Anna Kolliakou

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.

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.

Why do patients with psychosis use cannabis and are they ready to change their use

Numerous studies have shown that patients with psychosis are more likely to use illicit drugs than the general population, with cannabis being the most popular. There exists overwhelming evidence that cannabis use can contribute to the onset of schizophrenia and poor outcome in patients with established psychosis. Therefore, understanding why patients use cannabis and whether they are motivated to change their habits is important. The evidence is that patients with psychosis use cannabis for the same reasons the general population does, to ‘get high’, relax and have fun. There is little support for the ‘self‐medication’ hypothesis, while the literature points more towards an ‘alleviation of dysphoria’ model. There is a lack of research reporting on whether psychotic patients are ready to change their use of cannabis, which has obvious implications for identifying which treatment strategies are likely to be effective.

Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses.

BACKGROUND Clozapine 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. METHOD This 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. RESULTS Seventy 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). CONCLUSIONS For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

An Examination of Polygenic Score Risk Prediction in Individuals With First-Episode Psychosis

BACKGROUND Polygenic risk scores (PRSs) have successfully summarized genome-wide effects of genetic variants in schizophrenia with significant predictive power. In a clinical sample of first-episode psychosis (FEP) patients, we estimated the ability of PRSs to discriminate case-control status and to predict the development of schizophrenia as opposed to other psychoses. METHODS The sample (445 case and 265 control subjects) was genotyped on the Illumina HumanCore Exome BeadChip with an additional 828 control subjects of African ancestry genotyped on the Illumina Multi-Ethnic Genotyping Array. To calculate PRSs, we used the results from the latest Psychiatric Genomics Consortium schizophrenia meta-analysis. We examined the association of PRSs with case-control status and with schizophrenia versus other psychoses in European and African ancestry FEP patients and in a second sample of 248 case subjects with chronic psychosis. RESULTS PRS had good discriminative ability of case-control status in FEP European ancestry individuals (9.4% of the variance explained, p < 10-6), but lower in individuals of African ancestry (R2 = 1.1%, p = .004). Furthermore, PRS distinguished European ancestry case subjects who went on to acquire a schizophrenia diagnosis from those who developed other psychotic disorders (R2 = 9.2%, p = .002). CONCLUSIONS PRS was a powerful predictor of case-control status in a European sample of patients with FEP, even though a large proportion did not have an established diagnosis of schizophrenia at the time of assessment. PRS was significantly different between those case subjects who developed schizophrenia from those who did not, although the discriminative accuracy may not yet be sufficient for clinical utility in FEP.

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.

Neuropsychological, clinical and cognitive insight predictors of outcome in a first episode psychosis study

The outcome of first episode psychosis (FEP) is highly variable and difficult to predict. We studied prospectively the impact of poor insight and neuropsychological deficits on outcomes in a longitudinal cohort of 127 FEP patients. Participants were assessed on 5 domains of cognitive function and 2 domains of insight (clinical and cognitive). At 12 months, patients were assessed again for symptom severity and psychosocial function. Regression analyses revealed that cognitive insight (a measure of self-reflectiveness and self-certainty) was the best baseline predictor of overall psychopathology at 12 months whereas executive function performance at admission to the study indicated later severity of negative symptoms. Other neuropsychological and insight measures were poor predictors of psychosocial function at 1 year. The results suggest that specific neuropsychological and insight factors have separate predictive capacities indicating that they are distinct psychological processes in psychosis. Cognitive insight proved to be a useful prognostic indicator, and should be considered for future studies and as a potential focus for treatment.

Substance use, medication adherence and outcome one year following a first episode of psychosis

Both substance use and poor medication adherence are associated with poor outcome in psychosis. To clarify the contributions of substance use and poor medication adherence to poor outcome in the year following a first episode of psychosis, 205 patients were evaluated for use of tobacco, alcohol, cannabis and stimulants at their psychosis onset, and in a 1-year follow-up. Data on medication adherence and symptom remission were also collected. Patients had high rates of overall substance use before (37-65%) and after psychosis onset (45-66%). 44% showed poor medication adherence and 55% did not reach remission from psychosis. Nicotine dependence and cannabis use after psychosis onset significantly predicted both poor medication adherence and non-remission, and poor medication adherence mediated the effects of these substances on non-remission. In conclusion, medication adherence lies on the causal pathway between nicotine dependence and cannabis on the one hand and non-remission on the other.

Sexual dysfunction in people with prodromal or first-episode psychosis

BACKGROUND Sexual dysfunction is common in psychotic disorder but it is not clear whether it is intrinsic to the development of the illness or secondary to other factors. AIMS To compare sexual function in people at ultra-high risk (UHR) of a psychotic disorder, patients with first-episode psychosis predominantly taking antipsychotic drugs and healthy volunteers. METHOD Sexual function was assessed in a UHR group (n = 31), a group with first-episode psychosis (n = 37) and a matched control group of healthy volunteers (n = 56) using the Sexual Function Questionnaire. RESULTS There was a significant effect of group on sexual function (P<0.001). Sexual dysfunction was evident in 50% of the UHR group, 65% of first-episode patients and 21% of controls. Within the UHR group, sexual dysfunction was more marked in those who subsequently developed psychosis than in those who did not. Across all groups the severity of sexual dysfunction was correlated with the severity of psychotic symptoms (P<0.001). Within the first-episode group there was no significant difference in sexual dysfunction between patients taking prolactin-raising v. prolactin-sparing antipsychotics. CONCLUSIONS Sexual dysfunction is present prior to onset of psychosis, suggesting it is intrinsic to the development of illness unlikely to be related to the prolactin-raising properties of antipsychotic medication.

Role of Environmental Confounding in the Association between FKBP5 and First-Episode Psychosis.

Background: Failure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level. Methods: Two hundred and ninety-one first-episode psychosis cases from South London, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis. Results: Association at rs1360780 was not detected until the effects of the two environmental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23–6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. Moreover, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95). Conclusion: Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategies.