Influence of cannabis use on incidence of psychosis in people at clinical high risk.

AIMS: Evidence for case-control studies suggests that cannabis use is a risk factor for the development of psychosis. However, there have been limited prospective studies and the direction of this association remains controversial. The primary aim of the present study was to examine the association between cannabis use and the incidence of psychotic disorders in people at clinical high risk of psychosis. Secondary aims were to assess associations between cannabis use and the persistence of psychotic symptoms, and with functional outcome. METHODS: Current and previous cannabis use were assessed in individuals at clinical high risk of psychosis (n = 334) and healthy controls (n = 67), using a modified version of the Cannabis Experience Questionnaire. Participants were assessed at baseline and followed up for 2 years. Transition to psychosis and persistence of psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental States criteria. Level of functioning at follow up was assessed using the Global Assessment of Functioning disability scale. RESULTS: During follow up, 16.2% of the clinical high-risk sample developed psychosis. Of those who did not become psychotic, 51.4% had persistent symptoms and 48.6% were in remission. There was no significant association between any measure of cannabis use at baseline and either transition to psychosis, the persistence of symptoms, or functional outcome. CONCLUSIONS: These findings contrast with epidemiological data that suggest that cannabis use increases the risk of psychotic disorder.

Predictors of study drop-out and service disengagement in patients at clinical high risk for psychosis.

PURPOSE: Study drop-out during follow-up and service disengagement frequently occur in patients at clinical high risk for psychosis (CHR-P). However, little is known about their predictors. Therefore, we aimed to analyze the rate and reasons for drop-out and service disengagement in CHR-P patients and investigate their sociodemographic and clinical predictors. METHODS: Data from 200 patients of the prospective Früherkennung von Psychosen (FePsy) study were analyzed with competing risks survival models, considering drop-out and transition to psychosis as competing events. To investigate whether symptoms changed immediately before drop-out, t tests were applied. RESULTS: Thirty-six percent of patients dropped out within 5 years. Almost all drop-outs also disengaged from our service. Hence, study drop-out was used as a proxy for service disengagement. Patients with more severe baseline disorganized symptoms and a late inclusion into the study were significantly more likely to disengage. Immediately before disengagement, there was significant improvement in negative symptoms only. CONCLUSION: A considerable proportion of CHR-P patients disengaged from our clinical study and service. Patients who were included during a later study period with more assessments disengaged more often, which might have been due to more frequent invitations to follow-up assessments and thereby increasing participation burden. Hence, our study provides a cautionary note on high-frequency follow-up assessments. Larger-scale studies evaluating predictors on multiple domains would help to further elucidate drop-out and disengagement.

No associations between medial temporal lobe volumes and verbal learning/memory in emerging psychosis.

Grey matter (GM) volume alterations have been repeatedly demonstrated in patients with first episode psychosis (FEP). Some of these neuroanatomical abnormalities are already evident in the at-risk mental state (ARMS) for psychosis. Not only GM alterations but also neurocognitive impairments predate the onset of frank psychosis with verbal learning and memory (VLM) being among the most impaired domains. Yet, their interconnection with alterations in GM volumes remains ambiguous. Thus, we evaluated associations of different subcortical GM volumes in the medial temporal lobe with VLM performance in antipsychotic-naïve ARMS and FEP patients. Data from 59 ARMS and 31 FEP patients, collected within the prospective Früherkennung von Psychosen study, were analysed. Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging scanner. VLM was assessed using the California Verbal Learning Test and its factors Attention Span, Learning Efficiency, Delayed Memory and Inaccurate Memory. FEP patients showed significantly enlarged volumes of hippocampus, pallidum, putamen and thalamus compared to ARMS patients. A significant negative association between amygdala and pallidum volume and Attention Span was found in ARMS and FEP patients combined, which however did not withstand correction for multiple testing. Although we found significant between-group differences in subcortical volumes and VLM is among the most impaired cognitive domains in emerging psychosis, we could not demonstrate an association between low performance and subcortical GM volumes alterations in antipsychotic-naïve patients. Hence, deficits in this domain do not appear to stem from alterations in subcortical structures.

Pituitary gland volume in at-risk mental state for psychosis: a longitudinal MRI analysis.

INTRODUCTION: Pituitary enlargement has been reported in individuals with schizophrenic psychosis or an at-risk mental state for psychosis (ARMS). In a previous study, our group could show pituitary volume increase in first episode and ARMS patients with later transition to psychosis (ARMS-T). However, there are no longitudinal studies on this issue so far. We therefore examined longitudinally whether transition to psychosis would be accompanied by a further increase of pituitary volume in antipsychotic-naïve ARMS patients. METHODS: Magnetic resonance imaging (MRI) data were acquired from 23 antipsychotic-naïve individuals with an ARMS. Ten subjects developed psychosis (ARMS-T) and 13 did not (ARMS-NT). ARMS-T were re-scanned after the onset of psychosis, and ARMS-NT were re-scanned at the end of the study period. RESULTS: There was no significant difference of the pituitary volume between ARMS-T and ARMS-NT in our sample, and there were no significant pituitary volume changes over time. Discussion Longitudinally, we could not detect any further volumetric changes in the pituitary volume with transition to psychosis. CONCLUSIONS: This, together with the result of our previous study, could indicate that the perceived level of stress in ARMS patients is constantly high from very early onward.

Subjective long-term emotional and social effects of recreational MDMA use: the role of setting and intentions.

MDMA is a recreational drug commonly used to enhance euphoria, but it is also used in non-party settings with self-insight or social connection intentions. Yet, little is known about whether distinct consumer groups are formed based on consumption setting and intention. We aimed to characterize different types of recreational MDMA users based on consumption setting and intentions, and to examine their differences in perceptions of long-term social-emotional effects of MDMA use. We analyzed self-reports of 766 individuals (ages 18-61, mostly from Western countries), reporting on their MDMA consumption habits and perceived effects. We used a K-medoids clustering algorithm to identify distinct types of consumption settings and intentions. We identified three setting types - party settings with friends (N = 388), private home settings (N = 132), mixed settings (N = 246) - and three intention types - euphoria and energy (N = 302), self-insight (N = 219), mixed intentions (N = 245). Members of the self-insight and mixed intentions clusters reported considerably more long-term socio-emotional benefits than members of the euphoria and energy cluster. No differences were observed between the setting clusters. In this particular sample, more long-term benefits than harms were reported. Our findings suggest that the long-term social-emotional benefits of MDMA are associated with whether users seek self-insight or have mixed intentions.

Pharmacological and non-pharmacological predictors of the LSD experience in healthy participants.

The pharmacodynamic effects of lysergic acid diethylamide (LSD) are diverse and different in different individuals. Effects of other psychoactive substances have been shown to be critically influenced by non-pharmacological factors such as personality traits and mood states. The aim of this study was to determine pharmacological and psychological predictors of the LSD effects in healthy human subjects. This analysis is based on nine double-blind, placebo-controlled, cross-over studies with a total of 213 healthy subjects receiving between 25-200 µg LSD. The influence of sex, age, dose, body weight, pharmacogenetic, drug experience, personality, setting, and mood before drug intake on the peak autonomic and total subjective responses to LSD was investigated using multiple linear mixed effects models and Least Absolute Shrinkage and Selection Operator regression. Results were adjusted for LSD dose and corrected for multiple testing. LSD dose emerged as the most influential predictor, exhibiting a positive correlation with most response variables. Pre-drug mental states such as "Well-Being", "Emotional Excitability", and "Anxiety" were also important predictor for a range of subjective effects but also heart rate and body temperature. The trait "Openness to Experiences" was positively correlated with elevated ratings in "Oceanic Boundlessness" and mystical-type effects. Previous experiences with hallucinogens have been negatively associated with the overall altered state of consciousness and particularly with "Anxious Ego Dissolution". Acute anxiety negatively correlated with the genetically determined functionality of the Cytochrome 2D6 enzyme. In summary, besides the amount of drug consumed, non-pharmacological factors such as personal traits and current mood also significantly predicted the subjective drug experience. Sex and body weight were not significant factors in influencing the drug experience.

Individualized pretest risk estimates to guide treatment decisions in patients with clinical high risk for psychotic disorders.

INTRODUCTION: Clinical high risk for psychosis (CHR) states are associated with an increased risk of transition to psychosis. However, the predictive value of CHR screening interviews is dependent on pretest risk enrichment in referred patients. This poses a major obstacle to CHR outreach campaigns since they invariably lead to risk dilution through enhanced awareness. A potential compensatory strategy is to use estimates of individual pretest risk as a 'gatekeeper' for specialized assessment. We aimed to test a risk stratification model previously developed in London, UK (OASIS) and to train a new predictive model for the Swiss population. METHOD: The sample was composed of 513 individuals referred for CHR assessment from six Swiss early psychosis detection services. Sociodemographic variables available at referral were used as predictors whereas the outcome variable was transition to psychosis. RESULTS: Replication of the risk stratification model developed in OASIS resulted in poor performance (Harrel's c=0.51). Retraining resulted in moderate discrimination (Harrel's c=0.67) which significantly differentiated between different risk groups. The lowest risk group had a cumulative transition incidence of 6.4% (CI: 0-23.1%) over two years. CONCLUSION: Failure to replicate the OASIS risk stratification model might reflect differences in the public health care systems and referral structures between Switzerland and London. Retraining resulted in a model with adequate discrimination performance. The developed model in combination with CHR assessment result, might be useful for identifying individuals with high pretest risk, who might benefit most from specialized intervention.

Help-seeking and pathways to care in the early stages of psychosis.

PURPOSE: Delay in the treatment of a first psychotic episode can have a negative influence on the future course of the disease. In this context, it is important to examine pathways to care to understand factors contributing to delay in access to adequate care. METHODS: Using the Basel Interview for Psychosis, we examined the help-seeking behaviour of 61 individuals with an at-risk mental state for psychosis and 37 patients with a first episode of psychosis in a low threshold health care system as part of the Basel early detection of psychosis study. RESULTS: The median duration of untreated illness was 3.4 years, of untreated psychosis 12 months. Eighty-six percent of all individuals sought help of some kind before reaching our specialised early detection outpatient clinic, with a mean number of help-seeking contacts of 1.5 prior to referral. The most frequent first help-seeking contacts were family members or relatives n = 24 (26.7 %), close friends n = 17 (17.9 %), psychiatrists in private practice n = 13 (14.4 %) or general practitioners n = 11 (12.2 %). Most patients consulted other health professionals in the early course of the illness before reaching our specialised service; help-seeking with non-medical institutions was rare. Women had more help-seeking contacts than men before contact with our early detection clinic. CONCLUSIONS: Family, close friends and medical professionals play an important role in help-seeking leading to specialised psychiatric care. Men seek help less often; specific strategies for encouraging young, at-risk men to seek help should be developed.

Latent state-trait structure of BPRS subscales in clinical high-risk state and first episode psychosis.

To investigate the longitudinal latent state-trait structure of the different dimensions of psychosis symptoms in clinical high-risk state (CHRS) and first episode psychosis (FEP) individuals over a one year time-span. This paper examines if the symptom clusters Positive Symptoms, Negative Symptoms, Affectivity, Resistance, Activation, and Excitement according to the Brief Psychiatric Rating Scale (BPRS) differ in their trait and state characters in 196 CHRS and 131 FEP individuals. Statistical analysis was performed using latent state-trait analysis. On average, trait differences accounted for 72.2% of Positive Symptoms, 81.1% of Negative Symptoms, 57.0% of Affectivity, and 69.2% of Activation, whereas 15.0% of the variance of Resistance and 13.2% of the variance of Excitement were explained by trait differences. Explorative analyses showed a trait components' increase of 0.408 in Positive Symptoms from baseline up to the 9th month and an increase of 0.521 in Affectivity from baseline up to the 6th month. Negative Symptoms had the highest trait component levels of all subscales between baseline and 6 months. The finding that an increasing proportion of psychosis symptoms is persisting over time underlines the importance of early intervention programs in individuals with psychotic disorders.

Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is used both recreationally and therapeutically. Little is known about the factors influencing inter- and intra-individual differences in the acute response to MDMA. Effects of other psychoactive substances have been shown to be critically influenced by personality traits and mood state before intake. METHODS: We pooled data from 10 randomized, double-blind, placebo-controlled, cross-over studies performed in the same laboratory in 194 healthy subjects receiving doses of 75 or 125mg of MDMA. We investigated the influence of drug dose, body weight, sex, age, drug pre-experience, genetics, personality and mental state before drug intake on the acute physiological and psychological response to MDMA. RESULTS: In univariable analyses, the MDMA plasma concentration was the strongest predictor for most outcome variables. When adjusting for dose per body weight, we found that (a) a higher activity of the enzyme CYP2D6 predicted lower MDMA plasma concentration, (b) a higher score in the personality trait "openness to experience" predicted more perceived "closeness", a stronger decrease in "general inactivation", and higher scores in the 5D-ASC (5 Dimensions of Altered States of Consciousness Questionnaire) scales "oceanic boundlessness" and "visionary restructuralization", and (c) subjects with high "neuroticism" or trait anxiety were more likely to have unpleasant and/or anxious reactions. CONCLUSIONS: Although MDMA plasma concentration was the strongest predictor, several personality traits and mood state variables additionally explained variance in the response to MDMA. The results confirm that both pharmacological and non-pharmacological variables influence the response to MDMA. These findings may be relevant for the therapeutic use of MDMA.