Severe Neuroleptic Malignant Syndrome Research Articles

The neuroleptic malignant syndrome—a systematic case series analysis focusing on therapy regimes and outcome

Neuroleptic malignant syndrome (NMS) is a rare, potentially life-threatening antipsychotic-associated disorder that requires an efficient and timely therapy. The aim of the study was to compare the effectiveness of different NMS therapies and to analyze its outcome depending on NMS severity. Systematic search for NMS cases in biomedical databases. The focus of the analysis was on therapy with dantrolene, bromocriptine, and electroconvulsive therapy (ECT) when each was compared with symptomatic therapy. Primary outcomes were the survival rate and the duration of treatment. 405 case reports were included. Overall, no statistically significant differences regarding mortality rate or duration of treatment were found between dantrolene, bromocriptine, or ECT compared to supportive care. A subgroup analysis regarding NMS severity showed that the mortality under specific NMS pharmacotherapy (dantrolene, bromocriptine) and under ECT was significantly lower than under purely symptomatic therapy in severe NMS (P=0.018). The difference was not significant in mild and moderate cases. An overall superiority of the specific NMS therapy (dantrolene, bromocriptine, and ECT) was not found in this study. When regarding severity classification, specific therapies were superior but only in severe cases, and ECT showed the lowest mortality rate. In previous case series, an effect on survival or the duration of the disease could only be observed in part for specific therapies, but the evidence available is inconsistent. The results of this study support our hypothesis that NMS treatment with dantrolene, bromocriptine, and ECT is advantageous over purely symptomatic therapy in severe NMS cases.

Treatment of moderate neuroleptic malignant syndrome

Dear Editor, I read with interest the case presented by Petrone et al. published in your journal.1 The authors reported moderate to severe neuroleptic malignant syndrome (NMS) in a 63-year-old woman with depression after the administration of low-dose aripripazole for 12 days in addition to her previous treatment. However, I have some concerns about the management of NMS in this patient. They stopped all the patient’s medications and gave her only intravenous hydration for the management of NMS. After 12 days, the clinical condition of their patient showed improvement. It should be mentioned that the treatment algorithm for NMS proposed by Woodbury2 suggests that in moderate NMS cases first-line interventions may include the administration of lorazepam, bromocriptine, or amantadine, as well as the discontinuation of the antipsychotic medications and supportive therapy. If moderate NMS was diagnosed, why were the above-mentioned drugs not considered for this patient? It seems that these drugs are associated with faster recovery compared with supportive treatment alone.3Also, there is a published report of a patient with moderate NMS who has shown rapid response to intravenous valproate.4 What do the authors think about these treatment options that have not been considered in this case? References

Life-Threatening Hypocalcemia with Denosumab; Anaphylaxis in Two Children Receiving Etanercept; Fondaparinux Hepatotoxicity in a 6-Year-Old Child; Bullous Pemphigoid Induced by Dipeptidyl Peptidase-4 Inhibitors; Severe Neuroleptic Malignant Syndrome with Deep Coma Associated with Aripiprazole; Quetiapine-Induced Tardive Oculogyric Crisis

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers.

A Case of Neurotoxic Syndrome With the Use of Long-Acting Risperidone and Subsequent Olanzapine and Paroxetine

To the Editor: Administration of medications that affect brain dopamine and serotonin neurotransmission are occasionally associated with neurotoxic, behavioral, and autonomic syndromes, variously described as the neuroleptic malignant syndrome (NMS) and the toxic serotonin syndrome.1 We describe such a syndrome with the use of long-acting risperidone and subsequent olanzapine and paroxetine. Case report. Ms A, a 38-year-old woman, presented to our emergency department in 2009 for difficulty with swallowing and talking and profound drooling of saliva. She had a history of paranoid schizophrenia and amphetamine and heroin dependence and had had a severe head injury 15 months previously for which she underwent temporal craniectomy (with evidence of a right temporal lobe gliosis on follow-up computed tomography scans). For the past year, she was being treated with long-acting risperidone injection 37.5 mg intramuscularly every 2 weeks, lithium carbonate 250 mg bid, and oral risperidone 3 mg, taken at night. She was observed to have extrapyramidal symptoms, which were treated with benztropine. In an attempt to reduce these symptoms, these medications were stopped, and she was prescribed olanzapine 10 mg, taken at night, and paroxetine 20 mg, taken in the morning. Benztropine was continued. Over the next month, she developed progressive dysphagia, severe sialorrhea, occasional low-grade fever, frequent and profuse sweating, unsteadiness of gait, falls, and progressively slowed movements. Over the course of hospitalization, we observed the following: muscle rigidity (lead-pipe, all 4 extremities), coarse tremors of the hands, tachycardia, labile blood pressure, severe nausea, and tongue fasciculations. She had no cognitive, psychotic, or affective symptoms. There was no evidence of agitation, myoclonus, hyperreflexia, incoordination, shivering, or diarrhea (Sternbach criteria for serotonin syndrome2). Findings of laboratory investigations were all within normal limits except for mildly elevated liver function tests. Serum creatine kinase level was 40 U/L. She met DSM-IV research criteria for NMS (333.92).3 She was treated with benztropine 4 mg/d, and all other medications were stopped. All symptoms resolved within 8 days. Two days prior to discharge, she had paranoid thinking. In light of her history and emerging symptoms, olanzapine 5 mg at night was instituted. There was no reemergence of physical or psychiatric symptoms on follow-up. This case provides several insights into the symptomatology and pathophysiology of NMS and serotonin syndrome. The patient developed NMS/serotonin syndrome symptoms on treatment with a combination of paroxetine and olanzapine. There were no features of NMS/serotonin syndrome in the preceding months when she was being treated with oral and depot risperidone and lithium carbonate, although she did have significant extrapyramidal symptoms. The patient met DSM-IV criteria for NMS. However, she did not have the symptoms of severe NMS, such as a marked creatine phosphokinase elevation, hyperthermia, and an altered sensorium. The fact that she was on treatment with an atypical antipsychotic and that her symptoms were detected early probably accounted for this. Several of the patient's symptoms could also be explained by a serotonin syndrome.1 Nausea, for example, is not a typical feature of NMS but is frequently seen in serotonin syndrome. Abrupt discontinuation of antipsychotic treatment is a well-recognized although rare predisposing factor for the development of NMS. Although her medications were stopped, the patient was on depot risperidone treatment and would have had therapeutic plasma concentrations for several weeks. Risperidone has high antagonistic D2 receptor affinity, and the institution of olanzapine would have had a similar effect, although olanzapine is a relatively weaker D2 antagonist than risperidone.4 This would have resulted in a hypodopaminergic state, which is one of the postulated mechanisms for the development of NMS.5 Paroxetine is a potent and specific inhibitor of 5-HT reuptake,6 whereas olanzapine has high antagonistic affinity at 5-HT2A receptors and low agonistic affinity at 5-HT1A receptors.4 This would have resulted in significantly increased serotonergic neurotransmission at the 5-HT1A receptor. Hyperstimulation of the 5-HT1A receptor in the brain stem and spinal cord has been implicated in the pathophysiology of both the serotonin syndrome and NMS.7 In addition, there is substantial evidence that the serotonin system inhibits dopaminergic function at the level of the origin of the dopamine system in the midbrain as well as at the terminal dopaminergic fields in the forebrain.8 Furthermore, studies suggest that traumatic brain injury patients show an increase in serotonergic and noradrenergic neurotransmission and a dysfunction in mesolimbic and mesocortical dopaminergic neurotransmission.5,9 The net effect of all these actions in this patient would have been a greatly increased serotonergic neurotransmission and a greatly decreased dopaminergic neurotransmission. This could explain the pathophysiology of the toxidrome in this case and explain the symptom overlap between NMS and serotonin syndrome that this patient displayed. This case highlights the need for caution and vigilance in the use of selective serotonin reuptake inhibitor–atypical antipsychotic combinations, particularly in patients with preexisting brain injury.

Intensivmedizinisches Management des malignen neuroleptischen Syndroms – Literaturübersicht mit Fallbeispiel

We report a case of severe neuroleptic malignant syndrome developing in a 28-year-old female patient following deliberate self-poisoning with atypical antipsychotic drugs and serotonin reuptake inhibitors. Because of an increasing loss of consciousness she was rapidly transferred to an Intensive Care Unit. Following this, she became progressively febrile associated with rhabdomyolysis and life-threatening organ dysfunctions. Due to fast diagnosis and immediate therapy the patient was treated successfully. This article describes etiology, pathophysiology and symptoms of neuroleptic malignant syndrome. In addition therapeutic options are discussed.

Problems in three Japanese drug users with Human Immunodeficiency Virus infection

Numbers of individuals infected with Human Immunodeficiency Virus (HIV) are increasing in Japan. The majority of them are Men who have sex with men and a part of them take drugs as 'Sex drug' at their sexual intercourse. Especially, Amyl nitrite, Methamphetamine, 5-methoxy-N, N-diisopropyltryptamine (5-MeO-DIPT; Foxy), and 3, 4-methylenedioxy- methamphetamine (MDMA; Ecstasy) are used, and they sometimes cause the physical and mental disorders. However, the actual drug inducing troubles among Japanese HIV-infected drug users had not yet been discussed enough. In this report, we describe three cases with HIV infection; a case developed severe neuroleptic malignant syndrome (NMS) after taking 5-MeO-DIPT, a case with persistent convulsion due to multiple drug intake and a case with rhabdomyolysis due to the non-subjective methamphetamine intake. Through these cases, we raise and discuss several underlying problems associated with drug use among HIV-infected individuals.

Endovascular cooling in a patient with neuroleptic malignant syndrome

We report a case of severe neuroleptic malignant syndrome with hyperthermia, rhabdomyolysis and hepatic failure where we applied endovascular cooling in order to reverse hyperthermia. After rapid normalization of core temperature at 37.5 degrees C, the patient's condition improved and CK levels dropped. However, upon withdrawl of endovascular temperature control there was a relapse. This is the first case where endovascular cooling was applied successfully in neuroleptic malignant syndrome.

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome

Aripiprazole as the Causative Agent of Neuroleptic Malignant Syndrome

Aripiprazole as the Causative Agent of Neuroleptic Malignant Syndrome

Possible Neuroleptic Malignant Syndrome With Aripiprazole and Fluoxetine

Back to table of contents Previous article Next article Letter to the EditorFull AccessPossible Neuroleptic Malignant Syndrome With Aripiprazole and FluoxetineHARPREET S. DUGGAL, M.D., D.P.M., and JOSEPH KITHAS, M.D., HARPREET S. DUGGALSearch for more papers by this author, M.D., D.P.M., and JOSEPH KITHASSearch for more papers by this author, M.D., Pittsburgh, Pa.Published Online:1 Feb 2005https://doi.org/10.1176/appi.ajp.162.2.397-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: There are rare reports of neuroleptic malignant syndrome occurring with a combination of atypical antipsychotics and selective serotonin reuptake inhibitors (1). We describe a similar case with a combination of aripiprazole and fluoxetine.Mr. A, a 43-year-old man, was admitted to our hospital with severe depression and psychotic symptoms. Three weeks before, he had been admitted to a different hospital for similar symptoms and had been given bupropion and risperidone, titrated up to 150 mg/day and 1 mg/day, respectively. However, for unapparent reasons, these medications were discontinued abruptly after a week, and Mr. A was given aripiprazole, started at 30 mg/day, and fluoxetine, 20 mg/day. A week later, Mr. A was discharged from the hospital with the same regimen. Subsequently, after taking these medications for about 2 weeks, Mr. A came to us with complaints of muscle stiffness, restlessness, and fever of a week’s duration. In addition, he also had depressive and some psychotic symptoms, but his family’s predominant concern was his physical symptoms.Upon examination, Mr. A exhibited marked psychomotor retardation, mask-like facies, and severe rigidity, with cog-wheeling, sialorrhea, tremors, and akathisia. He had fever (99.8°F), labile blood pressure (148/99–137/89 mm Hg), and tachycardia (110 bpm). He was fully oriented and did not display any cognitive deficits. Laboratory investigations revealed elevated creatine phosphokinase (248 IU/liter; normal range=0–200) and alanine aminotransferase (61 IU/liter; normal range=0–35) levels, whereas the results of renal function tests, a CBC, and a urine examination were normal. Although Mr. A had stopped taking aripiprazole 2 days before he came to visit us, his symptoms had shown little improvement. Fluoxetine was discontinued, and Mr. A was treated symptomatically with benztropine and acetaminophen and had an uneventful recovery within a week, with his creatine phosphokinase level returning to normal (138 IU/liter).Although this patient had the core symptoms of neuroleptic malignant syndrome, including rigidity, fever, and autonomic instability and met the DSM-IV criteria for neuroleptic malignant syndrome, the symptoms of severe neuroleptic malignant syndrome, such as a marked creatine phosphokinase elevation, hyperthermia, and an altered sensorium, were absent. Early recognition of this condition, the use of an atypical antipsychotic (aripiprazole), and the patient’s discontinuation of aripiprazole may have contributed to his mild presentation of neuroleptic malignant syndrome. Serotonin syndrome, another differential in this case, cannot be ruled out, but the patient did not exhibit autonomic features, such as hyperhidrosis and diarrhea, or muscular signs, such as hyperreflexia and myoclonus, which are typical of this syndrome. The Physicians’ Desk Reference documents that two “possible” cases of neuroleptic malignant syndrome occurred during aripiprazole treatment in a premarketing worldwide clinical database, although we found no reports of neuroleptic malignant syndrome occurring with aripiprazole on PUBMED. Given that aripiprazole is a functional dopamine receptor agonist in a hypodopaminergic state (as occurs in neuroleptic malignant syndrome), the presentation of this syndrome may be different from other atypical antipsychotics. Serotonin 5-HT1A agonism, another hypothetical mechanism for neuroleptic malignant syndrome (2), can also be implicated in this case because aripiprazole is a partial agonist at this receptor. Of interest, this is also the mechanism underlying serotonin syndrome (3), and both neuroleptic malignant syndrome and serotonin syndrome have been considered under the rubric of catatonic syndromes (4). Although fluoxetine (an inhibitor of CYP2D6) alone has been associated with neuroleptic malignant syndrome (5), it may have further increased levels of aripiprazole (which is metabolized by CYP2D6). This, compounded with the altered dopamine balance due to abrupt withdrawal of risperidone, may have made the patient more vulnerable to neuroleptic malignant syndrome, as supported by reports of neuroleptic malignant syndrome after withdrawal of atypical antipsychotics (6).

Lebensbedrohliches malignes neuroleptisches Syndrom unter Olanzapin

The frequency of neuroleptic malignant syndrome (NMS) after clozapine or olanzapine is low and often of non-serious nature. A 49 year-old female patient developed NMS 12 days after olanzapine re-exposure. Olanzapine was stopped, the patient was transferred to an ICU and received a course of nine uni- and bilateral ECT treatments. This led to remission. 14 months earlier the patient had presented with a first severe NMS episode after haloperidol depot injection and 4 days after starting oral clozapine. Following the first NMS episode olanzapine (20 mg per day) was administered for 11 months without adverse effects.

Efficacy of Prolonged Large-Dose Dantrolene for Severe Neuroleptic Malignant Syndrome

TSUJIMOTO, SABURO; MAEDA, KAYOKO; SUGIYAMA, TOMOHIRO; YOKOCHI, AYUMU; CHIKUSA, HIROAKI; MARUYAMA, KAZUO Author Information

Electroconvulsive treatment of neuroleptic malignant syndrome: a review and report of cases

Objective: Neuroleptic malignant syndrome (NMS) is a potentially lethal adverse effect of neuroleptic medication, with no satisfactory treatment currently available. Electroconvulsive therapy (ECT) has been anecdotally reported to be effective in its treatment. We review 45 published case reports of ECT for NMS and describe nine new cases, to examine its effectiveness, the likelihood of adverse reactions, and the theoretical implications of such treatment. Method: The authors used Medline to identify reports in the English literature where ECT was used in cases of suspected NMS. In addition, the charts of patients referred to the second author for treatment of NMS were reviewed and cases in which ECT used were identified. Results: The case reports suggest that ECT is effective in many individuals with NMS, even when drug therapy has failed. The response is usually apparent after a few treatments, generally up to six. The response is not predictable on the basis of age, gender, psychiatric diagnosis or any particular feature of NMS including catatonia. Electroconvulsive therapy is a relatively safe treatment in NMS, although the risk of cardiovascular complications should be considered. Malignant hyperthermia due to the anaesthesia associated with ECT has not been reported in patients with NMS, and succinylcholine has been used safely with the exception of one report of fever and raised creatine kinase levels and another report of hyperkalemia. Conclusions: Electroconvulsive therapy is the preferred treatment in severe NMS, cases where the underlying psychiatric diagnosis is psychotic depression or catatonia, and in cases where lethal catatonia cannot be ruled out. The effectiveness of ECT for the treatment of NMS has theoretical implications for the relationship between NMS and catatonia, and the possible pathophysiological mechanisms that underlie these disorders.

Efficacy of Prolonged Large-Dose Dantrolene for Severe Neuroleptic Malignant Syndrome

Efficacy of Prolonged Large-Dose Dantrolene for Severe Neuroleptic Malignant Syndrome