Antipsychotic Rechallenge After an Adverse Event

Second-generation antipsychotics (SGAs) are associated with a range of adverse effects in patients with schizophrenia, including infections such as pneumonia.¹ The association between SGAs and pneumonia is most robust for clozapine.¹Pneumonia in patients with schizophrenia is associated with worse outcomes, and patients who survive are at increased risk for recurrence.² However, the risks of recurrent adverse events due to SGAs are not well characterized.

Hung and colleagues³ estimated the risk of recurrent pneumonia after reexposure to antipsychotic medication in a nested case-control study. Among a nationwide cohort of patients aged 18 to 65 with schizophrenia (based on at least one discharge diagnosis) who were hospitalized for pneumonia between 2000 and 2008 (n = 2201), the researchers identified 494 subjects who had a recurrent episode of pneumonia (more than 30 days after the initial episode of pneumonia).

Three matched controls (n = 1438) with schizophrenia and one episode of pneumonia were selected from the cohort for each patient with recurrent pneumonia. Cases and controls were matched on age, sex, and year of baseline admission for pneumonia. Data on antipsychotic medications-type, duration, and defined daily dose-were retrieved from prescription files. The incidence of recurrent pneumonia was calculated, and risks were analyzed using survival analysis.

The incidence of recurrent pneumonia was 7.7 cases per 100 person-years; it did not differ between men and women but was higher with increasing age. Patients with recurrent pneumonia had more physical illnesses and used more concomitant medications than controls. Of all first- and second-generation antipsychotic medications, only clozapine was associated with a significantly increased risk of recurrent pneumonia (adjusted risk ratio [RR] = 1.40; 95% confidence interval [CI], 1.05-1.88; P = .025). Current use of clozapine was associated with an increased, dose-dependent risk of recurrent pneumonia. By contrast, risperidone was associated with a significantly decreased risk of recurrent pneumonia (RR = 0.62; 95% CI, 0.46-0.84; P = .002).

Many patients who received clozapine before the initial episode of pneumonia had used clozapine prior to the recurrent pneumonia. Compared with subjects who were not reexposed to clozapine after the initial episode of pneumonia, rechallenge with clozapine was associated with a significant, almost 2-fold increased risk of recurrent pneumonia (RR = 1.99; 95% CI, 1.10-3.59; P = .023). Recurrent pneumonia was significantly more common in females reexposed to clozapine (RR = 4.93) than in males.

The researchers concluded that clozapine is associated with a dose-dependent increased risk of recurrent pneumonia, especially among females reexposed to clozapine after an episode of clozapine-related pneumonia. This is the first known study to investigate the association between antipsychotic exposure and recurrent pneumonia. An important limitation of the study is that patients with pneumonia who were not hospitalized were excluded.

The bottom line
In patients with clozapine-related pneumonia, physicians should be aware of the significantly increased risk of recurrence when clozapine is reintroduced.

References:

1. Kuo CJ, Tang SY, Liao YT, et al. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull. 2013;39:648-657.
2. Garcia-Vidal C, Carratala J, Fernanadez-Sabe N, et al. Aetiology of, and risk factors for, recurrent community-acquired pneumonia. Clin Microbiol Infect. 2009;15:1033-1038.
3. Hung GC, Liu HC, Yang SY, et al. Antipsychotic reexposure and recurrent pneumonia in schizophrenia: a nested case-control study. J Clin Psychiatry. 2015. dx.doi.org/10.4088/JCP.14m09301.