Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

Objective Treatment resistance complicates the management of schizophrenia. Research and clinical translation is limited by inconsistent definitions. To address this we evaluated current approaches and then developed consensus criteria and guidelines. Method A systematic review of randomized antipsychotic clinical trials in treatment resistant schizophrenia was performed. Definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed by a working group of researchers and clinicians through i) a multi-phase, mixed methods approach; ii) identifying key criteria via an online survey; and iii) meetings to achieve consensus. Results 42 studies met inclusion criteria. Of these, 21 (50%) studies did not provide operationalized criteria, whilst in others, criteria varied considerably, particularly regarding symptom severity, prior treatment duration and antipsychotic dose thresholds. Important for the inability to compare results, only two (5%) studies utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) ≥moderate functional impairment; 3) prior treatment consisting of ≥2 different antipsychotic trials, each for a minimum duration and dose; 4) adherence systematically assessed and meeting minimum criteria; 5) ideally at least one prospective treatment trial; 6) criteria that clearly separated responsive from treatment resistant patients. Conclusions There is considerable variation in current approaches to defining treatment resistance in schizophrenia. We present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment and treatment response in schizophrenia, providing a benchmark for research and clinical translation.

The vulnerability for hospitalization with a range of psychiatric diagnoses may increase with younger gestational age. Similar associations were not observed for nonoptimal fetal growth and low Apgar score.

Cannabis use is associated with an earlier age of onset of psychosis (AOP). However, the reasons for this remain debated. Methods: We applied a Cox proportional hazards model to 410 first-episode psychosis patients to investigate the association between gender, patterns of cannabis use, and AOP. Results: Patients with a history of cannabis use presented with their first episode of psychosis at a younger age (mean years = 28.2, SD = 8.0; median years = 27.1) than those who never used cannabis (mean years = 31.4, SD = 9.9; median years = 30.0; hazard ratio [HR] = 1.42; 95% CI: 1.16-1.74; P < .001). This association remained significant after controlling for gender (HR = 1.39; 95% CI: 1.11-1.68; P < .001). Those who had started cannabis at age 15 or younger had an earlier onset of psychosis (mean years = 27.0, SD = 6.2; median years = 26.9) than those who had started after 15 years (mean years = 29.1, SD = 8.5; median years = 27.8; HR = 1.40; 95% CI: 1.06-1.84; P = .050). Importantly, subjects who had been using high-potency cannabis (skunk-type) every day had the earliest onset (mean years = 25.2, SD = 6.3; median years = 24.6) compared to never users among all the groups tested (HR = 1.99; 95% CI: 1.50-2.65; P < .0001); these daily users of highpotency cannabis had an onset an average of 6 years earlier than that of non-cannabis users. Conclusions: Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.

A focus on the different symptom domains of schizophrenia may lead to endophenotypic markers being identified, e.g. for negative symptoms and cognitive deficits (as well as for positive symptoms) that can promote the development of novel therapeutics, which will rationally target cellular and molecular targets, rather than just the dopamine 2 receptor. Future developments will target additional processes, including glutamatergic, cholinergic and cannabinoid receptor targets and will utilize personalized medicine techniques, such as pharmacogenetic variants and biomarkers allowing for a tailored and safer use of antipsychotics.

It is unknown how genetic variants conferring liability to psychiatric disorders survive in the population despite strong negative selection. However, this is key to understanding their etiology and designing studies to identify risk variants. Objectives: To examine the reproductive fitness of patients with schizophrenia and other psychiatric disorders vs their unaffected siblings and to evaluate the level of selection on causal genetic variants. Design: We measured the fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse and their unaffected siblings compared with the general population. Setting: Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register. Participants: In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden. Main Outcome Measures: Fertility ratio (FR), reflecting the mean number of children compared with that of the general population, accounting for age, sex, family size, and affected status. Results: Except for women with depression, affected patients had significantly fewer children (FR range for those with psychiatric disorder, 0.23-0.93; PϽ10 Ϫ10). This reduction was consistently greater among men than women, suggesting that male fitness was particularly sensitive. Although sisters of patients with schizophrenia and bipolar disorder had increased fecundity (FR range, 1.02-1.03; PϽ.01), this was too small on its own to counterbalance the reduced fitness of affected patients. Brothers of patients with schizophrenia and autism showed reduced fecundity (FR range, 0.94-0.97; PϽ.001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; PϽ10 Ϫ10). In the case of depression, this more than compensated for the lower fecundity of affected individuals. Conclusions: Our results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism. Bipolar disorder did not seem to be under strong negative selection. Vulnerability to depression, and perhaps substance abuse, may be preserved by balancing selection, suggesting the involvement of common genetic variants in ways that depend on other genes and on environment.

BackgroundClozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated.MethodThis is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not.ResultsSeventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25–4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44–9.56); and patients of male gender (OR 3.13 95% CI 1.35–7.23).ConclusionsFor the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

SummaryBackgroundAlthough the association between psychotic illness and cigarette smoking is well known, the reasons are unclear why people with psychosis are more likely to smoke than are the general population. We aimed to test several hypotheses. First, that daily tobacco use is associated with an increased risk of psychotic illness in both case-control and prospective studies. Second, that smoking is associated with an earlier age at onset of psychotic illness. Finally, that an earlier age at initiation of smoking is associated with an increased risk of psychosis. We also aimed to derive an estimate of the prevalence of smoking in patients presenting with their first episode of psychosis.MethodsWe searched Embase, Medline, and PsycINFO and selected observational studies in which rates of smoking were reported in people with psychotic disorders, compared with controls. We calculated the weighted mean difference for age at onset of psychosis and age at initiation of smoking. For categorical outcomes, we calculated odds ratios from cross-sectional studies and risk ratios from prospective studies.FindingsOf 3717 citations retrieved, 61 studies comprising 72 samples met inclusion criteria. The overall sample included 14 555 tobacco users and 273 162 non-users. The prevalence of smoking in patients presenting with their first episode of psychosis was 0·57 (95% CI 0·52–0·62; p<0·0001). In case-control studies, the overall odds ratio for the first episode of psychosis in smokers versus non-smokers was 3·22 (95% CI 1·63–6·33), with some evidence of publication bias (Egger's test p=0·018, Begg's test p=0·007). For prospective studies, we calculated an overall relative risk of new psychotic disorders in daily smokers versus non-smokers of 2·18 (95% CI 1·23–3·85). Daily smokers developed psychotic illness at an earlier age than did non-smokers (weighted mean difference −1·04 years, 95% CI −1·82 to −0·26). Those with psychosis started smoking at a non-significantly earlier age than did healthy controls (−0·44 years, 95% CI −1·21 to 0·34).InterpretationDaily tobacco use is associated with increased risk of psychosis and an earlier age at onset of psychotic illness. The possibility of a causal link between tobacco use and psychosis merits further examination.FundingNIHR Maudsley Biomedical Research Centre.