Young Adults at Greater Risk of Adverse Events with Clozapine than Older Adults

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In a new study, older adults with treatment-resistant schizophrenia reported significantly fewer adverse events of clozapine than young adults.¹

“Contrary to our expectation, we found that significantly more side effects were reported in patients aged less than 55 years than in patients aged 55 years or older, both in the first 3 months of treatment with clozapine and after 3 months,” wrote investigators.

Investigators, led by Floor C. E. Groenewald, from the University of Utrecht in Utrecht, the Netherlands, sought to compare the adverse events of clozapine between older adults aged ≥ 55 years old and younger adults aged 18 – 55 years with treatment-resistant schizophrenia.

First synthesized in 1959, it would be 3 decades before the FDA approved clozapine for treatment-resistant schizophrenia in 1989. At the time of writing, it remains the only agent to receive such an indication from the FDA.²

Clozapine has been through hurdles due to its potential for inducing neutropenia, causing individuals to have too few neutrophils which fight off certain infections. Due to this, in many countries, patients who take clozapine have regular blood monitoring.

“In the countries with indefinite monthly monitoring, this can seem off-putting to patients, depending on how this prospect and the potential benefits of starting clozapine are presented by clinicians,” wrote the author of a recently published editorial in The Lancet Psychiatry. “For clinicians, taking the time to make a shared decision by discussing such factors can be off-putting within a busy schedule.”

A 2023 study using data from Australia and Aotearoa New Zealand from 1990 – 2022 found people now taking clozapine had a reduced average weekly incidence rate of neutropenia of 0.001% by 2 years, suggesting monitoring could be concluded after 2 years.3

Citing this apparent increase in risk for adverse events, Groenewald and colleagues sought to compare the effects of use stratified by patient age. The team obtained data from a retrospective cohort study in a large psychiatric institute in the Netherlands, including 284 participants diagnosed with treatment-resistant schizophrenia who started taking clozapine between 2011 and 2020. Specifically, they compared the number and type of adverse events, as well as the number of treatment discontinuations and the time until discontinuation due to adverse events, of older adults versus younger adults.

The young age group (n = 183) reported significantly greater adverse events in the first 3 months of treatment (Mann-Whitney U = 7341.5; P = .004) and after those months (Mann–Whitney U = 5668.5; P < .001) compared to the older age group (n = 101). The adverse events reported significantly more in the younger age group were sedation (76%), hypersalivation (67.2%), weight gain (40.4%), dizziness (32.2%), tachycardia (31.7%), constipation (30.6%), nausea (18%), and heartburn (10.9%). Only extrapyramidal symptoms were significantly reported more frequently in the older age group.

The investigators observed no significant difference in the number of treatment discontinuations due to adverse events for younger and older adults (23% vs. 21.8%; Chi-2 = .051, df = 1; P = .821). They also found no significant difference for time until discontinuation due to adverse events (b = .091, SE = .335; P = .798).

“Our results, if replicated, suggest that older patients with schizophrenia may not be more vulnerable to side effects than younger adults,” investigators wrote. “Future studies of clozapine should prospectively compare both the effectiveness and side effects of clozapine in younger versus older adults and use validated rating scales for both outcomes.”

^References

1. ^{Groenewald FCE, Kok RM. Side effects of clozapine in older adults with treatment-resistant schizophrenia compared to younger adults. Int J Geriatr Psychiatry. 2024;39(1):e6051. doi:10.1002/gps.6051}
2. ^{The Lancet Psychiatry. Clozapine: past, present, and future. Lancet Psychiatry. 2024;11(1):1. doi:10.1016/S2215-0366(23)00406-6}
3. ^{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. doi:10.1016/S2215-0366(23)00343-7}