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Clozapine Best Choice for Reducing SUD Risk in Schizophrenia?

Clozapine or antipsychotic polytherapy appear to be the best approach in reducing the risk for a substance use disorder (SUD) in adults with schizophrenia and for preventing relapse in patients with both diagnoses, results of a real-world study show.

“Our findings are in line with a recent meta-analysis showing superior efficacy of clozapine in schizophrenia and comorbid SUD, and other studies pointing toward clozapine’s superiority over other antipsychotics in the treatment of individuals with schizophrenia and comorbid SUD,” the investigators, led by Jari Tiihonen MD, PhD, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, write.

“The results on polypharmacy are in line with previous results from nationwide cohorts showing a favorable outcome compared with oral monotherapies among persons with schizophrenia in general,” they add.

The study was published online August 25 in The British Journal of Psychiatry.

Research Gap

Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid SUD is “very sparse, and more importantly, non-existent on the prevention of the development of SUDs in patients with schizophrenia,” the researchers note.

To investigate, they analyzed data on more than 45,000 patients with schizophrenia from Finnish and Swedish national registries, with follow-up lasting 22 years in Finland and 11 years in Sweden.

In patients with schizophrenia without SUD, treatment with clozapine was associated with lowest risk for an initial SUD in both Finland (adjusted hazard ratio [aHR], 0.20; 95% CI, 0.16-0.24) and Sweden (aHR, 0.35; 95% CI, 0.24-0.50), compared with no use or use of other antipsychotics.

In Finland, aripiprazole was associated with the second lowest risk for an initial SUD (aHR, 0.36; 95% CI, 0.24-0.55) and antipsychotic polytherapy the third lowest risk (aHR, 0.47; 95% CI, 0.42-0.53).

In Sweden, antipsychotic polytherapy was associated with second lowest risk for an initial SUD (aHR, 0.54; 95% CI, 0.44-0.66) and olanzapine the third lowest risk (aHR, 0.67; 95% CI, 0.53-0.84).

In both countries, the risk for relapse as indicated by psychiatric hospital admission and SUD-related hospital admission were lowest for clozapine, antipsychotic polytherapy and long-acting injectables, the investigators report.

Interpret With Caution

Reached for comment, Christoph U. Correll, MD, professor of psychiatry and molecular medicine, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, urged caution in interpreting the results.

“While the authors are experts in national database analyses and the study was conducted with state-of-the-art methodology, the onset of SUD analyses favoring clozapine are subject to survival bias and order effects,” Correll told Medscape Medical News.

“Since clozapine is generally used later in the illness and treatment course, after multiple other antipsychotics have been used, and since SUDs generally occur early in the illness course, most SUDs will already have arisen by the time that clozapine is considered and used,” Correll said.

“A similar potential bias exists for long-acting injectables (LAIs), as these have generally also been used late in the treatment algorithm,” he noted.

In terms of the significant reduction of SUD-related hospitalizations observed with clozapine, the “order effect” could also relevant, Correll said, because over time, patients are less likely to be nonadherent and hospitalized and clozapine is systematically used later in life than other antipsychotics.

“Why antipsychotic polytherapy came out as the second-best treatment is much less clear. Clearly head-to-head randomized trials are needed to follow up on these interesting an intriguing naturalistic database study data,” said Correll.

This study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Tiihonen and three co-authors have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their institution. Correll reports having been a consultant and/or advisor to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Niven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He has also provided expert testimony for Janssen and Otsuka; served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma, and Quantic.

Br J Psychiatry. Published online August 25, 2022. Source

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