Clozapine Adverse Drug Reactions and Efficacy

MQ-Illustrations/AdobeStock

CASE VIGNETTE

“Ms Hat” is a 48-year-old Caucasian woman with a history of chronic schizoaffective disorder. She has been treated with clozapine 500 mg/day since 2016, with remission of positive psychopathology and cessation of illicit substance use (methamphetamine). For the first 5 years on clozapine, all of her absolute neutrophil counts (ANCs) were normal. From 2021 to 2023, she had multiple episodes of mild neutropenia, but also many normal values. She was referred to hematology twice during that time period, but unfortunately missed both appointments. In April 2024, Ms Hat had many instances of moderate neutropenia and clozapine was held. However, her ANCs remained low. In June 2024, she was seen in consultation by hematology, and clozapine was deemed to be the offending agent. Subsequently, her ANC dropped further to 100-500 cells/mm3 for a period of approximately 10 days, though she had no signs or symptoms of infection. After 2 months off of clozapine, her ANC returned to normal at 2200 cells/mm3.

Although she has not required inpatient psychiatric hospitalization, her positive symptoms have recurred. She expresses interest in a future retrial of clozapine, given multiple failed trials with other antipsychotics and her response to clozapine. As her psychiatrist, how would you proceed?

Approximately 1 in 3 patients do not have an adequate response to first-line antipsychotics and have treatment-resistant schizophrenia (TRS).^1,2 Clozapine is the most efficacious antipsychotic for patients with TRS.³ However, clozapine is also associated with a significant burden of severe adverse drug reactions (ADR), including neutropenia, myocarditis, and gastrointestinal hypomotility.^4-6 Other common clozapine-associated ADRs include sedation, metabolic syndrome, orthostatic hypotension, tachycardia, sialorrhea, and nocturnal enuresis.^7-9 Few studies have investigated the prevalence of clozapine-associated ADRs outside of clinical trials and inpatient settings. Similarly few studies have investigated subjective self-reported perceptions of clozapine treatment. Therefore, studies in outpatients using self-report measures and examining associations with demographics would reflect the majority of patients treated with clozapine. Genetic studies have also not identified robust predictors of clozapine-associated ADRs and response to clozapine.

The Current Study

In the ClozaGene study, Lind et al recruited over 1000 Australians prescribed clozapine.¹⁰ Participants completed a self-report questionnaire focusing on demographics, clozapine experience, and mental health. Participants were recruited using the Services Australia mail-out service. Individuals were aged 18 to 65, living in Australia, and had 1 or more dispensed prescriptions for clozapine within the last 4.5 years. Exclusion criteria were addresses corresponding to health care, correctional, or aged-care facilities. Letters were sent to 17,731 individuals. Participants could complete study assessments either by pencil-and-paper (n=900) or online (n=121) forms. The forms collected self-report data on demographics as well as clozapine use, efficacy, and ADRs. Participants also completed the Questionnaire for Psychotic Experiences Screening. Participants were asked to consent for the research team to review their blood pathology results, which was provided by 77% (n=781) of the study sample. Saliva samples for genotyping have been provided thus far by n=771 participants.

Logistic regression was used to compare the prevalence of binary demographic and self-report variables between males and females. One-way ANOVA tests were used to compare self-reported clozapine dosage levels and clozapine-associated ADRs between males and females.

Mean subject age was 46 and 58% were male. Approximately 70% of participants were living in metropolitan areas, 90% of participants self-reported being diagnosed with schizophrenia, 45% of participants reported 2 or more diagnoses, and 66% of participants completed the survey themselves, whereas 17% and 10% were helped by a family member of support worker.

Approximately 93% of participants reported they were currently taking clozapine, 96% of whom for more than 1 year. Males reported significantly higher mean daily dosages of clozapine than females (345 vs 312 mg/day), and 38% of participants reported taking 1 or more antipsychotic medications in addition to clozapine.

The most commonly reported clozapine-associated ADRs were sialorrhea (80%), weight gain (71%), constipation (57%), and sleeping more than 10 hours/night (53%). Approximately 24% reported “heart problems,” 20% type 2 diabetes, 8% “reduction in white blood cells (neutropenia),” and 7% seizures. Females were more likely to report weight gain and constipation, and males were more likely to report sexual dysfunction. Males reported fewer overall clozapine-associated ADRs than females (5.1 vs 5.8). Among participants with previous but not current use (n=69), the estimated prevalence of clozapine cessation due to myocarditis and neutropenia was 1% and 0.4%, respectively.

Regarding the benefits of clozapine, participants most often endorsed a reduction in delusions/paranoia (66%), hallucinations (56%), and restored control over the behavior (47%). Approximately 88% of participants perceived that clozapine worked moderately or very well. Approximately half of the participants reported being free of hallucinations (51%) or delusions (42%) in the preceding 2 weeks, while one-third reported no psychotic symptoms.

Study Conclusions

The authors concluded that almost 97% of participants reported experiencing 1 or more clozapine-associated ADRs, with a mean number of over 5 ADRs, most commonly sialorrhea, weight gain, constipation, and excessive sleeping. The estimated prevalence of clozapine cessation due to myocarditis and neutropenia was 1% and 0.4%, respectively. Study strengths included the large sample size. Potential limitations included participation bias due to a low participation rate (6%). Findings could also be affected by recall bias and may not be generalizable to non-Australian users of clozapine.

The Bottom Line

The present study highlights the high rate of ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and adverse effects. Future analyses of pathology data will clarify relationships between clozapine adherence, blood levels, and ADRs.

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, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Siskind D, Orr S, Sinha S, et al. Rates of treatment-resistant schizophrenia from first-episode cohorts: systematic review and meta-analysis. Br J Psychiatry. 2022;220(3):115-120.

2. Howes OD, McCutcheon R, Agid O, et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174(3):216-229.

3. Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first-and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209(5):385-392.

4. Northwood K, Myles N, Clark SR, et al. Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study. Lancet Psychiatry. 2024;11(1):27-35.

5. Siskind D, Sidhu A, Cross J, et al. Systematic review and meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy. Aust N Z J Psychiatry. 2020;54(5):467-481.

6. Every-Palmer S, Nowitz M, Stanley J, et al. Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: a cross sectional study. EBioMedicine. 2016;5:125-134.

7. Fernandez-Egea E, Chen S, Jenkins C, et al. The effect of clozapine on self-reported duration of sleep and its interaction with 23 other medications: a 5-year naturalistic study. J Clin Psychopharmacol. 2021;41(5):534-539.

8. Henderson DC, Nguyen DD, Copeland PM, et al. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry. 2005;66(9):1116-1121.

9. Chen S-Y, Ravindran G, Zhang Q, Kisely S, Siskind D. Treatment strategies for clozapine-induced sialorrhea: a systematic review and meta-analysis. CNS Drugs. 2019;33(3):225-238.

10. Lind PA, Parker RK, Northwood K, et al. Clozapine efficacy and adverse drug reactions among a nationwide study of 1021 Australians prescribed clozapine: the ClozaGene study. Schizophr Bull. 2024:sbae065.