James H. MacCabe

Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.

UNLABELLED 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 high-potency 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.

Excellent school performance at age 16 and risk of adult bipolar disorder: national cohort study

BACKGROUND Anecdotal and biographical reports suggest that bipolar disorder may be associated with high IQ or creativity, but evidence for any such connection is weak. AIMS To investigate possible associations between scholastic achievement and later bipolar disorder, using prospective data, in a whole-population cohort study. METHOD Using individual school grades from all individuals finishing compulsory schooling in Sweden between 1988 and 1997, we tested associations between scholastic achievement at age 15-16 and hospital admission for psychosis between ages 17 and 31, adjusting for potential confounders. RESULTS Individuals with excellent school performance had a nearly fourfold increased risk of later bipolar disorder compared with those with average grades (hazard ratio HR = 3.79, 95% CI 2.11-6.82). This association appeared to be confined to males. Students with the poorest grades were also at moderately increased risk of bipolar disorder (HR = 1.86, 95% CI 1.06-3.28). CONCLUSIONS These findings provide support for the hypothesis that exceptional intellectual ability is associated with bipolar disorder.

Fecundity of Patients With Schizophrenia, Autism, Bipolar Disorder, Depression, Anorexia Nervosa, or Substance Abuse vs Their Unaffected Siblings

CONTEXT 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; P < 10-10). 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; P < .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; P < .001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; P < 10-10). 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.

Advancing Maternal Age Is Associated With Increasing Risk for Autism: A Review and Meta-Analysis

OBJECTIVE We conducted a meta-analysis of epidemiological studies investigating the association between maternal age and autism. METHOD Using recommended guidelines for performing meta-analyses, we systematically selected, and extracted results from, epidemiological scientific studies reported before January 2012. We calculated pooled risk estimates comparing categories of advancing maternal age with and without adjusting for possible confounding factors. We investigated the influence of gender ratio among cases, ratio of infantile autism to autism spectrum disorder (ASD), and median year of diagnosis as effect moderators in mixed-effect meta-regression. RESULTS We found 16 epidemiological papers fulfilling the a priori search criteria. The meta-analysis included 25,687 ASD cases and 8,655,576 control subjects. Comparing mothers ≥ 35 years with mothers 25 to 29 years old, the crude relative risk (RR) for autism in the offspring was 1.52 (95% confidence interval [CI] = 1.12-1.92). Comparing mothers ≥ 35 with mothers 25-29, [corrected] the adjusted relative risk (RR) for autism in the offspring was 1.31 (95% CI = 1.19-1.45). [corrected] For mothers <20 compared with mothers 25 to 29 years old, there was a statistically significant decrease in risk (RR = 0.76; 95% confidence interval = 0.60-0.97). Almost all studies showed a dose-response effect of maternal age on risk of autism. The meta-regression suggested a stronger maternal age effect in the studies with more male offspring and for children diagnosed in later years. CONCLUSIONS The results of this meta-analysis support an association between advancing maternal age and risk of autism. The RR increased monotonically with increasing maternal age. The association persisted after the effects of paternal age and other potential confounders had been considered, supporting an independent relation between higher maternal age and autism.

How Genes and Environmental Factors Determine the Different Neurodevelopmental Trajectories of Schizophrenia and Bipolar Disorder

The debate endures as to whether schizophrenia and bipolar disorder are separate entities or different manifestations of a single underlying pathological process. Here, we argue that this sterile argument obscures the fact that the truth lies somewhere in between. Thus, recent studies support a model whereby, on a background of some shared genetic liability for both disorders, patients with schizophrenia have been subject to additional genetic and/or environmental factors that impair neurodevelopment; for example, copy number variants and obstetric complications are associated with schizophrenia but not with bipolar disorder. As a result, children destined to develop schizophrenia show an excess of neuromotor delays and cognitive difficulties while those who later develop bipolar disorder perform at least as well as the general population. In keeping with this model, cognitive impairments and brain structural abnormalities are present at first onset of schizophrenia but not in the early stages of bipolar disorder. However, with repeated episodes of illness, cognitive and brain structural abnormalities accumulate in both schizophrenia and bipolar disorder, thus clouding the picture.

Maternal smoking during pregnancy and school performance at age 15.

Background: Smoking during pregnancy has been suggested to have long-term consequences for neuropsychologic development in the offspring, including behavioral problems, attention deficit disorders, and antisocial behavior. Also, findings from several studies indicate an association with impaired cognitive function in the children. Methods: In a population-based Swedish cohort study, we examined possible associations between maternal smoking in pregnancy and educational achievement in the offspring at age 15 years among more than 400,000 male and female students born 1983 through 1987. Generalized estimating equation models were used to evaluate associations of maternal smoking, other maternal characteristics, and birth characteristics with school performance. Odds ratios (ORs) were used as a measure of risk. Results: In a model adjusted for maternal characteristics, maternal smoking compared with no tobacco use during pregnancy was associated with an increased risk of poor scholastic achievement: for 1–9 cigarettes per day, the OR was 1.59 (95% confidence interval = 1.59–1.63) and for 10 or more cigarettes per day, the OR was 1.92 (1.86–1.98). These risks remained unchanged when we also adjusted for smoking-related pregnancy outcomes such as fetal growth restriction and preterm birth. However, if the mother had smoked in her first pregnancy, but not in her second pregnancy, the younger sibling was also at increased risk of poor school performance. Conclusion: Observed associations between maternal smoking during pregnancy and poor cognitive performance in the offspring might not be causal. We suggest that associations reported in earlier studies may instead reflect the influence of unmeasured characteristics that differ between smokers and nonsmokers.

Does tobacco use cause psychosis? Systematic review and meta-analysis

Summary Background Although 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. Methods We 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. Findings Of 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 (Eggers test p=0·018, Beggs 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). Interpretation Daily 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. Funding NIHR Maudsley Biomedical Research Centre.

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors 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, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) 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 or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Scholastic achievement at age 16 and risk of schizophrenia and other psychoses: a national cohort study.

BACKGROUND There is abundant evidence that schizophrenia is associated with cognitive deficits in childhood. However, previous studies investigating school performance have been inconclusive. Furthermore, there are several biological and social factors that could confound the association. We investigated whether school performance at age 16 is associated with risk of adult schizophrenia and other psychoses in a large national cohort, while controlling for multiple confounders. METHOD Using a national sample of 907 011 individuals born in Sweden between 1973 and 1983, we used Cox regression to assess whether scholastic achievement at age 15-16 predicted hospital admission for psychosis between ages 17 and 31, adjusting for potential confounders. RESULTS Poor school performance was associated with increased rates of schizophrenia [hazard ratio (HR) 3.9, 95% confidence interval (CI) 2.8-5.3], schizo-affective disorder (HR 4.2, 95% CI 1.9-9.1) and other psychoses (HR 3.0, 95% CI 2.3-4.0). Receiving the lowest (E) grade was significantly associated with risk for schizophrenia and other psychoses in every school subject. There was no evidence of confounding by migrant status, low birthweight, hypoxia, parental education level or socio-economic group. CONCLUSIONS Poor school performance across all domains is strongly associated with risk for schizophrenia and other psychoses.

Decline in cognitive performance between ages 13 and 18 years and the risk for psychosis in adulthood: a Swedish longitudinal cohort study in males

CONTEXT Clear evidence from many prospective, population-based studies indicates that patients who develop psychosis in adulthood experienced various cognitive deficits during childhood and adolescence. However, it is unclear whether these deficits become more severe during adolescence. OBJECTIVE To assess the influence of cognitive developmental trajectories in adolescence and young adulthood on the risk for psychosis in adulthood. DESIGN Longitudinal cohort study. SETTING Academic research. POPULATION-BASED COHORTS: Four population-based cohorts of adolescent boys and young men born in Sweden in 1953, 1967, 1972, and 1977, totaling 10,717 individuals, and followed up through December 31, 2006. EXPOSURE Scores on tests of verbal, spatial, and inductive ability at age 13 years and in equivalent tests at army conscription (age 18 years). MAIN OUTCOME MEASURE Hospital admissions for nonaffective or affective psychoses in adulthood. RESULTS A relative decline (compared with the unaffected population) in verbal ability between ages 13 and 18 years was associated with increased risk for schizophrenia and for other nonaffective and affective psychoses (adjusted hazard ratio for schizophrenia for an increase of 1 SD in verbal ability, 0.59; 95% CI, 0.40-0.88; P = .009). Decline between ages 13 and 18 years was a much stronger predictor of psychosis than the verbal ability score at age 18 years alone. The association remained significant after adjustment for urbanicity, parental educational level, and family history of psychosis and persisted when cases with onset before age 25 years were excluded, indicating that this was not a prodromal effect. CONCLUSIONS A relative decline in cognitive performance in adolescence and young adulthood, particularly in verbal ability, is associated with increased risk for psychosis in adulthood, and a relative decline in verbal ability between ages 13 and 18 years is a stronger predictor of psychosis than verbal ability at age 18 years alone. This suggests an impairment of late neurodevelopment affecting the acquisition of verbal skills in adolescent boys and young men who later develop psychosis.