Clozapine Versus Other Atypical Antipsychotics for Bipolar Disorder

Summary

The clinical use of clozapine has been an unequivocal advance in the treatment of schizophrenia, a chronic and severe mental illness. A wealth of clinical data demonstrates it offers enhanced efficacy on both positive and negative symptomatology, improving cognition, functioning and quality of life. It is also associated with improved compliance and a continued efficacy in long-term treatment that can be translated into a reduction of suicidality and all-cause mortality. Because of preclinical evidence that it modulates neuroplasticity and prefrontal cortex connectivity, clozapine may be an interesting strategy for further severe psychotic illnesses. Nevertheless, even considering the growing use of other atypical antipsychotics in the management of bipolar disorder, a role for clozapine has been poorly defined. The clinical evidence-base for its use in this condition is largely based on uncontrolled naturalistic trials and retrospective studies and chart reviews. Several of these have supported clozapine's efficacy in treatment-resistant bipolar disorder. Possibly because of clozapine's profile of adverse effects and lack of interest from pharmaceutical companies, only two randomized trials have examined its effectiveness. Both suggest clinically relevant antimanic and mood-stabilizing properties. Therefore, the primary objective of this trial is to determine the effectiveness of clozapine for treatment-resistant bipolar disorder. Secondary objectives include examining the effects of treatment with clozapine on cognition and functioning of patients with bipolar disorder. Tolerability and safety of long-term clozapine use will also be examined. To that end, the investigators will conduct a clinical trial with 54 patients with a history of treatment resistance. Patients will be randomized to either open-label treatment with clozapine, in combination with lithium or valproate, or open-label treatment with an atypical antipsychotic with consistent evidence of efficacy in the treatment of bipolar disorder (olanzapine, quetiapine or risperidone), also in combination with lithium or valproate. Patients will be followed for one-year and time to all-cause treatment failure will be the primary outcome measure. It is the belief of the investigators that this study will generate meaningful clinical data of tremendous importance to validate clozapine as a legitimate treatment option for treatment-resistant bipolar disorder.

Conditions

• Bipolar Disorder

Interventions

DRUG

Clozapine

Flexible dosage, with up-titration according to standard schedules employed for schezophrenia

DRUG

Risperidone

Risperidone, in a flexible dosage

DRUG

Olanzapine

Olanzapine, flexible dosage

DRUG

Quetiapine

Quetiapine, flexible dosage

Sponsors & Collaborators

• Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.

  collaborator OTHER_GOV

• Conselho Nacional de Desenvolvimento Científico e Tecnológico

  collaborator OTHER_GOV

• Hospital de Clinicas de Porto Alegre

  lead OTHER

Principal Investigators

• PEDRO V MAGALHAES, M.D., Ph.D. · Hospital de Clínicas de Porto Alegre / Universidade Federal do Rio Grande do Sul

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2015-10-31

Primary Completion

2019-06-30

Completion

2020-12-31

Countries

• Brazil

Study Locations