Benzodiazepines and clozapine co-prescription in clinical practice: a systematic review and expert recommendations

Introduction: Adverse drug reactions may be increased by combining benzodiazepines and drugs related (BZDR) with clozapine. We aimed to synthesize clinically relevant information on the risks and benefits co-prescribing clozapine and BZDR. Methods: A systematic review was performed on articles identified with MEDLINE, Web of Sciences and PsycINFO search from inception through August 2024 using the algorithm ‘clozapine’ AND ‘benzodiazepines’ Results: Clozapine-BZDR co-prescription is associated with an increased risk of cardiorespiratory collapse, aspiration pneumonia, pneumonia and delirium. To reduce the risk of cardiorespiratory collapse and aspiration pneumonia, BZDR should be avoided the week before clozapine initiation and during the first week of titration. If BZDR are maintained, clozapine should be very slowly titrated, close monitoring of symptoms of pneumonia for at least two weeks and therapeutic drug monitoring are required. Delirium should be assessed daily in the weeks following initiation of clozapine-BZDR treatment. Contrasting with the high frequency of clozapine-BZDR co-prescription in clinical practice, its benefits are poorly documented. Case reports suggest that the co-prescription of clozapine and clonazepam may benefit tardive dyskinesia. Conclusion: Further studies are required to verify that clonazepam may be a weak inducer of clozapine metabolism and to optimize the safety of clozapine-BZDR co-prescription. PROSPERO: CRD42024561716.