Reply
We agree with Kikuchi that the diversity of diagnoses may have obscured clozapine's risk–benefit balance in our paper.Reference Balbuena, Halayka, Lee, Ahmed, Hinz and Kolla1 Hence, our findings may have reflected the lower range of the overall benefit of clozapine. Table 1 shows the expected count of re-hospitalisation events stratified by index diagnosis in adult patients. These were calculated using flexible survival models implemented in the stpm3 Stata package.Reference Lambert2
Table 1 Re-hospitalisation counts by drug group and diagnosis per 1000 person-months

The figures in Table 1 show that clozapine had fewer relapse events compared with other drugs in patients with schizophrenia and schizoaffective disorders. In patients with bipolar disorder, the relapse events were the same, but clozapine had higher adverse event counts. The reverse was true in those with schizoaffective disorders: lower relapse event counts for clozapine but the same adverse event counts as other drugs. The child and youth cohort could not be stratified by diagnosis because of low numbers.
We agree with Kikuchi that the adverse events analysis was tilted in favour of other antipsychotics. Suicide attempts and deaths were not available in the data, so clozapine's benefit is probably underestimated,Reference Forte, Pompili, Imbastaro, De Luca, Mastrangelo and Montalbani3 while adverse events more specific to other drugs are probably underestimated.
The decision to exclude unmedicated periods was deliberate, since our objective was a head-to-head comparison of medications. In a previous paperReference Peters, Shamloo, Lodhi, Marcoux, Jackson and Halayka4 we found that over a 5-year period, people with schizophrenia, on average, spent 11 months without medication and only 17 days on clozapine. Within-person analysis was considered, but this technique discards the records of people who did not switch from other drugs to clozapine or vice versa. In our data, these patients made up the majority.
In summary, our register-based study shows that clozapine is an effective medication, with benefits and risks that require balancing.
Data availability
The data supporting Table 1 are available from the Canadian Institute of Health Information. Restrictions apply to the availability of these data, which were used under licence for this study. Data are available from the authors with the permission of the Canadian Institute of Health Information, which can be obtained by writing to help@cihi.ca.
Author contributions
S.H. wrote C++ code for the data in Table 1. L.B. created the statistical model and wrote the paper. Both authors approved the content.
Funding
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Declaration of interest
None.
Analytical code availability
The code for reproducing Table 1 is publicly available at https://github.com/lloydxeno/antipsychotics/blob/main/correspondence
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