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Hopefully, neuroleptic malignant syndrome is not something we all see every day. Is there a treatment one should consider beyond medical supportive care?
Hi! Jim Phelps here for the Psychopharmacology Institute. Here’s a reminder of some of the basics about neuroleptic malignant syndrome and its treatment approaches. Of course, we associate neuroleptic malignant syndrome—NMS—with antipsychotics, as what the name implies. Rarely, it can also be caused by antidepressants and metoclopramide—which, of course, is an antipsychotic of sorts—and by abrupt discontinuation of dopamine agonists in the treatment of Parkinson’s disease. Risk factors include dehydration, malnutrition, agitation, the use of first-generation antipsychotics, parenteral antipsychotics, and comedication with lithium. The last on that list of factors are preexisting organic brain damage, alcohol and drug addiction, and, of course, a history of NMS.
What causes NMS? Unfortunately, that is still largely a mystery. Acute dopaminergic hypoactivity is still assumed to be the crucial pathophysiologic factor. Some researchers consider NMS and malignant catatonia to be 2 disorders on the same spectrum since they feature a number of important overlapping symptoms—including immobility, mutism, and rigidity—as well as similar treatment response to benzodiazepines and ECT. Differential diagnoses for NMS that have to be taken into account include malignant catatonia, malignant hyperthermia, serotonin syndrome, anticholinergic syndrome, CNS infection, tetanus, and lithium intoxication.
As far as treatment goes, control of hydration is acutely necessary given the hyperpyrexia that goes with this condition. It is also important to manage creatine kinase elevation and provide other supportive measures, like mechanical cooling, nutritional supplementation, and monitoring laboratory values. In other words, patients with NMS will need the ICU setting most of the time for circulatory stabilization, prophylactic anticoagulation, cardiac rhythm control, and, if necessary, ventilation. But sometimes, even all that isn’t enough. NMS can be lethal, so direct treatment of neuroleptic malignant syndrome has been tried principally with muscle relaxants—namely dantrolene—and with dopamine agonists, like bromocriptine and ECT.
Before we examine the evidence for the efficacy of these modalities, note that the authors tip their hat to the controversial use of lorazepam, noting that it is recommended only in cases with either mild symptoms or uncertain diagnosis. They also note that there are treatment recommendations for anti-Parkinson drugs, like amantadine, levodopa/carbidopa, and apomorphine. While this starts to sound like what cancer treatment used to, where the existence of many different approaches suggests that none of them work very well, the authors of this review go on to perform a systematic case report analysis to help us narrow all these options down and evaluate evidence for their efficacy.
The authors ask, does specific NMS therapy with dantrolene, bromocriptine, or ECT have better outcomes than purely symptomatic therapy? They looked at 405 NMS cases and their outcome rates under ECT and specific NMS pharmacotherapy.
And lo, the mortality rates were the same as just getting medical therapy. However, for severe NMS, the mortality rate was significantly lower with the specific NMS therapies of bromocriptine, dantrolene, and ECT compared to purely symptomatic therapy. The authors go on to note that the rate of comorbidities was higher in the group that received these specific NMS drugs than in the group that got symptomatic therapy. So, it’s plausible that the effects of dantrolene and bromocriptine on mortality might have been less pronounced than one would otherwise expect because it was a more difficult patient population, with more medical comorbidities.
In conclusion, this review is a useful reminder of some of the fundamental details of NMS, and according to the authors’ research question, it’s also an indication that dantrolene, bromocriptine, and perhaps ECT should be considered for severe NMS cases—not the mild or moderate ones. Finally, a reexamination of differential diagnoses of NMS vs malignant catatonia might be wise since dantrolene and bromocriptine would not be indicated for the catatonia.
Abstract
The Neuroleptic Malignant Syndrome—A Systematic Case Series Analysis Focusing on Therapy Regimes and Outcome
L Kuhlwilm, C Schönfeldt-Lecuona, M Gahr, B J Connemann, F Keller, A Sartorius
Introduction: 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.
Method: 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.
Result: 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.
Discussion: 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.
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Reference
Kuhlwilm, L., Schönfeldt‐Lecuona, C., Gahr, M., Connemann, B. J., Keller, F., & Sartorius, A. (2020). The neuroleptic malignant syndrome—a systematic case series analysis focusing on therapy regimes and outcome. Acta Psychiatrica Scandinavica, 142(3), 233-241.
