A miR-137-Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing.

BACKGROUND: miR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. METHODS: Using RNA sequencing data from postmortem prefrontal cortex (N = 522), we identified a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of coexpression prediction and associated them with functional magnetic resonance imaging activation in healthy volunteers (n1 = 214; n2 = 136; n3 = 2075; n4 = 1800) and with short-term treatment response in patients with schizophrenia (N = 427). RESULTS: In 4652 human participants, we found that 1) schizophrenia risk genes were coexpressed in a biologically validated set enriched for miR-137 targets; 2) increased expression of miR-137 target risk genes was mediated by low prefrontal miR-137 expression; 3) alleles that predict greater gene set coexpression were associated with greater prefrontal activation during emotion processing in 3 independent healthy cohorts (n1, n2, n3) in interaction with age (n4); and 4) these alleles predicted less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia. CONCLUSIONS: The functional translation of miR-137 target gene expression linked with schizophrenia involves the neural substrates of emotion processing.

Primary and secondary negative symptoms severity and the use of psychiatric care resources in schizophrenia spectrum disorders: A 3-year follow-up longitudinal retrospective study.

Negative symptoms represent one of the core features of schizophrenia spectrum disorders (SSD), strongly correlated with low remission rates, poor real-world functioning, and worse quality of life. Despite the body of evidence attesting the role of negative symptoms in determining worse outcomes in SSD, few studies have directly investigated their impact on the use of psychiatric services and even fewer research have examined the differential impact between primary versus secondary negative symptoms. The present study aims to investigate whether SSD subjects with high levels of primary and of secondary negative symptoms at an index hospitalization show a different use of psychiatric services in the subsequent 3 years. A total of 429 subjects were included in the study. Results show that SSD patients with high levels of negative symptoms are characterized by an overall greater use of high-cost resources, with more admissions in the hospital acute care psychiatric ward and in high intensity residential inpatient services. Moreover, while primary negative symptoms appear to play a role in determining a greater use of psychiatric services, high levels of secondary negative symptoms are associated with an increased use of most psychiatric resources, especially of high-cost ones. In conclusion, negative symptoms have a relevant impact on the pattern of psychiatric resources utilization in SSD patients. While scientific research continues to look for effective treatments for primary negative symptoms, clinicians should pay particular attention to secondary negative symptoms, as these also have important consequences but may benefit from appropriate treatment.

Autistic Symptoms in Schizophrenia: Impact on Internalized Stigma, Well-Being, Clinical and Functional Characteristics.

Autism Spectrum Disorders (ASD) symptoms and internalized stigma (or self-stigma) can have a negative impact on cognitive and functional outcomes in people living with schizophrenia. Aim of the present study were to assess and compare internalized stigma, subjective well-being and other socio-demographic, clinical and functional characteristics in people diagnosed with schizophrenia with and without prominent autistic features. Ninety-four inpatients were assessed with measures of internalized stigma, subjective well-being, global clinical severity, schizophrenia symptoms severity, real-world functioning, medication side effects and attitude toward prescribed medications. Subjects with high levels of ASD symptoms were identified with the PANSS Autism Severity Score and compared to other participants. Predictors of prominent ASD features were also assessed. Thirteen patients showed prominent ASD symptoms. They were characterized by fewer years of education, worse real-world functioning and greater symptoms severity. No between-group differences were observed regarding subjective well-being and global internalized stigma severity; however, participants in the "autistic schizophrenia" group showed better stigma resistance. A worse clinical condition and fewer years of education emerged as predictors of autistic schizophrenia. Despite showing a more severe clinical presentation of the disorder and worse functional impairment, participants with prominent ASD symptoms do not present worse subjective well-being or more severe internalized stigma; on the contrary, they show better stigma resistance. ASD symptoms could therefore play a protective role in the internalization of stigma.

Adult ADHD and sleep disorders: Prevalence, severity and predictors of sleep disorders in a sample of Italian psychiatric outpatients.

OBJECTIVE: Sleep disorders are frequent in adult subjects diagnosed with ADHD. The aims of the present study were to assess the prevalence and the severity of sleep disorders in a sample of Italian psychiatric outpatients, to compare the prevalence and severity of sleep disorders in patients with and without diagnosis of adult ADHD, and to evaluate the role of ADHD as an individual predictor of sleep disturbances severity. METHOD: 634 outpatients accessing psychiatric services were assessed with the Mini-International Neuropsychiatric Interview (MINI) Plus V. 5.0.0 interview and the Adult ADHD self-report Scale Symptoms Checklist (ASRS)-V 1.1 Short Form. Patients positive to the ASRS-V 1.1 were assessed with the Diagnostic Interview for ADHD in Adults (DIVA) 2.0. Sleep disorders and sleep disturbances' severity were assessed with the PROMIS Adult Sleep Disturbance Scale. RESULTS: Sleep disorders were more frequent (p < 0.001) and sleep disturbances were more severe (d = 1.26, p < 0.001) in subjects diagnosed with adult ADHD compared to other outpatients. Among the 44 subjects diagnosed with ADHD, 15 (34.1%) reported no or slight sleep disturbances, 9 (20.5%) a mild sleep disorder, 17 (38.6%) a moderate sleep disorder and 3 (6.8%) a severe sleep disorder. ADHD diagnosis, multiple psychiatric comorbidity and history of suicide attempts emerged as individual predictors of worse sleep disturbances. CONCLUSION: Sleep disorders are more frequent and severe in subjects diagnosed with ADHD compared to other adult outpatients. Sleep disturbances might represent an intrinsic feature in adult ADHD subjects, presenting important clinical repercussions, and should be routinely evaluated and monitored in this population.

Internalized stigma among people with schizophrenia: Relationship with socio-demographic, clinical and medication-related features.

BACKGROUND: People with schizophrenia are at high risk of suffering from stigma and internalizing it. Recently, a better understanding of the stigma process has shifted the attention from public stigma to self-stigma, which is deeply debilitating. This study aimed to assess factors associated to self-stigma by evaluating socio-demographic, clinical and treatment-related variables in a group of subjects diagnosed with schizophrenia and to identify predictors of high internalized stigma. METHODS: Ninety-four inpatients accessing rehabilitative centers with a diagnosis of schizophrenia were included in this cross-sectional study. Measures included both patient-rated scales, assessing internalized stigma, attitude toward medications, side effects experience and subjective well-being, and clinician-rated scales, assessing schizophrenia symptoms and global clinical severity and antipsychotic-related side effects. RESULTS: Twenty-one patients (22.3%) showed high internalized stigma while 73 (77.7%) did not. Patients experiencing more medication adverse effects and worse subjective well-being were more likely to suffer from internalized stigma according to a logistic regression analysis. Extrapyramidal, psychic and some autonomic reactions also emerged as individual predictors of self-stigma in a separate regression analysis. CONCLUSIONS: Self-stigma and subjective medication side effects perception represent a relevant issue in patients' life and should be carefully taken into account in clinical practice.

Adult ADHD: Prevalence and Clinical Correlates in a Sample of Italian Psychiatric Outpatients.

Objective: ADHD remains a largely underdiagnosed disorder in Europe and especially in Italy. Aims of the present study were to assess the prevalence of ADHD and its clinical and demographic correlates in a large sample of Italian outpatients. Method: 634 outpatients accessing psychiatric services were assessed with the Mini-International Neuropsychiatric Interview (MINI) Plus V. 5.0.0 interview and the Adult ADHD self-report Scale Symptoms Checklist (ASRS)-V 1.1 Short Form. Patients positive to the ASRS-V 1.1 were assessed with the Diagnostic Interview for ADHD in Adults (DIVA) 2.0. Results: Of the total patients' sample, 81 (12.8%) were positive on the ASRS-V 1.1. After performing the DIVA 2.0, 44 patients (6.9%) met the criteria for Adult ADHD. Significant clinical and demographic differences between ADHD positive and negative groups were found. Conclusion: The prevalence and correlates of ADHD comorbidity in our outpatient psychiatric population were comparable to those found in other high-income countries. Considering the prevalence of ADHD and its impact on functioning, implementing specific knowledge on this subject is needed.

Association study between HTR2A rs6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients.

Antipsychotic drugs are the preferred choice for schizophrenia treatment; however, response is highly variable. In the context of the search for predictors of antipsychotic treatment effectiveness, the evaluation of response within 2 weeks has been indicated to predict long-term outcome. Moreover, a focus on symptomatological domains could be helpful to better characterize antipsychotic response, identifying more specific predictors. Pharmacogenetic studies have indicated a role for rs6313 in the serotonin receptor gene HTR2A in affecting response to antipsychotics, with heterogeneous results. With the aim to test for the first time the application of a dimensional approach for the evaluation of early response, we carried out a genetic association study between rs6313 and antipsychotic response in two groups of schizophrenia patients in monotherapy with risperidone (n = 121) and olanzapine (n = 100). Patients were evaluated at the baseline and after 1 and 2 weeks of treatment. When comparing early responders versus early nonresponders, no association was detected for the two drugs separately, whereas by taking into consideration the two drugs together it was observed that carriers of the T allele had a higher response probability compared to noncarriers. Considering 2-week improvements, changes in PANSS total scores, subscores and in PANSS Emsley's symptomatological dimensions were associated with rs6313 for both risperidone and olanzapine. Moreover, the repeated measures analysis indicated an association of rs6313 with the disorganized thought dimension for risperidone, and with the depressive and anxiety dimensions for olanzapine. These data add support to the hypothesis that the HTR2A gene is involved in antipsychotic treatment outcome.

Author Correction: A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Treatment-Resistant Schizophrenia: Genetic and Neuroimaging Correlates.

Schizophrenia is a severe neuropsychiatric disorder that affects approximately 0.5-1% of the population. Response to antipsychotic therapy is highly variable, and it is not currently possible to predict those patients who will or will not respond to antipsychotic medication. Furthermore, a high percentage of patients, approximately 30%, are classified as treatment-resistant (treatment-resistant schizophrenia; TRS). TRS is defined as a non-response to at least two trials of antipsychotic medication of adequate dose and duration. These patients are usually treated with clozapine, the only evidence-based pharmacotherapy for TRS. However, clozapine is associated with severe adverse events. For these reasons, there is an increasing interest to identify better targets for drug development of new compounds and to establish better biomarkers for existing medications. The ability of antipsychotics to improve psychotic symptoms is dependent on their antagonist and reverse agonist activities at different neuroreceptors, and some genetic association studies of TRS have focused on different pharmacodynamic factors. Some genetic studies have shown an association between antipsychotic response or TRS and neurodevelopment candidate genes, antipsychotic mechanisms of action (such as dopaminergic, serotonergic, GABAergic, and glutamatergic) or pharmacokinetic factors (i.e., differences in the cytochrome families). Moreover, there is a growing body of literature on the structural and functional neuroimaging research into TRS. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify resistant patients earlier. Studies examining the neuropharmacological mechanisms of antipsychotics, including clozapine, can help to improve our knowledge of their action on the central nervous system, with further implications for the discovery of biomarkers and the development of new treatments. The identification of the underlying mechanisms of TRS is a major challenge for developing personalized medicine in the psychiatric field for schizophrenia treatment. The main goal of precision medicine is to use genetic and brain-imaging information to improve the safety, effectiveness, and health outcomes of patients via more efficiently targeted risk stratification, prevention, and tailored medication and treatment management approaches. The aim of this review is to summarize the state of art of pharmacogenetic, pharmacogenomic and neuroimaging studies in TRS.

Paliperidone extended-release in the short- and long-term treatment of schizophrenia.

Paliperidone is a second-generation antipsychotic drug belonging to the class of benzisoxasole derivatives. Paliperidone is the major active metabolite of risperidone (9-OH-risperidone) and, as such, is comparable to the latter in terms of pharmacodynamic properties. However, due to its peculiar characteristics, paliperidone may be particularly useful in the treatment of schizophrenic patients. In this critical review of the literature the efficacy and tolerability in the short- and in the long-term have been evaluated in patients with schizophrenia. Taking into account the tolerability and efficacy data, together with the use of innovative sustained-release formulation, with a peculiar pharmacokinetic profile that allows single daily administration, paliperidone can be considered a valid option both for the short and the long-term treatment of schizophrenia.

Effectiveness of Cognitive Remediation in Early Versus Chronic Schizophrenia: A Preliminary Report.

Background: Many evidences have demonstrated the effectiveness of cognitive remediation on cognition and functioning in patients with schizophrenia. Some researchers speculate that cognitive deficits are more amenable to remediation during earlier phases of illness than in chronicity. Therefore, cognitive rehabilitation should be used as an early intervention, seeking to produce durable functional changes in the early course of schizophrenia. Although there is strong evidence that cognitive remediation is effective in adult schizophrenia, there is little evidence about its efficacy and long-term generalized effectiveness in the early course of the disease. In this paper, we intended to investigate the possibility that cognitive remediation may produce more beneficial effects when applied in the early phase of the illness compared to chronic patients. Materials and methods: Data were gathered from a database used for a previous study performed by our group, in which 56 patients with schizophrenia received a cognitive remediation intervention. In a post hoc analysis, patients with a duration of illness shorter than 5 years were defined as "early course" patients, while patients with a duration of illness longer than 5 years were defined as "chronic." Clinical, neuropsychological, and functional outcome variables were assessed at baseline and after treatment. Result: Of the 56 patients included in the study, 11 were "early course" and 45 were "chronic." Both the early course group and the chronic group showed significant improvements in all the clinical, neurocognitive, and functional parameters analyzed. A significantly greater improvement in early course patients compared with chronic patients emerged in clinical and functional measures. No differential change was observed between early course patients and chronic patients in the cognitive composite score. Conclusion: Our study confirms the effectiveness of cognitive remediation in improving clinical, cognitive, and functional parameters in patients with schizophrenia, both in patients in the early course and in chronic patients. However, patients in the early course showed a differential, greater change in clinical and functional parameters compared to chronic patients. Although this study has some limitations, it confirms the effectiveness of cognitive remediation interventions, particularly if applied in the early course of the illness.

Well-being in patients with schizophrenia, mood and personality disorders attending psychiatric services in the community. A controlled study.

BACKGROUND: Poor attention is paid by recent research to the prevalence of mental well-being in psychiatric patients and the comparison between groups with different diagnoses. Data suggest that the presence of mental illness does not necessarily mean the absence of well-being, particularly in stable outpatients. METHODS: A consecutive series of 375 patients attending two community mental health centers was given the Mental Health Continuum Short Form (MHC-SF) and the Clinical Global Impression - Severity scale. Diagnoses were made after the MINI Neuropsychiatric Interview and a chart review of all relevant clinical information. The flourishing category and the three components of MHC-SF were used to rate well-being. A total of 274 controls were taken from the employees at a local firm. RESULTS: The rates of flourishing mental health were: 33.1% schizophrenia, 36.6% bipolar disorder, 23.3% unipolar depression, 24.4% cluster B personality disorder, and 53.3% controls (p < 0.001). The comparison of the three MHC components across diagnostic groups found that unipolar depression and cluster B personality patients had significantly lower scores compared to bipolar and schizophrenia patients. Flourishing mental health was detected more often in males than females (34.9% vs. 24.1% - p < 0.05). For schizophrenia patients indices of well-being were better in those on depot medications. CONCLUSIONS: Psychiatric outpatients with major mental illness have lower rates of well-being compared to controls, although about one-third is flourishing. Patients with unipolar depression and cluster B personality disorder may deserve special attention when planning intervention for fostering well-being.

Paliperidone palmitate in short- and long-term treatment of schizophrenia.

Poor adherence to treatment remains a major problem in the management of patients with schizophrenia. In the 60s, first generation antipsychotics in depot formulation have been introduced on the market with the aim to improve adherence to therapy. However, the limited effectiveness on negative symptoms and the tendency to induce extrapyramidal side effects has limited their use. Currently there are five second-generation antipsychotic long-acting formulations and the use of these drugs has definitely changed perspective: they are no more restricted as compounds intended to improve compliance, but they can be considered first-line drugs with proven efficacy and good tolerability. In this narrative review the efficacy and tolerability of paliperidone palmitate, as well as the economic impact of the use of this particular molecule, have been evaluated in the short- and long-term treatment of schizophrenia. Taking into account the results of different studies, paliperidone, especially in his long-acting formulation, can be considered a viable and effective treatment for patients with schizophrenia, both in the short- and in the long term.

Esperienze di switch a cariprazina in pazienti affetti da schizofrenia con ricorrenze.

Nel trattamento a lungo termine dei pazienti affetti da schizofrenia, il problema delle ricadute di malattia è di fondamentale rilevanza clinica e tuttora dibattuto. Una possibile strategia di intervento, in caso di riacutizzazione, è quella dello switch da un farmaco antipsicotico a un altro. Sarebbe utile, in questo senso, avere a disposizione molecole in grado di garantire uno stato di remissione clinica persistente nel tempo. Fra queste è possibile senz'altro considerare cariprazina, un farmaco di recente introduzione, dotato di un profilo d'azione unico rispetto agli altri antipsicotici, sia tipici che atipici.

Looking through autistic features in schizophrenia using the PANSS Autism Severity Score (PAUSS).

Autism spectrum disorder (ASD) and schizophrenia share several features. However, the assessment of ASD in schizophrenia is difficult. Aim of this study is to investigate the possibility to use the PANSS Autism Severity Score (PAUSS) to recognize autistic features in schizophrenia. The PAUSS was administered to 75 patients with schizophrenia, previously assessed with ASD diagnostic scales. PAUSS total scores were higher in patients with ASD, compared to those without ASD. Patients with PAUSS score higher than the cut-off proposed for ASD showed specific neuropsychological and functional characteristics. The PAUSS may be useful to identify patients with schizophrenia autistic features.

Psychomotor agitation in subjects hospitalized for an acute exacerbation of Schizophrenia.

The aims of this study were to establish the prevalence of moderate and severe psychomotor agitation in patients hospitalized for an active phase of schizophrenia, the associations between psychomotor agitation and patients' demographic and clinical variables, the intra-individual stability of the agitated/non-agitated dichotomy in independent psychotic breakdowns. The study was performed on a database relative to 630 inpatients hospitalized with a diagnosis of schizophrenia. Psychomotor agitation was measured with the Positive and Negative Syndrome Scale - Excited Component (PANSS-EC). Prevalence of moderate and severe psychomotor agitation was 40.5% and 23.7%, respectively. Non-agitated patients were older, with longer illness history and duration of untreated psychosis, were more frequently on antipsychotic medication, had lower incidence of recent use of substances, and functioned better before the index hospitalization than moderately and/or severely agitated patients. Non-agitated patients had lower scores for total PANSS and Emsley's positive and anxiety dimensions. Compared with the severely agitated group, non-agitated and moderately agitated patients scored more in Emsley's depression dimension. Poor functioning before index hospital admission, higher scores for negative subscale and Emsley's positive dimension and use of substances exerted an effect on risk of psychomotor agitation.

A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme.

Recently, by whole exome sequencing of schizophrenia (SCZ) patients, we identified a subject that was homozygous for a novel missense substitution (c.391 A > G) in the glutamate acid decarboxylase 1 (GAD1) gene. GAD1 encodes for GAD67 enzyme, catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Here, we studied the impact of this mutation on GAD67 activity, dimerization and subcellular localization. Biochemical assay revealed that c.391 A > G reduces GAD67 enzymatic activity by ~30%, probably due to the impaired homodimerization of homozygous mutants as highlighted by proximity ligation assays. The mutational screening of 120 genes of the "GABAergic system" in a cohort of 4,225 SCZ cases and 5,834 controls (dbGaP: phs000473.v1.p2), did not identify other cases that were homozygous for ultra-rare variants in GAD1, but highlighted an increased frequency of cases that were homozygous for rare variants in genes of the GABA system (SCZ: 0.14% vs. Controls: 0.00%; p-value = 0.0055). In conclusion, this study demonstrates the functional impact of c.391 A > G variant and its biological effect makes it a good candidate as risk variant for SCZ. This study also supports an involvement of ultra-rare variants in GABAergic genes in the etiopathogenesis of SCZ.

At-risk gambling in patients with severe mental illness: Prevalence and associated features.

Background and aims The primary objective of this study was to investigate the prevalence of at-risk gambling in a large, unselected sample of outpatients attending two community mental health centers, to estimate rates according to the main diagnosis, and to evaluate risk factors for gambling. Methods All patients attending the centers were evaluated with the Canadian Problem Gambling Index and the Mini International Neuropsychiatric Interview. Diagnoses were checked with the treating psychiatrists and after a chart review of the university hospital discharge diagnoses. Results The rate of at-risk gambling in 900 patients was 5.3%. In those who gambled over the last year, 10.1% were at-risk gamblers. The rates in the main diagnostic groups were: 4.7% schizophrenia and related disorders, 4.9% bipolar disorder, 5.6% unipolar depression, and 6.6% cluster B personality disorder. In 52.1% of the cases, at-risk gambling preceded the onset of a major psychiatric disorder. In a linear regression analysis, a family history of gambling disorder, psychiatric comorbidities, drug abuse/dependence, and tobacco smoking were significantly associated with at-risk gambling. Discussion and conclusion The results of this study evidenced a higher rate of at-risk gambling compared to community estimates and call for a careful screening for gambling in the general psychiatric population.

Factors Associated With Response and Resistance to Cognitive Remediation in Schizophrenia: A Critical Review.

Cognitive impairment is a central feature of schizophrenia and has shown to play a crucial role in the psychosocial function of the disorder. Over the past few years, several cognitive remediation (CR) interventions have been developed for schizophrenia, whose effectiveness has also been widely demonstrated by systematic reviews and meta-analysis studies. Despite these evidences, many questions remain open. In particular, the identification of CR response predictors in patients with schizophrenia is still a topic with equivocal findings and only a few studies have looked for the relationship between CR response or resistance and the biological, socio-demographic, clinical and cognitive features in schizophrenia. The current knowledge on positive or negative response predictors to CR treatment in schizophrenia include: age, duration of illness, premorbid adjustment, baseline cognitive performance, intrinsic motivation, hostility, disorganized symptoms, neurobiological reserve, genetic polymorphisms, the amounts of antipsychotics, the type of CR, etc. The aim of this review is to identify neurobiological, psychopathological, cognitive, and functional predictors of CR response or resistance in schizophrenia, taking into account both cognitive and functional outcome measures. The information obtained could be very useful in planning integrated and personalized interventions, also with a better use of the available resources.

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways.

Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically complex disorders.