Interaction between cannabis consumption and childhood abuse in psychotic disorders: preliminary findings on the role of different patterns of cannabis use.

AIM: Several studies have suggested that lifetime cannabis consumption and childhood abuse synergistically contribute to the risk for psychotic disorders. This study aimed to extend existing findings regarding an additive interaction between childhood abuse and lifetime cannabis use by investigating the moderating role of type and frequency of cannabis use. METHODS: Up to 231 individuals presenting for the first time to mental health services with psychotic disorders and 214 unaffected population controls from South London, United Kingdom, were recruited as part of the Genetics and Psychosis study. Information about history of cannabis use was collected using the Cannabis Experiences Questionnaire. Childhood physical and sexual abuse was assessed using the Childhood Experience of Care and Abuse Questionnaire. RESULTS: Neither lifetime cannabis use nor reported exposure to childhood abuse was associated with psychotic disorder when the other environmental variable was taken into account. Although the combination of the two risk factors raised the odds for psychosis by nearly three times (adjusted OR = 2.94, 95% CI: 1.44-6.02, P = 0.003), no evidence of interaction was found (adjusted OR = 1.46, 95% CI: -0.54 to 3.46, P = 0.152). Furthermore, the association of high-potency cannabis and daily consumption with psychosis was at least partially independent of the effect of childhood abuse. CONCLUSIONS: The heavy use of high-potency cannabis increases the risk of psychosis but, in addition, smoking of traditional resin (hash) and less than daily cannabis use may increase the risk for psychosis when combined with exposure to severe childhood abuse.

Perinatal Asphyxia in Rat Alters Expression of Novel Schizophrenia Risk Genes.

Epidemiological studies suggest that obstetric complications, particularly those related to hypoxia during labor and delivery, are a risk factor for development of schizophrenia. The impact of perinatal asphyxia on postnatal life has been studied in a rodent model of global hypoxia, which is accompanied by cesarean section birth. This asphyxia model shows several behavioral, pharmacological, neurochemical, and neuroanatomical abnormalities in adulthood that have relevance to schizophrenia. Further, it is suggested that schizophrenia has a strong genetic component, and indeed novel candidate genes were recently identified by a genome-wide association study. Here, we examined alteration in the novel schizophrenia risk genes, CNNM2, CSMD1, and MMP16 in the brains of rats undergoing cesarean section with or without global hypoxia. The brain regions studied were the prefrontal cortex, striatum, and hippocampus, which are all relevant to schizophrenia. Risk gene expression was measured at three time periods: neonatal, adolescence, and adulthood. We also performed an in vitro analysis to determine involvement of these genes in CNS maturation during differentiation of human neuronal and glial cell lines. Cnnm2 expression was altered in the brains of asphyxia model rats. However, Csmd1 and Mmp16 showed altered expression by exposure to cesarean section only. These findings suggest that altered expression of these risk genes via asphyxia and cesarean section may be associated, albeit through distinct pathways, with the pathobiology of schizophrenia.

Jumping to conclusions, neuropsychological functioning, and delusional beliefs in first episode psychosis.

BACKGROUND: The "jumping to conclusions" (JTC) data-gathering bias is implicated in the development and maintenance of psychosis but has only recently been studied in first episode psychosis (FEP). In this study, we set out to establish the relationship of JTC in FEP with delusions and neuropsychological functioning. METHODS: One hundred and eight FEP patients and 101 age-matched controls completed assessments of delusions, general intelligence (IQ), working memory (WM), and JTC (the probabilistic reasoning "beads" task). RESULTS: Half the FEP participants jumped to conclusions on at least 1 task, compared with 25% of controls (OR range 2.1 to 3.9; 95% CI range 1.5 to 8.0, P values ≤ .02). JTC was associated with clinical, but not nonclinical delusion severity, and with neuropsychological functioning, irrespective of clinical status. Both IQ and delusion severity, but not WM, were independently associated with JTC in the FEP group. CONCLUSIONS: JTC is present in FEP. The specific association of JTC with clinical delusions supports a state, maintaining role for the bias. The associations of JTC with neuropsychological functioning indicate a separable, trait aspect to the bias, which may confer vulnerability to psychosis. The work has potential to inform emerging interventions targeting reasoning biases in early psychosis.

Emergency department admission and mortality rate for suicidal behavior. A follow-up study on attempted suicides referred to the ED between January 2004 and December 2010.

BACKGROUND: The international literature reports that for every completed suicide there are between 8 and 22 visits to an Emergency Department (ED) for attempted suicide/suicidal behavior. AIMS: To describe the characteristics of admission to emergency departments (EDs) for suicide-related presenting complaints in the metropolitan area of Bologna; to estimate the risk for all-cause mortality and for suicide; to identify the profiles of subjects most at risk. METHOD: Follow-up of patients admitted to the EDs of the metropolitan area of Bologna between January 2004 and December 2010 for attempted suicide. A Cox model was used to evaluate the association between sociodemographic variables and the general mortality risk. RESULTS: We identified 505 cases of attempted suicide, which were more frequent for female subjects, over the weekend, and at night (8:00 p.m./8:00 a.m.). The most used suicide methods were psychotropic drugs, sharp or blunt objects, and jumping from high places. In this cohort, 3.6% of subjects completed suicide (4.5% of males vs. 2.9% of females), 2.3% within 1 year of the start of follow-up. The most common causes of death were drug use and hanging. In the multivariate analysis, those who used illicit drugs 24 hr prior to admission to the ED (hazard ratio [HR] = 3.46, 95% CI = 1.23-9.73) and patients who refused the treatment (HR = 6.74, 95% CI = 1.86-24.40) showed an increased mortality risk for suicide. CONCLUSION: Deliberate self-harm patients presenting to the ED who refuse treatment represent a specific target group for setting up dedicated prevention schemes.

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.

What can we learn about schizophrenia from studying the human model, drug-induced psychosis?

When drug-induced psychoses were first identified in the mid-20th century, schizophrenia was considered a discrete disease with a likely genetic cause. Consequently, drug-induced psychoses were not considered central to understanding schizophrenia as they were thought to be phenocopies rather than examples of the illness secondary to a particular known cause. However, now that we know that schizophrenia is a clinical syndrome with multiple component causes, then it is clear that the drug-induced psychoses have much to teach us. This article shows how the major neuropharmacological theories of schizophrenia have their origins in studies of the effects of drugs of abuse. Research into the effects of LSD initiated the serotonergic model; amphetamines the dopamine hypothesis, PCP and ketamine the glutamatergic hypothesis, while most recently the effects of cannabis have provoked interest in the role of endocannabinoids in schizophrenia. None of these models account for the complete picture of schizophrenia; rather the various drug models mimic different aspects of the illness. Determining the different molecular effects of those drugs whose pharmacological effects do and do not mimic the various aspects of schizophrenia has much to teach us concerning the pathogenesis of the illness.

Current cannabis use and age of psychosis onset: a gender-mediated relationship? Results from an 8-year FEP incidence study in Bologna.

This study examined the relationship between gender, illicit drug use and age of onset of psychosis. We analysed data from an epidemiologically based cohort of 160 subjects with first-episode psychosis from community mental health centers. Cannabis was associated with an earlier onset of psychosis compared to other drugs, especially among women.

Social disadvantage: cause or consequence of impending psychosis?

BACKGROUND: An association between social disadvantage and established psychosis is well documented in the literature, but there remains a lack of data on the social circumstances of patients before they became ill. We investigated whether social disadvantage at, and prior to, first contact with psychiatric services, is associated with psychosis. METHOD: We collected information on social disadvantage in childhood and adulthood from 278 cases presenting with their first episode of psychosis to the South London and Maudsley National Health Service Foundation Trust and from 226 controls recruited from the local population. Three markers of childhood social disadvantage and 3 markers of disadvantage in adulthood were analyzed. RESULTS: Long term separation from, and death of, a parent before the age of 17 years were both strongly associated with a 2- to 3-fold-increased odds of psychosis. Cases were also significantly more likely to report 2 or more markers of adult social disadvantage than healthy controls (OR = 9.03) at the time of the first presentation with psychosis, independent of a number of confounders. When we repeated these analyses for long-standing adult social disadvantage, we found that the strength of the association decreased but still remained significant for 1 year (OR = 5.67) and 5 years (OR = 2.57) prior to the first contact. CONCLUSIONS: Social disadvantage indexes exposure to factors operating prior to onset that increase the risk of psychosis, both during childhood and adulthood.

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.

Pre-morbid Conduct Disorder symptoms are associated with cannabis use among individuals with a first episode of psychosis.

BACKGROUND: Early cannabis use has consistently been associated with an increased risk for the later development of psychosis. Studies suggest that Conduct Disorder (CD) is more common amongst young people who later go on to develop psychosis. CD has been associated with greater and earlier cannabis use in general population samples. Based on this evidence, we hypothesised that among patients experiencing their first episode of psychosis, the presence of CD symptoms prior to age 15 would be associated with cannabis use. METHOD: 102 patients experiencing a first episode of psychosis were interviewed to assess CD symptoms prior to age 15 and use of cannabis and other substances. RESULTS: The number of CD symptoms was significantly associated with lifetime cannabis use (odds ratio=5.41 (1.76-16.57), p=0.03) and with first use of cannabis before age 14 (odds ratio=1.46 (1.12-1.92), p=0.006), after controlling for stimulant/hallucinogen use and level of education. CONCLUSIONS: Among patients experiencing a first episode of psychosis, CD symptoms were significantly associated with use of cannabis and with use by age 14. Among individuals vulnerable for psychosis, CD symptoms may independently increase the likelihood of cannabis use which in turn increases the risk of psychosis.

High-potency cannabis and the risk of psychosis.

BACKGROUND: People who use cannabis have an increased risk of psychosis, an effect attributed to the active ingredient Delta 9-tetrahydrocannabinol (Delta 9-THC). There has recently been concern over an increase in the concentration of Delta 9-THC in the cannabis available in many countries. AIMS: To investigate whether people with a first episode of psychosis were particularly likely to use high-potency cannabis. METHOD: We collected information on cannabis use from 280 cases presenting with a first episode of psychosis to the South London & Maudsley National Health Service (NHS) Foundation Trust, and from 174 healthy controls recruited from the local population. RESULTS: There was no significant difference between cases and controls in whether they had ever taken cannabis, or age at first use. However, those in the cases group were more likely to be current daily users (OR = 6.4) and to have smoked cannabis for more than 5 years (OR = 2.1). Among those who used cannabis, 78% of the cases group used high-potency cannabis (sinsemilla, 'skunk') compared with 37% of the control group (OR 6.8). CONCLUSIONS: The finding that people with a first episode of psychosis had smoked higher-potency cannabis, for longer and with greater frequency, than a healthy control group is consistent with the hypothesis that Delta 9-THC is the active ingredient increasing risk of psychosis. This has important public health implications, given the increased availability and use of high-potency cannabis.