Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia

The prevalence of mental disorders among homeless people in high-income countries: An updated systematic review and meta-regression analysis

Background Homelessness continues to be a pressing public health concern in many countries, and mental disorders in homeless persons contribute to their high rates of morbidity and mortality. Many primary studies have estimated prevalence rates for mental disorders in homeless individuals. We conducted a systematic review and meta-analysis of studies on the prevalence of any mental disorder and major psychiatric diagnoses in clearly defined homeless populations in any high-income country. Methods and findings We systematically searched for observational studies that estimated prevalence rates of mental disorders in samples of homeless individuals, using Medline, Embase, PsycInfo, and Google Scholar. We updated a previous systematic review and meta-analysis conducted in 2007, and searched until 1 April 2021. Studies were included if they sampled exclusively homeless persons, diagnosed mental disorders by standardized criteria using validated methods, provided point or up to 12-month prevalence rates, and were conducted in high-income countries. We identified 39 publications with a total of 8,049 participants. Study quality was assessed using the JBI critical appraisal tool for prevalence studies and a risk of bias tool. Random effects meta-analyses of prevalence rates were conducted, and heterogeneity was assessed by meta-regression analyses. The mean prevalence of any current mental disorder was estimated at 76.2% (95% CI 64.0% to 86.6%). The most common diagnostic categories were alcohol use disorders, at 36.7% (95% CI 27.7% to 46.2%), and drug use disorders, at 21.7% (95% CI 13.1% to 31.7%), followed by schizophrenia spectrum disorders (12.4% [95% CI 9.5% to 15.7%]) and major depression (12.6% [95% CI 8.0% to 18.2%]). We found substantial heterogeneity in prevalence rates between studies, which was partially explained by sampling method, study location, and the sex distribution of participants. Limitations included lack of information on certain subpopulations (e.g., women and immigrants) and unmet healthcare needs. Conclusions Public health and policy interventions to improve the health of homeless persons should consider the pattern and extent of psychiatric morbidity. Our findings suggest that the burden of psychiatric morbidity in homeless persons is substantial, and should lead to regular reviews of how healthcare services assess, treat, and follow up homeless people. The high burden of substance use disorders and schizophrenia spectrum disorders need particular attention in service development. This systematic review and meta-analysis have been registered with PROSPERO (CRD42018085216). Trial registration PROSPERO CRD42018085216

Virtual Reality-Based Treatment Approaches in the Field of Substance Use Disorders

Purpose: Substance use disorders (SUD) are burdening chronic conditions characterized by high relapse rates despite severe negative consequences. Substance-related cues that elicit craving by means of automatic physiological and behavioural responses have long been suggested to predict relapse. One major mechanism contributing to relapse behaviour are cue-induced behavioural approach tendencies towards the addictive agent. Recently, there has been an emerging interest in virtual reality (VR)-based approaches to assess and modify craving and its related responses. This review aims at elucidating (1) VR techniques applied in the field of SUD, (2) VR as an induction/assessment tool for biopsychological correlates of craving and (3) VR-based therapeutic approaches. Findings: There is an emerging number of studies focusing on different substances of abuse incorporating VR in craving induction/assessment as well as therapy. Despite some limitations as missing of randomized controlled clinical trials with large samples and missing data on the long-term effects of VR treatment, the VR approach showed consistent results in eliciting and reducing craving across different substances. Summary: This review suggests virtual reality as a promising tool for the assessment and treatment of craving among individuals with substance use disorders. Because of its ecological validity, VR unifies the benefits of a laboratory setting with the advantages of a realistic environment. Further studies with large samples and randomized controlled clinical trials using more homogenous VR techniques as well as assessment of objective biophysiological craving markers are required

Laterality and body ownership: Effect of handedness on experience of the rubber hand illusion

Body ownership has mainly been linked to the right hemisphere and larger interhemispheric connectivity has been shown to be associated with greater right hemispheric activation. Mixed-handed participants tend to have more interhemispheric connectivity compared to extreme handed participants. The aim of this study was to examine whether feelings of ownership as assessed with the rubber hand illusion (RHI) are differentiated by handedness and differed between the left and right hand. Sinistrals-, dextrals-, and mixed-handed individuals (n = 63) were subjected to the RHI. Stroking was synchronously and asynchronously performed on both the participant's hand and a rubber hand. Outcome measures were an embodiment questionnaire and proprioceptive drift. In contrast to our hypotheses we show a similar experience of ownership for all groups, which may indicate no hemispheric specialization for the illusion. In addition, plasticity of ownership and body ownership are similar for the left hand and right hand in all participants, which suggests similar representations for both hands in the brain. This might be useful to maintain a coherent sense of the body in space

Context insensitivity during positive and negative emotional expectancy in depression assessed with functional magnetic resonance imaging

Patients with depression show an enhanced preoccupation with negative expectations and are often unable to look forward to positive events. Here we studied anticipatory emotional processes in unmedicated depressed patients using functional magnetic resonance imaging. Consistent with a negative processing bias, we hypothesized enhanced responses to negative and attenuated responses to positive expectancy cues in brain areas associated with emotional expectancy. Participants comprised 19 drug-free depressed patients and 19 matched healthy control subjects who viewed affective photographs. Pictures were preceded by an expectancy cue which signaled the emotional valence of the upcoming picture in half of the trials. Depressed patients showed attenuated blood-oxygen-level-dependent responses in the left lateral prefrontal cortex (inferior frontal gyrus, Brodmann area 44) during positive expectancy and—contrary to our hypothesis—in the right lateral orbitofrontal cortex (middle frontal gyrus, Brodmann area 47) during negative expectancy. This attenuation was specific for the anticipation (as opposed to the perception) of emotional pictures and correlated with a clinical measure of depressive symptoms. The observed attenuation suggests emotion-context insensitivity rather than a negative processing bias during anticipatory emotional processes in depression. This hyporeactivity may contribute to clinical features like anergia, apathy, and loss of motivation in the context of both positive and negative incentives