Marta Di Forti

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.

Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: The role of stress and of antipsychotic treatment

First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60min after awakening, and at 12 and 8pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p<0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=-0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.

Gene-Environment Interplay Between Cannabis and Psychosis

Cannabis use is considered a contributory cause of schizophrenia and psychotic illness. However, only a small proportion of cannabis users develop psychosis. This can partly be explained by the amount and duration of the consumption of cannabis and by its strength but also by the age at which individuals are first exposed to cannabis. Genetic factors, in particular, are likely to play a role in the short- and the long-term effects cannabis may have on psychosis outcome. This review will therefore consider the interplay between genes and exposure to cannabis in the development of psychotic symptoms and schizophrenia. Studies using genetic, epidemiological, experimental, and observational techniques will be discussed to investigate gene-environment correlation gene-environment interaction, and higher order interactions within the cannabis-psychosis association. Evidence suggests that mechanisms of gene-environment interaction are likely to underlie the association between cannabis and psychosis. In this respect, multiple variations within multiple genes--rather than single genetic polymorphisms--together with other environmental factors (eg, stress) may interact with cannabis to increase the risk of psychosis. Further research on these higher order interactions is needed to better understand the biological pathway by which cannabis use, in some individuals, may cause psychosis in the short- and long term.

Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: a pathway to smaller hippocampal volume.

BACKGROUND Reduced brain-derived neurotrophic factor (BDNF) levels have been reported in the serum and plasma of patients with psychosis. The aim of this cross-sectional case-control study was to investigate potential causes and consequences of reduced BDNF expression in these patients by examining the association between BDNF levels and measures of stress, inflammation, and hippocampal volume in first-episode psychosis. METHOD Brain-derived neurotrophic factor, interleukin (IL)-6, and tumor necrosis factor (TNF)-α messenger RNA levels were measured in the leukocytes of 49 first-episode psychosis patients (DSM-IV criteria) and 30 healthy controls, all aged 18 to 65 years, recruited between January 2006 and December 2008. Patients were recruited from inpatient and outpatient units of the South London and Maudsley National Health Service Foundation Trust in London, United Kingdom, and the healthy controls were recruited from the same catchment area via advertisement and volunteer databases. In these same subjects, we measured salivary cortisol levels and collected information about psychosocial stressors (number of childhood traumas, number of recent stressors, and perceived stress). Finally, hippocampal volume was measured using brain magnetic resonance imaging in a subsample of 19 patients. RESULTS Patients had reduced BDNF (effect size, d = 1.3; P < .001) and increased IL-6 (effect size, d = 1.1; P < .001) and TNF-α (effect size, d = 1.7; P < .001) gene expression levels when compared with controls, as well as higher levels of psychosocial stressors. A linear regression analysis in patients showed that a history of childhood trauma and high levels of recent stressors predicted lower BDNF expression through an inflammation-mediated pathway (adjusted R(2) = 0.23, P = .009). In turn, lower BDNF expression, increased IL-6 expression, and increased cortisol levels all significantly and independently predicted a smaller left hippocampal volume (adjusted R(2) = 0.71, P < .001). CONCLUSIONS Biological changes activated by stress represent a significant factor influencing brain structure and function in first-episode psychosis through an effect on BDNF.

Schizophrenia as a GSK-3 dysregulation disorder

Converging evidence suggests that the regulation of glycogen synthase kinase 3 (GSK-3) might be important in schizophrenia. Atypical and typical antipsychotic drugs alter GSK-3 activity, as do drugs that induce psychosis. GSK-3 regulatory pathways are altered in schizophrenia, and many of the genes associated with schizophrenia directly or indirectly regulate GSK-3 activity. We propose a variant on the neurodevelopment and dopamine hypotheses of schizophrenia, whereby (i) an early dysfunction in GSK-3 regulation has neurodevelopmental consequences that predispose to disease and (ii) dysfunction in GSK-3 regulation in the adult brain alters dopamine signalling events, causing psychotic symptoms and cognitive dysfunction. If, as we suggest, GSK-3 regulation is crucial to schizophrenia, the Wnt and insulin signalling pathways become targets for therapy.

Confirmation that the AKT1 (rs2494732) Genotype Influences the Risk of Psychosis in Cannabis Users

BACKGROUND Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect. METHODS In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis. RESULTS The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction = 8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio = 2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio = 13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio = 7.23 [95% confidence interval: 1.37, 38.12]). CONCLUSIONS Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users.

Drug-Induced Psychosis: How to Avoid Star Gazing in Schizophrenia Research by Looking at More Obvious Sources of Light

The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia.

Schizophrenia: from developmental deviance to dopamine dysregulation.

Two major theories of schizophrenia are respectively, the neurodevelopmental hypothesis and the dopamine hypothesis. Each of these has recently been revised. Firstly, the classical neurodevelopmental hypothesis has been modified to include the pathogenic effects of psychostimulants and cannabis abuse, and also of chronic social adversity; it is perhaps now more appropriately termed, the developmental hypothesis. Secondly, recent amendments to the dopamine hypothesis suggest that excess striatal dopamine is responsible for increased salience being given to insignificant events and thoughts, and that this underpins the development of psychotic symptoms. Traditionally, it has been thought that this striatal dopamine dysregulation might be secondary to frontal dysfunction. However, recent animal research shows that over-expression of striatal D(2) receptors results in frontal dysfunction manifesting as cognitive difficulties and animal equivalents of so-called negative symptoms. This raises the question whether early intervention may prevent the development of these latter problems. Finally, the two theories are beginning to be integrated through the growing evidence that all the developmental risk factors which increase risk of schizophrenia appear to act by facilitating dopamine dysregulation.

Cannabis use in young people: The risk for schizophrenia

Cannabis is one of the most commonly used illicit drugs, and despite the widely held belief that it is a safe drug, its long-term use has potentially harmful consequences. To date, the research on the impact of its use has largely been epidemiological in nature and has consistently found that cannabis use is associated with schizophrenia outcomes later in life, even after controlling for several confounding factors. While the majority of users can continue their use without adverse effects, it is clear from studies of psychosis that some individuals are more vulnerable to its effects than others. In addiction, evidence from both epidemiological and animal studies indicates that cannabis use during adolescence carries particular risk. Further studies are warranted given the increase in the concentration of the main active ingredient (Δ(9)-tetrahydrocannabinol) in street preparations of cannabis and a decreasing age of first-time exposure to cannabis.