful change ( Correll et al., 2011 ; Fusar-Poli et al., 2015 ). In acutely ill patients with predominantly positive symptoms who are more likely to respond well to treatment, the 50% cutoff would be a more clinically meaningful criterion; however, since even slight improvement might represent a clinically significant effect in a patient with atypical schizophrenia, the use of 25% cutoff is justified ( Correll et al., 2011 ; Fusar-Poli et al., 2015 ).

In this regard, the 44.44% (change from baseline: −20) and 41.31% (change from baseline: −19) improvement demonstrated on PANSS Negative Symptom subscale and PANSS-FSNS, respectively, are considered a clearly clinically relevant change. Beyond the impaired synkinesis and alternating movement of the arms and fingers, there were no other treatment-related physical dysfunctions. Change from baseline on the PANSS and CGI scales are shown over the course of treatment in Table 2 .

Table 2 Summary of symptom scale scores at weeks 16, 32, and 52.

Since our patient’s symptoms demonstrated strong improvement and tolerability was favorable, cariprazine therapy was continued. Improvement in both negative and positive symptoms was maintained over the course of treatment. At her later visits (32 and 52 weeks), PANSS total score was reduced to a level that was close to the minimum, and the decrease in negative symptom scores was considerable (PANSS-NSS=66.67% and PANS-FSNS=70.00% at both time points). The patient’s progress was also reflected in clinical and functional measurements, with the CGI-S score reduced to 2 (borderline mentally ill) and a CGI-I score of 1 (very much improved) indicating notable improvement.

Cariprazine has demonstrated broad spectrum efficacy in the treatment of positive and negative symptoms of schizophrenia. In a field where no treatment is available for difficult-to-treat negative symptoms, this case is unique and may have important implications for schizophrenia treatment. Despite experiencing approximately 8 years of untreated symptoms and functional impairment associated with predominantly negative symptom EOS, our 23-year-old female patient showed considerable symptomatic and functional improvement after several weeks of treatment with cariprazine. Given that the duration of untreated negative symptoms is associated with worse functional outcomes ( Boonstra et al., 2012 ), the remarkable improvement seen in this case shows how valuable cariprazine could be for patients with similar symptom presentations. Although it is not possible to generalize the observations and findings of this single case, it has the novelty of detecting a potential effect of cariprazine in a drug-naïve patient with marked negative symptoms of early-onset schizophrenia. To our knowledge, no cariprazine-related data has been published in this type of patients. A single case study is obviously far from being predictive for the efficacy of a drug, however, the results seen with this case are promising. With a dose recommended for patients with negative symptoms, our patient’s clinical condition, including positive, negative, and cognitive symptoms, as well as social functioning have improved notably, with the effect maintained for over 12 months. Generally, cariprazine has been well tolerated, with mild EPS observed after 8 weeks, but no metabolic, cardiac, or other side effects.

This case report suggests that the management of patients with EOS and prominent negative symptoms is achievable in everyday practice with cariprazine. More real-world clinical experience is needed to support this finding.

Data Availability Statement

All datasets generated for this study are included in the article/supplementary material.

Ethics Statement

Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Author Contributions

All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication.

This work was supported from Research and Technology Innovation Fund by the Hungarian National Brain Research Program (KTIA_NAP_ 2017-1.2.1-NKP-2017-00002). Editorial support for this case report was supported by funding from Gedeon Richter. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Acknowledgments

We are thankful to the patient and her family for giving us the opportunity to share her story in the form of a publication. Also, we acknowledge editorial assistance was provided by Carol Brown, MS, ELS, of Prescott Medical Communications Group, Chicago, Illinois, USA, a contractor of Gedeon Richter plc.

• ^ http://www.schizophrenia.com/szfacts.htm
• ^ https://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml

Arango, C., Garibaldi, G., Marder, S. R. (2013). Pharmacological approaches to treating negative symptoms: a review of clinical trials. Schizophr. Res. 150 (2-3), 346–352. doi: 10.1016/j.schres.2013.07.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Bartlet, J. (2014). Childhood-onset schizophrenia: what do we really know? Health Psychol. Behav. Med. 2 (1), 735–747. doi: 10.1080/21642850.2014.927738

Boonstra, N., Klaassen, R., Sytema, S., Marshall, M., De Haan, L., Wunderink, L., et al. (2012). Duration of untreated psychosis and negative symptoms–a systematic review and meta-analysis of individual patient data. Schizophr. Res. 142 (1-3), 12–19. doi: 10.1016/j.schres.2012.08.017

Clemmensen, L., Vernal, D. L., Steinhausen, H. C. (2012). A systematic review of the long-term outcome of early onset schizophrenia. BMC Psychiatry 12, 150. doi: 10.1186/1471-244X-12-150

Correll, C. U., Kishimoto, T., Nielsen, J., Kane, J. M. (2011). Quantifying clinical relevance in the treatment of schizophrenia. Clin. Ther. 33 (12), B16–B39. doi: 10.1016/j.clinthera.2011.11.016

Fusar-Poli, P., Papanastasiou, E., Stahl, D., Rocchetti, M., Carpenter, W., Shergill, S., et al. (2015). Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials. Schizophr. Bull. 41 (4), 892–899. doi: 10.1093/schbul/sbu170

Galderisi, S., Mucci, A., Buchanan, R. W., Arango, C. (2018). Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry 5 (8), 664–677. doi: 10.1016/S2215-0366(18)30050-6

Gauthier, L., Dehaut, F., Joanette, Y. (1989). A quantitative and qualitative test for visual neglect. Int. J. Clin. Neuropsychol. 11 (2), 49–54. doi: 10.1016/j.neuropsychologia.2010.04.018

CrossRef Full Text | Google Scholar

Groth-Marnat, G. (2009). “Handbook of Psychological Assessment”. Fifth ed. (Hoboken, NJ: Wiley).

Google Scholar

Hafner, H., Van der Heiden, W. (1997). Epidemiology of schizophrenia. Can. J. Psychiatry 42 (2), 139–151. doi: 10.1177/070674379704200204

Hsiao, R., McClellan, J. (2008). Substance abuse in early onset psychotic disorders. J. Dual Diagn. 4 (1), 87–99. doi: 10.1300/J374v04n01_06

Hsieh, S., Schubert, S., Hoon, C., Mioshi, E., Hodges, J. R. (2013). Validation of the Addenbrooke’s Cognitive Examination III in frontotemporal dementia and Alzheimer’s disease. Dement Geriatr. Cognit. Disord. 36 (3-4), 242–250. doi: 10.1159/000351671

Immonen, J., Jaaskelainen, E., Korpela, H., Miettunen, J. (2017). Age at onset and the outcomes of schizophrenia: A systematic review and meta-analysis. Early Interv Psychiatry 11 (6), 453–460. doi: 10.1111/eip.12412

Kao, Y. C., Liu, Y. P. (2010). Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. BMC Psychiatry 10, 63. doi: 10.1186/1471-244X-10-63

Kirkpatrick, B., Buchanan, R. W., Ross, D. E., Carpenter, J. (2001). A separate disease within the syndrome of schizophrenia. Arch. Gen. Psychiatry 58 (2), 165–1671. doi: 10.1001/archpsyc.58.2.165

Klosterkotter, J., Schultze-Lutter, F., Bechdolf, A., Ruhrmann, S. (2011). Prediction and prevention of schizophrenia: what has been achieved and where to go next? World Psychiatry 10 (3), 165–174. doi: 10.1007/s00406-018-0869-3

Krause, M., Zhu, Y., Huhn, M., Schneider-Thoma, J., Bighelli, I., Nikolakopoulou, A., et al. (2018). Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur. Arch. Psychiatry Clin. Neurosci. 268 (7), 625–639. doi: 10.1007/s00406-018-0869-3

Lehman, A. F., Lieberman, J. A., Dixon, L. B., McGlashan, T. H., Miller, A. L., Perkins, D. O., et al. (2010). “Practice guideline for the treatment of patients with schizophrenia”, 2nd ed. American Psychiatric Association. Avaialble at: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/schizophrenia.pdf .

Leucht, S., Kane, J. M., Kissling, W., Hamann, J., Etschel, E., Engel, R. R. (2005). What does the PANSS mean? Schizophr. Res. 79 (2-3), 231–238. doi: 10.1016/j.schres.2005.04.008

Leucht, S., Corves, C., Arbter, D., Engel, R. R., Li, C., Davis, J. M. (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373 (9657), 31–41. doi: 10.1016/S0140-6736(08)61764-X

Marder, S. R., Galderisi, S. (2017). The current conceptualization of negative symptoms in schizophrenia. World Psychiatry 16 (1), 14–24. doi: 10.1002/wps.20385

McGuffin, P. (2004). Nature and nurture interplay: schizophrenia. Psychiatr. Prax 31 Suppl 2, S189–S193. doi: 10.1055/s-2004-834565

Millan, M. J., Fone, K., Steckler, T., Horan, W. P. (2014). Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur. Neuropsychopharmacol. 24 (5), 645–692. doi: 10.1016/j.euroneuro.2014.03.008

Mucci, A., Merlotti, E., Ucok, A., Aleman, A., Galderisi, S. (2017). Primary and persistent negative symptoms: Concepts, assessments and neurobiological bases. Schizophr. Res. 186, 19–28. doi: 10.1016/j.schres.2016.05.014

Murru, A., Carpiniello, B. (2018). Duration of untreated illness as a key to early intervention in schizophrenia: A review. Neurosci. Lett. 669, 59–67. doi: 10.1016/j.neulet.2016.10.003

Nemeth, G., Laszlovszky, I., Czobor, P., Szalai, E., Szatmari, B., Harsanyi, J., et al. (2017). Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 389 (10074), 1103–1113. doi: 10.1016/S0140-6736(17)30060-0

Olie, J. P., Spina, E., Murray, S., Yang, R. (2006). Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study. Int. Clin. Psychopharmacol. 21 (3), 143–151. doi: 10.1097/01.yic.0000182121.59296.70

Penttila, M., Jaaskelainen, E., Hirvonen, N., Isohanni, M., Miettunen, J. (2014). Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis. Br. J. Psychiatry 205 (2), 88–94. doi: 10.1192/bjp.bp.113.127753

Perkins, D. O., Gu, H., Boteva, K., Lieberman, J. A. (2005). Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am. J. Psychiatry 162 (10), 1785–1804. doi: 10.1176/appi.ajp.162.10.1785

Rabinowitz, J., Werbeloff, N., Caers, I., Mandel, F. S., Stauffer, V., Menard, F., et al. (2013). Negative symptoms in schizophrenia–the remarkable impact of inclusion definitions in clinical trials and their consequences. Schizophr. Res. 150 (2-3), 334–338. doi: 10.1016/j.schres.2013.06.023

Riedel, M., Muller, N., Strassnig, M., Spellmann, I., Engel, R. R., Musil, R., et al. (2005). Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms. Eur. Arch. Psychiatry Clin. Neurosci. 255 (6), 432–437. doi: 10.1007/s00406-005-0622-6

Russell, ,. A. T. (1994). The Clinical Presentation of Childhood-Onset Schizophrenia. Schizophr. Bull. 20 (4), 631–646. doi: 10.1093/schbul/20.4.631

Stahl, S. M. (2003). Describing an atypical antipsychotic: Receptor binding and its role in pathophysiology. Prim Care Companion J. Clin. Psychiatry 5 (Suppl 3), 9–13.

Stahl, S. M. (2016). Mechanism of action of cariprazine. CNS Spectr. 21 (2), 123–127. doi: 10.1017/S1092852916000043

Veerman, S. R. T., Schulte, P. F. J., de Haan, L. (2017). Treatment for Negative Symptoms in Schizophrenia: A Comprehensive Review. Drugs 77 (13), 1423–1459. doi: 10.1007/s40265-017-0789-y

Keywords: cariprazine, schizophrenia, negative symptoms, early-onset schizophrenia, second-generation antipsychotic

Citation: Molnar MJ, Jimoh IJ, Zeke H, Palásti Á and Fedor M (2020) Early-Onset Schizophrenia With Predominantly Negative Symptoms: A Case Study of a Drug-Naive Female Patient Treated With Cariprazine. Front. Pharmacol. 11:477. doi: 10.3389/fphar.2020.00477

Received: 24 October 2019; Accepted: 26 March 2020; Published: 23 April 2020.

Reviewed by:

Copyright © 2020 Molnar, Jimoh, Zeke, Palásti and Fedor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Maria Judit Molnar, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

The Realities of Childhood Schizophrenia

Although the diagnostic criteria used in children are the same as adults, there are some key differences in clinical presentation of psychotic features. More in this podcast about childhood schizophrenia.

PSYCHPEARLS PODCAST

Child and adolescent psychiatrist Abhijit Ramanujam, MD, discusses clinically relevant issues in childhood schizophrenia. Dr Ramanujam is Regional Director of Community Psychiatry, Sacramento, CA .

Transcript edited for clarity. -Ed

Laurie Martin (LEM): How common is schizophrenia in children under the age of 18?

Abhijit Ramanujam, MD: The worldwide prevalence of early onset schizophrenia,that is symptoms prior to the age of 18yrs is estimated to be about 0.5% of the population,whereas childhood onset or very early onset schizophrenia which begins prior to the age of 13, has been estimated to be around 0.04% in the United States.Much less is known about the prevalence of childhood onset schizophrenia internationally.

LEM: Is there an age in which a child is too young to consider a diagnosis of schizophrenia? What do we know about early detection of schizophrenia and how soon can it be diagnosed?

Abhijit Ramanujam, MD: Although there is no official age considered too young for a diagnosis of schizophrenia, we have to keep in mind that childhood-onset schizophrenia that starts before aged 13 years is extremely rare.

Whenever a child is suspected of having schizophrenia, the clinical assessment should include a thorough personal, medication, psychosocial and family history as well as physical examination, neurological work-up, laboratory evaluation, and collateral information from family and schools.

In terms of diagnosis, DSM-5 diagnostic criteria for schizophrenia in childhood and adolescence are the same as those used for adult disorders. They include the presence of significant positive and negative symptoms during a 1-month period (such as delusions or hallucinations, disorganized speech, catatonic behavior, and negative symptoms such as lack of motivation and lack of socialization). Disturbance of functioning in 1 or more major areas and continued signs of disturbance for at least 6 months, as well as the exclusion of other psychiatric or medical diagnoses.

Although the diagnostic criteria used in children are the same as those for adults, there are some key differences in clinical presentation:

• Usually hallucinations are much more common than delusions in youth with schizophrenia as compared to adults. The most common hallucinations are auditory with comments or commands. These are often accompanied by visual and tactile hallucinations.

• Although hallucinations are more common, they are least likely to reported. Many youths may not disclose auditory hallucinations since they are scared that the voices may harm them.There may also be delusions associated with it such as "The voices tell me that they will kill me if I talk about them to anyone."

• Children and adolescents are more likely to exhibit negative symptoms such as being socially aloof or having a flat affect which can sometimes be mistaken for depression or lack of motivation for plain laziness as I have actually heard some of the parents describe it.

• Cognitive decline, in particular verbal memory, attention, and concentration, is significantly affected. Delay in language, motor, and social development, and delay or deviation in developmental milestones may be pronounced as well in childhood-onset schizophrenia; although these delays are not diagnostic, they are commonly observed.

LEM: What are the most commonly confused causes of schizophrenia-like behaviors?

Abhijit Ramanujam, MD: There are many other disorders that can be confused with schizophrenia-like behaviors.

The most common one I see is PTSD. PTSD symptoms can include flashbacks which some patients may describe as auditory hallucinations. Hypervigilance and flashbacks together can often be misinterpreted as paranoia and hallucinations. However, you will notice less disorganized thinking and usually symptoms begin after a traumatic event.

Another area is autism spectrum disorders. Misdiagnosis of autism spectrum disorders as a psychotic disorder also occurs very commonly. Common features such as impairment in social communication can be misinterpreted as negative symptoms of psychosis. Stereotyped use of language seen in autism can be confused with disorganized speech.

It is very important to obtain a thorough developmental history and a baseline thought processes which helps distinguish these 2 diagnoses.

Some patients may have a comorbid diagnosis of autism spectrum disorder and schizophrenia. In these cases, you will see a new onset delusion or hallucination lasting longer than 1 month. Disordered or delusional thinking will be distinctly different from the baseline. We usually notice a significant deterioration of social and general functioning with comorbid diagnoses. I sometimes noticed this in children who have been through multiple foster homes. A baseline thought process is difficult to establish in this case since past history is not readily available. These children are more likely to be wrongly diagnosed as having a disorganized thinking process as opposed to a social communication issue.

Schizoaffective disorder can be a difficult one to differentiate since a psychotic syndrome continues to evolve as a child progresses through the developmental process. Again, a thorough longitudinal symptom assessment would help distinguish the 2.

Major depressive disorders with psychotic features or bipolar disorder with psychosis should also be considered very carefully. Usually in depression with psychotic features, the psychosis is generally seen when the depressive disorder has significantly worsened. Guilt dominates in depressive psychosis. In case of bipolar disorder with psychotic features, you generally see psychosis during severe episodes of mood and not during lucid intervals.

Another area that is very important to remember is that in very young children before the age of 6, anxiety can itself present as hallucinations. Many children with symptoms of anxiety report, "Someone called my name;" they may also report visual hallucinations such as "Mama, I see a shadow every night passing by." Most of these children are healthy and nonpsychotic.

Anxiety-related visual hallucinations are very common in preschool children. Usually in the history, you will notice that there will be a precipitating event such as watching a scary movie or video game that triggered such reactions. Whereas in early-onset schizophrenia, you will notice a decline in cognitive function, attention, and concentration, as well as the presence of negative symptoms which indicate psychosis.

Sometimes, substance-induced psychosis that is secondary to steroid use can present very similarly to a primary psychotic disorder. Urine toxicology screens are very important. It is also important to remember that many of the newer recreational drugs may not be detected in current screens; hence a thorough history will help us distinguish between the 2.

In case of delirium, look for waxing and waning of symptoms or evidence of ingestion of substance or any other metabolic abnormalities, since these are usually seen in delirium and not a psychotic illness.

Other medical conditions may also mimic psychotic symptoms. Those include:

• Seizure disorder

• Medication induced

• Encephalitis

• Autoimmune disorder, such as systemic lupus erythematosus

• Metabolic disorder, such as Wilson disease

CASE VIGNETTES

I am only mentioning the positive pertinent factors in each of the following 3 cases for the sake of brevity. All names and identifying factors have been changed. This is for clinical purposes only.

Case presentation 1: Oppositional or something else?

PR is a 17-year-old boy who initially brought in by his father with chief complaints of “very oppositional, up to something, secretive, and angry.”

The father appeared remorseful due to his "busy schedule" for the last 3 to 4 years. His being away also coincided with a gradual deterioration of his son.

PR refused to talk other than state, "I hate them" [my parents].

Neuropsychological tests, detailed medical examinations, laboratory tests, and a urine drug screen came back negative; the clinical picture became clearer as we obtained collateral information.

The mother described her son demonstrated bizarre behavior. She also hesitatingly disclosed family psychiatric issues (many relatives with schizophrenia), which was initially minimized. “It is a taboo and we do not talk about it,” she said.

His siblings disclosed they are fearful of him "Since he stays up all night and talks to himself. He does not seem like our brother anymore."

School reported he was growing increasingly isolative and suspicious of other kids. His grades kept falling. Teachers also responded behavior that was indicative of PR being internally preoccupied.

The approach of the parents changed from “the boy just needs good disciplining” to a gradual understanding and compliance with the treatment plan.

I will discuss the treatment plan further below. But before that I would like to say that PR is doing much better than he was 3 years ago.

Case presentation 2: “The adopted boy who was ‘psychotic.’”

A was adopted at age 3 and was brought in for an evaluation by his adoptive mother at age 9. The adoptive mother insisted he was “psychotic” and fearful of ingesting food because he thought his mother had poisoned it.

On examination, the boy was found to have significant anxiety, ADHD symptoms, and social communication disorder.

His fear of contamination was misinterpreted as paranoia and delusional. He had also watched a “cold cases” forensic science documentary along with his brother a few months ago which was the precipitating factor. Further information revealed he had a family history of anxiety disorder but no family history of schizophrenia.

Case presentation 3: “My daughter is hearing voices.”

SK is a 7-year-old girl who was brought in for auditory hallucinations. A detailed history revealed a traumatic past (she had witnessed domestic violence). Although currently she lives in a safe environment, she continued to experience flashbacks in the form of auditory hallucinations. There was no family history of psychotic disorders.

After 6 months of cognitive behavioral therapy and trauma-related behavioral therapy, the patient is doing significantly better.

LEM: What are some of the common therapeutic approaches in the treatment of childhood schizophrenia?

Abhijit Ramanujam, MD: We can divide this into 2 sections.

Treatment during the prodromal stage. In this stage, medications are aimed at delaying or stopping progression to psychotic disorder amongst children who are considered high risk or those that have prodromal symptoms, such as disorganized behavior, paranoia or suspicion, or any unusual thought content that is below the threshold of a full-blown psychotic disorder.

Several medications have been tested in clinical trials. Trials of omega-3 fatty acids have shown mixed results. However, although clinical trials are mixed given the positive potential effects as well as the limited adverse effects of omega-3 fatty acids make it a good choice to consider.

Selective serotonin reuptake inhibitor antidepressants have been shown to be helpful in two naturalistic studies but have not been tested in a clinical trial. Initiating SSRIs along with omega-3 fatty acids is a grade 2 recommendation which basically means this is a suggestion, but clinicians could choose a reasonable alternative.

Clinical trials have not found antipsychotics to be efficacious in terms of delaying or preventing progression to psychosis.

Treatment of schizophrenia in youth. Antipsychotics are first-line treatment for confirmed schizophrenia. Several randomized trials have shown that antipsychotics reduce positive symptoms of schizophrenia, such as hallucinations and delusions. Antipsychotics eliminate or reduce the symptoms to a tolerable level in about 70% of the patients with schizophrenia.

Negative symptoms of schizophrenia, such as diminished emotional expression or lack of motivation is a little more difficult to treat.

We generally follow the age guidelines from the indications approved by the FDA in the United States which were based on the age of enrollees in the efficacy trials of antipsychotics in children with schizophrenia. These medications are aripiprazole, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, clozapine , and the first-generation agents, chlorpromazine, haloperidol, and perphenazine.

The current recommendation is to start with a second-generation antipsychotic with lower sedation and fewer problems with metabolic syndrome.

Clinical trials have not consistently found any one antipsychotic more effective than the others except clozapine, but due to adverse effects, it is reserved for use in treatment-resistant schizophrenia.

Hence, clinicians can select 1 amongst the above medications, based on patient age and medication adverse effect profile.

LEM: Can you talk about cardiometabolic risks or any other risks of treatment with antipsychotics, and do they outweigh clinical benefits?

Abhijit Ramanujam, MD: The adverse effect profiles of individual antipsychotic drugs vary widely. Children and adolescents compared with adults are at a high risk of many of the adverse effects associated with antipsychotic use

Common adverse effects associated with second-generation antipsychotics include weight gain and related metabolic effects, sedation, anticholinergic symptoms, elevated prolactin levels and extrapyramidal symptoms, cardiac effects, and sexual dysfunction.

Many of these drugs increase appetite and alter metabolic control. Children who are more vulnerable to these adverse effects are those with pre-existing conditions, such as obesity, diabetes, or elevated cholesterol. Clozapine and olanzapine carry significantly higher risk than other antipsychotics, whereas lurasidone and to an extent aripiprazole are associated with the lowest risk.

Clinicians should conduct routine short and long-term monitoring of weight, waist circumference, blood pressure, fasting glucose, and lipid profile of patients taking any of the antipsychotic drugs. For patients in whom weight gain is a concern, we tend to prescribe lurasidone. Whenever possible, we tend to avoid medication such as olanzapine which has a higher rate of metabolic abnormality.

Tardive dyskinesia is characterized by involuntary movements of the mouth, tongue, face, extremities, or trunk (including lip-smacking, tongue, and jaw movements, and facial grimacing). The symptoms are often initially mild; however, they can progress and become disfiguring or disabling. Tardive dyskinesia risk increases with age, time of exposure to medications, and prior development of extrapyramidal symptoms (EPS).

However tardive dyskinesia is less common in youth compared with adult and older adult populations—0.4% versus 6.8%. 1,2

The risk of tardive dyskinesia in children appears to be the greatest with first-generation antipsychotics with minimal or no risk seen with second-generation antipsychotics. 3 Clozapine has not shown to cause tardive dyskinesia. Patients on these medications should be formally assessed for tardive dyskinesia at least annually. Older adults should be assessed every 6 months.

Nausea and sedation are common adverse effects of antipsychotic treatment in all patients, but they often remit over time and should not be considered a reason to terminate treatment. As mentioned earlier although no one antipsychotic is better than the other, for patients with prominent insomnia we tend to use quetiapine.

Clinicians should routinely assess for fall risks in vulnerable population, given that many of these medications cause sedation as well as orthostatic hypotension. Anticholinergic effect, such as constipation, dry mouth, blurry vision, and urinary retention are fairly common. In the case of clozapine sialorrhea rather than dry mouth is common.

Extrapyramidal adverse effects. Second-generation antipsychotics have reduced incidence of akathisia, rigidity, bradykinesia, dysphagia, tremor, and acute dystonic reactions that constitute EPS. Among the second-generation antipsychotics, risperidone carries the highest risk, especially at doses greater than 4 mg/day; elevated risk is also noted with aripiprazole, asenapine, and lurasidone. Quetiapine and clozapine are preferred agents in patients with high risk for EPS. Patients on second-generation agents should be asked about restlessness, slow movements, shaking, and rigidity at baseline and weekly during dose increases.

We usually start with a second-generation antipsychotics because of their lower rates of extrapyramidal symptoms and tardive dyskinesia compared with the first-generation antipsychotics.

Prolactin elevation can occur in both men and women. Accordingly, patients may experience gynecomastia, galacturia, menstrual disturbance sexual dysfunction and infertility. Risperidone and paliperidone are more strongly associated with elevated prolactin. Olanzapine and aripiprazole, clozapine and quetiapine show little or no change in prolactin levels.

Patients on risperidone and paliperidone should be asked about changes in sexual function and abnormal lactation at each visit for 12-week and annually thereafter. A serum prolactin level is indicated if the patient develops signs of sexual dysfunction or galacturia.

Sexual adverse effects that cause dysfunction in all phases of sexual activity are quite common. It seems to be highest on patients who are prescribed risperidone and least amount patients were on aripiprazole. Clinicians are encouraged to ask about sexual functioning initially and at least annually thereafter.

QT prolongation can happen with many of the medications. A corrected QT interval greater than 500 or an increase in QT of 60 or more during antipsychotic treatment indicates significant risk. Ziprasidone appears to have a somewhat greater risk of QT prolongation. Olanzapine and risperidone have been associated with mild QT prolongation but neither carries a specific caution on this issue. Lurasidone and Abilify are the least likely to cause cardiac arrhythmias.

Routine monitoring of ECG with antipsychotics is not usually required in patients without cardiac risk factors. Rarely, cases of myocarditis and cardiomyopathy have been reported with quetiapine, Risperdal, and ziprasidone.

Orthostatic hypotension is frequently observed with clozapine, quetiapine, iloperidone, and paliperidone. This is somewhat less so with olanzapine, risperidone, and ziprasidone. It very rarely occurs with aripiprazole. The symptoms are generally benign and self-limiting but, in some cases, may necessitate a slowing in the rate of dose titration. Seizures have been associated with several second-generation antipsychotics and is dose dependent. Clozapine carries the highest risk among the second-generation antipsychotics. 4

Some of the less common adverse effects include neuroleptic malignant syndrome , cardiomyopathies, and cataracts. The use of antipsychotics in children should always be started with extreme caution at a low dose and titrated slowly.

LEM: Are there family or genetic factors to consider? What about trauma, sexual abuse, or domestic violence? Do these factors have any effect on children’s propensity to develop early-onset psychosis or psychotic symptoms?

Abhijit Ramanujam, MD: In terms of predisposing factors, genetic vulnerability, environmental factors, obstetric complications, trauma, social adversities, and substance use can all contribute to the risk for acquiring a primary psychotic disorder. Studies have shown the presence of a substance use disorder and co-occurring psychotic symptoms indicate an increased risk for developing a primary psychotic disorder.

Cannabis in particular has the potential to cause psychotic symptoms, although the studies are limited. However, the body of evidence is consistently increasing.

The birth cohort study of patients with schizophrenia reported an association between hypoxia during birth complications and early onset schizophrenia but not of adult-onset schizophrenia. Prematurity was found in 17% of early-onset psychosis in a schizophrenia spectrum disorder study. 5

Two large systematic studies demonstrate that 30% to 50% of patients with childhood onset schizophrenia had premorbid features of autism or had comorbid diagnoses of pervasive developmental disorders. 6 However, youth with early-onset schizophrenia frequently showed greater premorbid deficits in attention, learning, and socialization compared with their counterparts with adult-onset schizophrenia.

A meta-analysis reported strong evidence that childhood adversity was associated with an increased risk for psychosis in adults, although psychotic symptoms may also be present in PTSD. 7,8 Twin studies suggest that childhood-onset of schizophrenia may have a substantial genetic component. 9 A number of psychiatric disorders occur in higher frequency amongst first-degree relatives of children with schizophrenia.

For example, bipolar disorder prevalence is 6% in first degree relatives versus 2.4% in the general population. The same can be said for schizophrenia spectrum disorder: 10% in first-degree relatives versus 3.5% in general population. Anxiety disorders prevalence is 15% in first degree relatives versus 7.3% in the general population.

LEM: Is it too early to talk about long-acting injectable antipsychotic agents, or LAI, treatments?

Abhijit Ramanujam, MD: In terms of long-acting injectable antipsychotics, they have not been sufficiently studied in younger children to recommend their use.

LEM: From a child’s perspective, how do we build a daily routine of taking oral medications? What can one expect when there is a patient stops treatment abruptly?

Abhijit Ramanujam, MD: I strongly recommended a multimodal instead of medication-alone approach for a better outcome. First psychoeducation is key and is best provided early in treatment and frequently reviewed, provide children and their parents or guardian information about the illness, medications, and other interventions. It is highly useful to integrate family members and educate them to better support youth.

There are a few variables in terms of our approach based on the clinical presentation of the patient.

1. Family intervention. For patients with schizophrenia who have had a recent psychotic episode and have significant ongoing contact with family members, we recommend patients and family members receive a family intervention for at least 6 to 9 months. During family intervention, patient's family members receive education about the nature course treatment of schizophrenia.

It also involves correcting the erroneous notion that poor parenting was the cause of schizophrenia. Many parents are left to wonder what they could have done wrong to cause the illness and need help transitioning from the guilt and blame to acceptance and support.

Many times, family members may perceive the negative symptoms of schizophrenia, such as lack of motivation and asociality, as laziness. Furthermore, the clinician should teach early warning signs and explain the importance of medication adherence.

2. If the patient has had multiple relapses of schizophrenia and reside in a particularly stressful family environment, a more intensive problem-solving family therapy has been developed. In these cases, we identify and correct overly hostile and critical parent-patient interaction. Sometimes stressful family dynamics can be mitigated by finding outside rehabilitative activities or supported employment for the patient.

3. For individuals who experience persistent delusions or hallucinations despite adequate trials of antipsychotic medication, we recommend adjunctive treatment with cognitive-behavioral therapy over medication alone ( Grade 1B ).

The aim is to reduce the intensity of delusions and hallucinations or the subjective distress. It also helps individuals be more proactive in reducing the risk of relapse. It basically involves exploring the subjective nature of the symptoms, gently challenging the underlying assumptions and generating alternative interpretations. Many patients will strongly resist reevaluating delusional believes but one can reduce the related distress. Studies indicate that CBT is effective for chronic schizophrenia.

4. For children with schizophrenia who have deficits and skills needed for everyday activities we usually recommend social skills training along with antipsychotic medications. Social skills training is generally conducted several times a week. Children with observed deficits, such as problems with attention and working memory, should receive age-appropriate vocational skills training. This may include help with placement and support during employment. Therapeutic schools are also an option to educate children who struggle to understand the curriculum in typical school settings due to their illness.

Social skills training is necessary since negative symptoms of schizophrenia such as lack of motivation and lack of socialization do not respond well to medications. The ultimate goal of this training is to provide skills to community-based activities and improve the functioning.

5. For children with schizophrenia who experience persistent cognitive decline such as difficulty concentrating or remembering, cognitive remediation is recommended along with antipsychotic medications. The patient is asked to do simple information processing tasks and once they reach a certain threshold, they will move onto a slightly more complex task. PositScience is a self-contained computer software program that provides cognitive remediation in an outpatient setting. Studies indicate that this approach leads to an overall positive effect. 10

LEM: For clinicians concerned about treating schizophrenia, what advice can you offer?

AR: It is roughly estimated that 13% to 23% of people experience psychotic symptoms at some point in their lifetime. 11 Most clinicians will encounter patients with psychosis and thus will greatly benefit knowing how to recognize psychotic symptoms and make appropriate initial evaluation and management decisions.

Prompt diagnosis of schizophrenia and aggressive treatment is necessary to limit impairments in development and learning. Repeated or prolonged psychotic episodes have negative neuropsychological and structural brain defects on patients. Some evidence also suggests that prolonged periods of untreated psychosis may also result in increased resistance to conventional treatments.

Having said that, I encourage optimism and discourage nihilism when it comes to treating schizophrenia. Schizophrenia necessarily does not follow the path of progressive deterioration. The majority of patients respond very well to comprehensive treatment and as many as 20% can be expected to have a full recovery. There is much we can offer patients, and it is valuable to be aware of our current treatment options

1. Correll CU. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes . J Am Acad Child Adolesc Psychiatry. 2008;47(1):9.

2. Correll CU, Penzner JB, Parikh UH. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2006;15(1):177.

3. Correll C. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry. 2008;47(1):9.

4. Wu CS, Wang SC, Yeh IJ, Liu SK. Comparative risk of seizure with use of first- and second-generation antipsychotics in patients with schizophrenia and mood disorders . J Clin Psychiatry. 2016 May;77(5):e573-9.

5. Verdoux H, Geddes JR, Takei N, et al. Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data. Am J Psychiatry. 1997;154(9):1220.

6. Rapoport J, Chavez A, Greenstein D, et al. Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry. 2009;48(1):10.

7. Varese F, Smeets F, Drukker M, et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull. 2012;38(4):661. Epub 2012 Mar 29

8. Kessler RC, Sonnega A, Bromet E, et al. Posttraumatic stress disorder in the National Comorbidity Survey . Arch Gen Psychiatry. 1995;52(12):1048.

9. Kallmann FJ, Roth B. Genetic aspects of preadolescent schizophrenia. Am J Psychiatry. 1956;112(8):599.

10. Harvey PD, Balzer AM, Kotwickib RJ. Training engagement, baseline cognitive functioning, and cognitive gains with computerized cognitive training: A cross-diagnostic study. Schizophr Res Cogn. 2019;19:100150.

11. Perälä J, Suvisaari J, Saarni SI, et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry . 2007;64(1):19.

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Childhood-Onset Schizophrenia and Early-onset Schizophrenia Spectrum Disorders: An Update

Affiliations.

• 1 Child Psychiatry Branch, National Institutes of Mental Health (NIMH), National Institutes Health (NIH), Building 10, Room 4N313C, 10 Center Drive, Bethesda, MD 20814, USA. Electronic address: [email protected].
• 2 Healthy Foundations Group, 4350 East West Highway, Suite 200, Bethesda, Maryland 20814, USA.
• 3 National Institutes Health (NIH), NSC Building, Room 6104, 6001 Executive Boulevard, Rockville, MD 20852, USA.
• 4 National Institutes Health (NIH), Building 10-CRC, Room 6-5332, 10 Center Drive, Bethesda, MD 20814, USA.
• PMID: 31708054
• DOI: 10.1016/j.chc.2019.08.017

The clinical severity, impact on development, and poor prognosis of childhood-onset schizophrenia may represent a more homogeneous group. Positive symptoms in children are necessary for the diagnosis, and hallucinations are more often multimodal. In healthy children and children with a variety of other psychiatric illnesses, hallucinations are not uncommon and diagnosis should not be based on these alone. Childhood-onset schizophrenia is an extraordinarily rare illness that is poorly understood but seems continuous with the adult-onset disorder. Once a diagnosis is confirmed, aggressive medication treatment combined with family education and individual counseling may prevent further deterioration.

Keywords: Childhood psychosis; Childhood-onset schizophrenia; Schizophrenia.

Published by Elsevier Inc.

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Very early‑onset psychosis/schizophrenia: Case studies of spectrum of presentation and management issues

• November 2018
• Journal of Family Medicine and Primary Care 7(6)
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• All India Institute of Medical Sciences Bathinda

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Very early-onset psychosis/schizophrenia

Case studies of spectrum of presentation and management issues.

Aneja, Jitender 1, ; Singhai, Kartik 1 ; Paul, Karandeep 1

1 Department of Psychiatry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

Address for correspondence: Dr. Jitender Aneja, Department of Psychiatry, All India Institute of Medical Sciences, Jodhpur - 342 005, Rajasthan, India. E-mail: [email protected]

Schizophrenia occurs very uncommonly in children younger than 13 years. The disease is preceded by premorbid difficulties, familial vulnerability, and a prodromal phase. The occurrence of positive psychotic symptoms such as delusions and hallucinations depends on the level of cognitive development of child. Furthermore, at times it is very difficult to differentiate the psychopathology and sustain a diagnosis of schizophrenia in view of similarities with disorders such as autism, mood disorders, and obsessive compulsive disorders. Here, we present three case studies with varying presentation of childhood-onset psychosis/schizophrenia and associated management issues.

Introduction

Schizophrenia is a chronic severe mental illness with heterogeneous clinical profile and debilitating course. Research shows that clinical features, severity of illness, prognosis, and treatment of schizophrenia vary depending on the age of onset of illness.[ 1 2 ] Hence, age-specific research in schizophrenia has been emphasized. Although consistency has been noted in differentiating early-onset psychosis (onset <18 years of age) and adult-onset psychosis (onset >18 years), considerable variation is observed with regard to the age of childhood-onset schizophrenia or very early-onset psychosis/schizophrenia (VEOP/VEOS).[ 2 3 ] Most commonly, psychosis occurring at <13 years of age has been considered to be of very early onset and that between 13 and 17 years to be of adolescent onset.[ 4 ] Furthermore, VEOS has been considered to be rare and shown to have differing clinical features (including positive and negative symptoms, cognitive decline, and neuroimaging findings), course, and outcome when compared with that of early-onset or adult-onset schizophrenia.[ 3 ] Progress in acknowledgement of psychotic disorders in children in the recent times has led primary care physicians and paediatricians to increasingly serve as the principal identifiers of psychiatrically ill youth. In recent years, there has been substantial research in early intervention efforts (e.g., with psychotherapy or antipsychotic medicines) focused on the early stages of schizophrenia and on young people with prodromal symptoms.[ 5 ] Here, we report a series of cases with very early onset of psychosis/schizophrenia who had varying clinical features and associated management issues.

Case Reports

A 14-year-old boy, educated up to class 6, belonging to a family of middle socioeconomic status and residing in an urban area was brought with complaints of academic decline since 3 years and hearing voices for the past 2 years. The child was born out of a nonconsanguineous marriage, an unplanned, uneventful, but wanted pregnancy. The child attained developmental milestones as per age. From his early childhood, he was exposed to aggressive behavior of his father, who often attempted to discipline him and in this pursuit at times was abusive and aggressive toward him. Marital problems and domestic violence since marriage lead to divorce of parents when the child attained age of 10 years.

The following year, the child and the mother moved to maternal grandparents’ home and his school was also changed. Within a year of this, a decline in his academic performance with handwriting deterioration, and irritable and sad behaviour was noted. Complaints from school were often received by the mother where the child was found engaged in fist fights and undesirable behavior. He also preferred solitary activities and resented to eat with the rest of the family. In addition, a decline in performance of daily routine activities was seen. No history suggestive of depressive cognitions at that time was forthcoming. A private psychiatrist was consulted who treated him with sodium valproate up to 400 mg/day for nearly 2 months which led to a decline in his irritability and aggression. But the diagnosis was deferred and the medications were gradually tapered and stopped. Over the next 1 year, he also started hearing voices that fulfilled dimensions of commanding type of auditory hallucinations. He suspected that family members including his mother collude with the unknown persons, whose voices he heard and believed it was done to tease him. He eventually dropped out of school and was often found awake till late night, seen muttering to self, shouting at persons who were not around with further deterioration in his socialization and self-care. Another psychiatrist was consulted and he was now diagnosed with schizophrenia and treated inpatient for 2 weeks with risperidone 3 mg, olanzapine 2.5 mg, and oxcarbazepine 300 mg/day with some improvement in his symptoms. Significant weight gain with the medication lead to poor compliance which further led to relapse within 3 months of discharge. Frequent aggressive episodes over the next 1 year resulted in multiple hospital admissions. He was brought to us with acute exacerbation of symptoms and was receiving divalproex sodium 1500 mg/day, aripiprazole 30 mg/day, trifluperazine 15 mg/day, olanzapine 20 mg/day, and lorazepam injection as and when required. He was admitted for diagnostic clarification and rationalization of his medications. He had remarkable physical features of elongated face with large ears. Non-cooperation for mental state examination, and aggressive and violent behavior were noted. He was observed to be muttering and laughing to self. His mood was irritable, speech was laconic, and he lacked insight into his illness. We entertained a diagnosis of very early-onset schizophrenia and explored for the possibilities of organic psychosis, autoimmune encephalitis, and Fragile X syndrome. The physical investigations done are shown in Table 1 . Further special investigations in the form of rubella antibodies (serum IgG = 64.12 U/mL, IgM = 2.44 U/mL) and polymerase chain reaction for Fragile X syndrome (repeat size = 24) were normal. His intelligence quotient measured a year ago was 90, but he did not cooperate for the same during present admission. Initially, we reduced the medication and only kept him on aripiprazole 30 mg/day and added lurasidone 40 mg twice a day and discharged him with residual negative symptoms only. However, his hallucinations and aggression reappeared within 2 weeks of discharge and was readmitted. This time eight sessions of bilateral modified electroconvulsive therapy were administered and he was put on aripiprazole 30 mg/day, chlorpromazine 600 mg/day, sodium divalproex 1000 mg/day, and trihexyphenidyl 4 mg/day. The family was psychoeducated about the illness, and mother's expressed emotions and overinvolvement was addressed by supportive psychotherapy. Moreover, an activity schedule for the child was made, and occupational therapy was instituted. Dietary modifications in view of weight gain were also suggested. In the past 6 months, no episodes of violence came to our notice, though irritability on not meeting his demands is persistent. However, poor socialization, lack of motivation, apathy, weight gain subsequent to psychotropic medications, and aversion to start school are still unresolved. Influence of his multiple medications on bone marrow function is an impending issue of concern.

An 11-year-old boy, educated up to class 3, belonging to a rural family of lower socioeconomic status was brought with complaints of academic decline since 2 years, repetition of acts, irritability since a year, and adoption of abnormal postures since 6 months. He was born out of a nonconsanguineous marriage, uneventful birth, and pregnancy. He was third in birth order and achieved developmental milestones at an appropriate age. Since 2 years, he would not attend to his studies, had poor attention, and difficult memorization. He attributed it to lack of friends at school and asked for school change. There was no history of low mood, depressive cognitions, conduct problems, or bullying and he performed his daily routine like his premorbid self at that time. Since a year, he was observed to repeat certain acts such as pacing in the room from one end to another, continuously for up to 1–2 h, with intermittent stops and often insisted his mother to follow the suit, stand nearby him, or else he would clang on her. He prohibited other family members except his mother near him and would accept his meals only from her. He repeatedly sought assurance of his mother if he had spoken everything right. He also washed his hands repeatedly, up to 10–20 times at one time, and was unable to elaborate reason for the same. His mood during that period was largely irritable with no sadness or fearfulness. He mostly wore the same set of clothes, would be forced to take bath or get nails/hair trimmed, and efforts to these were often met with aggression from the patient. Eventually, he stopped going to school and his family sought faith healing. Within the next 5–6 months, his illness worsened. Fixed gaze, reduced eye blinking, smiling out of context, diminished speech, and refusal to eat food were the reasons for which he was brought to us. His physical examination was unremarkable and his mental state examination using the Kirby's method showed an untidy and ill-kempt child, with infrequent spontaneous acts, and occasional resentment for examination. He had an expressionless face, with occasional smiling to self, negativism, and mutism. No rigidity in any of the limb was observed. He was diagnosed with catatonic schizophrenia and probable obsessive compulsive disorder (vs mannerisms). We performed a battery of physical investigation to rule out organic psychosis [ Table 1 ]. He responded to injection lorazepam with which catatonia melted away. He was also prescribed olanzapine up to 15 mg/day, fluoxetine 20 mg/day, and dietary modification and lactulose for constipation. The family left against medical advice with 50%–60% clinical improvement [rating on Bush Francis Catatonia Rating scale (BFCRS) reduced from 10 to 4]. He relapsed within a month of discharge, initially with predominance of the probable obsessive compulsive symptoms. Fluoxetine was further increased to up to 60 mg/day. But within the next 2 months, the catatonic symptoms reappeared and he was readmitted. He had received olanzapine up to 25 mg/day, which was replaced with risperidone. In view of nonresponse to intravenous lorazepam, we administered him five sessions of modified bilateral Electro-convulsive therapy (ECT) (rating on BFCRS reduced from 8 to 0). The family was psychoeducated about the child's illness and the need for continuous treatment was emphasized. He was discharged with up to 80%–90% improvement. At follow-ups, he started participating at farm work of the family, took care of self, with some repetition of acts such as washing of hands, and denied any associated anxiety symptoms. However, efforts to re-enroll in school had been futile as the child did not agree for it. He has been maintaining at the same level since 6 months of discharge.

A 7-year-old girl, student of second class, belonging to a high socioeconomic status family living in an urban locality was brought with complaints of academic decline, irritability, and abnormal behavior for the past 9 months. The child was born out of a nonconsanguineous marriage, is first in order, and was a wanted child. Maternal health during pregnancy was normal, but the period of labor was prolonged beyond 18 h, so a lower segment caesarean section was performed. There was no history of birth-related complications and the child's birth weight was 2.80 kg. The child attained developmental milestones as per age. The child had a temperament characterized by high activity levels, below average threshold of distractibility, average ability to sustain attention and persist, easy to warm up, adaptation to new situations, and regular bowel and bladder habits. She was enrolled in school at the age of 4 years and progressed well till 9 months back when a decline in her academic interest was observed by her class teacher. Deterioration of her handwriting skills and avoidance of group activities in school were observed. Similarly, at home persistent irritable behavior was seen and her play activities with her siblings reduced. However, her biofunctions were normal during this period.

One month prior to visiting us, she started insisting on wearing the same dress. She wore the same colored or at times the same dress which she would not take off even at bed or bath time. In addition, a change in her mood from largely irritable to cheerful was noted. Her activity levels were increased and it would be difficult to make her sit quietly in class. Her speech output was more than her usual self and she talked incessantly. Her sleep duration also decreased and she started getting up 3–4 h earlier than her usual routine. In view of these symptoms, her family made first contact with us. Her physical examination was normal and mental state examination revealed her to be cheerful, overactive, and difficult to interrupt. She sang and danced during the interview. We diagnosed her with acute mania on the basis of clinical evaluation and assessment on MINI Kid 6.0.[ 6 ] The details of her physical examination are depicted in Table 1 . She was initially treated with olanzapine 5 mg/day which was later on increased to 10 mg/day. However, no response was observed with it in the next 2 weeks, so it was cross tapered with sodium valproate which was built up to 400 mg/day. She improved by nearly 50%, but her mood still remained cheerful/irritable. She did not resume her school and was brought irregularly for the follow-up. Within the next 2 months, she also started muttering to herself and made certain abnormal gestures. She often feared staying alone, or while going to bed insisted the lights to be kept on and ask someone to accompany her in the toilet unlike her previous self. When asked, she reported seeing a lady in white clothes, with no other details. She stopped asking for food on her own and remained lost in her fantasy world. However, her interest in dressing and appreciating herself in mirror persisted. Her mood during this period was mostly labile and often changed from cheerful to sad or irritable. As per the family, the medications were continued as advised. So in view of the emerging picture, the diagnosis was revised to schizo-affective disorder, and in addition to hike in dose of sodium valproate to 500 mg/day, risperidone 2 mg/day was also added. However, even after 8 weeks of treatment with this combination with hike of risperidone to 4 mg/day, there was no relief. The child is still symptomatic, does not go to school, and has significant dysfunction. Psychosocial intervention in the form of psychoeducation, activity scheduling for the child, and occupational therapy has been instituted in addition to the existing treatment regimen, but results are yet to be seen.

The older concept of neurodegenerative etiology of schizophrenia has been superseded by evolving neurodevelopmental nature of this disease. The latter has been attributed to initiation of the underlying pathophysiological processes long before the onset of clinical disease and interaction of the various genetic and environmental factors. The more accommodating theorist propose schizophrenia to be of neurodevelopmental in origin which in turn speeds the process of neurodegeneration.

On clinical front, VEOS is associated with a more insidious onset, prominent negative symptoms, auditory hallucinations, poorly formed delusions which is in part due to less developed cognitive abilities.[ 7 ] The presence of history of speech and language delay as well as motor development deficits have been observed in major studies on childhood-onset schizophrenia, be it the Maudsley early-onset schizophrenia project or the NIMH study.[ 8 9 ] Premorbid deficits in social adjustments and presence of autistic symptoms have also been shown. Moreover, the early onset of psychosis is associated with poor prognosis, worse overall functioning, and multiple hospitalizations.[ 7 ] The duration of untreated psychosis in childhood-onset psychosis has been shown to be smaller in hospital-based studies[ 10 ] and larger in community settings.[ 11 ] In addition, the presence of comorbidities and an organic etiology or history of maternal illness during pregnancy is a common finding in VEOS.[ 10 ] In addition, obsessive compulsive symptoms are frequently observed in first-episode drug-naive schizophrenia patients and have a poorer outcome, more severe impairment of social behavior, and lower functioning.[ 12 ] However, in many instances it is very difficult to differentiate the obsessive compulsive symptoms from the motor symptoms of schizophrenia such as stereotypy and mannerisms and varying degree of insight.[ 13 ]

In the present case series, all the children had an insidious onset of illness, with initial symptom of academic decline, and poorly formed psychotic symptoms/psychotic-like experiences. All the children reported here had dropped out of school, showed a shift in their interests, withdrew from social circle, appeared to be distant, had impaired self-care, and often lacked concern for others along with a range of mood disturbances. All these symptoms fit into the classical description of prodromal symptoms of schizophrenia.[ 14 ] In contrast to available evidence, no history of motor, speech, or language delay was noted in any of the child. Furthermore, no history suggestive of autistic features or problems in social adjustments prior to onset of illness was forthcoming.

However, the diagnosis of schizophrenia could be clearly made in the first case, while the second child had predominant catatonic and probably obsessive compulsive symptoms. It is difficult to ascertain the diagnosis of schizophrenia on the basis of presence of only catatonic symptoms and no delusions and hallucinations or negative symptoms as required by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition or International Classification of Diseases, Tenth Revision. However, it is very difficult to sustain any other diagnosis for the second child. In the third child, the illness has been evolving and the clinical picture changed from predominant mood symptoms to psychotic-like experiences at later stage. Therefore, at present a diagnosis of schizo-affective disorder is entertained. We could not find any possible organic etiology in any of the three cases with the best of our efforts.

With provision of pharmacological and psychosocial treatment in accordance to the available treatment guidelines,[ 15 ] remission was not achieved in two of the three children. Currently, the available evidence also suggests that the prognosis of childhood-onset schizophrenia is mainly poor as it disrupts the social and cognitive development and thus nearly two-third of children do not achieve remission.[ 16 ] On a positive note, we have been able to retain all the children in treatment.

Other issues faced by the families of three children and the treating team are briefly discussed below. In countries like India, where significant expenses are born by patients/family, associated stigma, limited social services, and the anti-psychotic related adverse effects raise the burden of care exponentially. In 2/3 index patients, the family bore the costs of special investigations, which was not possible in the second child and led to financial difficulties for the single mother of the first child. Adding on, the availability of rehabilitation services for children with major mental illnesses is scarce in various parts of our country. Furthermore, we successfully used ECT for management of acute disturbance in two of the three patients prior to the notification of Mental Health Care Act, 2017 that prohibits its use in minors. The case series also put forward a strong case for strengthening and sensitizing primary care physicians and pediatricians in identifying and treating cases of VEOP, since they are more likely to be the first points of contact with patients of the discussed age group. In view of the duration of untreated psychosis being a very eloquent prognostic factor for VEOP and the symptomatology of the same showing significant heterogeneity, armoring primary care physicians and pediatricians with the right skills to identify, treat, or refer patients with VEOP, especially in the prodromal period, might profoundly contribute in decreasing the morbidity and improving prognosis. Citing this lacuna which could be filled and used to our advantage, Stevens et al .[ 17 ] elaborated and discussed various questions which practitioners might find useful.

Childhood-onset schizophrenia is a rare occurrence. The current case series highlights differing clinical presentation of VEOS/VEOP in children and adolescents. Certain other issues pertinent to the management of VEOS/VEOP are also touched upon in this article. With the early recognition of childhood mental health illnesses, we need to build and strengthen ample child and adolescent mental health services in India.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

Acknowledgement

The authors thank Dr. Sonam Arora, MD, DNB (Pathology), for providing assistance in laboratory investigations and article writing.

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Childhood-onset schizophrenia is a severe form of psychotic disorder that occurs at age 12 years or younger and is often chronic and persistently debilitating, with worse outcomes than patients who have later onset of symptoms. [ 1 ]  The definition of childhood schizophrenia has evolved over time and is now believed to be a virulent childhood version of the same disorder exhibited in adolescents and adults. The differentiation and significance of “childhood-onset,” versus “early onset,” versus “adult onset” is being explored, especially as it pertains to its utility to determine prognosis. One study of 88 patients found the age cut-off of 12 years old to lack utility. They instead suggested a cut-off age of 14.7 years of age based on higher levels of positive symptoms and poorer psychosocial functioning under this cut-off and better outcomes over this cut-off. [ 1 ]

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) cautions that although the essential features of schizophrenia are the same in childhood, it is harder to diagnose. Symptoms such as disorganized speech and behavior, which are typically present in schizophrenia, also occur in many disorders of childhood onset (e.g., autism spectrum disorder, obsessive compulsive disorder, [ 2 ] and attention-deficit hyperactivity disorder). It is important to consider these more common disorders of childhood before attributing symptoms to schizophrenia. [ 3 ]

Diagnostic criteria (DSM-5)

DSM-5 diagnostic criteria for schizophrenia requires at least two of the following five symptoms to be present for a month. [ 3 ] At least one of these must be (1), (2), or (3):

Hallucinations

Disorganized speech

Grossly disorganized or catatonic behavior

Negative symptoms

Other criteria include a markedly lower level of functioning in one or more major areas, such as work or school, interpersonal relations or self-care; persistence of continuous signs of disturbance for at least 6 months; the ruling out of schizoaffective disorder ; and the exclusion of substance abuse or another medical condition that may be causing the disturbance.

In patients with a history of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms or schizophrenia are also present for at least 1 month (or less if successfully treated).

In addition to the five symptom domain areas identified in the diagnostic criteria, the assessment of cognition, depression, and mania symptom domains is vital for making critically important distinctions between schizophrenia and other psychotic disorders. The American Psychiatric Association removed schizophrenia subtypes from the DSM-5 because they didn’t appear to help with providing better targeted treatment, or predicting treatment response. However, those individuals meeting the criteria for catatonia would receive an additional diagnosis of catatonia associated with schizophrenia to indicate the presence of the comorbidity.

The following duration specifiers are used only after 1-year duration of the disorder and they are not in contradiction to the diagnostic course criteria:

First episode, currently in acute episode

First episode, currently in partial remission

First episode, currently in full remission

Multiple episodes, currently in acute episode

Multiple episodes, currently in partial remission

Multiple episodes, currently in full remission

The validity of a diagnosis of childhood-onset schizophrenia has been a point of concern for some, due to difficulty in differentiating pediatric patients’ reports of visual hallucinations from imaginary figures (which may be developmentally normal). One study on the validity of a diagnosis of early-onset schizophrenia in Denmark found a correspondence of 88.8%, comparing the diagnosis listed in the Denmark registry to a clinical diagnosis based on symptoms reported in patient records. The validity increased when the diagnosis was made on an inpatient unit (91.5%) as opposed to outpatient settings (71.9%). The validity of a diagnosis of the whole sample of early-onset schizophrenia was 83.5%, while the validity of only those with “very early onset schizophrenia” (synonymous with childhood-onset schizophrenia) was slightly lower at 82.8%. Interrater reliability was near-identical between the two groups. [ 4 ]

No definite single etiology of schizophrenia has been identified. Most theories accept both genetic and environmental contributions for the causation of childhood-onset schizophrenia (COS).

A review of the data from the Environmental Risk Longitudinal Twin Study of British Children found that childhood psychotic symptoms are familial and heritable. These symptoms are associated with social risk factors; cognitive impairments at age 5 years; home-rearing risk factors; behavioral, emotional, and educational problems at age 5 years; and comorbid conditions such as self-harm. Therefore, childhood psychotic disorders may be a marker of an impaired developmental process. [ 5 ]

In addition, compared with the usual onset of schizophrenia in late adolescence or early adulthood, the emergence of earlier-onset schizophrenia during childhood may be due to increased genetic loading for schizophrenia or early central nervous system (CNS) damage due to an environmental factor.

Genetic risk

Several factors suggest a genetic risk. First-degree relatives of patients with early-onset schizophrenia (EOS) have a 5 to 20 times higher risk of developing schizophrenia compared to the general population. First-degree relatives of children with schizophrenia have a higher prevalence rate of schizophrenia and schizophrenia spectrum disorders. [ 6 ]  A twin study in Denmark concluded the twin of a patient with schizophrenia had a 4.7 times increased risk of developing schizophrenia themselves if the first twin was diagnosed or presented with illness before 22 years old. They did not study more specific age ranges under 22 years old, but did say (based on their age divisions above 22 years) that overall decreasing age at first diagnosis significantly increased the risk of second-twin diagnosis. [ 7 ]

In the Pittsburgh High-Risk Study, findings among young relatives of schizophrenia patients included the following: [ 8 ]

High proportions of axis I psychopathology, especially attention deficit hyperactivity disorder (ADHD) and conduct disorder

Increased expressed emotion among relatives

A trend for more psychopathology in offspring of relatives with high expressed emotion

Impaired attention, spatial working memory, and executive functions

Increased soft neurologic signs

Volume reductions in the amygdala, hippocampus, and superior temporal gyrus

Decreased slow-wave sleep

First-degree relatives of individuals with schizophrenia have impairment in ocular smooth pursuit movements similar to that found on examination of patients with schizophrenia. One study found that healthy siblings of patients with COS had decreased cerebral gray matter in the same pattern as was seen in the patients. [ 9 ]  

Examination of National Institute of Mental Health patients with onset of schizophrenia before age 13 years revealed a 10% rate of cytogenetic abnormalities. [ 10 ] Certain genome mutations have also been significantly linked with EOS including 1q21.1, 15q13.3, and 22q11.2 deletion syndrome and could account for 0.5%–1% of cases. In addition, associations with several schizophrenia-susceptibility genes in adult patient cohorts were replicated in the childhood-onset schizophrenia patients, including DAOA , NRG1 , DTNBP1 , and GAD1 . [ 11 ] A study of Han Chinese patients found the gene rs139887 in SOX10 to be associated with males with early-onset schizophrenia. [ 12 ]  A different study of 385 Han Chinese patients found a specific polymorphism in the serotonin 2A receptor to “confer susceptibility to schizophrenia with early age of onset.” [ 13 ]  Rare genetic variations to miRNA (involved in brain development) were found to be 50% more prevalent in patients with early-onset schizophrenia than in the control population. [ 14 ]  There was also an excess of novel copy number variants that overlapped or disrupted known genes in patients when compared with the nontransmitted parental “control” chromosomes. [ 15 ]  A published case study in Boston revealed two patients who developed schizophrenia before 7 years of age who both possessed copy number variants at 16p13.11, a locus associated with both adult-onset schizophrenia and autism spectrum disorder. [ 16 ]

A study of 177 patients in Sweden found greater global DNA hypomethylation (conveying genetic instability) in leukocytes of patients with schizophrenia compared to controls, with this finding even more pronounced in patients with early-onset schizophrenia.{ref204-INVALID REFERENCE} Studies are underway to investigate the correlation of DNA methylation and gender differences in early-onset schizophrenia. [ 17 ]

Neurodevelopmental and neuroanatomical abnormalities

Several studies have described complications during pregnancy and delivery in adults who subsequently develop schizophrenia. The combination of genetic risk and evidence of acquired damage has suggested a neurodevelopmental theory with early CNS abnormalities that contribute to an increased vulnerability to schizophrenia later in life. An increase in minor dysmorphic features has suggested prenatal-onset problems. An increase in hypoxia-associated complications was demonstrated to increase the odds of developing earlier-onset schizophrenia.

The neuroanatomy of persons with COS has been examined by neuroimaging. As in adults with schizophrenia, the most consistent finding has been enlargement of the lateral ventricles. Although static in adults, the abnormalities in brain morphology evolve during adolescence. The possibility of a neurodegenerative process has been raised but also questioned. [ 18 ]

The literature has revealed a compelling story for gray matter deficits in individuals with COS. Specifically, Rapoport et al demonstrated that adolescents with schizophrenia have significantly greater decreases in frontal and temporal gray matter volumes than those observed in healthy age-matched controls (see the images below). [ 19 , 20 ] The investigators additionally found the children with schizophrenia to have more cortical gray matter loss than children with transient psychosis. 

Greenstein et al. reported that cortical thickness loss in childhood-onset schizophrenia appears to localize with age to prefrontal and temporal regions that are seen in patients with adult-onset schizophrenia, regardless of medication. [ 21 ]  Another study showed that childhood-onset schizophrenia patients who met criteria for remission had thicker gray matter in prefrontal, temporal, and parietal cortices compared with nonremitted patients, suggesting a possible relation of brain plasticity with prognosis. [ 22 ]

The Edinburgh High-Risk Study suggested that in high-risk subjects (defined as subjects who had at least 2 close relatives with schizophrenia) the change from vulnerability to psychosis may be preceded by reduction in size and deteriorating function of the temporal lobe. [ 23 ]

In a systematic review and meta-analysis of 66 papers comparing brain volume in patients with a first psychotic episode with volume in healthy controls, meta-analysis suggested that the whole brain and hippocampal volume are reduced and that ventricular volume is increased in affected patients relative to healthy controls. [ 24 ]  Furthermore, brain magnetic resonance scans obtained in childhood-onset schizophrenia subjects, their nonpsychotic full siblings, and matched health comparison subjects between the ages of 10 and 29 years that measured the total, left, and right hippocampal volumes showed that patients with childhood-onset schizophrenia had a fixed reduction in hippocampal volumes when compared with nonpsychotic siblings and health comparison subjects. In addition, no significant volumetric or trajectory differences were noted between nonpsychotic siblings and healthy comparison subjects. Therefore, decreased hippocampal volume may represent an intermediate disease phenotype. [ 25 ]

A study of siblings of patients with childhood-onset schizophrenia found an association between volumetric differences of the right superior frontal gyrus and cerebellum and late in learning performance on the weather prediction task (a test of cognitive skill learning). The authors suggested some of these volumetric abnormalities may be “potential endophenotype[s] for schizophrenia.” They suggested the genetic risk was “most apparent in adolescence” as these abnormalities normalized as the siblings reached adulthood. [ 26 ]

Studies of nonpsychotic siblings of childhood-onset schizophrenia patients have shown a pattern of prefrontal and temporal gray matter deficits during early ages that seem to normalize by the time the subjects reach late adolescence. [ 27 ] These results were replicated by Mattai et al., who also showed nonpsychotic siblings of childhood-onset schizophrenia patients have early gray matter deficits that improve over time, suggesting that late adolescence may be a critical time for greatest localization of deficits in probands or normalization in nonpsychotic siblings. [ 28 ]

A study looking at striatal volume and shape compared patients with childhood-onset schizophrenia, their siblings, and healthy controls. They found patients with childhood-onset schizophrenia displayed “subregional striatal shape differences,” particularly inward displacement of the anterior portion of the striatal head and outward displacement at the posterior portion of the striatal head. Siblings of these patients at least partially displayed these shape variations. [ 29 ] These findings are of particular interest as “tracts from the striatal head project extensively to the prefrontal cortex,” which shows cortical thickness deficits in patients with childhood-onset schizophrenia. [ 30 ]

Studies of white matter connectivity in childhood-onset schizophrenia have found abnormalities in the left and right cuneus (occipital lobe, visual cortex) in both patients with childhood-onset schizophrenia and their siblings, though they couldn’t find a statistically significant correlation between these abnormalities and the severity of clinical symptoms. [ 31 ] Another study of white matter abnormalities proposed abnormalities of the left inferior longitudinal fasciculus and left inferior fronto-occipital fasciculus as “possible biomarkers of vulnerability for developing schizophrenia.” [ 32 ] Another study observed white matter growth deficits in non-psychotic siblings of patients with childhood-onset schizophrenia, but these deficits normalized with age. [ 33 ]

A study reviewing MRI data asked if abnormal cortical maturation was confined to developmental modules in the brain. They found patients with childhood-onset schizophrenia had “altered maturational trajectories of cortical areas” involved in the cingulo-fronto-temporal developmental module. [ 34 ]

One study found patients with childhood-onset schizophrenia displayed “delayed maturation of occipitotemporal connectivity, with unaffected siblings displaying a milder phenotype.” This delay normalized in the unaffected siblings by mid-adolescence, and normalized in the patients with childhood-onset schizophrenia by early adulthood. Occipitotemporal connectivity is associated with the inferior longitudinal fasciculus, in which developmental delays may be associated with hallucinations. [ 35 ]

Patients diagnosed with childhood-onset schizophrenia were found to have reduced strength of short-distance functional connectivity, though “longer anatomical distances were relatively normal in the COS group.” The authors of that study found this to be consistent with the idea of “‘overpruning’ of short-distance connections” in childhood-onset schizophrenia. [ 36 ]

When studying working memory networks, it was found that patients diagnosed with early onset schizophrenia displayed a similar abnormal pattern of dorsolateral prefrontal cortex connectivity as adults diagnosed with schizophrenia. [ 37 ]

Cannabis use

Evidence from 6 longitudinal studies in 5 countries showed that regular cannabis use predicts an increased risk of a schizophrenia diagnosis or of reporting symptoms of psychosis. [ 38 ]

One study found that 74% of cannabis use disorders subjects had the onset of cannabis use disorder before the onset of positive psychotic symptoms. These subjects were predominately male, younger at study entry, had an earlier age at onset of positive symptoms, less educational attainment, a lower self-socioeconomic status, better premorbid childhood social adjustment, a trend for poorer premorbid childhood academic adjustment, less motor abnormalities, but more severe hallucinations and delusions.

However, in the multivariate analysis only male sex, worse socioeconomic status, better premorbid childhood social adjustment, and more severe positive symptoms at study entry were associated with a lifetime history of cannabis use disorder. The authors concluded that although cannabis use precedes the onset of illness in most patients, no significant association existed between onset of illness and cannabis use disorders that was not accounted for by demographic and clinical variables. [ 39 ]

Nevertheless, another study used the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) to assess for a possible association between cannabis use, traumatic events, and psychotic symptoms in adolescence. Cannabis use and childhood trauma were significantly associated with a risk of experiencing psychotic symptoms. When cannabis use and childhood trauma occurred within the same patient, the risk for psychotic symptoms increased beyond the risk posed by either factor alone. However, only 14 participants in the study reported experiencing psychotic symptoms. Therefore, these findings must be replicated. [ 40 ]

A 2012 study obtained T1-weighted MRIs from adolescents with earlier-onset schizophrenia (EOS), cannabis use disorders (CUD), EOS plus CUD, and healthy controls. In the EOS group and the CUD group, the left superior parietal region had smaller gray matter volumes compared with healthy controls. The combined EOS/CUD group showed similar findings, but no additive effect was found. Nevertheless, the combined EOS/CUD group had smaller gray matter volumes in the left thalamus compared with the CUD and healthy control groups. [ 41 ]

Early adolescent cannabis use coupled with a specific genetic vulnerability may be a risk factor for the development of schizophrenia.

A 2015 literature review concluded that “cannabis alters the course of psychosis by triggering early onset of disease in a vulnerable youth population.” While multiple theories as to how this might happen were noted—substance abuse influencing psychiatric disorders, psychiatric disorders influencing substance abuse, independent and mutually exclusive processes—they refrained from ascribing to one particular mechanism. [ 42 ]

Early childhood trauma

As previously stated, early childhood trauma has been correlated with childhood psychotic symptoms. One study found 93.1% of patients with early-onset schizophrenia “had experienced adverse life events during childhood,” 46.9% had “experienced traumatic events.” [ 4 ]

Specifically, Arsenault et al. obtained data from the Environmental Risk longitudinal Twin Study, which interviewed mothers when their children were aged 5, 7, 10, and 12 years on whether the children had experienced maltreatment by an adult, bullying by peers, or involvement in an accident. When the children were aged 12 years, they were asked about bullying experiences and psychotic symptoms. Children who experienced maltreatment by an adult or bullying by peers were more likely to report psychotic symptoms at age 12 years than were children who did not experience maltreatment. The finding of higher risk of psychotic disorders was observed whether these events occurred early in life or later in childhood. In addition, this finding remained significant when sex, socioeconomic deprivation, internalizing or externalizing problems, children’s genetic liability to developing psychosis, and IQ were controlled. [ 43 ]

Furthermore a prospective cohort study of 12-year-old children assessed the risk of psychotic symptoms using the Psychosis-like Symptoms Interview. Children who had been victims of bullying at ages 8 and/or 10 years, independent of prior psychopathology, family adversity, or child’s IQ, had a 2-fold increase in risk of psychotic symptoms. The risk increased when victimization was chronic or severe. [ 44 ]

One study also found a link between viral CNS infections and later psychosis. Specifically, a national cohort of children born between 1973-1985 was followed by using Swedish national registers to determine the association between CNS infections at age 0-12 years and admissions for nonaffective psychotic illnesses from the 14th birthday (N=2269). There was a slightly increased risk of nonaffective psychotic illness associated with viral CNS infections, as well as schizophrenia. There was no increased risk in relation to bacterial infections. Exposure to mumps virus or cytomegalovirus were associated with later psychosis. [ 45 ] However further research into this correlation is needed.

Some are focusing their attention on immunological markers as potential biomarkers of schizophrenia, some even working towards finding a causal relationship between immune processes and schizophrenia. One such study implicated an autoimmune component of schizophrenia, noting platelet-associated autoantibodies (PAA) to be elevated in patients with childhood-onset schizophrenia compared to a group of children diagnosed with conduct disorder. The authors of this study suggested measuring PAA as a possible diagnostic biomarker of childhood-onset schizophrenia. [ 46 ]  Another study found a statistically significant correlation between negative symptoms of early-onset schizophrenia and IL-4 and IL-10 levels. [ 47 ]

Neurotransmitters and schizophrenia

Most psychologic, pharmacologic, and neuroimaging studies of childhood-onset schizophrenia have suggested dysfunction in the prefrontal cortex and limbic system. The neurotransmitter implicated in the pathophysiology of schizophrenia is dopamine. Medications that increase dopaminergic activity may induce a schizophreniform psychosis, and medications that block postsynaptic D 2 receptors help alleviate symptoms of schizophrenia.

Other neurotransmitters may also be involved in the pathophysiology of schizophrenia. Glutamate has been implicated based, in part, on the production of psychotic symptoms by phencyclidine and the presence of N -methyl-D-aspartate (NMDA) receptor dysfunction. [ 48 ] Serotonin may be important. The new atypical antipsychotic medications have prominent serotonergic effects. Preliminary studies suggest gamma-aminobutyric acid (GABA) may be important. N-acetylaspartate may play a role as well, as one study found lower levels in the prefrontal cortex and thalamus in patients with early-onset schizophrenia. These levels responded and normalized after six months of treatment with atypical antipsychotics. [ 49 ]

Miscellaneous potential etiologies

No one single etiology has been identified for childhood-onset schizophrenia, and likely it is multifactorial. As such, many are attempting to identify potential causes, contributing factors, or biomarkers related to childhood-onset schizophrenia.

In a study of patients at a Nigerian tertiary care center, patients with childhood-onset versus adolescent-onset psychosis were more likely to have mothers who were ill during pregnancy or infancy. The authors suggested maternal illness may be a relevant component of childhood-onset schizophrenia. [ 50 ] Another study examined a possible link between early-onset schizophrenia and maternal small-cell lung cancer. Those authors suspected a connection due to the potentially prodromal aspect of the autoimmune nature of small-cell lung cancer. Their sample size was small, but they did find a statistically significant association between the two. [ 51 ]

Another study looked at the effect of oxidative stress in the pathogenesis of schizophrenia. The study authors found total antioxidant status was significantly associated with baseline cognitive function in early-onset psychosis (low total antioxidant status being associated with lower cognitive performance.) [ 52 ]

Childhood-onset schizophrenia (COS) is rare in the United States; in preadolescents, the estimated prevalence is less than 1 case per 10,000 population. The number of new cases significantly increases during late adolescence, reaching an approximate prevalence of 1% for later-onset schizophrenia. Data from the British National Surveillance study suggests the 1-year incidence of COS of 0.21/100,000 and 1-year outcomes were poor. One study found that 11% of patients with First Episode Schizophrenia and 23% of patients at Clinical High Risk for psychosis reported remembering their first psychotic symptoms as presenting in childhood. [ 53 ]

One study in Denmark found the incidence of early-onset schizophrenia to increase when comparing the time period of 1971–1994 to 1994–2010. However, diagnostic criteria for early-onset schizophrenia changed during this time including letting go of a previous restriction that only allowed the diagnosis to be made in inpatient settings. While diagnostic incidence may have increased, it may have been accounted for by these changes in diagnostic criteria. [ 54 ]

Globally, schizophrenia with an onset later in life appears to have an equal prevalence, with a possible increase in prevalence in urban populations. Most studies demonstrate an average male-to-female incidence of schizophrenia of 1.5–2:1; this ratio is continually being re-examined and challenged. [ 54 ] Males have a slight but statistically significant earlier age at onset, as well as higher rates of comorbid pervasive developmental disorder (PDD) and attention deficit/hyperactivity disorder (ADHS) when compared to females. The higher rates of comorbid PDD and ADHD with childhood-onset schizophrenia, however, mirror the same male-to-female ratios found in adult-onset schizophrenia. [ 55 ]

No studies of overall prevalence of childhood-onset schizophrenia in underdeveloped countries are available. A study of 409 pediatric patients with psychotic symptoms in Nigeria found 40.8% to have a diagnosis of schizophrenia, with 8.1% of the 409 patients being younger than 12 years old. Compared to pediatric patients with adolescent-onset psychotic symptoms, patients with childhood-onset psychotic symptoms were found to have less family history of psychiatric illness, more maternal illness during pregnancy, more illness in infancy, and overall more diagnoses of psychotic disorder due to another general medical condition as opposed to other diagnoses of psychosis. [ 50 ]

The 2006 Aetiology and Ethnicity in Schizophrenia and Other Psychoses Study (AESOP), a large, population-based case-control study conducted over two years in three study centers in England in adults, reported all psychoses were more common in the black and minority ethnic group compared with the white British group. [ 53 ] A British study of early-onset non-affective psychosis published in 2015 found no “preference” of gender, race, or ethnicity. [ 56 ]

One Finnish study also of early-onset schizophrenia found a statistical significance regarding birth interval. Patients with early-onset schizophrenia more often were born within 1–2 years of their nearest sibling. [ 57 ] Interestingly, the effect of season of birth on diagnosis of schizophrenia has been the focus of multiple studies. A 2017 study of data from Korean patients was consistent with studies of other nationalities finding a predominance of winter births (particularly January and February) for patients diagnosed with early-onset schizophrenia. [ 58 ]

In a child younger than 13 years, the onset of schizophrenia is rare and is generally insidious, carrying a worse prognosis. Onset of the disorder in the adolescent years is more common and may have an acute or insidious onset. In general, the earlier the onset of schizophrenia, the poorer the outcome.

The prognosis for childhood-onset schizophrenia and adolescent-onset schizophrenia is worse than that observed in adult-onset schizophrenia. As adults, these children experience the following:

Fewer close social relationships

Less likely to be married [ 59 ]

Less academic achievement

More unemployment

Less capacity for independent living

Patients with an onset before adolescence and those with an insidious onset appear to have a worse response to medication and a worse prognosis. Patients with early-onset non-affective psychosis displayed multiple readmissions and trials of multiple antipsychotics at one-year follow up. [ 56 ]

An increased risk of death from suicide is present in patients with schizophrenia. In large follow-up studies of childhood-onset schizophrenia, the mortality rate from suicide is 5–11%. Approximately 10% of adults with schizophrenia commit suicide. Children and adolescents with psychotic disorders were more likely to display suicidal behaviors (ideation 32% vs 6.7%, planning 20% vs 0%, attempts 20% vs 0%), and more likely to display these behaviors than even children and adolescents diagnosed with depression. No difference was appreciated in rates of suicidal behavior between children versus adolescents with a psychotic disorder. [ 60 ]

Violence is also a potential problem, particularly for the adolescent with paranoid ideation. Patients diagnosed with early-onset schizophrenia spectrum disorder were more likely to display violence before 15 years old, and “present early conduct problems,” but were also less likely to be violent after 18 years old compared to patients diagnosed with adult-onset schizophrenia. [ 59 ] Other complications arise from poor self-care, impulsivity leading to injury or sexually acquired diseases, and substance abuse. One study found early-onset psychosis (not just schizophrenia) was associated with more agitation and aggression, lifetime substance use disorder, antisocial personality disorder, and interaction with the legal system. [ 61 ]

In follow-up studies, more than 50% of children with schizophrenia have persistent severe impairment in social skills and limitations in academic and occupational achievement. One study published in 2016 found patients with childhood-onset schizophrenia spectrum disorder were twice as likely to be diagnosed with ADHD and twice as likely to have speech, language, and learning disabilities compared to patients with adolescence-onset schizophrenia. [ 62 ] Patients with early-onset schizophrenia performed worse on neurocognitive tests compared to the control group. But even more interestingly, patients with early-onset schizophrenia and a family burden of psychosis performed worse than those without a family burden of psychosis. [ 63 ]

The duration of untreated psychosis has been a point of study for many as it appears to have implications in prognosis, especially at two years. A longer duration of untreated psychosis along with a more severe clinical picture at first presentation was associated with a poorer two-year course. The authors of that study speculated this association to be a finding of arrested development rather than deterioration. [ 64 ] A longer duration of untreated psychosis was also associated with lower rates of PANSS remission at two-year follow-up. [ 65 ] Conversely, a shorter duration of untreated psychosis was associated with greater improvements in executive function. [ 66 ]

One small study found shorter gestational length did not increase the risk of early-onset schizophrenia diagnosis, but it did worsen neurocognition within the early-onset schizophrenia population. [ 67 ]

Psychoeducation is essential for families of children with schizophrenia. They need to be educated about the causes, symptoms, natural history, therapy, adverse effects of medication, and complications of childhood-onset schizophrenia.

Families must also know the warning signs of impending relapse. High levels of expressed emotion have been associated with an increased risk of relapse in adults with schizophrenia and can possibly contribute to problems in children with schizophrenia.

Once children with schizophrenia are in remission, teach them to self-monitor for signs of possible relapse. Inform these children about possible adverse effects of medication.

For patient education information, see Mental Health and Behavior Center , as well as Schizophrenia .

Lin A, Wardenaar KJ, Pontillo M, De Crescenzo F, Mazzone L, Vicari S, et al. Is it still correct to differentiate between early and very early onset psychosis?. Schizophr Res . 2016 Jan. 170 (1):211-6. [QxMD MEDLINE Link] .

Baytunca B, Kalyoncu T, Ozel I, Erermiş S, Kayahan B, Öngur D. Early Onset Schizophrenia Associated With Obsessive-Compulsive Disorder: Clinical Features and Correlates. Clin Neuropharmacol . 2017 Nov/Dec. 40 (6):243-245. [QxMD MEDLINE Link] .

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders . 4th ed. Washington, DC: APA; 1994.

Vernal DL, Stenstrøm AD, Staal N, Christensen AMR, Ebbesen C, Pagsberg AK, et al. Validation study of the early onset schizophrenia diagnosis in the Danish Psychiatric Central Research Register. Eur Child Adolesc Psychiatry . 2018 Aug. 27 (8):965-975. [QxMD MEDLINE Link] .

Polanczyk G, Moffitt TE, Arseneault L, et al. Etiological and clinical features of childhood psychotic symptoms: results from a birth cohort. Arch Gen Psychiatry . 2010 Apr. 67(4):328-38. [QxMD MEDLINE Link] .

Asarnow RF, Nuechterlein KH, Fogelson D, Subotnik KL, Payne DA, Russell AT, et al. Schizophrenia and schizophrenia-spectrum personality disorders in the first-degree relatives of children with schizophrenia: the UCLA family study. Arch Gen Psychiatry . 2001 Jun. 58(6):581-8. [QxMD MEDLINE Link] .

Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, et al. Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility? Analysis of Data From the Nationwide Danish Twin Register. EBioMedicine . 2017 Apr. 18:320-326. [QxMD MEDLINE Link] .

Keshavan MS, Diwadkar VA, Montrose DM, Stanley JA, Pettegrew JW. Premorbid characterization in schizophrenia: the Pittsburgh High Risk Study. World Psychiatry . 2004 Oct. 3(3):163-8. [QxMD MEDLINE Link] . [Full Text] .

Gogtay N, Sporn A, Clasen LS, Greenstein D, Giedd JN, Lenane M, et al. Structural brain MRI abnormalities in healthy siblings of patients with childhood-onset schizophrenia. Am J Psychiatry . 2003 Mar. 160(3):569-71. [QxMD MEDLINE Link] .

Addington AM, Rapoport JL. The genetics of childhood-onset schizophrenia: when madness strikes the prepubescent. Curr Psychiatry Rep . 2009 Apr. 11(2):156-61. [QxMD MEDLINE Link] . [Full Text] .

Addington AM, Gornick M, Duckworth J, et al. GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry . 2005 Jun. 10(6):581-8. [QxMD MEDLINE Link] .

Yuan A, Yi Z, Sun J, Du Y, Yu T, Zhang C, et al. Effect of SOX10 gene polymorphism on early onset schizophrenia in Chinese Han population. Neurosci Lett . 2012 Jul 19. 521 (2):93-7. [QxMD MEDLINE Link] .

Ni J, Lu W, Wu Z, Chen J, Yi Z, Zhang C. T102C polymorphism of serotonin 2A type receptor gene confers susceptibility to (early onset) schizophrenia in Han Chinese: an association study and meta-analysis. Asia Pac Psychiatry . 2013 Mar. 5 (1):24-30. [QxMD MEDLINE Link] .

Zhang F, Xu Y, Shugart YY, Yue W, Qi G, Yuan G, et al. Converging evidence implicates the abnormal microRNA system in schizophrenia. Schizophr Bull . 2015 May. 41 (3):728-35. [QxMD MEDLINE Link] .

Walsh T, McClellan JM, McCarthy SE, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science . 2008 Apr 25. 320(5875):539-43. [QxMD MEDLINE Link] .

Brownstein CA, Kleiman RJ, Engle EC, Towne MC, D'Angelo EJ, Yu TW, et al. Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports. Am J Med Genet A . 2016 May. 170A (5):1165-73. [QxMD MEDLINE Link] .

Melas PA, Rogdaki M, Ösby U, Schalling M, Lavebratt C, Ekström TJ. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. FASEB J . 2012 Jun. 26 (6):2712-8. [QxMD MEDLINE Link] .

Weinberger DR, McClure RK. Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain?. Arch Gen Psychiatry . 2002 Jun. 59(6):553-8. [QxMD MEDLINE Link] .

Rapoport JL, Giedd JN, Blumenthal J, Hamburger S, Jeffries N, Fernandez T, et al. Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry . 1999 Jul. 56(7):649-54. [QxMD MEDLINE Link] .

Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry . 2005 May. 10(5):434-49. [QxMD MEDLINE Link] .

Greenstein D, Lerch J, Shaw P, Clasen L, Giedd J, Gochman P, et al. Childhood onset schizophrenia: cortical brain abnormalities as young adults. J Child Psychol Psychiatry . 2006 Oct. 47(10):1003-12. [QxMD MEDLINE Link] .

Gogtay N, Rapoport JL. Childhood-onset schizophrenia: insights from neuroimaging studies. J Am Acad Child Adolesc Psychiatry . 2008 Oct. 47(10):1120-4. [QxMD MEDLINE Link] .

Johnstone EC, Lawrie SM, Cosway R. What does the Edinburgh high-risk study tell us about schizophrenia?. Am J Med Genet . 2002 Dec 8. 114(8):906-12. [QxMD MEDLINE Link] .

Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry . 2006 Jun. 188:510-8. [QxMD MEDLINE Link] .

Mattai A, Hosanagar A, Weisinger B, et al. Hippocampal volume development in healthy siblings of childhood-onset schizophrenia patients. Am J Psychiatry . 2011 Apr. 168(4):427-35. [QxMD MEDLINE Link] .

Wagshal D, Knowlton BJ, Cohen JR, Bookheimer SY, Bilder RM, Fernandez VG, et al. Cognitive correlates of gray matter abnormalities in adolescent siblings of patients with childhood-onset schizophrenia. Schizophr Res . 2015 Feb. 161 (2-3):345-50. [QxMD MEDLINE Link] .

Gogtay N, Vyas NS, Testa R, Wood SJ, Pantelis C. Age of onset of schizophrenia: perspectives from structural neuroimaging studies. Schizophr Bull . 2011 May. 37(3):504-13. [QxMD MEDLINE Link] . [Full Text] .

Mattai AA, Weisinger B, Greenstein D, et al. Normalization of cortical gray matter deficits in nonpsychotic siblings of patients with childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry . 2011 Jul. 50(7):697-704. [QxMD MEDLINE Link] .

Chakravarty MM, Rapoport JL, Giedd JN, Raznahan A, Shaw P, Collins DL, et al. Striatal shape abnormalities as novel neurodevelopmental endophenotypes in schizophrenia: a longitudinal study. Hum Brain Mapp . 2015 Apr. 36 (4):1458-69. [QxMD MEDLINE Link] .

Leh SE, Ptito A, Chakravarty MM, Strafella AP. Fronto-striatal connections in the human brain: a probabilistic diffusion tractography study. Neurosci Lett . 2007 May 29. 419 (2):113-8. [QxMD MEDLINE Link] .

Moran ME, Luscher ZI, McAdams H, Hsu JT, Greenstein D, Clasen L, et al. Comparing fractional anisotropy in patients with childhood-onset schizophrenia, their healthy siblings, and normal volunteers through DTI. Schizophr Bull . 2015 Jan. 41 (1):66-73. [QxMD MEDLINE Link] .

Epstein KA, Cullen KR, Mueller BA, Robinson P, Lee S, Kumra S. White matter abnormalities and cognitive impairment in early-onset schizophrenia-spectrum disorders. J Am Acad Child Adolesc Psychiatry . 2014 Mar. 53 (3):362-72.e1-2. [QxMD MEDLINE Link] .

Gogtay N, Hua X, Stidd R, Boyle CP, Lee S, Weisinger B, et al. Delayed white matter growth trajectory in young nonpsychotic siblings of patients with childhood-onset schizophrenia. Arch Gen Psychiatry . 2012 Sep. 69 (9):875-84. [QxMD MEDLINE Link] .

Alexander-Bloch AF, Reiss PT, Rapoport J, McAdams H, Giedd JN, Bullmore ET, et al. Abnormal cortical growth in schizophrenia targets normative modules of synchronized development. Biol Psychiatry . 2014 Sep 15. 76 (6):438-46. [QxMD MEDLINE Link] .

Zalesky A, Pantelis C, Cropley V, Fornito A, Cocchi L, McAdams H, et al. Delayed Development of Brain Connectivity in Adolescents With Schizophrenia and Their Unaffected Siblings. JAMA Psychiatry . 2015 Sep. 72 (9):900-8. [QxMD MEDLINE Link] .

Alexander-Bloch AF, Vértes PE, Stidd R, Lalonde F, Clasen L, Rapoport J, et al. The anatomical distance of functional connections predicts brain network topology in health and schizophrenia. Cereb Cortex . 2013 Jan. 23 (1):127-38. [QxMD MEDLINE Link] .

Kyriakopoulos M, Dima D, Roiser JP, Corrigall R, Barker GJ, Frangou S. Abnormal functional activation and connectivity in the working memory network in early-onset schizophrenia. J Am Acad Child Adolesc Psychiatry . 2012 Sep. 51 (9):911-20.e2. [QxMD MEDLINE Link] .

Degenhardt L, Hall W. Is cannabis use a contributory cause of psychosis?. Can J Psychiatry . 2006 Aug. 51(9):556-65. [QxMD MEDLINE Link] .

Sevy S, Robinson DG, Napolitano B, et al. Are cannabis use disorders associated with an earlier age at onset of psychosis? A study in first episode schizophrenia. Schizophr Res . 2010 Jul. 120(1-3):101-7. [QxMD MEDLINE Link] . [Full Text] .

Harley M, Kelleher I, Clarke M, et al. Cannabis use and childhood trauma interact additively to increase the risk of psychotic symptoms in adolescence. Psychol Med . 2010 Oct. 40(10):1627-34. [QxMD MEDLINE Link] .

Kumra S, Robinson P, Tambyraja R, et al. Parietal lobe volume deficits in adolescents with schizophrenia and adolescents with cannabis use disorders. J Am Acad Child Adolesc Psychiatry . 2012 Feb. 51(2):171-80. [QxMD MEDLINE Link] .

Bagot KS, Milin R, Kaminer Y. Adolescent Initiation of Cannabis Use and Early-Onset Psychosis. Subst Abus . 2015. 36 (4):524-33. [QxMD MEDLINE Link] .

Arseneault L, Cannon M, Fisher HL, Polanczyk G, Moffitt TE, Caspi A. Childhood trauma and children's emerging psychotic symptoms: A genetically sensitive longitudinal cohort study. Am J Psychiatry . 2011 Jan. 168(1):65-72. [QxMD MEDLINE Link] .

Schreier A, Wolke D, Thomas K, et al. Prospective study of peer victimization in childhood and psychotic symptoms in a nonclinical population at age 12 years. Arch Gen Psychiatry . 2009 May. 66(5):527-36. [QxMD MEDLINE Link] .

Dalman C, Allebeck P, Gunnell D, et al. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry . 2008 Jan. 165(1):59-65. [QxMD MEDLINE Link] .

Ebert T, Schechtman M, Ram A, Kosov I, Weizman A, Shinitzky M, et al. High circulatory titer of platelet-associated autoantibodies in childhood onset schizophrenia and its diagnostic implications. Neuropsychobiology . 2013. 68 (2):124-7. [QxMD MEDLINE Link] .

Şimşek Ş, Yıldırım V, Çim A, Kaya S. Serum IL-4 and IL-10 Levels Correlate with the Symptoms of the Drug-Naive Adolescents with First Episode, Early Onset Schizophrenia. J Child Adolesc Psychopharmacol . 2016 Oct. 26 (8):721-726. [QxMD MEDLINE Link] .

Clinton SM, Haroutunian V, Davis KL, Meador-Woodruff JH. Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am J Psychiatry . 2003 Jun. 160(6):1100-9. [QxMD MEDLINE Link] .

Gan JL, Cheng ZX, Duan HF, Yang JM, Zhu XQ, Gao CY. Atypical antipsychotic drug treatment for 6 months restores N-acetylaspartate in left prefrontal cortex and left thalamus of first-episode patients with early onset schizophrenia: A magnetic resonance spectroscopy study. Psychiatry Res . 2014 Jul 30. 223 (1):23-7. [QxMD MEDLINE Link] .

Okewole AO, Ogunwale A, Mosanya TJ, Ojo BM. A 12 year chart review of childhood and adolescent onset psychosis at a Nigerian tertiary mental health facility. J Child Adolesc Ment Health . 2016 Oct. 28 (3):189-197. [QxMD MEDLINE Link] .

Benros ME, Laursen TM, Dalton SO, Nordentoft M, Mortensen PB. The risk of schizophrenia and child psychiatric disorders in offspring of mothers with lung cancer and other types of cancer: a Danish nationwide register study. PLoS One . 2013. 8 (11):e79031. [QxMD MEDLINE Link] .

Martínez-Cengotitabengoa M, Micó JA, Arango C, Castro-Fornieles J, Graell M, Payá B, et al. Basal low antioxidant capacity correlates with cognitive deficits in early onset psychosis. A 2-year follow-up study. Schizophr Res . 2014 Jun. 156 (1):23-9. [QxMD MEDLINE Link] .

Woodberry KA, Serur RA, Hallinan SB, Mesholam-Gately RI, Giuliano AJ, Wojcik JD, et al. Frequency and pattern of childhood symptom onset reported by first episode schizophrenia and clinical high risk youth. Schizophr Res . 2014 Sep. 158 (1-3):45-51. [QxMD MEDLINE Link] .

Okkels N, Vernal DL, Jensen SO, McGrath JJ, Nielsen RE. Changes in the diagnosed incidence of early onset schizophrenia over four decades. Acta Psychiatr Scand . 2013 Jan. 127 (1):62-8. [QxMD MEDLINE Link] .

Ordóñez AE, Loeb FF, Zhou X, Shora L, Berman RA, Broadnax DD, et al. Lack of Gender-Related Differences in Childhood-Onset Schizophrenia. J Am Acad Child Adolesc Psychiatry . 2016 Sep. 55 (9):792-9. [QxMD MEDLINE Link] .

Tiffin PA, Kitchen CE. Incidence and 12-month outcome of childhood non-affective psychoses: British national surveillance study. Br J Psychiatry . 2015 Jun. 206 (6):517-8. [QxMD MEDLINE Link] .

Stenudd L, Hakko H, Räsänen P, Riala K. Sibling characteristics and early onset psychoses among the young adolescent patient population. Child Psychiatry Hum Dev . 2014. 45 (2):212-9. [QxMD MEDLINE Link] .

Kim JS, Park CM, Choi JA, Park E, Tchoe HJ, Choi M, et al. The association between season of birth, age at onset, and clozapine use in schizophrenia. Acta Psychiatr Scand . 2017 Nov. 136 (5):445-454. [QxMD MEDLINE Link] .

Vinokur D, Levine SZ, Roe D, Krivoy A, Fischel T. Age of onset group characteristics in forensic patients with schizophrenia. Eur Psychiatry . 2014 Mar. 29 (3):149-52. [QxMD MEDLINE Link] .

Lincoln SH, Norkett E, Graber K, Tembulkar S, Morelli N, Gonzalez-Heydrich J, et al. Suicidal behaviors in children and adolescents with psychotic disorders. Schizophr Res . 2017 Jan. 179:13-16. [QxMD MEDLINE Link] .

Huber CG, Hochstrasser L, Meister K, Schimmelmann BG, Lambert M. Evidence for an agitated-aggressive syndrome in early-onset psychosis correlated with antisocial personality disorder, forensic history, and substance use disorder. Schizophr Res . 2016 Aug. 175 (1-3):198-203. [QxMD MEDLINE Link] .

Jerrell JM, McIntyre RS. Factors Differentiating Childhood-Onset and Adolescent-Onset Schizophrenia:A Claims Database Study. Prim Care Companion CNS Disord . 2016. 18 (2): [QxMD MEDLINE Link] .

Hintze B, Borkowska A. Associations Between Cognitive Function, Schizophrenic Symptoms, and Functional Outcome in Early-onset Schizophrenia With and Without a Familial Burden of Psychosis. Isr J Psychiatry Relat Sci . 2015. 52 (3):6-12. [QxMD MEDLINE Link] .

Del Rey-Mejías Á, Fraguas D, Díaz-Caneja CM, Pina-Camacho L, Castro-Fornieles J, Baeza I, et al. Functional deterioration from the premorbid period to 2 years after the first episode of psychosis in early-onset psychosis. Eur Child Adolesc Psychiatry . 2015 Dec. 24 (12):1447-59. [QxMD MEDLINE Link] .

Fraguas D, Del Rey-Mejías A, Moreno C, Castro-Fornieles J, Graell M, Otero S, et al. Duration of untreated psychosis predicts functional and clinical outcome in children and adolescents with first-episode psychosis: a 2-year longitudinal study. Schizophr Res . 2014 Jan. 152 (1):130-8. [QxMD MEDLINE Link] .

Fraguas D, Merchán-Naranjo J, del Rey-Mejías Á, Castro-Fornieles J, González-Pinto A, Rapado-Castro M, et al. A longitudinal study on the relationship between duration of untreated psychosis and executive function in early-onset first-episode psychosis. Schizophr Res . 2014 Sep. 158 (1-3):126-33. [QxMD MEDLINE Link] .

Teigset CM, Mohn C, Rund BR. Gestational length affects neurocognition in early-onset schizophrenia. Psychiatry Res . 2016 Oct 30. 244:78-85. [QxMD MEDLINE Link] .

Jerrell JM, McIntyre RS, Deroche CB. Diagnostic clusters associated with an early onset schizophrenia diagnosis among children and adolescents. Hum Psychopharmacol . 2017 Mar. 32 (2): [QxMD MEDLINE Link] .

Ballageer T, Malla A, Manchanda R, Takhar J, Haricharan R. Is adolescent-onset first-episode psychosis different from adult onset?. J Am Acad Child Adolesc Psychiatry . 2005 Aug. 44(8):782-9. [QxMD MEDLINE Link] .

Mattai AA, Tossell J, Greenstein DK, Addington A, Clasen LS, Gornick MC, et al. Sleep disturbances in childhood-onset schizophrenia. Schizophr Res . 2006 Sep. 86(1-3):123-9. [QxMD MEDLINE Link] .

David CN, Greenstein D, Clasen L, et al. Childhood onset schizophrenia: high rate of visual hallucinations. J Am Acad Child Adolesc Psychiatry . 2011 Jul. 50(7):681-686.e3. [QxMD MEDLINE Link] . [Full Text] .

Sikich L. Diagnosis and evaluation of hallucinations and other psychotic symptoms in children and adolescents. Child Adolesc Psychiatr Clin N Am . 2013 Oct. 22 (4):655-73. [QxMD MEDLINE Link] .

Caplan R, Guthrie D, Fish B, Tanguay PE, David-Lando G. The Kiddie Formal Thought Disorder Rating Scale: clinical assessment, reliability, and validity. J Am Acad Child Adolesc Psychiatry . 1989 May. 28(3):408-16. [QxMD MEDLINE Link] .

Caplan R, Guthrie D, Tang B, Komo S, Asarnow RF. Thought disorder in childhood schizophrenia: replication and update of concept. J Am Acad Child Adolesc Psychiatry . 2000 Jun. 39(6):771-8. [QxMD MEDLINE Link] .

Caplan R, Siddarth P, Bailey CE, Lanphier EK, Gurbani S, Donald Shields W, et al. Thought disorder: A developmental disability in pediatric epilepsy. Epilepsy Behav . 2006 Jun. 8(4):726-35. [QxMD MEDLINE Link] .

Bourgou S, Halayem S, Amado I, Triki R, Bourdel MC, Franck N, et al. Theory of mind in adolescents with early-onset schizophrenia: correlations with clinical assessment and executive functions. Acta Neuropsychiatr . 2016 Aug. 28 (4):232-8. [QxMD MEDLINE Link] .

Bearden CE, Wu KN, Caplan R, Cannon TD. Thought disorder and communication deviance as predictors of outcome in youth at clinical high risk for psychosis. J Am Acad Child Adolesc Psychiatry . 2011 Jul. 50(7):669-80. [QxMD MEDLINE Link] . [Full Text] .

Gochman PA, Greenstein D, Sporn A, Gogtay N, Keller B, Shaw P, et al. IQ stabilization in childhood-onset schizophrenia. Schizophr Res . 2005 Sep 15. 77(2-3):271-7. [QxMD MEDLINE Link] .

Wagshal D, Knowlton BJ, Cohen JR, Poldrack RA, Bookheimer SY, Bilder RM, et al. Deficits in probabilistic classification learning and liability for schizophrenia. Psychiatry Res . 2012 Dec 30. 200 (2-3):167-72. [QxMD MEDLINE Link] .

Kendall T, Tyrer P, Whittington C, Taylor C. Assessment and management of psychosis with coexisting substance misuse: summary of NICE guidance. BMJ . 2011 Mar 23. 342:d1351. [QxMD MEDLINE Link] .

Karp BI, Garvey M, Jacobsen LK, Frazier JA, Hamburger SD, Bedwell JS, et al. Abnormal neurologic maturation in adolescents with early-onset schizophrenia. Am J Psychiatry . 2001 Jan. 158(1):118-22. [QxMD MEDLINE Link] .

Mayoral M, Bombín I, Castro-Fornieles J, González-Pinto A, Otero S, Parellada M, et al. Longitudinal study of neurological soft signs in first-episode early-onset psychosis. J Child Psychol Psychiatry . 2012 Mar. 53 (3):323-31. [QxMD MEDLINE Link] .

Erlenmeyer-Kimling L, Hans S, Ingraham L, Marcus J, Wynne L, Rehman A, et al. Handedness in children of schizophrenic parents: data from three high-risk studies. Behav Genet . 2005 May. 35(3):351-8. [QxMD MEDLINE Link] .

Bassett AS, Chow EW, AbdelMalik P, Gheorghiu M, Husted J, Weksberg R. The schizophrenia phenotype in 22q11 deletion syndrome. Am J Psychiatry . 2003 Sep. 160(9):1580-6. [QxMD MEDLINE Link] .

Consoli A, Raffin M, Laurent C, Bodeau N, Campion D, Amoura Z, et al. Medical and developmental risk factors of catatonia in children and adolescents: a prospective case-control study. Schizophr Res . 2012 May. 137 (1-3):151-8. [QxMD MEDLINE Link] .

Giannitelli M, Consoli A, Raffin M, Jardri R, Levinson DF, Cohen D, et al. An overview of medical risk factors for childhood psychosis: Implications for research and treatment. Schizophr Res . 2018 Feb. 192:39-49. [QxMD MEDLINE Link] .

Holmén A, Juuhl-Langseth M, Thormodsen R, Sundet K, Melle I, Rund BR. Executive function tests in early-onset psychosis: which one to choose?. Scand J Psychol . 2012 Jun. 53 (3):200-5. [QxMD MEDLINE Link] .

Greenstein D, Kataria R, Gochman P, Dasgupta A, Malley JD, Rapoport J, et al. Looking for childhood-onset schizophrenia: diagnostic algorithms for classifying children and adolescents with psychosis. J Child Adolesc Psychopharmacol . 2014 Sep. 24 (7):366-73. [QxMD MEDLINE Link] .

Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA . 2009 Oct 28. 302(16):1765-73. [QxMD MEDLINE Link] . [Full Text] .

Noguera A, Ballesta P, Baeza I, Arango C, de la Serna E, González-Pinto A, et al. Twenty-four months of antipsychotic treatment in children and adolescents with first psychotic episode: discontinuation and tolerability. J Clin Psychopharmacol . 2013 Aug. 33 (4):463-71. [QxMD MEDLINE Link] .

Jensen KG, Correll CU, Rudå D, Klauber DG, Stentebjerg-Olesen M, Fagerlund B, et al. Pretreatment Cardiometabolic Status in Youth With Early-Onset Psychosis: Baseline Results From the TEA Trial. J Clin Psychiatry . 2017 Sep/Oct. 78 (8):e1035-e1046. [QxMD MEDLINE Link] .

Howland RH. Update on newer antipsychotic drugs. J Psychosoc Nurs Ment Health Serv . 2011 Apr. 49(4):13-5. [QxMD MEDLINE Link] .

Fusar-Poli P, Valmaggia L, McGuire P. Can antidepressants prevent psychosis?. Lancet . 2007 Nov 24. 370(9601):1746-8. [QxMD MEDLINE Link] .

Harvey RC, James AC, Shields GE. A Systematic Review and Network Meta-Analysis to Assess the Relative Efficacy of Antipsychotics for the Treatment of Positive and Negative Symptoms in Early-Onset Schizophrenia. CNS Drugs . 2016 Jan. 30 (1):27-39. [QxMD MEDLINE Link] .

Jerrell JM, McIntyre RS, Deroche CB. Pharmacotherapy effectiveness for clinical subgroups among children and adolescents with early onset schizophrenia. Hum Psychopharmacol . 2017 Mar. 32 (2): [QxMD MEDLINE Link] .

Jardri R, Bubrovszky M, Demeulemeester M, Poulet E, Januel D, Cohen D, et al. Repetitive transcranial magnetic stimulation to treat early-onset auditory hallucinations. J Am Acad Child Adolesc Psychiatry . 2012 Sep. 51 (9):947-9. [QxMD MEDLINE Link] .

Gabriel D, Jakubovski E, Taylor JH, Artukoglu BB, Bloch MH. Predictors of treatment response and drop out in the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study. Psychiatry Res . 2017 Sep. 255:248-255. [QxMD MEDLINE Link] .

Puig O, Penadés R, Baeza I, De la Serna E, Sánchez-Gistau V, Bernardo M, et al. Cognitive remediation therapy in adolescents with early-onset schizophrenia: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry . 2014 Aug. 53 (8):859-68. [QxMD MEDLINE Link] .

Calvo A, Moreno M, Ruiz-Sancho A, Rapado-Castro M, Moreno C, Sánchez-Gutiérrez T, et al. Psychoeducational Group Intervention for Adolescents With Psychosis and Their Families: A Two-Year Follow-Up. J Am Acad Child Adolesc Psychiatry . 2015 Dec. 54 (12):984-90. [QxMD MEDLINE Link] .

Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry . 2010 Feb. 67(2):146-54. [QxMD MEDLINE Link] .

Grcevich SJ, Findling RL, Rowane WA, Friedman L, Schulz SC. Risperidone in the treatment of children and adolescents with schizophrenia: a retrospective study. J Child Adolesc Psychopharmacol . 1996 Winter. 6(4):251-7. [QxMD MEDLINE Link] .

McGorry PD, Yung AR, Phillips LJ, Yuen HP, Francey S, Cosgrave EM, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry . 2002 Oct. 59(10):921-8. [QxMD MEDLINE Link] .

Armenteros JL, Davies M. Antipsychotics in early onset Schizophrenia: Systematic review and meta-analysis. Eur Child Adolesc Psychiatry . 2006 Mar. 15(3):141-8. [QxMD MEDLINE Link] .

Findling RL, Robb A, Nyilas M, et al. A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Am J Psychiatry . 2008 Nov. 165(11):1432-41. [QxMD MEDLINE Link] .

Kryzhanovskaya L, Schulz SC, McDougle C, et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry . 2009 Jan. 48(1):60-70. [QxMD MEDLINE Link] .

Findling RL, Kline K, Mckenna K, et al. Efficacy and safety of quetiapine in adolescents with schizophrenia: a 6-week, double-blind, randomized, placebo-controlled trial. Presented at: 55th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Chicago, IL: October 28 to November 2, 2008.

Singh V, Vijapurkar U, Robb A, et al. Efficacy, safety and tolerability of paliperidone ER in adolescent patients with schizophrenia. Poster presented at: 65th Annual Meeting of the Society of Biological Psychiatry. New Orleans, LA: May 20–22, 2010.

Haas M, Unis AS, Armenteros J, Copenhaver MD, Quiroz JA, Kushner SF. A 6-week, randomized, double-blind, placebo-controlled study of the efficacy and safety of risperidone in adolescents with schizophrenia. J Child Adolesc Psychopharmacol . 2009 Dec. 19(6):611-21. [QxMD MEDLINE Link] .

Haas M, Eerdekens M, Kushner S, et al. Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-blind study. Br J Psychiatry . 2009 Feb. 194(2):158-64. [QxMD MEDLINE Link] .

Pandina G, Kushner S, Singer J, et al. Comparison of two risperidone dose ranges in adolescents with schizophrenia. Poster presentation, 54th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Boston, Massachusetts: 2007.

Singh V, Vijapurkar U, Robb A, et al. Efficacy, safety and tolerability of paliperidone ER in adolescent patients with schizophrenia. Poster presented at: 65th Annual Meeting of the Society of Biological Psychiatry. New Orleans, LA: May 20-22, 2010.

Findling R, Cavus I, Pappadopulos E, et al. Efficacy and safety of ziprasidone in adolescents with schizophrenia. Presented at: 2nd Biannual Meeting of the Schizophrenia International Research Society (SIRS). Venice, Italy: April 10-14, 2010.

ClinicalTrials.gov. Safety and tolerability of ziprasidone in adolescents with schizophrenia. Updated December 2, 2011. Available at https://clinicaltrials.gov/ct2/show/NCT00265382 . Accessed: January 12, 2012.

Sikich L, Hamer RM, Bashford RA, Sheitman BB, Lieberman JA. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology . 2004 Jan. 29(1):133-45. [QxMD MEDLINE Link] .

Arango C, Robles O, Parellada M, et al. Olanzapine compared to quetiapine in adolescents with a first psychotic episode. Eur Child Adolesc Psychiatry . 2009 Jul. 18(7):418-28. [QxMD MEDLINE Link] .

Kumra S, Frazier JA, Jacobsen LK, et al. Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry . 1996 Dec. 53(12):1090-7. [QxMD MEDLINE Link] .

Shaw P, Sporn A, Gogtay N, et al. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry . 2006 Jul. 63(7):721-30. [QxMD MEDLINE Link] .

Kumra S, Kranzler H, Gerbino-Rosen G, et al. Clozapine and "high-dose" olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry . 2008 Mar 1. 63(5):524-9. [QxMD MEDLINE Link] .

Pagsberg AK, Tarp S, Glintborg D, Stenstrøm AD, Fink-Jensen A, Correll CU, et al. Acute Antipsychotic Treatment of Children and Adolescents With Schizophrenia-Spectrum Disorders: A Systematic Review and Network Meta-Analysis. J Am Acad Child Adolesc Psychiatry . 2017 Mar. 56 (3):191-202. [QxMD MEDLINE Link] .

Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry . 2008 Nov. 165(11):1420-31. [QxMD MEDLINE Link] .

Correll CU, Penzner JB, Parikh UH, et al. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatr Clin N Am . 2006 Jan. 15(1):177-206. [QxMD MEDLINE Link] .

Olfson M, Gerhard T, Huang C, Lieberman JA, Bobo WV, Crystal S. Comparative effectiveness of second-generation antipsychotic medications in early-onset schizophrenia. Schizophr Bull . 2012 Jun. 38 (4):845-53. [QxMD MEDLINE Link] .

Walkup JT, Cottingham E. Antipsychotic-Induced Weight Gain and Metformin. J Am Acad Child Adolesc Psychiatry . 2017 Oct. 56 (10):808-810. [QxMD MEDLINE Link] .

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med . 2002 Feb 7. 346 (6):393-403. [QxMD MEDLINE Link] .

Correll CU, Kohegyi E, Zhao C, Baker RA, McQuade R, Salzman PM, et al. Oral Aripiprazole as Maintenance Treatment in Adolescent Schizophrenia: Results From a 52-Week, Randomized, Placebo-Controlled Withdrawal Study. J Am Acad Child Adolesc Psychiatry . 2017 Sep. 56 (9):784-792. [QxMD MEDLINE Link] .

Naguy A, Al-Tajali A. Bromocriptine mitigated paliperidone metabolic and neuro-hormonal side effects and improved negative domain in a case of early onset schizophrenia. Nord J Psychiatry . 2016. 70 (4):318-9. [QxMD MEDLINE Link] .

Couchman L, Bowskill SV, Handley S, Patel MX, Flanagan RJ. Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged <18 years: data from a therapeutic drug monitoring service, 1994-2010. Early Interv Psychiatry . 2013 May. 7 (2):122-30. [QxMD MEDLINE Link] .

Midbari Y, Ebert T, Kosov I, Kotler M, Weizman A, Ram A. Hematological and cardiometabolic safety of clozapine in the treatment of very early onset schizophrenia: a retrospective chart review. J Child Adolesc Psychopharmacol . 2013 Oct. 23 (8):516-21. [QxMD MEDLINE Link] .

Maher KN, Tan M, Tossell JW, Weisinger B, Gochman P, Miller R, et al. Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia. J Child Adolesc Psychopharmacol . 2013 Mar. 23 (2):110-6. [QxMD MEDLINE Link] .

Schneider C, Corrigall R, Hayes D, Kyriakopoulos M, Frangou S. Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia. Eur Psychiatry . 2014 Jan. 29 (1):1-10. [QxMD MEDLINE Link] .

Schneider C, Papachristou E, Wimberley T, Gasse C, Dima D, MacCabe JH, et al. Clozapine use in childhood and adolescent schizophrenia: A nationwide population-based study. Eur Neuropsychopharmacol . 2015 Jun. 25 (6):857-63. [QxMD MEDLINE Link] .

Kirkbride JB, Fearon P, Morgan C, Dazzan P, Morgan K, Tarrant J, et al. Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center AeSOP study. Arch Gen Psychiatry . 2006 Mar. 63(3):250-8. [QxMD MEDLINE Link] .

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) . 4th ed. Washington, DC: APA; 2000.

Spencer EK, Kafantaris V, Padron-Gayol MV, Rosenberg CR, Campbell M. Haloperidol in schizophrenic children: early findings from a study in progress. Psychopharmacol Bull . 1992. 28(2):183-6. [QxMD MEDLINE Link] .

Correll CU, Kratochvil CJ, March JS. Developments in pediatric psychopharmacology: focus on stimulants, antidepressants, and antipsychotics. J Clin Psychiatry . 2011 May. 72(5):655-70. [QxMD MEDLINE Link] .

Şimşek Ş, Gençoğlan S, Yüksel T, Kaplan İ, Aktaş H. Lower Brain-Derived Neurotropic Factor Levels in Untreated Adolescents With First-Episode Psychosis. J Clin Psychopharmacol . 2015 Oct. 35 (5):596-9. [QxMD MEDLINE Link] .

Bani-Fatemi A, Zai C, De Luca V. Early onset schizophrenia: Gender analysis of genome-wide potential methylation. Clin Chim Acta . 2015 Sep 20. 449:63-7. [QxMD MEDLINE Link] .

Panigrahi M, Padhy SK, Rathi R. Aripiprazole monotherapy in an adolescent worsens psychosis. Indian J Pharmacol . 2013 Mar-Apr. 45 (2):195-6. [QxMD MEDLINE Link] .

• Childhood schizophrenia. Early and late gray matter deficits in schizophrenia. Areas of gray matter loss, shown in red and yellow, spread from back-to-front (right to left) over 5 years in composite MRI scan data from 12 teens with childhood-onset schizophrenia, beginning at age 14 (left). Red and yellow denotes areas of greater loss. Source: Paul Thompson, MD, UCLA, Laboratory of Neuroimaging. NIMH media file.
• Childhood schizophrenia. Rate of gray matter loss. Composite MRI scan data showing areas of gray matter loss over 5 years, comparing 12 normal teens (left) and 12 teens with childhood-onset schizophrenia. Red and yellow denotes areas of greater loss. Front of brain is at left. Source: Paul Thompson, MD, UCLA, Laboratory of Neuroimaging. NIMH media file.

Contributor Information and Disclosures

Marshal E Ash, DO Resident Physician, Department of Psychiatry, Wright State University, Boonshoft School of Medicine Marshal E Ash, DO is a member of the following medical societies: American Psychiatric Association , Christian Medical and Dental Associations , Ohio Psychiatric Physicians Association Disclosure: Nothing to disclose.

Suzie C Nelson, MD, DFAACAP, FAPA Assistant Professor, Associate Training Director of Child and Adolescent Psychiatry Fellowship Program, Department of Psychiatry, Wright State University, Boonshoft School of Medicine; Child and Adolescent Psychiatrist, Director of Child Psychiatry Operations, Wright-Patterson Medical Center Suzie C Nelson, MD, DFAACAP, FAPA is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry , Christian Medical and Dental Associations Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Nothing to disclose.

Caroly Pataki, MD Health Sciences Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, David Geffen School of Medicine Caroly Pataki, MD is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry , New York Academy of Sciences , Physicians for Social Responsibility Disclosure: Nothing to disclose.

David W Dunn, MD Arthur B Richter Professor of Child Psychiatry, Professor of Child Neurology and Psychiatry, Departments of Neurology and Psychiatry, Director, Division of Child and Adolescent Psychiatry, Co-Director, Riley Child and Adolescent Psychiatry Clinics, Training Director, Child and Adolescent Psychiatry and Triple Board Program, Indiana University School of Medicine David W Dunn, MD is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry , American Academy of Neurology , American Association of Directors of Psychiatric Residency Training, American Epilepsy Society , American Psychiatric Association , Child Neurology Society , International Child Neurology Association , International League Against Epilepsy, Tuberous Sclerosis Alliance Disclosure: Honorarium for grant review committee for Department of Defense.

Annemarie K Loth, MD Child and Adolescent Psychiatry, St Louis Behavioral Medicine Institute Annemarie K Loth, MD is a member of the following medical societies: American Psychiatric Association , Indiana Psychiatric Society Disclosure: Nothing to disclose.

Angelo P Giardino, MD, PhD Clinical Associate Professor, Department of Pediatrics, Baylor College of Medicine; Medical Director, Texas Children's Health Plan, Inc

Angelo P Giardino, MD, PhD is a member of the following medical societies: Academic Pediatric Association , American Academy of Pediatrics , American Professional Society on the Abuse of Children , Harris County Medical Society , Helfer Society, and International Society for Prevention of Child Abuse and Neglect

Disclosure: Bayer Honoraria Review panel membership; Pfizer Grant/research funds Independent contractor; MedImmune Honoraria Review panel membership

Raj K Kalapatapu, MD Fellow, Addiction Psychiatry, Columbia University College of Physicians and Surgeons

Raj K Kalapatapu, MD is a member of the following medical societies: American Academy of Addiction Psychiatry , American Academy of Child and Adolescent Psychiatry , American Association for Geriatric Psychiatry , American Medical Association , and American Psychiatric Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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Childhood Adversities Increase the Risk of Psychosis: A Meta-analysis of Patient-Control, Prospective- and Cross-sectional Cohort Studies

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Filippo Varese, Feikje Smeets, Marjan Drukker, Ritsaert Lieverse, Tineke Lataster, Wolfgang Viechtbauer, John Read, Jim van Os, Richard P. Bentall, Childhood Adversities Increase the Risk of Psychosis: A Meta-analysis of Patient-Control, Prospective- and Cross-sectional Cohort Studies, Schizophrenia Bulletin , Volume 38, Issue 4, 18 June 2012, Pages 661–671, https://doi.org/10.1093/schbul/sbs050

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Evidence suggests that adverse experiences in childhood are associated with psychosis. To examine the association between childhood adversity and trauma (sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying) and psychosis outcome, MEDLINE, EMBASE, PsychINFO, and Web of Science were searched from January 1980 through November 2011. We included prospective cohort studies, large-scale cross-sectional studies investigating the association between childhood adversity and psychotic symptoms or illness, case-control studies comparing the prevalence of adverse events between psychotic patients and controls using dichotomous or continuous measures, and case-control studies comparing the prevalence of psychotic symptoms between exposed and nonexposed subjects using dichotomous or continuous measures of adversity and psychosis. The analysis included 18 case-control studies ( n = 2048 psychotic patients and 1856 nonpsychiatric controls), 10 prospective and quasi-prospective studies ( n = 41 803) and 8 population-based cross-sectional studies ( n = 35 546). There were significant associations between adversity and psychosis across all research designs, with an overall effect of OR = 2.78 (95% CI = 2.34–3.31). The integration of the case-control studies indicated that patients with psychosis were 2.72 times more likely to have been exposed to childhood adversity than controls (95% CI = 1.90–3.88). The association between childhood adversity and psychosis was also significant in population-based cross-sectional studies (OR = 2.99 [95% CI = 2.12–4.20]) as well as in prospective and quasi-prospective studies (OR = 2.75 [95% CI = 2.17–3.47]). The estimated population attributable risk was 33% (16%–47%). These findings indicate that childhood adversity is strongly associated with increased risk for psychosis.

Adverse childhood events including trauma is a common experience worldwide, with some estimates suggesting that about a third of the general population may be affected. 1 Evidence suggests that its effects in adulthood may include a range of negative social outcomes, including higher criminality, 2 a lower educational level 3 and lower general health and well-being. Adverse childhood events have also been related to a greater risk of psychiatric disorder 1 , 4 , 5 and, especially given its high prevalence, it is likely that it is an important determinant of mental ill-health. 6

A growing number of methodologically sound studies have examined child maltreatment (eg, sexual abuse, physical abuse, emotional/psychological abuse and neglect), peer victimization (eg, bullying), and experiences of parental loss and separation as risk factors for psychosis and schizophrenia. Nevertheless, the association between adverse childhood events and psychosis has been a topic of enduring controversy. Only narrative reviews have so far attempted to synthesize these findings, with inconsistent conclusions. 7–9 Therefore, a systematic quantitative synthesis of the existing data is required.

The present study presents a quantitative review and meta-analysis of the available empirical literature, examining the magnitude and consistency of the effects of different, widely-examined types of adversity and trauma observed in: (i) prospective cohort studies, (ii) large population-based cross-sectional studies, and (iii) case-control studies.

Search Strategy

We followed the Meta-analysis of Observational Studies in Epidemiology guidelines (see supplementary table S1 ). 10 Search terms regarding exposure to adversity were chosen based on the most widely studied types of traumatic experiences in the psychosis literature and represented overall exposure, physical, emotional and sexual abuse, physical and emotional neglect, bullying, and parental death. A systematic database search from 1906 up to 2011 was performed on PsychINFO, PubMed, EMBASE, and Web of Science using the following search themes: (“ child abuse ”; “ physical abuse ”; “ sexual abuse ”; “ psychological abuse ”; “ emotional abuse ”; neglect *; trauma *; advers *; maltreat *; bully *; bullied; victim *; “ expressed emotion ”; “ communication deviance ”; “ parental loss ”; separate *; discrimination ) combined with psychosis-related search terms (ie, psychosis ; psychoti *; schizo *; hallucinat *; delusion *; paranoi *) using the Boolean operator “and.” Medical Subject Headings (MeSH) were used to further expand the results of the database search, to identify all relevant studies ( table 1 and supplementary table S2 ). The present analysis focused exclusively on childhood trauma (defined as sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying). Other psychosocial adversities included in the original search (parental communication deviance, expressed emotion and discrimination) were not eligible for the present analysis.

Characteristics of Studies Reporting Adverse Childhood Events in Psychosis included in the Meta-Analysis

Note : ACE, Adverse Childhood Experiences Study; AESOP, Aetiology and Ethnicity in Schizophrenia and Other Psychoses; ALSPAC, Avon Longitudinal Study of Parents and Children 51 ; APMS, Adult Psychiatric Morbidity Survey; ASRB, Australian Schizophrenia Research Bank; EDSP, The Early Developmental Stages of Psychopathology; E-RISK, Environmental Risk Longitudinal Twin Study; ESPAT, Epidemiological Study of Psychopathology of Adolescents in Tsu; GLADS, Group for Longitudinal Affective Disorders Study; GROUP, Genetic Risk and Outcome in Psychosis; NCS, National Comorbidity Survey; NEMESIS, The Netherlands Mental Health Survey and Incidence Study; NFBC, Northern Finland 1966 Birth Cohort; TRAILS, Tracking Adolescents’ Individual Life Survey 52 ; VPCR, Victoria Psychiatric case register, Police Surgeon's Office and Victorian Institute of Forensic Medicine Institute; YHCSL, Youth Health Care Division of South Limburg (Maastricht).

Please note study type was defined on the base of how the included articles analyzed the data; for instance, a longitudinal study analyzing data in a cross-sectional manner was deemed as ‘cross-sectional’.

The following steps were taken to identify all relevant studies and reduce file drawer effects (publication bias due to the likelihood of studies being published depending on the statistical significance of their results): (1) electronic databases were searched for relevant unpublished material (eg, conference articles) from the year 2000 onward; (2) the database search was extended to reports published in Dutch, French, German, Italian, Portuguese, and Spanish; (3) the authors of all eligible reports were contacted and invited to send any relevant unpublished reports (see supplementary table S3 ); and (4) the reference lists and citations of eligible articles were examined to identify any eligible report not previously located through the database search (forward- and backward tracking of literature).

Inclusion and Validity

Only reports published after January 1980 were included because the first known empirical study on adverse childhood events and psychosis was published at this time 11 and the Diagnostic and Statistical Manual of Mental Disorders, Third Edition ( DSM-III ), was released in 1980, improving diagnostic consistency. Eligible studies employed the following methodologies: (1) prospective cohort studies and (2) large-scale cross-sectional studies investigating the association between childhood trauma and psychotic symptoms or illness; (3) case-control studies comparing the prevalence of adverse events between psychotic patients and controls using dichotomous or continuous measures; and (4) case-control studies comparing the prevalence of psychotic symptoms between exposed and nonexposed subjects using dichotomous or continuous measures for adverse childhood events and psychosis. Only reports with sufficient statistical information for the computation of effects comparable to other reported studies were included. When this information was not available (and was not provided by the authors contacted), the study was deemed ineligible.

Measures of childhood adversity and trauma were considered eligible if: (1) the adverse events were assessed at the individual level and (2) exposure was specifically measured prior to the age of 18 (including measures assessing trauma in childhood and adolescence without additional timing details). Types of trauma included in the current meta-analysis were defined as: childhood sexual abuse (sexual acts toward a child, including intercourse, touching, etc.), childhood physical abuse (violent acts leading to physical injury or harm, such as harsh physical punishment), childhood emotional abuse (exposure to behaviour that might result in trauma, such as harshness, name calling by parents during childhood), childhood physical neglect (failure of those who are responsible for physical care to provide this care during childhood, eg, by failing to provide food or clothes), childhood emotional neglect (failure of those who are responsible to provide emotional care to provide this care during childhood, eg, by being unresponsive to a child’s emotional needs), and bullying (an act of repetitively aggressive behavior by a peer with the intention to hurt the child, such as physical assault or intimidation or repeated name-calling). Parental death was defined as death of one of the parents before the age of 18. Parental loss or separation was deemed only eligible if this was equal to parental death due to the high heterogeneity in the definition of separation (varying between being separated from one of the parents for a period of 2 weeks to parental death).

Both diagnostic as well as dimensional measures of psychosis were considered eligible. Diagnostic outcomes were defined as a diagnosis of: psychotic disorder, schizophrenia, or schizoaffective disorder, based on DSM-III , DSM-III-R , DSM-IV , DSM IV-TR , Research Diagnostic Criteria, International Classification of Diseases, Ninth Revision ( ICD-9 ), ICD-10 , or psychiatrist or psychologist evaluation. Dimensional outcomes were defined in terms of individuals in the general population reporting psychotic symptoms, including subclinical psychotic experiences. Studies conducted on heterogeneous psychiatric samples, on participants with organic, drug-induced or secondary psychoses, or on prodromal samples were excluded. Similarly, studies using schizotypal personality measures were considered ineligible. In the case of studies with overlapping samples or when samples were reported in multiple articles, we selected the most appropriate based on the following criteria: (1) a definition of adversity exposure that most closely resembled the search terms used, (2) whether the articles had a specific focus on adversity as a main variable, and (3) (for longitudinal studies) duration of the follow-up period ( supplementary table S4 ).

Eligibility was assessed independently by 2 researchers following a 3-stage procedure: title screening, abstract screening, and whole article screening. Any intercoder discrepancy was resolved during regular consensus meetings. In the first phase, F.S. and F.V. screened all the titles independently. If one or both deemed a title to be eligible for further screening, this was included in the second phase (abstract screening) for further examination (F.S. and F.V. independently; agreement 93.4%). In the third phase, complete texts were examined to reach final decisions on inclusion (F.S. and F.V. or F.V. and R.L. independently) with agreeance levels of 96.6% (FV and FS) and 97.6% (FV and RL). All eligible reports were independently coded by 2 researchers. In case of disagreement, a third coder was consulted.

Effect Size Computation and Statistical Analyses

All analyses were carried out using the meta-analysis commands of Stata 11. 53 We choose ORs as the main outcome metric. When not reported in the primary studies, ORs and their associated variance component were estimated from available descriptive statistics (ie 2 × 2 tables) using standard computational techniques for dichotomous data. 54 , 55 In the case of studies reporting chi-square analysis for 2 × 2 data, the reported chi-square value and sample size were used to estimate effects of the r-family and were then converted to ORs using the computational methods described by Borenstein and colleagues. 55 Risk ratios were treated as ORs without further adjustment as the incidence of psychosis in the studied populations was low (ie, <10%). 56

To examine the global association between adverse childhood events and psychosis, a meta-analysis was carried out on the effects extracted from (1) studies exclusively focusing on single types of adversity (ie, any type of adverse experience considered in this review), as well as (2) studies providing a summary measure of exposure to multiple types of childhood adversity. In the absence of a summary measure of childhood adversity, the authors of studies reporting multiple effects (eg, separate effects for sexual abuse and physical abuse, but no global measure of trauma) were asked to provide additional information for computing summary effects. A similar procedure was employed for studies reporting multiple effects for the associations between adverse events and specific psychotic symptoms. When this information was not available, reports were excluded to avoid bias stemming from the violation of statistical independence. Furthermore, all analyses were also stratified by research design in order to assess whether findings differed across designs. Finally, for studies reporting unadjusted effects as well as effects adjusted for potential confounding, only unadjusted effects were included to improve comparability between studies.

The computation of summary effects was carried out under the random-effects model using the DerSimonian-Laird estimator. Heterogeneity analyses were carried out using the Q and I 2 statistics to examine and quantify the amount of observed variance accounted for by true heterogeneity rather than sampling error. 57 Meta-regression analysis was subsequently used to determine whether (1) differences in study design and (2) inclusion of adjusted or unadjusted effect sizes influenced the observed association between childhood adverse events and psychosis.

Additional analyses were carried out to test the effect of exposure to the specific types of adversity considered in this review (ie, sexual abuse, physical abuse, emotional/psychological abuse, neglect, bullying, and parental death). Due to the large overlap between the studies which examined these adversity-specific effects, these corollary analyses were treated as independent research syntheses and no attempt was made to statistically compare these effects using meta-regression or subgroup analyses.

Ancillary analyses consisted of (1) publication bias assessment 58 and implementation of the “trim and fill” method of Duval and Tweedie 59 (to assess and adjust for the potential influence of publication bias), (2) influence analyses (to identify potential outliers and investigate the influence of single studies on the present findings), and (3) sensitivity analyses for the effect of influential cases and the inclusion of studies controlling for clinical-demographic covariates.

Furthermore, the population attributable risk (PAR) was calculated, using the ORs obtained from the main analyses and the prevalence of childhood trauma. This prevalence was obtained by performing a meta-analysis using all studies included in the main analysis, with the exclusion of the case-control studies. A meta-analysis of these proportions and their SEs was carried out to get a weighted estimate of the proportion. We calculated the PAR 3 times in which we used the values of successively the lowerbound of the 95% confidence interval, the mean and the upperbound of the 95% confidence interval for both the weighted estimates of the proportion, and of the OR obtained from the main analyses.

The search strategy resulted in 27 898 articles. After title screening, 2721 articles were screened by abstract reading; 736 articles were included in the final screening phase, yielding 41 included articles (the study selection process is detailed in figure 1 ). Table 1 summarizes the characteristics of the eligible studies. Additional details about study design and outcome definitions are displayed in supplementary tables S2 and S4 .

Flowchart of studies included in meta-analysis.

Overall Association Between Adverse Childhood Events and Psychosis

As meta-regression revealed that the type of outcome measured in the primary studies (ie, diagnostic vs dimensional) did not influence the observed effect sizes (β = −.15, SE = .22, p = .50), all analyses were carried on the aggregated sample of effects. The results of the aggregated analysis are presented in figure 2 . The analysis comprised 18 case-control studies (with a total of 2048 psychotic patients and 1856 nonpsychiatric controls), 10 prospective and quasi-prospective studies (with a total of 41 803 respondents), and 8 population-based cross-sectional studies (with a total of 35 546 respondents). Trauma was significantly associated with an increased risk for psychosis with an OR = 2.78 (95% CI = 2.34–3.31). The magnitude of the summary effects of adversity on psychosis was largely comparable across different study designs (OR = 2.72 [95% CI = 1.90–3.88] for case-control studies; OR = 2.99 [95% CI = 2.12–4.20] for population-based cross-sectional studies; OR = 2.75 [95% CI = 2.17–3.47] for prospective studies), as indicated by the results of meta-regression analysis for the effect of study type (all p s > .05). The Q and I 2 tests indicated that the association between adverse events and psychosis was statistically heterogeneous in all analyses (all p s < .01), with high estimated proportions of true heterogeneity.

Forest plot (stratified by research design) for the meta-analysis examining the overall association between childhood adverse experiences and psychosis.

The PAR was calculated using the weighted proportion and the ORs obtained from the main analysis. The mean value of the weighted proportion over all studies was 0.27 (95% CI = 0.14, 0.4). The estimated PAR using the mean values of the calculated weighted proportion and the OR was 33%, with a lowest estimate of 16% (PAR calculation using the lowerbound of the 95% confidence interval for both the proportion and the OR) and a highest estimate of 47% (PAR calculation using the upperbound of the 95% confidence interval for both the proportion and the OR).

Associations Between Specific Types of Adversity and Psychosis

The results of separate meta-analyses which examined the effect of specific adverse experiences (sexual abuse, physical abuse, emotional/psychological abuse, neglect, bullying, and parental death) are presented in table 2 (forest plots are available as electronic supplementary material , supplementary figures S1 and S2 ). With the exception of parental death, statistically significant associations were observed between all types of childhood adversity and psychosis.

Results of the separate meta-analyses focusing on specific adverse experiences

Sensitivity Analyses

Egger’s test (B = 0.65, SE = 0.63, p = .31) indicated that the findings were not significantly influenced by small studies effects or other selection biases. Similarly, when the analysis was stratified by research design, the results of the Egger’s test were not significant for all analyses: population-based cross-sectional studies (B = 2.36, SE = 1.33, p = .13), prospective cohort (B = 0.44, SE = 1.26, p = .73) and patient-control studies (B = 0.52, SE = 1.25, p = .66) were unaffected by publication bias. In the aggregated analysis, the application of the trim and fill method identified 9 missing studies. When the estimated missing effects were included in the analysis, the global association between adversity and psychosis remained highly significant, k = 45; OR = 2.29 (95% CI = 1.91–2.74), p < .001. For the analyses stratified by research design, the application of the Duval and Tweedie method led to the identification of 7 hypothetically missing effects for the analysis of the patient-control studies, whereas no missing effects were evident for the analyses of epidemiological cross-sectional studies and prospective studies. In the analysis of the patient-control studies, the association between adverse childhood events and psychosis remained significant after the inclusion of these hypothetically missing effects, k = 25; OR = 1.85 (95% CI = 1.29–2.63), p < .001.

Influence analyses indicated that no study exerted undue influence on the main results of this research synthesis. As an additional sensitivity analysis, we excluded the effect extracted from Furuhawa et al, 13 the only eligible study for which a significant negative association between childhood trauma (death of one or both parents) and psychosis was estimated. The exclusion of this study did not alter the pattern of findings for the analyses focusing in the overall association between adversity and psychosis. However, the previously statistically nonsignificant association between parental death and psychosis was found to be significant after the exclusion of this potential outlier, k = 7, OR = 2.3 (95% CI = 1.63–3.24), p < .001.

Sensitivity analyses were carried out to examine the association between childhood adversity and psychosis in a subgroup of studies reporting adjusted ORs for confounding factors. The association between adversity and psychosis was significant in studies that controlled for the effect of gender ( k = 10, OR = 2.52 [95% CI = 2.00–3.19], p < .001), age ( k = 9, OR = 2.57 [95% CI = 2.00–3.31], p < .001), and socioeconomic status ( k = 6, OR = 3.01 [95% CI = 1.98–4.58], p < .001). When only studies which adjusted for any confound (ie, not limited to the 3 above) in their original analyses were considered, the association between adverse childhood events and psychosis remained significant; k = 12, OR = 2.72 (95% CI = 2.08–3.68), p < .001.

This review finds that childhood adversity and trauma substantially increases the risk of psychosis with an OR of 2.8. Furthermore, our findings suggest that if the adversities we examined as risk factors were entirely removed from the population (with the assumption that the pattern of the other risk factors remained unchanged), and assuming causality, the number of people with psychosis would be reduced by 33%. The association between childhood adversity and psychosis held for the occurrence of psychotic symptoms in the general population, as well as for the development of psychotic disorder in prospective studies; the association remained significant when studies were included that corrected for possible demographic and clinical confounders. The analyses focusing on the effect of specific traumas revealed that, with the exception of parental death (although this association became significant after the exclusion of a potential outlier), all types of adversity were related to an increased risk of psychosis, indicating that exposure to adverse experiences in general increases psychosis risk, regardless of the exact nature of the exposure. This meta-analysis found no evidence that any specific type of trauma is a stronger predictor of psychosis than any other. These findings suggest that other adversity-related variables such as age of exposure and multi-victimization might be more strongly related to psychosis risk than exposure type, which, it has been argued, 60 might affect the specific psychotic symptoms experienced.

The findings imply that exposure to adverse childhood events should be regarded as an important determinant of psychotic disorders. Although the reviewed cross-sectional studies did not allow us to ascertain the direction of causality, the included prospective studies provide evidence for temporal causality. Since childhood traumatic experiences tends to cosegregate so that being exposed to one type of adversity increases the risk of exposure to another, 4 dose-response effects of trauma on psychosis are of particular importance. However, most studies have not tested for dose-response relationships, and due to the heterogeneous methods in which dose-response effects were defined in those primary studies which did consider this issue, it was not possible to include a synthesis of these data in the current review. However, 9 out of 10 of the studies which tested for these associations were positive for a dose-response relation (see supplementary table S5 ).

Although several studies included in this meta-analysis used self-reported retrospective measures of childhood experiences, associations with psychosis were also observed in studies which employed other methods to assess trauma exposure. There is also evidence that the retrospective assessment of childhood trauma tends to underestimate rather than overreport real incidence rates 61 and studies have demonstrated the validity and reliability of retrospective reports of trauma in psychotic samples, showing that they are stable across time, unaffected by current symptoms, and are generally concordant with other sources of information. 62

Several limitations should be considered when interpreting these findings. First, there was substantial statistical heterogeneity for all outcomes and exposures of interest as the primary studies varied considerably in terms of their assessment of childhood adverse experiences (eg, in terms of severity, frequency, timing, duration etc) and assessment of psychosis outcomes. Heterogeneity in the data could also be a result of differences in the methodological quality of studies. However, exploration of the data showed that, even when only studies that controlled for confounders were included and regardless of study design, the effect of childhood adversity on psychosis remained, indicating that these parameters of methodological quality did not obscure the main effect found in the current meta-analysis. Moreover, studies included in this review controlled for other general demographic and clinical confounds such as comorbid psychopathology, 60 , 63–67 ethnicity, 63 , 68 educational attainment, 28 , 63 , 65 , 66 , 69 , 70 and IQ. 60 , 67 Other studies also controlled for variables which have been specifically linked to increased risk for psychosis such as drugs and cannabis use, 63 , 64 , 66 genetic liability (eg, family history of psychosis or other psychiatric disorder), 22 , 63 , 67 , 68 and urbanicity. 63 , 66 It is also worth nothing that studies which examined the interaction between childhood trauma and cannabis use have revealed that the risk of developing psychosis following childhood trauma is (at least partially) independent from that conveyed by cannabis exposure. 71 , 72 Similar results have been observed in studies which examined the relative contribution of childhood trauma while controlling for genetic vulnerability to psychotic symptoms or disorders. 73 , 74 Therefore, the quality of all included studies and the sensitivity analyses support the conclusion that childhood trauma is substantially associated with an increased risk for psychosis.

We cannot rule out the effect of proximal and distal interactions of adversity with other factors (eg, cannabis use, genes, urbanicity) in the current meta-analysis because most studies did not correct for these interactions or corrected for only a subset of these factors as possible moderators. However, since the analysis which included only adjusted ORs still showed a significant association it appears that there is a substantial true effect of childhood experience on psychosis. Additionally, due to a lack of studies focusing on specific age of trauma occurrence, it was not possible to address issues regarding the influence of age of exposure to psychosis outcome. Finally, the psychosis literature has tended to focus exclusively on hallucinatory and delusional symptoms and not on other symptoms. Therefore, the existing data did not allow us to test whether adversity was specifically associated with the development of specific symptoms.

In conclusion, our review of 41 studies found evidence that childhood adversity is substantially associated with an increased risk for psychosis. This finding, combined with other findings on the impact of traumatic experiences in childhood on both general health 6 and mental health 1 , 4 , 5 stress the importance of these disruptive experiences early in development on subsequent functioning in the adult. The implications of our findings for primary prevention are obvious and urgently in need of greater attention. 75 , 76 A range of psychosocial treatment approaches to psychosis, which are more likely to address the sequelae of adverse childhood events, have been found to be effective for many patients and should be made more available. 77

Our findings suggest that clinicians should routinely inquire about adverse events in childhood in order to develop comprehensive formulations and treatment plans when working with patients with schizophrenia or similar diagnoses. 78 Psychosocial interventions which have been used for patients affected by trauma might be considered among the treatment options for patients with psychosis. The current review focused on specific types of adverse events (abuse, neglect, parental death, and bullying). Nevertheless, adversity is a heterogeneous concept (including types of exposure not considered here, for instance medical illness, exposure to war, natural disasters, parental separation). Future studies should focus on differentiating adversity type, as well as consider the possible interaction between trauma and other risk factors (eg, cannabis, genetic risk), the developmental stage of exposure to trauma, and mechanisms linking adversity to specific positive and negative symptoms. 79 , 80

Economic and Social Research Council (RES-000-22-4251 to F.P. and R.P.B.); Geestkracht program of the Dutch Health Research Council (ZON-MW, 10-000-1002); the European Community's Seventh Framework Program (HEALTH-F2-2009-241909, Project EU-GEI).

We thank Zuzana Kasanova and Jennifer O’Brien for contributing to the literature retrieval for this research synthesis. We also thank the researchers who kindly provided information regarding their relevant published and unpublished studies: Louise Arseneault, Jon Allen, A.A. Bartels-Velthuis, Linda Bierer, Paul Bebbington, Christine Braehler, Mary Cannon, Kristin Daalman, Gavin Evans, Toshi Furukawa, Hyun-Sil Kim, Bernard Lerer, Ellen de Loore, Paul Lysaker, Kathryn McCabe, Kristina Muenzenmaier, Martine van Nierop, James Scott, Mark Shevlin, Iris Sommers, Elena Sorrento, Hanneke Wigman, and Dieter Wolke. The Authors have declared that there are no conflicts of interest in relation to the subject of this study.

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• psychotic disorders
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• death of parent

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Childhood-onset schizophrenia: what do we really know?

Jennifer bartlett.

a Department of Educational Psychology , University of Alberta , Edmonton, AB, Canada, T6G 0X6

Childhood-onset schizophrenia (COS) is a rare, chronic mental illness that is diagnosed in children prior to the age of 13. COS is a controversial diagnosis among clinicians and can be very difficult to diagnose for a number of reasons. Schizophrenia is a psychotic disorder characterized by hallucinations, delusions, flat affect, limited motivation and anhedonia. The psychotic nature of this disorder is quite disruptive to the child's emotional regulation, behavioural control and can reduce the child's ability to perform daily tasks that are crucial to adaptive functioning. Prior to the onset of schizophrenia, children often develop premorbid abnormalities, which are disturbances to a child's functioning that may serve as warning signs. These disturbances can manifest in a variety of behavioural ways and may include introversion, depression, aggression, suicidal ideation and manic-like behaviours. This article will review the clinical presentation of schizophrenia in children and examine the existing knowledge around aetiology, treatment approaches, assessment techniques and differential diagnostic considerations. Gaps in the literature are identified and directions for future research are discussed.

Introduction

Schizophrenia is a chronic mental illness characterized by two categories of symptoms: positive and negative. Positive symptoms include hallucinations, delusions, disorganized thinking and speech patterns and abnormal motor behaviour, which may include bizarre movements or catatonia (American Psychiatric Association, 2013 ; Coghill, Bonnar, Duke, Graham, & Seth, 2009 ). Negative symptoms include blunt or flat affect, lack of motivation, absence or diminished speech patterns, diminished interest in social interaction and anhedonia (American Psychiatric Association, 2013 ; Coghill et al., 2009 ). Schizophrenia most commonly emerges during early adulthood between the ages of 16 and 30, but it can also be diagnosed during childhood (The National Institute of Mental Health, 2009 ). A diagnosis of childhood-onset schizophrenia (COS) is given when the onset of the illness occurs prior to age 13 (Remschmidt et al., 2006 ; Sharma & Harvey, 2006 ). COS is a very rare illness and as such is poorly understood. This lack of understanding makes it difficult to accurately diagnose and, as a result, children with schizophrenia are often misdiagnosed. It is important that clinicians have an in-depth understanding of the manifestation and prognosis of COS in order to better recognize and treat it (Taylor, 1998 ). In addition to clinicians, it is also important that individuals and families struggling with schizophrenia are educated so that they can be better prepared to cope with it (Mayo Foundation for Medical Education and Research, 2013 ). COS has an estimated prevalence rate of approximately 1/10,000, and tends to occur more often in males than in females (Coghill et al., 2009 ; Sood & Kattimani, 2008 ). Although the presentation can be quite different in children, COS is diagnosed according to the same criteria for adult-onset schizophrenia with the exception of Criteria B. Criteria B states that the afflicted individual's level of functioning must be diminished. However, as this is difficult to assess in children, they instead must fail to meet the expected level of functioning for a child according to their age (American Psychiatric Association, 2013 ).

COS is very difficult to accurately diagnose, and as such many clinicians are reluctant to do so. One of the key difficulties in making this diagnosis is distinguishing between true hallucinations and delusions and a child's imaginative play (Coghill et al., 2009 ; Taylor, 1998 ). For example, many children have imaginary friends which may be mistaken for psychosis. Similarly, children with poor or underdeveloped language skills may mimic the disorganized thought and speech patterns observed in schizophrenia (Coghill et al., 2009 ). Children may be unable to reliably describe their experiences and symptoms due to a restricted vocabulary or a limited understanding of their internal experiences. As a result, healthcare professionals may be unable to collect the information needed to make a diagnosis (Taylor, 1998 ).

In cases of COS, there are often disturbances in the child's psychosocial functioning prior to the onset of the illness, which are referred to as premorbid abnormalities. Premorbid abnormalities can include a range of behaviours such as shyness, introversion, loneliness, depression, aggression, suicidality, theft and manic-like or bizarre behaviour (Eggers, Bunk, & Krause, 2000 ). One of the most commonly reported initial presenting issues in children is that they are struggling in school, which may be a direct result of the behavioural difficulties that arise in COS (Eggers et al., 2000 ; Schaeffer & Ross, 2002 ). Problematic behaviours are typically noted upon entering school at age 5 or 6, although families often report that the disruptive behaviours began prior to schooling (Schaeffer & Ross, 2002 ). As adult-onset schizophrenia develops between the ages of 16 and 30, premorbid abnormalities are not observed in these patients. However, some patients do experience prodromal symptoms prior to the active phase of schizophrenia, which are simply a mild form of hallucinations or delusions. Both children and adults with schizophrenia can experience the range of positive and negative symptoms, although children's delusions and hallucinations may be less complex than those of adults (American Psychiatric Association, 2013 ).

The diagnosis of COS is thought to be on a clinical continuum with adult-onset schizophrenia and appears to be relatively stable across time, continuing into adulthood (Hollis, 2000 ; Sharma & Harvey, 2006 ). Remschmidt et al. ( 2006 ) conducted a long-term study following 16 patients who were diagnosed with COS over the course of 42 years. At the time of follow-up, patients were assessed using a Global Assessment Scale revealing that the majority of patients had a poor outcome overall. The majority of patients displayed severe to moderate depressive symptoms, failed to graduate from secondary school or secure employment, and had a higher suicide rate than the general population. The majority of the patients displayed negative symptoms and a minority displayed positive symptoms. Overall, the long-term diagnostic stability of this set of patients was 91%, with only 7 of 16 patients having received an alternate diagnosis.

The prognosis of COS is generally quite poor (Eggers et al., 2000 ). Eggers et al. ( 2000 ) conducted a long-term study to examine the outcomes of 11 patients with COS. At the time of follow-up, approximately 41 years later, some clients were in a state of partial remission while others were not. The majority of patients experienced multiple schizophrenic episodes lasting only a short time, but two patients in particular had schizophrenic episodes that were of extended duration. These episodes included two catatonic episodes lasting 30 and 40 years, a paranoid episode of 30 years and a disorganized episode lasting 42 years. The majority of patients had poor social adjustment, and evidence suggests that patients who experienced catatonic episodes had the poorest social adjustment overall.

The underlying causes in the development of COS are varied and poorly understood. Furthermore, while there is research on the factors that contribute to the development of schizophrenia in general, very few studies have focused their investigation on COS. However, as COS is thought to be continuous with adult-onset schizophrenia and is a strong predictor of a continuation of the illness into adulthood, the mechanisms underlying the two are thought to be the same (Sharma & Harvey, 2006 ). As outlined in Table 1 , the most common aetiological risk factors include familial factors, obstetric and pre-natal complications, genetics and neurodevelopment.

Note: A summary of the aetiological risk factors for developing COS.

Familial factors

Very little research has investigated the impact of familial factors on the development and maintenance of COS. Evidence suggests that adverse experiences and negative familial interactions can contribute to the development of schizophrenic symptoms (Gallagher & Jones, 2013 ). More specifically, childhood neglect, such as being ignored or rejected, is associated with the development of negative symptoms. On the other hand, childhood mistreatment, such as physical or sexual abuse, is associated with the development of positive symptoms (Gallagher & Jones, 2013 ).

Obstetric and pre-natal complications

There is evidence to suggest that pre-natal infection can increase the likelihood of offspring developing schizophrenia in both childhood and adulthood (Brown et al., 2004 ; Coghill et al., 2009 ; Sharma & Harvey, 2006 ). Pre-natal exposure to the influenza virus during the first trimester of pregnancy appears to increase the risk of developing schizophrenia, making the offspring seven times more likely to develop this illness. However, pre-natal exposure during the second and third trimesters does not appear to increase the risk of developing schizophrenia (Brown et al., 2004 ). In addition to the influenza virus, pre-natal exposure to the Rubella virus, respiratory infection, analgesics and malnutrition have also been shown to increase the risk of developing COS (Clarke, Harley, & Cannon, 2006 ; Coghill et al., 2009 ; Sharma & Harvey, 2006 ). Lastly, obstetric complications during childbirth have also been identified as a risk factor for the development of COS. The experience of hypoxia in offspring during childbirth, a phenomenon where the body is deprived of oxygen for some period of time, increases the likelihood that offspring will develop COS (Coghill et al., 2009 ; Sharma & Harvey, 2006 ).

Evidence suggests there is a significant heritable component to COS. There are multiple genes and genetic mutations that have been hypothesized as being integral to COS and its hereditary nature (Coghill et al., 2009 ).

Although it is not specific to COS, the age of the paternal parent is one risk factor that has been identified in the development of schizophrenia. More specifically, a paternal parent with a more advanced age over the age of 30 at the time of conception appears to be associated with offspring developing schizophrenia. Furthermore, the older the paternal parent is, the more likely the offspring are to develop schizophrenia (Sipos et al., 2004 ; Zammit et al., 2003 ). It is hypothesized that this association exists due to a cell mutation that occurs as paternal age increases, although this mechanism is not well understood (Zammit et al., 2003 ).

There is also evidence to suggest that a family history of mental illness may increase the likelihood of offspring developing COS. In one sample of COS patients, approximately 80% of those patients had a family history of psychiatric disorders. More specifically, this association appears to exist only if the family has a history of either schizophrenia spectrum disorders or personality disorders (Margari et al., 2011 ). Interestingly, parents of children with schizophrenia are 10 times as likely to develop schizophrenia themselves (Coghill et al., 2009 ).

It is clear that there is a genetic contribution to the development of COS, but the nature of this contribution is poorly understood. Several studies have attempted to identify specific genes that may be associated with or serve as risk factors for the development of COS. One study identified up to 94 genes that were thought to be involved in the development of schizophrenia, which act through different biological pathways. The majority of these genes were related to the functionality of several neurotransmitters, or chemical signals within the brain, including dopamine, serotonin, glutamate and gamma-aminobutyric acid (GABA) (Greenwood et al., 2011 ). The genes associated with neurotransmitter signalling are thought to mediate susceptibility to schizophrenia, although it is unclear how (Greenwood et al., 2011 ). Lastly, there are certain chromosomal deletions that are thought to be associated with the development of COS, including deletions on chromosomes 1, 8, 15 and 22 (Coghill et al., 2009 ; The International Schizophrenia Consortium, 2008 ).

Neurodevelopmental model

The neurodevelopmental model of COS outlines the various structural, pathological and functional nuances of the brain that are associated with this illness, as well as the resulting cognitive implications.

During the process of neurodevelopment, the brain develops an excess of neural connections. As brain development progresses into adolescence, the brain changes by eliminating unnecessary and unused connections (Coghill et al., 2009 ; Sharma & Harvey, 2006 ). Post-mortem studies suggest that, among patients with schizophrenia, there are an abnormal number of neural connections. It is hypothesized that both hyper-aggressive and hypo-aggressive removal of neural connectivity can lead to the development of psychosis (Sharma & Harvey, 2006 ). There may be a greater reduction in neural connections than is considered normal, resulting in less connectivity and brain activity. Conversely, there may be too few neural connections eliminated, indicating excessive connectivity and brain activity (Coghill et al., 2009 ; Sharma & Harvey, 2006 ).

In COS, evidence suggests that the brain's ventricles can become enlarged which has been associated with a form of COS that is more difficult to treat and results in a much poorer outcome (Coghill et al., 2009 ; Sharma & Harvey, 2006 ). There is also a relationship between enlarged ventricles and the presence of persistent positive and negative symptoms. The causal direction of this relationship remains to be unclear; the persistence of these symptoms may directly result in changes to the brain's structure, or the brain's structure may give rise to persistent psychotic symptoms (Sharma & Harvey, 2006 ).

Similarly, it has been hypothesized that loss of grey brain matter as is typical in COS may in fact trigger the onset of this illness during childhood (Sharma & Harvey, 2006 ). A decrease in total cerebral volume occurs as a result of the gradual decline of grey matter, which has also been shown to be associated with poor premorbid functioning in children, prior to the onset of schizophrenia (Coghill et al., 2009 ; Sharma & Harvey, 2006 ). The presence of grey matter, particularly in large quantities, is associated with a higher premorbid IQ among children (Sharma & Harvey, 2006 ) which suggests that lower levels of intelligence in COS may be the direct result of the loss of grey matter characteristic of this illness.

Lastly, evidence suggests that the negative symptoms of schizophrenia are linked to a dysfunction of the brain's frontal lobe, indicating a deficit in executive functioning, such as memory, reasoning, problem solving and planning (Coghill et al., 2009 ; Sharma & Harvey, 2006 ). Positive symptoms, on the other hand, appear to be linked to a dysfunction within the temporal lobe of the brain, which may indicate deficits in memory, executive functioning, verbal expression and abstract thinking (Sharma & Harvey, 2006 ).

While it is clear that there are distinct abnormalities in the structure of the brain with COS, the factors that may trigger this abnormal development remain a mystery.

Differential diagnosis

The presence of overlapping symptomology and co-morbid disorders and the early age at which children experience psychotic-like symptoms can make it very difficult to accurately diagnose COS. One study showed that among a sample of 17 patients with COS, there were a total of 43 alternative diagnoses given prior to diagnosing schizophrenia (Schaeffer & Ross, 2002 ). Similarly, a five-year-old boy who experienced auditory hallucinations received a multitude of inaccurate diagnoses before being formally diagnosed with schizophrenia. The alternate diagnoses included pervasive developmental disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder and schizoaffective disorder (Schaeffer & Ross, 2002 ).

High rates of comorbidity have been found among patients with COS, particularly with ADHD and affective disorders, which makes differential diagnosis a crucial factor for consideration with this population (Ross, Heinlein, & Tregellas, 2006 ). There are a number of disorders that must be considered in the differential diagnosis of COS, including major depressive disorder, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder and schizotypal personality disorder. According to the literature, the three most common disorders that overlap with and are difficult to distinguish from COS are BD, autism spectrum disorder (ASD) and ADHD ( Table 2 ) (Dossetor, 2007 ; Ross et al., 2006 ; Schaeffer & Ross, 2002 ; Tahiroğlu, Çelik, & Avci, 2009 ).

Note: A summary of the similarities and differences between schizophrenia and BD, ASD and ADHD to aid in making a differential diagnosis.

BD in children can present with psychotic symptoms, thus sharing clinical features with COS (Pavuluri, Herbener, & Sweeney, 2004 ; Tahiroğlu et al., 2009 ). The most common psychotic symptoms present in children with BD are mood congruent and grandiose delusions (Pavuluri et al., 2004 ). This is an important distinction in the differential diagnosis of COS because, while the psychotic symptoms in BD appear to be consistent with the patient's affect, they occur in COS independent of affect (Pavuluri et al., 2004 ). A distinguishing feature between COS and BD is that, if delusions or hallucinations occur exclusively during periods of either depression or mania, then the recommended diagnosis is BD with psychotic features (American Psychiatric Association, 2013 ). Both COS and BD can present with changes in mood; where schizophrenia may present with elements of depression, BD can include both low and elated moods and irritability. Clinicians need to be aware of this overlap and carefully consider the presentation of affect before diagnosing COS. Additionally, BD may also present in children with audio, visual and tactile hallucinations, disorganized behaviour, catatonia and paranoia (American Psychiatric Association, 2013 ; Tahiroğlu et al., 2009 ).

Examining the mental state of a child can be difficult, but this becomes further complicated in the presence of a developmental delay. COS is sometimes misdiagnosed in cases of ASD due to the similarities in symptom presentation (Dossetor, 2007 ). The symptoms of ASD, such as disorganized speech and flat affect, can mimic the negative symptoms observed in COS (Dossetor, 2007 ). The social deficits seen in ASD may also be confused with the social impairment and atypical beliefs that children with schizophrenia often display (American Psychiatric Association, 2013 ). Children with autism often demonstrate stereotyped movements, thoughts, behaviours and interests. The degree of repetitiveness can appear bizarre, and it becomes difficult to distinguish whether or not they are the result of psychosis (Dossetor, 2007 ). A child with ASD can also be comorbidly diagnosed with COS, but only if there are prominent hallucinations or delusions present for at least one month (American Psychiatric Association, 2013 ).

Although there appears to be very little research on the differential diagnosis of ADHD from COS, it has been identified as a common misdiagnosis in cases of COS and is therefore an important disorder to distinguish from schizophrenia (Coghill et al., 2009 ; Ross et al., 2006 ; Schaeffer & Ross, 2002 ; Sharma & Harvey, 2006 ). It has been noted that among the many presenting symptoms of COS, attentional difficulties are commonly seen in children (Coghill et al., 2009 ; Schaeffer & Ross, 2002 ; Sharma & Harvey, 2006 ). Research suggests that the degree and frequency of impaired attention observed in COS is equal to the inattention found in ADHD-combined type, which includes aspects of both inattentive ADHD and hyperactive-impulsive ADHD (Egeland, 2010 ). The diagnosis of ADHD should not be made if inattention or hyperactivity occur exclusively alongside a psychotic episode or disorder (American Psychiatric Association, 2013 ).

The assessment of COS can be very complex and requires both formal testing and observation. Unfortunately, there is no one test or procedure that can determine the presence of COS, which is one of the many reasons why schizophrenia is difficult to diagnose in children.

There are tools that were developed to assess the presence and severity of COS, such as the Schedule for Affective Disorders and Schizophrenia, the Positive and Negative Symptom Scale and the Premorbid Adjustment Scale. The Schedule for Affective Disorders and Schizophrenia is a semi-structured diagnostic interview and has relatively good convergent and divergent validity (Coghill et al., 2009 ; Lauth et al., 2010 ). The Positive and Negative Symptom Scale is a robust tool used in the assessment of schizophrenia and related disorders (Coghill et al., 2009 ; Linden, Scheel, & Rettig, 2007 ). This scale is useful in evaluating the severity of the illness and is relatively easy to use (Linden et al., 2007 ). Lastly, the Premorbid Adjustment Scale allows for the assessment of premorbid functioning, as research indicates that certain premorbid symptoms are associated with the development of COS, and has good predictive and concurrent validity (Brill, Reichenberg, Weiser, & Rabinowitz, 2008 ; Eggers et al., 2000 ). The Premorbid Adjustment Scale can be used to assess for schizophrenia during childhood, adolescence and adulthood (Shapiro et al., 2009 ).

Neuropsychological assessments are also used in the identification of COS, particularly positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) (Coghill et al., 2009 ; Malhotra, Gupta, Bhattacharya, & Kapoor, 2006 ). Both PET and SPECT work by injecting a tracer into the patient that will allow for a visual examination of the physiological functioning of the brain by tracing blood flow (Malhotra et al., 2006 ). MRI is a neuroimaging technique that allows for the examination of brain structure, rather than function, and can aid in the identification of structural abnormalities (Coghill et al., 2009 ). If these tests yield functional and structural results consistent with the brain abnormalities typically found in COS, then this illness may be present and further testing should be done.

In conjunction with psychometric and neuropsychological testing, a psychiatric assessment should also be completed. Psychiatric assessments are more subjective and include a thorough examination of the various areas of development and functioning in a child's life. The areas that must be assessed include the child's developmental history such as their achievement of developmental milestones, family history of mental illness, a close examination of the child's mental state with particular emphasis on the presence or absence of psychotic symptoms, risk posed to the self or others, family functioning and medical history (Coghill et al., 2009 ). As COS is challenging to diagnose, clinicians may need to enlist a variety of assessment tools before issuing a formal diagnosis.

Treatment of COS requires an interdisciplinary team of healthcare professionals, which may include psychiatrists, psychologists, paediatricians, social workers and psychiatric nurses (Mayo Foundation for Medical Education and Research, 2013 ). The primary form of treatment for schizophrenia, including COS, is antipsychotic medication (Mayo Foundation for Medical Education and Research, 2013 ). Although very few studies have examined the efficacy and safety of antipsychotic use in children, they continue to be the first line of treatment for schizophrenia with this population (Mayo Foundation for Medical Education and Research, 2013 ). As outlined in Table 3 , there are two categories of antipsychotic medications, typical and atypical, which differ in efficacy and side effects (Mayo Foundation for Medical Education and Research, 2013 ). Typical antipsychotics, such as haloperidol and loxapine, also known as first generation antipsychotics, were the first antipsychotics to be developed (Armenteros & Davies, 2006 ). Typical antipsychotics are generally known as having the most adverse side effects, the most severe of which are the motor and movement disorders that can cause involuntary movements of the face, tongue, limbs and hands (Mayo Foundation for Medical Education and Research, 2013 ). Additional side effects may include weight gain, restlessness, anxiety, irritability and drowsiness (Sikich et al., 2008 ). Due to the severity of these side effects, typical antipsychotics are one of the last forms of treatment used with childhood schizophrenia (Mayo Foundation for Medical Education and Research, 2013 ).

Note: A summary of the types and forms of treatment available for COS.

The severity of typical antipsychotics are what led to the development of second generation, or atypical, antipsychotics. Atypical antipsychotics are usually the first medications used in the treatment of COS as they tend to have fewer side effects than their counterparts (Mayo Foundation for Medical Education and Research, 2013 ). The side effects of atypical antipsychotics include weight gain, diabetes, high cholesterol, seizures and, more rarely, movement disorders (Armenteros & Davies, 2006 ; Mayo Foundation for Medical Education and Research, 2013 ; Sikich et al., 2008 ).

Clozapine, Risperidone and Olanzapine are among the most commonly prescribed and researched atypical antipsychotics for the treatment of schizophrenia. Clozapine, in particular, is argued to be the most effective atypical antipsychotic medication for treating psychosis, and has been shown to be effective in treatment-resistant schizophrenia (Kumra et al., 2008 ; Shaw et al., 2006 ). However, Clozapine can have particularly dangerous side effects when used to treat children with schizophrenia, the most severe of which is neutropenia. Neutropenia is when a significant drop in white blood cell count occurs. Among a sample of 87 children and adolescents being treated with Clozapine, approximately half of them displayed mild to moderate neutropenia, which is much higher than the risk of neutropenia among adults. There appears to be certain risk factors that can increase the likelihood of developing this complication, including younger age, being male and being an African-American (Maher et al., 2013 ). There continues to be disagreement around the efficacy of typical versus atypical antipsychotic medication in the treatment of schizophrenia. Where some studies suggest that typical antipsychotics are more efficacious than atypical, others indicate there are no significant differences in their treatment of COS.

One study conducted a meta-analysis of 15 studies examining the effectiveness of typical and atypical antipsychotics. This meta-analysis revealed that children responded to atypical antipsychotics 55% of the time, in comparison to a response rate of 72% for typical antipsychotics. This study suggests that typical antipsychotics have greater efficacy in treating childhood schizophrenia than atypical antipsychotics (Armenteros & Davies, 2006 ). Another study compared the efficacy of two atypical antipsychotics with one typical antipsychotic in the treatment of childhood schizophrenia. Children appeared to respond most favourably to the typical antipsychotic with a response rate of 50%. However, this response rate was not significantly different from the response rates to the two atypical antipsychotics which were 34% and 46%. This suggests that both typical and atypical antipsychotics are equally effective in treating childhood schizophrenia (Sikich et al., 2008 ). These findings are consistent with subsequent research into the efficacy of antipsychotic medications, which indicate that both typical and atypical antipsychotics show similar reductions in the symptoms of schizophrenia with no one class of drug demonstrating greater or lesser efficacy (Findling et al., 2010 ).

It is clear that there is a lack of information and a need for further study on the efficacy of typical and atypical antipsychotic medication in the treatment of COS. The majority of these medications have not been approved by the Food and Drug Association for use on children, with the exception of Trifluoperazine, which has been approved for the treatment of schizophrenia in children between the ages of 6 and 12 years old, and Thioridazine (Maloney, Yakutis, & Frazier, 2012 ). However, despite this lack of knowledge, antipsychotic medication continues to be prescribed to children with schizophrenia. This is an important body of work that needs to be studied in order to educate health practitioners on the best practices in treating COS, and to enhance our understanding of the impact these medications, which were designed for adult use, can have on children.

Although their efficacy has not been investigated to date, there are also therapeutic interventions that can be used in treating schizophrenia ( Table 3 ) including individual therapy, family therapy and social skills training (Mayo Foundation for Medical Education and Research, 2013 ).

Individualized therapy with children can reduce their symptoms by helping them learn how to cope with the various stressors and challenges of living with schizophrenia. Therapy can help children improve their academic success, resolve difficulties at school and improve their ability to maintain relationships with peers (Mayo Foundation for Medical Education and Research, 2013 ).

Family therapy focuses on providing not only the child but the family unit with support and education in coping with a child's illness. Family members can then in turn support their children in working with their illness. Additionally, families can learn to improve their communication skills, work through family conflict and cope with family stress as related to the child's mental health (Mayo Foundation for Medical Education and Research, 2013 ). When using family-based interventions to improve schizophrenia, the families’ emotions are the catalysts for change (Kuipers, 2006 ). Families in which one or more members are suffering from schizophrenia are often characterized by high levels of anxiety and criticism. The goal of family therapy is to educate families about the illness, help them reduce their stress, develop coping techniques and improve their ability to problem solve. Working with the family unit rather than the individual child is beneficial because it can help the family develop a more positive style of interaction. Family members often fill the role of the caregiver and, as a result, may themselves suffer from depression, anxiety, feel burdened and become critical or negative towards the child with schizophrenia. Family therapy is intended to help family members improve their own mental health, develop skills to effectively cope with their own anxiety as well as the mentally ill family member and adopt a less critical attitude. By improving the family dynamic, the goal is that the individual with schizophrenia will in turn have lower anxiety and depression, thus decreasing the likelihood of a relapse (Kuipers, 2006 ). Family intervention for individuals with schizophrenia has been shown to reduce patient relapse rates, both during and following treatment, and appears to reduce the likelihood that patients will require hospitalization during the course treatment. It has shown to be particularly effective for schizophrenic patients who recently experienced a relapse or who present with persistent symptoms (NICE, 2003 ). It is unclear as to why family therapy may be helpful in the treatment of Schizophrenia, just as it is unclear as to how empirically efficacious it is in comparison to other treatment options. It has been hypothesized that family interventions work primarily due to the shift in family affect, which in turn can impact the individual with schizophrenia. A patient with a family that primarily expresses negative affect is more likely to suffer from higher levels of anxiety and depression, which may trigger a psychotic episode (Kuipers, 2006 ).

Lastly, teaching children social and academic skills is an important component to managing schizophrenia. Children with schizophrenia often struggle with interpersonal relationships and academic success, as well as everyday tasks including bathing and dressing themselves. The primary goal of this training is to provide children with skills that can improve their daily functioning (Mayo Foundation for Medical Education and Research, 2013 ).

Controversy

Diagnosing schizophrenia in childhood is a topic of controversy as it is a poorly understood illness and is incredibly rare (Sood & Kattimani, 2008 ). Given the difficulty in accurately diagnosing schizophrenia in children, the question becomes: Should clinicians be diagnosing COS at all?

The literature tells us that it is not uncommon for COS to be misdiagnosed when in fact another diagnosis may be more appropriate, such as BD or ASD (Dossetor, 2007 ; Kempf, Hussain, & Potash, 2005 ; Pavuluri et al., 2004 ; Tahiroğlu et al., 2009 ). When children are misdiagnosed with schizophrenia, they are likely to be exposed to a range of unnecessary and ineffective treatments, the most harmful of which are pharmacological. A child diagnosed with schizophrenia will be treated as such, most likely through the use of antipsychotic medication. However, if this diagnosis is inaccurate then antipsychotics will not provide them with the help they need, and may in fact cause damage as they are known to have severe side effects including weight gain and movement disorders (Armenteros & Davies, 2006 ; Sikich et al., 2008 ). Therefore, if a diagnosis is so difficult to confirm and the method of treatment is so severe, then it is arguably better to withhold such a diagnosis and look for alternative ways of helping the child.

Indeed many clinicians are reluctant to diagnose children with schizophrenia due to the complex nature of the illness. However, children with schizophrenia who are wrongly given alternate diagnoses due to a clinician's reluctance to diagnose COS will also suffer the effects of mis-medication. Similarly, if a clinician withholds a diagnosis of COS when a child in fact fits the diagnostic criteria, then they may be denying both the child and the family the treatment and support that they need (Coghill et al., 2009 ). While it is important that clinicians use extreme caution in assessing and diagnosing COS, it is arguably unethical to not appropriately diagnose a child who meets the diagnostic criteria for an illness due to a personal bias.

While there is no right or wrong answer to this controversial topic, it is clear that clinicians must demonstrate due diligence and be vigilant when considering the diagnosis of COS. The diagnosis of COS should be given when appropriate, but may require the clinician to carefully assess the client over an extended period of time before coming to that conclusion.

Concluding remarks

Antipsychotics are commonly used to treat children with COS despite the fact that they can have very severe and debilitating side effects (Armenteros & Davies, 2006 ; Sikich et al., 2008 ). Although they appear to be an effective form of treatment, research on COS has not examined how antipsychotic medications may affect the continuing development of children throughout life. Given that it is difficult to accurately diagnose COS and that the effects of antipsychotic medication on childhood development are unclear, it may be beneficial to examine safer alternative methods of treating psychosis beyond pharmacological intervention. Future research should aim to bridge these gaps by focusing on the neurodevelopmental and behavioural impact that antipsychotic medications can have on a developing child.

There continues to be significant gaps in the literature on the underlying causes of COS, and it is clear that further research needs to be done on this topic. While genetic and neurodevelopmental contributions have been examined, very little research has been done on the contribution of family dynamics and the home environment to the development, maintenance, severity and treatment of COS. Research indicates that family therapy can be used in the treatment of COS, and it has been hypothesized that this treatment may be effective by changing the family's affect, interactions, anxiety and criticisms (Kuipers, 2006 ). However, research has not yet adequately addressed the efficacy of this treatment. One study showed that among a sample of families who sought non-pharmacological treatment for COS, a minority of 33% found this treatment to be effective (Schaeffer & Ross, 2002 ). Although the majority of families did not find therapy helpful, approximately one-third did benefit from it, suggesting that this may be an avenue for future research and treatment. Additionally, if family therapy is in fact effective in improving COS, then this suggests that there are certain aspects of the familial environment that can promote or exacerbate this condition.

There appears to be many shared features in the presentation of COS and bipolar disorder. Schizophrenia can present with affective features just as BD can present with psychotic features (Dossetor, 2007 ; Pavuluri et al., 2004 ; Ross et al., 2006 ). Evidence suggests that these disorders have overlapping genetic markers and neurotransmitter dysfunction. Additionally, research is now demonstrating the successful use of atypical antipsychotics in the treatment of BD (Gentile, 2011 ; Möller, 2003 ). The degree to which these two disorders overlap suggests that they may not be entirely distinct from one another, but may in fact be on a continuum where schizophrenia and related disorders are at one end, and affective disorders are at the other. There is in fact emerging evidence to support this claim, although further research needs to be done (Keshavan et al., 2011 ). The observed hereditary overlap also raises the question as to whether schizophrenia and BD share a similar aetiology, a hypothesis that may warrant future study.

While COS remains somewhat of a mystery, a foundational knowledge of aetiology, treatment and challenges in diagnosis has been established. However, there continues to be gaps in our understanding of the mechanisms through which COS can arise as well as best practices in distinguishing and diagnosing COS from other childhood disorders. Future research should address these gaps, as well as the implication of the family environment in the development and maintenance of COS.

• American Psychiatric Association . Diagnostic and statistical manual of mental disorders . 5th ed. Arlington, VA: American Psychiatric Publishing; 2013. [ Google Scholar ]
• Armenteros J. L., Davies M. Antipsychotics in early onset schizophrenia: Systematic review and meta-analysis. European Child & Adolescent Psychiatry . 2006:141–148. [ PubMed ] [ Google Scholar ]
• Brill N., Reichenberg A., Weiser M., Rabinowitz J. Validity of the premorbid adjustment scale. Schizophrenia Bulletin . 2008:981–983. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Brown A. S., Begg M. D., Gravenstein S., Schaefer C. A., Wyatt R. J., Bresnahan M., Susser E. S. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Archives of General Psychiatry . 2004:774–780. [ PubMed ] [ Google Scholar ]
• Clarke M. C., Harley M., Cannon M. The role of obstetric events in schizophrenia. Schizophrenia Bulletin . 2006:3–8. doi: 10.1093/schbul/sbj028. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Coghill D., Bonnar S., Duke S. L., Graham J., Seth S. Child and adolescent psychiatry . Oxford, NY: Oxford University Press; 2009. [ Google Scholar ]
• Dossetor D. R. ‘All that glitters is not gold’: Misdiagnosis of psychosis in pervasive developmental disorders – a case series. Clinical Child Psychology and Psychiatry . 2007:537–548. [ PubMed ] [ Google Scholar ]
• Egeland J. Frequency of attention deficit in first-episode schizophrenia compared to ADHD. Applied Neuropsychology . 2010:125–134. [ PubMed ] [ Google Scholar ]
• Eggers C., Bunk D., Krause D. Schizophrenia with onset before the age of eleven: Clinical characteristics of onset and course. Journal of Autism and Developmental Disorders . 2000:29–38. [ PubMed ] [ Google Scholar ]
• Findling R. L., Johnson J. L., McClellan J., Frazier J. A., Vitiello B., Hamer R. M., Sikich L. Double-blind maintenance safety and effectiveness findings from the treatment of early-onset schizophrenia spectrum (TEOSS) study. Journal of the American Academy of Child & Adolescent Psychiatry . 2010:583–594. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Gallagher B. J., III, Jones B. J. Childhood stressors and symptoms of schizophrenia. Clinical Schizophrenia & Related Psychoses . 2013:124–130. [ PubMed ] [ Google Scholar ]
• Gentile S. Clinical usefulness of second-generation antipsychotics in treating children and adolescents diagnosed with bipolar or schizophrenic disorders. Pediatric Drugs . 2011:291–302. [ PubMed ] [ Google Scholar ]
• Greenwood T. A., Lazzeroni L. C., Murray S. S., Cadenhead K. S., Calkins M. E., Dobie D. J., Braff D. L. Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the consortium on the genetics of schizophrenia. American Journal of Psychiatry . 2011:930–946. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Hollis C. Adult outcomes of child- and adolescent-onset schizophrenia: Diagnostic stability and predictive validity. American Journal of Psychiatry . 2000:1652–1659. [ PubMed ] [ Google Scholar ]
• Kempf L., Hussain N., Potash J. B. Mood disorder with psychotic features, schizoaffective disorder, and schizophrenia with mood features: Trouble at the borders. International Review of Psychiatry . 2005:9–19. [ PubMed ] [ Google Scholar ]
• Keshavan M. S., Morris D. W., Sweeney J. A., Pearlson G., Thaker G., Seidman L. J., Tamminga C. A dimensional approach to the psychosis spectrum between bipolar disorder and schizophrenia: The schizo-bipolar scale. Schizophrenia Research . 2011:250–254. doi: 10.1016/j.schres.2011.09.005. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Kuipers E. Family interventions in schizophrenia: Evidence for efficacy and proposed mechanisms of change. Journal of Family Therapy . 2006:73–80. [ Google Scholar ]
• Kumra S., Kranzler H., Gerbino-Rosen G., Kester H. M., DeThomas C., Cullen K., Kane J. M. Clozapine versus “high-dose” olanzapine in refractory early-onset schizophrenia: An open-label extension study. Journal of Child and Adolescent Psychopharmacology . 2008:307–316. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Lauth B., Arnkelsson G. B., Magnússon P., Skarphéðinsson G. Á., Ferrari P., Pétursson H. Validity of K-SADS-PL (schedule for affective disorders and schizophrenia for school-age children – present and lifetime version) depression diagnoses in an adolescent clinical population. Nordic Journal of Psychiatry . 2010:409–420. [ PubMed ] [ Google Scholar ]
• Linden M., Scheel T., Rettig K. Validation of the factorial structure of the positive and negative syndrome scale in use by untrained psychiatrists in routine care. International Journal of Psychiatry in Clinical Practice . 2007:53–60. [ PubMed ] [ Google Scholar ]
• Maher K. N., Tan M., Tossell J. W., Weisinger B., Gochman P., Miller R., Gogtay N. Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia. Journal of Child and Adolescent Psychopharmacology . 2013:110–116. doi: 10.1089/cap.2011.0136. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Malhotra S., Gupta N., Bhattacharya A., Kapoor M. Study of childhood onset schizophrenia (COS) using SPECT and neuropsychological assessment. Indian Journal of Psychiatry . 2006:215–222. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Maloney A. E., Yakutis L. J., Frazier J. A. Empirical evidence for psychopharmacologic treatment in early-onset psychosis and schiophrenia. Child and Adolescent Psychiatric Clinics of North America . 2012:885–909. [ PubMed ] [ Google Scholar ]
• Margari F., Petruzzelli M. G., Lecce P. A., Todarello O., DeGiacomo A., Lucarelli E., Margari L. Familial liability, obstetric complications and childhood development abnormalities in early onset schizophrenia: a case control study. BioMed Central . 2011:60–66. doi: 10.1186/1471-244X-11-60. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Mayo Foundation for Medical Education and Research 1998–2013 Childhood schizophrenia . Retrieved from http://www.mayoclinic.com/health/childhood-schizophrenia/DS00868 .
• Möller H. J. Bipolar disorder and schizophrenia: Distinct illness or a continuum? Journal of Clinical Psychiatry . 2003:23–28. [ PubMed ] [ Google Scholar ]
• NICE . Schizophrenia; full national clinical guidelines on core interventions in primary and secondary care . London: Gaskell Press; 2003. [ Google Scholar ]
• Pavuluri M. N., Herbener E. S., Sweeney J. A. Psychotic symptoms in pediatric bipolar disorder. Journal of Affective Disorders . 2004:19–28. doi: 10.1016/S0165-0327(03)00053-3. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Remschmidt H., Martin M., Fleischhaker C., Theisen F. M., Hennighausen K., Gutenbrunner C., Schulz E. Forty-two years later: The outcome of childhood-onset schizophrenia. Journal of Neural Transmission . 2006:505–512. doi: 10.1007/s00702-006-0553-z. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Ross R. G., Heinlein S., Tregellas H. High rates of comorbidity are found in childhood-onset schizophrenia. Schizophrenia Research . 2006:90–95. [ PubMed ] [ Google Scholar ]
• Schaeffer J. L., Ross R. G. Childhood-onset schizophrenia: Premorbid and prodromal diagnostic and treatment histories. Journal – American Academy of Child and Adolescent Psychiatry . 2002:538–545. doi: 10.1097/00004583-200205000-00011. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Shapiro D. I., Marenco S., Spoor E. H., Egan M. F., Weinberger D. R., Gold J. M. The premorbid adjustment scale as a measure of developmental compromise in patients with schizophrenia and their healthy siblings. Schizophrenia Research . 2009:136–142. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sharma T., Harvey P. D. The early course of schizophrenia . Oxford, NY: Oxford University Press; 2006. [ Google Scholar ]
• Shaw P., Sporn A., Gogtay N., Overman G. P., Greenstein D., Gochman P., Rapoport J. L. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Archives of General Psychiatry . 2006:721–730. [ PubMed ] [ Google Scholar ]
• Sikich L., Frazier J., McClellan J., Findling R., Vitiello B., Ritz L., Lieberman J. Double-blind comparison of first-and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: Findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. American Journal of Psychiatry . 2008:1420–1431. [ PubMed ] [ Google Scholar ]
• Sipos A., Rasmussen F., Harrison G., Tynelius P., Lewis G., Leon D. A., Gunnell D. Paternal age and schizophrenia: A population based cohort study. British Medical Journal (International Edition) 2004:1070–1073. doi: 10.1136/bmj.38243.672396.55. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Sood M., Kattimani S. Childhood onset schizophrenia: Clinical features, course and outcome. Journal of Indian Association for Child and Adolescent Mental Health . 2008:28–37. Retrieved from http://eric.ed.gov/?id=EJ918872 . [ Google Scholar ]
• Tahiroğlu A. Y., Çelik G. G., Avci A. Atypical symptoms before the first episode in bipolar children and adolescents. Neuropsychiatry . 2009:34–36. [ Google Scholar ]
• Taylor E. H. Advances in the diagnosis and treatment of children with serious mental illness. Child Welfare . 1998:311–332. [ PubMed ] [ Google Scholar ]
• The International Schizophrenia Consortium Rare chromosomal deletions and duplicates increase risk of schizophrenia. Nature . 2008:237–241. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• The National Institute of Mental Health 2009 What is schizophrenia? Retrieved from http://www.nimh.nih.gov/health/publications/schizophrenia/index.shtml .
• Zammit S., Allebeck P., Dalman C., Lundberg I., Hemmingson T., Owen M. J., Lewis G. Paternal age and risk for schizophrenia. The British Journal of Psychiatry . 2003:405–408. [ PubMed ] [ Google Scholar ]

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• Published: 22 February 2024

Linking childhood trauma to the psychopathology of schizophrenia: the role of oxytocin

• Yuan-Jung Chen 1 ,
• Mong-Liang Lu   ORCID: orcid.org/0000-0002-8281-8193 1 , 2 , 3 ,
• Yi-Hang Chiu 1 , 2 ,
• Chenyi Chen   ORCID: orcid.org/0000-0001-8050-6754 2 , 4 , 5 ,
• Vitor Hugo Jesus Santos 6 &
• Kah Kheng Goh   ORCID: orcid.org/0000-0003-2677-3944 1 , 2 , 3 , 4 , 5  

Schizophrenia volume  10 , Article number:  24 ( 2024 ) Cite this article

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• Developmental biology
• Schizophrenia

Childhood trauma has been linked to schizophrenia, but underlying biological mechanisms remain elusive. This study explored the potential role of plasma oxytocin as a mediator in the relationship between childhood trauma and the psychopathology of schizophrenia. 160 patients with schizophrenia and 80 age- and sex-matched healthy controls were assessed for childhood trauma experiences using the Childhood Trauma Questionnaire and structured interviews. Psychopathology was evaluated using the Positive and Negative Syndrome Scale and plasma oxytocin levels were measured. Results showed that patients with schizophrenia had lower oxytocin levels and higher childhood trauma scores than healthy controls. There was a significant correlation between childhood trauma scores and psychopathology, with plasma oxytocin levels being inversely associated with psychopathology, except for positive symptoms. Hierarchical regression analysis indicated that both childhood trauma scores and plasma oxytocin levels significantly predicted psychopathology. Plasma oxytocin levels partially mediated the relationship between childhood trauma and schizophrenia psychopathology. This study underscores the potential role of oxytocin in bridging the gap between childhood trauma and schizophrenia.

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Introduction.

Childhood trauma is recognized as a factor indicating vulnerability to psychotic symptoms and schizophrenia 1 , 2 . Evidence indicates that patients with schizophrenia are more likely to report a history of childhood adversity or trauma than healthy controls are 3 . Research has consistently identified increased risks of developing psychotic disorders and schizophrenia in the context of various factors among individuals with the experience of child adversity or trauma 4 , 5 , though establishing direct causality remains complex. Patients with schizophrenia who experienced childhood trauma are typically younger age at schizophrenia onset 6 , 7 , have worse psychotic symptoms 8 , 9 , have more severe functional impairment 10 , 11 , respond to treatment more poorly 12 , and have an even higher risk of suicide 13 than those who did not experience childhood trauma.

Despite the well-established relationship between childhood trauma and schizophrenia, the mechanisms underlying the association, particularly the biological mechanisms, are poorly understood. Few studies have explored the possible factors mediating this relationship, such as neurotransmitters and hormones. Oxytocin, a hormonal neuropeptide that regulates social cognition, social affiliation, stress, learning and memory 14 , has been reported to have a role in regulating the expression of schizophrenia 15 . Both human and animal studies have explored the role of oxytocin in the development of schizophrenia 16 , particularly its impact on social cognition. Studies examining the endogenous oxytocin levels of patients with schizophrenia have reported mixed findings, with some suggesting that the endogenous oxytocin levels in these patients are lower than those in the healthy population 17 . Oxytocin dysregulation has been demonstrated to be associated with several symptom domains of schizophrenia, particularly negative symptoms and social cognition. A negative correlation between endogenous oxytocin levels and negative symptoms has been reported in numerous studies 18 , 19 . Oxytocin is critical to the regulation of social cognition in schizophrenia, indicating that patients with higher endogenous oxytocin levels are associated with more effective recognition of facial emotions 20 and social cues 21 . These findings elucidate the role of oxytocin in the pathophysiology of schizophrenia and have inspired growing research on the therapeutic potential of exogenous oxytocin; some clinical trials have reported encouraging results 22 , 23 , but the overall findings have been inconsistent. Several factors, such as dosage, route of administration, and individual variations in endogenous oxytocin levels and oxytocin receptor gene, can interfere with treatment efficacy 16 , 24 , 25 . Furthermore, it is plausible that individuals with inherently lower endogenous oxytocin levels and oxytocin receptor gene polymorphisms 26 , 27 , potentially due to factors like childhood trauma, may respond more effectively to intranasal oxytocin treatment. This suggests that intranasal oxytocin could be a viable therapeutic option for patients with schizophrenia, particularly those with a history of childhood trauma. However, further research is required to explore this hypothesis, determine the optimal target groups and treatment course, and gain a more thorough understanding of the mechanisms underpinning the relationship between schizophrenia and oxytocin 28 .

Childhood trauma can have wide-ranging impacts; while some forms involve physical harm, others primarily result in psychological or emotional impacts. These experiences can potentially affect the developing brain, leading to dysregulation in neurotransmitter systems and hormonal production, which may contribute to deficits in behavioral, cognitive, and emotional regulation 29 . Oxytocinergic dysfunction is one of the most studied hormonal disturbances. Most studies have identified an inverse relation between childhood trauma and endogenous oxytocin concentration 30 , 31 ; however, a positive association has also been reported 32 , 33 . A previous systematic review concluded that reduced oxytocin levels were associated with the history of trauma, supporting the assumption that adversity in early life alters oxytocin homeostasis in the long term 34 . Polymorphism of the oxytocin receptor gene moderates the link between the incidence of childhood abuse and social relationships 35 , implying that childhood trauma may influence the oxytocinergic system through genetic mechanisms. The aforementioned evidence indicates that childhood trauma disrupts the oxytocinergic system, and this disruption may be associated with the progression of schizophrenia. Whether oxytocin mediates the path from childhood trauma to schizophrenia is unconfirmed.

This study explored the relationship between childhood trauma and the clinical symptoms of schizophrenia to investigate the role of plasma oxytocin in this association. New treatment modalities must be developed to address the insufficiency of existing therapies, particularly in alleviating negative symptoms and social cognitive deficits. The identification of key mediators is the first step toward developing new therapeutic agents. In accordance with the literature, we hypothesized the following: (1) patients with schizophrenia are more likely to have childhood trauma experiences and to have experienced more severe trauma compared with healthy controls, (2) patients with schizophrenia have lower plasma oxytocin levels than do healthy controls, (3) a positive correlation exists between the severity of childhood trauma and the severity of schizophrenia psychopathology, and (4) plasma oxytocin levels mediate the relationship between childhood trauma and the severity of schizophrenia psychopathology, with lower plasma oxytocin levels associated with more severe childhood trauma and psychopathology.

Participants and procedures

This cross-sectional study was conducted between August 2020 and April 2022. The study protocol was approved by the Joint Institutional Review Board of Taipei Medical University (Approval No. N202008006, dated August 19, 2020). All procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All participants provided written informed consent. Patients with schizophrenia were recruited from the psychiatry outpatient clinic, and healthy controls were enrolled through advertisement. A total of 240 individuals joined the study: 160 patients with schizophrenia and 80 healthy controls matched by age and sex. All participants were aged 20–65 years and capable of providing written informed consent. The Structured Clinical Interview for DSM-5 36 was used as an interview guide by trained psychiatrists to assess diagnoses of any mental disorders for all participants. A patient with schizophrenia was included only if they (i) met the diagnosis criteria for schizophrenia and had been administered a stable dosage of antipsychotic treatment for at least 28 days and (ii) had no current or lifetime mental disorders except for schizophrenia spectrum disorder. Healthy controls were excluded if they or their first-degree relatives had a history of mental disorders. Any participant was excluded if they had a severe neurological disorder, epilepsy, intellectual disability, a neurocognitive disorder, history of substance use disorder, renal disease, or another severe, life-threatening medical condition. They were also excluded if they were pregnant, breastfeeding, or receiving hormonal therapy. No additional treatment was provided to any participant. The patients with schizophrenia received their treatment as usual after recruitment. All assessments were conducted in a private location. Blood tests were performed by nurses on the research team.

Childhood trauma

All participants were asked to complete the Childhood Trauma Questionnaire—Short Form (CTQ-SF 37 ; to screen for and assess the severity of any childhood trauma. The CTQ-SF consists of 28 items and is scored on a 5-point scale. It measures five types of childhood trauma: emotional abuse, emotional neglect, physical abuse, physical neglect, and sexual abuse. The questionnaire has been translated into Chinese, with its reliability confirmed (Cronbach’s α = 0.57 to 0.90; intraclass coefficient = 0.67 to 0.85 38 . Participants who scored at or above the designated moderate exposure cutoff point on each subscale (specifically, ≥10 for physical abuse, ≥13 for emotional abuse, ≥8 for sexual abuse, ≥10 for physical neglect, and ≥15 for emotional neglect) were categorized as individuals with a documented history of childhood trauma exposure 38 . To enhance the validity of these self-reported scores, individual interviews were conducted with all participants. These interviews were carried out by trained psychiatrists following a structured protocol, where they delved deeper into the experiences indicated in the CTQ-SF. Participants were asked to elaborate on their responses, and the psychiatrists probed for specific details and examples of the reported experiences. This process was crucial to ascertain that the reported events met the criteria for childhood trauma as defined in our research context and to distinguish between actual trauma events and other negative, but non-traumatic, childhood experiences. For cross-validation, these detailed clarifications obtained during the interviews were used alongside the questionnaire responses.

Psychopathology

The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the severity of the psychotic symptoms of patients with schizophrenia. The PANSS is a well-established and widely used scale consisting of 30 items and scored on a 7-point scale; it evaluates the positive, negative, and general psychopathological symptoms of schizophrenia 39 . Studies have demonstrated the robust psychometric properties of this instrument, including the favorable validity of the Chinese version 40 .

Oxytocin laboratory assessment

Given the challenges of directly measuring central oxytocin levels, we utilized plasma oxytocin levels in our study, informed by studies that identified a positive correlation between central and peripheral concentrations 41 . Phlebotomies were performed in the morning from 8am to 10am. All participants were instructed to abstain from tobacco, caffeine, and analgesics on the day of blood sampling to prevent interference with their plasma oxytocin levels 42 , 43 . The blood samples were maintained on ice until centrifugation at 3000 rpm for 15 min at 4 °C. Isolated plasma was then divided into 1-mL aliquots and stored at −80 °C immediately until the time of assay. Plasma oxytocin levels were determined using an enzyme immunosorbent assay kit (Catalog number: EKE-051-01, Phoenix Pharmaceuticals, Burlingame, CA, USA) with an oxytocin detection range of 0 to 100 ng/mL. Each plasma sample was assayed twice, and the mean of the two measurements was used in the analysis. We calculated the intra-assay coefficient of variation (CV) by assessing the variability in repeated measurements of the same sample within a single plate during a single run, using two random samples from each plate. The CV for each sample was determined by computing the standard deviation of the first and second results, then dividing this value by the duplicate mean, and finally multiplying by 100. The average CV of all these random samples was taken as the intra-assay CV. For the inter-assay CV, we gauged the variability in measurements of the same sample across different plates. We determined the plate means for the results of two random samples from different plates and then used these values to calculate the overall mean, standard deviation, and CV. The inter-assay and intra-assay coefficients of variation were both less than 5%, and no significant cross reactivity or interference between oxytocin and analogs was observed.

Demographic characteristics, disease-specific variables, and cognitive function were added to the analysis as covariates, as they potentially influence the relationships between childhood trauma, oxytocin, and psychopathology. The inclusion of age and sex as confounders is based on their known influence on the onset, progression, and psychopathology of schizophrenia 44 , 45 , as well as their potential impact on plasma oxytocin levels 46 . Regarding disease-specific variables, the age of schizophrenia onset and illness duration were considered colliders of childhood trauma and plasma oxytocin levels 47 , 48 . Antipsychotics were recorded and converted into chlorpromazine-equivalent doses 49 , considering their established relevance in schizophrenia psychopathology and plasma oxytocin levels 15 , 50 . The Mini-Mental State Examination (MMSE) scores and years of education were included as confounders due to their potential impact on cognitive function, which may confound the relationship between childhood trauma and psychopathology 51 , 52 . The MMSE 53 is a 21-item instrument with scores ranging from 0 to 30 to assess the following domains: orientation, registration and recall, attention and calculation, language, repetition, and the ability to follow written and verbal instructions. The decision to incorporate these covariates was informed by both empirical evidence and theoretical considerations, aiming to elucidate the complex interplay between these variables and the psychopathology of schizophrenia.

Statistical analysis

All collected data were transcribed in Microsoft Excel and then transferred to SPSS Statistics version 26.0 (IBM, Armonk, NY, USA) for coding and analysis. The normality of distributions was determined using the Kolmogorov–Smirnov test. The demographic characteristics, disease-specific variables, MMSE scores, plasma oxytocin levels, CTQ-SF scores, and PANSS scores are expressed as the mean ( M ) with standard deviation ( SD ). Independent sample t -tests were employed to compare continuous variables between the schizophrenia group and healthy controls, with Cohen’s d used to quantify effect size. The variables under comparison included demographic characteristics (age, sex, years of education, and MMSE score); plasma oxytocin levels; scores for each component of the CTQ-SF and the number of types of childhood trauma. Pearson’s chi-square test was applied to assess the categorical variable, namely, the prevalence of various types of childhood trauma among healthy controls and patients with schizophrenia, with effect sizes determined using Cramér’s V (φ c ). A series of one-way analyses of variance (ANOVAs) were employed to investigate the relationship between various types of childhood trauma and the severity of schizophrenia symptoms, as measured by the PANSS. Eta-squared (η 2 ) was used to quantify the effect size for each ANOVA performed, providing a measure of the strength of the associations.

Pearson’s correlation coefficients were calculated to examine the correlations between psychopathology (measured by the PANSS total score, positive scale, negative scale, and general psychopathology scale) and other continuous variables, including plasma oxytocin levels, CTQ-SF score, demographic characteristics (sex, age, and years of education), disease-specific variables (age of schizophrenia onset, duration of illness, and antipsychotic dose), and MMSE score. Hierarchical regression analysis was used to investigate whether childhood trauma and plasma oxytocin levels accounted for unique variance in the psychopathology (measured by PANSS total score) of schizophrenia beyond that explained by other covariates (i.e., sex, age, years of education, age of schizophrenia onset, antipsychotic dose, and MMSE score). The covariates were included in the regression analysis model hierarchically in accordance with a time series. Finally, to explore the potential association between plasma oxytocin levels and the psychopathology (measured by PANSS total score) of schizophrenia, and how this might relate to childhood trauma, a mediation analysis was conducted using SPSS macro-PROCESS version 4.1 (model 4) 54 ; after the data had been bias-corrected and percentile-method bootstrapped, with the data resampled 5,000 times. Exploratory analyses were performed to determine the best-fit model for the mediation analysis. The covariates incorporated into the mediation analysis were sex, age, years of education, age of schizophrenia onset, antipsychotic dose, and MMSE score. As the issue of multiple comparisons was present in this study, Bonferroni correction was applied to adjust the significance level. All probability values are reported at the two-tailed level for statistical significance at p  < 0.05.

Demographic characteristics, plasma oxytocin levels, childhood trauma, and psychopathology

The demographic characteristics and childhood trauma of the patients with schizophrenia and healthy controls are presented in Table 1 . No significant differences between the two groups in terms of age and sex, but there was a significant difference in the years of education, with the schizophrenia group having lower years of education compared to the healthy group ( t  = −2.093, p  = 0.038). All participants underwent the MMSE evaluation and were found to have normal cognitive function, with no intergroup differences being discovered. Figure 1 illustrates the distribution of plasma oxytocin levels in patients with schizophrenia compared to healthy controls. In comparison with the healthy controls, the patients with schizophrenia had significantly lower plasma oxytocin levels ( t  = −5.543, p  < 0.001). The total scores in the CTQ-SF, as well as the scores in all the subscales, were higher for the patients with schizophrenia than for the healthy controls ( p  < 0.001). Comparison of the prevalence of different trauma types between healthy controls and patients with schizophrenia revealed a higher prevalence of all types of childhood trauma in the latter group: physical abuse ( p  < 0.001), emotional abuse ( p  = 0.004), sexual abuse ( p  = 0.008), physical neglect ( p  = 0.012), emotional neglect ( p  = 0.015), as well as a greater number of trauma types ( p  < 0.001). Table 1 provides information about the psychopathology and disease-specific variables of the patients with schizophrenia.

Distribution of plasma oxytocin levels between patients with schizophrenia and healthy controls.

Table 2 revealed significant associations between childhood trauma and PANSS scores among patients with schizophrenia. Patients who reported experiencing any form of childhood trauma—and who scored at or above the designated moderate exposure cutoff points on each subscale of the CTQ-SF, thus categorized as individuals with a documented history of childhood trauma exposure—consistently had higher PANSS total scores. This indicates more severe psychopathology compared to those without such childhood trauma history. Specifically, emotional abuse and emotional neglect were associated with the highest increases in PANSS total scores, as well as in scores for negative symptoms and general psychopathology. The effect sizes, as indicated by η 2 , ranged from moderate to large across different types of childhood trauma, with emotional neglect showing the most substantial impact on all measured aspects of the PANSS subdomains.

Correlations between psychopathology and other variables

Correlation analysis within the schizophrenia cohort, as detailed in Table 3 , indicated a significant correlation between the total CTQ-SF score and the total PANSS score ( r  = 0.699, p  < 0.001). Additionally, all scores for the CTQ-SF subscales were significantly correlated with the total PANSS score and the scores for its subdomains scores, except for positive symptoms. Besides, the higher number of childhood trauma types experienced, the greater severity of schizophrenia psychopathology, measured by the total PANSS score ( r  = 0.738, p  < 0.001) and the scores for its subdomains, namely positive symptoms ( r  = 0.843, p  < 0.001), negative symptoms ( r  = 0.951, p  < 0.001), and general psychopathology ( r  = 0.845, p  < 0.001). Plasma oxytocin levels were inversely correlated with the total PANSS score ( r  = −0.688, p  < 0.001) and the scores for its subdomains, except for positive symptoms.

Age of schizophrenia onset was discovered to have a negative association with the total PANSS score, negative symptoms, and general psychopathology; however, after applying the Bonferroni correction, this association remained significant only for negative symptoms ( r  = −0.203, p  = 0.040), indicating that earlier onset is associated with more severe negative symptoms. Regarding the other variables, the correlations were nonsignificant except for a negative association between the MMSE score and negative symptoms ( r  = −0.223, p  = 0.020).

Hierarchical regression analysis of predictors of psychopathology

The results of the hierarchical regression analysis are provided in Table 4 . The variables were included in succeeding steps: (a) model 1 predicted psychopathology from only sex and age, (b) CTQ-SF score was added for model 2, (c) educational years was added for model 3, (d) age of schizophrenia onset was added for model 4, (e) antipsychotic dose and MMSE score was added for model 5, and (f) plasma oxytocin levels were added for model 6. The result of model 2 revealed that the CTQ-SF score served as a significant predictor of psychopathology, explaining 47.7% of the variation (Δ R 2  = 0.477, p  < 0.001). The result of model 6 demonstrated that oxytocin levels accounted for an additional 6.1% change in the prediction of psychopathology (Δ R 2  = 0.052, p  < 0.001). Additional hierarchical regression analyses predicting the PANSS subdomains scores were presented in Supplementary Table S1 .

Mediation effect of plasma oxytocin

Mediation analysis results, presented in Table 5 , demonstrated a significant regression coefficient between childhood trauma and plasma oxytocin levels ( p  < 0.001), and between plasma oxytocin levels and the psychopathology of schizophrenia ( p  < 0.001). The bootstrapped unstandardized indirect effect was significant (β = 0.183, SE  = 0.044, 95% confidence interval [CI] [0.102, 0.272]), indicating that plasma oxytocin levels partially mediate the effect of childhood trauma on the schizophrenia psychopathology. The regression coefficients remained robust when controlling for covariates presented in the study such as age, sex, years of education, MMSE score, age of schizophrenia onset, and antipsychotic dosage. The overall mediation model was significant ( R 2  = 0.517, F  = 23.195, p  < 0.001). Furthermore, additional analyses were conducted and presented in Supplementary Tables S2 and S3 , where the correlations between PANSS scores and the number of childhood trauma types were examined, as well as their implications in hierarchical regression and mediation analysis. These analyses corroborated the initial findings that using total CTQ-SF scores, underscoring the robustness of the results. All exploratory analyses conducted to determine the best-fit model for the mediation analysis are presented in Supplementary Table S4 .

The results of this study indicated that any childhood trauma experienced by the participants was more severe on average in the patients with schizophrenia than in the healthy controls, as reflected in the significant difference between CTQ-SF scores and in the prevalence of positive responses for various types of childhood trauma. The patients with schizophrenia also had lower oxytocin levels, which is consistent with our hypothesis and supports the idea that oxytocinergic system dysfunction is associated with schizophrenia. We further investigated the link between childhood trauma and psychopathology severity in patients with schizophrenia, determining a positive correlation between these two variables; plasma oxytocin levels were inversely correlated with both factors. To provide new insights into these associations, we examined the role of oxytocin through mediation analysis. After controlling for covariates, oxytocin was found to exert a partial mediation effect on the relationship between childhood trauma and the psychopathology of schizophrenia.

Our findings align with the existing literature indicating that patients with schizophrenia experience more severe childhood trauma, which is substantiated by both the higher CTQ-SF total scores and the increased prevalence of all trauma types in this population, with the existence of potential threshold and dose–response effects 55 , 56 , 57 , 58 . This observed gradation in childhood trauma severity and its association with the spectrum of schizophrenia symptoms highlight the intricacy of trauma’s impact on the disorder. Our findings reveal that a categorical approach to assessing childhood trauma—classifying individuals based on whether their experiences meet a certain threshold of severity—aligns with heightened positive symptoms in schizophrenia. In contrast, our correlation analysis did not show a direct relationship between the continuous severity of childhood trauma and positive symptoms. Our results may suggest that while childhood trauma, in general, is associated with an exacerbation of psychopathology, the specific relationship with positive symptoms may become more pronounced only after surpassing a certain threshold of trauma severity. This nuanced effect is in line with the notion that various trauma subtypes may influence the development of schizophrenia to differing extents, highlighting the potential for threshold effects in the trauma-psychopathology nexus, as supported by a meta-analysis indicating that all trauma subtypes may confer a substantial risk of psychosis 4 . The significant correlation between the number of childhood trauma types and the severity of psychopathology in our schizophrenia cohort further reinforces the concept of a dose-response relationship, where a greater number of trauma experiences correlates with more severe symptoms of the disorder 59 , 60 . Such severity may trigger a series of neurobiological changes, including HPA axis dysregulation, genetic vulnerabilities, and epigenetic modifications, contributing to the altered brain structure and function observed in schizophrenia 61 .

The interplay between childhood trauma and schizophrenia is multifaceted, with research suggesting that the dissociative states stemming from adversity could amplify cognitive deficits. Such deficits may blur the distinction between internal thoughts and external reality, potentially leading to hallucinations. These hallucinations may manifest as a variation of posttraumatic intrusive memories 62 or emerge from errors in source monitoring 63 , 64 . Notably, auditory verbal hallucinations have been linked to these cognitive challenges in discerning internal from external auditory information, a difficulty that may be exacerbated by dissociative states induced by childhood trauma 65 , 66 , 67 , and potentially related to oxytocinergic system dysfunctions 68 . Furthermore, delusions, particularly those connected to trauma-induced negative beliefs, can arise from a compromised ability to form secure attachments due to childhood negligence, fostering distrust and paranoia. This attachment failure and the ensuing paranoia may be moderated by genetic factors, including polymorphisms in the oxytocin receptor gene 69 , 70 . Moreover, attachment style has been implicated in the development of negative symptoms 71 , 72 , with poor attachment possibly leading to interpersonal dysfunction. This dysfunction has been hypothesized as an adaptive deactivation of the attachment system in response to the fear of rejection or threat 73 , further complicating the clinical presentation of schizophrenia. These findings are consistent with evidence linking various trauma subtypes to schizophrenia, particularly to negative symptoms and general psychopathology. However, our results indicate that the association with positive symptoms is less pronounced, a finding that diverges from some studies emphasizing the childhood trauma-positive symptom connection 58 , 74 , yet aligns with others that have found a stronger link between childhood trauma, especially neglectful trauma, and negative symptoms 75 , 76 , 77 .

Building on this, the nuances in the relationships between specific childhood trauma types and schizophrenia symptoms become evident. Although sexual abuse was found to have a weaker association with schizophrenia in our study, it is essential to consider the broader context of research. For instance, the literature presents mixed evidence on sexual abuse’s connection with schizophrenia, with some studies indicating a particular association with positive symptoms, while others do not find a strong link to negative symptoms 78 , 79 , 80 , 81 . This variability suggests that positive and negative symptoms may emerge through distinct pathways related to the impact of sexual abuse. Furthermore, the potential for underreporting of sexual abuse due to stigma, guilt, or embarrassment 82 , as well as the dissociative amnesia 83 , introduces additional challenges in assessing the true strength of these associations. Such complexities underscore the need for a careful examination of how different childhood trauma experiences contribute to the heterogeneity of schizophrenia’s symptomatology.

Our study contributes to the growing body of literature that posits the oxytocinergic system as a potential mediator in the pathway from childhood trauma to the development of schizophrenia. This study introduces a potential new explanation for the trajectory from childhood trauma to schizophrenia, with oxytocin possibly playing a significant role. However, the intricate mechanisms through which childhood trauma disrupts the oxytocinergic system are still an area of active exploration. The disruption of early attachment processes, which are intricately linked to oxytocin regulation, appears to be a contributing factor to the emergence of negative symptoms and general psychopathology 84 , 85 , 86 . The resulting alteration in oxytocin levels might influence key neural pathways, including those involving oxytocin’s interaction with dopaminergic pathways, regulation of the amygdala, and adjustment of social information processing 87 , which provide potential explanations for our observations. Indeed, oxytocin dysregulation could exacerbate social cognitive deficits, potentially leading to enhanced paranoia, social withdrawal, and comorbid affective disorders, as evidenced by our findings and supported by recent studies 27 , 88 , 89 . This proposition aligns with our observation that oxytocin levels are associated with various symptom domains of schizophrenia.

Furthermore, initial molecular insights suggest that the impact of childhood trauma may extend to the genetic regulation of oxytocin production and receptor expression 90 , potentially via epigenetic modifications like DNA methylation 91 or single nucleotide polymorphisms 92 , both of which can induce stress-related pathology 93 . This genetic vulnerability, compounded by adverse environmental exposures, may contribute to a ‘gene × environment’ interplay that underpins the schizophrenia phenotype. While oxytocin’s role in this complex interplay is significant, it is likely not the sole mediator. Our study echoes the broader schizophrenia research that implicates factors such as chronic stress and systemic inflammation as additional contributing elements to the psychopathology 61 , 94 . As such, our findings underscore the need for a multifactorial approach to understand the full scope of schizophrenia’s etiology and pathophysiology, considering both neurobiological and environmental influences.

To our knowledge, this is the first study to explore oxytocin’s mediating role in the relationship between childhood trauma and schizophrenia. However, the findings must be interpreted cautiously due to the study’s limitations. The retrospective nature of the CTQ-SF raises concerns about recall bias and potential underreporting of childhood trauma 95 , although prior research supports the validity of retrospective reporting 96 . We attempted to minimize bias by conducting interviews to clarify and validate participant responses. Nevertheless, future research employing mediation analyses and a prospective design would be invaluable in confirming the mediating role of oxytocin. Oxytocin levels are subject to various influences, such as stress, inflammation, circadian rhythm, nicotine use 97 , and reproductive status 46 , which could act as uncontrolled confounders. We have attempted to control for some of these by excluding nicotine use, pregnancy, breastfeeding, hormonal therapy, and menstruation from our participant criteria. We requested that participants refrain from tobacco use on the day of blood sampling. We also ensured that blood sampling did not occur during menstruation. Additionally, the potential influence of antipsychotic medication on oxytocin levels should be considered. Furthermore, while we standardized antipsychotic dosages to chlorpromazine-equivalent doses, the lack of differentiation between antipsychotic types is a limitation given their distinct effects on oxytocin levels. Subsequent studies should differentiate between antipsychotic classes to better understand their impact on oxytocin and schizophrenia. Furthermore, assessing oxytocin levels both before and after antipsychotic treatment would be instrumental in better understanding the dynamic between medication and oxytocin regulation in schizophrenia. Moreover, while peripheral oxytocin levels correlate with central levels 41 , they are not a perfect substitute. Direct measurements of central oxytocin remain impractical, posing a challenge for accurately assessing its role in schizophrenia. Additionally, our study specifically included participants with schizophrenia who had been on stable medication for at least 28 days to minimize the confounding effects of fluctuating medication levels on oxytocin levels and psychopathology. While this approach was aimed at strengthening the internal validity of our findings, it may also have inadvertently introduced a selection bias. By selecting more clinically stable participants, our findings may not fully represent the broader schizophrenia population, particularly those not on consistent medication regimens or those with additional comorbidities. This could potentially limit the generalizability of our results to all cases of schizophrenia. The cross-sectional design also means we cannot establish causal links or account for variations in trauma timing 98 . Despite these limitations, we constructed mediation models based on the assumption of oxytocin’s stability over time, aiming to elucidate its relationship with psychopathology of schizophrenia. Future longitudinal studies are necessary to confirm these relationships over time. Our study underscores the significance of oxytocin in understanding the biological impact of childhood trauma on schizophrenia, highlighting the need for further investigation into the genetic factors that may affect oxytocin regulation following trauma. Identifying specific genetic variants linked to schizophrenia susceptibility could provide valuable insights for therapeutic interventions. Future clinical trials might consider including individuals with a history of childhood trauma or those with suboptimal oxytocin levels to discern who might benefit most from oxytocin supplementation.

Childhood trauma is recognized a major risk factor in the development of schizophrenia. In this cross-sectional study, we delved into the underlying mechanisms, examining the role of oxytocin in mediating the effects of childhood trauma on the development of schizophrenia. Consistent with prior research, our findings confirm a positive correlation between childhood trauma and the severity of schizophrenia, as well as an inverse correlation between oxytocin levels and these variables. Significantly, our findings suggest that oxytocin partially mediates the relationship between childhood trauma and the clinical manifestations of schizophrenia, indicating the childhood trauma may potentially led to oxytocin dysregulation, which in turn could increase the clinical severity of schizophrenia. These insights reinforce the crucial need for preventive measures, early recognition, and targeted interventions in schizophrenia, particularly in individuals with a history of childhood trauma. The potential of oxytocin as a therapeutic avenue for alleviating symptoms offers a promising direction for future clinical research and treatment strategies in schizophrenia.

Data availability

Supplementary information is available for this paper. The datasets generated during and/or analyzed during this study are available from the corresponding author upon reasonable request.

Trotta, A., Murray, R. M. & Fisher, H. L. The impact of childhood adversity on the persistence of psychotic symptoms: a systematic review and meta-analysis. Psychol. Med. 45 , 2481–2498 (2015).

Article   CAS   PubMed   Google Scholar  

Read, J., van Os, J., Morrison, A. P. & Ross, C. A. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr. Scand. 112 , 330–350 (2005).

Matheson, S. L., Shepherd, A. M., Pinchbeck, R. M., Laurens, K. R. & Carr, V. J. Childhood adversity in schizophrenia: a systematic meta-analysis. Psychol. Med. 43 , 225–238 (2013).

Varese, F. et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr. Bull. 38 , 661–671 (2012).

Article   PubMed   PubMed Central   Google Scholar  

Morgan, C. et al. Threat, hostility and violence in childhood and later psychotic disorder: population-based case-control study. Br. J. Psychiatry 217 , 575–582 (2020).

İngeç, C. & Evren Kılıçaslan, E. The effect of childhood trauma on age of onset in patients with schizophrenia. Int. J. Soc. Psychiatry 66 , 763–769 (2020).

Article   PubMed   Google Scholar  

Li, X. B. et al. Childhood trauma associates with clinical features of schizophrenia in a sample of Chinese inpatients. Psychiatry Res. 228 , 702–707 (2015).

Akbey, Z. Y., Yildiz, M. & Gündüz, N. Is there any association between childhood traumatic experiences, dissociation and psychotic symptoms in schziophrenic patients? Psychiatry Investig. 16 , 346–354 (2019).

Bailey, T. et al. Childhood trauma is associated with severity of hallucinations and delusions in psychotic disorders: a systematic review and meta-analysis. Schizophr. Bull. 44 , 1111–1122 (2018).

Hjelseng, I. V. et al. Childhood trauma is associated with poorer social functioning in severe mental disorders both during an active illness phase and in remission. Schizophr. Res. 243 , 241–246 (2022).

Aas, M. et al. A systematic review of cognitive function in first-episode psychosis, including a discussion on childhood trauma, stress, and inflammation. Front. Psychiatry 4 , 182 (2014).

Misiak, B. & Frydecka, D. A history of childhood trauma and response to treatment with antipsychotics in first-episode schizophrenia patients: preliminary results. J. Nerv. Ment. Dis. 204 , 787–792 (2016).

Mohammadzadeh, A., Azadi, S., King, S., Khosravani, V. & Sharifi Bastan, F. Childhood trauma and the likelihood of increased suicidal risk in schizophrenia. Psychiatry Res. 275 , 100–107 (2019).

Froemke, R. C. & Young, L. J. Oxytocin, neural plasticity, and social behavior. Annu. Rev. Neurosci. 44 , 359–381 (2021).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Rich, M. E. & Caldwell, H. K. A role for oxytocin in the etiology and treatment of schizophrenia. Front. Endocrinol. (Lausanne) 6 , 90 (2015).

Goh, K. K., Chen, C. H. & Lane, H. Y. Oxytocin in schizophrenia: pathophysiology and implications for future treatment. Int. J. Mol. Sci. 22 , 2146 (2021).

Ferreira, A. C. & Osório, F. L. Peripheral oxytocin concentrations in psychiatric disorders—a systematic review and methanalysis: Further evidence. Prog. Neuropsychopharmacol. Biol. Psychiatry 117 , 110561 (2022).

Strauss, G. P. et al. Plasma oxytocin levels predict olfactory identification and negative symptoms in individuals with schizophrenia. Schizophr. Res. 162 , 57–61 (2015).

Kéri, S., Kiss, I. & Kelemen, O. Sharing secrets: oxytocin and trust in schizophrenia. Soc. Neurosci. 4 , 287–293 (2009).

Goldman, M., Marlow-O’Connor, M., Torres, I. & Carter, C. S. Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits. Schizophr. Res. 98 , 247–255 (2008).

Strauss, G. P. et al. Plasma oxytocin levels predict social cue recognition in individuals with schizophrenia. Schizophr. Res. 162 , 47–51 (2015).

De Coster, L., Lin, L., Mathalon, D. H. & Woolley, J. D. Neural and behavioral effects of oxytocin administration during theory of mind in schizophrenia and controls: a randomized control trial. Neuropsychopharmacology 44 , 1925–1931 (2019).

Modabbernia, A. et al. Intranasal oxytocin as an adjunct to risperidone in patients with schizophrenia : an 8-week, randomized, double-blind, placebo-controlled study. CNS Drugs 27 , 57–65 (2013).

Zheng, W. et al. Adjunctive intranasal oxytocin for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. Schizophr. Res. 206 , 13–20 (2019).

Article   ADS   PubMed   Google Scholar  

Feifel, D., Shilling, P. D. & MacDonald, K. A review of oxytocin’s effects on the positive, negative, and cognitive domains of schizophrenia. Biol. Psychiatry 79 , 222–233 (2016).

Erdozain, A. M. & Peñagarikano, O. Oxytocin as treatment for social cognition, not there yet. Front. Psychiatry 10 , 930 (2019).

Goh, K. K., Kanahara, N., Chiu, Y. H. & Lu, M. L. The impact of childhood trauma exposure on social functioning in schizophrenia: the moderated mediation role of oxytocin and oxytocin receptor gene polymorphisms. Psychol. Med. 1–13. https://doi.org/10.1017/s003329172300274x (2023).

Bradley, E. R. & Woolley, J. D. Oxytocin effects in schizophrenia: reconciling mixed findings and moving forward. Neurosci. Biobehav. Rev. 80 , 36–56 (2017).

De Bellis, M. D. & Zisk, A. The biological effects of childhood trauma. Child Adolesc. Psychiatr. Clin. N. Am. 23 , 185–222 (2014).

Opacka-Juffry, J. & Mohiyeddini, C. Experience of stress in childhood negatively correlates with plasma oxytocin concentration in adult men. Stress 15 , 1–10 (2012).

Heim, C. et al. Lower CSF oxytocin concentrations in women with a history of childhood abuse. Mol. Psychiatry 14 , 954–958 (2009).

Seltzer, L. J., Ziegler, T., Connolly, M. J., Prososki, A. R. & Pollak, S. D. Stress-induced elevation of oxytocin in maltreated children: evolution, neurodevelopment, and social behavior. Child Dev. 85 , 501–512 (2014).

Mizuki, R. & Fujiwara, T. Association of oxytocin level and less severe forms of childhood maltreatment history among healthy Japanese adults involved with child care. Front. Behav. Neurosci. 9 , 138 (2015).

Donadon, M. F., Martin-Santos, R. & Osório, F. L. The associations between oxytocin and trauma in humans: a systematic review. Front. Pharmacol. 9 , 154 (2018).

Ebbert, A. M., Infurna, F. J., Luthar, S. S., Lemery-Chalfant, K. & Corbin, W. R. Examining the link between emotional childhood abuse and social relationships in midlife: the moderating role of the oxytocin receptor gene. Child Abuse Negl. 98 , 104151 (2019).

First, M. B., Williams, J. B., Karg, R. S. & Spitzer, R. L. SCID-5-CV: Structured Clinical Interview for DSM-5 Disorders: Clinician Version (American Psychiatric Association Publishing, 2016).

Bernstein, D. P. et al. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Neglect. 27 , 169–190 (2003).

Cheng, Y.-C., Chen, C.-H., Chou, K.-R., Kuo, P.-H. & Huang, M.-C. Reliability and factor structure of the chinese version of childhood trauma questionnaire-short form in patients with substance use disorder. Taiwanese J. Psychiatry 32 , 52–62 (2018).

Google Scholar  

Kay, S. R., Fiszbein, A. & Opler, L. A. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 13 , 261–276 (1987).

Cheng, J. J., Ho, H., Chang, C.-J., Lan, S.-Y. & Hwu, H.-G. Positive and Negative Syndrome Scale (PANSS): establishment and reliability study of a Mandarin Chinese language version. Taiwanese J. Psychiatry 10 , 251–258 (1996).

Valstad, M. et al. The correlation between central and peripheral oxytocin concentrations: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 78 , 117–124 (2017).

Wu, L. et al. Caffeine inhibits hypothalamic A(1)R to excite oxytocin neuron and ameliorate dietary obesity in mice. Nat. Commun. 8 , 15904 (2017).

Article   ADS   CAS   PubMed   PubMed Central   Google Scholar  

Zhang, K. M. et al. Nicotine enhances GABAergic inhibition of oxytocin mRNA-expressing neuron in the hypothalamic paraventricular nucleus in vitro in rats. Neurosci. Lett. 638 , 5–11 (2017).

Häfner, H., Maurer, K., Löffler, W. & Riecher-Rössler, A. The influence of age and sex on the onset and early course of schizophrenia. Br. J. Psychiatry 162 , 80–86 (1993).

Castle, D., Sham, P. & Murray, R. Differences in distribution of ages of onset in males and females with schizophrenia. Schizophr. Res. 33 , 179–183 (1998).

Marazziti, D. et al. Sex-related differences in plasma oxytocin levels in humans. Clin. Pract. Epidemiol. Ment. Health 15 , 58–63 (2019).

Hogg, B. et al. Psychological trauma as a transdiagnostic risk factor for mental disorder: an umbrella meta-analysis. Eur. Arch. Psychiatry Clin. Neurosci. 273 , 397–410 (2023).

Rubin, L. H. et al. Peripheral oxytocin and vasopressin are associated with clinical symptom severity and cognitive functioning in midlife women with chronic schizophrenia. Schizophr. Res. 195 , 409–411 (2018).

Woods, S. W. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J. Clin. Psychiatry 64 , 663–667 (2003).

Kiss, A. & Osacka, J. The effect of amisulpride, olanzapine, quetiapine, and aripiprazole single administration on c-Fos expression in vasopressinergic and oxytocinergic neurons of the rat hypothalamic paraventricular nucleus. Neuropeptides 87 , 102148 (2021).

Ong, H. L. et al. Performance of Mini-Mental State Examination (MMSE) in long-stay patients with schizophrenia or schizoaffective disorders in a psychiatric institute. Psychiatry Res. 241 , 256–262 (2016).

Talreja, B. T., Shah, S. & Kataria, L. Cognitive function in schizophrenia and its association with socio-demographics factors. Ind. Psychiatry J. 22 , 47–53 (2013).

Folstein, M. F., Folstein, S. E. & McHugh, P. R. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatric Res. 12 , 189–198 (1975).

Article   CAS   Google Scholar  

Hayes, A. F. Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-based Approach 3rd edn, 732 (Guilford publications, 2022).

Mall, S. et al. The relationship between childhood trauma and schizophrenia in the Genomics of Schizophrenia in the Xhosa people (SAX) study in South Africa. Psychol. Med. 50 , 1570–1577 (2020).

Kelleher, I. et al. Childhood trauma and psychosis in a prospective cohort study: cause, effect, and directionality. Am. J. Psychiatry 170 , 734–741 (2013).

De-Nardin, E. M. S., Muratori, C. A., Ribeiro, I. S., Huguete, R. B. & Salgado, J. V. Childhood trauma is associated with onset of symptoms, functioning and cognition in patients with schizophrenia. Trends Psychiatry Psychother. 44 , e20190081 (2022).

PubMed   PubMed Central   Google Scholar  

Liu, J. et al. Adverse childhood experiences and positive psychotic symptoms: a nationally representative study in Singapore. Child Abuse Negl. 131 , 105778 (2022).

Croft, J. et al. Association of Trauma Type, Age of Exposure, and Frequency in Childhood and Adolescence With Psychotic Experiences in Early Adulthood. JAMA Psychiatry 76 , 79–86 (2019).

Pruessner, M. et al. Impact of childhood trauma on positive and negative symptom remission in first episode psychosis. Schizophr Res. 231 , 82–89 (2021).

Popovic, D. et al. Childhood trauma in schizophrenia: current findings and research perspectives. Front. Neurosci. 13 , 274–274 (2019).

Garety, P. A., Kuipers, E., Fowler, D., Freeman, D. & Bebbington, P. E. A cognitive model of the positive symptoms of psychosis. Psychol. Med. 31 , 189–195 (2001).

Brookwell, M. L., Bentall, R. P. & Varese, F. Externalizing biases and hallucinations in source-monitoring, self-monitoring and signal detection studies: a meta-analytic review. Psychol. Med. 43 , 2465–2475 (2013).

Waters, F., Woodward, T., Allen, P., Aleman, A. & Sommer, I. Self-recognition deficits in schizophrenia patients with auditory hallucinations: a meta-analysis of the literature. Schizophr Bull. 38 , 741–750 (2012).

Perona-Garcelán, S. et al. Dissociative experiences as mediators between childhood trauma and auditory hallucinations. J. Trauma Stress 25 , 323–329 (2012).

Varese, F., Barkus, E. & Bentall, R. P. Dissociation mediates the relationship between childhood trauma and hallucination-proneness. Psychol. Med. 42 , 1025–1036 (2012).

Varese, F., Udachina, A., Myin‐Germeys, I., Oorschot, M. & Bentall, R. P. The relationship between dissociation and auditory verbal hallucinations in the flow of daily life of patients with psychosis. Psychosis 3 , 14–28 (2011).

Article   Google Scholar  

Lee, H., King, A. P., Li, Y. & Seng, J. S. Oxytocin receptor gene, post-traumatic stress disorder and dissociation in a community sample of European American women. BJPsych Open 8 , e104 (2022).

Sitko, K., Bentall, R. P., Shevlin, M., O’Sullivan, N. & Sellwood, W. Associations between specific psychotic symptoms and specific childhood adversities are mediated by attachment styles: an analysis of the National Comorbidity Survey. Psychiatry Res. 217 , 202–209 (2014).

Zheng, S. et al. Oxytocin Receptor Gene (OXTR) and Childhood Adversity Influence Trust. Psychoneuroendocrinology 121 , 104840 (2020).

van Dam, D. S., Korver-Nieberg, N., Velthorst, E., Meijer, C. J. & de Haan, L. Childhood maltreatment, adult attachment and psychotic symptomatology: a study in patients, siblings and controls. Soc. Psychiatry Psychiatr. Epidemiol. 49 , 1759–1767 (2014).

Degnan, A., Berry, K., Humphrey, C. & Bucci, S. The role of attachment and dissociation in the relationship between childhood interpersonal trauma and negative symptoms in psychosis. Clin. Psychol. Psychother. 29 , 1692–1706 (2022).

Liotti, G. & Gumley, A. In Psychosis, Trauma and Dissociation: Emerging Perspectives on Severe Psychopathology 117–133 (Wiley Blackwell, 2008).

Bentall, R. P., Wickham, S., Shevlin, M. & Varese, F. Do specific early-life adversities lead to specific symptoms of psychosis? A study from the 2007 the Adult Psychiatric Morbidity Survey. Schizophr. Bull. 38 , 734–740 (2012).

Pruessner, M. et al. Gender differences in childhood trauma in first episode psychosis: Association with symptom severity over two years. Schizophr. Res. 205 , 30–37 (2019).

Struck, N. et al. Childhood maltreatment and adult mental disorders—the prevalence of different types of maltreatment and associations with age of onset and severity of symptoms. Psychiatry Res. 293 , 113398 (2020).

Mansueto, G. et al. Childhood adversity, symptoms, and cortisol in first episode psychosis: a cross-sectional, secondary, observational analysis of a subsample of FEP patients. Nord. J. Psychiatry 77, 432–439 (2023).

Hailes, H. P., Yu, R., Danese, A. & Fazel, S. Long-term outcomes of childhood sexual abuse: an umbrella review. Lancet Psychiatry 6 , 830–839 (2019).

Werbeloff, N. et al. Childhood sexual abuse in patients with severe mental Illness: demographic, clinical and functional correlates. Acta Psychiatr. Scand. 143 , 495–502 (2021).

Read, J., Agar, K., Argyle, N. & Aderhold, V. Sexual and physical abuse during childhood and adulthood as predictors of hallucinations, delusions and thought disorder. Psychol. Psychother. 76 , 1–22 (2003).

Chae, S., Sim, M., Lim, M., Na, J. & Kim, D. Multivariate analysis of relationship between childhood trauma and psychotic symptoms in patients with schizophrenia. Psychiatry Investig. 12 , 397–401 (2015).

Friedman, T. & Tin, N. N. Childhood sexual abuse and the development of schizophrenia. Postgrad. Med. J. 83 , 507–508 (2007).

Khosravi, M., Bakhshani, N. M. & Kamangar, N. Dissociation as a causal pathway from sexual abuse to positive symptoms in the spectrum of psychotic disorders. BMC Psychiatry 21 , 266 (2021).

Scatliffe, N., Casavant, S., Vittner, D. & Cong, X. Oxytocin and early parent-infant interactions: a systematic review. Int. J. Nurs. Sci 6 , 445–453 (2019).

Sharma, S. R., Gonda, X., Dome, P. & Tarazi, F. I. What’s Love Got to do with it: Role of oxytocin in trauma, attachment and resilience. Pharmacol. Ther. 214 , 107602 (2020).

Ludmer, J. A. et al. Association between maternal childhood maltreatment and mother-infant attachment disorganization: moderation by maternal oxytocin receptor gene and cortisol secretion. Horm. Behav. 102 , 23–33 (2018).

Ellenbogen, M. A. Oxytocin and facial emotion recognition. Curr. Top. Behav. Neurosci. 35 , 349–374 (2018).

Millan, M. J. & Bales, K. L. Towards improved animal models for evaluating social cognition and its disruption in schizophrenia: the CNTRICS initiative. Neurosci. Biobehav. Rev. 37 , 2166–2180 (2013).

Goh, K. K. & Lu, M. L. Relationship between the domains of theory of mind, social dysfunction, and oxytocin in schizophrenia. J. Psychiatr. Res. 155 , 420–429 (2022).

Uhrig, S. et al. Reduced oxytocin receptor gene expression and binding sites in different brain regions in schizophrenia: a post-mortem study. Schizophr. Res. 177 , 59–66 (2016).

Ramo-Fernández, L. et al. Associations between childhood maltreatment and DNA methylation of the oxytocin receptor gene in immune cells of mother-newborn dyads. Transl. Psychiatry. 11 , 449 (2021).

Julian, M. M. et al. Associations between oxytocin receptor gene (OXTR) polymorphisms, childhood trauma, and parenting behavior. Dev. Psychol. 55 , 2135–2146 (2019).

Kraaijenvanger, E. J. et al. Epigenetic variability in the human oxytocin receptor (OXTR) gene: a possible pathway from early life experiences to psychopathologies. Neurosci. Biobehav. Rev. 96 , 127–142 (2019).

Wang, L. et al. The mediating effect of brain-derived neurotrophic factor levels on childhood trauma and psychiatric symptoms in patients with first-episode schizophrenia. Aust. N. Z. J. Psychiatry 56 , 828–835 (2022).

Baldwin, J. R., Reuben, A., Newbury, J. B. & Danese, A. Agreement between prospective and retrospective measures of childhood maltreatment: a systematic review and meta-analysis. JAMA Psychiatry 76 , 584–593 (2019).

Scott, K. M., McLaughlin, K. A., Smith, D. A. & Ellis, P. M. Childhood maltreatment and DSM-IV adult mental disorders: comparison of prospective and retrospective findings. Br. J. Psychiatry 200 , 469–475 (2012).

Zanos, P. et al. Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration. Neurosci. Lett. 600 , 33–37 (2015).

Teicher, M. H., Samson, J. A., Anderson, C. M. & Ohashi, K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat. Rev. Neurosci. 17 , 652–666 (2016).

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Acknowledgements

The authors gratefully acknowledge Prof. Ming-Chyi Huang for providing the Chinese Version of Childhood Trauma Questionnaire-Short Form. This manuscript was edited by Wallace Academic Editing. This study was supported by Wan-Fang Hospital, Taipei Medical University (grant numbers 111-wf-eva-21, 112-wf-eva-31, TMU111-AE1-B22) in Taipei City, Taiwan; the National Science and Technology Council (grant numbers MOST110-2314-B-038-072-MY3, MOST110-2314-B-038-073, and MOST111-2314-B-038-065-MY3) in Taipei City, Taiwan; and the Higher Education Sprout Project by the Ministry of Education (grant number DP2-TMU-112-N-08) in Taipei City, Taiwan. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

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Department of Psychiatry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Yuan-Jung Chen, Mong-Liang Lu, Yi-Hang Chiu & Kah Kheng Goh

Psychiatric Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Mong-Liang Lu, Yi-Hang Chiu, Chenyi Chen & Kah Kheng Goh

Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Mong-Liang Lu & Kah Kheng Goh

Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei, Taiwan

Chenyi Chen & Kah Kheng Goh

The Innovative and Translational Research Center of Brain Consciousness, Taipei Medical University, Taipei, Taiwan

Department of Psychiatry and Mental Health, Faculty of Health Sciences (FCS-UBI), Cova da Beira University Hospital Center, Covilhã, Portugal

Vitor Hugo Jesus Santos

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Contributions

Yuan-Jung Chen: Data curation, Formal analysis, Writing—original draft, Writing—review & editing. Mong-Liang Lu: Conceptualization, Investigation, Formal analysis, Validation, Resources, Supervision. Yi-Hang Chiu: Investigation, Validation, Resources, Supervision. Chenyi Chen: Methodology, Validation, Resources, Supervision. Vitor Hugo Jesus Santos: Validation, Writing—review & editing. Kah Kheng Goh: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Validation, Writing—original draft, Writing—review & editing, Visualization, Funding acquisition.

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Correspondence to Kah Kheng Goh .

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Chen, YJ., Lu, ML., Chiu, YH. et al. Linking childhood trauma to the psychopathology of schizophrenia: the role of oxytocin. Schizophr 10 , 24 (2024). https://doi.org/10.1038/s41537-024-00433-9

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Received : 29 October 2023

Accepted : 31 December 2023

Published : 22 February 2024

DOI : https://doi.org/10.1038/s41537-024-00433-9

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