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Tetrabenazine for Partial Responders

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ClinicalTrials.gov Identifier: NCT00362804
Recruitment Status : Completed
First Posted : August 10, 2006
Last Update Posted : July 6, 2012
Sponsor:
Collaborator:
Stanley Medical Research Institute
Information provided by (Responsible Party):
Gary Remington, Centre for Addiction and Mental Health

Tracking Information
First Submitted Date  ICMJE August 9, 2006
First Posted Date  ICMJE August 10, 2006
Last Update Posted Date July 6, 2012
Study Start Date  ICMJE February 2002
Actual Primary Completion Date January 2006   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 4, 2008)
  • BPRS [ Time Frame: weekly assessments ]
  • CGI [ Time Frame: weekly assessment ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 9, 2006)
  • BPRS
  • CGI
  • GAF/NOSIE
  • CDS
  • SAS
  • AIMS
  • BAS
  • UKU (a general measure of adverse effects)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 4, 2008)
  • GAF/NOISE [ Time Frame: weekly ]
  • SAS [ Time Frame: weekly ]
  • AIMS [ Time Frame: weekly ]
  • BAS [ Time Frame: weeekly ]
  • UKU (a general measure of adverse effects) [ Time Frame: weekly ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tetrabenazine for Partial Responders
Official Title  ICMJE Augmentation of Antipsychotic Partial Responders With Tetrabenazine
Brief Summary

Purpose of Study:

A) To improve outcome in large population of antipsychotic patients with schizophrenia or schizoaffective who are only partial responders B) To increase understanding of pharmacology and mechanisms of action underlying antipsychotic effect

Hypothesis/Objectives of the Study:

Tetrabenazine, through its pre-synaptic action, should augment the post-synaptic effects of an antipsychotic.

Background and Rationale for the study:

Preliminary evidence that other amine-depleting agents e.g., reserpine, can induce such an effect

Detailed Description

Since the 1950's, antipsychotics have been used as the mainstay treatment to control symptoms of schizophrenia. However, soon after their introduction it became apparent that a substantial number of individuals show a less than optimal response to these drugs - as many as 30% of schizophrenics using conventional antipsychotics derive little benefit. Furthermore, 'atypical' generation antipsychotics such as clozapine which proves to be the most beneficial for partial responders and represents the cornerstone of treatment-resistant schizophrenia, offers a response rate as low as 30% in those showing an inadequate response. Moreover, many individuals decline clozapine as an option, or cannot tolerate it.

For these reasons, augmentation strategies play an important role in the treatment of antipsychotic partial responders. We have systematically reviewed the different augmentation options, and reached the conclusion that most such strategies are theoretically speculative and empirically unsupported.

At the same time though, we recognize that augmentation strategies are common practice in the clinical setting. With so many individuals showing only a partial response to antipsychotic treatment (typical or atypical), it has become a practical reality in efforts to offer further improvement. Often, this come in the form of adding one or even more antipsychotics, although the evidence for such an approach is less than compelling and neuroimaging from our centre has cautioned against this approach.

With a variety of other potential augmentation strategies available, we have chosen to focus on tetrabenazine (TBZ), which is currently licensed here in Canada for the management of hyperkinetic movement disorders.

The choice of TBZ as an augmentation strategy arises from several lines of investigation:

  • TBZ, like reserpine, is a pre-synaptic monoamine-depleting agent or inhibitor of vesicular monoamine transporter, and hence will act to dampen abnormal dopamine release in patients already on a primary post-synaptic D2 blocking compound, as is the case (to varying degrees) with all antipsychotics currently available.
  • There are anecdotal reports with reserpine, indicating that it can augment response in patients showing only a partial response to antipsychotic (atypical, as well as typical) partial responders.
  • TBZ appears to have a low-affinity post-synaptic D2 effect, still well below the 80% threshold where one begins to see motor side effects.
  • TBZ has inherent anti-dyskinetic properties, thereby offering an additional secondary benefit.

We are proposing to carry out a controlled double-blind trial, using TBZ off-label in patients with schizophrenia or schizoaffective disorder only partially responsive to antipsychotics. We feel that the choice of this approach is empirically sound and, in fact, offers advantages to the more common approach of adding several antipsychotics. Our decision to maintain out focus on the dopaminergic system arises from the growing body of evidence that dopamine blockade, particularly at the level of the D2 receptor, is central to antipsychotic activity, in combination with the lack of current evidence supporting the distinct advantages of incorporating other systems.

Given the limited success with augmentation strategies in schizophrenic patients to date, any evidence of efficacy and safety with this combination will add considerably to options that might be considered in the clinical setting. This same information could also prove very useful in shaping investigations related to the pharmacology of schizophrenia and development of future compounds.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Schizophrenia
  • Schizoaffective Disorder
Intervention  ICMJE Drug: Tetrabenazine
The initial TBZ dose will be 12.5 mg and the dose will be increased to 25 mg at Week 2. Thereafter, the dose can be decreased to 12.5 mg or increased in 12.5 mg increments at weekly intervals, depending on clinical response and tolerability, to a maximum of 75 mg/day. For 37.5 and 50 mg daily, administration will be BID i.e., 25 mg QAM, 12.5 or 25 mg QHS. For 62.5 or 75 mg daily, a TID dosing will be employed i.e., 25 mg QAM, 12.5 or 25 mg QPM, 25 mg QHS
Study Arms  ICMJE Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 4, 2012)
41
Original Enrollment  ICMJE
 (submitted: August 9, 2006)
60
Actual Study Completion Date  ICMJE January 2006
Actual Primary Completion Date January 2006   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • has been on an antipsychotic medication for at least 3 months and achieved the maximum dose vis à vis tolerability/side effects.
  • Partial response to antipsychotic medication (CGI > 4; BPRS [Anchored, 18-item] total > 30; single item score > 4 on 2 positive symptom items)
  • has been on at least 2 previous antipsychotic trials of 4-6 weeks in duration at a dose reaching 400-600 mg chlorpromazine (or equivalent) with no clinical improvement

Exclusion Criteria:

  • age < 18 or > 65
  • previous documentation of hypersensitivity to tetrabenazine
  • SCID criteria for a current depressive episode
  • MAOI administration within 2 weeks of tetrabenazine treatment
  • concomitant desipramine use
  • diagnosis of idiopathic Parkinson's disease and/or levodopa treatment
  • current unstable medical illness and current substance abuse
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00362804
Other Study ID Numbers  ICMJE 240/2001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gary Remington, Centre for Addiction and Mental Health
Study Sponsor  ICMJE Centre for Addiction and Mental Health
Collaborators  ICMJE Stanley Medical Research Institute
Investigators  ICMJE
Principal Investigator: Gary Remington, MD Centre for Addiction and Mental Health
PRS Account Centre for Addiction and Mental Health
Verification Date July 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP