Neuroleptic-induced Tardive Dyskinesia
Conditions
Keywords
sarizotan, neuroleptic-induced tardive dyskinesia
Brief summary
TD is a troublesome and potentially irreversible side effect associated with the use of neuroleptics. While the newer neuroleptics are improved in this regard, they all still carry the risk of TD. The present study proposes that sarizotan is a potential agent for treating neuroleptic-induced TD based on preliminary data indicating efficacy in the management of dyskinesias associated with Parkinson's disease. Its efficacy is further substantiated by pre-clinical data obtained from the vacuous chewing movement (VCM) model in rats, a model we employ ourselves in investigating the relationship between D2 occupancy and TD. The present study also examines the effects of sarizotan on cognitive function, given the association between TD and cognitive deficits.
Detailed description
The primary objective of the study is to assess the safety and the anti-dyskinetic properties of sarizotan at various dosages for neuroleptic-induced TD. The secondary objective of the study is to assess the effects of sarizotan on cognitive function in patients with neuroleptic-induced TD. The diagnosis of neuroleptic-induced TD will be confirmed by history and physical examination. Patients will be evaluated at baseline, 2, 4, 8, and 12 weeks. Safety will be assessed by vital signs, ECG, routine blood tests, the ACTH stimulation test, and the clinician's and patient's global impression of tolerability. Procedures: For efficacy, the primary outcome variable will be changes in the Abnormal Involuntary Movement Scale (AIMS), and a baseline score of \>3 ('moderate') will be required for item 8 (Severity of Abnormal Movements). Quantitative evaluation of movements will be carried out in two ways. The first involves a series of instrumental and clinical measures that were developed as a battery for the assessment of antipsychotic-induced parkinsonism and TD. The second means of quantifying the movements involves the use of video recording, with independent evaluation by several raters (Appendix I). Such approaches have gained popularity in the quantification of movement disorders as a means of improving reliability. Secondary measures will include the positive and negative syndrome scale (PANSS) and other movement disorder scales (Simpson-Angus Rating Scales) for acute extrapyramidal symptoms (EPS), and the Barnes Akathisia Rating Scale (BARS). Global impressions of efficacy and tolerability by the clinician (CGI) and by the patients (PGI) will be recorded at all study visits after the commencement of treatment. To assess potential cognitive changes that may occur in conjunction with TD changes, a battery of neuropsychological tests will be carried out at baseline and endpoint (see Appendix II). To assess the relationship with primary negative symptoms such as the deficit syndrome, the total and sub-scales of the Positive and Negative Syndrome Scale will be evaluated.
Interventions
DRUGSarizotan
The dose of sariztan HCI for each patient in the drug arm will be given 2mg b.i.d. orally during the first 4 weeks of treatment. If efficacy is inadequate and there are no safety concerns, the option to raise the dose to 5mg b.i.d is given. After 8 weeks of treatment, the option to raise the dose to 7mg bid is given. Dose may remain the same or may be decreased again to the previous dose.
OTHERPlacebo
Placebo for each patient randomized to the placebo arm will be given placebo (oral, twice daily) in a pill form for 12 weeks
Sponsors
Merck KGaA, Darmstadt, Germany
Centre for Addiction and Mental Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* The patient meets the Schooler and Kane Diagnostic Criteria (25) for Tardive Dyskinesia as established by history and physical examination. * a score of 3 or above for item 8 of the AIMS scale (Severity of Abnormal Movements) at baseline. * For female patients: either the patient is surgically sterile, has been post-menopausal for at least 12 months, or she is using a reliable method of contraception (single-barrier methods alone will not be considered sufficiently reliable) and provides a negative pregnancy test at the screening visit. * on a stable dose of his/her current antipsychotic (either typical or atypical) and movement disorder medication (e.g. anticholinergics) for at least one month before randomisation. For depot antipsychotics, this period will be at least one dosing interval. * The patient gives full written informed consent for participation in the study. * The patient has a level of understanding of English or Tamil sufficient to communicate effectively with the investigator and study staff, and to be able to complete the computerised neurocognitive test battery where necessary
Exclusion criteria
*
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Degree of change in the Abnormal Involuntary Movement Scale | 12 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Change in PANSS | 12 weeks |
| Change in Simpson-Angus Rating Scales for acute EPS | 12 weeks |
| Change in Barnes Akathisia Rating Scale | 12 weeks |
Countries
Canada, India
Outcome results
None listed