Neuroleptic malignant syndrome (NMS) refers to the combination of hyperthermia, rigidity, and autonomic dysregulation that can occur as a serious complication of the use of antipsychotic drugs. Delay first used the term in 1960, after observing patients treated with high-potency antipsychotics.[1]
Even the newer atypical antipsychotics, which are not classified accurately as neuroleptics, can cause NMS. The list of atypical antipsychotic drugs that may cause NMS include olanzapine,[2] risperidone, paliperidone, aripiprazole, ziprasidone, amisulpride, and quetiapine.[3] Clozapine may also be associated with the development of NMS, but it appears to be less likely to manifest with extrapyramidal features, including rigidity and tremor. In general, over the past 30 years, the syndrome has been associated with a variety of drugs that lead to decreased dopamine receptor activation.[4]
While some clear risk factors for neuroleptic malignant syndrome are present, the low incidence of this syndrome and the consequent difficulty in studying it in a controlled, prospective manner make clinical features, predisposing conditions, treatment, and prognosis difficult to define.
Following is a case vignette of a patient with neuroleptic malignant syndrome that developed several days after the start of treatment with the atypical antipsychotic olanzapine.
A 66-year-old white male was hospitalized for increasingly aggressive behavior. He had no prior psychiatric admissions. On the day of admission after he sustained a fall, a CT scan of the brain revealed a subarachnoid hemorrhage at the right superior sulcus and a possible hemorrhagic contusion at the left frontal lobe. Over the course of hospitalization, the patient had a series of CT scans showing resolution of the hemorrhage. He was started on olanzapine for intermittent agitation. Olanzapine was titrated to 7.5 mg daily.
Ten days later the patient became abruptly somnolent with body temperature reaching 39.7 º C and severe muscle rigidity in both upper and lower extremities. He had severe diaphoresis and fluctuation of blood pressure and pulse. Laboratory data revealed elevation of white blood cells to 14800 K/L, creatine phosphokinase to 2800 U/L (normal < 174 U/L), and mild elevation of serum alanine and aspartate aminotransferase. MRI of the brain, CSF studies, and chest radiograph were unremarkable. A presumptive diagnosis of neuroleptic malignant syndrome was made. Olanzapine was immediately discontinued and supportive care was initiated.
Intravenous lorazepam was given as needed every 4 hours for behavioral agitation along with a fixed 0.5 mg intravenous push twice daily. The patient received a total of 8.5 mg of lorazepam in the first 24 hours and 3 mg the next day. Fever and muscular rigidity resolved in 24 hours. All other manifestations of neuroleptic malignant syndrome resolved in 9 days.
The most widely accepted mechanism by which antipsychotics cause neuroleptic malignant syndrome is that of dopamine D2 receptor antagonism. In this widely accepted model, central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to increased muscle rigidity and tremor via extrapyramidal pathways. Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heat-dissipating mechanisms. Peripherally, antipsychotics lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can contribute to hyperthermia, rigidity, and muscle cell breakdown.
Beyond these direct effects, D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system. The resulting sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction. This model suggests that patients with baseline high levels of sympathoadrenal activity might be at increased risk. While this has not been proven in controlled studies, several such states have been proposed as risk factors for neuroleptic malignant syndrome.[5]
Direct muscle toxicity also has been proposed as a mechanism of neuroleptic malignant syndrome.
Neuroleptic malignant syndrome is associated with the use of various antipsychotic medicines, most frequently neuroleptics (the older antipsychotics). Development of neuroleptic malignant syndrome appears to be independent of the conditions that these medicines treat.
The syndrome can occur after any duration of treatment, although two thirds of cases occur within the first week. The frequency has been variably reported as 0.07–2.2% of patients taking neuroleptics.[6] Data largely come from case control studies rather than prospective randomized trials.
The frequency of neuroleptic malignant syndrome internationally parallels the use of antipsychotics, especially neuroleptics, in a given region. No data suggest geographic or racial variation. The one large randomized trial conducted in China showed an incidence of 0.12% in patients taking neuroleptics.[7] A retrospective study conducted in India showed an incidence of 0.14%.[8]
Mortality from neuroleptic malignant syndrome is very difficult to quantify due both to the case report designs of most of the literature and to the inconsistency of the diagnostic parameters used.
No data suggest geographic or racial variation.
Incidence is higher in males.
Neuroleptic malignant syndrome tends to start with muscular rigidity and progress to hyperthermia with autonomic instability and a fluctuating level of consciousness. Compared to disease in adults, neuroleptic malignant syndrome in children and adolescents tends to present with more dystonia and less tremor.
All classes of antipsychotics have been associated with neuroleptic malignant syndrome, including low-potency neuroleptics, high-potency neuroleptics, and the newer (or atypical) antipsychotics. Neuroleptic malignant syndrome has been reported most frequently in patients taking haloperidol and chlorpromazine.
The most important intervention is to discontinue all antipsychotics. In most cases, symptoms will resolve in 1-2 weeks. Neuroleptic malignant syndrome precipitated by long-acting depot injections of antipsychotics can last as long as a month. During the course of neuroleptic malignant syndrome, use supportive care aggressively. The value of other interventions, such as dantrolene, amantadine, bromocriptine, and electroconvulsive therapy, is uncertain.[28]
Specific drug therapies, such as dantrolene, amantadine, bromocriptine, and electroconvulsive therapy, have an uncertain role in the treatment of neuroleptic malignant syndrome. While they generally are felt to be helpful, they have been found to be deleterious in some studies.
Clinical Context: Stimulates muscle relaxation by modulating skeletal muscle contractions at a site beyond myoneural junction and by acting directly on the muscle itself.
Can be administered PO/IV. IV form is much more expensive and should be reserved for patients unable to take oral medications.
Clinical Context: Strong dopamine D2 receptor agonist and partial dopamine D1 receptor agonist. Often administered with oral dantrolene.
Clinical Context: Antiviral agent effective against influenza A. Has a proposed role in altering the release and uptake of dopamine and has been used to treat Parkinson disease. Infrequently used to treat NMS.
In order for a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. The role of other dopamine receptor subtypes currently is unclear.
Clinical Context: Depresses all levels of CNS (eg, limbic and reticular formation) possibly by increasing activity of GABA.
Individualize dosage and increase cautiously to avoid adverse effects.
Clinical Context: Sedative hypnotic with short onset of effects and intermediate-long half-life.
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it might depress all levels of CNS, including limbic and reticular formation.
Used in a small number of patients unresponsive to above measures. In most cases, a continuous IV infusion of diazepam or lorazepam has been utilized.