NMS is believed to be caused by reduced dopamine activity in the brain associated with dopamine antagonists, interruptions in nigrostriatal dopamine pathways, or withdrawal of dopaminergic medications.3 However, dopamine D2 receptor blocking potential is not directly linked to the occurrence of NMS.6 Other mechanisms include genetic susceptibility and different CNS neurotransmitter disturbances.7

NMS develops in an estimated 0.02% to 2.5% of patients treated with antipsychotics.8-10 The syndrome appears to occur slightly less frequently with SGAs than with FGAs.6,10

Risk factors. NMS can develop at any age, in men and women, and in patients with psychiatric or medical illness.11,12 In addition to antipsychotics, other medications—including antiemetics and sedatives—can cause NMS. The syndrome has been triggered when Parkinson’s disease patients stop taking or reduce the dose of a dopamine agonist or switch from 1 dopamine agonist to another.13,14

Symptoms usually develop during the first 2 weeks of pharmacotherapy but may start after the initial dose or during long-term stable therapy.15 Although some studies found NMS development to be dose-independent, multiple cases have demonstrated an association with dose changes. Death occurs from dysautonomic manifestations and systemic complications.

NMS AND SGAS
We reviewed 88 reports of NMS cases associated with 6 SGAs: olanzapine, clozapine, risperidone, ziprasidone, quetiapine, and aripiprazole. In this article, we cite representative cases only; readers interested in the full literature search can find this evidence and its references in the Case Reports Table.

NMS cases were fairly evenly distributed across all age groups (Figure 1). SGAs were implicated in NMS when used as monotherapy in 9 cases (10%) and in combination with other psychotropics in 41 cases (47%). We could not find medication regimen data for 38 cases (43%).
Our review suggests that a history of NMS is a risk factor for developing another episode. Twenty cases showed a clear history of NMS, and 2 cases reported 3 different NMS episodes in each patient.19,21
In the cases we reviewed, NMS developed more often among men than women (Figure 2). The reason is not clear. One hypothesis suggests that men are more likely to present with severe agitation that requires aggressive antipsychotic treatment.14,22
Previous reports suggested that parenteral antipsychotic administration might increase NMS risk. Most NMS cases in our review involved oral administration, perhaps because parenteral SGAs have become available only recently. In the future, increased use of parenteral SGAs might increase the incidence of NMS.
The NMS mortality rate associated with SGAs was lower than that linked to FGAs.6 This finding, however, may be influenced by increasing awareness of NMS among physicians, resulting in earlier diagnosis and treatment.6


Figure 1
NMS incidence across age groups

CAN’T DRAG TABLE
Incidence is dispersed fairly evenly; elderly patients may be less likely to be prescribed an antipsychotic than other age groups.
Source: Reference 5

Figure 2
NMS: More common in men

CAN’T DRAG TABLE
Men may be at higher risk because they are more likely to present with severe agitation and receive larger doses of potent antipsychotics.
Source: References 14,22


FINDINGS FOR SPECIFIC SGAS
Aripiprazole. Because aripiprazole is the newest SGA, data on its association with NMS are limited. Our review looked at 2 cases. Both patients had atypical NMS features, including absence of fever and mild CPK elevation. In 1 case, aripiprazole was used to treat agitation in a 13-year-old girl with history of NMS. This resulted in a mild increase in tachycardia and brief worsening of serum CPK but did not significantly affect temperature, respiratory rate, or blood pressure.

Clozapine. Several NMS cases have been connected to clozapine monotherapy (6 cases) or combination therapy (22 cases). Compared with NMS caused by other antipsychotics, clozapine-induced NMS occurred sooner after patients started the drug or restarted it after discontinuation. NMS has developed in patients receiving chronic steady doses of clozapine, after dosage increases, and after other medications have been added.

Clozapine-treated patients need to be closely monitored for agranulocytosis symptoms, so any other adverse effects—such as initial symptoms of NMS—likely will be detected early. Some reports suggested that clozapine-induced NMS may feature fewer extrapyramidal side effects and a lower-than-typical increase in CPK. In the cases we reviewed, however, NMS presentations ranged from typical—with a highly elevated CPK—to mild with no rigidity and mild or no CPK elevation. Two of 28 cases reported neurologic sequelae, including severe truncal ataxia and dysmetria.

Clozapine has been used to treat patients with a history of NMS who experience psychotic relapse. In several cases, however, NMS recurred after clozapine was started. In 1 case, a third rechallenge with slow titration of clozapine was successful.

Olanzapine. Some studies have found olanzapine-induced NMS to be rare (rate ≤0.01%), but our review found 36 such cases. Ten patients (30%) had a history of NMS. Olanzapine dosing did not correlate with NMS—in 11 cases NMS occurred with daily doses ≤10 mg.

As with clozapine, the presentation of olanzapine-induced NMS varies widely. Onset from within 8 hours of starting olanzapine to after 2½ years of stable olanzapine dosing has been reported. Some cases have featured a typical NMS presentation. Atypical presentations have included:

• extremely elevated serum sodium
• absence of rigidity
• normal CPK
• generalized tonic-clonic seizures preceding NMS onset
• anterograde amnesia
• deficits in learning verbal information.

Olanzapine challenge for patients with a history of NMS often has triggered recurring NMS.
Quetiapine. NMS has been reported in patients receiving quetiapine monotherapy and combination therapy. Patients who previously experienced NMS after taking an FGA have developed quetiapine-induced NMS, as have some with a history of Lewy body disease. Two patients treated with quetiapine developed CPK elevations to almost 9,000 U/L (normal <171 U/L)—without other NMS features—that improved after discontinuing the medication.

Risperidone. NMS among patients taking risperidone occurs more frequently in those with history of NMS or who restart risperidone after discontinuation. Time to NMS occurrence after starting risperidone varies from hours to months. Atypical presentations include delayed fever, delayed muscle rigidity, massive intestinal bleeding, massive CPK elevation (such as 46,420 U/L), and hyponatremia instead of hypernatremia.

Ziprasidone. Administering IM ziprasidone or combining any form of the drug with other psychotropics increases NMS risk. Although most cases featured typical presentations, 1 case reported absence of muscle rigidity, which is present in >90% of patients with NMS associated with FGAs.


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