Gene Discovery for Complex Traits: Lessons from Africa.

The genetics of African populations reveals an otherwise "missing layer" of human variation that arose between 100,000 and 5 million years ago. Both the vast number of these ancient variants and the selective pressures they survived yield insights into genes responsible for complex traits in all populations.

Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.

Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.

Genetic heterogeneity in human disease.

Strong evidence suggests that rare mutations of severe effect are responsible for a substantial portion of complex human disease. Evolutionary forces generate vast genetic heterogeneity in human illness by introducing many new variants in each generation. Current sequencing technologies offer the possibility of finding rare disease-causing mutations and the genes that harbor them.

Debate: Involuntary treatment - not whether, but when and what else is needed.

Involuntary treatment is a complex dialectic balancing self-autonomy and the individual's right to consent to treatment with society's duty to protect those suffering from severe mental illness who are at risk of causing harm to themselves or others. When necessary, involuntary treatment should provide evidence-based and medically justified care, with sufficient oversight and due process to protect the rights of patients. Clinically, the issue is not whether involuntary treatment should ever be used, but rather what other services are needed to enhance the quality of care within comprehensive community systems of care, thus limiting or preventing the need for involuntary interventions while also improving the outcomes of individuals affected by severe mental illness.

Practitioner Review: Psychosis in children and adolescents.

Psychotic symptoms, including hallucinations, delusions, and disorganized thinking and behaviors, are the hallmarks of schizophrenia; but may also present in the context of other psychiatric and medical conditions. Many children and adolescents describe psychotic-like experiences, which can be associated with other types of psychopathology and past experiences (e.g., trauma, substance use, and suicidality). However, most youth reporting such experiences do not have, nor will ever develop, schizophrenia or another psychotic disorder. Accurate assessment is critical because these different presentations have different diagnostic and treatment implications. For this review, we focus primarily on the diagnosis and treatment of early onset schizophrenia. In addition, we review the development of community-based first-episode psychosis programming, and the importance of early intervention and coordinated care.

De novo mutation in RING1 with epigenetic effects on neurodevelopment.

RING1 is an E3-ubiquitin ligase that is involved in epigenetic control of transcription during development. It is a component of the polycomb repressive complex 1, and its role in that complex is to ubiquitylate histone H2A. In a 13-year-old girl with syndromic neurodevelopmental disabilities, we identified a de novo mutation, RING1 p.R95Q, which alters a conserved arginine residue in the catalytic RING domain. In vitro assays demonstrated that the mutant RING1 retains capacity to catalyze ubiquitin chain formation, but is defective in its ability to ubiquitylate histone H2A in nucleosomes. Consistent with this in vitro effect, cells of the patient showed decreased monoubiquitylation of histone H2A. We modeled the mutant RING1 in Caenorhabditis elegans by editing the comparable amino acid change into spat-3, the suggested RING1 ortholog. Animals with either the missense mutation or complete knockout of spat-3 were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance. Relevant to our patient, animals heterozygous for either the missense or knockout allele also showed neuronal defects. Our results support three conclusions: mutation of RING1 is the likely cause of a human neurodevelopmental syndrome, mutation of RING1 can disrupt histone H2A ubiquitylation without disrupting RING1 catalytic activity, and the comparable mutation in C. elegans spat-3 both recapitulates the effects on histone H2A ubiquitylation and leads to neurodevelopmental abnormalities. This role for RING1 adds to our understanding of the importance of aberrant epigenetic effects as causes of human neurodevelopmental disorders.

Debate: Putting psychiatric hospitalization for children and adolescents in its place: it is time to create a system of care that works.

Inpatient psychiatric care is the most expensive resource within the pediatric mental health system and is too often justified based on the lack of more appropriate and effective services. Rates of readmission are high, and data regarding long-term benefits are lacking. The continuum of care needs to be realigned to meet the needs of children and families, with investments in intensive community-based services and evidence-based training while limiting the use of acute inpatient care to those patients whose clinical presentations require and benefit from that level of service.

Commentary: Getting kids what they need, where they are, when they need it: home-based services in a continuum of care - a commentary on Boege et al. (2021).

In this edition of CAMH, Boege and colleague's 4-year follow-up study supports intensive home-based treatment as a viable alternative to inpatient hospitalization. Youth receiving home-based multimodal treatment fared just as well as those who remained hospitalized longer, with higher parental satisfaction. This study contributes to a sparse evidence base regarding longitudinal outcomes of psychiatric inpatient and intensive outpatient treatments for children and adolescents. Although mental illness is prevalent and increasing among youth, existing systems of care are often inadequate to provide flexible, effective, interdisciplinary team-based treatments, and supports for children and their families. Innovative approaches to providing evidence-based care and tracking outcomes are needed to strengthen the continuum of care.

Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.

Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.

Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia.

Chimeric genes can be caused by structural genomic rearrangements that fuse together portions of two different genes to create a novel gene. We hypothesize that brain-expressed chimeras may contribute to schizophrenia. Individuals with schizophrenia and control individuals were screened genome wide for copy-number variants (CNVs) that disrupted two genes on the same DNA strand. Candidate events were filtered for predicted brain expression and for frequency < 0.001 in an independent series of 20,000 controls. Four of 124 affected individuals and zero of 290 control individuals harbored such events (p = 0.002); a 47 kb duplication disrupted MATK and ZFR2, a 58 kb duplication disrupted PLEKHD1 and SLC39A9, a 121 kb duplication disrupted DNAJA2 and NETO2, and a 150 kb deletion disrupted MAP3K3 and DDX42. Each fusion produced a stable protein when exogenously expressed in cultured cells. We examined whether these chimeras differed from their parent genes in localization, regulation, or function. Subcellular localizations of DNAJA2-NETO2 and MAP3K3-DDX42 differed from their parent genes. On the basis of the expression profile of the MATK promoter, MATK-ZFR2 is likely to be far more highly expressed in the brain during development than the ZFR2 parent gene. MATK-ZFR2 includes a ZFR2-derived isoform that we demonstrate localizes preferentially to neuronal dendritic branch sites. These results suggest that the formation of chimeric genes is a mechanism by which CNVs contribute to schizophrenia and that, by interfering with parent gene function, chimeras may disrupt critical brain processes, including neurogenesis, neuronal differentiation, and dendritic arborization.

An evolutionary perspective on complex neuropsychiatric disease.

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields the greatest possible range of insight into genes critical to human brain development. In this perspective, we explore some of the relationships between genes, adaptation, and history that can be illuminated by an evolutionary perspective on studies of complex neuropsychiatric disease in diverse populations.

An Optimized Version of the Positive and Negative Symptoms Scale (PANSS) for Pediatric Trials.

OBJECTIVE: The accepted primary outcome measure for evaluating psychotic symptoms is decades old, long, and initially designed for adults. Surprisingly, the psychometric properties of primary outcome measures have never been reported for a pediatric sample using modern methods. The present study's aim is to use a pediatric sample to evaluate the psychometrics of the most used primary outcome measure in pediatric schizophrenia trials, the Positive and Negative Syndrome Scale (PANSS). METHOD: To evaluate the factor structure, item characteristics, and treatment sensitivity of the PANSS in a pediatric sample, secondary analyses of PANSS data at baseline and weekly throughout an 8-week randomized double-blind study of 3 antipsychotic agents (registered and previously published) were conducted. Subjects were 118 youths receiving outpatient psychiatric treatment for schizophrenia spectrum disorders (mean age = 14.26 years, SD = 2.41 years). RESULTS: A 10-item short form, keeping 2 strongest items for each factor, had r = 0.89 with the full-length scale. Each of the five 2-item subscales has alphas ranging from 0.66 to 0.84. Item Response Theory (IRT) found that the 10-item scale and 2-item subscores had high reliability across the severity range typical of those for clinical trials. Criterion validity was high, with equal sensitivity to clinical changes over time. CONCLUSION: A 10-item PANSS version eliminates weaker items in the pediatric population while preserving coverage of 5 factors and similar sensitivity to clinical changes over time. It thus may be more appropriate for subsequent pediatric trials, and for clinical use when time and efficiency are paramount.

Narrative Review: Impairing Emotional Outbursts: What They Are and What We Should Do About Them.

OBJECTIVE: Impairing emotional outbursts, defined by extreme anger or distress in response to relatively ordinary frustrations and disappointments, impact all mental health care systems, emergency departments, schools, and juvenile justice programs. However, the prevalence, outcome, and impact of outbursts are difficult to quantify because they are transdiagnostic and not explicitly defined by current diagnostic nosology. Research variably addresses outbursts under the rubrics of tantrums, anger, irritability, aggression, rage attacks, or emotional and behavioral dysregulation. Consistent methods for identifying and assessing impairing emotional outbursts across development or systems of care are lacking. METHOD: The American Academy of Child and Adolescent Psychiatry Presidential Task Force (2019-2021) conducted a narrative review addressing impairing emotional outbursts within the limitations of the existing literature and independent of diagnosis. RESULTS: Extrapolating from the existing literature, best estimates suggest that outbursts occur in 4%-10% of community children (preschoolers through adolescents). Impairing emotional outbursts may respond to successful treatment of the primary disorder, especially for some children with attention-deficit/hyperactivity disorder whose medications have been optimized. However, outbursts are generally multi-determined and often represent maladaptive or deficient coping strategies and responses. CONCLUSION: Evidence-based strategies are necessary to address factors that trigger, reinforce, or excuse the behaviors and to enhance problem-solving skills. Currently available interventions yield only modest effect sizes for treatment effect. More specific definitions and measures are needed to track and quantify outbursts and to design and assess the effectiveness of interventions. Better treatments are clearly needed.

Emotional and Behavioral Dysregulation in Severe Mental Illness.

Emotional and behavioral dysregulation are common in severe mental illnesses, including schizophrenia, bipolar disorder, and borderline personality disorder. Emotional instability and behavioral outbursts can be driven by internal processes and/or environmental triggers and interpersonal interactions. Understanding the underlying diagnosis is important in determining the best course of treatment. Disorder-specific treatments are important in addressing underlying drivers of emotional dysregulation, irritability, and aggression. Coping skills training and behavioral modification strategies have broad applicability and are useful for aggression and irritability. Treatment planning to address emotion dysregulation and aggression in severe mental illness should address psychiatric comorbidities, substance use, and medication adherence.

A tipping point in neuropsychiatric genetics.

Severe neuropsychiatric disorders are so genetically heterogeneous that virtually every unrelated patient harbors different clinically significant alleles. By studying schizophrenia in the Ashkenazi Jewish founder population, Lencz and co-authors identified rare severe alleles each shared by a few patients. Experimental evaluation of an implicated protocadherin allele revealed failure to form homophilic cellular aggregates as a possible mechanism for defective development of neural circuits.

Adaptation and validation of a computerized neurocognitive battery in the Xhosa of South Africa.

OBJECTIVE: Large-scale studies have revolutionized biomedical research, and neurocognitive tests can help elucidate the biological basis of neuropsychiatric diseases. However, studies have predominantly been conducted in Western settings. We describe the development and validation of a computerized battery (PennCNB) with the Xhosa population of South Africa. METHOD: Individuals with schizophrenia (n = 525) and a normative comparison group (n = 744) were balanced on age, sex, education, and region. Participants provided blood samples, were assessed psychiatrically, and were administered a PennCNB translation to isiXhosa, including measures of executive functions, episodic memory, complex cognition, social cognition, and sensorimotor speed. Feasibility was examined with test completion rates and input from administrators, and psychometric structural validity and associations with clinical and demographic characteristics were examined. RESULTS: Tests were well tolerated by participants, as >87% had one (or fewer) test missing. Results suggested a similar factor structure to prior PennCNB studies in Western contexts, and expected age and sex effects were apparent. Furthermore, a similar profile of schizophrenia was observed, with neurocognitive deficits most pronounced for executive functions, especially attention, as well as memory, social cognition, and motor speed relative to complex cognition and sensorimotor speed. CONCLUSIONS: Results support the feasibility of implementing a culturally adapted computerized neurocognitive battery in sub-Saharan African settings and provide evidence supporting the concurrent validity of the translated instrument. Thus, the PennCNB is implementable on a large scale in non-Western contexts, shows expected factor structure, and can detect cognitive deficits associated with neuropsychiatric disorders. Obtaining valid measures of cognition by nonspecialized proctors is especially suitable in resource-limited settings, where traditional testing is prohibitive. Future work should establish normative standards, test-retest reliability, and sensitivity to treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

First-dose pharmacokinetics of lithium carbonate in children and adolescents.

This study examines the pharmacokinetics of oral doses of lithium carbonate immediate-release capsules after administration of 600 or 900 mg in children and adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, bipolar I disorder. Lithium plasma concentrations were followed over 48 to 72 hours in 39 subjects (20 male and 19 female subjects; ages, 7-17 years) with mixed or manic episodes enrolled at 7 clinical sites participating in the Collaborative Lithium Trials. Population pharmacokinetic modeling was performed using NONMEM, and influences of patient covariates on pharmacokinetics parameters were examined. The pharmacokinetics of lithium was best described using a 2-compartment model with a lag time and first-order absorption. There was considerable variability in lithium exposures. Lithium clearance related best to fat-free mass. Inclusion of fat-free mass as a covariate reduced the between-subject variability from 52% to 42%. Lithium clearances did not vary systematically with age group, dose, sex, or creatinine clearances. Allometrically scaled clearance and volume of distribution from the population analysis were within the range reported in adults. Single-dose profiles of lithium in young patients with BP-1 show marked variability. Therefore, ongoing serum monitoring is needed during continued therapy. The developed population pharmacokinetic model may be used to predict other dosage regimens, support scaling from adult to pediatric pharmacokinetics, and support the design of future clinical trials.

Interpersonal and social rhythm therapy for adolescents with bipolar disorder: treatment development and results from an open trial.

BACKGROUND: In adolescents and adults, bipolar disorder (BD) is associated with significant morbidity, mortality, and impairment in psychosocial and occupational functioning. IPSRT is an empirically supported adjunctive psychotherapy for adults with bipolar disorder, which has been shown to help delay relapse, speed recovery from a bipolar depressive episode, and increase occupational and psychosocial functioning in adults with BD. This study is designed to describe the adolescent-specific developmental adaptations made to IPSRT (i.e., IPSRT-A) and to report the results from an open trial of IPSRT-A with 12 adolescents with a bipolar spectrum disorder. METHOD: Interpersonal and Social Rhythm Therapy was adapted to be developmentally relevant to adolescents with bipolar disorder. Twelve adolescents (mean age 16.5+/-1.3 years) diagnosed with a bipolar spectrum disorder participated in 16-18 sessions of adjunctive IPSRT-A over 20 weeks. Manic, depressive, and general symptoms and global functioning were measured at baseline, monthly during treatment, and at post-treatment. Adolescent satisfaction with treatment was also measured. RESULTS: Feasibility and acceptability of IPSRT-A were high; 11/12 participants completed treatment, 97% of sessions were attended, and adolescent-rated satisfaction scores were high. IPSRT-A participants experienced significant decreases in manic, depressive, and general psychiatric symptoms over the 20 weeks of treatment. Participants' global functioning increased significantly as well. Effect sizes ranged from medium-large to large. CONCLUSIONS: IPSRT-A appears to be a promising adjunctive treatment for adolescents with bipolar disorder. A current randomized controlled trial is underway to examine effects of adjunctive IPSRT-A on psychiatric symptoms and psychosocial functioning.

A Pilot Evaluation of Dialectical Behavioural Therapy in Adolescent Long-Term Inpatient Care.

BACKGROUND: There is a paucity of research investigating psychosocial treatments for youth receiving long-term residential care. OBJECTIVE: This study describes the implementation and impact of dialectical behavioural therapy (DBT) in a long-term psychiatric hospital located in the United States of America. METHOD: Changes in overall functioning, number of psychotropic medications prescribed, non-suicidal self-injurious behaviour (NSIB), and locked seclusions were investigated in 106 consecutive unique adolescent patients who received DBT. In addition, a comparison group of historical controls was used to examine the effect of DBT in youth with the highest rates of NSIB. RESULTS: A statistically significant increase in overall functioning, as well as a decrease in number of psychotropic medications and non-suicidal self-injurious behaviour (NSIB) was observed within the DBT group. A decrease in locked seclusions was not observed. Accounting for the effects of age, gender, length of stay, and time, youth who received DBT were less likely to engage in NSIB relative to historical controls. CONCLUSIONS: These preliminary data suggest that DBT is beneficial for youth with NSIB in long term inpatient psychiatric care.