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Melatonin and its use in the treatment of tardive dyskinesia
David F. McAuley, Pharm.D.
GlobalRPh Inc.

Introduction: 
     Antipsychotics continue to be the mainstay of drug intervention in the management of schizophrenia, however, long-term treatment with antipsychotics is associated with a variety of movement disorders including the most disabling of which is tardive dyskinesia (TD).1  Tardive dyskinesia is a late complication of prolonged neuroleptic treatment and occurs in up to 50% of patients hospitalized with chronic schizophrenia.1,2  The pathophysiology of this disorder is still unclear and currently no definite treatment exists.3  Several theories have been developed relating to the cause of this movement disorder including dopamine receptor supersensitivity and oxidative stress-induced neurotoxicity in the nigrostriatal system.1  

     In the past 10 years, preclinical studies that have focused on the administration of antipsychotics to animals, as well as clinical studies of oxidative processes in patients given antipsychotic medications, have continued to support the possibility that neurotoxic free radical production may be related to antipsychotic treatment.3  Further, this neurotoxic free radical production may be contributing to the development of dyskinetic disorders.3  Because of this hypothesis, evidence has accumulated for the efficacy of antioxidants, with an early focus on vitamin E (alpha-tocopherol), in the treatment and prevention of tardive dyskinesia.1,3  Many of the early studies suggested only a modest effect of vitamin E on existing tardive dyskinesia, however, later studies failed to show a significant effect. Evidence has continued to accumulate for the oxidative damage (free radical) hypothesis. Researchers searched for a much more potent antioxidant considering the less than desirable outcomes with vitamin E. Many of these searches led to melatonin, a potent antioxidant thought to be 6 to 10 times more active than vitamin E as an antioxidant.3,4  

     Melatonin is an endogenous hormone synthesized in the pineal gland and besides being a potent anti-oxidant, it also attenuates dopaminergic activity in the striatum and dopamine release from the hypothalamus.1,4,5  Thus, it may have a beneficial effect for both the treatment and prevention of tardive dyskinesia.1 
  

Available evidence: 
     In 2001, E. Shamir and associates performed a double blind, placebo-controlled, crossover study to evaluate the efficacy of 10 mg per day of melatonin for 6 weeks in 22 patients with schizophrenia and tardive dyskinesia. The primary outcome measure was the change from baseline in the Abnormal Involuntary Movement Scale (AIMS) score. No adverse events or side effects were noted with melatonin. Results: The decrease (mean +/- SD) in AIMS score was 2.45 +/- 1.92 for the melatonin and 0.77 +/- 1.11 for the placebo treatment groups (P<.001). Authors’ conclusion: “This is the first clinical evidence for efficacy of melatonin in the treatment of tardive dyskinesia.” The authors also stated that treatment was more effective in patients who had worse symptoms (higher AIMS score) at baseline.1   


    DRUGDEX® provided information on a study completed in 2003 (design: double-blind, placebo-controlled trial comparing the effectiveness of melatonin 2 mg per day versus placebo for 4 weeks.) n=19. Mean age, 74 years +/- 9.5 years. Patients met the criteria for schizophrenia and neuroleptic-induced TD. Results: Melatonin 2mg (lower dose) was found to be ineffective in the treatment of tardive dyskinesia.6,7 


     In 2003, Naidu PS et al reported that chronic treatment with neuroleptics led to the development of abnormal oral movements in rats (referred to as vacuous chewing movements (VCMs)). Melatonin dose-dependently (1, 2, and 5 mg/kg) reversed the haloperidol-induced VCM and tongue protrusions frequencies. Further analysis revealed that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the forebrain glutathione (GSH) levels. Coadministration of melatonin (1, 2, and 5 mg/kg) along with haloperidol significantly reduced the lipid peroxidation and restored the decreased GSH levels. However, a lower dose of melatonin (1 mg/kg) failed to reverse chronic haloperidol-induced decreases in forebrain GSH, SOD, and catalase levels. The authors concluded that melatonin could be screened as a potential drug candidate for the prevention or treatment of neuroleptic-induced orofacial dyskinesia.


     In 2003, L. Nelson and associates reviewed the available literature regarding the use of melatonin in the treatment of tardive dyskinesia. Literature was identified through MEDLINE (1966-September 2002), PsycINFO (1967-September 2002), and references of relevant articles. Review articles, case reports/series, and animal and human studies were reviewed. After all of the evidence was reviewed, the authors concluded that there is a lack of data evaluating the use of melatonin in tardive dyskinesia. Further, methodological issues limited the utility of the few controlled studies that were evaluated. The authors’ final conclusion: "There are inadequate data at the present time to support the use of melatonin in patients with TD."8   

     The Natural Medicines Comprehensive Database states that taking melatonin orally 10 mg daily seems to decrease symptoms by 24-30% in some patients with TD after six weeks of treatment.4 
  

Conclusion: 
     Potent antioxidants appear to have a role in the treatment of tardive dyskinesia based on the oxidative damage caused by chronic antipsychotic administration. There appears to be early support for the potent anti-oxidant melatonin. The efficacy of melatonin appears to be dose dependent, with lower doses showing little to no improvement in this disorder. Finally, It appears more studies are needed to determine if higher doses of melatonin will provide greater efficacy and also to determine the recommended length of therapy. 
  

References:
 
1) Shamir E, Barak Y, Shalman I, Laudon M, Zisapel N, Tarrasch R, Elizur A, Weizman R. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry. 2001 Nov;58(11):1049-52. 
  
2) Naidu PS, Singh A, Kaur P, Sandhir R, Kulkarni SK. Possible mechanism of action in melatonin attenuation of haloperidol-induced orofacial dyskinesia. Pharmacol Biochem Behav. 2003 Feb;74(3):641-8. 
  
3) Lohr JB. Oxidative mechanisms and tardive dyskinesia. CNS Drugs. 2003; Vol. 17 (1): pp. 47-62. 
  
4) Anonymous. Melatonin. Natural Medicines Comprehensive Database: www.naturaldatabase.com 
Scientific Name: N-acetyl-5-methoxytryptamine 
  
5) Reiter RJ, Tan DX, Cabrera J, D’Arpa D, Sainz RM, Mayo JC, Ramos S. The oxidant/ antioxidant network: role of melatonin. Biol Signals Recept. 1999;8:56-63.   
6) Klasco RK (Ed): DRUGDEX® System. Thomson Micromedex, Greenwood Village, Colorado (Edition expires [Nov 2005]). 
  
7) Shamir E, Barak Y, Plopsky I, Zisapel N, Elizur A, Weizman A. Is melatonin treatment effective for tardive dyskinesia? J Clin Psychiatry. 2000 Aug;61(8):556-8. 
  
8) Nelson LA, McGuire JM, Hausafus SN. Melatonin for the treatment of tardive dyskinesia. Ann Pharmacother. 2003 Jul-Aug;37(7-8):1128-31.

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