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 paper^{Reference 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.