Tetrabenazine for Partial Responders
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional

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.
    

Intervention name(s): Tetrabenazine
Intervention type(s): Drug
Intervention description(s): 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
Intervention MeSH terms: Tetrabenazine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: tetrabenazine; partial response; psychosis; schizophrenia; schizoaffective disorder; partial response to antipsychotics