RESEARCH UPDATE
CASE VIGNETTE
“Mr Kent” is a 34-year-old Caucasian male with a 15+ year history of chronic treatment-resistant schizoaffective disorder. He has been on clozapine for over 10 years. His current psychotropic medications for the past year include clozapine 650 mg at bedtime, aripiprazole 10 mg at bedtime, lithium 900 mg at bedtime, and clonazepam 0.5 mg twice daily as needed for anxiety. He has not had any psychiatric hospitalizations in the past 3 years. He lives independently in an apartment furnished by his parents, who check on him regularly. He presents to the outpatient clinic for his monthly appointment, accompanied by his mother, who typically remains in the waiting room. At the most recent visit, his mother denied any specific concerns; Mr Kent reports he is doing “fine.” He denies hallucinations in all sensory modalities and does not appear to attend to internal stimuli. He denies suspiciousness and no delusions are noted. He also denies being depressed. He has chronic negative symptoms, including poverty of speech, diminished interests, apathy, and asociality. He does enjoy watching sports on television and typically isolates in his apartment, with no social contacts outside of family. Mr Kent smokes 10 cigarettes a day, and he does not drink alcohol or use illicit drugs. Today, he is noted to have decreased hygiene (malodorous) that is more prominent than previous visits. He is without physical complaints. As his psychiatrist, would you make any changes to his psychotropic medications?
Although clozapine is the gold-standard antipsychotic medication for treatment-resistant schizophrenia (TRS), only about 40% of patients respond to clozapine monotherapy.1 As a result, many clinicians will treat patients with TRS with psychotropic polypharmacy as an adjunct to clozapine, despite the absence of clear and consistent evidence for its long-term efficacy.2,3 Safety risks of psychotropic polypharmacy include adverse cardiometabolic effects, extrapyramidal symptoms, drug-drug interactions, and mortality.4 Therefore, a better understanding of real-world prescribing patterns is essential to balance risks and benefits of polypharmacy in this patient population. Studies outside of Canada have reported a prevalence of polypharmacy in adjunct to clozapine in TRS of 18% to 44%.5
The Current Study
Preobrazenski et al performed a retrospective chart review of 667 adults treated with clozapine at the Royal Ottawa Mental Health Centre, a tertiary psychiatric hospital in eastern Ontario, Canada.6 The primary objective was to quantify the prevalence of and the characteristics associated with polypharmacy in patients treated with clozapine. The authors reviewed charts of patients dispensed clozapine between 2017-2020, and active status in the Health Canada-mandated Clozaril patient registry was confirmed. Demographic and clinical data were extracted for each patient. The primary diagnoses of patients were schizophrenia (78%) and schizoaffective disorder (19%).
The authors defined clozapine polypharmacy as augmenting the concurrent prescription of clozapine with 1 or more other psychotropic medications on the index date.2 Augmenting medications were classified in 5 categories: antipsychotics, mood stabilizers, antidepressants, benzodiazepines, and other psychotropics. Associations between categorical variables were analyzed using chi-square tests and continuous nonnormal variables with Wilcoxon rank-sum tests. For the main comparisons (polypharmacy and diagnosis), odds ratios with 95% confidence intervals were calculated.
Five-hundred fifty (83%) of the 663 patients were prescribed at least 1 additional psychotropic, which constituted the polypharmacy group. Four charts lacked information about additional psychotropic medications and were excluded. The median number of concomitant drug classes in the polypharmacy group was 2 (interquartile range 1-3). The most common augmenting agents were other antipsychotics (64%), antidepressants (47%), mood stabilizers (31%), and benzodiazepines (29%). The most frequent pattern of augmentation was clozapine plus another antipsychotic. The most common individual augmenting agents were valproate/divalproex (21%) and aripiprazole (15%).
Polypharmacy was significantly more prevalent in patients with schizoaffective disorder compared to schizophrenia (91% vs 81%). The polypharmacy group was also older than the clozapine monotherapy group (median age 46 vs 38), had more females (88% vs 81%), and had higher rates of respiratory disease (17% vs 7%) and diabetes (17% vs 8%). By contrast, there was no difference between groups with regards to smoking and ethnicity. One-hundred forty-three patients (21%) had at least 1 hospitalization during the study period, with no significant differences between the polypharmacy (22%) and clozapine monotherapy (18%) groups
Study Conclusions
The authors concluded that clozapine augmentation with additional psychotropic medications was common, with polypharmacy in over 80% of patients, and over half of patients being prescribed a second antipsychotic. Most augmentation regimens involved either a second antipsychotic, or a second antipsychotic plus an antidepressant. Polypharmacy was more common in patients with schizoaffective disorder, older patients, and in patients with respiratory disease or diabetes.
Study limitations include the retrospective design, and that the duration and dosage of non-clozapine medications was not available. A referral bias may have contributed to the high rates of polypharmacy, as the catchment area of Royal Ottawa Mental Health Centre serves patients with severe schizophrenia-spectrum disorders.
The Bottom Line
Psychotropic polypharmacy in patients with TRS is extremely common. There is a need to optimize medication management in this patient population to both ameliorate symptoms and minimize adverse effects of augmentation in patients treated with clozapine.
Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times.
The author reports that he receives research support from Augusta University.
References
1. Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62(11):772-777.
2. Fleischhacker WW, Uchida H. Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol. 2014;17(7):1083-1093.
3. Lahteenvuo M, Tiihonen J. Antipsychotic polypharmacy for the management of schizophrenia: evidence and recommendations. Drugs. 2021;81(11):1273-1284.
4. Højlund M, Kohler-Forsberg O, Gregersen AT, et al. Prevalence, correlates, tolerability-related outcomes, and efficacy-related outcomes of antipsychotic polypharmacy: a systematic review and meta-analysis. Lancet Psychiatry. 2024;11(12):975-989.
5. Buckley P, Miller A, Olsen J, et al. When symptoms persist: clozapine augmentation strategies. Schizophr Bull. 2021; 27(4):615-628.
6. Preobrazenski N, Hsieh T, Robertson C, et al. Polypharmacy in clozapine-treated patients: a retrospective analysis of 667 patients in Ottawa, Canada. Psychiatry Res. 2025;352(2025):116684.
