Aims: We performed a latent class analysis (LCA) in a sample ascertained for addiction phenotypes to investigate cocaine use disorder (CoUD) subgroups related to polysubstance addiction (PSA) patterns and characterized their differences with respect to psychiatric and somatic comorbidities. Design: Cross-sectional study Setting: United States Participants: Adult participants aged 18-76, 39% female, 47% African American, 36% European American with a lifetime DSM-5 diagnosis of CoUD (N=7,989) enrolled in the Yale-Penn cohort. The control group included 2,952 Yale-Penn participants who did not meet for alcohol, cannabis, cocaine, opioid, or tobacco use disorders. Measurements: Psychiatric disorders and related traits were assessed via the Semi-structured Assessment for Drug Dependence and Alcoholism. These features included substance use disorders (SUD), family history of substance use, sociodemographic information, traumatic events, suicidal behaviors, psychopathology, and medical history. LCA was conducted using diagnoses and diagnostic criteria of alcohol, cannabis, opioid, and tobacco use disorders. Findings: Our LCA identified three subgroups of PSA (i.e., low, 17%; intermediate, 38%; high, 45%) among 7,989 CoUD participants. While these subgroups varied by age, sex, and racial-ethnic distribution (p<0.001), there was no difference in education or income (p>0.05). After accounting for sex, age, and race-ethnicity, the CoUD subgroup with high PSA had higher odds of antisocial personality disorder (OR=21.96 vs. 6.39, difference-p=8.08e-6), agoraphobia (OR=4.58 vs. 2.05, difference-p=7.04e-4), mixed bipolar episode (OR=10.36 vs. 2.61, difference-p=7.04e-4), posttraumatic stress disorder (OR=11.54 vs. 5.86, difference-p=2.67e-4), antidepressant medication use (OR=13.49 vs. 8.02, difference-p=1.42e-4), and sexually transmitted diseases (OR=5.92 vs. 3.38, difference-p=1.81e-5) than the low-PSA CoUD subgroup. Conclusions: We found different patterns of PSA in association with psychiatric and somatic comorbidities among CoUD cases within the Yale-Penn cohort. These findings underscore the importance of modeling PSA severity and comorbidities when examining the clinical, molecular, and neuroimaging correlates of CoUD.

RP received a research grant from Alkermes. RP and JG are paid for their editorial work on the journal Complex Psychiatry. JG and HRK are named as inventors on PCT patent application #15/878,640 entitled: Genotype-guided dosing of opioid agonists, filed January 24, 2018. HRK is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sophrosyne Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which for the past three years was supported by Alkermes, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics, and is paid for his editorial work on the journal Alcohol: Clinical and Experimental Research. The other authors have no competing interests to report.

This study was supported by the National Institutes of Health (R33 DA047527, R21 DC018098, and RF1 MH132337), One Mind, and the VISN 4 Mental Illness Research, Education and Clinical Center at the Crescenz VAMC. The Yale-Penn cohort was supported by multiple grants from the National Institutes of Health (RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535).

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The studies were approved by the institutional review boards at Yale School of Medicine (APT Foundation, New Haven, CT, USA), the University of Connecticut Health Center (Farmington, CT, USA), the University of Pennsylvania Perelman School of Medicine (Philadelphia, PA, USA), Medical University of South Carolina (Charleston, SC, USA), and McLean Hospital (Belmont, MA, USA) and written informed consent was obtained from each participant.

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