TY - JOUR
AU - Brunetti,, Luigi
AB - Purpose A case of neuroleptic malignant syndrome (NMS) secondary to aripiprazole in a schizophrenic patient previously managed with clozapine is reported. Summary A 42-year-old Caucasian woman with a history of schizophrenia (chronic paranoid type) arrived at the emergency department (ED) with a chief complaint of altered mental status and oliguria. The patient was previously managed with clozapine for 14 years, which was well tolerated until the patient developed urinary retention. As a result, clozapine was gradually discontinued over several weeks. Aripiprazole 30 mg orally once daily was initiated four days before her arrival at the ED. Approximately four days after starting aripiprazole therapy, the patient began experiencing tremors, confusion, and rigidity. Physical examination revealed poor inspiratory effort, diffuse abdominal tenderness, and decreased muscle strength. Initial blood work confirmed acute renal failure and leukocytosis. The patient developed both hypokalemia and hypomagnesemia; her urine myoglobin level was suggestive of rhabdomyolysis. In light of her fever, encephalopathy, autonomic instability, elevated creatine kinase levels, and muscle rigidity, a diagnosis of NMS was made. Supportive care in the form of cooling blankets, electrolyte management, and blood pressure control was provided to the patient. Bromocriptine was also initiated to restore her dopamine balance. Twenty days after the initial presentation, the patient was initiated on paliperidone 3 mg orally at bedtime, which was slowly increased to 9 mg over several weeks. Follow-up evaluation demonstrated no signs or symptoms of NMS. Laboratory test values were also within normal limits. Conclusion A 42-year-old Caucasian woman with schizophrenia who could no longer tolerate therapy with clozapine developed NMS secondary to the initiation of aripiprazole. Antiparkinson agents, Antipsychotic agents, Aripiprazole, Bromocriptine, Clozapine, Neuroleptic malignant syndrome, Paliperidone, Schizophrenia, Toxicity Neuroleptic malignant syndrome (NMS), first described by Delay et al.1 in 1960, is a rare, potentially life-threatening condition, occurring in 0.02–3.23% of psychiatric inpatients receiving neuroleptic agents.2 Neuroleptic agents, particularly early-generation, high-potency antipsychotics, have often been implicated in NMS. More recently, atypical antipsychotics have also been identified as potential culprits.2 Patients with NMS typically have muscle rigidity (“leadpipe rigidity”), hyperthermia (temperature of >38 °C), altered mental status, and autonomic instability.3 Temperature elevations may not be present in NMS induced by atypical antipsychotics.4 Laboratory test values often reveal leukocytosis, metabolic acidosis, electrolyte abnormalities (hypocalcemia, hypomagnesemia, hypokalemia), coagulopathies, and elevations in serum creatine kinase (CK).3 Complications may include acute renal failure precipitated by rhabdomyolysis, venous thromboembolism, multiple-system failure, aspiration pneumonia, and coma.3,5 NMS is believed to result from dopamine depletion in the central nervous system (CNS). Many medications have the capability of disrupting the dopamine balance in the CNS (Figure 1).5 Symptoms may be related to the site of dopaminergic blockade or depletion: hyperthermia (anterior hypothalamus), muscle contraction (corpus striatum), altered mental status (basal ganglia), and autonomic instability (spinal cord).5 In addition, serotonin and other neurotransmitters, such as gamma-aminobutyric acid and acetylcholine, may be involved.2,6 Muscle rigidity and altered mental status often precede hyperthermia and autonomic dysfunction.7 Risk factors include a high neuroleptic dosage, rapid dosage adjustment, and intramuscular administration of the neuroleptic agent.8 The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), defines NMS as severe muscle rigidity and hyperthermia (core features) associated with the use of antipsychotic agents.9 In addition, two or more of the following symptoms must be present: diaphoresis, dysphagia, tremors, incontinence, altered mental status, mutism, tachycardia, increased or labile blood pressure, leukocytosis, and muscle injury (evidenced by elevated CK levels). There have been concerns that the DSM-IV criteria are too stringent for diagnosing atypical-antipsychotic-induced NMS and may result in delayed recognition and treatment; however, these criteria are widely used in both research and clinical settings.10 Another set of criteria, the Sachdev11 NMS rating scale, offers clinicians a tool to grade the severity of disease as well as monitor patient progress. Ultimately, a diagnosis of NMS is generally one of exclusion. Treatment consists of supportive care and frequent monitoring of blood pressure, cardiac rhythm, and arterial oxygen saturation of functional hemoglobin. Hyperthermia is managed with cooling blankets. Urinary alkalization and i.v. hydration may assist in preventing renal failure. I.V. fluids and parenteral nutrition are often required due to respiratory distress and dysphagia. Venous thromboembolism prophylaxis is prudent, as the risk is heightened in this population. Bromocriptine, a centrally acting dopamine agonist, may aid in restoring dopamine balance. Dantrolene or benzodiazepines may have a role in managing muscle rigidity, which in turn reduces fever.12 We report a case of aripiprazole-induced NMS in a patient previously managed with clozapine. Case report A 42-year-old Caucasian woman with a history of schizophrenia (chronic paranoid type, diagnosed at age 15) arrived at the emergency department (ED) in 2008 with a chief complaint of altered mental status and oliguria. For the past 14 years she had been managed with clozapine and was attending individualized outpatient psychosocial therapy twice weekly. These treatments allowed her to function well and live independently in her own apartment. Her medical history also included hypertension, diabetes mellitus, obesity (body mass index, 37.7 kg/m2; weight, 109 kg; height, 170 cm), and seasonal allergies. Her home medications included the following, all of which were taken orally: clozapine 125 mg daily, divalproex sodium 1000 mg in the morning and 500 mg in the evening, pioglitazone hydrochloride 30 mg daily, amlodipine besylate 10 mg daily, glyburide 2.5 mg daily, enalapril maleate 10 mg daily, hydrochlorothiazide 25 mg daily, and fexofenadine hydrochloride 60 mg daily. Clozapine therapy was well tolerated until recently, when the patient reported urinary retention. As a result, clozapine was gradually discontinued over several weeks. Aripiprazole 30 mg orally once daily was initiated four days before her arrival at the ED. The patient’s family reported a decline in her mental status shortly after the initiation of aripiprazole. They stated that she had become confused, lethargic, and tremulous, adding that she was often staring into space and talking to herself, had a suppressed appetite, and was most likely hearing voices. The patient was catatonic upon arrival at the ED. Additional symptoms included chills, diaphoresis, extremity weakness, and muscle rigidity. The patient’s vital signs in the ED were as follows: temperature, 101.2 °F; heart rate, 111 beats/min; respiratory rate, 20 breaths/min; and blood pressure, 175/87 mm Hg. Pulse oximetry revealed an oxygen saturation of 92% on room air. A physical examination revealed poor inspiratory effort, diffuse abdominal tenderness, and decreased muscle strength. Initial laboratory test values confirmed acute renal failure, with a blood urea nitrogen concentration of 31 mg/dL (normal range, 7–18 mg/dL) and a serum creatinine concentration of 1.7 mg/dL (normal range, 0.8–1.3 mg/dL). Leukocytosis was present (white blood cell count, 15,300 cells/μL [normal range, 4,000–10,000 cells/μL]). The patient developed both hypokalemia (serum potassium, 3.2 mmol/L [normal range, 3.5–5.1 mmol/L]) and hypomagnesemia (serum magnesium, 1.3 mg/dL [normal range, 1.5–2.1 mmol/L]). A urine toxicology screen yielded negative results. Urine myoglobin levels were elevated, suggestive of rhabdomyolysis. The patient was admitted to the general medical floor and aggressively hydrated with i.v. fluids. Bilateral costophrenic angle blunting and questionable in-filtrates were identified on her chest radiograph, supporting the initiation of empirical levofloxacin for possible pneumonia. In an effort to control the patient’s blood pressure, home blood pressure medications were restarted. A computed tomography (CT) scan of the head was negative for bleeding. The psychiatry department was consulted and recommended that all of her psychiatric medications be held except for lorazepam for agitation and anxiety. She was placed on one-to-one observation as a safety precaution due to her erratic behavior. During her first night of hospital admission, she developed increasing dyspnea with productive cough and wheezing. Her oxygen requirements increased to 50% fraction of inspired oxygen via a Venturi mask. Acute respiratory distress was thought to be secondary to dysphagia with subsequent development of aspiration pneumonia. Aspiration precautions were put into effect. Pulmonary embolus and deep venous thrombosis were ruled out with a CT angiogram of the chest and lower-extremity venous Doppler studies, respectively. On hospital day 2, the neurology department was consulted. At this time, the patient’s CK levels were critically elevated (2989 units/L; normal range, 35–232 units/L) and her CK-MB isoenzyme level was high (15.5 ng/mL; normal range, 0–3.6 ng/mL). In light of her fever, encephalopathy, autonomic instability, elevated CK level, and muscle rigidity, the patient was diagnosed with NMS. On hospital day 3, the patient was transferred to the intensive care unit for closer monitoring due to her autonomic instability and deteriorating condition. Bromocriptine mesylate 5 mg via nasogastric tube three times daily was ordered in an effort to restore her dopamine balance. Hyperthermia was aggressively managed with cooling blankets to maintain a temperature below 100.5 °F. CK levels were monitored daily and responded well to i.v. fluids and bromocriptine. On hospital day 5, muscle rigidity was noticeably decreased, and bedside physical therapy was initiated. The next day, her hospital course was complicated by severe lower-extremity pain secondary to muscle damage, which required pharmacologic management. Over the next several days, the patient’s mental status continued to improve, and she eventually was able to walk with assistance. Approximately 15 days after she was admitted to the hospital, her muscle rigidity and autonomic instability resolved, and her CK levels normalized. Her pain medications were tapered as her lower-extremity pain subsided. Bromocriptine was slowly tapered as her mental status returned to baseline. When medically cleared, the patient was transferred to the psychiatric ward. Twenty days after her arrival at the ED, paliperidone 3 mg orally at bedtime was initiated and slowly increased to 9 mg at bedtime over several weeks. Neuroleptic rechallenge with an alternative agent, paliperidone, was tolerated well. Follow-up evaluation demonstrated no signs or symptoms of NMS. Laboratory test values were also within normal limits. Divalproex sodium was also restarted (level at discharge was 90.2 μg/mL), and the patient was discharged on benztropine mesylate and venlafaxine hydrochloride in addition to her previous maintenance medications. The duration of her hospital stay (medical and psychiatric floors) was 30 days. After discharge, the patient’s clinical status was observed closely, and periodic CK testing has confirmed the success of rechallenge with paliperidone. Discussion Aripiprazole, an atypical antipsychotic, has a relatively benign safety profile. Common adverse effects include headache, agitation, anxiety, insomnia, akathisia, asthenia, extrapyramidal reactions, and tremor.13 Compared with other antipsychotics, aripiprazole appears to offer the clinician an excellent choice, with negligible anticholinergic effects, weight gain, and hyperprolactinemia—symptoms commonly seen with other agents.14 The exact mechanism of action of aripiprazole remains unknown; however, similar to other atypical antipsychotics, it displays activity at dopamine (D2), serotonin type 1 (5-HT1A), and serotonin type 2 (5-HT2A) receptors. Unlike other atypical antipsychotics, aripiprazole displays partial agonism at the D2 and 5-HT1A receptors and antagonism at 5-HT2A receptors. Activity at the α1-adrenergic and histamine H1 receptors (antagonism) may be responsible for the drug’s therapeutic benefit and its toxicity. Its unique mechanism, specifically its partial D2 agonism, has been touted to limit the development of hypodopaminergic states15; therefore, the development of NMS in aripiprazole-treated patients should be limited. A total of 15 cases of aripiprazole-induced NMS have been published, including our case.6,16–28 The 14 cases published elsewhere are summarized in Table 1. The Naranjo et al.29 adverse-drug-reaction probability scale was applied to our case and revealed that the likelihood of an association between aripiprazole and NMS was possible (score of 4). There is a wide range of severity among the case reports published when evaluated using the Sachdev11 scale, with the current case representing the highest symptom severity reported to date (19). The majority of case reports met the DSM-IV criteria for NMS. There have been concerns raised due to the inconsistencies of several case reports and the overlap of NMS symptomatology with other comorbidities, particularly catatonia.30,31 There may be nondrug causes of NMS; however, case reports implicating atypical antipsychotics as the likely cause continue to surface. Our patient shares similar characteristics with several of the previously reported aripiprazole-induced NMS cases, particularly previous intolerance to antipsychotics or switching to a new agent. Our patient could no longer tolerate therapy with clozapine and was switched to aripiprazole. Approximately 47% of patients reported to develop NMS secondary to aripiprazole have not responded to a previous antipsychotic or switched from another antipsychotic. It is critical for clinicians to be aware of factors contributing to an increased risk in order to place NMS high on the list of differential diagnoses in patients exhibiting symptoms consistent with NMS. This will avoid unnecessary delays in the recognition and treatment of NMS, a complication with mortality rates as high as 20%.32 Our case also provides further evidence that NMS involves a more complex mechanism than dopamine depletion alone, since aripiprazole is a partial dopamine agonist. This notion is further strengthened with evidence that even the weakest dopamine antagonist, clozapine, has also been reported to cause NMS.33 Although there has been a report of NMS with paliperidone,34 neuroleptic rechallenge with paliperidone was successful in our patient. Why patients develop NMS with one antipsychotic and not another remains to be elucidated. A genetic component may explain increased susceptibility by some individuals.35 Patients who are homozygous for a mutated CYP2D6 J allele (poor metabolizers) may be at an increased risk of NMS.36 Many of the agents that have been implicated in NMS are substrates of cytochrome P-450 isoenzyme (CYP) 2D6, including aripiprazole and clozapine. Although paliperidone is a substrate of CYP2D6, there have been no differences identified in the pharmacokinetics of paliperidone between extensive metabolizers and slow metabolizers of CYP2D6.37 Inhibition of CYP2D6 may result in increased concentrations of aripiprazole, thereby conferring an increased risk. This was not an issue in our patient, as she was not on concurrent therapy with a CYP2D6 inhibitor; however, it would be of value to further research the role of CYP2D6 inhibition or polymorphisms in NMS. Some researchers have speculated that agents with less dopamine antagonism may be less likely to cause NMS.15 The current case does not support this theory. Although aripiprazole is thought to be a dopamine stabilizer, reports of this antipsychotic as the mitigating agent in NMS continue to surface. Further research is warranted to determine why certain patients can tolerate some antipsychotics but are unable to tolerate others. Conclusion A 42-year-old Caucasian woman with schizophrenia who could no longer tolerate therapy with clozapine developed NMS secondary to the initiation of aripiprazole. Figure and Table Figure 1 Open in new tabDownload slide The impact of medications on dopamine balance in the central nervous system at both the presynaptic and postsynaptic levels. DA = dopamine, D2 = dopamine type 2, COMT = catechol O-methyltransferase, 3-MT = 3-methoxytyramine, HVA = homovanillic acid, MAO = monoamine oxidase. Reprinted from reference 5, with permission. Copyright © 2004 Elsevier. Figure 1 Open in new tabDownload slide The impact of medications on dopamine balance in the central nervous system at both the presynaptic and postsynaptic levels. DA = dopamine, D2 = dopamine type 2, COMT = catechol O-methyltransferase, 3-MT = 3-methoxytyramine, HVA = homovanillic acid, MAO = monoamine oxidase. Reprinted from reference 5, with permission. Copyright © 2004 Elsevier. Table 1 Published Cases of Aripiprazole-Induced Neuroleptic Malignant Syndrome (NMS)a Ref. Patient Age and Sex Aripiprazole Dosage (mg/day) Time to NMS Onset (Days) Concomitant Psychoactive Medications DSM-IV Criteria for NMS Met? Sachdev11 NMS Rating Scale Scoreb 6 43 yr, male 30 14 Fluoxetine Yes 8 16 42 yr, male 30 ~9 Quetiapinec No 7 17 17 yr, male 15 3 Benztropined Yes 15 18 23 yr, female 30 14 Methamphetamine dependence Yes 9 19 19 yr, male 30 21 Lithium Yes 11 20 25 yr, male NA 7 Escitalopramd No 13 21 34 yr, male 15 67 Olanzapine,c lorazepam, flunitrazepam, benztropine Yes 18 22 14 yr, female 5 2 Quetiapinec,d No 14 23 18 yr, female Overdose 0.5 None reported Yes 15 24 57 yr, female 10 2 None reported Yes 14 25 43 yr, male 15 22 Risperidonec Yes 14 26 12 yr, male 10 2 Methylphenidate Yes . . .e 27 71 yr, female 15 270 None reported Yes 15 28 33 yr, male 10 ~45 Olanzapine, benztropine Yes 9 Ref. Patient Age and Sex Aripiprazole Dosage (mg/day) Time to NMS Onset (Days) Concomitant Psychoactive Medications DSM-IV Criteria for NMS Met? Sachdev11 NMS Rating Scale Scoreb 6 43 yr, male 30 14 Fluoxetine Yes 8 16 42 yr, male 30 ~9 Quetiapinec No 7 17 17 yr, male 15 3 Benztropined Yes 15 18 23 yr, female 30 14 Methamphetamine dependence Yes 9 19 19 yr, male 30 21 Lithium Yes 11 20 25 yr, male NA 7 Escitalopramd No 13 21 34 yr, male 15 67 Olanzapine,c lorazepam, flunitrazepam, benztropine Yes 18 22 14 yr, female 5 2 Quetiapinec,d No 14 23 18 yr, female Overdose 0.5 None reported Yes 15 24 57 yr, female 10 2 None reported Yes 14 25 43 yr, male 15 22 Risperidonec Yes 14 26 12 yr, male 10 2 Methylphenidate Yes . . .e 27 71 yr, female 15 270 None reported Yes 15 28 33 yr, male 10 ~45 Olanzapine, benztropine Yes 9 a DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; NA = not available. b Maximum score of 36; higher scores indicate greater severity. Scores are estimates based on available information in case reports. c Discontinued upon aripiprazole initiation. d Patient did not respond to at least one previous antipsychotic. e Not enough information to score. Open in new tab Table 1 Published Cases of Aripiprazole-Induced Neuroleptic Malignant Syndrome (NMS)a Ref. Patient Age and Sex Aripiprazole Dosage (mg/day) Time to NMS Onset (Days) Concomitant Psychoactive Medications DSM-IV Criteria for NMS Met? Sachdev11 NMS Rating Scale Scoreb 6 43 yr, male 30 14 Fluoxetine Yes 8 16 42 yr, male 30 ~9 Quetiapinec No 7 17 17 yr, male 15 3 Benztropined Yes 15 18 23 yr, female 30 14 Methamphetamine dependence Yes 9 19 19 yr, male 30 21 Lithium Yes 11 20 25 yr, male NA 7 Escitalopramd No 13 21 34 yr, male 15 67 Olanzapine,c lorazepam, flunitrazepam, benztropine Yes 18 22 14 yr, female 5 2 Quetiapinec,d No 14 23 18 yr, female Overdose 0.5 None reported Yes 15 24 57 yr, female 10 2 None reported Yes 14 25 43 yr, male 15 22 Risperidonec Yes 14 26 12 yr, male 10 2 Methylphenidate Yes . . .e 27 71 yr, female 15 270 None reported Yes 15 28 33 yr, male 10 ~45 Olanzapine, benztropine Yes 9 Ref. Patient Age and Sex Aripiprazole Dosage (mg/day) Time to NMS Onset (Days) Concomitant Psychoactive Medications DSM-IV Criteria for NMS Met? Sachdev11 NMS Rating Scale Scoreb 6 43 yr, male 30 14 Fluoxetine Yes 8 16 42 yr, male 30 ~9 Quetiapinec No 7 17 17 yr, male 15 3 Benztropined Yes 15 18 23 yr, female 30 14 Methamphetamine dependence Yes 9 19 19 yr, male 30 21 Lithium Yes 11 20 25 yr, male NA 7 Escitalopramd No 13 21 34 yr, male 15 67 Olanzapine,c lorazepam, flunitrazepam, benztropine Yes 18 22 14 yr, female 5 2 Quetiapinec,d No 14 23 18 yr, female Overdose 0.5 None reported Yes 15 24 57 yr, female 10 2 None reported Yes 14 25 43 yr, male 15 22 Risperidonec Yes 14 26 12 yr, male 10 2 Methylphenidate Yes . . .e 27 71 yr, female 15 270 None reported Yes 15 28 33 yr, male 10 ~45 Olanzapine, benztropine Yes 9 a DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; NA = not available. b Maximum score of 36; higher scores indicate greater severity. Scores are estimates based on available information in case reports. c Discontinued upon aripiprazole initiation. d Patient did not respond to at least one previous antipsychotic. e Not enough information to score. Open in new tab Footnotes The authors have declared no potential conflicts of interest. References 1 Delay J Pichot P Lemperiere T et al. . [ A non-phenothiazine and non-reserpine major neuroleptic, haloperidol, in the treatment of psychoses .] Ann Med Psychol . 1960 ; 118 : 145 – 52 . In French . WorldCat 2 Pelonero AL Levenson JL Pandurangi AK . Neuroleptic malignant syndrome: a review . Psychiatr Serv . 1998 ; 49 : 1163 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Caroff SN . The neuroleptic malignant syndrome . Med Clin N Am . 1993 ; 77 : 185 – 202 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Caroff SN Mann SC Campbell C . Atypical antipsychotics and neuroleptic malignant syndrome . Psychiatr Ann . 2000 ; 5 : 314 – 21 . 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TI - Neuroleptic malignant syndrome secondary to aripiprazole initiation in a clozapine-intolerant patient
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp090243
DA - 2010-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/neuroleptic-malignant-syndrome-secondary-to-aripiprazole-initiation-in-Pj8v0S8Emv
SP - 1254
VL - 67
IS - 15
DP - DeepDyve
ER -