Childhood Onset Psychosis: A large UK case series

Childhood Onset Psychosis: A large UK case series | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Childhood Onset Psychosis: A large UK case series Mitra S Sato, Anthony James, Marinos Kyriakopoulos, Anna C Need This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6574363/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Oct, 2025 Read the published version in European Child & Adolescent Psychiatry → Version 1 posted 4 You are reading this latest preprint version Abstract Childhood-Onset Psychosis (COP) is a rare and severe variant of schizophrenia, with a UK incidence of ~ 1 in 500,000. This paper presents the largest UK case series of COP, comprising 39 families (105 individuals) recruited between 2016 and 2019. It is also the most ethnically diverse collection of COP cases worldwide, with 36% European ancestry, 23% South Asian, 18% African, 10% Mixed ancestry and 13% Other. All probands were hospitalised and diagnosed with a psychotic disorder by age 13, including schizoaffective disorder, paranoid schizophrenia, childhood-onset schizophrenia and other nonorganic psychotic disorders. The cohort had a male-to-female ratio of 1:1.4, with females diagnosed at a higher mean age (11 years 9 months) than males (10 years 6 months). While 54% of probands had no reported first-degree family history of psychiatric illness, 59% presented with comorbid neurodevelopmental conditions. Approximately one-third were treated with clozapine, reflecting the severity and treatment resistance of the cases. Childhood onset psychosis (COP) childhood onset schizophrenia (COS) young onset diverse comorbid neurodevelopmental disorders treatment resistant. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Childhood-Onset Psychosis (COP), defined by the onset of psychosis by age 13 represents a difficult diagnostic and treatment challenge 1 – 5 . It generally is accepted to have an incidence of less than 1 in 500,000 in the UK 1 , 6 . It is defined by the same diagnostic criteria as adult-onset schizophrenia (AOS) 5 , 7 – 10 but its early manifestation introduces unique clinical and prognostic complexities 1 , 7 , 9 , 9 , 11 – 16 . The symptomatology of COP is notably severe, with auditory hallucinations being a prominent feature 17 – 25 . Visual and tactile hallucinations, delusions, thought disorder, and negative symptoms such as affective flattening and withdrawal are also significant 3 , 11 , 17 , 19 , 20 , 24 – 26 . These symptoms alongside suicidal behaviours often lead to hospitalisation 18 , 27 . Diagnosing COP is difficult 8 , 27 . Hallucinations can be part of the normal developmental spectrum 8 , 27 , 28 , yet they are also present in a range of conditions including autism 29 and affective disorders 30 . A key to diagnosis lies in the persistence and severity of symptoms and their impact on function 12 , 31 – 33 , a task complicated by the developmental variability in symptom expression across childhood and adolescence 34 . The rarity of COP is reflected in the lack of large, representative cohorts. The National Institute of Mental Health's (NIMH) cohort of childhood-onset schizophrenia (COS) cases 7 , 9 , 27 , which used stringent criteria for recruitment, has yielded invaluable insights but also excluded a substantial portion of the COP population, particularly those with intellectual disabilities. A study from Nigeria 35 included 33 COP cases, while other case series report much smaller numbers 36 – 39 . A series of genomic findings from COS patients have been reported across different studies, including over 80 cases from the US 40 – 42 , 37 from Israel 43 and 10 from China 44 , however, no overview of clinical and demographic characteristics were provided. Comorbid conditions are frequent in COP 5 , 25 , 45 , 46 , ranging from mood disorders 11 and ADHD 1 to autism spectrum disorder 46 , 47 to profound language and motor developmental delays 1 , 25 . Such comorbidities lead to phenotypic heterogeneity and are prognostically significant, with earlier and more severe premorbid disturbances correlating with worse outcomes 2 . Neurobiologically, COP is continuous with AOS 7 – 10 , sharing similar structural brain abnormalities and cognitive deficits 2 . COP, however, has more pronounced cognitive and developmental disturbances 7 – 10 . The treatment for COP is complex 48 – 50 . Antipsychotics are only partly effective and have adverse effects 51 , 52 . The second-generation antipsychotics, with reduced extrapyramidal side effects 53 , carry risks of metabolic and cardiovascular complications 54 – 57 . This necessitates careful monitoring and underscores the need for comprehensive treatment plans incorporating both pharmacological and psychosocial interventions 48 – 50 . The heterogeneity of COP in the clinic, in contrast to the careful curated cohorts that are used for clinical research, combined with the likelihood that any individual clinician may only see one or a few COP patients in their career, means that the diagnosis and treatment of COP cannot easily be guided by published literature. This paper aims to help fill this gap by providing data from a cohort of patients diagnosed with COP in the UK. Methodology Study Design Families with children diagnosed with psychotic disorders by age 13 were recruited post-diagnosis from Child and Adolescent Mental Health Services (CAMHS) through clinician referrals. Siblings, both parents and any other affected family members were included where possible. Ethical approval was granted (REC reference 15/SC/0206; IRAS ID 170402). Inclusion and Exclusion Criteria All participants provided consent if over 16 and assent if under 16 with parental consent. The study obtained ethical approval to include adult relatives (including parents) with intellectual disabilities or other conditions affecting informed consent. Exclusion criteria included prematurity (birth weight < 1500g), brain injury (e.g., perinatal hypoxia), substance abuse prior to diagnosis and known medical conditions or severe abuse that could explain the psychosis. Data Collection Data collected from consented participants included: Medical Records : Psychiatric, neurological, and general health history. Diagnoses were made in accordance with the Multiaxial ICD-10 classification of child and adolescent psychiatric disorders (World Health Organization, 1996) and confirmed as part of this study using the ICD-10 diagnostic criteria for research (World Health Organization, 1993). Cognitive Testing : Post-diagnosis IQ data were obtained either from descriptive entries in medical records or from Wechsler Abbreviated Scale of Intelligence II (WASI-II) assessments conducted as part of this study. For participants with documented IQ test results in their medical records the available data was used directly. For participants assessed with the WASI-II, the standard WASI-II classification ranges were applied. Specifically, scores below 70 categorised as ‘extremely low’ were referred to as “ID”. Interviews : Developmental history, family psychiatric history, and environmental factors. Statistical analysis All analyses were performed using R (version 4.2.2). Missing data were excluded, and for statistical tests significance was set at p < 0.05. Visualisations were created using ggplot2 and related R packages. Results Demographics A total of 105 individuals were recruited including 39 probands with COP. Demographic characteristics are summarised in Table 1 . Males were diagnosed at a significantly younger age (10.6 ± 1.9 years) than females (11.9 ± 1.5 years; p = 0.037). Onset type also differed significantly between sexes ( p = 0.046) with females more likely to present with acute onset (61%) compared to males (44%). Ancestry and immigration status did not significantly differ between sexes ( p = 0.256 and p = 0.613, respectively). Table 1 Demographics of the cohort. Continuous variables are presented as mean ± standard deviation (SD) (Mann-Whitney U test), categorical as frequencies (%) (Chi-squared). "Mixed Afr and Eur" refers to one European and one African parent. "Other" includes Middle Eastern, East Asian and Hispanic. Significant results marked *. Characteristic Males (n = 16, 41%) Females (n = 23, 59%) Total (n = 39) p-value (test) Mean age at diagnosis (years) 10.6 ± 1.9 11.9 ± 1.5 11.3 ± 1.8 0.037* (Mann-Whitney U) Onset type (%) 0.046* (χ 2 ) Acute 7 (44) 14 (61) 21 (54) Insidious 9 (56) 9 (39) 18 (46) Ancestry (%) 0.256 (χ 2 ) European 5 (31) 9 (39) 14 (36) South Asian 2 (12) 7 (30) 9 (23) African 5 (31) 2 (9) 7 (18) Mixed Afr and Eur 1 (6) 3 (13) 4 (10) Other 3 (19) 2 (9) 5 (13) Immigration 0.613 (χ 2 ) First generation 2(12) 1(4) 3(8) Second generation 9(56) 13(57) 22(56) Non-immigrant 5(31) 9(39) 14(36) The cohort's ancestry composition deviates from the UK population (Fig. 1 ). Diagnoses All probands had a primary psychotic disorder diagnosis and were hospitalised at least once. The split of diagnoses, along with the prevalence of positive and negative symptoms is detailed in Table 2 . Table 2 Diagnoses and symptom frequencies. Diagnoses and symptoms stratified by sex and presented as frequency (n) and proportion (%) of the total count (n = 39). Category Sub-category Frequency(n) Proportion(%) Males(n = 16) Females(n = 23) Diagnoses Other nonorganic psychotic disorders 21 54 10 11 Schizoaffective disorder 8 21 3 5 Schizophrenia 6 15 2 4 Bipolar disorder with psychotic symptoms 2 5 1 1 Delusional disorder 1 3 0 1 Depression with psychotic symptoms 1 3 0 1 Symptoms Positive Symptoms Hallucinations (all types) 39 100 Auditory 37 95 Visual 31 79 Olfactory 4 10 Somatic 3 8 Tactile 1 3 Delusions (all types) 32 82 Capgras 6 15 Persecutory 5 13 Grandiose 4 10 Negative Symptoms Behavioural difficulties 36 92 Sleep disturbances 29 74 Anxiety 36 92 Suicidal ideation 10 26 Family history Most cases were sporadic, with no first-degree relative diagnosed with a psychiatric illness (22/39, 56%). Those with at least one parent diagnosed with schizophrenia accounted for 8/39 (21%) while the remaining 9/39 (23%) had a parent with a psychiatric illness other than schizophrenia, including depression (n = 7) and anxiety disorder (n = 2). Family history was further analysed (Suppl. Figure 1). There was no significant difference when stratified by diagnostic age group (c 2 = 0.09, p = 0.95) or by sex (c 2 = 0.01, p = 0.99). Intellectual functioning Premorbid IQ was unavailable for most cases therefore school reports and parental interviews were used to categorise them as having average, above average or below average cognitive functioning (Fig. 2 A). Post-diagnosis IQ scores were available for 24 probands, assessed using prior medical records or WASI-II at recruitment (Fig. 2 B-C). IQ data for 15 probands were unavailable due to missing records or testing constraints. Post-diagnosis IQ was significantly lower in individuals with premorbid developmental delay (t-test, p = 0.033, suppl. Figure 2A) but not significantly impacted by comorbidities (suppl. Figure 2B). Speech and language delay were present in 46% (n = 18) probands. Antipsychotic treatment At the time of recruitment, all probands were taking antipsychotics, with 5 individuals (12.8%) receiving two concurrently. Clozapine was most frequently prescribed(n = 14, 35.9%), and appeared more frequent in probands diagnosed at an older age (Suppl. Table 1); however, this was not statistically significant (χ²=1.18, p = 0.55). Olanzapine was prescribed in 9 cases (23.1%), followed by risperidone (6 probands, 15.4%), and aripiprazole and quetiapine, each in 4 probands (10.3%). Mood stabilisers were recorded in 6 individuals (15.4%), including sodium valproate, lithium carbonate, and carbamazepine. Antidepressants were prescribed in 7 cases (17.9%), with sertraline and fluoxetine most frequently represented. Sleep aids, primarily melatonin, were used in 6 probands (15.4%). Adjunctive therapies were common, including antidiabetic medications (5 cases, 12.8%), laxatives (3 cases, 7.7%), anticholinergics (3 cases, 7.7%), and vitamin supplements. These findings highlight the pharmacological complexity often required in this population. Age and diagnostic delay Males were diagnosed significantly earlier than females (p = 0.037, Mann-Whitney U; Fig. 3 ), though symptom onset ages showed no sex differences (mean: 9.4 years; p = 0.63). This suggests possible diagnostic delays may underlie sex differences in diagnostic age. The majority of the cohort were diagnosed within two years of symptom onset (n = 23, 59%) though delays of up to eight years occurred (Fig. 4 ). Prolonged delays (≥ 5 years, n = 7) were more common among females. Discussion This study presents a large case series of childhood onset psychosis collected in England between 2016–2019. Compared with published incidence estimates from the only other UK study 6 , which identified 8 confirmed cases per year, our cohort of 39 cases over 3 years (~ 13 cases per year) suggests a high level of case ascertainment and likely captures the majority of new incidences. Although not all patients were newly diagnosed at recruitment, the scale and breadth of identification – through national inpatient services and outpatient referrals – make this one of the largest datasets assembled for this rare condition nationally. Unlike other studies 1 , 9 , 27 , this dataset prioritises inclusivity and reflects childhood psychosis as seen in community and clinical settings. While the size of the cohort highlights the scale of recruitment effort, it remains likely that some cases were not identified due to underdiagnosis, challenges in clinical recognition, delayed referrals, or barriers to research participation, as discussed below. Despite these limitations, this cohort provides valuable insight into better understanding of COP within the UK healthcare and population setting. The cohort’s ethnic makeup differs from the general UK population 58 , with White British underrepresented (Fig. 1 ) and a notable presence of minority European groups. Studies show that white ethnic minorities face a 50% increased risk of psychosis compared to White British individuals likely due to migration stress and socioeconomic challenges 59 , 60 . Notably, nearly a third of the cohort is of South Asian ancestry, consistent with a 2–4 times higher risk of psychosis reported in this group 59 . Almost half the cohort are reportedly first- or second-generation immigrant families, reflecting a substantial representation of multicultural households. Among first-generation families, early childhood migration (before age 2) was observed in 2/3, a critical period linked to increased psychosis risk 61 – 64 . Second-generation immigrants, comprising over a third of the cohort, showed a higher prevalence of psychosis, aligning with studies indicating a twofold increased risk compared to non-immigrants 65 , 66 . While these patterns are consistent with known risk factors for psychosis, comparisons with the general population are made with caution. This cohort was not randomly sampled and factors such as being diagnosed, healthcare and research participation access may have influenced the demographic distribution. However, the alignment of the observed differences with existing epidemiological evidence underscores the relevance of ancestry and migration-related exposures in COP. Family history was broadly similar across the cohort (Suppl. Figure 1) with 44% (17/39) reporting a parent with schizophrenia or another psychiatric illness. These exceed the 33% previously reported for COS 67 , likely reflecting the broader inclusion criteria in this study. Most cases (56%) were sporadic or involved extended family neuropsychiatric histories, likely reflecting a combination of complex genetic and socioenvironmental contributors 68 . Cognitive decline emerged as a key theme with indications that participants might perform more poorly on IQ assessments following diagnosis. Males showed greater decline than females (Fig. 2 ) with larger drops in those with developmental delays (Suppl. Figure 2A), consistent with the literature 69 – 71 . Poorer premorbid functioning, linked to worse prognoses 72 – 75 may explain these findings. This pattern aligns with reductions in global cognitive functioning seen in COS 76 – 78 , attributed by the NIMH group to disrupted brain connectively, particularly in social-cognitive and sensorimotor regions 79 . However, interpretation of the IQ scores is constrained by methodological limitations. Given the scores were derived from medical records or home-based assessments, reliability could potentially be impacted 80 . Additionally, the lack of a systematic socio-economic status evaluation in this cohort, a known influence on IQ measurement 81 , further restricts conclusions. Clozapine was prescribed to 38.5% (n = 15) of the cohort following inadequate responses to at least two antipsychotics, consistent with its role as a third-line treatment 82 – 84 . Females were twice as likely as males to receive clozapine particularly those with diagnostic delays potentially due to their older age at diagnosis. Adult studies show lower clozapine rates in females 85 , while adolescent studies report no gender disparities 86 . Clozapine’s use in youth is approached cautiously due to side effects with 40% of UK psychiatrists avoiding it in under 18s 87 (Suppl. Table 1). Polypharmacy was common, with antidepressants (e.g., sertraline) and mood stabilisers (e.g., sodium valproate) prescribed to manage comorbid symptoms, possibly aligning with practices aimed at improving symptom management 88 , 89 . Despite limited data in the younger populations, there are reports of increased risk of adverse drug reactions with psychotropic polypharmacy 90 . These findings reflect the complexity of pharmacological management in COP and underscore the need for integrated treatment approaches. While clozapine remains a key option for treatment-resistant cases 1 , 27 , 52 , its use should be complemented by psychological interventions such as cognitive-behavioural therapy (CBT), family therapy, and educational support 7 . Diagnostic patterns highlight gender differences, with females more often diagnosed at age 13, while diagnoses before this age were evenly distributed. In younger probands, males frequently presented with externalising behaviours, such as ADHD or learning disabilities, which likely drew earlier clinical attention 91 . In contrast, females exhibited mood- and anxiety-related symptoms that align with literature on internalising presentations but may delay any diagnosis of schizophrenia if misattributed to stress or mood disorders 92 .The broader symptomatology observed in females at ages 10–11, includes ASD, anxiety, and OCD. The literature 93 – 99 suggests externalising behaviours in males prompt earlier clinical attention, while females’ internalising symptoms and better social functioning may delay diagnosis. Stigma around mental illness, particularly in minority communities 100 , can delay diagnosis as families may avoid seeking help or attribute symptoms to non-medical causes. In two cases, care was initially sought abroad due to cultural or religious beliefs delaying local treatment. South Asian ancestry was similarly represented across age groups with females consistently outnumbering males. Cultural stigma, especially in South Asian families may explain the older diagnostic age for some probands aligning with reports of mental health stigma in this community 101 . More broadly, cultural norms often socialise females to mask emotions whilst males express visible behaviours 102 , 103 , potentially contributing to later diagnoses in the females in this study. This study's greatest strength lies in its inclusivity, distinguishing it from others that often exclude individuals with intellectual disabilities or non-English speakers 9 . By capturing the majority of families with affected children we ensured representation of groups frequently left out of research. Ethical approval allowed personal consultees to provide consent for participants with intellectual disabilities. Language barriers were addressed through interpreters and translated materials, and home visits were conducted nationwide for families unable to travel to reduce burden. Instead of lengthy diagnostic tools like K-SADs 104 , targeted questions and use of medical records ensured efficient data collection, with follow-ups conducted when one parent was unavailable. These efforts produced a robust, diverse dataset – setting a new standard for inclusivity in research. However, there are several limitations. First, inconsistencies in IQ testing conducted at varying ages and under different conditions make it difficult to distinguish true cognitive decline from age-related differences in test performance. Second, while our inclusive recruitment approach is a strength, it may have impacted data quality. Efforts to address language barriers using interpreters and translated materials, while effective, risked losing subtle cultural nuances. Despite tailored questionnaires, this may have affected data granularity. Third, cultural factors, including varying parental beliefs about psychiatric symptoms, likely influenced symptom reporting and potentially reporting of relevant family history, introducing sociocultural variability into the dataset. Finally, the absence of standardised diagnostic interviews such as K-SADs may limit comparability with other studies. However, diagnostic stability was ensured as all had been CAMHS inpatients during their clinical care, had undergone multiple assessments by experienced clinicians and had diagnoses confirmed using operationalised diagnostic criteria. In conclusion, this study presents the largest and most ethnically diverse cohort of COP cases of unknown cause in the UK. By inclusively recruiting and excluding only cases with clear non-genetic causes, we likely captured the majority of affected families. Despite its diversity, the cohort’s clinical presentation aligns closely with global COP studies, reflecting consistent core clinical features across socially diverse populations. Declarations Author Contribution ACN and TJ developed the study concept, wrote the original protocol and obtained ethical approval. TJ and MK identified eligible participants. MSS and ACN performed recruitment and collected data. MSS performed the data analysis, drafted the main manuscript and prepared all figures and tables. All authors reviewed and approved the final manuscript. Acknowledgement We thank all participants and their families. Special thanks to Drs. Sumi Handy, Jane Whittaker, Tim Hawkins, Kouser Shaik, Amulya Nadkarni, Fiona Padgett, Morris Zwi, Gillian Rose, Jon Goldin, Nicoletta Gentili, Virginia Valle, Sarojeet Ganguly, Isabelle Ellory, Rajeev Biradar, Catherine O’Callahan, and Niloufar Mirhaghani for their efforts in identifying patients. We also thank the research management teams across all participating Trusts for their support, Dr Fotios Drenos for his helpful comments and support staff Armandina Almanza-Gutierrez, Claudia Adele, and Dominic Zimmerman from Imperial College London for their assistance during recruitment. References Driver DI, Thomas S, Gogtay N, Rapoport JL (2020) Childhood-Onset Schizophrenia and Early-onset Schizophrenia Spectrum Disorders: An Update. Child Adolesc Psychiatr Clin N Am. 10.1016/j.chc.2019.08.017 Rapoport JL, Gogtay N (2011) Childhood onset schizophrenia: Support for a progressive neurodevelopmental disorder. Int J Dev Neurosci 29:251–258 Asarnow JR (1994) Annotation: Childhood-Onset Schizophrenia . vol. 35 1345–1371 McClellan J, Werry J (1994) Practice parameters for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry. 10.1097/00004583-199406000-00002 Gochman P, Miller R, Rapoport JL (2011) Childhood-onset schizophrenia: The challenge of diagnosis. Curr Psychiatry Rep 13:321–322 Tiffin PA, Kitchen CEW (2015) Incidence and 12-month outcome of childhood non-affective psychoses: British national surveillance study. Br J Psychiatry 206:517–518 Hollis C, Rapoport J (2011) Child and Adolescent Schizophrenia. Schizophrenia: Third Ed. 10.1002/9781444327298.ch3 Jacobsen LK, Rapoport JL, Research Update (1998) Childhood-onset Schizophrenia: Implications of Clinical and Neurobiological Research. J Child Psychol Psychiatry. 10.1111/1469-7610.00305 Gordon CT et al (1994) Childhood-onset schizophrenia: An NIMH study in progress. Schizophr Bull. 10.1093/schbul/20.4.697 Alaghband-Rad J, Hamburger SD, Giedd JN, Frazier JA, Rapoport JL (1997) Childhood-onset schizophrenia: biological markers in relation to clinical characteristics. Am J Psychiatry 154:64–68 RUSSELL AT, BOTT L, SAMMONS C (1989) The Phenomenology of Schizophrenia Occurring in Childhood. J Am Acad Child Adolesc Psychiatry. 10.1097/00004583-198905000-00017 Nicolson R (2000) Lessons from childhood-onset schizophrenia. Brain Res Rev 31:147–156 Eggers C (1978) Course and prognosis of childhood schizophrenia. J Autism Child Schizophr. 10.1007/BF01550275 Eggers C (1989) Schizo-affective psychoses in childhood: A follow-up study. J Autism Dev Disord. 10.1007/BF02211850 ALAGHBAND-RAD J et al (1995) Childhood-Onset Schizophrenia: The Severity of Premorbid Course. J Am Acad Child Adolesc Psychiatry 34:1273–1283 Schaeffer JL, Ross RG (2002) Childhood-Onset Schizophrenia: Premorbid and Prodromal Diagnostic and Treatment Histories. J Am Acad Child Adolesc Psychiatry. 10.1097/00004583-200205000-00011 Spencer EK, Campbell M (1994) Children with schizophrenia: Diagnosis, phenomenology, and pharmacotherapy. Schizophr Bull. 10.1093/schbul/20.4.713 Asarnow RF, Asarnow JR (1994) Childhood-onset schizophrenia: editors’ introduction. Schizophr Bull 20:591–597 KOLVIN I (1971) Studies in the Childhood Psychoses: Diagnostic Criteria and Classification. Br J Psychiatry 118:381–384 KOLVIN I (1971) Studies in the Childhood Psychoses. Br. J. Psychiatry 118, 381 LP – 384 GREEN WH et al (1984) A Comparison of Schizophrenic and Autistic Children. J Am Acad Child Psychiatry. 10.1016/S0002-7138(09)60317-4 Green, W. & Padron-Gayol, M. Schizophrenia with childhood onset: a phenomenological study of 38 cases. … Acad. Child … 31, 968–976 (1992) Werry JS, McClellan JM, Chard L (1991) Childhood and adolescent schizophrenic, bipolar, and schizoaffective disorders: a clinical and outcome study. J Am Acad Child Adolesc Psychiatry 30:457–465 Cheng X et al (2021) Comparison of clinical characteristics and treatment efficacy in childhood-onset schizophrenia and adolescent-onset schizophrenia in mainland China: A retrospective study. Early Interv Psychiatry. 10.1111/eip.13121 Di Luzio M et al (2023) Clinical features and comorbidity in very early-onset schizophrenia: a systematic review. Front Psychiatry 14 Correll CU et al (2024) Identification and treatment of individuals with childhood-onset and early-onset schizophrenia. Eur Neuropsychopharmacol 82:57–71 Driver DI, Gogtay N, Rapoport JL (2013) Childhood onset schizophrenia and early onset schizophrenia spectrum disorders. Child Adolesc Psychiatr Clin N Am 22:539–555 Hollis C (1995) Child and adolescent (juvenile onset) schizophrenia. A case control study of premorbid developmental impairments. Br J Psychiatry. 10.1192/bjp.166.4.489 Kumra S et al (1998) Multidimensionally impaired disorder’: Is it a variant of very early- onset schizophrenia? J Am Acad Child Adolesc Psychiatry 37:91–99 Dalhaug KC, Storvik K, Kildahl AN (2022) Undiagnosed Psychotic Disorder in Autistic Individuals with Intellectual Disabilities and Suspected Obsessive-Compulsive Disorder: An Explorative, Clinical Study. https://doi.org /10.1080/19315864 . 2117880 (2022) 10.1080/19315864.2022.2117880 Americans N et al (2013) The ICD-10 Classification of Mental and Behavioural Disorders. IACAPAP E-Textb Child Adolesc Ment Health 55:135–139 Biedermann F, Fleischhacker WW (2016) Psychotic disorders in DSM-5 and ICD-11. CNS Spectr 21:349–354 Association AP (2013) American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders Fifth Edition . Arlington 10.1176/appi.books.9780890425596.744053 Kelleher I et al (2012) Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies. Psychol Med 42:1857–1863 Okewole AO, Ogunwale A, Mosanya TJ, Ojo BM (2016) A 12 year chart review of childhood and adolescent onset psychosis at a Nigerian tertiary mental health facility. J Child Adolesc Ment Health 28:189–197 Pantano T, Fu IL, Curatolo E, Martins CB, Elkis H (2016) Thought and language disorders in very early onset schizophrenia,schizoaffective disorder and bipolar disorder. Rev Psiquiatr Clin 43:67–73 Rad F et al (2022) Diagnosis stability and outcome of psychotic episodes in a Romanian group of children and adolescents. Med (Baltim) 101:E30288 Galitzer H et al (2021) Functional outcomes and patient satisfaction following inpatient treatment for childhood-onset schizophrenia spectrum disorders vs non-psychotic disorders in children in the United Kingdom. Early Interv Psychiatry 15:412–419 Anagnostopoulou N, Kyriakopoulos M, Alba A (2019) Psychological interventions in psychosis in children and adolescents: a systematic review. Eur Child Adolesc Psychiatry 28:735–746 Smedemark-Margulies N et al (2016) A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia. Mol Case Stud 2:a001008–a001008 Brownstein CA et al (2016) 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 170:1165–1173 Mavros CF et al (2018) De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report. BMC Med Genet. 10.1186/s12881-018-0711-9 Alkelai A et al (2021) Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia. J Hum Genet 66:339–343 Huang H et al (2023) Comprehensive analysis of circRNA expression profile and circRNA-miRNA-mRNA network susceptibility to very early-onset schizophrenia. Schizophr Heidelb Ger 9:70 Downs JM et al (2017) The Association Between Comorbid Autism Spectrum Disorders and Antipsychotic Treatment Failure in Early-Onset Psychosis. J Clin Psychiatry 78:e1233–e1241 Rapoport J, Chavez A, Greenstein D, Addington A, Gogtay N (2009) Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry 48:10–18 Pina-Camacho L, Parellada M, Kyriakopoulos M (2016) Autism spectrum disorder and schizophrenia: boundaries and uncertainties. BJPscyh Adv 22:316–324 Asarnow JR, Tompson MC, McGrath EP, Annotation (2004) Childhood-onset schizophrenia: Clinical and treatment issues. J Child Psychol Psychiatry. 10.1111/j.1469-7610.2004.00213.x Kasoff LI, Ahn K, Gochman P, Broadnax DD, Rapoport JL (2016) Strong Treatment Response and High Maintenance Rates of Clozapine in Childhood-Onset Schizophrenia. J Child Adolesc Psychopharmacol 26, cap.2015.0103-cap.2015.0103 Clark AF, Lewis SW (1998) Treatment of schizophrenia in childhood and adolescence. J Child Psychol Psychiatry. 10.1017/S0021963098003242 Gogtay N, Rapoport J (2008) Clozapine use in children and adolescents. Expert Opin Pharmacother. 10.1517/14656566.9.3.459 Frazier JA et al (1994) An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry 33:658–663 James AC, Broome MR (2017) Antipsychotics in adolescent-onset psychosis: a work in progress. Lancet Psychiatry 4:e16–e17 Newcomer JW, Leucht S (2009) Metabolic adverse effects associated with antipsychotic medications. Book Ch28 Correll CU, Carlson HE (2006) Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry 45:771–791 Correll CU (2008) Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents. J Clin Psychiatry 69(Suppl 4):26–36 Harrison-Woolrych ML (2007) Evaluating medicines: let’s use all the evidence. Med J Aust 186:662 Office for National Statistics (2011) Census Aggregate Data. UK Data Serv. (2016) Kirkbride JB et al (2008) Psychoses, ethnicity and socio-economic status. Br J Psychiatry J Ment Sci 193:18–24 Zolkowska K, Cantor-Graae E, McNeil TF (2001) Increased rates of psychosis among immigrants to Sweden: is migration a risk factor for psychosis? Psychol Med 31:669–678 Anderson KK, Cheng J, Susser E, McKenzie KJ, Kurdyak P (2015) Incidence of psychotic disorders among first-generation immigrants and refugees in Ontario. CMAJ Can Med Assoc J J Assoc Medicale Can 187:E279–E286 Veling W, Hoek HW, Selten J-P, Susser E (2011) Age at migration and future risk of psychotic disorders among immigrants in the Netherlands: a 7-year incidence study. Am J Psychiatry 168:1278–1285 Howes OD, Murray RM (2014) Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet Lond Engl 383:1677–1687 Bentall RP, Wickham S, Shevlin M, Varese F (2012) 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 Bourque F, van der Ven E, Malla A (2011) A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants. Psychol Med 41:897–910 Fossion P et al (2002) Psychiatric disorders and social characteristics among second-generation Moroccan migrants in Belgium: an age-and gender-controlled study conducted in a psychiatric emergency department. Eur Psychiatry J Assoc Eur Psychiatr 17:443–450 Asarnow RF et al (2001) Schizophrenia and schizophrenia-spectrum personality disorders in the first-degree relatives of children with schizophrenia: The UCLA Family Study. Arch Gen Psychiatry. 10.1001/archpsyc.58.6.581 Owen MJ, Sawa A, Mortensen PB (2016) Schizophrenia Lancet. 10.1016/S0140-6736(15)01121-6 Ordóñez AE et al (2016) Lack of Gender-Related Differences in Childhood-Onset Schizophrenia. J Am Acad Child Adolesc Psychiatry 55:792–799 Sporn AL et al (2004) Pervasive developmental disorder and childhood-onset schizophrenia: Comorbid disorder or a phenotypic variant of a very early onset illness? Biol Psychiatry 55:989–994 Ross RG, Heinlein S, Tregellas H (2006) High rates of comorbidity are found in childhood-onset schizophrenia. Schizophr Res 88:90–95 Stentebjerg-Olesen M, Pagsberg AK, Fink-Jensen A, Correll CU, Jeppesen P (2016) Clinical characteristics and predictors of outcome of schizophrenia-spectrum psychosis in children and adolescents: A systematic review. J Child Adolesc Psychopharmacol. 10.1089/cap.2015.0097 Black K et al (2001) Duration of untreated psychosis predicts treatment outcome in an early psychosis program. Schizophr Res. 10.1016/S0920-9964(00)00144-4 Done DJ, Crow TJ, Johnstone EC, Sacker A (1994) Childhood antecedents of schizophrenia and affective illness: Social adjustment at ages 7 and 11. BMJ 10.1136/bmj.309.6956.699 Jones P, Murray R, Jones P, Rodgers B, Marmot M (1994) Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet. 10.1016/S0140-6736(94)90569-X Armita A et al (2025) Neurocognitive dysfunctions in childhood-onset schizophrenia: A systematic review. Schizophr Res Cogn 40:100342 Frangou S (2010) Cognitive function in early onset schizophrenia: a selective review. Front Hum Neurosci 3:79 Bedwell JS et al (1996) 156 Why Does Postpsychotic IQ Decline in Childhood-Onset Schizophrenia? https://doi.org /10.1176/ajp.156.12 . 1996–1997 (1999) Berman RA et al (2016) Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhoodonset schizophrenia. Brain. 10.1093/brain/awv306 McKinney WS, Williford DN, Abbeduto L, Schmitt LM (2024) The impact of social-environmental factors on IQ in syndromic intellectual developmental disabilities. J Clin Transl Sci 8:e59 Hanscombe KB et al (2012) Socioeconomic Status (SES) and Children’s Intelligence (IQ): In a UK-Representative Sample SES Moderates the Environmental, Not Genetic, Effect on IQ. PLoS ONE 7:e30320 NICE guideline. Psychosis and Schizophrenia in Children and Young People. vol (2013) 24 (2013) Kumra S et al (1996) Childhood-onset schizophrenia: A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry. 10.1001/archpsyc.1996.01830120020005 Sporn AL et al (2007) Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry 46:1349–1356 Wellesley Wesley E et al (2021) Gender disparities in clozapine prescription in a cohort of treatment-resistant schizophrenia in the South London and Maudsley case register. Schizophr Res 232:68–76 Fulone I, Silva MT, Lopes LC (2021) Gender differences in the use of atypical antipsychotics in early-onset schizophrenia: a nationwide population-based study in Brazil. BMC Psychiatry 21:320 Cirulli G (2005) Clozapine prescribing in adolescent psychiatry: survey of prescribing practice in in-patient units. Psychiatr Bull 29:377–380 Fleischhacker WW, Uchida H (2014) Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol 17:1083–1093 Barnes TRE, Marder SR (2011) Principles of Pharmacological Treatment in Schizophrenia. In: Weinberger DR, Harrison PJ (eds) Schizophrenia. Wiley-Blackwell, Oxford, UK, pp 515–524. doi: 10.1002/9781444327298.ch24 . Recalt A (2022) Long-Term Physiological Harms of Exposure to Prescribed Psychotropic Drugs in Children Aged 6 to 12: a Population-Based Retrospective Cohort Study. University of California, Los Angeles Thorup A et al (2007) Gender Differences in Young Adults With First-Episode Schizophrenia Spectrum Disorders at Baseline in the Danish OPUS Study. J Nerv Ment Dis 195:396–405 Riecher-Rössler A, Häfner H (2000) Gender aspects in schizophrenia: bridging the border between social and biological psychiatry. Acta Psychiatr Scand Suppl 58–62. 10.1034/j.1600-0447.2000.00011.x Hasson R, Fine JG (2012) Gender differences among children with ADHD on continuous performance tests: a meta-analytic review. J Atten Disord 16:190–198 Lau TWI et al (2021) Gender differences in externalizing and internalizing problems in Singaporean children and adolescents with attention-deficit/hyperactivity disorder. Child Adolesc Psychiatry Ment Health 15:3 Gaub M, Carlson CL (1997) Gender differences in ADHD: a meta-analysis and critical review. J Am Acad Child Adolesc Psychiatry 36:1036–1045 Biederman J et al (2002) Influence of gender on attention deficit hyperactivity disorder in children referred to a psychiatric clinic. Am J Psychiatry 159:36–42 Abikoff HB et al (2002) Observed classroom behavior of children with ADHD: relationship to gender and comorbidity. J Abnorm Child Psychol 30:349–359 Ghanizadeh A, Mohammadi MR, Moini R (2008) Comorbidity of psychiatric disorders and parental psychiatric disorders in a sample of Iranian children with ADHD. J Atten Disord 12:149–155 Levy F, Hay DA, Bennett KS, McStephen M (2005) Gender differences in ADHD subtype comorbidity. J Am Acad Child Adolesc Psychiatry 44:368–376 Gary FA (2005) Stigma: barrier to mental health care among ethnic minorities. Issues Ment Health Nurs 26:979–999 Mirza A, Birtel MD, Pyle M, Morrison AP (2019) Cultural Differences in Psychosis: The Role of Causal Beliefs and Stigma in White British and South Asians. J Cross-Cult Psychol 50:441–459 Brody LR, Hall JA (2008) Gender and Emotion in Context. in Zahn-Waxler C (2000) The Development of Empathy, Guilt, and Internalization of Distress. In: Davidson RJ (ed) Anxiety, Depression, and Emotion. Oxford University Press, pp 222–265. doi: 10.1093/acprof:oso/9780195133585.003.0011 . CAPLAN R, GUTHRIE D, FISH B, TANGUAY PE (1989) DAVID-LANDO, G. The Kiddie Formal Thought Disorder Rating Scale: Clinical Assessment, Reliability, and Validity. J Am Acad Child Adolesc Psychiatry. 10.1097/00004583-198905000-00018 Additional Declarations No competing interests reported. Supplementary Files suppldoc.docx Cite Share Download PDF Status: Published Journal Publication published 27 Oct, 2025 Read the published version in European Child & Adolescent Psychiatry → Version 1 posted Editorial decision: Revision requested 12 May, 2025 Editor assigned by journal 02 May, 2025 Submission checks completed at journal 02 May, 2025 First submitted to journal 01 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6574363","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":452763963,"identity":"c9db298f-fff9-4acf-bdab-aabba3d7635e","order_by":0,"name":"Mitra S Sato","email":"","orcid":"","institution":"Imperial College London","correspondingAuthor":false,"prefix":"","firstName":"Mitra","middleName":"S","lastName":"Sato","suffix":""},{"id":452763964,"identity":"121771c5-e194-419c-90dc-768ec2a69e94","order_by":1,"name":"Anthony James","email":"","orcid":"","institution":"University of Oxford, Warneford Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"James","suffix":""},{"id":452763965,"identity":"3c633128-09d5-4186-bf3f-8de063d4f040","order_by":2,"name":"Marinos Kyriakopoulos","email":"","orcid":"","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Marinos","middleName":"","lastName":"Kyriakopoulos","suffix":""},{"id":452763966,"identity":"a2898594-e1cd-4adc-bbca-080689720713","order_by":3,"name":"Anna C Need","email":"data:image/png;base64,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","orcid":"","institution":"Imperial College London","correspondingAuthor":true,"prefix":"","firstName":"Anna","middleName":"C","lastName":"Need","suffix":""}],"badges":[],"createdAt":"2025-05-01 22:08:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6574363/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6574363/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00787-025-02895-3","type":"published","date":"2025-10-27T15:58:41+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82615374,"identity":"c76ac8bb-9373-4aa0-8596-fa1ea50e359b","added_by":"auto","created_at":"2025-05-13 11:35:47","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":52662,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAncestry distribution\u003c/strong\u003e: Ethnic minorities are overrepresented, Europeans underrepresented compared to the UK census. Percentages above bars.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6574363/v1/d995910e97179a49db621ca6.jpg"},{"id":82615377,"identity":"54c4f85f-4a7e-406b-af42-d6ba23d59d99","added_by":"auto","created_at":"2025-05-13 11:35:47","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":73101,"visible":true,"origin":"","legend":"\u003cp\u003ePremorbid and post-diagnosis IQ distribution. (A) distribution of premorbid estimated IQ categories based on school records. (B) distribution of post-diagnosis IQ scores (n=24). (C) post-diagnosis IQ categories. *ID= see data collection section.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6574363/v1/cc6f2253239f70ab7c719d47.jpg"},{"id":82615375,"identity":"0b4e9348-4e08-4413-afb5-1a9ca244978d","added_by":"auto","created_at":"2025-05-13 11:35:47","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34956,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAge at diagnosis by sex.\u003c/strong\u003e Individual ages at diagnosis, stratified by sex. Black diamonds indicate mean ages (male: 10.6 years; female: 11.9 years). The difference is statistically significant (p = 0.037, Mann-Whitney U-test).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6574363/v1/1e66bee74c1c0ee352d835d0.jpg"},{"id":82615376,"identity":"852646a4-c020-4fb1-a191-ef38250b5057","added_by":"auto","created_at":"2025-05-13 11:35:47","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":62181,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of diagnostic delays. \u003c/strong\u003eThe number of individuals by diagnostic delays in years.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6574363/v1/d7862068f53902f4d8fea10f.jpg"},{"id":95040056,"identity":"cfd272e8-4be2-4dbd-b7fc-537f76367e3c","added_by":"auto","created_at":"2025-11-03 16:08:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":921229,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6574363/v1/75a55d29-ccbb-4c15-8029-450a2146a314.pdf"},{"id":82615379,"identity":"361dc039-bdc2-4b84-b253-a7f4c388d85e","added_by":"auto","created_at":"2025-05-13 11:35:47","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":301251,"visible":true,"origin":"","legend":"","description":"","filename":"suppldoc.docx","url":"https://assets-eu.researchsquare.com/files/rs-6574363/v1/2bd8f1a604fdf2cfbb331aad.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Childhood Onset Psychosis: A large UK case series","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChildhood-Onset Psychosis (COP), defined by the onset of psychosis by age 13 represents a difficult diagnostic and treatment challenge\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. It generally is accepted to have an incidence of less than 1 in 500,000 in the UK\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. It is defined by the same diagnostic criteria as adult-onset schizophrenia (AOS)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e but its early manifestation introduces unique clinical and prognostic complexities\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e–\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe symptomatology of COP is notably severe, with auditory hallucinations being a prominent feature\u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Visual and tactile hallucinations, delusions, thought disorder, and negative symptoms such as affective flattening and withdrawal are also significant\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e–\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. These symptoms alongside suicidal behaviours often lead to hospitalisation\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDiagnosing COP is difficult\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Hallucinations can be part of the normal developmental spectrum\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, yet they are also present in a range of conditions including autism\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e and affective disorders\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. A key to diagnosis lies in the persistence and severity of symptoms and their impact on function\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e–\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, a task complicated by the developmental variability in symptom expression across childhood and adolescence\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe rarity of COP is reflected in the lack of large, representative cohorts. The National Institute of Mental Health's (NIMH) cohort of childhood-onset schizophrenia (COS) cases\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, which used stringent criteria for recruitment, has yielded invaluable insights but also excluded a substantial portion of the COP population, particularly those with intellectual disabilities. A study from Nigeria\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e included 33 COP cases, while other case series report much smaller numbers\u003csup\u003e\u003cspan additionalcitationids=\"CR37 CR38\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e–\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. A series of genomic findings from COS patients have been reported across different studies, including over 80 cases from the US\u003csup\u003e\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e–\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e, 37 from Israel\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e and 10 from China\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e, however, no overview of clinical and demographic characteristics were provided.\u003c/p\u003e \u003cp\u003eComorbid conditions are frequent in COP\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e, ranging from mood disorders\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e and ADHD\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e to autism spectrum disorder\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e to profound language and motor developmental delays\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Such comorbidities lead to phenotypic heterogeneity and are prognostically significant, with earlier and more severe premorbid disturbances correlating with worse outcomes\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Neurobiologically, COP is continuous with AOS\u003csup\u003e\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, sharing similar structural brain abnormalities and cognitive deficits\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. COP, however, has more pronounced cognitive and developmental disturbances\u003csup\u003e\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe treatment for COP is complex\u003csup\u003e\u003cspan additionalcitationids=\"CR49\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e–\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. Antipsychotics are only partly effective and have adverse effects\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e. The second-generation antipsychotics, with reduced extrapyramidal side effects\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e, carry risks of metabolic and cardiovascular complications\u003csup\u003e\u003cspan additionalcitationids=\"CR55 CR56\" citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e–\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. This necessitates careful monitoring and underscores the need for comprehensive treatment plans incorporating both pharmacological and psychosocial interventions\u003csup\u003e\u003cspan additionalcitationids=\"CR49\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e–\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe heterogeneity of COP in the clinic, in contrast to the careful curated cohorts that are used for clinical research, combined with the likelihood that any individual clinician may only see one or a few COP patients in their career, means that the diagnosis and treatment of COP cannot easily be guided by published literature. This paper aims to help fill this gap by providing data from a cohort of patients diagnosed with COP in the UK.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003eStudy Design\u003c/p\u003e\u003cp\u003eFamilies with children diagnosed with psychotic disorders by age 13 were recruited post-diagnosis from Child and Adolescent Mental Health Services (CAMHS) through clinician referrals. Siblings, both parents and any other affected family members were included where possible. Ethical approval was granted (REC reference 15/SC/0206; IRAS ID 170402).\u003c/p\u003e\u003cp\u003eInclusion and Exclusion Criteria\u003c/p\u003e\u003cp\u003eAll participants provided consent if over 16 and assent if under 16 with parental consent. The study obtained ethical approval to include adult relatives (including parents) with intellectual disabilities or other conditions affecting informed consent. Exclusion criteria included prematurity (birth weight \u0026lt; 1500g), brain injury (e.g., perinatal hypoxia), substance abuse prior to diagnosis and known medical conditions or severe abuse that could explain the psychosis.\u003c/p\u003e\u003cp\u003eData Collection\u003c/p\u003e\u003cp\u003eData collected from consented participants included:\u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cem\u003eMedical Records\u003c/em\u003e: Psychiatric, neurological, and general health history. Diagnoses were made in accordance with the Multiaxial ICD-10 classification of child and adolescent psychiatric disorders (World Health Organization, 1996) and confirmed as part of this study using the ICD-10 diagnostic criteria for research (World Health Organization, 1993).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cem\u003eCognitive Testing\u003c/em\u003e: Post-diagnosis IQ data were obtained either from descriptive entries in medical records or from Wechsler Abbreviated Scale of Intelligence II (WASI-II) assessments conducted as part of this study. For participants with documented IQ test results in their medical records the available data was used directly. For participants assessed with the WASI-II, the standard WASI-II classification ranges were applied. Specifically, scores below 70 categorised as ‘extremely low’ were referred to as “ID”.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cem\u003eInterviews\u003c/em\u003e: Developmental history, family psychiatric history, and environmental factors.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll analyses were performed using R (version 4.2.2). Missing data were excluded, and for statistical tests significance was set at p \u0026lt; 0.05. Visualisations were created using ggplot2 and related R packages.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDemographics\u003c/p\u003e \u003cp\u003eA total of 105 individuals were recruited including 39 probands with COP. Demographic characteristics are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Males were diagnosed at a significantly younger age (10.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 years) than females (11.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 years; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037). Onset type also differed significantly between sexes (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046) with females more likely to present with acute onset (61%) compared to males (44%). Ancestry and immigration status did not significantly differ between sexes (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.256 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.613, respectively).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eDemographics of the cohort.\u003c/b\u003e Continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) (Mann-Whitney U test), categorical as frequencies (%) (Chi-squared). \"Mixed Afr and Eur\" refers to one European and one African parent. \"Other\" includes Middle Eastern, East Asian and Hispanic. Significant results marked *.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMales (n\u0026thinsp;=\u0026thinsp;16, 41%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemales (n\u0026thinsp;=\u0026thinsp;23, 59%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value (test)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean age at diagnosis (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.037* (Mann-Whitney U)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnset type (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.046* (χ\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsidious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAncestry (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.256 (χ\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouth Asian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfrican\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed Afr and Eur\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmigration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.613 (χ\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst generation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecond generation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22(56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-immigrant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9(39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14(36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe cohort's ancestry composition deviates from the UK population (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDiagnoses\u003c/p\u003e \u003cp\u003eAll probands had a primary psychotic disorder diagnosis and were hospitalised at least once. The split of diagnoses, along with the prevalence of positive and negative symptoms is detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDiagnoses and symptom frequencies. Diagnoses and symptoms stratified by sex and presented as frequency (n) and proportion (%) of the total count (n\u0026thinsp;=\u0026thinsp;39).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSub-category\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrequency(n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProportion(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMales(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemales(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eDiagnoses\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther nonorganic psychotic disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSchizoaffective disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSchizophrenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBipolar disorder with psychotic symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDelusional disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDepression with psychotic symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSymptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive Symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"9\" rowspan=\"10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eHallucinations (all types)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"9\" nameend=\"c6\" namest=\"c5\" rowspan=\"10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAuditory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVisual\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOlfactory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSomatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTactile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eDelusions (all types)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCapgras\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePersecutory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrandiose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative Symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBehavioural difficulties\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"3\" nameend=\"c6\" namest=\"c5\" rowspan=\"4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSleep disturbances\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnxiety\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSuicidal ideation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFamily history\u003c/p\u003e \u003cp\u003eMost cases were sporadic, with no first-degree relative diagnosed with a psychiatric illness (22/39, 56%). Those with at least one parent diagnosed with schizophrenia accounted for 8/39 (21%) while the remaining 9/39 (23%) had a parent with a psychiatric illness other than schizophrenia, including depression (n\u0026thinsp;=\u0026thinsp;7) and anxiety disorder (n\u0026thinsp;=\u0026thinsp;2). Family history was further analysed (Suppl. Figure\u0026nbsp;1). There was no significant difference when stratified by diagnostic age group (c\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.09, p\u0026thinsp;=\u0026thinsp;0.95) or by sex (c\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.01, p\u0026thinsp;=\u0026thinsp;0.99).\u003c/p\u003e \u003cp\u003eIntellectual functioning\u003c/p\u003e \u003cp\u003ePremorbid IQ was unavailable for most cases therefore school reports and parental interviews were used to categorise them as having average, above average or below average cognitive functioning (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Post-diagnosis IQ scores were available for 24 probands, assessed using prior medical records or WASI-II at recruitment (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB-C). IQ data for 15 probands were unavailable due to missing records or testing constraints. Post-diagnosis IQ was significantly lower in individuals with premorbid developmental delay (t-test, p\u0026thinsp;=\u0026thinsp;0.033, suppl. Figure\u0026nbsp;2A) but not significantly impacted by comorbidities (suppl. Figure\u0026nbsp;2B). Speech and language delay were present in 46% (n\u0026thinsp;=\u0026thinsp;18) probands.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAntipsychotic treatment\u003c/p\u003e \u003cp\u003eAt the time of recruitment, all probands were taking antipsychotics, with 5 individuals (12.8%) receiving two concurrently. Clozapine was most frequently prescribed(n\u0026thinsp;=\u0026thinsp;14, 35.9%), and appeared more frequent in probands diagnosed at an older age (Suppl. Table\u0026nbsp;1); however, this was not statistically significant (χ\u0026sup2;=1.18, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.55). Olanzapine was prescribed in 9 cases (23.1%), followed by risperidone (6 probands, 15.4%), and aripiprazole and quetiapine, each in 4 probands (10.3%). Mood stabilisers were recorded in 6 individuals (15.4%), including sodium valproate, lithium carbonate, and carbamazepine. Antidepressants were prescribed in 7 cases (17.9%), with sertraline and fluoxetine most frequently represented. Sleep aids, primarily melatonin, were used in 6 probands (15.4%). Adjunctive therapies were common, including antidiabetic medications (5 cases, 12.8%), laxatives (3 cases, 7.7%), anticholinergics (3 cases, 7.7%), and vitamin supplements. These findings highlight the pharmacological complexity often required in this population.\u003c/p\u003e \u003cp\u003eAge and diagnostic delay\u003c/p\u003e \u003cp\u003eMales were diagnosed significantly earlier than females (p\u0026thinsp;=\u0026thinsp;0.037, Mann-Whitney U; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), though symptom onset ages showed no sex differences (mean: 9.4 years; p\u0026thinsp;=\u0026thinsp;0.63). This suggests possible diagnostic delays may underlie sex differences in diagnostic age. The majority of the cohort were diagnosed within two years of symptom onset (n\u0026thinsp;=\u0026thinsp;23, 59%) though delays of up to eight years occurred (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Prolonged delays (\u0026ge;\u0026thinsp;5 years, n\u0026thinsp;=\u0026thinsp;7) were more common among females.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study presents a large case series of childhood onset psychosis collected in England between 2016\u0026ndash;2019. Compared with published incidence estimates from the only other UK study\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, which identified 8 confirmed cases per year, our cohort of 39 cases over 3 years (~\u0026thinsp;13 cases per year) suggests a high level of case ascertainment and likely captures the majority of new incidences. Although not all patients were newly diagnosed at recruitment, the scale and breadth of identification \u0026ndash; through national inpatient services and outpatient referrals \u0026ndash; make this one of the largest datasets assembled for this rare condition nationally. Unlike other studies\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, this dataset prioritises inclusivity and reflects childhood psychosis as seen in community and clinical settings. While the size of the cohort highlights the scale of recruitment effort, it remains likely that some cases were not identified due to underdiagnosis, challenges in clinical recognition, delayed referrals, or barriers to research participation, as discussed below. Despite these limitations, this cohort provides valuable insight into better understanding of COP within the UK healthcare and population setting.\u003c/p\u003e \u003cp\u003eThe cohort\u0026rsquo;s ethnic makeup differs from the general UK population\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e, with White British underrepresented (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and a notable presence of minority European groups. Studies show that white ethnic minorities face a 50% increased risk of psychosis compared to White British individuals likely due to migration stress and socioeconomic challenges\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e,\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e. Notably, nearly a third of the cohort is of South Asian ancestry, consistent with a 2\u0026ndash;4 times higher risk of psychosis reported in this group\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e. Almost half the cohort are reportedly first- or second-generation immigrant families, reflecting a substantial representation of multicultural households. Among first-generation families, early childhood migration (before age 2) was observed in 2/3, a critical period linked to increased psychosis risk\u003csup\u003e\u003cspan additionalcitationids=\"CR62 CR63\" citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e. Second-generation immigrants, comprising over a third of the cohort, showed a higher prevalence of psychosis, aligning with studies indicating a twofold increased risk compared to non-immigrants\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e,\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e. While these patterns are consistent with known risk factors for psychosis, comparisons with the general population are made with caution. This cohort was not randomly sampled and factors such as being diagnosed, healthcare and research participation access may have influenced the demographic distribution. However, the alignment of the observed differences with existing epidemiological evidence underscores the relevance of ancestry and migration-related exposures in COP.\u003c/p\u003e \u003cp\u003eFamily history was broadly similar across the cohort (Suppl. Figure\u0026nbsp;1) with 44% (17/39) reporting a parent with schizophrenia or another psychiatric illness. These exceed the 33% previously reported for COS\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e, likely reflecting the broader inclusion criteria in this study. Most cases (56%) were sporadic or involved extended family neuropsychiatric histories, likely reflecting a combination of complex genetic and socioenvironmental contributors\u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCognitive decline emerged as a key theme with indications that participants might perform more poorly on IQ assessments following diagnosis. Males showed greater decline than females (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) with larger drops in those with developmental delays (Suppl. Figure\u0026nbsp;2A), consistent with the literature\u003csup\u003e\u003cspan additionalcitationids=\"CR70\" citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e. Poorer premorbid functioning, linked to worse prognoses\u003csup\u003e\u003cspan additionalcitationids=\"CR73 CR74\" citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e may explain these findings. This pattern aligns with reductions in global cognitive functioning seen in COS\u003csup\u003e\u003cspan additionalcitationids=\"CR77\" citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u003c/sup\u003e, attributed by the NIMH group to disrupted brain connectively, particularly in social-cognitive and sensorimotor regions\u003csup\u003e\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e. However, interpretation of the IQ scores is constrained by methodological limitations. Given the scores were derived from medical records or home-based assessments, reliability could potentially be impacted\u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u003c/sup\u003e. Additionally, the lack of a systematic socio-economic status evaluation in this cohort, a known influence on IQ measurement\u003csup\u003e\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u003c/sup\u003e, further restricts conclusions.\u003c/p\u003e \u003cp\u003eClozapine was prescribed to 38.5% (n\u0026thinsp;=\u0026thinsp;15) of the cohort following inadequate responses to at least two antipsychotics, consistent with its role as a third-line treatment\u003csup\u003e\u003cspan additionalcitationids=\"CR83\" citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u003c/sup\u003e. Females were twice as likely as males to receive clozapine particularly those with diagnostic delays potentially due to their older age at diagnosis. Adult studies show lower clozapine rates in females\u003csup\u003e\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u003c/sup\u003e, while adolescent studies report no gender disparities\u003csup\u003e\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u003c/sup\u003e. Clozapine\u0026rsquo;s use in youth is approached cautiously due to side effects with 40% of UK psychiatrists avoiding it in under 18s\u003csup\u003e\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e\u003c/sup\u003e (Suppl. Table\u0026nbsp;1). Polypharmacy was common, with antidepressants (e.g., sertraline) and mood stabilisers (e.g., sodium valproate) prescribed to manage comorbid symptoms, possibly aligning with practices aimed at improving symptom management\u003csup\u003e\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e,\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e\u003c/sup\u003e. Despite limited data in the younger populations, there are reports of increased risk of adverse drug reactions with psychotropic polypharmacy\u003csup\u003e\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e\u003c/sup\u003e. These findings reflect the complexity of pharmacological management in COP and underscore the need for integrated treatment approaches. While clozapine remains a key option for treatment-resistant cases\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e, its use should be complemented by psychological interventions such as cognitive-behavioural therapy (CBT), family therapy, and educational support\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDiagnostic patterns highlight gender differences, with females more often diagnosed at age 13, while diagnoses before this age were evenly distributed. In younger probands, males frequently presented with externalising behaviours, such as ADHD or learning disabilities, which likely drew earlier clinical attention\u003csup\u003e\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e\u003c/sup\u003e. In contrast, females exhibited mood- and anxiety-related symptoms that align with literature on internalising presentations but may delay any diagnosis of schizophrenia if misattributed to stress or mood disorders\u003csup\u003e\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e\u003c/sup\u003e.The broader symptomatology observed in females at ages 10\u0026ndash;11, includes ASD, anxiety, and OCD. The literature\u003csup\u003e\u003cspan additionalcitationids=\"CR94 CR95 CR96 CR97 CR98\" citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e\u003c/sup\u003e suggests externalising behaviours in males prompt earlier clinical attention, while females\u0026rsquo; internalising symptoms and better social functioning may delay diagnosis.\u003c/p\u003e \u003cp\u003eStigma around mental illness, particularly in minority communities\u003csup\u003e\u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e\u003c/sup\u003e, can delay diagnosis as families may avoid seeking help or attribute symptoms to non-medical causes. In two cases, care was initially sought abroad due to cultural or religious beliefs delaying local treatment. South Asian ancestry was similarly represented across age groups with females consistently outnumbering males. Cultural stigma, especially in South Asian families may explain the older diagnostic age for some probands aligning with reports of mental health stigma in this community\u003csup\u003e\u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e\u003c/sup\u003e. More broadly, cultural norms often socialise females to mask emotions whilst males express visible behaviours\u003csup\u003e\u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e,\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e\u003c/sup\u003e, potentially contributing to later diagnoses in the females in this study.\u003c/p\u003e \u003cp\u003eThis study's greatest strength lies in its inclusivity, distinguishing it from others that often exclude individuals with intellectual disabilities or non-English speakers\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. By capturing the majority of families with affected children we ensured representation of groups frequently left out of research. Ethical approval allowed personal consultees to provide consent for participants with intellectual disabilities. Language barriers were addressed through interpreters and translated materials, and home visits were conducted nationwide for families unable to travel to reduce burden. Instead of lengthy diagnostic tools like K-SADs\u003csup\u003e\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e\u003c/sup\u003e, targeted questions and use of medical records ensured efficient data collection, with follow-ups conducted when one parent was unavailable. These efforts produced a robust, diverse dataset \u0026ndash; setting a new standard for inclusivity in research.\u003c/p\u003e \u003cp\u003eHowever, there are several limitations. First, inconsistencies in IQ testing conducted at varying ages and under different conditions make it difficult to distinguish true cognitive decline from age-related differences in test performance. Second, while our inclusive recruitment approach is a strength, it may have impacted data quality. Efforts to address language barriers using interpreters and translated materials, while effective, risked losing subtle cultural nuances. Despite tailored questionnaires, this may have affected data granularity. Third, cultural factors, including varying parental beliefs about psychiatric symptoms, likely influenced symptom reporting and potentially reporting of relevant family history, introducing sociocultural variability into the dataset. Finally, the absence of standardised diagnostic interviews such as K-SADs may limit comparability with other studies. However, diagnostic stability was ensured as all had been CAMHS inpatients during their clinical care, had undergone multiple assessments by experienced clinicians and had diagnoses confirmed using operationalised diagnostic criteria.\u003c/p\u003e \u003cp\u003eIn conclusion, this study presents the largest and most ethnically diverse cohort of COP cases of unknown cause in the UK. By inclusively recruiting and excluding only cases with clear non-genetic causes, we likely captured the majority of affected families. Despite its diversity, the cohort\u0026rsquo;s clinical presentation aligns closely with global COP studies, reflecting consistent core clinical features across socially diverse populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eACN and TJ developed the study concept, wrote the original protocol and obtained ethical approval. TJ and MK identified eligible participants. MSS and ACN performed recruitment and collected data. MSS performed the data analysis, drafted the main manuscript and prepared all figures and tables. All authors reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank all participants and their families. Special thanks to Drs. Sumi Handy, Jane Whittaker, Tim Hawkins, Kouser Shaik, Amulya Nadkarni, Fiona Padgett, Morris Zwi, Gillian Rose, Jon Goldin, Nicoletta Gentili, Virginia Valle, Sarojeet Ganguly, Isabelle Ellory, Rajeev Biradar, Catherine O\u0026rsquo;Callahan, and Niloufar Mirhaghani for their efforts in identifying patients. We also thank the research management teams across all participating Trusts for their support, Dr Fotios Drenos for his helpful comments and support staff Armandina Almanza-Gutierrez, Claudia Adele, and Dominic Zimmerman from Imperial College London for their assistance during recruitment.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDriver DI, Thomas S, Gogtay N, Rapoport JL (2020) Childhood-Onset Schizophrenia and Early-onset Schizophrenia Spectrum Disorders: An Update. Child Adolesc Psychiatr Clin N Am. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.chc.2019.08.017\u003c/span\u003e\u003cspan address=\"10.1016/j.chc.2019.08.017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRapoport JL, Gogtay N (2011) Childhood onset schizophrenia: Support for a progressive neurodevelopmental disorder. Int J Dev Neurosci 29:251\u0026ndash;258\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsarnow JR (1994) \u003cem\u003eAnnotation: Childhood-Onset Schizophrenia\u003c/em\u003e. vol. 35 1345\u0026ndash;1371\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcClellan J, Werry J (1994) Practice parameters for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00004583-199406000-00002\u003c/span\u003e\u003cspan address=\"10.1097/00004583-199406000-00002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGochman P, Miller R, Rapoport JL (2011) Childhood-onset schizophrenia: The challenge of diagnosis. Curr Psychiatry Rep 13:321\u0026ndash;322\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTiffin PA, Kitchen CEW (2015) Incidence and 12-month outcome of childhood non-affective psychoses: British national surveillance study. Br J Psychiatry 206:517\u0026ndash;518\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHollis C, Rapoport J (2011) Child and Adolescent Schizophrenia. Schizophrenia: Third Ed. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/9781444327298.ch3\u003c/span\u003e\u003cspan address=\"10.1002/9781444327298.ch3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJacobsen LK, Rapoport JL, Research Update (1998) Childhood-onset Schizophrenia: Implications of Clinical and Neurobiological Research. J Child Psychol Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/1469-7610.00305\u003c/span\u003e\u003cspan address=\"10.1111/1469-7610.00305\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGordon CT et al (1994) Childhood-onset schizophrenia: An NIMH study in progress. Schizophr Bull. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/schbul/20.4.697\u003c/span\u003e\u003cspan address=\"10.1093/schbul/20.4.697\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlaghband-Rad J, Hamburger SD, Giedd JN, Frazier JA, Rapoport JL (1997) Childhood-onset schizophrenia: biological markers in relation to clinical characteristics. Am J Psychiatry 154:64\u0026ndash;68\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRUSSELL AT, BOTT L, SAMMONS C (1989) The Phenomenology of Schizophrenia Occurring in Childhood. J Am Acad Child Adolesc Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00004583-198905000-00017\u003c/span\u003e\u003cspan address=\"10.1097/00004583-198905000-00017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNicolson R (2000) Lessons from childhood-onset schizophrenia. Brain Res Rev 31:147\u0026ndash;156\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEggers C (1978) Course and prognosis of childhood schizophrenia. J Autism Child Schizophr. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/BF01550275\u003c/span\u003e\u003cspan address=\"10.1007/BF01550275\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEggers C (1989) Schizo-affective psychoses in childhood: A follow-up study. J Autism Dev Disord. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/BF02211850\u003c/span\u003e\u003cspan address=\"10.1007/BF02211850\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eALAGHBAND-RAD J et al (1995) Childhood-Onset Schizophrenia: The Severity of Premorbid Course. J Am Acad Child Adolesc Psychiatry 34:1273\u0026ndash;1283\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchaeffer JL, Ross RG (2002) Childhood-Onset Schizophrenia: Premorbid and Prodromal Diagnostic and Treatment Histories. J Am Acad Child Adolesc Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00004583-200205000-00011\u003c/span\u003e\u003cspan address=\"10.1097/00004583-200205000-00011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpencer EK, Campbell M (1994) Children with schizophrenia: Diagnosis, phenomenology, and pharmacotherapy. Schizophr Bull. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/schbul/20.4.713\u003c/span\u003e\u003cspan address=\"10.1093/schbul/20.4.713\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsarnow RF, Asarnow JR (1994) Childhood-onset schizophrenia: editors\u0026rsquo; introduction. Schizophr Bull 20:591\u0026ndash;597\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKOLVIN I (1971) Studies in the Childhood Psychoses: Diagnostic Criteria and Classification. Br J Psychiatry 118:381\u0026ndash;384\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKOLVIN I (1971) Studies in the Childhood Psychoses. \u003cem\u003eBr. J. Psychiatry\u003c/em\u003e 118, 381 LP \u0026ndash; 384\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGREEN WH et al (1984) A Comparison of Schizophrenic and Autistic Children. J Am Acad Child Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0002-7138(09)60317-4\u003c/span\u003e\u003cspan address=\"10.1016/S0002-7138(09)60317-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreen, W. \u0026amp; Padron-Gayol, M. Schizophrenia with childhood onset: a phenomenological study of 38 cases. \u003cem\u003e\u0026hellip; Acad. Child \u0026hellip;\u003c/em\u003e 31, 968\u0026ndash;976 (1992)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWerry JS, McClellan JM, Chard L (1991) Childhood and adolescent schizophrenic, bipolar, and schizoaffective disorders: a clinical and outcome study. J Am Acad Child Adolesc Psychiatry 30:457\u0026ndash;465\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng X et al (2021) Comparison of clinical characteristics and treatment efficacy in childhood-onset schizophrenia and adolescent-onset schizophrenia in mainland China: A retrospective study. Early Interv Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/eip.13121\u003c/span\u003e\u003cspan address=\"10.1111/eip.13121\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi Luzio M et al (2023) Clinical features and comorbidity in very early-onset schizophrenia: a systematic review. Front Psychiatry 14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorrell CU et al (2024) Identification and treatment of individuals with childhood-onset and early-onset schizophrenia. Eur Neuropsychopharmacol 82:57\u0026ndash;71\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDriver DI, Gogtay N, Rapoport JL (2013) Childhood onset schizophrenia and early onset schizophrenia spectrum disorders. Child Adolesc Psychiatr Clin N Am 22:539\u0026ndash;555\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHollis C (1995) Child and adolescent (juvenile onset) schizophrenia. A case control study of premorbid developmental impairments. Br J Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1192/bjp.166.4.489\u003c/span\u003e\u003cspan address=\"10.1192/bjp.166.4.489\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumra S et al (1998) Multidimensionally impaired disorder\u0026rsquo;: Is it a variant of very early- onset schizophrenia? J Am Acad Child Adolesc Psychiatry 37:91\u0026ndash;99\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDalhaug KC, Storvik K, Kildahl AN (2022) Undiagnosed Psychotic Disorder in Autistic Individuals with Intellectual Disabilities and Suspected Obsessive-Compulsive Disorder: An Explorative, Clinical Study. \u003cem\u003ehttps://doi.org\u003c/em\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e/10.1080/19315864\u003c/span\u003e\u003cspan address=\"http:///10.1080/19315864\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003cem\u003e2117880\u003c/em\u003e (2022) \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/19315864.2022.2117880\u003c/span\u003e\u003cspan address=\"10.1080/19315864.2022.2117880\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmericans N et al (2013) The ICD-10 Classification of Mental and Behavioural Disorders. IACAPAP E-Textb Child Adolesc Ment Health 55:135\u0026ndash;139\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBiedermann F, Fleischhacker WW (2016) Psychotic disorders in DSM-5 and ICD-11. CNS Spectr 21:349\u0026ndash;354\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAssociation AP (2013) \u003cem\u003eAmerican Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders Fifth Edition\u003c/em\u003e. \u003cem\u003eArlington\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1176/appi.books.9780890425596.744053\u003c/span\u003e\u003cspan address=\"10.1176/appi.books.9780890425596.744053\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKelleher I et al (2012) Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies. Psychol Med 42:1857\u0026ndash;1863\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkewole AO, Ogunwale A, Mosanya TJ, Ojo BM (2016) A 12 year chart review of childhood and adolescent onset psychosis at a Nigerian tertiary mental health facility. J Child Adolesc Ment Health 28:189\u0026ndash;197\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePantano T, Fu IL, Curatolo E, Martins CB, Elkis H (2016) Thought and language disorders in very early onset schizophrenia,schizoaffective disorder and bipolar disorder. Rev Psiquiatr Clin 43:67\u0026ndash;73\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRad F et al (2022) Diagnosis stability and outcome of psychotic episodes in a Romanian group of children and adolescents. Med (Baltim) 101:E30288\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGalitzer H et al (2021) Functional outcomes and patient satisfaction following inpatient treatment for childhood-onset schizophrenia spectrum disorders vs non-psychotic disorders in children in the United Kingdom. Early Interv Psychiatry 15:412\u0026ndash;419\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnagnostopoulou N, Kyriakopoulos M, Alba A (2019) Psychological interventions in psychosis in children and adolescents: a systematic review. Eur Child Adolesc Psychiatry 28:735\u0026ndash;746\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmedemark-Margulies N et al (2016) A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia. Mol Case Stud 2:a001008\u0026ndash;a001008\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrownstein CA et al (2016) 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 170:1165\u0026ndash;1173\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMavros CF et al (2018) De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report. BMC Med Genet. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12881-018-0711-9\u003c/span\u003e\u003cspan address=\"10.1186/s12881-018-0711-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlkelai A et al (2021) Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia. J Hum Genet 66:339\u0026ndash;343\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang H et al (2023) Comprehensive analysis of circRNA expression profile and circRNA-miRNA-mRNA network susceptibility to very early-onset schizophrenia. Schizophr Heidelb Ger 9:70\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDowns JM et al (2017) The Association Between Comorbid Autism Spectrum Disorders and Antipsychotic Treatment Failure in Early-Onset Psychosis. J Clin Psychiatry 78:e1233\u0026ndash;e1241\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRapoport J, Chavez A, Greenstein D, Addington A, Gogtay N (2009) Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry 48:10\u0026ndash;18\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePina-Camacho L, Parellada M, Kyriakopoulos M (2016) Autism spectrum disorder and schizophrenia: boundaries and uncertainties. BJPscyh Adv 22:316\u0026ndash;324\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsarnow JR, Tompson MC, McGrath EP, Annotation (2004) Childhood-onset schizophrenia: Clinical and treatment issues. J Child Psychol Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1469-7610.2004.00213.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1469-7610.2004.00213.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKasoff LI, Ahn K, Gochman P, Broadnax DD, Rapoport JL (2016) Strong Treatment Response and High Maintenance Rates of Clozapine in Childhood-Onset Schizophrenia. J Child Adolesc Psychopharmacol 26, cap.2015.0103-cap.2015.0103\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClark AF, Lewis SW (1998) Treatment of schizophrenia in childhood and adolescence. J Child Psychol Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1017/S0021963098003242\u003c/span\u003e\u003cspan address=\"10.1017/S0021963098003242\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGogtay N, Rapoport J (2008) Clozapine use in children and adolescents. Expert Opin Pharmacother. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1517/14656566.9.3.459\u003c/span\u003e\u003cspan address=\"10.1517/14656566.9.3.459\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrazier JA et al (1994) An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry 33:658\u0026ndash;663\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJames AC, Broome MR (2017) Antipsychotics in adolescent-onset psychosis: a work in progress. Lancet Psychiatry 4:e16\u0026ndash;e17\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNewcomer JW, Leucht S (2009) Metabolic adverse effects associated with antipsychotic medications. \u003cem\u003eBook Ch28\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorrell CU, Carlson HE (2006) Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry 45:771\u0026ndash;791\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorrell CU (2008) Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents. J Clin Psychiatry 69(Suppl 4):26\u0026ndash;36\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarrison-Woolrych ML (2007) Evaluating medicines: let\u0026rsquo;s use all the evidence. Med J Aust 186:662\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOffice for National Statistics (2011) Census Aggregate Data. \u003cem\u003eUK Data Serv.\u003c/em\u003e (2016)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirkbride JB et al (2008) Psychoses, ethnicity and socio-economic status. Br J Psychiatry J Ment Sci 193:18\u0026ndash;24\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZolkowska K, Cantor-Graae E, McNeil TF (2001) Increased rates of psychosis among immigrants to Sweden: is migration a risk factor for psychosis? Psychol Med 31:669\u0026ndash;678\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnderson KK, Cheng J, Susser E, McKenzie KJ, Kurdyak P (2015) Incidence of psychotic disorders among first-generation immigrants and refugees in Ontario. CMAJ Can Med Assoc J J Assoc Medicale Can 187:E279\u0026ndash;E286\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVeling W, Hoek HW, Selten J-P, Susser E (2011) Age at migration and future risk of psychotic disorders among immigrants in the Netherlands: a 7-year incidence study. Am J Psychiatry 168:1278\u0026ndash;1285\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHowes OD, Murray RM (2014) Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet Lond Engl 383:1677\u0026ndash;1687\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBentall RP, Wickham S, Shevlin M, Varese F (2012) 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\u0026ndash;740\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourque F, van der Ven E, Malla A (2011) A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants. Psychol Med 41:897\u0026ndash;910\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFossion P et al (2002) Psychiatric disorders and social characteristics among second-generation Moroccan migrants in Belgium: an age-and gender-controlled study conducted in a psychiatric emergency department. Eur Psychiatry J Assoc Eur Psychiatr 17:443\u0026ndash;450\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsarnow RF et al (2001) Schizophrenia and schizophrenia-spectrum personality disorders in the first-degree relatives of children with schizophrenia: The UCLA Family Study. Arch Gen Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/archpsyc.58.6.581\u003c/span\u003e\u003cspan address=\"10.1001/archpsyc.58.6.581\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOwen MJ, Sawa A, Mortensen PB (2016) Schizophrenia Lancet. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(15)01121-6\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(15)01121-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrd\u0026oacute;\u0026ntilde;ez AE et al (2016) Lack of Gender-Related Differences in Childhood-Onset Schizophrenia. J Am Acad Child Adolesc Psychiatry 55:792\u0026ndash;799\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSporn AL et al (2004) Pervasive developmental disorder and childhood-onset schizophrenia: Comorbid disorder or a phenotypic variant of a very early onset illness? Biol Psychiatry 55:989\u0026ndash;994\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoss RG, Heinlein S, Tregellas H (2006) High rates of comorbidity are found in childhood-onset schizophrenia. Schizophr Res 88:90\u0026ndash;95\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStentebjerg-Olesen M, Pagsberg AK, Fink-Jensen A, Correll CU, Jeppesen P (2016) Clinical characteristics and predictors of outcome of schizophrenia-spectrum psychosis in children and adolescents: A systematic review. J Child Adolesc Psychopharmacol. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1089/cap.2015.0097\u003c/span\u003e\u003cspan address=\"10.1089/cap.2015.0097\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlack K et al (2001) Duration of untreated psychosis predicts treatment outcome in an early psychosis program. Schizophr Res. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0920-9964(00)00144-4\u003c/span\u003e\u003cspan address=\"10.1016/S0920-9964(00)00144-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDone DJ, Crow TJ, Johnstone EC, Sacker A (1994) Childhood antecedents of schizophrenia and affective illness: Social adjustment at ages 7 and 11. \u003cem\u003eBMJ\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmj.309.6956.699\u003c/span\u003e\u003cspan address=\"10.1136/bmj.309.6956.699\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJones P, Murray R, Jones P, Rodgers B, Marmot M (1994) Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(94)90569-X\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(94)90569-X\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmita A et al (2025) Neurocognitive dysfunctions in childhood-onset schizophrenia: A systematic review. Schizophr Res Cogn 40:100342\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrangou S (2010) Cognitive function in early onset schizophrenia: a selective review. Front Hum Neurosci 3:79\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBedwell JS et al (1996) 156 Why Does Postpsychotic IQ Decline in Childhood-Onset Schizophrenia? \u003cem\u003ehttps://doi.org\u003c/em\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e/10.1176/ajp.156.12\u003c/span\u003e\u003cspan address=\"http:///10.1176/ajp.156.12\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 1996\u0026ndash;1997 (1999)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerman RA et al (2016) Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhoodonset schizophrenia. Brain. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/brain/awv306\u003c/span\u003e\u003cspan address=\"10.1093/brain/awv306\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcKinney WS, Williford DN, Abbeduto L, Schmitt LM (2024) The impact of social-environmental factors on IQ in syndromic intellectual developmental disabilities. J Clin Transl Sci 8:e59\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHanscombe KB et al (2012) Socioeconomic Status (SES) and Children\u0026rsquo;s Intelligence (IQ): In a UK-Representative Sample SES Moderates the Environmental, Not Genetic, Effect on IQ. PLoS ONE 7:e30320\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNICE guideline. Psychosis and Schizophrenia in Children and Young People. vol (2013) 24 (2013)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumra S et al (1996) Childhood-onset schizophrenia: A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/archpsyc.1996.01830120020005\u003c/span\u003e\u003cspan address=\"10.1001/archpsyc.1996.01830120020005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSporn AL et al (2007) Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry 46:1349\u0026ndash;1356\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWellesley Wesley E et al (2021) Gender disparities in clozapine prescription in a cohort of treatment-resistant schizophrenia in the South London and Maudsley case register. Schizophr Res 232:68\u0026ndash;76\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFulone I, Silva MT, Lopes LC (2021) Gender differences in the use of atypical antipsychotics in early-onset schizophrenia: a nationwide population-based study in Brazil. BMC Psychiatry 21:320\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCirulli G (2005) Clozapine prescribing in adolescent psychiatry: survey of prescribing practice in in-patient units. Psychiatr Bull 29:377\u0026ndash;380\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleischhacker WW, Uchida H (2014) Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol 17:1083\u0026ndash;1093\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarnes TRE, Marder SR (2011) Principles of Pharmacological Treatment in Schizophrenia. In: Weinberger DR, Harrison PJ (eds) Schizophrenia. Wiley-Blackwell, Oxford, UK, pp 515\u0026ndash;524. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/9781444327298.ch24\u003c/span\u003e\u003cspan address=\"10.1002/9781444327298.ch24\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRecalt A (2022) Long-Term Physiological Harms of Exposure to Prescribed Psychotropic Drugs in Children Aged 6 to 12: a Population-Based Retrospective Cohort Study. University of California, Los Angeles\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThorup A et al (2007) Gender Differences in Young Adults With First-Episode Schizophrenia Spectrum Disorders at Baseline in the Danish OPUS Study. J Nerv Ment Dis 195:396\u0026ndash;405\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiecher-R\u0026ouml;ssler A, H\u0026auml;fner H (2000) Gender aspects in schizophrenia: bridging the border between social and biological psychiatry. Acta Psychiatr Scand Suppl 58\u0026ndash;62. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1034/j.1600-0447.2000.00011.x\u003c/span\u003e\u003cspan address=\"10.1034/j.1600-0447.2000.00011.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHasson R, Fine JG (2012) Gender differences among children with ADHD on continuous performance tests: a meta-analytic review. J Atten Disord 16:190\u0026ndash;198\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLau TWI et al (2021) Gender differences in externalizing and internalizing problems in Singaporean children and adolescents with attention-deficit/hyperactivity disorder. Child Adolesc Psychiatry Ment Health 15:3\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaub M, Carlson CL (1997) Gender differences in ADHD: a meta-analysis and critical review. J Am Acad Child Adolesc Psychiatry 36:1036\u0026ndash;1045\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBiederman J et al (2002) Influence of gender on attention deficit hyperactivity disorder in children referred to a psychiatric clinic. Am J Psychiatry 159:36\u0026ndash;42\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbikoff HB et al (2002) Observed classroom behavior of children with ADHD: relationship to gender and comorbidity. J Abnorm Child Psychol 30:349\u0026ndash;359\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhanizadeh A, Mohammadi MR, Moini R (2008) Comorbidity of psychiatric disorders and parental psychiatric disorders in a sample of Iranian children with ADHD. J Atten Disord 12:149\u0026ndash;155\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevy F, Hay DA, Bennett KS, McStephen M (2005) Gender differences in ADHD subtype comorbidity. J Am Acad Child Adolesc Psychiatry 44:368\u0026ndash;376\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGary FA (2005) Stigma: barrier to mental health care among ethnic minorities. Issues Ment Health Nurs 26:979\u0026ndash;999\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMirza A, Birtel MD, Pyle M, Morrison AP (2019) Cultural Differences in Psychosis: The Role of Causal Beliefs and Stigma in White British and South Asians. J Cross-Cult Psychol 50:441\u0026ndash;459\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrody LR, Hall JA (2008) Gender and Emotion in Context. in\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZahn-Waxler C (2000) The Development of Empathy, Guilt, and Internalization of Distress. In: Davidson RJ (ed) Anxiety, Depression, and Emotion. Oxford University Press, pp 222\u0026ndash;265. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/acprof:oso/9780195133585.003.0011\u003c/span\u003e\u003cspan address=\"10.1093/acprof:oso/9780195133585.003.0011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCAPLAN R, GUTHRIE D, FISH B, TANGUAY PE (1989) DAVID-LANDO, G. The Kiddie Formal Thought Disorder Rating Scale: Clinical Assessment, Reliability, and Validity. J Am Acad Child Adolesc Psychiatry. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00004583-198905000-00018\u003c/span\u003e\u003cspan address=\"10.1097/00004583-198905000-00018\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-child-and-adolescent-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ecap","sideBox":"Learn more about [European Child \u0026 Adolescent Psychiatry](http://link.springer.com/journal/787)","snPcode":"787","submissionUrl":"https://submission.nature.com/new-submission/787/3","title":"European Child \u0026 Adolescent Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Childhood onset psychosis (COP), childhood onset schizophrenia (COS), young onset, diverse, comorbid neurodevelopmental disorders, treatment resistant.","lastPublishedDoi":"10.21203/rs.3.rs-6574363/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6574363/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChildhood-Onset Psychosis (COP) is a rare and severe variant of schizophrenia, with a UK incidence of ~\u0026thinsp;1 in 500,000. This paper presents the largest UK case series of COP, comprising 39 families (105 individuals) recruited between 2016 and 2019. It is also the most ethnically diverse collection of COP cases worldwide, with 36% European ancestry, 23% South Asian, 18% African, 10% Mixed ancestry and 13% Other. All probands were hospitalised and diagnosed with a psychotic disorder by age 13, including schizoaffective disorder, paranoid schizophrenia, childhood-onset schizophrenia and other nonorganic psychotic disorders. The cohort had a male-to-female ratio of 1:1.4, with females diagnosed at a higher mean age (11 years 9 months) than males (10 years 6 months). While 54% of probands had no reported first-degree family history of psychiatric illness, 59% presented with comorbid neurodevelopmental conditions. Approximately one-third were treated with clozapine, reflecting the severity and treatment resistance of the cases.\u003c/p\u003e","manuscriptTitle":"Childhood Onset Psychosis: A large UK case series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 11:35:42","doi":"10.21203/rs.3.rs-6574363/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-12T19:56:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-02T16:41:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-02T16:40:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Child \u0026 Adolescent Psychiatry","date":"2025-05-01T21:52:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-child-and-adolescent-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ecap","sideBox":"Learn more about [European Child \u0026 Adolescent Psychiatry](http://link.springer.com/journal/787)","snPcode":"787","submissionUrl":"https://submission.nature.com/new-submission/787/3","title":"European Child \u0026 Adolescent Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f0ddf2d9-7000-4349-b5a6-0762bd3b4dd0","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:03:44+00:00","versionOfRecord":{"articleIdentity":"rs-6574363","link":"https://doi.org/10.1007/s00787-025-02895-3","journal":{"identity":"european-child-and-adolescent-psychiatry","isVorOnly":false,"title":"European Child \u0026 Adolescent Psychiatry"},"publishedOn":"2025-10-27 15:58:41","publishedOnDateReadable":"October 27th, 2025"},"versionCreatedAt":"2025-05-13 11:35:42","video":"","vorDoi":"10.1007/s00787-025-02895-3","vorDoiUrl":"https://doi.org/10.1007/s00787-025-02895-3","workflowStages":[]},"version":"v1","identity":"rs-6574363","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6574363","identity":"rs-6574363","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}