Persistence of Antipsychotic Use After Clozapine Discontinuation: A Real‐World Study Across Antipsychotics

Abstract

Although clozapine treatment is often discontinued due to limited efficacy or low tolerability, there is a lack of guidelines and evidence on treatment options after discontinuation of clozapine in patients with schizophrenia. Persistence has proven to be an adequate indicator for treatment effectiveness in patients with schizophrenia. The aim of this study was, therefore, to compare persistence of antipsychotic use between antipsychotic treatment options in patients after stopping clozapine treatment. Registry data from a prescription database representative of the Dutch population (1996-2017) was collected to investigate persistence in patients with schizophrenia who had been using clozapine for ≥ 90 days. Persistence with antipsychotics after clozapine discontinuation was analyzed using Cox-proportional hazard regression models. Our study population consisted of 321 participants, of whom 138 re-initiated clozapine and 183 started some other antipsychotic in the year after clozapine discontinuation (N = 518 antipsychotic use periods, N = 9,178 months). Second-generation antipsychotics (SGAs) as a group were associated with better persistence compared to first-generation antipsychotics (adjusted hazard ratio (aHR), 0.73; 95% confidence interval (CI) 0.57-0.93; P = 0.011). Compared with other antipsychotics, the following oral monotherapy antipsychotics were associated with significantly better persistence: restarting clozapine (aHR 0.48; 95% CI 0.32-0.71; P < 0.001) and switching to risperidone (aHR 0.52; 95% CI 0.32-0.84; P = 0.008) or olanzapine (aHR 0.55; 95% CI 0.35-0.87; P = 0.010). Sensitivity analyses confirmed the results. In conclusion, oral SGAs are associated with better persistence than alternative antipsychotic treatment options in patients discontinuing clozapine for undefined reasons. Especially clozapine (except in those with previous serious adverse reactions to clozapine), olanzapine and risperidone should be considered as oral monotherapy for these patients.

Second-Generation Antipsychotics’ Effectiveness and Tolerability: A Review of Real-World Studies in Patients with Schizophrenia and Related Disorders

“…Most studies evaluated the effectiveness of SGAs vs. FGAs [ 55 , 56 , 57 , 59 , 62 , 65 ]. Olanzapine, in particular, emerged as an effective treatment option among the atypical agents [ 51 ].…”

“…Persistence, adherence, or failure to treatment, as well as the rate of SGAs discontinuation or risk of hospitalization, were analyzed in most studies [ 52 , 53 , 54 , 55 , 57 , 58 , 59 , 60 , 61 , 62 , 64 , 65 ]. Overall, olanzapine demonstrated superior real-world effectiveness vs. risperidone in relapse-free survival and psychiatric hospitalization [ 61 ].…”

“…Overall, olanzapine demonstrated superior real-world effectiveness vs. risperidone in relapse-free survival and psychiatric hospitalization [ 61 ]. Moreover, switching to clozapine, to risperidone or to olanzapine oral monotherapy was also associated with significantly better persistence in treatment [ 62 ]. In addition, Hatta et al (2022) [ 65 ] suggested that switching to LAIs or APs polytherapy might be more likely associated with a low treatment failure rate [ 65 ].…”

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

“…In addition to supportive care, termination of concomitant serotonergic medication might be indicated as well as short-term use of cyproheptadine for moderate and severe cases 272 . Current evidence supports olanzapine as well as risperidone and long-acting aripiprazole as the best alternative options 277,278 , but without matching the efficacy of a clozapine rechallenge [279][280][281] .…”

“…Hence, discontinuation of clozapine often leads to a considerable worsening of psychopathology with potentially severe short-and long-term clinical and functional consequences 151,277,278,282,283 . While withdrawal symptoms also contribute to this deterioration, supersensitivity mechanisms [284][285][286][287][288] and a lack of sufficiently effective alternative antipsychotics are regarded as the main causes 271 .…”