Risperidone

Risperidone has been associated with probably the largest number of cases of atypical antipsychotic-induced NMS. ^{Reference Belvederi Murri, Guaglianone, Bugliani, Calcagno, Respino and Serafini9,Reference Ananth, Parameswaran, Gunatilake, Burgoyne and Sidhom17} It has been noted more frequently in the younger age group who had been antipsychotic naive. A severe clinical picture of typical NMS has been encountered, marked by rigidity, extrapyramidal symptoms, fever and highly elevated CPK levels. Tachycardia was more common than diaphoresis and autonomic dysregulation occurred frequently. ^{Reference Belvederi Murri, Guaglianone, Bugliani, Calcagno, Respino and Serafini9}

Clozapine

Cases of clozapine-induced NMS, reported since the 1980s, typically occurred with rapid dose increases. Also, many patients who developed clozapine-induced NMS had a history of NMS with other antipsychotics. Tachycardia, tachypnoea, diaphoresis and autonomic lability were encountered frequently, possibly due to clozapine acting on adrenergic and muscarinic receptors. ^{Reference Jann, Grimsley, Gray and Chang18} Rigidity and extrapyramidal symptoms were rare, possibly due to the lower affinity of clozapine to the D₂ receptor. The increases in CPK were lower and delayed when compared with other antipsychotics. The occurrence of fever and autonomic instability in patients receiving clozapine in the absence of rigidity may necessitate ruling out the diagnosis of clozapine-related agranulocytosis before a diagnosis of NMS. ^{Reference Amore, Zazzeri and Berardi19} The clinical severity of clozapine-induced NMS has been described to be lower than with other antipsychotics, and hence such cases have infrequently required intensive care unit admissions. The infrequent occurrence of rigidity and extrapyramidal symptoms in patients with clozapine-induced NMS require a high degree of suspicion for this diagnosis. However, certain researchers have suggested that clozapine-induced NMS should not be considered as a diagnosis in the absence of typical features of NMS. ^{Reference Karagianis, Phillips, Hogan and LeDrew20}

Olanzapine

Although olanzapine has been reported to present with the typical features of NMS, extrapyramidal symptoms and fever were absent in a small proportion of patients. Autonomic imbalances and diaphoresis are frequent, and are often the first signs to appear in patients with olanzapine-induced NMS. Nausea was infrequent, probably due to the antiemetic purported properties of olanzapine, ^{Reference Licup and Baumrucker21} but neurological impairments such as hemiplegia, ataxia and seizures have been reported. ^{Reference Belvederi Murri, Guaglianone, Bugliani, Calcagno, Respino and Serafini9} Several cases have been reported in patients receiving other medications apart from antipsychotics, for example mood stabilisers and antidepressants, and the clinical picture of NMS has been more severe in such patients. ^{Reference Belvederi Murri, Guaglianone, Bugliani, Calcagno, Respino and Serafini9}

Amisulpride

Several cases of amisulpride-induced NMS have been described in the literature, ^{Reference Musshoff, Doberentz and Madea22,Reference Tsai, Yang, Yen, Chen and Yang23} many reported in elderly males. The clinical profile primarily involves an altered mental state, frequent rigidity and high levels of CPK, whereas high fever, tremor and other autonomic symptoms have been reported less frequently. The lower propensity to cause autonomic symptoms is probably due to low affinity in amisulpride for muscarinic, adrenergic, serotonergic and histamine receptors than in other antipsychotics. ^{Reference Horacek, Bubenikova-Valesova, Kopecek, Palenicek, Dockery and Mohr24}

Quetiapine

Quetiapine-induced NMS has been primarily reported in the elderly, although it has also been described in children. ^{Reference Detweiler, Sullivan, Sharma, Kim and Detweiler25} Clinically, it presents with extrapyramidal symptoms and prominent autonomic symptoms such as tachycardia, blood pressure fluctuations, tachypnoea and diaphoresis. These prominent autonomic symptoms may be consequent to noradrenaline reuptake inhibition, histaminergic antagonism and serotonin toxicity associated with the use of quetiapine. ^{Reference Tsai, Yang, Yen, Chen and Yang23} The outcome of quetiapine-induced NMS has been relatively poor, probably due to the older age of patients in whom it has been reported. ^{Reference Belvederi Murri, Guaglianone, Bugliani, Calcagno, Respino and Serafini9}

Aripiprazole

Several case reports and case series have accumulated on the occurrence of NMS in patients receiving aripiprazole. ^{Reference Chen, Su and Chang26,Reference Tseng, Chang, Chang, Wang, Cheng and Wu27} Rigidity and altered mental state seem to be present frequently in such patients, while fever, diaphoresis and tachypnoea are less frequent. NMS has been reported to occur more commonly with fast upward titration of dosages of aripiprazole. The severity and duration of NMS seem lower than in other antipsychotic medications, probably due to the partial dopamine agonist activity of aripiprazole. Aripiprazole has also been implicated in combination antipsychotic regimens, when used alongside other atypical antipsychotics such as clozapine. ^{Reference Tseng, Chang, Chang, Wang, Cheng and Wu27}

Ziprasidone

Few cases of ziprasidone-induced NMS have been described. ^{Reference Leibold, Patel and Hasan28,Reference Ozen, Yumru, Savas, Cansel and Herken29} The onset of NMS in these patients has been generally abrupt, with most displaying typical features such as alterations of mental state, fever, diaphoresis, tachycardia, blood pressure alterations, leukocytosis, tremor, and other extrapyramidal symptoms with high CPK. No fatality has been reported with ziprasidone to date, and recovery is usually achieved in about 10 days.

Paliperidone

Paliperidone has a similar pharmacodynamic profile to risperidone, but it has a lower affinity for dopamine receptors and higher serotonin antagonist activity. Paliperidone-induced NMS has been described mainly in patients who have been previously treated with other atypical antipsychotics and have had a recent dose increase or cross-titrations. ^{Reference Mantas, Kalabokis, Goulia, Tourlakopoulos, Hyphantis and Mavreas30,Reference Teng and Lane31} Paliperidone-induced NMS presents with a typical clinical profile with mental state alteration, rigidity, diaphoresis, hyperpyrexia, tremor and other extrapyramidal symptoms, and the outcome is favourable, with resolution achieved in all cases.

Zotepine

Several cases of zotepine-induced NMS have been described in the literature. ^{Reference Musshoff, Doberentz and Madea22,Reference Hsu, Lin, Chen, Tsang and Huang32} Rapid dose escalation was reported in one case, although NMS has also developed with the usual titration pattern. Zotepine-associated NMS presents with alterations of mental state, rigidity, diaphoresis, fever, tachycardia and leukocytosis, with less frequent occurrence of tremor, tachypnoea and alterations in blood pressure.

Other atypical antipsychotics and summary

At present, there is a single case report of iloperidone being considered as a cause of NMS. ^{Reference Guanci, Aggarwal and Schleifer33} The patient, who had schizophrenia, developed mutism, diaphoresis, diffuse lead pipe rigidity and tachycardia without fever or marked increase in CPK levels. The outcome was favourable, but the patient also required anticoagulation therapy for the management of comorbid pulmonary embolism.

Blonanserin was reported as a cause of NMS in a 30-year-old female with intellectual impairment. ^{Reference Ohoyama, Tanii, Motomura, Konishi, Nakagawa and Matsumoto34} The patient presented with fever, tachycardia, rigidity, extrapyramidal symptoms and leukocytosis after the initiation of blonanserin. Symptomatic improvement was seen after discontinuation.

Although different atypical antipsychotics have different NMS clinical symptom profiles, rigidity, tremor and fever are encountered less frequently with atypical antipsychotics, whereas diaphoresis is quite common. Clozapine is particularly associated with atypical presentations of NMS with infrequent CPK level elevations. Risperidone, on the other hand, produces a clinical picture more similar to the NMS induced by typical antipsychotics. Some of the atypical antipsychotics have also been associated with serious features such as myoglobinuria and acute renal failure. ^{Reference Patel and Brunetti35,Reference Borovicka, Bond and Gaughan36}

Diagnostic uncertainty

The clinical picture and features of NMS with atypical antipsychotics seem to be different from those of typical antipsychotics. This had led to uncertainty over the diagnosis of NMS in patients on atypical antipsychotics who manifest only few of the NMS symptoms. ^{Reference Picard, Lindsay, Strawn, Kaneria, Patel and Keck38} Among the core symptoms of NMS, fever is often encountered less frequently in patients with atypical antipsychotic-induced NMS. ^{Reference Picard, Lindsay, Strawn, Kaneria, Patel and Keck38} The issue is further complicated by the various operational definitions of NMS. ^{Reference Picard, Lindsay, Strawn, Kaneria, Patel and Keck38} The DSM-IV-TR defines NMS as the presence of severe muscle rigidity and elevated temperature after antipsychotic initiation along with two or more of: diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, or laboratory evidence of muscle injury (elevated CPK level). Various other criteria for NMS have been postulated, each with varying emphasis on the individual symptoms and signs. ^{Reference Caroff and Mann39} Another set of criteria defines NMS in patients with either three major symptoms (hyperthermia, rigidity, elevated CPK level) or two major and four minor symptoms (diaphoresis, tachycardia, tachypnoea, abnormal blood pressure, leukocytosis, altered consciousness). ^{Reference Levenson40} Yet another diagnostic system defines NMS through the presence of extrapyramidal symptoms and fever (⩾37°C) alongside three minor symptoms within a 48-hour period. ^{Reference Addonizio, Susman and Roth41} This may potentially mean that a case fulfilling the diagnosis of NMS according to one set of criteria may not do so with another set. The DSM-5 has taken a pragmatic approach of not explicitly stating the number of criteria required for the diagnosis of NMS.

It has been proposed that with the growing awareness of NMS, those in the early course of its development may benefit from early identification and immediate treatment. This may lead to an abortive course of NMS development, with an incomplete picture and only few of the criteria being met. Hence, some authors have proposed a dimensional concept of NMS, which takes into consideration the minor and subthreshold forms of NMS. ^{Reference Picard, Lindsay, Strawn, Kaneria, Patel and Keck38,Reference Odagaki42} This is likely to further our knowledge about NMS pathophysiology, clinical profile subtypes and appropriate management strategies.

Furthermore, various other medical and neurological conditions may present with a clinical picture similar to NMS (briefly mentioned in Box 2). Patient condition may require expedient decisions so that a rational line of management can be instituted. Hence, the clinician may need to take a brief and focused history for being reasonably sure about the diagnosis. Neuroimaging and electroencephalogram may be helpful for ruling out neurological pathologies mimicking NMS. For example, in patients with psychosis, catatonia may be considered as a differential diagnosis, especially when the patient is mute and exhibits staring. It may not be possible to exhaustively rule out all differential diagnoses, and at times management may need to be started on an empirical basis.