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Parkinsonism induced by high doses of diazepam
BIOL PSYCHIATRY 1985;20:451--460
455
Parkinsonism Induced by High Doses of Diazepam B. E. Suranyi-Cadotte, J. N. Nestoros, N. P. V. Nair, S. Lal, and S. Gauthier
Introduction Diazepam, a benzodiazepine that enhances GABAergic mechanisms (Costa and Guidotti 1979), inhibits dopaminergic function in animals (Wood 1982). This had led to the use of this agent in the treatment of schizophrenia. Although relatively small doses are ineffective (Nestoros 1980), large doses of diazepam are reported to exert a beneficial effect in this disorder (Beckmann and Haas 1980). While studying 27 schizophrenic patients receiving high doses of diazepam (100 mg/day or more), we observed that 4 subjects developed parkinsonism. We now report these findings.
Methods The 27 patients for the study met Research Diagnostic Criteria for schizophrenia (Spitzer et al. 1977); all had received neuroleptic agents for a minimum of 6 months. Neuroleptics were discontinued 10 days prior to starting oral diazepam, which was administered in progressively increasing doses, to reach maximum tolerated dose. Parkinsonian symptoms were rated
From the Douglas Hospital Research Centre (B.E.S.-C, J.N.N, N.P.V.N., S.L., and S.G.); the Department of Psychiatry, Montreal General Hospital (S.L.); and the Montreal Neurological Institute (S.G.), Montreal, Quebec, Canada. Address reprint requests to Dr. B. E. Suranyi-Cadotte, Douglas Hospital Research Centre, 6875 LaSalle Blvd., Verdun, Quebec H4H IR3, Canada. Received August 17, 1984; revised October 9, 1984.
using the Simpson and Angus Rating Scale (Simpson and Angus 1970), before, during, and following discontinuation of diazepam. The four subjects who developed parkinsonism had been on continuous neuroleptics for 6 months to 4 years prior to withdrawal; none of these four subjects had clinically evident parkinsonian symptoms or had required anticholinergic agents prior to treatment with diazepam.
Results and D i s c u s s i o n The psychiatric findings have been reported in part elsewhere (Nestoros et al. 1982). Four of the subjects developed scores of 10 or more on the Simpson and Angus Rating Scale (Table 1) out of a maximum possible score of 40. Onset of parkinsonism occurred within 5-17 weeks after discontinuation of neuroleptics, when patients had been receiving diazepam for 1--8 weeks. Clinically, prominent features included stooped posture, stiffness of arm, leg, and neck muscles, cogwheel rigidity of wrists and elbows, excessive salivation, finger tremor, and, in one instance, persistent tremor involving all limbs and at times the entire body. With the development of parkinsonian symptoms, anticholinergic drugs were started in all subjects and the dose of diazepam was reduced. Despite these measures, high scores (10 or more) persisted. This is in contrast to the observed efficacy of antimuscarinic agents in neuroleptic-induced parkinsonism, which may often be evident within a few
456
Brief Reports
BIOL PSYCHIATRY
1985;20:451-460
Table 1. Diazepam-Induced Parkinsonism During and after diazepam withdrawal Neuroleptic Before withdrawal diazepam Treatment Dose Patient Age/sex (days) score* Scorea day (mg/day) Otherdrugs 1
27/F
10
3
27 26
8 13
24
18
24
23
10
28
3 22 22
41 42 47
20
52
200 100
None Benztropine
(6 rag/day) Benztropine (6 mg/da~0 None Benztropine (6 mg/day) None Benztropine 50
Comments
Diazepam discontinued on day 20;
anticholinergics administered from day 9 to 28
(6 nag/day) 2
55/M
14
1
12
57
I0
62
3 23
75 56 119
23
124
16
129
8
134
3
14 l0
139 14 17
5
22
2
32
None None 350 None 175 Procyclidine (15 rag/day) 50 Procyclidine (15 rag/day) None Benztropine (6 rag/day)
Diazepam discontinued on day 54; anticholinergics
admires"t e ~ from day 43 to 64
None Benzetropine
(6 rng/day) 3
4
30/M
56/F
70
98
2
2
11
None None 400 None 280 Procyelidine (15 mg/day) 100 Procyclidine (15 rag/day) 50 Procyclidine (15 rag/day) None Procyclidine (15 rag/day) None None 140 None 140 Procyclidine (10 mg/day) 70 Procyelidine (I0 mg/day) None None
Diazepam discontinued on day 131; anticholinergics administered from days 57 to 136
Diazepam discontinued on day 25; anticholinergics administered from day 15 to 24
*Scorederivedfrom the SimpsonAngus Scale (Simpsonand Angus 1970).
days of initiating treatment (Ayd 1961; Simpson 1970; Hornykiewicz 1975). All scores returned to baseline within 1-3 weeks following discontinuation of diazepam. Benzodiazepines, which potentiate G A B A at the receptor level (Costa 1979), have been shown to decrease dopamine release in the rat nigrostriatal pathway (Wood 1982) and to block picrotoxin-induced increases in striatal dopamine
release (Cheramy et al. 1977). These animal data suggest that diazepam interacts with a GABA/benzodiazepine receptor complex to inhibit dopamine release (Wood 1982). Such an effect could account for the development of parkinsonism in our patients. In this regard, diazepam decreases homovanillic acid concentrations in ventricular cerebral spinal fluid (CSF) in man (Papeschi et al. 1972). Ninety percent of pa-
Brief Reports
BIOLPSYCHIATRY
457
1985;20:451-460
tients who develop neuroleptic-induced parkinsonism do so within 72 days (Ayd 1961). After discontinuation of neuroleptics, most patients are free of extrapyramidal signs within a few weeks, though in some cases, signs may persist for several months (Hall et al. 1956; Hershon et al. 1972) and, rarely, as long as a year (Marsden et al. 1975). We consider it unlikely that a residual neuroleptic-induced parkinsonism accounts for our observations, as none of the subjects had clinical evidence of parkinsonism while on neuroleptic drugs. Also, following neuroleptic withdrawal and prior to diazepam treatment, parkinsonism scores were 3 or less in all four subjects. High-dose benzodiazepines are currently being used with increasing frequency in the treatment of neuroleptic-resistant schizophrenia (Beckman and Haas 1980; Nestoros et al. 1982), but why parkinsonism develops in only some persons is unclear. Whether or not prior neuroleptic treatment predisposes individuals to develop diazepam-induced parkinsonism is unknown.
References Ayd FJ (1961): A survey of drug-induced extrapyramidal reactions. JAMA 175:1054-1060. Beckmann H, Haas S (1980): High dose diazeparn in schizophrenia. Psychopharmacology (Bed) 71:79-82. Cheramy A, Nieonllon A, Giowinski J (1977): Blockade of the picrotoxin-induced in vivo release of dopamine in the cat caudate nucleus by diazepam. Life Sci 20:811-816. Costa E (1979): The role of gamma-aminobutyric acid in the action of 1,4-benzodiazepines. Trends Pharmacol Sci 1:41--44. Costa E, Guidotti A (1979): Molecular mechanisms in the receptor action of benzodiazepines. Annu Rev Pharmacol Toxicol 19:531-545.
Hall RA, Jackson RB, Swain JN (1956): Neurotoxic reactions resulting from chlorpromazine administration. JAMA 161:214-218. Hershon HI, Kennedy PF, McGuire ILl (1972): Persistence of extrapyramidal disorders and psychiatric relapse after withdrawal of long-term phenothiazine therapy. Br J Psychiatry 120:41-50. Hornykiewicz O (1975): Parkinsonism induced by dopaminergic antagonists. In Calne DB, Barbeau A (eds), Advances in Neurology, vol 9. New York: Raven, 1975. Marsden CD, Tarsy D, Baldessarini RJ (1975): Spontaneous and drug-induced movement disorders in psychotic patients. In Benson DF, Blumer D (eds), Psychiatric Aspects of Neurologic Disease. Orlando, FL: Grune & Stratton, pp 219-266. Nestoros JN (1980): Benzodiazepines in schizophrenia: A need for reassessment. Int Pharmacopsychiatry 15:171-179. Nestoros JN, Suranyi-CadotteBE, Spees RC, Schwartz G, Nair NPV (1982): Diazepam in high doses is effective in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 6:513-516. Papeschi R, Molina-Negro P, Sourkes TL, Erba G (1972): The concentration of homovanillic acid and 5-hydroxyindoleacetic acid in ventricular and lumbar CSF. Neurology (Minneap) 22:115 I-1159. Simpson GM (1970): Controlled studies of antiparkinsonism agents in the treatment of drug-induced extrapyramidal symptoms. Acta Psychiatr Scand (Suppl) 212:44-51. Simpson GM, Angus JW (1970): A rating scale for extrapyramidal side effects. Acta Psychiatr Scand (Suppl) 212:11-19. Spitzer RL, Endicott J, Robins E (1977): Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders. ed 3. New York: Biometrics Research. Wood PL (1982): Action of GABAergic agents on dopamine metabolism in the nigrostriatal pathway of the rat. J Pharmacol Exp Ther 222:674-679. Wood PL, Etienne P, Lal S, Nair NPV (1982): GABAergic regulation of nigrostriatal neurons: Coupling of benzodiazepine and GABA receptors. Prog Neuropsychopharmacol Biol Psychiatry 6:471--474.
455
Parkinsonism Induced by High Doses of Diazepam B. E. Suranyi-Cadotte, J. N. Nestoros, N. P. V. Nair, S. Lal, and S. Gauthier
Introduction Diazepam, a benzodiazepine that enhances GABAergic mechanisms (Costa and Guidotti 1979), inhibits dopaminergic function in animals (Wood 1982). This had led to the use of this agent in the treatment of schizophrenia. Although relatively small doses are ineffective (Nestoros 1980), large doses of diazepam are reported to exert a beneficial effect in this disorder (Beckmann and Haas 1980). While studying 27 schizophrenic patients receiving high doses of diazepam (100 mg/day or more), we observed that 4 subjects developed parkinsonism. We now report these findings.
Methods The 27 patients for the study met Research Diagnostic Criteria for schizophrenia (Spitzer et al. 1977); all had received neuroleptic agents for a minimum of 6 months. Neuroleptics were discontinued 10 days prior to starting oral diazepam, which was administered in progressively increasing doses, to reach maximum tolerated dose. Parkinsonian symptoms were rated
From the Douglas Hospital Research Centre (B.E.S.-C, J.N.N, N.P.V.N., S.L., and S.G.); the Department of Psychiatry, Montreal General Hospital (S.L.); and the Montreal Neurological Institute (S.G.), Montreal, Quebec, Canada. Address reprint requests to Dr. B. E. Suranyi-Cadotte, Douglas Hospital Research Centre, 6875 LaSalle Blvd., Verdun, Quebec H4H IR3, Canada. Received August 17, 1984; revised October 9, 1984.
using the Simpson and Angus Rating Scale (Simpson and Angus 1970), before, during, and following discontinuation of diazepam. The four subjects who developed parkinsonism had been on continuous neuroleptics for 6 months to 4 years prior to withdrawal; none of these four subjects had clinically evident parkinsonian symptoms or had required anticholinergic agents prior to treatment with diazepam.
Results and D i s c u s s i o n The psychiatric findings have been reported in part elsewhere (Nestoros et al. 1982). Four of the subjects developed scores of 10 or more on the Simpson and Angus Rating Scale (Table 1) out of a maximum possible score of 40. Onset of parkinsonism occurred within 5-17 weeks after discontinuation of neuroleptics, when patients had been receiving diazepam for 1--8 weeks. Clinically, prominent features included stooped posture, stiffness of arm, leg, and neck muscles, cogwheel rigidity of wrists and elbows, excessive salivation, finger tremor, and, in one instance, persistent tremor involving all limbs and at times the entire body. With the development of parkinsonian symptoms, anticholinergic drugs were started in all subjects and the dose of diazepam was reduced. Despite these measures, high scores (10 or more) persisted. This is in contrast to the observed efficacy of antimuscarinic agents in neuroleptic-induced parkinsonism, which may often be evident within a few
456
Brief Reports
BIOL PSYCHIATRY
1985;20:451-460
Table 1. Diazepam-Induced Parkinsonism During and after diazepam withdrawal Neuroleptic Before withdrawal diazepam Treatment Dose Patient Age/sex (days) score* Scorea day (mg/day) Otherdrugs 1
27/F
10
3
27 26
8 13
24
18
24
23
10
28
3 22 22
41 42 47
20
52
200 100
None Benztropine
(6 rag/day) Benztropine (6 mg/da~0 None Benztropine (6 mg/day) None Benztropine 50
Comments
Diazepam discontinued on day 20;
anticholinergics administered from day 9 to 28
(6 nag/day) 2
55/M
14
1
12
57
I0
62
3 23
75 56 119
23
124
16
129
8
134
3
14 l0
139 14 17
5
22
2
32
None None 350 None 175 Procyclidine (15 rag/day) 50 Procyclidine (15 rag/day) None Benztropine (6 rag/day)
Diazepam discontinued on day 54; anticholinergics
admires"t e ~ from day 43 to 64
None Benzetropine
(6 rng/day) 3
4
30/M
56/F
70
98
2
2
11
None None 400 None 280 Procyelidine (15 mg/day) 100 Procyclidine (15 rag/day) 50 Procyclidine (15 rag/day) None Procyclidine (15 rag/day) None None 140 None 140 Procyclidine (10 mg/day) 70 Procyelidine (I0 mg/day) None None
Diazepam discontinued on day 131; anticholinergics administered from days 57 to 136
Diazepam discontinued on day 25; anticholinergics administered from day 15 to 24
*Scorederivedfrom the SimpsonAngus Scale (Simpsonand Angus 1970).
days of initiating treatment (Ayd 1961; Simpson 1970; Hornykiewicz 1975). All scores returned to baseline within 1-3 weeks following discontinuation of diazepam. Benzodiazepines, which potentiate G A B A at the receptor level (Costa 1979), have been shown to decrease dopamine release in the rat nigrostriatal pathway (Wood 1982) and to block picrotoxin-induced increases in striatal dopamine
release (Cheramy et al. 1977). These animal data suggest that diazepam interacts with a GABA/benzodiazepine receptor complex to inhibit dopamine release (Wood 1982). Such an effect could account for the development of parkinsonism in our patients. In this regard, diazepam decreases homovanillic acid concentrations in ventricular cerebral spinal fluid (CSF) in man (Papeschi et al. 1972). Ninety percent of pa-
Brief Reports
BIOLPSYCHIATRY
457
1985;20:451-460
tients who develop neuroleptic-induced parkinsonism do so within 72 days (Ayd 1961). After discontinuation of neuroleptics, most patients are free of extrapyramidal signs within a few weeks, though in some cases, signs may persist for several months (Hall et al. 1956; Hershon et al. 1972) and, rarely, as long as a year (Marsden et al. 1975). We consider it unlikely that a residual neuroleptic-induced parkinsonism accounts for our observations, as none of the subjects had clinical evidence of parkinsonism while on neuroleptic drugs. Also, following neuroleptic withdrawal and prior to diazepam treatment, parkinsonism scores were 3 or less in all four subjects. High-dose benzodiazepines are currently being used with increasing frequency in the treatment of neuroleptic-resistant schizophrenia (Beckman and Haas 1980; Nestoros et al. 1982), but why parkinsonism develops in only some persons is unclear. Whether or not prior neuroleptic treatment predisposes individuals to develop diazepam-induced parkinsonism is unknown.
References Ayd FJ (1961): A survey of drug-induced extrapyramidal reactions. JAMA 175:1054-1060. Beckmann H, Haas S (1980): High dose diazeparn in schizophrenia. Psychopharmacology (Bed) 71:79-82. Cheramy A, Nieonllon A, Giowinski J (1977): Blockade of the picrotoxin-induced in vivo release of dopamine in the cat caudate nucleus by diazepam. Life Sci 20:811-816. Costa E (1979): The role of gamma-aminobutyric acid in the action of 1,4-benzodiazepines. Trends Pharmacol Sci 1:41--44. Costa E, Guidotti A (1979): Molecular mechanisms in the receptor action of benzodiazepines. Annu Rev Pharmacol Toxicol 19:531-545.
Hall RA, Jackson RB, Swain JN (1956): Neurotoxic reactions resulting from chlorpromazine administration. JAMA 161:214-218. Hershon HI, Kennedy PF, McGuire ILl (1972): Persistence of extrapyramidal disorders and psychiatric relapse after withdrawal of long-term phenothiazine therapy. Br J Psychiatry 120:41-50. Hornykiewicz O (1975): Parkinsonism induced by dopaminergic antagonists. In Calne DB, Barbeau A (eds), Advances in Neurology, vol 9. New York: Raven, 1975. Marsden CD, Tarsy D, Baldessarini RJ (1975): Spontaneous and drug-induced movement disorders in psychotic patients. In Benson DF, Blumer D (eds), Psychiatric Aspects of Neurologic Disease. Orlando, FL: Grune & Stratton, pp 219-266. Nestoros JN (1980): Benzodiazepines in schizophrenia: A need for reassessment. Int Pharmacopsychiatry 15:171-179. Nestoros JN, Suranyi-CadotteBE, Spees RC, Schwartz G, Nair NPV (1982): Diazepam in high doses is effective in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 6:513-516. Papeschi R, Molina-Negro P, Sourkes TL, Erba G (1972): The concentration of homovanillic acid and 5-hydroxyindoleacetic acid in ventricular and lumbar CSF. Neurology (Minneap) 22:115 I-1159. Simpson GM (1970): Controlled studies of antiparkinsonism agents in the treatment of drug-induced extrapyramidal symptoms. Acta Psychiatr Scand (Suppl) 212:44-51. Simpson GM, Angus JW (1970): A rating scale for extrapyramidal side effects. Acta Psychiatr Scand (Suppl) 212:11-19. Spitzer RL, Endicott J, Robins E (1977): Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders. ed 3. New York: Biometrics Research. Wood PL (1982): Action of GABAergic agents on dopamine metabolism in the nigrostriatal pathway of the rat. J Pharmacol Exp Ther 222:674-679. Wood PL, Etienne P, Lal S, Nair NPV (1982): GABAergic regulation of nigrostriatal neurons: Coupling of benzodiazepine and GABA receptors. Prog Neuropsychopharmacol Biol Psychiatry 6:471--474.