Aripiprazole as the Causative Agent of Neuroleptic Malignant Syndrome

Sir: Neuroleptic malignant syndrome (NMS) is a rare and potentially life-threatening neurologic emergency commonly associated with the use of antipsychotic medications. As a class, atypical antipsychotic agents have lower associated rates of extrapyramidal symptoms and are less likely to induce NMS as compared to conventional antipsychotics. One of the newest agents in the atypical antipsychotic class is aripiprazole. We report the case of a 71-year-old woman with paranoid schizophrenia, who presented with NMS while on single-agent therapy with aripiprazole. In our review of the literature, this is the first reported case of NMS induced by aripiprazole as the single causative agent in an elderly patient. Increasingly, family physicians find themselves as the primary providers for patients with mental health needs. In the case of patients taking antipsychotic medications for any in a broad array of psychiatric diagnoses, recognizing adverse therapeutic reactions is extremely important. Neuroleptic malignant syndrome, although rare, is a well-documented life-threatening condition that has been associated with antipsychotic or neuroleptic medications. The reported incidence rate of NMS ranges from 0.02% to 3% in patients who take neuroleptic agents.1 Neuroleptic malignant syndrome is typically characterized by high fever, muscular rigidity, and mental status changes, along with characteristic laboratory findings including creatinine phosphokinase (CPK) elevation and often leukocytosis. NMS has been observed in every class of neuroleptic medication, but has been reported most often in high-potency agents like haloperidol.2 It is less often associated with low-potency agents like chlorpromazine and the newer neuroleptics such as risperidone and olanzapine.3 The antiemetic medications meto-clopramide and promethazine have also been implicated as causative agents of NMS. Atypical antipsychotics have proven useful in the treatment of a wide spectrum of psychiatric conditions including dementia, delirium, psychosis, agitation, and affective disorders.4,5 When compared to the first-generation “conventional” antipsy-chotic drugs, atypical antipsychotic drugs demonstrate enhanced efficacy and safety owing to their pharmacologic differences.6 The conventional antipsychotic drugs are high-affinity antagonists of dopamine D2 receptors, resulting in effective management of psychotic symptoms but high rates of neurologic side effects such as extrapyramidal symptoms and tardive dyskinesia.7 In contrast, the atypical agents have lower affinity for dopamine D2 receptors and greater affinities for other neuroreceptors, including those for serotonin and norepinephrine.7 Despite the lower rates of extrapyramidal symptoms relative to conventional antipsychotics, cardiovascular side effects, NMS, weight gain, hyperprolactinemia, diabetes, and hyperlipidemia have been reported with atypical antipsychotics.8 Aripiprazole represents one of the most recent additions to the atypical antipsychotic class. In comparison to the other atypicals, it possesses a unique mechanism of action that may limit the development of hypodopaminergic states. Aripiprazole is a dopamine D2-receptor partial agonist with partial agonist activity at serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors. At clinically used doses, aripiprazole results in an almost complete saturation of D2-like dopamine receptors, yet the incidence of extrapyramidal side effects is no higher than with placebo; it is felt that the most likely explanation for this is the weak partial agonism of the drug at D2-like dopamine receptors.9 Case report. Ms. A, a 71-year-old white woman with a history of pre-hypertension and paranoid schizophrenia, presented to the hospital in March 2006 with an abrupt change in her baseline mental status, noted skin flushing, and worsening tardive dyskinesia consisting of grimacing, tongue protrusion, lip sucking, and upper extremity choreiform movements. For the past 9 months, the patient had been taking aripiprazole at a dose of 15 mg daily, having only a subtle escalation of abnormal buccaloral muscle movements and upper arm athetosis in the 4 weeks preceding presentation. Eight days prior to her emergency department presentation, the patient's aripiprazole dose was decreased to 10 mg daily, and she was given a 1-week course of benztropine at 1 mg daily for these extrapyramidal reactions. A review of the patient's medication list revealed no other medications or supplements. On examination, Ms. A's rectal temperature was 106.5°F, her pulse was 137 beats per minute, her respiratory rate was 22 breaths per minute, and her blood pressure ranged from 99/54 mm Hg to 147/100 mm Hg. The patient was uncomfortable and in moderate distress. She exhibited marked muscle rigidity in addition to her obvious choreoathetoid movements. Her speech was initially slurred, but she became mute as her evaluation continued. There was a mild rise in her CPK level, which was initially 78 U/L and then increased to 103 U/L 8 hours later. Further studies revealed no leukocytosis, a normal complete metabolic panel, normal urine analysis, and brain computed tomography demonstrating only atrophic changes consistent with the patient's age. Given the patient's medical history and presentation, the diagnosis of NMS was made. Ms. A received intravenous hydration, cooling blankets, and ice packs applied to her axilla and groin. She was also given bromocriptine 2.5 mg every 8 hours, in addition to benztropine 1 mg daily. Aripiprazole treatment was stopped, and she was placed on treatment with lorazepam 1 to 2 mg as needed for the remainder of her hospitalization. The patient remained in the intensive care unit for 2 days awaiting stabilization of her autonomic lability and downward trend in CPK. She was then relocated to the medical ward, where, aside from mild tardive dyskinesia, she continued an uneventful recovery. Five days after her admission, the patient was transferred to a psychiatric hospital under the care of her psychiatrist. Neuroleptic agents have been shown to be highly effective and in general, safe, obtaining widespread use in medicine. However, it is imperative to note that all antipsychotics have been reported as having the ability to induce NMS, including rare reports of NMS caused by clozapine, olanzapine, and risperidone.10 This case presents a unique occurrence of one of the newest atypical antipsychotics, aripiprazole, causing NMS in an elderly patient. It is clear that, given this patient's medication history and clinical presentation, she would be classified as having moderate to severe NMS according to the neuroleptic-induced catatonia–neuroleptic malignant syndrome (NIC-NMS) scoring system proposed by Hynes and Vickar,11 shown in Table 1. In keeping with the concept of NIC-NMS as a single spectrum disorder, this patient would have scored 6, indicating moderate to severe NMS. Additionally, the NIC-NMS scoring system attributes additional severity based on CPK levels greater than 200 U/L. Although this patient's CPK peaked below this level, a likely explanation was the timely recognition of NMS. Her CPK levels would most likely have increased had there not been an abrupt discontinuation of aripiprazole in conjunction with early administration of bromocriptine to restore lost dopaminergic tone. It should also be noted that the use of serum CPK level as a major criterion for the diagnosis of NMS has been brought into question due to its lack of specificity.12–14 Nonetheless, assessing the patient for the presence of rhabdomyolysis, for which CPK is the most sensitive test, is an invaluable component in the assessment of NMS and its comorbidities.15,16 Table 1. Stages in Severity of Neuroleptic-Induced Catatonia–Neuroleptic Malignant Syndrome Spectruma NMS can be ambiguous in its presentation. It has been suggested that extreme temperature elevations and extrapyramidal symptoms occur less frequently in NMS attributed to atypical antipsychotics compared to conventional antipsychotics.10 Although infrequent, this case and 2 previously published cases of NMS in which pyrexia was absent illustrate that NMS can occur with aripiprazole.17,18 Further investigation is warranted to determine if the incidence of aripiprazole-induced NMS is greater than that of other atypical antipsychotics. Nonetheless, the roles of vigilance and patient education for those taking antipsychotic medications, whether typical or atypical, remain the key in averting the life-threatening complications of NMS. With the shortage of mental health services, the management of these patients is falling in the hands of primary care providers.19 It is vital that these providers be able to recognize NMS along with its causative agents and implement appropriate care.