Xenazine in Late Dyskinetic Syndrome With Neuroleptics

Tetrabenazine is classified as a central monoamine depleting agent. In vitro studies have shown that it is an inhibitor of the vesicular monamine transporter 2 (VMAT2), resulting in synaptic dopamine depletion. This effect explains the reduction of hyperkinetic movement disorders.

Although tetrabenazine enjoys a reputation of very good efficacy in tardive syndromes, with good tolerance, it is still yet to empiricism because studies are few andf most importantly, of low level of evidence according the criteria of Evidence Based Medicine.

This is a randomized, multicenter, parallel group, double-blind placebo (tetrabenazine/placebo: 1/1), in two comparative conditions before and after 10 weeks of treatment with tetrabenazine (5-week titration to a maximum dose of 200 mg/day and 5 weeks at stable dose).

Study enrollment is proposed to patients fulfilling inclusion criteria.

The study should process as follows:

• Patients give their informed consent for participation after presentation of the study by the investigator.
• Visit V0: Given the patient's signed consent, global clinical examination, blood sampling, vital signs (weight, height, arterial tension, ECG are performed as well as a neurological examination (MMS). For women in childbearing potential, a urinary pregnancy test will be realized. It is noteworthy that a psychiatric consultation dating less than one month is required.
• Visit V1: patient is randomized in one of the two arms: tetrabenazine or placebo. Some tests are performed at baseline:

• Neurologic: ESRS, AIMS, CGI, UPDRSIII, MMS;
• Quality of life auto-questionnaires: SF36, Epworth; The treatment is prescribed following a titration phase during 5 weeks, a stable dose during 5 weeks, and a wash-out period during 2 weeks.
• At V2 (1 week after V1), V3 (3 weeks after V1) and V5 (7 weeks after V1): global clinical examination is performed and prescription observance is checked.
• At V4 (5 weeks after V1), V6 (10 weeks after V1) and V7 (12 weeks after V1): neurological (ESRS, AIMS, CGI, UPDRSIII, auto questionnaire SF36, Epworth, neuropsychological examination (MADRS), psychiatric examination (only at V6), vital signs and prescription observance.

Inclusion criteria

• Adult (age over 18) or adult under judicial protection (tutor or curator).
• Patient with late dyskinetic syndrome with neuroleptics yielding functional disability and/or impact in every day's life, according to the investigator, and/or the patient and/or the patient's family.
• Patient with persistent late dyskinetic syndrome, even if the neuroleptic has been stopped for more than 6 months or patient with late dyskinetic syndrome under neuroleptic treatment unchanged for at least 3 months and which would a priori not need any dose variation during the study time.
• MADRS < 18
• QTc < 450 ms for men and < 470 for women.

Exclusion criteria

• Lack of social insurance
• Neuroleptic treatment less than 3 months
• Insanity according to the DSM IV and MMS < 24
• Predominant akathisia
• Psychiatric disease not stabilized for more than 6 months and/or which could require a neuroleptic treatment adaptation during study time.
• Pregnancy and lactating
• Women in genital activity without efficient contraception method (IUD or estrogen-progestin pill)
• Hypersensitivity to tetrabenazine
• Renal failure
• Drugs: Non-selective MAOIs, dopaminergic (or other antiparkinsonian)
• Other severe pathology
• Patient non compliant to protocol, at the investigator's appreciation
• Simultaneous participation to other clinical trial
• Congenital galactosemia, glucose malabsorption or lactase deficiency