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Abstract

Atypical antipsychotics have been reported to increase serum creatine kinase (SCK) and sometimes result in clinically important rhabdomyolysis. We describe an unusual case of rhabdomyolysis and acute renal failure in a 40-year-old woman taking risperidone 2.5 mg/day for more than a year. No other risk factors for rhabdomyolysis were identified.

Key words

 Risperidone, severe rhabdomyolysis

History

Patient A., a 40-year-old women with a borderline personality disorder and depression was admitted to the Intensive Care Unit with severe rhabdomyolysis and acute kidney- and liver failure. She was found lying on the floor at home for an unknown period of time. She complained of general weakness and muscle pain, especially in the lower extremities. Four days before presentation in the ER, she had diarrhea. Her medication included clomipramine 100 mg, lithium 400 mg, risperidone 2,5 mg, Lorazepam 2 mg en Nozinan 25 mg.

Physical examination showed an intention tremor, minor muscle weakness of the lower extremities en tender calf muscles. Blood pressure was 140/100 mmHg with a pulse of 100 bpm and a rectal temperature of 38,6 degrees Celsius. Her pupils were isocore and reactive to light with a horizontal nystagmus. Laboratory findings showed serum creatine kinase (SCK) of 119.800 U/L (normal 0 – 145 U/L) and a high serum creatinine and high liver enzymes (Table 1). Serum Lithium concentration was within the therapeutic range (0,7 mmol/L). Shortly after admittance to the ICU, SCK levels rose to 351100 U/L regardless of aggressive fluid resuscitation. She developed anuria and her kidney- and liver failure worsened. She was started on continuous venovenous hemofiltration (CVVH) as a renal replacement therapy. Unfortunately, anuria persisted and SCK levels rose further. The patient was transferred to another ICU where intermittent hemodialysis could be started. Her recovery was prosperous and the patient was discharged to a psychiatric ward after one week. After 3 months her kidney- en liver function was completely restored.

	Day 1	Day 2	Day 4	Day 6	Reference values
SCK	119800	196100	42960	7500	0-145 U/L
Creatinin	233	358	510	197	46-95 umol/L
Bilirubin	16	7	11	7	3-17 umol/L
AF	58	86	90	128	40-125 U/L
yGT	15	14	40	58	0-38 U/L
ASAT	3290	2495	883	402	0-31 U/L
ALAT	482	619	337	371	0-34 U/L
LDH	4962	3702	1563	933	0-247 U/L

Table 1. Laboratory findings (SCK, bilirubin en liver enzymes of Patient A during the first 6 days.

Differential diagnosis

We considered several possibilities in the differential diagnosis of severe rhabdomyolysis in this patient [1]. Lithium intoxication after a recent episode of diarrhea was dismissed due to a therapeutic concentration. Rhabdomyolysis due to trauma and an extended period of immobilization was not likely due to the extreme severity of SCK levels (in trauma up to 100.000 U/L) [2] and the lack of secondary signs of prolonged immobilization or muscle-injury. There was no history of epileptic seizures, nor were there any post-epileptic symptoms.

The possibility of serotonin syndrome (SS) or malignant neuroleptic syndrome (MNS) was also considered because of patient’s atypical antipsychotics and fever at admittance [3]. Serotonin syndrome or malignant neuroleptic syndrome has a significant overlap in symptomatology with autonomic dysfunction and altered mental state and both can be a potential life -threatening consequence of the use of atypical antipsychotics. Our patient did not meet the criteria for SS or MNS [4].

Discussion

Risperidone is subscribed to patients suffering from schizophrenia, bipolar depression and aggression in M. Alzheimer. Risperidone is an atypical antipsychotic drug with strong anti-serotonin (5-HT2) en anti-dopamine (D2) activity. It is also an agonist for alpha1, alpha2 and histamine receptors. The side effects are diverse but in more than 10% side effects include Parkinsonism, sleep disorders, headache or lowered mental status.

Marked increases in SCK activity of the skeletal muscles, not related to muscle activity, trauma or MNS have been reported in up to 10% of patients taking atypical antipsychotic drugs [5-8]. We therefore postulated that her symptoms could be attributed to Risperidone [9], which she started taking a year earlier. Onset of symptoms with high SCK vary between 5 days [6] to several years [10] of treatment, although in most cases patients developed rhabdomyolysis after initiating risperidone within 1 month [6]. Generally rise of SCK is self-limiting after withdrawal of Risperidone [7,8]. The magnitude of SCK elevation is associated with the prevalence of myoglobinuria [7]. The mechanism is not yet fully understood. Necrosis and a massive rise in SCK can occur when 5-HT2A receptors are blocked, increasing the permeability of the sarcolemma in the skeletal muscle. Calcium-influx is believed to occur due to a reduced function of the Na-K -ATPase pump in the membrane of the muscle cell. This activates intracellular proteases that in turn break down myofibrils. This then results in muscle-enzymes and other proteins like creatine kinase and myoglobin to leak to the circulation. This hypothesis supports the role of risperidone in Rhabdomyolysis [11].

Treatment

Because volume depletion and acidosis increase the nephrotoxic effect of myoglobin, treatment is aimed at fluid resuscitation [9]. In some cases, as with our patient, in the first 24 hours as much as 6 - 10 liters fluids must be administered. The aim in treating a patient with rhabdomyolysis is to create a forced diuresis in excess of 200 ml/hour [7] until a significant decrease in serum creatininekinase is seen. The serum creatininekinase follow-up can be used as a measure of the effect of therapy. The ultimate goal is a normalization of the serum creatininekinase. Early hemofiltration or hemodialysis can potentially prevent irreversible damage to the kidneys.

References

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2. Zutt R, van der Kooi AJ, Linthorst GE, Wanders RJ, de Visser M (2014) Rhabdomyolysis: review of the literature. Neuromuscul Disord 24: 651-659. [Crossref]
3. Perry PJ, Wilborn CA (2012) Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry 24: 155-62. [Crossref]
4. Nisijima K (2012) Elevated creatine kinase does not necessarily correspond temporarily with onset of muscle rigidity in neuroleptic malignant syndrome: a report of two cases. Neuropsychiatr Dis Treat 8: 615-618. [Crossref]
5. Keshavan M (1993) Muscarinic effects of clozapine and negative symptoms. Arch Gen Psychiatry 50: 835. [Crossref]
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