Clomipramine induced neuroleptic malignant syndrome and pyrexia of unknown origin

Neuroleptic malignant syndrome is uncommon. Its major characteristics—classically, fever, muscular rigidity, and raised serum creatinine kinase concentration—occur unpredictably and often in association with dopamine blocking drugs (box).¹ We present a case of neuroleptic malignant syndrome occurring in association with clomipramine, a drug not noted for dopamine blockade. Greater awareness of the possibility of this potentially life threatening syndrome occurring in patients treated with antidepressants may be useful given the continued increase in the prescribing of antidepressants of all classes.

Case report

A 57 year old man—a long term inpatient with frontal lobe dementia in an old age psychiatry ward—was admitted to an acute medical assessment unit in January 2003. He presented with sweating, pyrexia, muscle rigidity, decreased responsiveness, and urinary incontinence (table). At the time of admission he was taking clomipramine and promazine, both started in 2001. He was empirically diagnosed as having urinary tract infection and was prescribed intravenous and then oral antibiotics. He improved and returned to his long stay ward. Urine and blood cultures showed no growth during this admission. In May 2003, his condition deteriorated again with all previous symptoms and signs recurring. At this stage, promazine was stopped and further medical assessment was requested and again he was diagnosed as having urinary tract infection, and a course of antibiotics was prescribed. In addition to routine investigation, a liver ultrasound was done which showed no abnormality. Once again urine and blood cultures showed no growth. His condition improved, and he was transferred back to his base ward. Later the same month the man's sweating, pyrexia, muscular rigidity, and decreased responsiveness returned. At this stage, an opinion was sought from the department of medicine for the elderly. Due to the length of his history and the lack of a positive microbiological culture, a drug reaction was suspected and his current medication, ciprofloxacin and clomipramine, was stopped. Within 48 hours all symptoms had resolved, and he was provisionally diagnosed as having neuroleptic malignant syndrome. In June 2003 there was a trial reintroduction of clomipramine. After only three doses, however, the previously noted symptoms rapidly recurred again, resolving on withdrawal of the drug. A report was sent to the Committee on Safety of Medicines and the supplier of clomipramine.

Table 1.

Clinical data on admission and after reintroduction of clomipramine

Date	Medication	Temperature (°C)	Creatinine phosphokinase concentration (U/l)	C reactive protein (mg/l)	White blood count (109/l)	Heart rate (beats/min)	Blood pressure (mm Hg)
Admission 1	Clomipramine 20 mg/day	37.5	186	<10	11.4	78	130/80
	Promazine 50 mg thrice daily; 100 mg nightly
Admission 2	Clomipramine 20 mg/day	38.2	N/A	38	15.1	104	120/98
Admission 3*	Clomipramine 20 mg/day	38.6	840	28	18.5	118	158/92
	Ciprofloxacin 250 mg twice daily
Rechallenge	Clomipramine 20 mg/day	38.3	247	N/A	12.5	100	120/80
After 7 days	No drugs	37.5	869	N/A	11.8	82	N/A

N/A=not available

^*Admission to geriatric medicine unit.

Discussion

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