Clomipramine induced neuroleptic malignant syndrome and pyrexia of unknown origin
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《英国医生杂志》
1 Royal Cornhill Hospital, Aberdeen AB25 2ZH, 2 Woodend Hospital, Aberdeen
Correspondence to: A M Haddow alison.haddow@gpct.grampian.scot.nhs.uk
Introduction
Pyrexia related to clomipramine has been reported on only four occasions to the Committee on Safety of Medicines, therefore some care was need in labelling this drug as responsible for this man's problems. A database search for "neuroleptic malignant syndrome" or "suspected neuroleptic malignant syndrome" occurring in association with clomipramine found just over 50 reports received worldwide since product launch, two thirds of cases came from Japan, two from the United Kingdom, and four from the United States. To the authors knowledge there have been just two other published case reports published where clomipramine may have been a factor in hyperthermic reactions. Other drugs, however, were also implicated in these cases.2 3 In this case promazine was coprescribed until May 2003. But symptoms recurred even after stopping this. A number of factors were felt to support the diagnosis in this case. Firstly, on retrospective analysis, it was noted that on his admissions to the acute medical assessment ward clomipramine had either been unavailable or refused by the patient, hence, it is suggested, his apparent response to antibiotic therapy. Secondly, there was rapid resolution of his symptoms when the drug was purposefully withheld. Finally, his symptoms rapidly recurred when the drug was reintroduced.
Diagnostic criteria for neuroleptic malignant syndrome based on Levenson1 and Sternbach6
Neuroleptic malignant syndrome
Major criteria
Fever
Muscular rigidity
Raised creatinine phosphokinase
Minor criteria
Tachycardia
Labile blood pressure
Tachypnoea
Altered consciousness
Sweating
Leucocytosis
Diagnostic threshold
Three major or two major and four minor criteria plus supportive history
Serotonin syndrome
At least three of
Mental status change
Agitation
Myoclonus
Hyperreflexia
Sweating
Shivering
Tremor
Diarrhoea
Incoordination
Fever
Plus exclusion of
Infection, metabolic upset, substance misuse
No recent commencement or withdrawal of neuroleptic agent
The most widely accepted mechanism for neuroleptic malignant syndrome is of blockage of dopamine receptors in the nigrostriatal tracts.4 More recently, however, it has been suggested that it is the balance between serotonin and dopamine that is the important factor.5 It is notable that the serotonin syndrome, a syndrome felt to relate to drug induced excess serotonin neurotransmission, shares many characteristics with the neuroleptic malignant syndrome (box).6 It has been hypothesised that these two syndromes share a common mechanism, that of imbalance between dopamine and serotonin in the nigrostriatal pathways, with blockage of dopamine or stimulation of serotonin giving the same clinical end point.7 A recent published case where the addition of a potent serotonin reuptake inhibitor to olanzapine appeared to precipitate neuroleptic malignant syndrome would appear to support this theory.8 Clomipramine, although more potent than many other antidepressants, has only weak antagonistic effect at the dopamine receptor, therefore, it is suggested here that it is its inhibition of serotonin reuptake that was the more important factor in precipitating neuroleptic malignant syndrome in this case.9 10
Interestingly, further review of the patient's drug history found that he had been diagnosed as having a serotonin syndrome presumed to be related to sertraline in April 2001. That these two related syndromes occurred in the same man could suggest he may have been in some way predisposed to such reactions. Attempts so far to find a genetic basis for such a predisposition have so far been inconclusive.11 More fruitful for further research may be the observation that patients with organic neuropsychiatric disorders disease appear be more sensitive to all side effects of neuroleptic agents.12
Neuroleptic malignant syndrome is rare—prospective studies show incidence ranging 0.07-2.2% in patients treated with neuroleptic drugs. With the large number of prescriptions for antidepressants in the United Kingdom, however, these rates are not insignificant.13-18 In Scotland alone, with a population of about 5 million, in the year 2002, there were more than 3.8 million individual prescriptions for antidepressants, an increase of 7% on the previous year.19 The recognition that such a serious condition with an estimated mortality of about 20%, even higher rates being reported in patients known to have organic brain disease, can occur with such commonly prescribed drugs would appear to be an important lesson.20
Neuroleptic malignant syndrome can be precipitated by clomipramine and possibly other antidepressants
We thank David Clark for his helpful comments on an earlier draft.
Contributors: Eileen Howitt, pharmacy manager, was involved in correspondence with the drug company and in preparation of a drug review for the patient, Tom MacEwan was the patient's RMO and adviser to the authors. AMH did the literature search and collated information on psychiatry. MW prepared the table and collated information ongeriatric medicine. DH was involved in direct patient care, liaison with general medical wards, and collation of clinical data. HL was involved in the clinical care of the patient and prepared the first summary of the geriatric medicine contact after consultation with other authors before the literature search and writing of the case report. AMH is guarantor.
Funding: None.
Competing interests: None declared.
References
Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry 1985;142: 1137-45.
Stevens E, Roman A, Houa M, Razavi D, Jaspar N. Severe hyperthermia during tetrabenazine therapy for tardive dyskinesia. Intensive Care Med 1998;24: 369-71.
Ansseau M, Reynolds CF, Kupfer DJ, Ponclet PF, Franck G, Dresse AE, et al. Central dopaminergic and noradrenergic blockade in a patient with neuroleptic malignant syndrome. J Clin Psychiatry 1986;47: 320-1.
Adnet P, Lesteval P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth 2000;85: 129-35.
Ames D, Wirshing W. Ecstasy, the serotonin syndrome and neuroleptic malignant syndrome: a possible link? JAMA 1993;269: 869.
Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148: 705-13.
Lane R, Baldwin D. Selective serotonin reuptake inhibititor: induced serotonin syndrome. J Clin Psychopharmacol 1997;17: 208-91.
Kontaxakis V, Havaki-Kontaxaki B, Pappa D, Katritsis D, Christodoulou G. Neuroleptic malignant syndrome after addition of paroxetine to olanzapine J Clin Psychopharmacol 2003;23: 671-2.
Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 1984;230: 94-102.
Tatsumi M, Groshan K, Blakely R, Richelso E. Pharmacological profile of antidepressant and related compounds at human monoamine transporters. Eur J Pharmacol 1997;340: 249-58.
Kawanshi C. Genetic predisposition to neuroleptic malignant syndrome. Am J Pharmacogenomics 2003;3: 89-95.
Ballard C, Grace J, McKeith I, Holmes C. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease. Lancet 1998;351: 1032-3.
Spivak B, Maline DI, Kozyrev VN, Mester R, Neduva SA, Ravilov RS, et al. Frequency of neuroleptic malignant syndrome in a large psychiatric hospital in Moscow. Eur Psychiatry 2000;15: 330-3.
Keck PE, Sebastianelli J, Pope HG, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a state psychiatric hospital. J Clin Psychiatry 1989;50: 352-5.
Gelenberg AJ, Bellinghausen B, Wojcik JD, Falk WE, Sachs GS. A prospective survey of neuroleptic malignant syndrome in a short term psychiatric hospital. Am J Psychiatry 1988;145: 4517-8.
Hermesh H, Aizenberg D, Weizman A, Lapidot M, Mayor C, Munitz H. Risk for definite neuroleptic malignant syndrome. Br J Psychiatry 1992;161: 254-7.
Naganuma H, Fujii I. Incidence and risk factors in neuroleptic malignant syndrome. Acta Psychiatrica Scandinavica 1994;90: 424-6.
Deng MZ, Chen GQ, Phillips MR. Neuroleptic malignant syndrome in 12 of 9792 Chinese inpatients exposed to neuroleptics: a prospective study. Am J Psychiatry 1990;147: 1149-55.
Information and Statistics Division Common Services Agency. Prescription cost analysis for Scotland. Scotland: ISDCSA, 2004. (Search via www.isdscotland.org.)
Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry 1989;50: 18-25.(Alison M Haddow, acting c)
Correspondence to: A M Haddow alison.haddow@gpct.grampian.scot.nhs.uk
Introduction
Pyrexia related to clomipramine has been reported on only four occasions to the Committee on Safety of Medicines, therefore some care was need in labelling this drug as responsible for this man's problems. A database search for "neuroleptic malignant syndrome" or "suspected neuroleptic malignant syndrome" occurring in association with clomipramine found just over 50 reports received worldwide since product launch, two thirds of cases came from Japan, two from the United Kingdom, and four from the United States. To the authors knowledge there have been just two other published case reports published where clomipramine may have been a factor in hyperthermic reactions. Other drugs, however, were also implicated in these cases.2 3 In this case promazine was coprescribed until May 2003. But symptoms recurred even after stopping this. A number of factors were felt to support the diagnosis in this case. Firstly, on retrospective analysis, it was noted that on his admissions to the acute medical assessment ward clomipramine had either been unavailable or refused by the patient, hence, it is suggested, his apparent response to antibiotic therapy. Secondly, there was rapid resolution of his symptoms when the drug was purposefully withheld. Finally, his symptoms rapidly recurred when the drug was reintroduced.
Diagnostic criteria for neuroleptic malignant syndrome based on Levenson1 and Sternbach6
Neuroleptic malignant syndrome
Major criteria
Fever
Muscular rigidity
Raised creatinine phosphokinase
Minor criteria
Tachycardia
Labile blood pressure
Tachypnoea
Altered consciousness
Sweating
Leucocytosis
Diagnostic threshold
Three major or two major and four minor criteria plus supportive history
Serotonin syndrome
At least three of
Mental status change
Agitation
Myoclonus
Hyperreflexia
Sweating
Shivering
Tremor
Diarrhoea
Incoordination
Fever
Plus exclusion of
Infection, metabolic upset, substance misuse
No recent commencement or withdrawal of neuroleptic agent
The most widely accepted mechanism for neuroleptic malignant syndrome is of blockage of dopamine receptors in the nigrostriatal tracts.4 More recently, however, it has been suggested that it is the balance between serotonin and dopamine that is the important factor.5 It is notable that the serotonin syndrome, a syndrome felt to relate to drug induced excess serotonin neurotransmission, shares many characteristics with the neuroleptic malignant syndrome (box).6 It has been hypothesised that these two syndromes share a common mechanism, that of imbalance between dopamine and serotonin in the nigrostriatal pathways, with blockage of dopamine or stimulation of serotonin giving the same clinical end point.7 A recent published case where the addition of a potent serotonin reuptake inhibitor to olanzapine appeared to precipitate neuroleptic malignant syndrome would appear to support this theory.8 Clomipramine, although more potent than many other antidepressants, has only weak antagonistic effect at the dopamine receptor, therefore, it is suggested here that it is its inhibition of serotonin reuptake that was the more important factor in precipitating neuroleptic malignant syndrome in this case.9 10
Interestingly, further review of the patient's drug history found that he had been diagnosed as having a serotonin syndrome presumed to be related to sertraline in April 2001. That these two related syndromes occurred in the same man could suggest he may have been in some way predisposed to such reactions. Attempts so far to find a genetic basis for such a predisposition have so far been inconclusive.11 More fruitful for further research may be the observation that patients with organic neuropsychiatric disorders disease appear be more sensitive to all side effects of neuroleptic agents.12
Neuroleptic malignant syndrome is rare—prospective studies show incidence ranging 0.07-2.2% in patients treated with neuroleptic drugs. With the large number of prescriptions for antidepressants in the United Kingdom, however, these rates are not insignificant.13-18 In Scotland alone, with a population of about 5 million, in the year 2002, there were more than 3.8 million individual prescriptions for antidepressants, an increase of 7% on the previous year.19 The recognition that such a serious condition with an estimated mortality of about 20%, even higher rates being reported in patients known to have organic brain disease, can occur with such commonly prescribed drugs would appear to be an important lesson.20
Neuroleptic malignant syndrome can be precipitated by clomipramine and possibly other antidepressants
We thank David Clark for his helpful comments on an earlier draft.
Contributors: Eileen Howitt, pharmacy manager, was involved in correspondence with the drug company and in preparation of a drug review for the patient, Tom MacEwan was the patient's RMO and adviser to the authors. AMH did the literature search and collated information on psychiatry. MW prepared the table and collated information ongeriatric medicine. DH was involved in direct patient care, liaison with general medical wards, and collation of clinical data. HL was involved in the clinical care of the patient and prepared the first summary of the geriatric medicine contact after consultation with other authors before the literature search and writing of the case report. AMH is guarantor.
Funding: None.
Competing interests: None declared.
References
Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry 1985;142: 1137-45.
Stevens E, Roman A, Houa M, Razavi D, Jaspar N. Severe hyperthermia during tetrabenazine therapy for tardive dyskinesia. Intensive Care Med 1998;24: 369-71.
Ansseau M, Reynolds CF, Kupfer DJ, Ponclet PF, Franck G, Dresse AE, et al. Central dopaminergic and noradrenergic blockade in a patient with neuroleptic malignant syndrome. J Clin Psychiatry 1986;47: 320-1.
Adnet P, Lesteval P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth 2000;85: 129-35.
Ames D, Wirshing W. Ecstasy, the serotonin syndrome and neuroleptic malignant syndrome: a possible link? JAMA 1993;269: 869.
Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148: 705-13.
Lane R, Baldwin D. Selective serotonin reuptake inhibititor: induced serotonin syndrome. J Clin Psychopharmacol 1997;17: 208-91.
Kontaxakis V, Havaki-Kontaxaki B, Pappa D, Katritsis D, Christodoulou G. Neuroleptic malignant syndrome after addition of paroxetine to olanzapine J Clin Psychopharmacol 2003;23: 671-2.
Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 1984;230: 94-102.
Tatsumi M, Groshan K, Blakely R, Richelso E. Pharmacological profile of antidepressant and related compounds at human monoamine transporters. Eur J Pharmacol 1997;340: 249-58.
Kawanshi C. Genetic predisposition to neuroleptic malignant syndrome. Am J Pharmacogenomics 2003;3: 89-95.
Ballard C, Grace J, McKeith I, Holmes C. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease. Lancet 1998;351: 1032-3.
Spivak B, Maline DI, Kozyrev VN, Mester R, Neduva SA, Ravilov RS, et al. Frequency of neuroleptic malignant syndrome in a large psychiatric hospital in Moscow. Eur Psychiatry 2000;15: 330-3.
Keck PE, Sebastianelli J, Pope HG, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a state psychiatric hospital. J Clin Psychiatry 1989;50: 352-5.
Gelenberg AJ, Bellinghausen B, Wojcik JD, Falk WE, Sachs GS. A prospective survey of neuroleptic malignant syndrome in a short term psychiatric hospital. Am J Psychiatry 1988;145: 4517-8.
Hermesh H, Aizenberg D, Weizman A, Lapidot M, Mayor C, Munitz H. Risk for definite neuroleptic malignant syndrome. Br J Psychiatry 1992;161: 254-7.
Naganuma H, Fujii I. Incidence and risk factors in neuroleptic malignant syndrome. Acta Psychiatrica Scandinavica 1994;90: 424-6.
Deng MZ, Chen GQ, Phillips MR. Neuroleptic malignant syndrome in 12 of 9792 Chinese inpatients exposed to neuroleptics: a prospective study. Am J Psychiatry 1990;147: 1149-55.
Information and Statistics Division Common Services Agency. Prescription cost analysis for Scotland. Scotland: ISDCSA, 2004. (Search via www.isdscotland.org.)
Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry 1989;50: 18-25.(Alison M Haddow, acting c)