Switching Antipsychotics: Abrupt Discontinuation Versus Overlap

Clozapine has been demonstrated to be clinically superior to other antipsychotics in treatment-resistant schizophrenia (TRS), and is positioned as such in treatment guidelines. Because it is relegated to use in TRS, guidelines require that it only be used after other antipsychotics have failed; accordingly, clinicians routinely contend with stopping the previous antipsychotic in making the switch to clozapine. Perhaps because of its numerous and potentially severe side effects, the issue of clozapine titration has frequently been addressed, although to our knowledge no study has, as of yet, assessed the comparability of gradual vs. immediate antipsychotic discontinuation in switching to clozapine. To address the gap in knowledge specific to clozapine, the investigators conducted a pilot, 8-week, double-blind, randomized controlled trial examining immediate vs. gradual antipsychotic discontinuation in patients with schizophrenia undergoing a switch to clozapine.

Clozapine has been demonstrated to be clinically superior to other antipsychotics in treatment-resistant schizophrenia (TRS), and is positioned as such in treatment guidelines. Because it is relegated to use in TRS, guidelines require that it only be used after other antipsychotics have failed; accordingly, clinicians routinely contend with stopping the previous antipsychotic in making the switch to clozapine. Perhaps because of its numerous and potentially severe side effects, the issue of clozapine titration has frequently been addressed, although to our knowledge no study has, as of yet, assessed the comparability of gradual vs. immediate antipsychotic discontinuation in switching to clozapine. While the question has not been asked vis-à-vis clozapine, there have been several studies examining gradual vs. immediate antipsychotic discontinuation in switching antipsychotics. Immediate antipsychotic discontinuation is associated with the following risks: (1) withdrawal/discontinuation symptoms or rebound syndromes related to cholinergic, histaminergic, and serotonergic activity; (2) supersensitivity syndromes (e.g., withdrawal dyskinesia, supersensitivity psychosis); and (3) exacerbation/re-emergence of symptoms secondary to diminished response with newly introduced antipsychotic. On the other hand, gradual antipsychotic discontinuation is associated with the risk of worsening/emergent side effects. This said, all of the studies, including one meta-analysis, report no differences in efficacy and safety between immediate and gradual discontinuation strategies in antipsychotic switching. However, it should be also noted that all of the studies were conducted under an open-label design or a single-blind design. To address the gap in knowledge specific to clozapine, the investigators conducted a pilot, 8-week, double-blind, randomized controlled trial examining immediate vs. gradual antipsychotic discontinuation in patients with schizophrenia undergoing a switch to clozapine.

The antipsychotic drugs that patients took at baseline were prepared in unmarked capsules, with the dose adjusted to provide a 25% reduction weekly over the next 3 weeks. The dose tapering schedule was as follows: 3 capsules at baseline, 2 capsules at week 1, 1 capsule at week 2, and 0 capsules at week 3. All capsules contained placebo (i.e., the antipsychotic drugs were abruptly discontinued). Clozapine was gradually increased to 300 mg/day according to the following schedule: 12.5 mg/day at day 0 and increased by 25 mg/day to 300 mg/day at day 12, with this dose maintained for three weeks and thereafter adjusted according to clinical judgment. Concomitant medications were kept constant throughout the study period.

The antipsychotic drugs that patients took at baseline were prepared in unmarked capsules, with the dose adjusted to provide a 25% reduction weekly over the next 3 weeks. The dose tapering schedule was as follows: 3 capsules at baseline, 2 capsules at week 1, 1 capsule at week 2, and 0 capsules (i.e., the antipsychotic drugs were discontinued) at week 3. Clozapine was gradually increased to 300 mg/day according to the following schedule: 12.5 mg/day at day 0 and increased by 25 mg/day to 300 mg/day at day 12, with this dose maintained for three weeks and thereafter adjusted according to clinical judgment. Concomitant medications were kept constant throughout the study period.

Change in the Abnormal Involuntary Movement Scale (AIMS) overall severity scores from baseline to 8 weeks

Change in the Calgary Depression Scale for Schizophrenia (CDSS) total scores from baseline to 8 weeks

Inclusion Criteria: Outpatients with a diagnosis of schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV (SCID-I) Candidacy for a trial of clozapine, defined as an inadequate clinical response to ≥ two antipsychotics (detailed in a pivotal clozapine study) and/or intolerable side effects Exclusion Criteria: Active substance use disorder; inability to undergo a trial of clozapine for medical reasons (e.g., myeloproliferative disorder or history of drug-induced granulocytopenia) Evidence of significant nonadherence, defined as ≤75% adherence following patient interview, review of records, and discussion with treating physician and caregivers

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