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Original Article |

Melatonin Treatment for Tardive Dyskinesia:  A Double-blind, Placebo-Controlled, Crossover Study FREE

Eyal Shamir, MD; Yoram Barak, MD; Irena Shalman, MD; Moshe Laudon, PhD; Nava Zisapel, PhD; Ricardo Tarrasch, MA; Avner Elizur, MD; Ronit Weizman, MD
[+] Author Affiliations

From the Abarbanel Mental Health Center, Bat-Yam, Israel (Drs Shamir, Barak, Shalman, and Elizur); Sackler Faculty of Medicine (Drs Shamir, Barak, Shalman, Elizur, and Weizman), Department of Neurobiochemistry, Faculty of Life Sciences (Dr Zisapel), and Department of Psychology (Mr Tarrasch), Tel Aviv University, Neurim Pharmaceuticals Ltd (Drs Laudon and Zisapel), and Tel Aviv Mental Health Center (Dr Weizman), Tel Aviv, Israel.


Arch Gen Psychiatry. 2001;58(11):1049-1052. doi:10.1001/archpsyc.58.11.1049.
Text Size: A A A
Published online

Background  Antipsychotics remain the mainstay of drug intervention in the management of schizophrenia. However, long-term treatment with antipsychotics is associated with a variety of movement disorders, the most disabling of which is tardive dyskinesia (TD), which occurs in up to 50% of patients hospitalized with chronic schizophrenia. The pathophysiology of TD is still unclear and no definite treatment exists. Both dopamine receptor supersensitivity and oxidative stress–induced neurotoxicity in the nigrostriatal system are apparently implicated. The pineal hormone melatonin is a potent antioxidant and attenuates dopaminergic activity in the striatum and dopamine release from the hypothalamus. Thus, it may have a beneficial effect for both the treatment and prevention of TD.

Methods  Using a double-blind, placebo-controlled, crossover study, we evaluated the efficacy of 10 mg/d of melatonin for 6 weeks in 22 patients with schizophrenia and TD. The primary outcome measure was the change from baseline in Abnormal Involuntary Movement Scale (AIMS) score.

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). No adverse events or side effects were noted.

Conclusion  This is the first clinical evidence for efficacy of melatonin in the treatment of TD.

Figures in this Article

SCHIZOPHRENIA IS a chronic, usually lifelong psychiatric disorder that requires many hospitalizations and complex psychosociobiological interventions. Blockade of the postsynaptic dopamine D2 receptor by antipsychotic medications results in improvement of psychosis in schizophrenia. However, a broad spectrum of hyperkinesias is associated with long-term exposure to these drugs. Tardive dyskinesia (TD) is estimated to occur in 3% to 5% of patients treated with antipsychotics during the first 5 years of treatment and 68% after 20 to 25 years of exposure to typical antipsychotics.14 The introduction of atypical antipsychotics reportedly lowers the risk of TD.5 However, TD is often refractory to treatment despite the numerous approaches attempted throughout the years.6 Thus, there is a need for more rigorous studies to assess the role of new strategies, such as vitamin E and branched chain amino acids, in the treatment of TD.6,7

The pathophysiology of antipsychotic-induced TD is still considered unclear and controversial.8 Antioxidants, specifically vitamin E, have been studied as possible agents for both the treatment and prevention of TD. Meta-analysis of published studies demonstrates a modest effect in reducing severity and a better outcome in new-onset TD.6 However, a multicenter, long-term, well-controlled, randomized Veterans Affairs trial of vitamin E vs placebo in a large cohort found no evidence for efficacy of vitamin E in the treatment of TD.9 Melatonin is 6 to 10 times more effective as an antioxidant than vitamin E and exerts its actions through detoxification of a variety of free radicals and stimulation of several antioxidant enzymes.10 Moreover, recent evidence makes melatonin an even more tempting candidate for study in the treatment of TD. Pineal calcification and low endogenous melatonin levels have been associated with TD in patients with schizophrenia who are treated with antipsychotics.11 Melatonin has been shown to exert antioxidant effect on dopaminergic neurons12 as well as dopaminergic-modulating activities13 and thus may be efficacious in the treatment of TD. The aim of the present study was to evaluate the effect of melatonin on TD in a double-blind, placebo-controlled, crossover study.

SUBJECTS

Twenty-four patients with schizophrenia were recruited from the inpatient psychiatry service of the Abarbanel Mental Health Center (Bat-Yam, Israel). Diagnosis of schizophrenia was established following a structured interview (Structured Clinical Interview for DSM-IV) administered by a board-certified psychiatrist (E.S. or Y.B.). All patients met DSM-IV criteria for both schizophrenia and antipsychotic-induced TD. Exclusion criteria were comorbid neurological illness, substance abuse, and concurrent participation in another study.

Twenty-four patients were eligible and included in the randomization phase. Randomization was performed using sealed envelopes. Two female patients were discharged from the hospital before initiation of the study and are not included in the analysis. The mean ± SD age of the 22 patients (11 women and 11 men) was 64.2 ± 14.3 years (range, 28-82 years). The mean ± SD duration of illness was 24.8 ± 8.7 years (range, 13-43 years; median, 23.5 years). Current antipsychotic medications were as follows: haloperidol, 13 patients; chlorpromazine, 4 patients; perphenazine, 3 patients; and zuclopenthixol, 2 patients. The antipsychotic medication regimens remained unchanged throughout the study. Average dose of current antipsychotic medications was 202.2 mg/d of chlorpromazine equivalents. Additional concomitant medications were as follows: anticholinergics, 12 patients; benzodiazepines, 5 patients; antidepressants, 4 patients; and mood stabilizers, 5 patients. The regimens of these additional medications also remained unchanged throughout the study. All study patients were previously and currently hospitalized in our center. Mean cumulative lifetime exposure of the patients randomized to neuroleptic medications was 3.82 × 106 mg of chlorpromazine equivalents (SD, 3.7 × 106 mg; median, 2.4 × 106 mg; range, 0.70-13.14 × 106 mg).

Information on the cumulative and current medications was recorded from patients' medical charts.

PROCEDURE AND OUTCOME MEASURES

In a randomized, double-blind, crossover design, each patient was given 2 tablets (5 mg each, 10 mg/d) of controlled-release melatonin (Circadin; Neurim Pharmaceuticals Ltd, Tel Aviv, Israel) or 2 placebo tablets identical in appearance. Tablets were administered at 8 PM every night for 6 weeks. After a washout period (following melatonin or placebo treatment) of 4 weeks, the patients received 6 weeks of treatment with the other preparation. Both patients and physicians were blinded to group allocation. Medication and placebo were dispensed by the hospital's pharmacy and added to the patients' ongoing treatment regimen. Treatment with a controlled-release dosage form was chosen because it mimics the pattern of melatonin's endogenous profile.14 The Abnormal Involuntary Movement Scale (AIMS) was chosen to assess TD severity, since it has been shown to have good psychometric properties15 and is generally accepted as an outcome measure sensitive to changes in TD in pharmacological trials.16 The AIMS was administered by a single psychiatrist (I.S.) between 10 AM and noon, at baseline, and at the end of weeks 6 (end of phase 1), 10 (end of washout period), and 16 (end of phase 2). Severity of movements was rated on a scale of 0 to 4. The mean ± SD total AIMS score (items 1-7) in this population at baseline was 10.50 ± 5.30 (range, 3-22). The study protocol was approved by the institutional review board (Abarbanel Mental Health Center) and the Israeli Ministry of Health Committee for Studies in Human Subjects. Written informed consent was obtained from all participants following a detailed explanation of the nature of the study.

STATISTICAL ANALYSIS

The incomplete data from the 2 dropout patients were not included in the analyses. Change in AIMS score (treatment period vs baseline or washout period) with melatonin and placebo was calculated for each patient. To check whether the effect of melatonin differed from that of placebo, the Wilcoxon signed rank test was performed comparing the 2 effects; the α level of significance was set at .05. To test whether there was a significant difference in the effect of melatonin when given before or after placebo, the Mann-Whitney-Wilcoxon test was performed on the ranks of the differences between the 2 measurements (placebo, melatonin) of the AIMS score of each patient, comparing the placebo-melatonin group vs the melatonin-placebo group. Data are presented as mean ± SD.

After unblinding code following database lock, it was found that 10 patients (5 women and 5 men; mean age, 62.8 ± 11.4 years) received placebo first and 12 patients (6 women and 6 men; mean age, 65.4 ± 16.6 years) received melatonin first. No adverse events or side effects possibly, probably, or definitely related to the study medication were recorded during the study.

Following 6 weeks of treatment with melatonin, the mean AIMS score (items 1-7) decreased from 10.27 ± 5.38 (range, 3-22) to 7.82 ± 4.82 (range, 1-20). Treatment of the same patients with placebo resulted in a decrease in AIMS score from 9.09 ± 4.25 (range, 3-21) to 8.32 ± 4.18 (range, 3-21).

The decrease in AIMS score from baseline (or washout) values was significantly higher with melatonin treatment compared with placebo (2.45 ± 1.92 vs 0.77 ± 1.11, respectively; Wilcoxon signed rank test, z = −3.27, 2-tailed P = .001). Of the 22 patients, 17 patients' symptoms improved more with melatonin than with placebo, in 4 there was no difference between the 2 treatments, and only 1 patient's condition improved with placebo more than melatonin.

Individual patient data on the change from baseline (or washout) in total AIMS score are shown in Figure 1. There was no significant difference between the total AIMS score at the end of the washout period and baseline, indicating that washout was long enough. In addition, there was no significant difference between change in AIMS score with different order of treatment, ie, placebo-melatonin vs melatonin-placebo (χ2 = 0.13; P = .72, Mann-Whitney-Wilcoxon test).

Place holder to copy figure label and caption

Improvement of total Abnormal Involuntary Movement Scale (AIMS) score as a function of baseline AIMS score in patients taking either melatonin (10 mg, controlled release) or placebo. After 6 weeks of treatment, patients entered a 4-week washout period and then crossed over for an additional 6 weeks of treatment. The AIMS was scored at baseline and at the end of weeks 6 (end of first treatment period), 10 (end of washout period), and 16 (end of second treatment period, after crossover).

Graphic Jump Location

Clinically significant outcome in the treatment of TD is usually defined as a reduction in total AIMS score greater than 3 points.16 In the present study, 7 patients showed clinical improvement during the melatonin treatment compared with only 1 during placebo treatment (McNemar test, χ2 = 11.53, P<.001). In addition, only 2 patients showed no change in AIMS score during melatonin treatment, whereas 11 patients showed no change during the placebo treatment (McNemar test, χ2 = 6.67, P<.01) (Figure 1). Improvement by 30% or more was noted in 9 of the 22 patients treated with melatonin and in none given placebo.

These results indicate efficacy of melatonin treatment for 6 weeks in treating TD in a placebo-controlled trial. The effects of melatonin (a mean decrease of 2.45 ± 1.92 with melatonin compared with 0.77 ± 1.11 with placebo from baseline scores of 10.27 ± 5.38 and 9.09 ± 4.25, respectively) compare favorably with those attained by treatment with vitamin E (1200 IU/d) for the same period (6 weeks). With vitamin E, mean improvement in the AIMS score was reported to be 1.2 to 2.0 vs 0.2 to 2.0 with placebo,9,1722 but the significance of vitamin E treatment vs placebo was not unequivocally demonstrated. It remains to be studied whether the efficacy of melatonin will further increase with longer treatment or with larger doses of the hormone. The clinical efficacy of melatonin in TD may be explained by its antioxidant properties. Oxidative stress and elevated levels of lipid peroxidation have been implicated in haloperidol toxicity.23,24 Evidence to support these animal studies includes elevated levels of lipid peroxidation with haloperidol treatment in patients with psychoses.24 Furthermore, addition of the antioxidant vitamin E to ongoing haloperidol treatment results in some improvement in patients with TD symptoms.6 Melatonin was shown to be a potent antioxidant in vitro and in vivo.10 Specifically, it has been shown to prevent haloperidol-induced oxidative neurotoxicity23 and 6-hydroxydopamine–induced neuronal death in the nigrostriatal dopaminergic system.12 In addition, melatonin enhances the expression of glial cell line–derived neurotrophic factor, a growth factor preferentially selective for dopamine neurons.25 Such neuroprotective mechanisms may be relevant to the anti-TD effect of melatonin.

Theoretically, a neuroprotective effect should prevail after the cessation of drug use and is expected to be more pronounced in patients who have a lower cumulative exposure to antipsychotics (because those presumably have a lesser and perhaps reversible neurodegenerative damage). Yet, we found that the order of administration of placebo and melatonin in our crossover designed trial did not significantly alter the outcome of the treatment. Moreover, treatment was more effective in patients who had worse symptoms (higher AIMS score) at baseline. It seems, therefore, that the effect of melatonin is mostly pharmacological. However, given the brevity of the present investigation, we cannot rule out the possibility that some neuroprotection might also be involved.

It is proposed that TD is associated with dopamine receptor supersensitivity4; thus, the beneficial effects of melatonin in TD may be due to modulatory effect on dopamine release. Inhibition by melatonin of dopamine release from specific brain areas has been demonstrated in vitro in rats,13 sheep, and hamsters.26 In addition, melatonin was able to reduce excitability of nigrostriatal neurons27 and increase the affinity of dopamine D2 receptors in the rat striatum.28 The relevance of these mechanisms to TD in humans remains to be elucidated.

A reduction in nigrostriatal dopaminergic activity could theoretically lead to worsening of parkinsonian adverse effects and akathisia, as is supported by findings in animal models of Parkinson disease.29 Although we did not observe any such effects of melatonin in our study, this possibility warrants further investigation. Notably, in a previous study,30 we found that a lower dose of melatonin (2 mg/d) for a shorter period (4 weeks) was not significantly different from placebo in the treatment of TD. Thus, it appears that the beneficial effect may be dose and/or duration dependent.

The limitations of the present study are the relatively small sample size, midrange duration of treatment, and the fact that the patients were all inpatients, possibly reflecting more severe and chronic illness. An additional limitation is the absence of systematic quantification of other movement disorders during melatonin treatment, possibly hindering the ability to speculate on the mode of action of melatonin treatment in TD.

In conclusion, the results of the present study demonstrate that melatonin treatment is beneficial for antipsychotic-induced TD. To our knowledge, this is the first study to demonstrate clinically meaningful improvement of TD symptoms with melatonin. The brevity of our studies does not allow us to speculate on whether melatonin is able to reverse the neural pathologic condition. This issue needs to be investigated with larger samples and longer treatments.

Accepted for publication March 23, 2001.

Corresponding author and reprints: Eyal Shamir, MD, Abarbanel Mental Health Center, 15 KKL St, Bat-Yam 59100, Israel (e-mail: drshamir@hotmail.com).

Kane  JMWoerner  MBorenstein  MWegner  JLieberman  J Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull. 1986;22254- 258
Morgenstern  HGlazer  WM Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medications: results of the Yale Tardive Dyskinesia Study. Arch Gen Psychiatry. 1993;50723- 733
Link to Article
Glazer  WMMorgenstern  HDoucette  JT Predicting the long-term risk of tardive dyskinesia in outpatients maintained on neuroleptic medications. J Clin Psychiatry. 1993;54133- 139
Cardoso  FJankovic  J Dystonia and dyskinesia. Psychiatr Clin North Am. 1997;20821- 838
Link to Article
Beasley  CMDellva  MATamura  RNMorgenstern  HGlazer  WMFerguson  KTollefson  GD Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry. 1999;17423- 30
Link to Article
Barak  YSwartz  MShamir  EStein  DWeizman  A Vitamin E (alpha-tocopherol) in the treatment of tardive dyskinesia: a statistical meta-analysis. Ann Clin Psychiatry. 1998;10101- 105
Link to Article
Richardson  MABevans  MLWeber  JBGonzalez  JJFlynn  CJAmira  LRead  LLSuckow  RFMaher  TJ Branched chain amino acids decrease tardive dyskinesia symptoms. Psychopharmacology (Berl). 1999;143358- 364
Link to Article
Feltner  DEHertzman  M Progress in the treatment of tardive dyskinesia: theory and practice. Hosp Community Psychiatry. 1993;4425- 34
Adler  LRotrosen  JEdson  RLavori  PLohr  JHitzemann  RRaisch  DCaligiuri  MTracy  KVeterans Affairs Cooperative Study #394 Study Group, Vitamin E treatment for tardive dyskinesia. Arch Gen Psychiatry. 1999;56836- 841
Link to Article
Reiter  RJTan  DXCabrera  JD'Arpa  DSainz  RMMayo  JCRamos  S The oxidant/antioxidant network: role of melatonin. Biol Signals Recept. 1999;856- 63
Link to Article
Rao  MGross  GStrebel  BBraunig  PHuber  GKlosterkotter  J Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects. Psychiatry Res. 1990;34243- 257
Link to Article
Kim  YSJoo  WSJin  BKCho  YHBaik  HHPark  CW Melatonin protects 6-OHDA-induced neuronal death of nigrostriatal dopaminergic system. Neuroreport. 1998;92387- 2390
Link to Article
Zisapel  NEgozi  YLaudon  M Inhibition of dopamine release by melatonin: regional distribution in the rat brain. Brain Res. 1982;246161- 163
Link to Article
Garfinkel  DZisapel  N The use of melatonin for sleep. Nutrition. 1998;141- 2
Link to Article
Lane  RDGlazer  WMHansen  TEBerman  WHKramer  SI Assessment of tardive dyskinesia using the Abnormal Involuntary Movement Scale. J Nerv Ment Dis. 1985;173353- 357
Link to Article
Lohr  JBCadet  JLLohr  MAJeste  DVWyatt  RJ Alpha-tocopherol in tardive dyskinesia. Lancet. 1987;1913- 914
Link to Article
Egan  MFHyde  TMAlbers  GWElkashef  AAlexander  RCReeve  ABlum  ASaenz  REWyatt  RJ Treatment of tardive dyskinesia with vitamin E. Am J Psychiatry. 1992;149773- 777
Shriqui  CLBradwejn  JAnnable  LJones  BD Vitamin E in the treatment of tardive dyskinesia: a double-blind placebo-controlled study. Am J Psychiatry. 1992;149391- 393
Adler  LAPeselow  ERotrosen  JDuncan  ELee  MRosenthal  MAngrist  B Vitamin E treatment of tardive dyskinesia. Am J Psychiatry. 1993;1501405- 1407
Dabiri  LMPasta  DDarby  JKMosbacher  D Effectiveness of vitamin E for treatment of long-term tardive dyskinesia. Am J Psychiatry. 1994;151925- 926
Lam  LCChiu  HFHung  SF Vitamin E in the treatment of tardive dyskinesia: a replication study. J Nerv Ment Dis. 1994;182113- 114
Link to Article
Adler  LAEdson  RLavori  PPeselow  EDuncan  ERosenthal  MRotrosen  J Long-term treatment effects of vitamin E for tardive dyskinesia. Biol Psychiatry. 1998;43868- 872
Link to Article
Post  AHolsboer  FBehl  C Induction of NF-κB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-κB and neuroprotection by antioxidants. J Neurosci. 1998;188236- 8246
Pai  BNJanakiramaiah  NGangadhar  BNRavindranath  V Depletion of glutathione and enhanced lipid peroxidation in the CSF of acute psychotics following haloperidol administration. Biol Psychiatry. 1994;36489- 491
Link to Article
Tang  YPMa  YLChao  CCChen  KYLee  EH Enhanced glial cell line-derived neurotrophic factor mRNA expression upon (−)-deprenyl and melatonin treatments. J Neurosci Res. 1998;53593- 604
Link to Article
Malpaux  BThiery  JCChemineau  P Melatonin and the seasonal control of reproduction. Reprod Nutr Dev. 1999;39355- 366
Link to Article
Escames  GAcuna Castroviejo  DVives  F Melatonin-dopamine interaction in the striatal projection area of sensorimotor cortex in the rat. Neuroreport. 1996;7597- 600
Link to Article
Hamdi  A Melatonin administration increases the affinity of D2 dopamine receptors in the rat striatum. Life Sci. 1998;632115- 2120
Link to Article
Willis  GLArmstrong  SM Orphan neurones and amine excess: the functional neuropathology of Parkinsonism and neuropsychiatric disease. Brain Res Brain Res Rev. 1998;27177- 242
Link to Article
Shamir  EBarak  YPlopsky  IZisapel  NElizur  AWeizman  A Is melatonin treatment effective for tardive dyskinesia? J Clin Psychiatry. 2000;61556- 558
Link to Article

Figures

Place holder to copy figure label and caption

Improvement of total Abnormal Involuntary Movement Scale (AIMS) score as a function of baseline AIMS score in patients taking either melatonin (10 mg, controlled release) or placebo. After 6 weeks of treatment, patients entered a 4-week washout period and then crossed over for an additional 6 weeks of treatment. The AIMS was scored at baseline and at the end of weeks 6 (end of first treatment period), 10 (end of washout period), and 16 (end of second treatment period, after crossover).

Graphic Jump Location

Tables

References

Kane  JMWoerner  MBorenstein  MWegner  JLieberman  J Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull. 1986;22254- 258
Morgenstern  HGlazer  WM Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medications: results of the Yale Tardive Dyskinesia Study. Arch Gen Psychiatry. 1993;50723- 733
Link to Article
Glazer  WMMorgenstern  HDoucette  JT Predicting the long-term risk of tardive dyskinesia in outpatients maintained on neuroleptic medications. J Clin Psychiatry. 1993;54133- 139
Cardoso  FJankovic  J Dystonia and dyskinesia. Psychiatr Clin North Am. 1997;20821- 838
Link to Article
Beasley  CMDellva  MATamura  RNMorgenstern  HGlazer  WMFerguson  KTollefson  GD Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry. 1999;17423- 30
Link to Article
Barak  YSwartz  MShamir  EStein  DWeizman  A Vitamin E (alpha-tocopherol) in the treatment of tardive dyskinesia: a statistical meta-analysis. Ann Clin Psychiatry. 1998;10101- 105
Link to Article
Richardson  MABevans  MLWeber  JBGonzalez  JJFlynn  CJAmira  LRead  LLSuckow  RFMaher  TJ Branched chain amino acids decrease tardive dyskinesia symptoms. Psychopharmacology (Berl). 1999;143358- 364
Link to Article
Feltner  DEHertzman  M Progress in the treatment of tardive dyskinesia: theory and practice. Hosp Community Psychiatry. 1993;4425- 34
Adler  LRotrosen  JEdson  RLavori  PLohr  JHitzemann  RRaisch  DCaligiuri  MTracy  KVeterans Affairs Cooperative Study #394 Study Group, Vitamin E treatment for tardive dyskinesia. Arch Gen Psychiatry. 1999;56836- 841
Link to Article
Reiter  RJTan  DXCabrera  JD'Arpa  DSainz  RMMayo  JCRamos  S The oxidant/antioxidant network: role of melatonin. Biol Signals Recept. 1999;856- 63
Link to Article
Rao  MGross  GStrebel  BBraunig  PHuber  GKlosterkotter  J Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects. Psychiatry Res. 1990;34243- 257
Link to Article
Kim  YSJoo  WSJin  BKCho  YHBaik  HHPark  CW Melatonin protects 6-OHDA-induced neuronal death of nigrostriatal dopaminergic system. Neuroreport. 1998;92387- 2390
Link to Article
Zisapel  NEgozi  YLaudon  M Inhibition of dopamine release by melatonin: regional distribution in the rat brain. Brain Res. 1982;246161- 163
Link to Article
Garfinkel  DZisapel  N The use of melatonin for sleep. Nutrition. 1998;141- 2
Link to Article
Lane  RDGlazer  WMHansen  TEBerman  WHKramer  SI Assessment of tardive dyskinesia using the Abnormal Involuntary Movement Scale. J Nerv Ment Dis. 1985;173353- 357
Link to Article
Lohr  JBCadet  JLLohr  MAJeste  DVWyatt  RJ Alpha-tocopherol in tardive dyskinesia. Lancet. 1987;1913- 914
Link to Article
Egan  MFHyde  TMAlbers  GWElkashef  AAlexander  RCReeve  ABlum  ASaenz  REWyatt  RJ Treatment of tardive dyskinesia with vitamin E. Am J Psychiatry. 1992;149773- 777
Shriqui  CLBradwejn  JAnnable  LJones  BD Vitamin E in the treatment of tardive dyskinesia: a double-blind placebo-controlled study. Am J Psychiatry. 1992;149391- 393
Adler  LAPeselow  ERotrosen  JDuncan  ELee  MRosenthal  MAngrist  B Vitamin E treatment of tardive dyskinesia. Am J Psychiatry. 1993;1501405- 1407
Dabiri  LMPasta  DDarby  JKMosbacher  D Effectiveness of vitamin E for treatment of long-term tardive dyskinesia. Am J Psychiatry. 1994;151925- 926
Lam  LCChiu  HFHung  SF Vitamin E in the treatment of tardive dyskinesia: a replication study. J Nerv Ment Dis. 1994;182113- 114
Link to Article
Adler  LAEdson  RLavori  PPeselow  EDuncan  ERosenthal  MRotrosen  J Long-term treatment effects of vitamin E for tardive dyskinesia. Biol Psychiatry. 1998;43868- 872
Link to Article
Post  AHolsboer  FBehl  C Induction of NF-κB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-κB and neuroprotection by antioxidants. J Neurosci. 1998;188236- 8246
Pai  BNJanakiramaiah  NGangadhar  BNRavindranath  V Depletion of glutathione and enhanced lipid peroxidation in the CSF of acute psychotics following haloperidol administration. Biol Psychiatry. 1994;36489- 491
Link to Article
Tang  YPMa  YLChao  CCChen  KYLee  EH Enhanced glial cell line-derived neurotrophic factor mRNA expression upon (−)-deprenyl and melatonin treatments. J Neurosci Res. 1998;53593- 604
Link to Article
Malpaux  BThiery  JCChemineau  P Melatonin and the seasonal control of reproduction. Reprod Nutr Dev. 1999;39355- 366
Link to Article
Escames  GAcuna Castroviejo  DVives  F Melatonin-dopamine interaction in the striatal projection area of sensorimotor cortex in the rat. Neuroreport. 1996;7597- 600
Link to Article
Hamdi  A Melatonin administration increases the affinity of D2 dopamine receptors in the rat striatum. Life Sci. 1998;632115- 2120
Link to Article
Willis  GLArmstrong  SM Orphan neurones and amine excess: the functional neuropathology of Parkinsonism and neuropsychiatric disease. Brain Res Brain Res Rev. 1998;27177- 242
Link to Article
Shamir  EBarak  YPlopsky  IZisapel  NElizur  AWeizman  A Is melatonin treatment effective for tardive dyskinesia? J Clin Psychiatry. 2000;61556- 558
Link to Article

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