A Double-Blind, Randomised, Parallel-Group Comparison of Ethyl-Eicosapentaenoic Acid (Ethyl-EPA) Versus Placebo as Add-on Medication in Patients With Established Tardive Dyskinesia

Background:

One of the major limitations of conventional antipsychotics is their high propensity to cause extrapyramidal symptoms (EPS). Tardive dyskinesia (TD) in particular causes problems, insofar as it is common, and resistant to treatment. TD is under-recognised in clinical settings. However, prevalence studies indicate that 5% of patients treated with conventional antipsychotics develop TD each year for the first eight years with an average reported prevalence rate in the region between 17 and 23%. Although in the majority of cases the disorder is mild and not distressing, TD contributes to social and vocational impairment, as well as to the further stigmatization of the illness. A minority develop severe symptoms, which are extremely distressing and disabling, and may even be life-threatening. Treatment of TD is difficult. Dose-reduction or discontinuation of antipsychotic medication may paradoxically result in exacerbation of the TD symptoms, and also run the risk of precipitating a psychotic relapse. With the exception of clozapine and possibly botulinum toxin (for tardive dystonia), vitamin E7 and vitamin B6, little evidence exists to indicate efficacy for any treatment modality for TD.

The novel antipsychotics have had a huge impact upon the treatment of schizophrenia. The major advantage of these agents over their predecessors is their reduced risk of inducing EPS (and probably TD). However, high acquisition costs have limited their availability worldwide and many patients will continue to be exposed to conventional antipsychotics for the foreseeable future. Development of an effective and affordable treatment for TD would therefore be of great benefit.

Rationale for this trial:

One possible candidate for an effective and affordable treatment for TD is eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid obtained from marine and plant sources. In addition to the evidence suggesting that EPA may improve the symptoms of schizophrenia when combined with standard antipsychotic treatment, there is also reason to believe that EPA may have a role in the treatment of TD. An open study in 20 hospitalised subjects with chronic schizophrenia reported a significant inverse correlation between dietary EPA and severity of TD. Treatment of these subjects with a standard EPA-rich marine oil for 6 weeks resulted in significant improvement in TD. We recently completed a 12-week randomised, double-blind study with ethyl-EPA 3g/day versus placebo as add-on to standard antipsychotic treatment, in forty subjects with chronic, refractory schizophrenia (submitted for publication). While there were no differences between the groups for the changes in the Extrapyramidal Symptom Rating Scale (ESRS) for parkinsonism, dystonia or akathisia scores, the ethyl-EPA group showed a significantly greater reduction in ESRS dyskinesia scores at 12 weeks (p=0.008). This result is potentially of great importance. Given the chronic nature of illness in our sample, most of these dyskinetic symptoms are likely to have been due to TD. This same study also reported a significant advantage for the ethyl-EPA group in terms of overall symptom reduction (PANSS total) (p=0.03), and analysis of co-variance indicated an association between PANSS total score reduction and ESRS dyskinesia score reduction.