- Email: [email protected]
Carbamazepine in the treatment of neuroleptic malignant syndrome
BRIEF REPORTS i
Carbamazepine in the Treatment of Neuroleptic Malignant Syndrome Pierre Thomas, Michel Maron, Claire Rascle, Olivier Cottencin, Guillaume Vaiva, and Michel Goudemand
Background: Neuroleptic malignan' syndrome (NMS) is a potentially lethal adverse effect to neuroleptic drugs. Methods: We report on 2 cases where NMS dramatically improved with carbamazepine. Inc,!dental removal and reapplication of carbamazepine atte,:ts to its effectiveness for this condition. Results: ,4 34-year-old woman treated for a major depressive disorder experienced NMS with a phenothiazine. Her condition dramatically improved in 8 hours after she was administered carbamazepine. Since carbamazepine was discontinued, NMS recurred in 10 hours and remitted anew within less than 24 hours aider reintroduction. A 31-year-old woman experiencing a s'chizoaffective disorder displayed NMS with aphenothiazine and a bu~,rophenone. NMS completely resolved within 8 hours after she was administered carbamazepine. NMS recurred within 12 hours after carbamazepine discontinuation. Conclusions: These data thus accoimt for a cause-effect relationship between carbamazepine administration and NMS relief and argue against the neuroleptic withdrawal to be responsible by itselffor NMS relief Biol Psychiatry 1998;43:303-305 © 1998 Socie~' of Biological Psychiatry. K e y W o r d s : Carbamazepine, neumleptic malignant syndrome, neuroleptic, adverse event, treatment, affective disorder
Introduction 'euroleptic malignant syndrome (NMS) is a potentially lethal adverse response to neuroleptic drugs. It is characterized by muscular rigidity, impaired consciousness, hyperpyrexia, and autonomic instability (Fink 1996). Prompt recognition of the syndrome, neuroleptic withdrawal, and medical supportive treatment are the most effective measures (Buckley and Hutchinson 1995). NMS
N
From the Department of Psychiatry, School of Medicine, Centre Hospitalier Regional et Universitaire, University of Lille ?-, Lille, France. Address reprint request to Dr. Pierre Thomas, Dep~s'tment of Psychiatry, School of Medicine, Centre Hospitalier Regional et Uniw~rsitaire, University of Lille 2, 6 rue du Pr Laguesse, 59037 Lille cedex, France. Received January 2, 1997; revised March 4, 1997: accepted April 4, 1997.
© 1998 Society of Biological Psychiatry
often requires the patient to be transferred to an intensive care unit, thereby interrupting psychiatric care. W e report 2 cases in which NMS dramatically improved with carbamazepine. Incidental removal and reapplication of carbamazepine attests to its effectiveness for this condition.
Case One Miss A, a 34-year-old music teacher with a prior psychiatric history of unipolar depression, was treated for 4 weeks with dothiepin (100 mg daily) and nordazepam, a long half-life benzodiazepine (30 mg daily), for a depressive recurrence, As she displayed guilty ideation with a fear of dying, she was administered oral low doses of cyamemazine, a major sedative phenothiazine (10 mg T.I.D.). Her condition worsened within 24 hours with both stuporous and uncontrollable agitated states. On admission, she refused food and drink and had an hallucinatory experience of horror scenes. Pulse was 110 beats/min, temperature was 38.5°C, and laboratory measures were within normal limits, with no increase in creatine phosphokinase. Repeated electroencephalograms (EEGs) demonstrated diffuse slow waves with occasional rhythm modifications that could not eliminate seizure disorder, although Miss A had no past history of epilepsy. Computed tomography (CT) scan showed no abnormalities. Despite cyamemazine discontinuation and parenteral hydration, her condition worsened, with consciousness impairment, generalized rigidity, tremor, diaphoresis, incontinence, hypertension, temperature reaching 40°C, and leukocytosis. NMS was diagnosed. Carbamazepine (600 mg) was administered through a feeding tube. Her condition dramatically improved in 8 hours, with a complete recovery of consciousness, and resolution of motor and autonomic disorders. Twenty-four hours later, a genital hemorrhage due to a fibroma required here transfer to the gynecological department, where a fibromectomy was performed. Carbamazepine was discontinued, and NMS recurred 10 hours later. Carbamazepine (600 mg) was reintroduced, producing complete resolution of NMS within 24 hours; 3 days later, carbamazepine serum level was 5.7 mg/mL. Carbamazepine was maintained with dose adjustment to maintain serum levels within the therapeutic range. NMS did not recur despite the reintroduction of haloperidol due to the persistence of delusions. Miss A was discharged 3 months later, recovered, receiving carbamazepine (400 mg three times daily) and haloperidol (5 mg daily). 0006-3223/98/$19.00 PII S0006-3223(97 )00450-2
304
BIOL PSYCHIATRY
Brief Reports
1998;43:303-305
Case Two Mrs. B, a 31-year-old hospital staff member with a history of schizoaffective disorder, experienced a recurrence of delusions following a progressive and untreated major depressive disorder. She was started on neuroleptic treatment upon admission. After receiving 10 rng haloperidol and 25 mg cyamemazine, Mrs. B displayed general muscular rigidity, clouded consciousness, posturing, staring, diaphoresis, temperature exceeding 38.5°C, pulse of 120 beats/min, and elevated blood pxessure. Laboratory, examination showed leukocytosis (11,800/mm 3) and a moderate increase in creatine phosphokinase (840 UI/L). EEG and CT scan were considered within normal limits. NMS was diagnosed. Carbamazepine was administered via a feedirg tube, 600 mg on first administration then 200 mg T.I.D. The syndrome completely resolved within 8 hours, disclosing hallucinatory and depressive symptoms. The patient regained consciousress and the autonomic symptoms resolved prior to a reduztion of muscular rigidity. Haloperidol (4 mg daily) was reintroduced without NMS relapse. She developed a skin eruption 72 hours later, requiring carbamazepine discontinuation. As haloperidol was maintained, NMS features recurred within 12 hours after carbamazepine discontinuation. Haloperidol was then promptly discontinued and supportive care was administered. The patient progressively recovered frora NMS within a week. She', was discharged, recovered, 4 weeks later on a maintenance treatment of sulpiride, a benzamidic neuroleptic (300 mg twice daily), and viloxazine, a norepinephrine reuptake inhibitor (300 mg daily).
Discussion Both patients met the DSM-IV (AmeJ'ican Psychiatric Association 1994) criteria for NMS, and both were receiving neuroleptic medications. All NMS symptoms were present with the exception of elevated creatine kinase (CPK) levels. A CPK increase that re,sults in skeletal muscle damage (Guerrera and Romero 1993) has reported to be inconstant and related to the duration of the syndrome (Goldwasser et al 1989). It might he argued that the short duration of NMS prevented a CPK elevation in both these cases. NMS improvement is usually observed with supportive care within 2--4 days after discontinuation of neuroleptics, and a progressive recovery is generally observed within 5-14 days (Rosebush et al 1991). A rapid resolution of NMS after the first or second electroconvulsive therapy (ECT) treatment has been reported for a few patients (Addonizio et al 1987). The condition of both of our patients dramatically improved within 8 hours. In both cases, NMS reappeared as carbamazepine was withdrawn. The first patient resumed recovery following the reintroduction of carbamazepine. Although unintentional, this observation fulfilled the criteria for a positive withdrawal and rechallenge trial. These data reveal a cause-effect
relationship between carbamazepine administration and NMS relief, and argue against neuroleptic withdrawal itself being responsible for NMS relief. The effectiveness of carbamazepine in relieving NMS is consistent with published clinical data: 1) previous reports of attenuated forms of NMS with concomitant treatment with neuroleptic and carbamazepine (Muller et al 1988; Dalkin and Lee 1990); 2) the occurrence of NMS following carbamazepine withdrawal while neuroleptics were maintained (Keepers 1990; Sullivan 1987); 3) dramatic improvement of catatonia, which shares common features with NMS, after carbamazepine administration (Rankel and Rankel 1988; Revuelta et al 1994). Carbamazepine displays multiple levels of pharmacologic action, potentially interacting with several neurotransmitters. Carbamazepine effects on dopamine activity in the hypothalamus (Coulter and Corrigan 1991) or on gamma-aminobutyric acid regulation (Clark et al 1995) may be hypothesized to explain the clinical recovery we observed in these 2 patients. The effectiveness of carbamazepine in reducing NMS may also be explained by its anticonvulsant effect, as it has been proposed in catatonia after either carbamazepine treatment (Rankel and Rankel 1988) or treatment that increases brain seizure thresholds such as benzodiazepines, barbiturates, and ECT (Fink 1996). The efficiency of carbamazepine in interrupting the potentially lethal course of NMS needs to be confirmed. Since early clinical recognition of the syndrome remains essential, these 2 cases encourage trials of carbemazepine in patients with NMS.
References Addonizio G, Susman VL, Roth SD (1987): Neuroleptic malignant syndrome: A review and analysis of 115 cases. Biol Psychiatry 22:1004-1020. American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press. Buckley P, Hutchinson M (1995): Neuroleptic malignant syndrome. J Neurol Neurosurg Psychiatry 58:271-273. Clark M, Massenburg GS, Weiss SR (1995): Analysis of the hippocampal GABA A receptor system in kindled rat by autoradiographic and in situ hybridization techniques: Contingent tolerance to carbamazepine. Brain Res Mol Brain Res 26:309-319. Coulter F, Corrigan FM (1991): Carbamazepine and NMS. Br J Psychiatry' 158:434-435. Dalkin T, Lee AS (1990): Carbamazepine and forme fruste neuroleptic malignant syndrome. Br J Psychiatry 157:437438. Fink M (1996): Neuroleptic malignant syndrome and catatonia: One entity or two. Biol Psychiatry 39"1-4.
Brief Reports
BIOL PSYCHIATRY
305
1998;43:303-305
Goldwasser HD, Hooper JF, Spears NM (1989): Concomitant treatment of neuroleptic malignant syndrome and psychosis. Br J Psychiatry 154:102-104. Guerrera RJ, Romero JA (1993): Enzyme elevation in the neuroleptic malignant syndrome. Biol Psychiatry 34:634640. Keepers GA (1990): Neuroleptic malignant syndrome associated with withdrawal from carbamazepine. Am J Psychiatry 147: 1687. Muller T, Becker T, Fritze J (1988): Neuroleptic malignant syndrome after clozapine plus carbamazepine. Lancet ii: 8626-8627.
Rankel HW, Rankel LE (1988): Carbamazepine in the treatment of catatonia. Am J Psychiatry 145:361-362. Revuelta E, Bordet R, Piquet T, Gwache M, Destee M, Goudemand M (1994): Catatonie aigue et syndrome malin des neuroleptique, Un cas au cours d'une psychose infantile. Encephale 20:351-354. Rosebush PI, Stewart T, Mazurek MF (1991): The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care. Br J Psychiatry 159:709-712. Sullivan CF (1987): A possible variant of the neuroleptic malignant syndrome. Br J Psychiatry 151:689-690.
Carbamazepine in the Treatment of Neuroleptic Malignant Syndrome Pierre Thomas, Michel Maron, Claire Rascle, Olivier Cottencin, Guillaume Vaiva, and Michel Goudemand
Background: Neuroleptic malignan' syndrome (NMS) is a potentially lethal adverse effect to neuroleptic drugs. Methods: We report on 2 cases where NMS dramatically improved with carbamazepine. Inc,!dental removal and reapplication of carbamazepine atte,:ts to its effectiveness for this condition. Results: ,4 34-year-old woman treated for a major depressive disorder experienced NMS with a phenothiazine. Her condition dramatically improved in 8 hours after she was administered carbamazepine. Since carbamazepine was discontinued, NMS recurred in 10 hours and remitted anew within less than 24 hours aider reintroduction. A 31-year-old woman experiencing a s'chizoaffective disorder displayed NMS with aphenothiazine and a bu~,rophenone. NMS completely resolved within 8 hours after she was administered carbamazepine. NMS recurred within 12 hours after carbamazepine discontinuation. Conclusions: These data thus accoimt for a cause-effect relationship between carbamazepine administration and NMS relief and argue against the neuroleptic withdrawal to be responsible by itselffor NMS relief Biol Psychiatry 1998;43:303-305 © 1998 Socie~' of Biological Psychiatry. K e y W o r d s : Carbamazepine, neumleptic malignant syndrome, neuroleptic, adverse event, treatment, affective disorder
Introduction 'euroleptic malignant syndrome (NMS) is a potentially lethal adverse response to neuroleptic drugs. It is characterized by muscular rigidity, impaired consciousness, hyperpyrexia, and autonomic instability (Fink 1996). Prompt recognition of the syndrome, neuroleptic withdrawal, and medical supportive treatment are the most effective measures (Buckley and Hutchinson 1995). NMS
N
From the Department of Psychiatry, School of Medicine, Centre Hospitalier Regional et Universitaire, University of Lille ?-, Lille, France. Address reprint request to Dr. Pierre Thomas, Dep~s'tment of Psychiatry, School of Medicine, Centre Hospitalier Regional et Uniw~rsitaire, University of Lille 2, 6 rue du Pr Laguesse, 59037 Lille cedex, France. Received January 2, 1997; revised March 4, 1997: accepted April 4, 1997.
© 1998 Society of Biological Psychiatry
often requires the patient to be transferred to an intensive care unit, thereby interrupting psychiatric care. W e report 2 cases in which NMS dramatically improved with carbamazepine. Incidental removal and reapplication of carbamazepine attests to its effectiveness for this condition.
Case One Miss A, a 34-year-old music teacher with a prior psychiatric history of unipolar depression, was treated for 4 weeks with dothiepin (100 mg daily) and nordazepam, a long half-life benzodiazepine (30 mg daily), for a depressive recurrence, As she displayed guilty ideation with a fear of dying, she was administered oral low doses of cyamemazine, a major sedative phenothiazine (10 mg T.I.D.). Her condition worsened within 24 hours with both stuporous and uncontrollable agitated states. On admission, she refused food and drink and had an hallucinatory experience of horror scenes. Pulse was 110 beats/min, temperature was 38.5°C, and laboratory measures were within normal limits, with no increase in creatine phosphokinase. Repeated electroencephalograms (EEGs) demonstrated diffuse slow waves with occasional rhythm modifications that could not eliminate seizure disorder, although Miss A had no past history of epilepsy. Computed tomography (CT) scan showed no abnormalities. Despite cyamemazine discontinuation and parenteral hydration, her condition worsened, with consciousness impairment, generalized rigidity, tremor, diaphoresis, incontinence, hypertension, temperature reaching 40°C, and leukocytosis. NMS was diagnosed. Carbamazepine (600 mg) was administered through a feeding tube. Her condition dramatically improved in 8 hours, with a complete recovery of consciousness, and resolution of motor and autonomic disorders. Twenty-four hours later, a genital hemorrhage due to a fibroma required here transfer to the gynecological department, where a fibromectomy was performed. Carbamazepine was discontinued, and NMS recurred 10 hours later. Carbamazepine (600 mg) was reintroduced, producing complete resolution of NMS within 24 hours; 3 days later, carbamazepine serum level was 5.7 mg/mL. Carbamazepine was maintained with dose adjustment to maintain serum levels within the therapeutic range. NMS did not recur despite the reintroduction of haloperidol due to the persistence of delusions. Miss A was discharged 3 months later, recovered, receiving carbamazepine (400 mg three times daily) and haloperidol (5 mg daily). 0006-3223/98/$19.00 PII S0006-3223(97 )00450-2
304
BIOL PSYCHIATRY
Brief Reports
1998;43:303-305
Case Two Mrs. B, a 31-year-old hospital staff member with a history of schizoaffective disorder, experienced a recurrence of delusions following a progressive and untreated major depressive disorder. She was started on neuroleptic treatment upon admission. After receiving 10 rng haloperidol and 25 mg cyamemazine, Mrs. B displayed general muscular rigidity, clouded consciousness, posturing, staring, diaphoresis, temperature exceeding 38.5°C, pulse of 120 beats/min, and elevated blood pxessure. Laboratory, examination showed leukocytosis (11,800/mm 3) and a moderate increase in creatine phosphokinase (840 UI/L). EEG and CT scan were considered within normal limits. NMS was diagnosed. Carbamazepine was administered via a feedirg tube, 600 mg on first administration then 200 mg T.I.D. The syndrome completely resolved within 8 hours, disclosing hallucinatory and depressive symptoms. The patient regained consciousress and the autonomic symptoms resolved prior to a reduztion of muscular rigidity. Haloperidol (4 mg daily) was reintroduced without NMS relapse. She developed a skin eruption 72 hours later, requiring carbamazepine discontinuation. As haloperidol was maintained, NMS features recurred within 12 hours after carbamazepine discontinuation. Haloperidol was then promptly discontinued and supportive care was administered. The patient progressively recovered frora NMS within a week. She', was discharged, recovered, 4 weeks later on a maintenance treatment of sulpiride, a benzamidic neuroleptic (300 mg twice daily), and viloxazine, a norepinephrine reuptake inhibitor (300 mg daily).
Discussion Both patients met the DSM-IV (AmeJ'ican Psychiatric Association 1994) criteria for NMS, and both were receiving neuroleptic medications. All NMS symptoms were present with the exception of elevated creatine kinase (CPK) levels. A CPK increase that re,sults in skeletal muscle damage (Guerrera and Romero 1993) has reported to be inconstant and related to the duration of the syndrome (Goldwasser et al 1989). It might he argued that the short duration of NMS prevented a CPK elevation in both these cases. NMS improvement is usually observed with supportive care within 2--4 days after discontinuation of neuroleptics, and a progressive recovery is generally observed within 5-14 days (Rosebush et al 1991). A rapid resolution of NMS after the first or second electroconvulsive therapy (ECT) treatment has been reported for a few patients (Addonizio et al 1987). The condition of both of our patients dramatically improved within 8 hours. In both cases, NMS reappeared as carbamazepine was withdrawn. The first patient resumed recovery following the reintroduction of carbamazepine. Although unintentional, this observation fulfilled the criteria for a positive withdrawal and rechallenge trial. These data reveal a cause-effect
relationship between carbamazepine administration and NMS relief, and argue against neuroleptic withdrawal itself being responsible for NMS relief. The effectiveness of carbamazepine in relieving NMS is consistent with published clinical data: 1) previous reports of attenuated forms of NMS with concomitant treatment with neuroleptic and carbamazepine (Muller et al 1988; Dalkin and Lee 1990); 2) the occurrence of NMS following carbamazepine withdrawal while neuroleptics were maintained (Keepers 1990; Sullivan 1987); 3) dramatic improvement of catatonia, which shares common features with NMS, after carbamazepine administration (Rankel and Rankel 1988; Revuelta et al 1994). Carbamazepine displays multiple levels of pharmacologic action, potentially interacting with several neurotransmitters. Carbamazepine effects on dopamine activity in the hypothalamus (Coulter and Corrigan 1991) or on gamma-aminobutyric acid regulation (Clark et al 1995) may be hypothesized to explain the clinical recovery we observed in these 2 patients. The effectiveness of carbamazepine in reducing NMS may also be explained by its anticonvulsant effect, as it has been proposed in catatonia after either carbamazepine treatment (Rankel and Rankel 1988) or treatment that increases brain seizure thresholds such as benzodiazepines, barbiturates, and ECT (Fink 1996). The efficiency of carbamazepine in interrupting the potentially lethal course of NMS needs to be confirmed. Since early clinical recognition of the syndrome remains essential, these 2 cases encourage trials of carbemazepine in patients with NMS.
References Addonizio G, Susman VL, Roth SD (1987): Neuroleptic malignant syndrome: A review and analysis of 115 cases. Biol Psychiatry 22:1004-1020. American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press. Buckley P, Hutchinson M (1995): Neuroleptic malignant syndrome. J Neurol Neurosurg Psychiatry 58:271-273. Clark M, Massenburg GS, Weiss SR (1995): Analysis of the hippocampal GABA A receptor system in kindled rat by autoradiographic and in situ hybridization techniques: Contingent tolerance to carbamazepine. Brain Res Mol Brain Res 26:309-319. Coulter F, Corrigan FM (1991): Carbamazepine and NMS. Br J Psychiatry' 158:434-435. Dalkin T, Lee AS (1990): Carbamazepine and forme fruste neuroleptic malignant syndrome. Br J Psychiatry 157:437438. Fink M (1996): Neuroleptic malignant syndrome and catatonia: One entity or two. Biol Psychiatry 39"1-4.
Brief Reports
BIOL PSYCHIATRY
305
1998;43:303-305
Goldwasser HD, Hooper JF, Spears NM (1989): Concomitant treatment of neuroleptic malignant syndrome and psychosis. Br J Psychiatry 154:102-104. Guerrera RJ, Romero JA (1993): Enzyme elevation in the neuroleptic malignant syndrome. Biol Psychiatry 34:634640. Keepers GA (1990): Neuroleptic malignant syndrome associated with withdrawal from carbamazepine. Am J Psychiatry 147: 1687. Muller T, Becker T, Fritze J (1988): Neuroleptic malignant syndrome after clozapine plus carbamazepine. Lancet ii: 8626-8627.
Rankel HW, Rankel LE (1988): Carbamazepine in the treatment of catatonia. Am J Psychiatry 145:361-362. Revuelta E, Bordet R, Piquet T, Gwache M, Destee M, Goudemand M (1994): Catatonie aigue et syndrome malin des neuroleptique, Un cas au cours d'une psychose infantile. Encephale 20:351-354. Rosebush PI, Stewart T, Mazurek MF (1991): The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care. Br J Psychiatry 159:709-712. Sullivan CF (1987): A possible variant of the neuroleptic malignant syndrome. Br J Psychiatry 151:689-690.