NMS is an idiosyncratic and potentially life-threatening complication of antipsychotic drug use.

Symptoms of NMS may develop gradually over a period of hours to days and can often overlap with symptoms of general medical illness. The major clinical findings in patients with NMS are presented in Table 16-2. Many symptoms of NMS are nonspecific and overlap with symptoms common to other psychiatric and medical conditions. The diagnosis of NMS is also complicated by the waxing and waning nature of the clinical picture.
Autonomic instability coupled with motor abnormalities is essential to the diagnosis of NMS.

Autonomic alterations can include cardiovascular alterations with cardiac arrhythmias and labile blood pressure.

Low-grade fever progressing to severe hyperthermia may also be present. Motor findings may overlap with other motor abnormalities in psychiatric illness, for example, rigidity/dystonia can be confused with simple dystonia or with EPS. Mutism can be a sign of severe psychosis or catatonia alone, although this does occur with NMS. Behavioral features such as agitation can also overlap with other psychiatric syndromes; however, the presence of delirium or seizures is a harbinger of more serious general medical illness (including drug withdrawal) or NMS. Laboratory findings may reveal an increased creatine kinase secondary to myonecrosis from sustained muscular rigidity. Liver enzymes may be elevated, but their relation to NMS is unclear.
Leukocytosis is also often present.

Risk factors for the development of NMS (see Table 16-1) include the use of high-dose antipsychotics, rapid dose escalation, 1M injection of antipsychotics, dehydration, agitation, or a prior history of NMS. Some factors may be related to severity of illness (e.g., severely ill patients often have poor oral intake and become dehydrated, are more likely to be placed in restraints, and require 1M injection of an antipsychotic) rather than causative factors.

Although NMS is most common during the first few weeks of antipsychotic drug therapy, it can occur at any time during therapy.

Treatment of this potentially fatal disorder is largely supportive. Specific interventions include discontinuation of antipsychotics (an option that may take a long period of time in individuals treated with depot antipsychotics); dantrolene (a muscle relaxant) is used to treat rigidity and decrease myonecrosis; and bromocriptine (a dopamine agonist) is sometimes used to reverse dopamine blocking effects of antipsychotics. Symptom management including intensive care with cardiac monitoring and intubation may be necessary. Symptoms of NMS overlap with serotonin syndrome (Table 16-3). However, in NMS, muscular rigidity .and increased creatine kinase are prominent findings. In addition, serotonin syndrome develops in response to the use of multiple medications that affect serotonin function (especially monoamine oxidase inhibitors [MAOls D, whereas NMS develops in response to antipsychotic medications. In patients using both MAOls and antipsychotics (e.g., refractory psychotic depression), the differential diagnosis can be quite difficult.