Association of extent of cannabis use and psychotic like intoxication experiences in a multi-national sample of first episode psychosis patients and controls.

BACKGROUND: First episode psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in patients and controls and whether this differs between groups. METHODS: We analysed data on patients who had ever used cannabis (n = 655) and controls who had ever used cannabis (n = 654) across 15 sites from six countries in the EU-GEI study (2010-2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use. RESULTS: Caseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences (p ⩽ 0.001). For psychotic-like experiences (PEs) there was a significant interaction for caseness × frequency of use (p < 0.001) and caseness × money spent on cannabis (p = 0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no significant interaction for euphoric experiences (p > 0.5). CONCLUSIONS: FEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher levels of cannabis use compared to controls. This suggests a specific psychotomimetic response in FEP patients related to heavy cannabis use. Clinicians should enquire regarding cannabis related PEs and advise that lower levels of cannabis use are associated with less frequent PEs.

Early magnetic resonance imaging biomarkers of schizophrenia spectrum disorders: Toward a fetal imaging perspective.

There is mounting evidence to implicate the intrauterine environment as the initial pathogenic stage for neuropsychiatric disease. Recent developments in magnetic resonance imaging technology are making a multimodal analysis of the fetal central nervous system a reality, allowing analysis of structural and functional parameters. Exposures to a range of pertinent risk factors whether preconception or in utero can now be indexed using imaging techniques within the fetus' physiological environment. This approach may determine the first "hit" required for diseases that do not become clinically manifest until adulthood, and which only have subtle clinical markers during childhood and adolescence. A robust characterization of a "multi-hit" hypothesis may necessitate a longitudinal birth cohort; within this investigative paradigm, the full range of genetic and environmental risk factors can be assessed for their impact on the early developing brain. This will lay the foundation for the identification of novel biomarkers and the ability to devise methods for early risk stratification and disease prevention. However, these early markers must be followed over time: first, to account for neural plasticity, and second, to assess the effects of postnatal exposures that continue to drive the individual toward disease. We explore these issues using the schizophrenia spectrum disorders as an illustrative paradigm. However, given the potential richness of fetal magnetic resonance imaging, and the likely overlap of biomarkers, these concepts may extend to a range of neuropsychiatric conditions.

Cannabis use in patients with early psychosis is associated with alterations in putamen and thalamic shape.

Around half of patients with early psychosis have a history of cannabis use. We aimed to determine if there are neurobiological differences in these the subgroups of persons with psychosis with and without a history of cannabis use. We expected to see regional deflations in hippocampus as a neurotoxic effect and regional inflations in striatal regions implicated in addictive processes. Volumetric, T1w MRIs were acquired from people with a diagnosis psychosis with (PwP + C = 28) or without (PwP - C = 26) a history of cannabis use; and Controls with (C + C = 16) or without (C - C = 22) cannabis use. We undertook vertex-based shape analysis of the brainstem, amygdala, hippocampus, globus pallidus, nucleus accumbens, caudate, putamen, thalamus using FSL FIRST. Clusters were defined through Threshold Free Cluster Enhancement and Family Wise Error was set at p < .05. We adjusted analyses for age, sex, tobacco and alcohol use. The putamen (bilaterally) and the right thalamus showed regional enlargement in PwP + C versus PwP - C. There were no areas of regional deflation. There were no significant differences between C + C and C - C. Cannabis use in participants with psychosis is associated with morphological alterations in subcortical structures. Putamen and thalamic enlargement may be related to compulsivity in patients with a history of cannabis use.

Psychotic-like experiences with cannabis use predict cannabis cessation and desire to quit: a cannabis discontinuation hypothesis.

BACKGROUND: Evidence suggests that cannabis-induced psychotic-like experiences may be a marker of psychosis proneness. The effect of such experiences on cannabis use has not systematically been examined. METHODS: We undertook a mixed-methods online survey of 1231 cannabis users (including 926 continued users) using the Cannabis Experiences Questionnaire. We examined the effect of psychotic-like and pleasurable experiences on cessation of cannabis and intention to quit. Socio-demographic variables, cannabis use parameters and substance misuse history were included as covariates. Free-text data explored subjective reasons for changes in use. RESULTS: Cessation of cannabis use was associated with greater psychotic-like experiences [p < 0.001, Exp(B) 1.262, 95% confidence interval (CI) 1.179-1.351], whilst continued cannabis users were more likely to report pleasurable experiences [p < 0.001, Exp(B) 0.717, 95% CI 0.662-0.776]. Intention to quit cannabis in continued users was associated with greater psychotic-like experiences [p < 0.003, Exp(B) 1.131, 95% CI 1.044-1.225], whilst intention to not quit was significantly associated with increased pleasurable experiences [p < 0.015, Exp(B) 0.892, 95% CI 0.814-0.978]. Whereas former users clearly ascribed cessation to negative experiences, continued users who expressed intention to quit less readily ascribed the intention to negative experiences. CONCLUSIONS: Elucidation of psychotic-like experiences may form the basis of a therapeutic intervention for those who wish to quit. Cessation in those with cannabis-induced psychotomimetic experiences may offset the risk for the development of a psychotic disorder, in this higher risk group.

The natural course of anxiety disorders in the elderly: a systematic review of longitudinal trials.

BACKGROUND: The anxiety disorders are a prevalent mental health problem in older age with a considerable impact on quality of life. Until recently there have been few longitudinal studies on anxiety in this age group, consequently most of the evidence to date has been cross-sectional in nature. METHODS: We undertook a literature search of Medline, PsycINFO, the Cochrane trials database and the TRIP medical database to identify longitudinal studies which would help elucidate natural history and prognosis of anxiety disorders in the elderly. RESULTS: We identified 12 papers of 10 longitudinal studies in our Review. This represented 34,691 older age participants with 5,199 with anxiety disorders including anxious depression and 3,532 individuals with depression without anxiety. Relapse rates of anxiety disorders are high over 6 year follow-up with considerable migration to mixed anxiety-depression and pure depressive mood episodes. Mixed anxiety-depression appears to be a poorer prognostic state than pure anxiety or pure depression with higher relapse rates across studies. In community settings treatment rates are low with 7-44% of the anxious elderly treated on antidepressant medications. CONCLUSIONS: To our knowledge this is the first Systematic Review of longitudinal trials of anxiety disorders in older people. Major longitudinal studies of the anxious elderly are establishing the high risk of relapse and persistence alongside the progression to depression and anxiety depression states. There remains considerable under-treatment in community studies. Specialist assessment and treatment and major public health awareness of the challenges of anxiety disorders in the elderly are required.

Psychosis, psychedelic substance misuse and head injury: A case report and 23 year follow-up.

BACKGROUND: This study describes the case of a 57 year old gentleman with a previous severe brain injury who developed a severe psychotic disorder 19 years after the injury. This appears to have been precipitated by heavy psychedelic substance use, including cannabis, salvia divinorum, ketamine, LSD, cocaine and DMT amongst others. The psychosis remained in the absence of drug intoxication and was associated with prominent apathy, lack of concern and abulia. CASE STUDY: This study discusses the heavy psychedelic substance misuse possibly potentiating a transition to psychosis in this individual. Little work has been undertaken in this area as substance misuse has traditionally been an exclusion criteria for investigating psychosis in this patient group. CONCLUSIONS: It is suggested that psychedelic substance misuse should be investigated as a risk factor for psychotic illness in patients with brain injury, as this case clearly suggests.

The effectiveness of dopamine agonists for treatment of neuropsychiatric symptoms post brain injury and stroke.

OBJECTIVE: Traumatic brain injury and stroke are among the leading causes of neurological disability worldwide. Although dopaminergic agents have long been associated with improvement of neuropsychiatric outcomes, to date much of the evidence to date has been in case reports and case series or open label trials. METHODS: We undertook a systematic review of double-blinded randomised controlled trials (RCT) to determine the effect of dopaminergic agents on pre-defined outcomes of (a) apathy; (b) psychomotor retardation; (c) behavioural management and (d) cognitive function. Databases searched were: Medline, EMBASE, and PsychInfo for human studies. The Cochrane Clinical Trials Database and the TRIP Medical database were also searched. All identified studies, were further hand-searched. RESULTS: We identified six studies providing data on 227 participants, 150 of whom received dopaminergic therapy. Trials were compromised by cross-over design, inadequate wash out period, small numbers and heterogeneous outcome measures. However one good quality RCT demonstrates the efficacy of amantadine in behavioural management. One further RCT shows methylphenidate-levodopa is efficacious for mood post-stroke. One study shows rotigotine to improve hemi-inattention caused by prefrontal damage. CONCLUSION: Our systematic review demonstrates an evolving evidence base to suggest some benefits in agitation and aggression, mood and attentional deficits. However, there are key limitations of the studies undertaken to date involving small numbers of participants, heterogeneous outcome measures, and variable study designs. There is a need for on-going large prospective double-blind RCTs in these medications using standardised criteria and outcomes to fully understand their effectiveness in this patient group.

A brief note from Pakistan: reflections from a British psychiatrist.

A British general adult psychiatrist born and trained in the UK, who also considers himself Pakistani, had the opportunity to spend 2 weeks running a psychiatric clinic in a remote hospital in the Punjab province of Pakistan. In this article he offers some reflections on the unexpected culture shock he felt, on the hospital system, the patients he treated and their resilience in such a poor country.

Tracking subjects' strategies in behavioural choice experiments at trial resolution.

Investigating how, when, and what subjects learn during decision-making tasks requires tracking their choice strategies on a trial-by-trial basis. Here, we present a simple but effective probabilistic approach to tracking choice strategies at trial resolution using Bayesian evidence accumulation. We show this approach identifies both successful learning and the exploratory strategies used in decision tasks performed by humans, non-human primates, rats, and synthetic agents. Both when subjects learn and when rules change the exploratory strategies of win-stay and lose-shift, often considered complementary, are consistently used independently. Indeed, we find the use of lose-shift is strong evidence that subjects have latently learnt the salient features of a new rewarded rule. Our approach can be extended to any discrete choice strategy, and its low computational cost is ideally suited for real-time analysis and closed-loop control.

Trajectories of adolescent psychotic-like experiences and early cannabis exposure: Results from a Finnish Birth Cohort Study.

BACKGROUND: Longitudinal studies examining the effect of cannabis exposure (CE) on the prognosis of adolescents with psychotic-like experiences (PLEs) are scarce. We examined trajectories of mental health in adolescents with PLEs and cannabis exposure. METHODS: The Northern Finland Birth Cohort 1986 (n = 6552) with linkage to nationwide register data was used. Information on lifetime cannabis exposure was collected when participants were aged 15/16. Register-based outcome data on diagnoses made in clinical practice were obtained until age 33. Logistic regression was used to study the association of PLE/CE patterns and subsequent psychiatric disorders. The group with neither PLEs nor CE was utilized as the reference group. Parental psychiatric disorders, family structure, sex, frequent alcohol intoxications, daily smoking and illicit substance use other than cannabis were adjusted for. RESULTS: In all, 6552 subjects (49.2 % males) were included in analysis. PLEs with cannabis exposure were associated with any psychiatric disorder (OR = 2.59; 95 % CI 1.82-3.68), psychotic disorders (OR = 3.86; 95 % CI 1.83-8.11), mood disorders (OR 4.07; 95 % CI 2.74-6.04), depressive disorders (OR = 4.35; 95 % CI 2.93-6.48), anxiety disorders (OR = 2.06; 95 % CI 1.34-3.17) and substance use disorders (OR = 2.26; 95 % CI 1.13-4.50) compared to reference group. Effect sizes were greater for group with both PLEs and cannabis use than for group with PLEs only. CONCLUSIONS: Early-onset cannabis use is an adverse prognostic marker for adolescents with PLEs after extensive confounder control including other substance use.

Is early exposure to cannabis associated with bipolar disorder? Results from a Finnish birth cohort study.

BACKGROUND AND AIMS: There are few longitudinal studies assessing the association of cannabis use and subsequent onset of bipolar disorder. We aimed to measure the association between early cannabis exposure and subsequent bipolar disorder. DESIGN, SETTING AND PARTICIPANTS: Observational study linking a sample from the northern Finland birth cohort 1986 (n = 6325) to nation-wide register data to examine the association of life-time cannabis exposure at age 15/16 years and subsequent bipolar disorder until age 33 (until the end of 2018); 6325 individuals (48.8% males) were included in the analysis. MEASUREMENTS: Cannabis exposure was measured via self-report. Bipolar disorder was measured via bipolar disorder-related diagnostic codes (ICD-10: F30.xx, F31.xx) collected from the Care Register for Health Care 2001-18, the Register of Primary Health Care Visits 2011-18, the medication reimbursement register of the Social Insurance Institution of Finland 2001-05 and the disability pensions of the Finnish Center for Pensions 2001-16. Potential confounders included demographic characteristics, parental psychiatric disorders, emotional and behavioral problems and other substance use. FINDINGS: Three hundred and fifty-two adolescents (5.6%) reported any cannabis use until the age of 15-16 years. Of the whole sample, 66 (1.0%) were diagnosed with bipolar disorder. Adolescent cannabis use was associated with bipolar disorder [hazard ratio (HR) = 3.46; 95% confidence interval (CI) = 1.81-6.61]. This association remained statistically significant after adjusting for sex, family structure and parental psychiatric disorders (HR = 3.00; 95% CI = 1.47-6.13) and after further adjusting for adolescent emotional and behavioral problems (HR = 2.34; 95% CI = 1.11-4.94). Further adjustments for frequent alcohol intoxications, daily smoking and lifetime illicit drug use attenuated the associations to statistically non-significant. CONCLUSIONS: In Finland, the positive association between early cannabis exposure and subsequent development of bipolar disorder appears to be confounded by other substance use.

Are researchers getting the terms used to denote different types of recreational cannabis right?-a user perspective.

BACKGROUND: While current cannabis research has advanced our understanding into the effects of its individual components, there is a pressing need to identify simple terminology that is understood in the same way by researchers and users of cannabis. Current categorisation in research focuses on the two main cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD); and two different species of cannabis: indica and sativa. Recreational cannabis has also been categorised by researchers as 'skunk' or 'hash'. Focusing on individuals who use cannabis frequently, this study aimed to identify views on current terms used to denote different types of cannabis and to identify terms validated by participants. These views were extracted from responses of the Cannabis Experiences Questionnaire (CEQ), a widely used instrument in the literature. METHODS: We qualitatively analysed 236 free-text responses from Question 23 of the CEQ survey (using Iterative Categorisation) relating to categorization and consumption methods. Data was used from a previous study (Sami et al., Psychol Med 49:103-12, 2019), which recruited a convenience sample of 1231 participants aged 18 years and above who had previously used cannabis. RESULTS: Regarding type of cannabis used, specific strain names (n = 130), concentrates (n = 37), indica/sativa (n = 22) and THC/CBD terms (n = 22) were mentioned. Other terms used were hybrids (n = 10), origins of specific strains (n = 17), edibles (n = 8), and herbal cannabis (n = 7). Regarding problems with specific terms, participants were skeptical about terms such as skunk and super skunk (n = 78) preferring terms like THC/CBD, indica/sativa, specific marketed strains and references to preparation methods. CONCLUSIONS: The results suggest a disparity between the common terms used by researchers in academia and those used by cannabis consumers. While there are advantages and limitations of using these terms to bridge views of researchers and individuals who use cannabis, this study underscores the importance of formally assessing chemical constituents rather than relying on self-report data and of incorporating cannabis user views on current terms used in research, potentially also incorporating descriptors of preparation and consumption methods.

Eye movements in patients in early psychosis with and without a history of cannabis use.

It is unclear whether early psychosis in the context of cannabis use is different from psychosis without cannabis. We investigated this issue by examining whether abnormalities in oculomotor control differ between patients with psychosis with and without a history of cannabis use. We studied four groups: patients in the early phase of psychosis with a history of cannabis use (EPC; n = 28); patients in the early phase of psychosis without (EPNC; n = 25); controls with a history of cannabis use (HCC; n = 16); and controls without (HCNC; n = 22). We studied smooth pursuit eye movements using a stimulus with sinusoidal waveform at three target frequencies (0.2, 0.4 and 0.6 Hz). Participants also performed 40 antisaccade trials. There were no differences between the EPC and EPNC groups in diagnosis, symptom severity or level of functioning. We found evidence for a cannabis effect (χ2 = 23.14, p < 0.001), patient effect (χ2 = 4.84, p = 0.028) and patient × cannabis effect (χ2 = 4.20, p = 0.04) for smooth pursuit velocity gain. There was a large difference between EPC and EPNC (g = 0.76-0.86) with impairment in the non cannabis using group. We found no significant effect for antisaccade error whereas patients had fewer valid trials compared to controls. These data indicate that impairment of smooth pursuit in psychosis is more severe in patients without a history of cannabis use. This is consistent with the notion that the severity of neurobiological alterations in psychosis is lower in patients whose illness developed in the context of cannabis use.

Association of cannabis with glutamatergic levels in patients with early psychosis: Evidence for altered volume striatal glutamate relationships in patients with a history of cannabis use in early psychosis.

The associative striatum, an established substrate in psychosis, receives widespread glutamatergic projections. We sought to see if glutamatergic indices are altered between early psychosis patients with and without a history of cannabis use and characterise the relationship to grey matter. 92 participants were scanned: Early Psychosis with a history of cannabis use (EPC = 29); Early Psychosis with minimal cannabis use (EPMC = 25); Controls with a history of cannabis use (HCC = 16) and Controls with minimal use (HCMC = 22). Whole brain T1 weighted MR images and localised proton MR spectra were acquired from head of caudate, anterior cingulate and hippocampus. We examined relationships in regions with known high cannabinoid 1 receptor (CB1R) expression (grey matter, cortex, hippocampus, amygdala) and low expression (white matter, ventricles, brainstem) to caudate Glutamine+Glutamate (Glx). Patients were well matched in symptoms, function and medication. There was no significant group difference in Glx in any region. In EPC grey matter volume explained 31.9% of the variance of caudate Glx (p = 0.003) and amygdala volume explained 36.9% (p = 0.001) of caudate Glx. There was no significant relationship in EPMC. The EPC vs EPMC interaction was significant (p = 0.042). There was no such relationship in control regions. These results are the first to demonstrate association of grey matter volume and striatal glutamate in the EPC group. This may suggest a history of cannabis use leads to a conformational change in distal CB1 rich grey matter regions to influence striatal glutamatergic levels or that such connectivity predisposes to heavy cannabis use.

The 2019 Schizophrenia International Research Society Conference, 10-14 April, Orlando, Florida: A summary of topics and trends.

The Schizophrenia International Research Society (SIRS) recently held its first North American congress, which took place in Orlando, Florida from 10-14 April 2019. The overall theme of this year's congress was United in Progress - with the aim of cultivating a collaborative effort towards advancing the field of schizophrenia research. Student travel awardees provided reports of the oral sessions and concurrent symposia that took place during the congress. A collection of these reports is summarized and presented below and highlights the main themes and topics that emerged during the congress. In summary, the congress covered a broad range of topics relevant to the field of psychiatry today.

Premorbid Adjustment and IQ in Patients With First-Episode Psychosis: A Multisite Case-Control Study of Their Relationship With Cannabis Use.

Psychotic patients with a lifetime history of cannabis use generally show better cognitive functioning than other psychotic patients. Some authors suggest that cannabis-using patients may have been less cognitively impaired and less socially withdrawn in their premorbid life. Using a dataset comprising 948 patients with first-episode psychosis (FEP) and 1313 population controls across 6 countries, we examined the extent to which IQ and both early academic (Academic Factor [AF]) and social adjustment (Social Factor [SF]) are related to the lifetime frequency of cannabis use in both patients and controls. We expected a higher IQ and a better premorbid social adjustment in psychotic patients who had ever used cannabis compared to patients without any history of use. We did not expect such differences in controls. In both patients and controls, IQ was 3 points higher among occasional-users than in never-users (mean difference [Mdiff] = 2.9, 95% CI = [1.2, 4.7]). Both cases and control daily-users had lower AF compared to occasional (Mdiff = -0.3, 95% CI = [-0.5; -0.2]) and never-users (Mdiff = -0.4, 95% CI = [-0.6; -0.2]). Finally, patient occasional (Mdiff = 0.3, 95% CI = [0.1; 0.5]) and daily-users (Mdiff = 0.4, 95% CI = [0.2; 0.6]) had better SF than their never-using counterparts. This difference was not present in controls (Fgroup*frequency(2, 2205) = 4.995, P = .007). Our findings suggest that the better premorbid social functioning of FEP with a history of cannabis use may have contributed to their likelihood to begin using cannabis, exposing them to its reported risk-increasing effects for Psychotic Disorders.

Are cannabis-using and non-using patients different groups? Towards understanding the neurobiology of cannabis use in psychotic disorders.

A substantial body of credible evidence has accumulated that suggest that cannabis use is an important potentially preventable risk factor for the development of psychotic illness and its worse prognosis following the onset of psychosis. Here we summarize the relevant evidence to argue that the time has come to investigate the neurobiological effects of cannabis in patients with psychotic disorders. In the first section we summarize evidence from longitudinal studies that controlled for a range of potential confounders of the association of cannabis use with increased risk of developing psychotic disorders, increased risk of hospitalization, frequent and longer hospital stays, and failure of treatment with medications for psychosis in those with established illness. Although some evidence has emerged that cannabis-using and non-using patients with psychotic disorders may have distinct patterns of neurocognitive and neurodevelopmental impairments, the biological underpinnings of the effects of cannabis remain to be fully elucidated. In the second and third sections we undertake a systematic review of 70 studies, including over 3000 patients with psychotic disorders or at increased risk of psychotic disorder, in order to delineate potential neurobiological and neurochemical mechanisms that may underlie the effects of cannabis in psychotic disorders and suggest avenues for future research.