What a psychiatrist needs to know about copy number variants

Copy number variants (CNVs) are structural changes in chromosomes that result in deletions, duplications, inversions or translocations of large DNA segments. Eleven confirmed CNV loci have been identified as rare but important risk factors in schizophrenia. These CNVs are also associated with other neurodevelopmental disorders and medical/physical comorbidities. Although the penetrance of the CNVs for schizophrenia (the chance that CNV carriers will develop the disorder) is modest, the penetrance of CNVs for any early-onset developmental disorder (e.g. intellectual disability or autism) is much higher. Testing for CNVs is now affordable and being used in clinical genetics and neurodevelopmental disorders clinics. It is possible that testing will be expanded to psychiatric clinics. This article provides a clinically relevant overview of recent CNV findings in schizophrenia and related disorders

Predicting post-traumatic stress disorder: validation of the Trauma Screening Questionnaire in victims of assault

Background. No accurate means of determining which individuals will develop post-traumatic stress disorder (PTSD) following a traumatic event has yet been identified. This study aimed to determine the validity of the Trauma Screening Questionnaire (TSQ) in predicting the development of PTSD following assault. Method. Five hundred and sixty-two individuals who presented to an emergency unit following assault completed the TSQ between 1 and 3 weeks later. The Davidson Trauma Scale (DTS) was completed by the same individuals at 1 month and 6 months following assault to determine the presence of PTSD. The predictive power of the TSQ was determined by statistical tests. Results. The TSQ was an effective means of predicting future PTSD, with a sensitivity of 0·85, specificity 0·89, negative predictive value (NPV) 0·98 and efficiency 0·90. The positive predictive value (PPV) was lower (0·48), probably as a result of the relatively low prevalence of PTSD at 1 month (11%) and 6 months (8%) following the assault. Conclusions. This study suggests that the TSQ can be used between 1 and 3 weeks after assault to help identify individuals who will develop PTSD

Reasons for discontinuing clozapine: a cohort study of patients commencing treatment

Background Clozapine is uniquely effective in the management of treatment-resistant schizophrenia (TRS). However, a substantial proportion of patients discontinue treatment and this carries a poor prognosis. Methods We investigated the risk factors, reasons and timing of clozapine discontinuation in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. Reasons for discontinuation of clozapine and duration of treatment were obtained from case notes and Cox regression was employed to test the association of baseline clinical factors with clozapine discontinuation. Results A total of 142 (45%) patients discontinued clozapine within two years. By studying the reasons for discontinuations due to a patient decision, we found that adverse drug reactions (ADRs) accounted for over half of clozapine discontinuations. Sedation was the most common ADR cited as a reason for discontinuation and the risk of discontinuation due to ADRs was highest in the first few months of clozapine treatment. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR = 2.12, 95% CI 1.30–3.47). Conclusions Living in a deprived neighbourhood was strongly associated with clozapine discontinuation. Clinical management to reduce the burden of ADRs in the first few months of treatment may have a significant impact and help more patients experience the benefits of clozapine treatment

Association of rare copy number variants with risk of depression

Importance: The role of large, rare copy number variants (CNVs) in neuropsychiatric disorders is well established, but their association with common psychiatric disorders, such as depression, remains unclear. Objective: To examine the association of a group of 53 CNVs associated with neurodevelopmental disorders and burden of rare CNVs with risk of depression. Design, Setting, and Participants: This case-control study used data from the UK Biobank study sample, which comprised 502 534 individuals living in the United Kingdom. Individuals with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia, or bipolar affective disorder diagnoses were excluded. Analyses were further restricted to individuals of European genetic ancestry (n = 407 074). The study was conducted from January 2017 to September 2018. Exposures: CNV carrier status. Main Outcomes and Measures: For the primary outcome, individuals who reported that a physician had told them they had a depression diagnosis were defined as cases. Analyses were repeated using 2 alternative depression definitions: self-reported lifetime depression with current antidepressant prescription at the time of visit 1, and hospital discharge diagnosis of depression. Results: Copy number variants were identified in 488 366 individuals aged 37 to 73 years. In total, 407 074 individuals with European genetic ancestry (220 201 female [54.1%]; mean [SD] age of 56.9 [8.0] years) were included in the study. Of these individuals, 23 979 (5.9%) had self-reported lifetime depression and 383 095 (94.1%) reported no lifetime depression. The group of 53 neurodevelopmental CNVs was associated with self-reported depression (odds ratio [OR], 1.34; 95% CI, 1.19-1.49, uncorrected P = 1.38 × 10−7), and these results were consistent when using 2 alternative definitions of depression. This association was partially explained by physical health, educational attainment, social deprivation, smoking status, and alcohol consumption. A strong independent association remained between the neurodevelopmental CNVs and depression in analyses that incorporated these other measures (OR, 1.26; 95% CI, 1.11-1.43; P = 2.87 × 10−4). Eight individual CNVs were nominally associated with risk of depression, and 3 of these 8 CNVs (1q21.1 duplication, Prader-Willi syndrome duplication, and 16p11.2 duplication) survived Bonferroni correction for the 53 CNVs tested. After the exclusion of carriers of neurodevelopmental CNVs, no association was found between measures of CNV burden and depression. Conclusions and Relevance Neurodevelopmental CNVs appear to be associated with depression, extending the spectrum of clinical phenotypes that are associated with CNV carrier status

The penetrance of copy number variations for schizophrenia and developmental delay

Background: Several recurrent copy number variants (CNVs) have been shown to increase the risk of developing schizophrenia (SCZ), developmental delay (DD), autism spectrum disorders (ASD), and various congenital malformations (CM). Their penetrance for SCZ has been estimated to be modest. However, comparisons between their penetrance for SCZ or DD/ASD/CM, or estimates of the total penetrance for any of these disorders have not yet been made. Methods: We use data from the largest available studies on SCZ and DD/ASD/CM, including a new sample of 6882 cases and 6316 controls, to estimate the frequencies of 70 implicated CNVs in carriers with these disorders, healthy control subjects, and the general population. On the basis of these frequencies, we estimate their penetrance. We also estimate the strength of the selection pressure against CNVs and correlate this against their overall penetrance. Results: The rates of nearly all CNVs are higher in DD/ASD/CM compared with SCZ. The penetrance of CNVs is at least several times higher for the development of a disorder from the group of DD/ASD/CM. The overall penetrance of SCZ-associated CNVs for developing any disorder is high, ranging between 10.6% and 100%. Conclusions: CNVs associated with SCZ have high pathogenicity. The majority of the increased risk conferred by CNVs is toward the development of an earlier-onset disorder, such as DD/ASD/CM, rather than SCZ. The penetrance of CNVs correlates strongly with their selection coefficients. The improved estimates of penetrance will provide crucial information for genetic counselling

Treatment resistant schizophrenia: precision genetics or more of the same? [Conference Abstract]

Background: It is not known whether treatment-resistant schizophrenia (TRS) represents a distinct biological sub-type or simply a more severe form of the same condition. Furthermore little is known about the genetic architecture of treatment resistant schizophrenia (TRS). In this study we use large-scale genetic data to answer 3 questions: 1. Are polygenic and CNV burdens higher in TRS than generic schizophrenia (Sz) samples i.e. those not selected for treatment response -suggesting a more severe form of the condition? 2. Do GWAS and CNV analyses identify genetic risk factors specific to TRS? 3. Do genes identified by GWAS and CNV analyses in TRS hit glutamate and dopamine pathways at different rates than in generic Sz? Methods: 9000 samples of those taking clozapine constituted the TRS sample-cases with a clinical diagnosis of TRS, together with 10 000 healthy controls. The TRS GWAS and CNV analysis followed established procedures for calling, QC and analysis. Polygenic overlap, training on PGC2 schizophrenia, was compared between TRS and generic Sz samples as were rates of CNVs. To identify genetic variants specific to TRS we sought to replicate SNPs from the GWAS in a sample of TRS (n=3000) versus non-TRS cases (n=3000). The pathway analyses focused on dopamine and glutamate/NMDA receptor gene sets. Results: There was evidence that TRS is associated with a minimally stronger polygenic signal than generic Sz samples (r2 (TRS)=0.17, r2 (generic Sz)=0.14). After combining all TRS samples we identified eleven genome-wide significant SNPs in GWAS, 4 of which appear were specific to TRS. The genes associated with these SNPs are involved in neural cell adhesion and neurogenesis. Rates of CNVs were broadly equivalent between samples. There were differences in CNVs hitting genes in dopamine and glutamate pathways. CNVs in TRS cases were associated more strongly with glutamate pathways than in generic Sz. In contrast there was evidence for weaker association for CNVs hitting dopamine pathways in TRS compared with generic Sz. Conclusion: Our results highlight specific polymorphisms associated with TRS and thus point toward the involvement of distinct molecular pathways. There is evidence for a somewhat stronger polygenic signal in TRS compared to generic schizophrenia but no evidence that large CNVs occur at a higher rate in TRS. We present genetic data indicating novel gene set findings that implicate weaker dopamine and stronger glutamate signals for CNVs in TRS compared with generic Sz

Clinical questions and uncertainty - prolactin measurement in patients with schizophrenia and bipolar disorder

Many antipsychotic medications have the potential to raise prolactin levels leading to a range of negative consequences. In addition to symptoms such as gynaecomastia, galactorrhoea, menstrual irregularities and sexual dysfunction it is becoming clear that there are a number of important and potentially serious long-term consequences, including a loss of bone mineral density and a possible association with the development of breast cancer. It is clear, therefore, that the tendency to raise prolactin should be an important consideration in the use of antipsychotics but, to a large degree, this area has been neglected in clinical practice and research when compared with other potential adverse effects. We consider some of the practical clinical issues in prolactin measurement and the management of high results. We will identify the areas of uncertainty that remain for clinicians and consider the practical questions that future research should address

What a psychiatrist needs to know about copy number variants

Copy number variants (CNVs) are structural changes in chromosomes that result in deletions, duplications, inversions or translocations of large DNA segments. Eleven confirmed CNV loci have been identified as rare but important risk factors in schizophrenia. These CNVs are also associated with other neurodevelopmental disorders and medical/physical comorbidities. Although the penetrance of the CNVs for schizophrenia (the chance that CNV carriers will develop the disorder) is modest, the penetrance of CNVs for any early-onset developmental disorder (e.g. intellectual disability or autism) is much higher. Testing for CNVs is now affordable and being used in clinical genetics and neurodevelopmental disorders clinics. It is possible that testing will be expanded to psychiatric clinics. This article provides a clinically relevant overview of recent CNV findings in schizophrenia and related disorders