Childhood Trauma And Cannabis Interactions In Affecting Psychosis Onset: Role Of The Anterior-Posterior Axis Of The Hippocampus and Differences In Cannabis Use Before or After Psychosis Onset

Importance: Cannabis (CA) and childhood trauma (CHT) independently increase the risk of developing psychosis. The interaction between CA and CHT in relation to psychosis risk and its association with endocannabinoid receptor rich brain regions such as the hippocampus (HP), remains to be elucidated. Objective: To determine whether CA use and CHT interact to increase risk of developing psychosis and/or lower age of psychosis onset (AO) through mediation by the HP and the contribution of cognition and the genetic risk, as measured by schizophrenia polygene scores (SZ-PGRS). Design: This is a cross-sectional, case-control study. Setting: Multicenter study in 5 metropolitan US regions. Participants: 1288 participants, including 493 healthy controls (HC); 210 participants affected by bipolar disorder type 1 with psychosis; 281 by schizoaffective disorder; and 304 with schizophrenia diagnosed using the DSM IV-TR criteria. The HC subjects had no DSM Axis 1 disorder and no first-degree relative with psychotic illness. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): CHT was assessed using the self-reported Childhood Trauma Questionaire (CTQ); CA use, abuse, and dependence were assessed by self reports and trained clinical interviewers. Neuroimaging, symptomatology and cognition were also assessed. Main Outcome(s) and Measure(s): The relation between time of psychosis onset i.e. time of first appearance of symptoms, measures of CHT, and CA use mediated by the HP, cognition and the SZ-PGRS. Results: In survival analysis, low CTQ and CA acted synergistically to lower AO. At high CHT or abuse/dependence CA, CHT or CA were individually sufficient to affect AO. CHT relation with AO is mediated by the HP volume in CA users before AO. Higher SZ-PGRS in probands versus HC, was driven by probands with CA use before AO. Cognition was inversely related to CHT, and positively with higher AO. Conclusions and Relevance: CA use and CHT interact to be associated with lower age of psychosis onset when moderate. CHT effect on AO is mediated by the HP in probands with CA use before AO. Moreover, recreational use of CA lowers AO and affects cognition negatively. Importantly, severe CHT is associated with lower age of psychosis onset irrespective of exposure to cannabis; while abuse/dependence levels of CA use are also sufficient to affect age at psychosis onset irrespective of CHT exposure.