Effectiveness of clozapine augmentation with specific doses of other antipsychotics in schizophrenia: a meta‐analysis from two nationwide cohorts

Although clozapine is the most effective medication for treatment‐resistant schizophrenia, response is inadequate in over half of people with that condition. There is limited guidance available on effective clozapine augmentation strategies. We studied the comparative effectiveness of specific doses of oral olanzapine, quetiapine, risperidone and aripiprazole augmentation of clozapine treatment on the risk of hospitalization due to a psychotic episode, as a marker for severe relapse, among patients with schizophrenia or schizoaffective disorder. In this population‐based study, patients with one of those diagnoses receiving clozapine were identified from Finnish (years 1995‐2017, N=14,053) and Swedish (years 2006‐2021, N=8,743) nationwide registers. The risk of hospitalization due to a psychotic episode associated with periods of antipsychotic augmentation of clozapine treatment vs. same‐dose clozapine monotherapy was assessed by a within‐individual design, using each individual as his/her own control to eliminate selection bias, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately; then results were combined using a random‐effect meta‐analysis. Secondary outcomes were somatic hospitalization, and hospitalization for psychosis or a somatic cause. The only augmentation associated with a significantly decreased risk of hospitalization due to psychosis in both countries was medium‐dose (9 to <16.5 mg/day) aripiprazole combined with high‐dose (≥330 mg/day) clozapine, and this combination was associated with the best outcome in the meta‐analysis (adjusted hazard ratio, aHR=0.68, 95% CI: 0.62‐0.75, p<0.0001). Among patients using medium‐dose (180 to <330 mg/day) clozapine, medium‐dose aripiprazole augmentation was the only treatment more effective than clozapine monotherapy after Bonferroni correction (aHR=0.79, 95% CI: 0.70‐0.91, p=0.0006). The use of all high‐dose augmentations was associated with an increased risk of hospitalization due to psychosis. Only aripiprazole augmentations were associated with a decreased risk of hospitalization for psychosis or a somatic cause, and the lowest risk was observed for medium‐dose aripiprazole plus high‐dose clozapine (aHR=0.70, 95% CI: 0.58‐0.84, p=0.0001). This meta‐analysis of two nationwide cohorts, totaling almost 23,000 patients using clozapine, indicates that medium‐dose aripiprazole augmentation of clozapine treatment is associated with a 20‐30% decreased risk of severe relapse compared with clozapine monotherapy within the same individuals, while augmentation with higher doses of aripiprazole (as well as with high doses of all other antipsychotics) is associated with an increased relapse risk.