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.

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.

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.

Continued versus discontinued cannabis use in patients with psychosis: a systematic review and meta-analysis.

BACKGROUND: Although the link between cannabis use and development of psychosis is well established, less is known about the effect of continued versus discontinued cannabis use after the onset of psychosis. We aimed to summarise available evidence focusing on the relationship between continued and discontinued cannabis use after onset of psychosis and its relapse. METHODS: In this systematic review and meta-analysis, we searched MEDLINE for articles published in any language from the database inception date up until April 21, 2015 that included a sample of patients with a pre-existing psychotic disorder with a follow-up duration of at least 6 months. We used a combination of search terms for describing cannabis, the outcome of interest (relapse of psychosis), and the study population. We excluded studies if continued cannabis use or discontinued cannabis use could not be established. We compared relapse outcomes between those who continued (CC) or discontinued (DC) cannabis use or were non-users (NC). We used summary data (individual patient data were not sought out) to estimate Cohen's d, which was entered into random effects models (REM) to compare CC with NC, CC with DC, and DC with NC. Meta-regression and sensitivity analyses were used to address the issue of heterogeneity. FINDINGS: Of 1903 citations identified, 24 studies (16 565 participants) met the inclusion criteria. Independent of the stage of illness, continued cannabis users had a greater increase in relapse of psychosis than did both non-users (dCC-NC=0·36, 95% CI 0·22-0·50, p<0·0001) and discontinued users (dCC-DC=0·28, 0·12-0·44, p=0·0005), as well as longer hospital admissions than non-users (dCC-NC=0·36, 0·13 to 0·58, p=0·02). By contrast, cannabis discontinuation was not associated with relapse (dDC-NC=0·02, -0·12 to 0·15; p=0·82). Meta-regression suggested greater effects of continued cannabis use than discontinued use on relapse (dCC-NC=0·36 vs dDC-NC=0·02, p=0·04), positive symptoms (dCC-NC=0·15 vs dDC-NC=-0·30, p=0·05) and level of functioning (dCC-NC=0·04 vs dDC-NC=-0·49, p=0·008) but not on negative symptoms (dCC-NC=-0·09 vs dDC-NC=-0·31, p=0·41). INTERPRETATION: Continued cannabis use after onset of psychosis predicts adverse outcome, including higher relapse rates, longer hospital admissions, and more severe positive symptoms than for individuals who discontinue cannabis use and those who are non-users. These findings point to reductions in cannabis use as a crucial interventional target to improve outcome in patients with psychosis. FUNDING: UK National Institute of Health Research.