Efficacy of Docosahexaenoic Acid on Tardive Dyskinesia

Tardive Dyskinesia Clinical Trial

Official title:

Randomized, Double-Blind, Placebo-Controlled Trial on the Efficacy of Omega-3 Supplementation With Docosahexaenoic Acid (DHA) on Tardive Dyskinesia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00621634
• Other study ID #: HD06.067
• Status: Recruiting
• Phase: Phase 2
• First received: February 12, 2008
• Last updated: February 21, 2008
• Start date: February 2008

Study information

• Verified date: September 2007
• Source: Université de Montréal
• Contact: Pierre J. Blanchet, MD, PhD
• Phone: (514) 890-8123
• Email: Pierre.J.Blanchet[@]umontreal.ca
• Is FDA regulated: No
• Health authority: Canada: Natural Health Products Directorate, Health Canada
• Study type: Interventional

Clinical Trial Summary

Tardive dyskinesia (TD) is a well-known complication of antipsychotic drug therapy in individuals treated for mental disorders such as schizophrenia. It typically consists of purposeless, involuntary movements involving the mouth area or the trunk and limb muscles, occurring within months or years of drug use. The annual incidence of TD in the population treated with antipsychotic drugs is between 1-5%, but the risk is 5-fold greater in older individuals. Once triggered, TD is often irreversible and untreatable. Its cause is unknown, but an imbalance between chaotic mechanisms triggered by the drugs and natural protective factors fighting against these may provide an explanation. One way to activate this protective response is to supplement the diet with high doses of essential fatty acids of the omega-3 class, which constitute a critical component of nerve cell membranes. Using this strategy, one research team showed a 50% reduction in the severity of TD-like movements in mice treated with docosahexaenoic acid (DHA). We hypothesize that DHA supplements can do the same in patients living with schizophrenia displaying TD movements. Forty (40) subjects between 30-75 years of age will be recruited. The participants will be randomized and equally distributed in two groups to take either DHA capsules (3 grams a day) or matching placebo for 12 weeks, after providing informed consent, and TD will be measured with a magnetic tracker system and clinical scales. The finding of a beneficial effect with DHA against TD would improve the quality of life for thousands of patients under long-term antipsychotic drug treatment.

Description:

Background

Tardive dyskinesia (TD) is a well-known complication of antipsychotic drug (APD) therapy in individuals treated for mental disorders such as schizophrenia. It typically consists of purposeless, involuntary movements involving the oro-facial area, trunk, and/or limb muscles, occurring within months or years of APD use. Twisting and protruding movements of the tongue, lip smacking and puckering, and chewing movements, are often observed. Oral dyskinesia may cause pain, traumatic lesions, tooth wear, impaired retention of prosthetic devices, chewing difficulty, dysphagia, speech impairment, as well as social embarrassment. The annual incidence of TD in the population treated with these drugs is between 1-5%, but the risk in older individuals is 5-fold greater. The second-generation ("atypical") APDs have substantially reduced the short-term risk of TD, but the annual incidence of TD in older individuals taking these drugs remains comparable to that of younger adults treated with first-generation APDs. The cause of TD is unknown. Since all APDs are blockers of dopamine D2 receptors in the brain, researchers hypothesized that these receptors (or their signaling pathways) become supersensitive in such a way to promote TD. APDs also modulate the expression of a number of brain factors belonging to the nuclear receptor family, including Retinoid X Receptors (RXR) and Nur77, which are overexpressed following chronic APD treatment. These factors, seemingly mounting an adaptive response to fend off adverse drug reactions such as TD, may become incompetent or insufficient over time in those individuals developing TD. One way to activate this response is to supplement the diet with high doses of essential fatty acids of the omega-3 class, which constitute a critical component of nerve cell membranes and modulate a variety of brain receptors. Once triggered, TD is often irreversible and untreatable. However, one team recently showed a 50% reduction in the severity of TD-like movements in mice treated with docosahexaenoic acid (DHA).

Hypothesis

Since there is an apparent close relationship between retinoid receptors and dopamine systems in the human brain and DHA is a RXR agonist, our working hypothesis is that DHA will reduce TD intensity in patients living with schizophrenia by increasing the transcriptional activity along these pathways.

Objective

To evaluate the clinical impact of DHA on the intensity of TD in humans.

Study design

Forty (40) subjects between 30-75 years of age will be recruited. The participants will be randomized and equally distributed in parallel groups to take either DHA (3 grams a day) or matching placebo capsules for 12 weeks, after providing informed consent. The study will use questionnaires, venous blood sampling, as well as clinical scales, to monitor the psychiatric condition, the lipid profile, and TD intensity at the beginning and end of the study. Brief and simple tasks will also be completed with a motion analysis system using magnetic sensors in order to measure body movements and TD with accuracy.

Outcome

The finding of a beneficial effect with DHA against TD would improve the quality of life for thousands of patients under long-term APD treatment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years to 75 Years

Eligibility

Inclusion Criteria:

• chronic schizophrenia patients under long-term antipsychotic drug treatment, stable for at least 3 months before study entry;

• presence of tardive dyskinesia following Schooler-Kane research criteria (mild intensity (2/4 points) in at least two body segments, or moderate intensity (3/4 points) for at least one body segment);

• patients capable to understand the goals and procedures of the study, and to provide informed consent;

• women of childbearing age will be requested to use an effective contraceptive method throughout the study.

Exclusion Criteria:

• subjects with medical conditions susceptible to significantly increase the risk of adverse effects, or to interfere with the conduct of the study; in particular, those with a history of coronary artery disease, pancreatitis, diabetes, coagulation disorders, or hemorrhagic conditions;

• those regularly taking aspirin, anticoagulants, or oral lipid-lowering agents;

• those with fasting baseline triglyceride values >4.0 mmol/L, or with cholesterol values >8 mmol/L ;

• those intolerant or allergic to fish, seafood, or any other substance contained in the study medication or matching placebo;

• those who have abused illegal street drugs during the past year;

• those unlikely to comply with the study requirements;

• those who consume natural health products of marine or vegetable source, containing omega-3 essential fatty acids;

• women who are pregnant or breastfeeding.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Dyskinesias
• Tardive Dyskinesia

Intervention

Dietary Supplement:
• Omega-3 fish oil capsules (including DHA)
Fish oil capsules of 1000 mg ea., including DHA 460-540 mg/capsule 2 capsules TID daily at mealtime for 12 consecutive weeks
• Placebo
Corn/Soybean (1:1) placebo 1000 mg capsules 2 capsules TID daily at mealtime for 12 consecutive weeks

Locations

Country	Name	City	State
Canada	Louis-H.-Lafontaine Hospital	Montreal	Quebec
Canada	Notre-Dame Hospital/CHU Montreal	Montreal	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Université de Montréal	National Alliance for Research on Schizophrenia and Depression

Country where clinical trial is conducted

Canada, 

References & Publications (3)

Beaudry G, Langlois MC, Weppe I, Rouillard C, Lévesque D. Contrasting patterns and cellular specificity of transcriptional regulation of the nuclear receptor nerve growth factor-inducible B by haloperidol and clozapine in the rat forebrain. J Neurochem. 2000 Oct;75(4):1694-702. — View Citation

Ethier I, Kagechika H, Shudo K, Rouillard C, Lévesque D. Docosahexaenoic acid reduces haloperidol-induced dyskinesias in mice: involvement of Nur77 and retinoid receptors. Biol Psychiatry. 2004 Oct 1;56(7):522-6. — View Citation

Langlois MC, Beaudry G, Zekki H, Rouillard C, Lévesque D. Impact of antipsychotic drug administration on the expression of nuclear receptors in the neocortex and striatum of the rat brain. Neuroscience. 2001;106(1):117-28. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical rating scales (AIMS, St.Hans)		Baseline, Week 2, Week 14	No
Secondary	Quantitative motor testing (kinematic parameters)		Baseline, Week 14	No
Secondary	Monitoring of psychopathology (Neuro-Psychiatric Inventory, Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia)		Baseline, Week 2, Week 14	Yes
Secondary	Erythrocyte membrane phospholipid profile (gas chromatography)		Baseline, Week 14	Yes