Fiona Gaughran

Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study

BACKGROUND The risk of individuals having adverse effects from drug use (eg, alcohol) generally depends on the frequency of use and potency of the drug used. We aimed to investigate how frequent use of skunk-like (high-potency) cannabis in south London affected the association between cannabis and psychotic disorders. METHODS We applied adjusted logistic regression models to data from patients aged 18-65 years presenting to South London and Maudsley NHS Foundation Trust with first-episode psychosis and population controls recruited from the same area of south London (UK) to estimate the effect of the frequency of use, and type of cannabis used on the risk of psychotic disorders. We then calculated the proportion of new cases of psychosis attributable to different types of cannabis use in south London. FINDINGS Between May 1, 2005, and May 31, 2011, we obtained data from 410 patients with first-episode psychosis and 370 population controls. The risk of individuals having a psychotic disorder showed a roughly three-times increase in users of skunk-like cannabis compared with those who never used cannabis (adjusted odds ratio [OR] 2·92, 95% CI 1·52-3·45, p=0·001). Use of skunk-like cannabis every day conferred the highest risk of psychotic disorders compared with no use of cannabis (adjusted OR 5·4, 95% CI 2·81-11·31, p=0·002). The population attributable fraction of first-episode psychosis for skunk use for our geographical area was 24% (95% CI 17-31), possibly because of the high prevalence of use of high-potency cannabis (218 [53%] of 410 patients) in our study. INTERPRETATION The ready availability of high potency cannabis in south London might have resulted in a greater proportion of first onset psychosis cases being attributed to cannabis use than in previous studies. FUNDING UK National Institute of Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health, SLaM and the Institute of Psychiatry at Kings College London, Psychiatry Research Trust, Maudsley Charity Research Fund, and th European Communitys Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909 [Project EU-GEI]).

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.

Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder

INTRODUCTION FGF-2 is important for stem cell proliferation, neocortical development and adult neuronal survival and growth. Reduced frontal cortical FGF-2 expression is described in major depression and is attenuated by antidepressants. We determined the distribution of hippocampal FGF-2 and its receptor (FGFR1) mRNA in post-mortem brains of people who suffered from major depression, bipolar disorder and schizophrenia and those of controls. METHODS FGF-2 and FGFR1 mRNA were measured within hippocampal CA1, CA4 regions and the dentate gyrus (DG), using in situ hybridization. Within hippocampal regions, cellular staining was compared between diagnostic groups, using repeated measures analysis of variance. RESULTS The density of FGF-2 mRNA+ cells in CA4 was reduced in depression compared to controls. The percentage of FGFR1 mRNA+ cells was higher in depression (CA1 and CA4) and schizophrenia (CA4) than in controls. FGFR1 mRNA expression was higher in depression than in the other groups in CA1, CA4 and DG. Overall FGF-2 mRNA expression was higher in DG than in CA1 and CA4. CONCLUSIONS We found raised measures of FGFR1 mRNA+ in major depression and, less so, in schizophrenia, along with reduced FGF-2 mRNA density in depression. Perturbations of FGF regulation could be relevant to the pathogenesis of both disorders as FGF-2 and FGFR1 are implicated in normal hippocampal synaptology, stem cell recruitment, and connectivity, and are modulated by corticosteroids.

Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis.

IMPORTANCE Among nontraditional cardiovascular risk factors, recent influenzalike infection is associated with fatal and nonfatal atherothrombotic events. OBJECTIVES To determine if influenza vaccination is associated with prevention of cardiovascular events. DATA SOURCES AND STUDY SELECTION A systematic review and meta-analysis of MEDLINE (1946-August 2013), EMBASE (1947-August 2013), and the Cochrane Library Central Register of Controlled Trials (inception-August 2013) for randomized clinical trials (RCTs) comparing influenza vaccine vs placebo or control in patients at high risk of cardiovascular disease, reporting cardiovascular outcomes either as efficacy or safety events. DATA EXTRACTION AND SYNTHESIS Two investigators extracted data independently on trial design, baseline characteristics, outcomes, and safety events from published manuscripts and unpublished supplemental data. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up. MAIN OUTCOMES AND MEASURES Random-effects Mantel-Haenszel risk ratios (RRs) and 95% CIs were derived for composite cardiovascular events, cardiovascular mortality, all-cause mortality, and individual cardiovascular events. Analyses were stratified by subgroups of patients with and without a history of acute coronary syndrome (ACS) within 1 year of randomization. RESULTS Five published and 1 unpublished randomized clinical trials of 6735 patients (mean age, 67 years; 51.3% women; 36.2% with a cardiac history; mean follow-up time, 7.9 months) were included. Influenza vaccine was associated with a lower risk of composite cardiovascular events (2.9% vs 4.7%; RR, 0.64 [95% CI, 0.48-0.86], P = .003) in published trials. A treatment interaction was detected between patients with (RR, 0.45 [95% CI, 0.32-0.63]) and without (RR, 0.94 [95% CI, 0.55-1.61]) recent ACS (P for interaction = .02). Results were similar with the addition of unpublished data. CONCLUSIONS AND RELEVANCE In a meta-analysis of RCTs, the use of influenza vaccine was associated with a lower risk of major adverse cardiovascular events. The greatest treatment effect was seen among the highest-risk patients with more active coronary disease. A large, adequately powered, multicenter trial is warranted to address these findings and assess individual cardiovascular end points.

Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis

Type 2 diabetes mellitus (T2DM) is highly predictive of cardiovascular diseases and can have particularly deleterious health impacts in people with severe mental illness (SMI), i.e. schizophrenia, bipolar disorder or major depressive disorder. This meta‐analysis aimed: a) to describe pooled frequencies of T2DM in people with SMI; b) to analyze the influence of demographic, illness and treatment variables as well as T2DM assessment methods; and c) to describe T2DM prevalence in studies directly comparing persons with each specific SMI diagnosis to general population samples. The trim and fill adjusted pooled T2DM prevalence among 438,245 people with SMI was 11.3% (95% CI: 10.0%‐12.6%). In antipsychotic‐naïve participants, the prevalence of T2DM was 2.9% (95% CI: 1.7%‐4.8%). There were no significant diagnostic subgroup differences. A comparative meta‐analysis established that multi‐episode persons with SMI (N=133,470) were significantly more likely to have T2DM than matched controls (N=5,622,664): relative risk, RR=1.85, 95% CI: 1.45‐2.37, p<0.001. The T2DM prevalence was consistently elevated in each of the three major diagnostic subgroups compared to matched controls. Higher T2DM prevalences were observed in women with SMI compared to men (RR=1.43, 95% CI: 1.20‐1.69, p<0.001). Multi‐episode (versus first‐episode) status was the only significant predictor for T2DM in a multivariable meta‐regression analysis (r2=0.52, p<0.001). The T2DM prevalence was higher in patients prescribed antipsychotics, except for aripriprazole and amisulpride. Routine screening and multidisciplinary management of T2DM is needed. T2DM risks of individual antipsychotic medications should be considered when making treatment choices.

Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large‐scale meta‐analysis of 3,211,768 patients and 113,383,368 controls

People with severe mental illness (SMI) – schizophrenia, bipolar disorder and major depressive disorder – appear at risk for cardiovascular disease (CVD), but a comprehensive meta‐analysis is lacking. We conducted a large‐scale meta‐analysis assessing the prevalence and incidence of CVD; coronary heart disease; stroke, transient ischemic attack or cerebrovascular disease; congestive heart failure; peripheral vascular disease; and CVD‐related death in SMI patients (N=3,211,768) versus controls (N=113,383,368) (92 studies). The pooled CVD prevalence in SMI patients (mean age 50 years) was 9.9% (95% CI: 7.4‐13.3). Adjusting for a median of seven confounders, patients had significantly higher odds of CVD versus controls in cross‐sectional studies (odds ratio, OR=1.53, 95% CI: 1.27‐1.83; 11 studies), and higher odds of coronary heart disease (OR=1.51, 95% CI: 1.47‐1.55) and cerebrovascular disease (OR=1.42, 95% CI: 1.21‐1.66). People with major depressive disorder were at increased risk for coronary heart disease, while those with schizophrenia were at increased risk for coronary heart disease, cerebrovascular disease and congestive heart failure. Cumulative CVD incidence in SMI patients was 3.6% (95% CI: 2.7‐5.3) during a median follow‐up of 8.4 years (range 1.8‐30.0). Adjusting for a median of six confounders, SMI patients had significantly higher CVD incidence than controls in longitudinal studies (hazard ratio, HR=1.78, 95% CI: 1.60‐1.98; 31 studies). The incidence was also higher for coronary heart disease (HR=1.54, 95% CI: 1.30‐1.82), cerebrovascular disease (HR=1.64, 95% CI: 1.26‐2.14), congestive heart failure (HR=2.10, 95% CI: 1.64‐2.70), and CVD‐related death (HR=1.85, 95% CI: 1.53‐2.24). People with major depressive disorder, bipolar disorder and schizophrenia were all at increased risk of CVD‐related death versus controls. CVD incidence increased with antipsychotic use (p=0.008), higher body mass index (p=0.008) and higher baseline CVD prevalence (p=0.03) in patients vs. controls. Moreover, CVD prevalence (p=0.007), but not CVD incidence (p=0.21), increased in more recently conducted studies. This large‐scale meta‐analysis confirms that SMI patients have significantly increased risk of CVD and CVD‐related mortality, and that elevated body mass index, antipsychotic use, and CVD screening and management require urgent clinical attention.

How much physical activity do people with schizophrenia engage in? A systematic review, comparative meta-analysis and meta-regression

OBJECTIVE Physical activity (PA) improves health outcomes in people with schizophrenia. It is unclear how much PA people with schizophrenia undertake and what influences PA participation. We conducted a meta-analysis to investigate PA levels and predictors in people with schizophrenia. METHOD Major databases were searched from inception till 02/2016 for articles measuring PA (self-report questionnaire (SRQ) or objective measure (e.g. accelerometer)) in people with schizophrenia, including first episode psychosis (FEP). A random effects meta-analysis and meta-regression analysis were conducted. RESULTS 35 studies representing 3453 individuals with schizophrenia (40.0years; 64.0% male) were included. Engagement in light PA was 80.44min (95% CI 68.32-92.52, n=2658), 47.1min moderate-vigorous PA (95% CI 31.5-62.8, n=559) and 1.05min (95% CI 0.48-1.62, n=2533) vigorous PA per day. People with schizophrenia engaged in significantly less moderate (hedges g=-0.45, 95% CI -0.79 to -0.1, p=0.01) and vigorous PA (g=-0.4, 95% CI -0.60 to -0.18) versus controls. Higher light to moderate, but lower vigorous PA levels were observed in outpatients and in studies utilizing objective measures versus SRQ. 56.6% (95% CI 45.8-66.8, studies=12) met the recommended 150min of moderate physical activity per week. Depressive symptoms and older age were associated with less vigorous PA in meta-regression analyses. CONCLUSIONS Our data confirm that people with schizophrenia engage in significantly less moderate and vigorous PA versus controls. Interventions aiming to increase PA, regardless of intensity are indicated for people with schizophrenia, while specifically increasing moderate-vigorous PA should be a priority given the established health benefits.

How sedentary are people with psychosis? A systematic review and meta-analysis

OBJECTIVE Sedentary behavior (SB) is an independent risk factor for cardiovascular disease and mortality. We conducted a meta-analysis to investigate SB levels and predictors in people with psychosis. METHOD Major electronic databases were searched from inception till 09/2015 for articles measuring SB with a self-report questionnaire (SRQ) or objective measure (e.g. accelerometer) in people with psychosis, including schizophrenia spectrum and bipolar disorders. A random effects meta-analysis and meta regression analysis were conducted. RESULTS Thirteen studies were eligible including 2033 people with psychosis (mean age 41.3years (range 25.1-60), 63.2% male (range 35-89%), body mass index 28.7 (range 25.9-32.1). The trim and fill analysis demonstrated people with psychosis spent 660.8min (95% CI 523.2-798.4, participants=2033) or 11.0h (95% CI 8.72-13.3) per day being sedentary. Objective measures of SB recorded significantly higher levels (p<0.001) of SB (12.6h per day, 95% CI 8.97-16.2, studies=7, participants=254) compared to self-report SB (6.85h per day, 95% CI 4.75-8.96, studies=6, participants=1779). People with psychosis engaged in significantly more SB than controls (g=1.13, 95% CI 0.496-1.77, P<0.001, n psychosis=216, n controls=159) equating to a mean difference of 2.80 (95% CI 1.47-4.1) hours per day. Multivariate meta-regression confirmed that objective measurement of SB predicted higher levels of sedentariness. CONCLUSIONS People with psychosis engage in very high levels of sedentary behavior in their waking day and current SRQ may underestimate SB. Given that SB is an independent predictor of cardiovascular disease, future interventions specifically targeting the prevention of SB are warranted.

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.

Immunity and schizophrenia: Autoimmunity, cytokines, and immune responses

As is evident from the present account, there is no single or persuasive argument that signals emanating from the immune system are directly involved in the etiology of schizophrenia. We do not even know if we are dealing with a single disorder with a single causality; almost certainly we are not. The precise etiology of schizophrenia, as with so many neurological disorders, remains obscure. However, there is abundant evidence in schizophrenia of mutual dysregulation of neuronal function and immune system activity. Although this evidence is not always consistent, a pattern emerges suggesting aspects of immune activity being involved in the pathology of neuronal development that characterizes schizophrenia. Exposure to infective agents, HLA associations, autoimmune associations, disturbances in lymphocyte populations, and cytokine imbalances with a skew toward Th2 activity are supportive of this view. That the evidence is not always consistent is a testament to the complexity and heterogeneity of the disorder, to confounding by antipsychotics that themselves are immunomodulatory, and to the multifaceted nature, with all its checks and balances, of the immune system itself.