Interaction of Cannabis Use Disorder and Striatal Connectivity in Antipsychotic Treatment Response

Abstract

Antipsychotic (AP) medications are the mainstay for the treatment of schizophrenia spectrum disorders (SSD), but their efficacy is unpredictable and widely variable. Substantial efforts have been made to identify prognostic biomarkers that can be used to guide optimal prescription strategies for individual patients. Striatal regions involved in salience and reward processing are disrupted as a result of both SSD and cannabis use, and research demonstrates that striatal circuitry may be integral to response to AP drugs. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the relationship between a history of cannabis use disorder (CUD) and a striatal connectivity index (SCI), a previously developed neural biomarker for AP treatment response in SSD. Patients were part of a 12-week randomized, double-blind controlled treatment study of AP drugs. A sample of 48 first-episode SSD patients with no more than 2 weeks of lifetime exposure to AP medications, underwent a resting-state fMRI scan pretreatment. Treatment response was defined a priori as a binary (response/nonresponse) variable, and a SCI was calculated in each patient. We examined whether there was an interaction between lifetime CUD history and the SCI in relation to treatment response. We found that CUD history moderated the relationship between SCI and treatment response, such that it had little predictive value in SSD patients with a CUD history. In sum, our findings highlight that biomarker development can be critically impacted by patient behaviors that influence neurobiology, such as a history of CUD.

Striatal Functional Connectivity in Psychosis Relapse: A Comparison Between Antipsychotic Adherent and Non-Adherent Patients at the Time of Relapse

“…To our knowledge, this is the first functional neuroimaging study of psychosis relapse explicitly designed to remove the confounder of antipsychotic treatment non-adherence. We expand on prior work on the application of the SCI as a prognostic biomarker of antipsychotic response in first episode psychosis 15 , and the effect of cannabis use on treatment response, 41 to psychosis relapse. As predicted by our hypothesis, the SCI values were significantly lower for individuals whose symptom worsening occurred despite ongoing antipsychotic treatment (i.e., BAMM) than for those who had discontinued antipsychotic drugs prior to relapse (i.e., APF).…”

“…Once we had generated connectivity maps or each phase encoding direction with and without GSR, we proceeded to calculate the SCI for each of them, following a similar approach as in previous research 15,41 . Briefly, we extracted the 91 striatal functional connections that were used to calculate the SCI in the original Sarpal et al study 15 , and applied to those the same weights as in the original study, to compute a SCI values per scan session in each phase encoding direction (i.e., AP vs PA), which were later averaged into a single SCI value per scan (i.e, study participant), generating a SCI value using GSR and another using No GSR.…”

The pharmacological treatment of schizophrenia: How far have we come?

“…In a cohort of 41 individuals with first episode schizophrenia receiving 12 weeks of antipsychotic medication, lower SCI values prior to treatment onset, reflecting more aberrant striatal resting state functional connectivity, were associated with treatment response, predicting it with ~80% sensitivity and specificity, which was replicated in an independent cohort. Further validity of the SCI has been provided by its application to study the effects of cannabis use on treatment response in schizophrenia 59 . Most recently, the development of prognostic biomarkers for treatment response in the context of psychotic relapse has shown promise 60 .…”

Characterization of Childhood Trauma, Hippocampal Mediation and Cannabis Use in a Large Dataset of Psychosis and Non-Psychosis Individuals

“…The interaction of CHT and CA on the process of psychosis has been evaluated in relation to symptomatology and cognition 12 ; but data on the age of onset of psychosis and mediation of CHT and CA by biological substrates and brain regions is limited 27,63 . Studies on the accumulation of different genetic and environmental factors on risk of psychosis have indicated involvement of the basal ganglia in the interaction 81,82,80 . Abnormalities of white matter derived fractional anisotropy in individuals affected by psychosis with high load of CHT and CA compared to controls and unaffected siblings has been shown 27 as well as some evidence of a combined effect of childhood adversities and SZ polygenic risk, greater than the sum of each alone 2 .…”

“…17 Studies on the accumulation of different genetic and environmental factors on risk of psychosis have indicated involvement of the basal ganglia. 18 Abnormalities of white matter derived fractional anisotropy have been shown in individuals affected by psychosis with high load of CT and CA compared to controls and unaffected siblings. 17 There is some evidence of a combined effect of SZ-PGRS with CT, greater than the sum of each alone.…”