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A placebo-controlled trial of valproate in tardive dyskinesia
Brief
Reports
References Carroll BJ (1979): Prediction of treatment outcome with lithium. Arch Gen Psychiatry 36:870. Evrard JL, Banman P, Peru R, et al (1978): Lithium concentration in saliva, plasma and RBC of patients given lithium acetate. Acta Psychiatr Scand 58:67. Mendels J, Frazer A (1974): Alteration in cell membrane activity in depression. Am J Psychiatry 131:1240. Mendels J, Frazer A (1973): Intracellular lithium concentration and clinical response: Towards a membrane theory of depression. J Psychiatr Res 10:9.
BIOL PSYCHIATRY 1985;20:199-228
205
Naylor GJ, McNamee liB, Moody JP (1971): Changes in erythroeytic sodium and potassium on recovery from a depressive illness. Br J Psychiatry 118:212. Naylor GJ, Dick DAT, Dick EG (1976): Erythroeytic membrane cation carrier relapse rate of manic depressive illness and response to lithium. Psychol Med 6:257. Pandey GN, Goel I, David JM (1979): Effect of neuroleptic drugs on lithium uptake by the human erythrocytes. Clin Pharmacol Ther 26:86. Sengupta N, Datta SC, Sengupta DC (1981): Altered kinetics of membrane ATPase in mental illness. Biochem Med 26:277.
A Placebo-Controlled Trial of Valproate in Tardive Dyskinesia Henry A. Nasrallah, Frederick J. Dunner, and Mona McCalleyWhitters
Tardive dyskinesia (TD) is a frequently persistent disorder of oral, facial, truncal, or choreiform movements that appears in about 25% of patients chronically treated with neuroleptics (Jeste and Wyatt 1981). There is still no known treatment for TD, although trials with numerous drugs have been done (Nasrallah 1979). In a review of treatments of TD over the past 20 years, Jeste and Wyatt (1982) found that in double-blind controlled studies, the highest rate of improvement in TD was obtained with do-
From the Veterans Administration Medical Center and the Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa 52240. Supported by the Veterans Administration Merit Review Program and National Institutes of Health grant RR59 GCRC. Address reprint requests to: Henry A. Nasranah, M.D., Psychiatry Service, V.A. Medical Center, Iowa City, Iowa 52240. Received May 3, 1984; revised August 20, 1984.
pamine antagonist drugs followed by gammaaminobutyric acid (GABA)-ergic drugs. Valproate is an anticonvulsant drug that l~as been shown to increase brain GABA levels, probably through inhibition of GABA degradative enzymes (Godin et al. 1969). There have been four reports of valproate in TD. The initial study by Linnoila et al. (1976) in 32 patients for 2 weeks using a dose of 900 mg/day produced improvement in 17 cases. Serum levels of valproate were obtained but were not found to be related to clinical improvement. Chien et al. (1978) used 120(O1600 mg/day for 3 weeks and reported improvement in three of five patients. No blood levels were obtained. Gibson (1978) found no improvement in 25 TD patients treated with 600 mg/day of valpmate for 4 weeks, but no serum levels of the drug were measured. Casey and Hammerstad (1979) reported im-
206
Brief Reports
BIOL PSYCHIATRY
1985;20:199-228
provement in one patient when serum levels of valproate exceeded 65 p~g/ml. (The therapeutic anticonvulsive serum level range is 50-100 I~g/ml.) No controlled studies have been conducted to demonstrate whether improvement with valproate in TD is related to a specific serum concentration threshold. The present report discusses a placebo-controlled double-blind crossover study of valproate with serum levels monitoring. The study was designed to investigate the relationship between clinical improvement in TD symptoms and serum concentrations of valproate.
Method Ten chronic schizophrenic and schizoaffective patients who fulfilled the research diagnostic criteria (Schooler and Kane 1982) for persistent TD of over a 2-year duration consented to participate in the study. Patient characteristics are shown in Table 1. The patients were maintained on any medications they were receiving at the time of referral to the study. Valproate administration was conducted in an A-B-A design, with placebo capsules given for 3 weeks, followed by matching valproate capsules (1000--2500 mg/day in four divided doses) for 4 weeks, followed by placebo capsules for 3 weeks. Patients were videotaped
weekly and the tape was edited for any verbal cues regarding medications or side effects; finally the segments were coded and presented in random order. Two psychiatrists, blind to the drug or study design, rated the patients using the Abnormal Involuntary Movement Scale (AIMS). Blood samples for serum valproate concentrations were drawn at the end of the active period to determine the maximum steadystate levels of valproate achieved.
Results The results of the AIMS ratings for TD patients treated with valproate and placebo are shown in Table 2. One patient (patient 10) dropped out of the study because of severe side effects (confusion and disorientation). There were no overall significant changes in patients during the valproate period as compared with either placebo period (Wilcoxon Rank Sum Test). Individually, three patients showed slight improvement (29-33%), three patients showed moderate to marked worsening ( - 50 to - 214%), and three patients showed no change (0--9%). The serum valproate concentrations for all patients are shown in Table 3. All patients achieved levels in the therapeutic range (50-100 ~ml) and the mean for the group was 83.8
Table 1. Demographic Data on Tardive Dyskinesia Patients Treated with Valproate Patient number
Sex
Age (years)
Diagnosis
1 2 3
F M M
69 32 39
Paranoid schizophrenia Nonparanoid schizophrenia Nonparanoid schizophrenia
4 5 6 7 8
M F M M F
41 67 26 58 35
Schizoaffective Paranoid disorder Schizoaffective Schizoaffective Paranoid schizophrenia
9 10
F M
49 63
Paranoid schizophrenia Paranoid disorder
Current medication None Navane (thiothixene), 20 mg qid Stelazine (trifluoperazine), I0 nag qid Mellaril (thioridazine), 200 nag qid None Navane (thiothixene), 20 mg qid Haldol (haloperidol), 4 mg qid Loxitane (Ioxapine succinate), 40 nag qid Mellaril (thioridazine), 300 nag qid Lopressor (metoprolol), 100 mg qid
"Patient 10 was withdrawn from the study due to side effects during the active phase.
Duration of TD (years) 5 2 2 2 23 4 2 2 3 8
Brief Reports
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1985;20:199-228
Table 2. Total AIMSa Ratings for Tardive Dyskinesia Patients Treated with Placebo and Valproateb Total AIMS rating* Patient number
Placebo
Active
1
8.0
2 3 4 5 6 7 8 9
3.0 7.0 8.0 21.0 11.0 17.0 3.5 9.0
Mean SD
9.72 5.91
Percentage change
Placebo
Placebo vs. active a
Active vs. placebo e
5.5
8.0
+ 31
- 45
2.0 5.0 12.0 21.0 10.0 17.0 11.0 I 1.0
2.0 6.0 11.0 20.0 12.0 17.0 9.0 11.0
+33 + 29 - 50 0 +9 0 -214 - 22
0 - 20 + 8 +5 - 20 0 + 18 0
10.50 5.95
10.68 5.43
"Abnormal Involuntary Movement Scale. beach score is the mean of weekly ratings for each period. "Wilcoxon Rank Sum Test (nonsignificant). '%'alproate period compared with pretreatment placebo period. "Posttreatment placebo period compared with valproate period.
p.g/ml. No significant correlation was found between the serum concentrations and clinical response to valproate. The mean for the three improved patients was 88.3 I~g/ml, for the three unchanged patients 83.5 i~g/ml, and for the three worsened patients 72.4 i~g/ml. As for side effects, two of three neurolepticfree patients and two of seven patients on neu-
roleptic maintenance therapy experienced nausea with or without vomiting. It is possible that the antiemetic effects of neuroleptics protected some patients against the valproate-induced nausea and vomiting. No relationship could be found between clinical response and the age or gender of the patients.
Table 3. Valproate Serum Concentrations and Side Effects in Tardive Dyskinesia Patients ~ Patient number
Level c (l~g/ ml)
Ib
93.0
2 3 4 5b 6 7 8 9 10b
79.5 92.3 58.0 83.8 61.0 94.0 98.5 95.7
Side effects Nausea Nausea
Mild nausea with emesis
Mild nausea with emesis Confused and inappropriate (was withdrawn from the study)
q'herapeutic levels = 50-100 p.g/ml for the management of seizures. bPatients who were neuroleptic free during valproate trials. 'Mean serum concentration of valproate = 83.8 gg/ml.
208
BIOLPSYCHIATRY 1985;20:199-228
Brief Reports
Discussion
References
The data produced in this controlled study suggest that valproate, even at adequate serum concentrations, does not produce a significant improvement of symptoms in patients with persistent TD. This finding is consistent with previous negative reports of the efficacy of valproate in TD (Chien et al. 1978; Gibson et al. 1978) and also of the lack of efficacy in Huntington.'s disease (Shoulson et al. 1976) and L-DOPA-induced dyskinesia (Price et al. 1978). It should also be noted, however, that while some patients showed mild symptomatic relief with valproate, others in this study showed definite worsening (patients 4, 8, and 9), while others experienced no change. The possible existence of different subtypes of TD that may account for these discrepant responses cannot be ruled out. Furthermore, other GABA agonists have produced significant improvement in TD (Singh et al. 1982; Tamminga et al. 1979), raising the question whether valproate actually increases GABA levels in the brain or acts as a GABA agonist at anticonvulsive serum concentrations. The results of this study coupled with other negative studies do not encourage further work with valproate in TD, and in fact may discourage it because of the noticeable worsening of the condition in some patients. Nevertheless, investigations into the role of other GABA agonists in TD should continue, as the literature tends to support the hypothesis that GABA agonists may be useful in the management of TD (Jeste and Wyatt 1982).
Casey DE, Hammerstad, JP (1979): Sodium valproate in tardive dyskinesia. J Clin Psychiatry 40:483--485. Chien CP, Jung K, Ross-Townsend A (1978): Efficacies of agents related to GABA, dopamine and acetylcholine in the treatment of tardive dyskinesia. Psychopharmacol Bull 14:20-22. Gibson AC (1978): Sodium valproate and tardive dyskinesia. Br J Psychiatry 133:82.
We acknowledge the valuable cooperation of the nursing staff at the V.A. Medical Center, Psychiatry Service, and the ClinicalResearchCenterat the Universityof Iowa(Barry Sherman, M.D. Director).
Godin Y, Heiner L, Mark J e t al (1969): Effects of di-n-propylacetate, an anticonvulsant compound, on GABA metabolism. JNeurochem 16:867-873. Jeste DV, Wyatt RJ (1981): Changing epidemiology of tardive dyskinesia. Am J Psychiatry 138:297-309. Jeste DV, Wyatt RJ (1982): Therapeutic strategies against tardive dyskinesia. Two decades of experience. Arch Gen Psychiatry 39:803-816. Linnoila M, Viukkari M, Hietala O (1976): Effect of sodium valproate on tardive dyskinesia. Br J Psychiatry 129:114-9. Nasrallah HA (1979): Methodological issues in tardive dyskinesia research. Schiz Bull 5:1-3. Price PA, Parkes JD, Marsden CD (1978): Sodium valproate in the treatment of levodopa-induced dyskinesia. J Neurol Neurosurg Psychiatry 41:702-706. Schooler NR, Kane JM (1982): Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 39:486-487. Shoulson K, Kartzinel R, Chase TN (1976): Huntington's disease: Treatment with dipropylacetic acid and gamma-amino-butyric acid. Neurology 26:61-63. Singh MM, Becker RE, Pitman RK, et al (1982): Diazepam-induced changes in tardive dyskinesia. Biol Psychiatry 17:729-742. Tamminga CA, Crayton JW, Chase TN (1979): Improvement in tardive dyskinesia after muscimol therapy. Arch Gen Psychiatry 36:595-598.
Reports
References Carroll BJ (1979): Prediction of treatment outcome with lithium. Arch Gen Psychiatry 36:870. Evrard JL, Banman P, Peru R, et al (1978): Lithium concentration in saliva, plasma and RBC of patients given lithium acetate. Acta Psychiatr Scand 58:67. Mendels J, Frazer A (1974): Alteration in cell membrane activity in depression. Am J Psychiatry 131:1240. Mendels J, Frazer A (1973): Intracellular lithium concentration and clinical response: Towards a membrane theory of depression. J Psychiatr Res 10:9.
BIOL PSYCHIATRY 1985;20:199-228
205
Naylor GJ, McNamee liB, Moody JP (1971): Changes in erythroeytic sodium and potassium on recovery from a depressive illness. Br J Psychiatry 118:212. Naylor GJ, Dick DAT, Dick EG (1976): Erythroeytic membrane cation carrier relapse rate of manic depressive illness and response to lithium. Psychol Med 6:257. Pandey GN, Goel I, David JM (1979): Effect of neuroleptic drugs on lithium uptake by the human erythrocytes. Clin Pharmacol Ther 26:86. Sengupta N, Datta SC, Sengupta DC (1981): Altered kinetics of membrane ATPase in mental illness. Biochem Med 26:277.
A Placebo-Controlled Trial of Valproate in Tardive Dyskinesia Henry A. Nasrallah, Frederick J. Dunner, and Mona McCalleyWhitters
Tardive dyskinesia (TD) is a frequently persistent disorder of oral, facial, truncal, or choreiform movements that appears in about 25% of patients chronically treated with neuroleptics (Jeste and Wyatt 1981). There is still no known treatment for TD, although trials with numerous drugs have been done (Nasrallah 1979). In a review of treatments of TD over the past 20 years, Jeste and Wyatt (1982) found that in double-blind controlled studies, the highest rate of improvement in TD was obtained with do-
From the Veterans Administration Medical Center and the Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa 52240. Supported by the Veterans Administration Merit Review Program and National Institutes of Health grant RR59 GCRC. Address reprint requests to: Henry A. Nasranah, M.D., Psychiatry Service, V.A. Medical Center, Iowa City, Iowa 52240. Received May 3, 1984; revised August 20, 1984.
pamine antagonist drugs followed by gammaaminobutyric acid (GABA)-ergic drugs. Valproate is an anticonvulsant drug that l~as been shown to increase brain GABA levels, probably through inhibition of GABA degradative enzymes (Godin et al. 1969). There have been four reports of valproate in TD. The initial study by Linnoila et al. (1976) in 32 patients for 2 weeks using a dose of 900 mg/day produced improvement in 17 cases. Serum levels of valproate were obtained but were not found to be related to clinical improvement. Chien et al. (1978) used 120(O1600 mg/day for 3 weeks and reported improvement in three of five patients. No blood levels were obtained. Gibson (1978) found no improvement in 25 TD patients treated with 600 mg/day of valpmate for 4 weeks, but no serum levels of the drug were measured. Casey and Hammerstad (1979) reported im-
206
Brief Reports
BIOL PSYCHIATRY
1985;20:199-228
provement in one patient when serum levels of valproate exceeded 65 p~g/ml. (The therapeutic anticonvulsive serum level range is 50-100 I~g/ml.) No controlled studies have been conducted to demonstrate whether improvement with valproate in TD is related to a specific serum concentration threshold. The present report discusses a placebo-controlled double-blind crossover study of valproate with serum levels monitoring. The study was designed to investigate the relationship between clinical improvement in TD symptoms and serum concentrations of valproate.
Method Ten chronic schizophrenic and schizoaffective patients who fulfilled the research diagnostic criteria (Schooler and Kane 1982) for persistent TD of over a 2-year duration consented to participate in the study. Patient characteristics are shown in Table 1. The patients were maintained on any medications they were receiving at the time of referral to the study. Valproate administration was conducted in an A-B-A design, with placebo capsules given for 3 weeks, followed by matching valproate capsules (1000--2500 mg/day in four divided doses) for 4 weeks, followed by placebo capsules for 3 weeks. Patients were videotaped
weekly and the tape was edited for any verbal cues regarding medications or side effects; finally the segments were coded and presented in random order. Two psychiatrists, blind to the drug or study design, rated the patients using the Abnormal Involuntary Movement Scale (AIMS). Blood samples for serum valproate concentrations were drawn at the end of the active period to determine the maximum steadystate levels of valproate achieved.
Results The results of the AIMS ratings for TD patients treated with valproate and placebo are shown in Table 2. One patient (patient 10) dropped out of the study because of severe side effects (confusion and disorientation). There were no overall significant changes in patients during the valproate period as compared with either placebo period (Wilcoxon Rank Sum Test). Individually, three patients showed slight improvement (29-33%), three patients showed moderate to marked worsening ( - 50 to - 214%), and three patients showed no change (0--9%). The serum valproate concentrations for all patients are shown in Table 3. All patients achieved levels in the therapeutic range (50-100 ~ml) and the mean for the group was 83.8
Table 1. Demographic Data on Tardive Dyskinesia Patients Treated with Valproate Patient number
Sex
Age (years)
Diagnosis
1 2 3
F M M
69 32 39
Paranoid schizophrenia Nonparanoid schizophrenia Nonparanoid schizophrenia
4 5 6 7 8
M F M M F
41 67 26 58 35
Schizoaffective Paranoid disorder Schizoaffective Schizoaffective Paranoid schizophrenia
9 10
F M
49 63
Paranoid schizophrenia Paranoid disorder
Current medication None Navane (thiothixene), 20 mg qid Stelazine (trifluoperazine), I0 nag qid Mellaril (thioridazine), 200 nag qid None Navane (thiothixene), 20 mg qid Haldol (haloperidol), 4 mg qid Loxitane (Ioxapine succinate), 40 nag qid Mellaril (thioridazine), 300 nag qid Lopressor (metoprolol), 100 mg qid
"Patient 10 was withdrawn from the study due to side effects during the active phase.
Duration of TD (years) 5 2 2 2 23 4 2 2 3 8
Brief Reports
BIOLPSYCHIATRY
207
1985;20:199-228
Table 2. Total AIMSa Ratings for Tardive Dyskinesia Patients Treated with Placebo and Valproateb Total AIMS rating* Patient number
Placebo
Active
1
8.0
2 3 4 5 6 7 8 9
3.0 7.0 8.0 21.0 11.0 17.0 3.5 9.0
Mean SD
9.72 5.91
Percentage change
Placebo
Placebo vs. active a
Active vs. placebo e
5.5
8.0
+ 31
- 45
2.0 5.0 12.0 21.0 10.0 17.0 11.0 I 1.0
2.0 6.0 11.0 20.0 12.0 17.0 9.0 11.0
+33 + 29 - 50 0 +9 0 -214 - 22
0 - 20 + 8 +5 - 20 0 + 18 0
10.50 5.95
10.68 5.43
"Abnormal Involuntary Movement Scale. beach score is the mean of weekly ratings for each period. "Wilcoxon Rank Sum Test (nonsignificant). '%'alproate period compared with pretreatment placebo period. "Posttreatment placebo period compared with valproate period.
p.g/ml. No significant correlation was found between the serum concentrations and clinical response to valproate. The mean for the three improved patients was 88.3 I~g/ml, for the three unchanged patients 83.5 i~g/ml, and for the three worsened patients 72.4 i~g/ml. As for side effects, two of three neurolepticfree patients and two of seven patients on neu-
roleptic maintenance therapy experienced nausea with or without vomiting. It is possible that the antiemetic effects of neuroleptics protected some patients against the valproate-induced nausea and vomiting. No relationship could be found between clinical response and the age or gender of the patients.
Table 3. Valproate Serum Concentrations and Side Effects in Tardive Dyskinesia Patients ~ Patient number
Level c (l~g/ ml)
Ib
93.0
2 3 4 5b 6 7 8 9 10b
79.5 92.3 58.0 83.8 61.0 94.0 98.5 95.7
Side effects Nausea Nausea
Mild nausea with emesis
Mild nausea with emesis Confused and inappropriate (was withdrawn from the study)
q'herapeutic levels = 50-100 p.g/ml for the management of seizures. bPatients who were neuroleptic free during valproate trials. 'Mean serum concentration of valproate = 83.8 gg/ml.
208
BIOLPSYCHIATRY 1985;20:199-228
Brief Reports
Discussion
References
The data produced in this controlled study suggest that valproate, even at adequate serum concentrations, does not produce a significant improvement of symptoms in patients with persistent TD. This finding is consistent with previous negative reports of the efficacy of valproate in TD (Chien et al. 1978; Gibson et al. 1978) and also of the lack of efficacy in Huntington.'s disease (Shoulson et al. 1976) and L-DOPA-induced dyskinesia (Price et al. 1978). It should also be noted, however, that while some patients showed mild symptomatic relief with valproate, others in this study showed definite worsening (patients 4, 8, and 9), while others experienced no change. The possible existence of different subtypes of TD that may account for these discrepant responses cannot be ruled out. Furthermore, other GABA agonists have produced significant improvement in TD (Singh et al. 1982; Tamminga et al. 1979), raising the question whether valproate actually increases GABA levels in the brain or acts as a GABA agonist at anticonvulsive serum concentrations. The results of this study coupled with other negative studies do not encourage further work with valproate in TD, and in fact may discourage it because of the noticeable worsening of the condition in some patients. Nevertheless, investigations into the role of other GABA agonists in TD should continue, as the literature tends to support the hypothesis that GABA agonists may be useful in the management of TD (Jeste and Wyatt 1982).
Casey DE, Hammerstad, JP (1979): Sodium valproate in tardive dyskinesia. J Clin Psychiatry 40:483--485. Chien CP, Jung K, Ross-Townsend A (1978): Efficacies of agents related to GABA, dopamine and acetylcholine in the treatment of tardive dyskinesia. Psychopharmacol Bull 14:20-22. Gibson AC (1978): Sodium valproate and tardive dyskinesia. Br J Psychiatry 133:82.
We acknowledge the valuable cooperation of the nursing staff at the V.A. Medical Center, Psychiatry Service, and the ClinicalResearchCenterat the Universityof Iowa(Barry Sherman, M.D. Director).
Godin Y, Heiner L, Mark J e t al (1969): Effects of di-n-propylacetate, an anticonvulsant compound, on GABA metabolism. JNeurochem 16:867-873. Jeste DV, Wyatt RJ (1981): Changing epidemiology of tardive dyskinesia. Am J Psychiatry 138:297-309. Jeste DV, Wyatt RJ (1982): Therapeutic strategies against tardive dyskinesia. Two decades of experience. Arch Gen Psychiatry 39:803-816. Linnoila M, Viukkari M, Hietala O (1976): Effect of sodium valproate on tardive dyskinesia. Br J Psychiatry 129:114-9. Nasrallah HA (1979): Methodological issues in tardive dyskinesia research. Schiz Bull 5:1-3. Price PA, Parkes JD, Marsden CD (1978): Sodium valproate in the treatment of levodopa-induced dyskinesia. J Neurol Neurosurg Psychiatry 41:702-706. Schooler NR, Kane JM (1982): Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 39:486-487. Shoulson K, Kartzinel R, Chase TN (1976): Huntington's disease: Treatment with dipropylacetic acid and gamma-amino-butyric acid. Neurology 26:61-63. Singh MM, Becker RE, Pitman RK, et al (1982): Diazepam-induced changes in tardive dyskinesia. Biol Psychiatry 17:729-742. Tamminga CA, Crayton JW, Chase TN (1979): Improvement in tardive dyskinesia after muscimol therapy. Arch Gen Psychiatry 36:595-598.