Atypical Neuroleptic Malignant Syndrome or Serotonin Toxicity Associated with Atypical Antipsychotics?

Abstract

Atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) have been prescribed extensively, often in combination with each other. When toxic encephalopathy develops with neuromuscular and autonomic symptoms in a patient taking medication including atypical antipsychotics, it has tended to be diagnosed as neuroleptic malignant syndrome (NMS). However, there have recently been several case reports where the diagnosis of serotonin syndrome is given or raised as a likely differential diagnosis to such cases. In the present review, the author addressed himself to the issues surrounding the neurotoxic reaction to the treatment regimen containing atypical antipsychotics, focusing on the "atypical" forms of NMS and pathophysiological as well as clinical features of serotonin toxicity. Although NMS is idiosyncratic in nature, it appears practically useful to comprehend this syndrome as a spectrum-based concept. Likewise, serotonin toxicity is a broad spectrum of clinical syndromes in close connection with serotomimetic drug use, including varied severity. Some of atypical antipsychotics, i.e., perospirone, aripiprazole, ziprasidone, clozapine, and quetiapine, have been shown to behave as partial agonists at 5-HT1A receptors, providing direct evidence that these atypical antipsychotics are serotomimetic per se. The reciprocal interaction between the dopaminergic and serotonergic systems disturbed by either dopaminergic blockers or serotonergic enhancers leads to the disruption of homeostasis, with typical forms of NMS and serotonin syndrome representing the ends of the common pathophysiological background. The practical and flexible way to consider and manage such cases with updated knowledge derived from basic research should be warranted to be beneficial to our patients.

Psychotropic discontinuation leading to an NMS‐like condition

“…[11][12][13][14] However, there are several case reports in which patients have not presented with all the core symptoms, leading to such cases being termed 'atypical NMS'. The diagnosis and the uncertainly of the nature and course of this condition have been discussed by Picard et al, 15 Odagaki 16 and Trollor et al 17 Our patient had altered consciousness, fever, sweating, elevated CPK and WBC, tachycardia, tachypnoea and incontinence but no documented reports of rigidity, as this was not checked due to his aggression. This case could be described as atypical NMS as the patient had most of the core criteria of NMS other than extrapyramidal symptoms.…”

Encephalopathy Associated with Psychotropic Drug Therapy

“…In response to the editorial by Fink (1996a), Northhoff (1996) also contributed a correspondence against the notion that NMS and catatonia were variants of the same disorder. The similar debate has been held on the discrimination between NMS and SS (Fink, 1996b;Kontaxakis et al, 2003;Odagaki, 2009;Steele et al, 2011). It is beyond the scope of this article to have a detailed discussion on the possibility that NMS belongs to a spectrum of the same disorder that contains catatonia and/or SS.…”

“…This spectrum-based concept of NMS (Fig. 1) may be practically useful to comprehend the progression of symptoms, at least in typical cases (Odagaki, 2009). Fig.…”

“…1. The typical progression of symptoms of NMS from the mildest stage I (drug-induced parkinsonism) through stage V or the severest form of NMS (Odagaki, 2009). Stages I-V are originally proposed by Woodbury and Woodbury (1992) and adapted by Strawn et al (2007).…”

“…The following features are raised by Gillman (1999) for differentiation between the two syndromes: NMS, slow onset (days to weeks) and slow progression over 24-72 hours in association with neuroleptics versus SS, both rapid onset and rapid progression (minutes to hours) in association with a combination of serotonergic drugs; NMS, bradykinesia and lead pipe rigidity versus SS, hyperkinesias and clonus; and NMS, an idiosyncratic reaction to therapeutic dosages versus SS, a manifestation of toxicity (usually to a combination of drugs) to which everyone is liable. The differential diagnosis between SS and NMS can be further complicated when atypical antipsychotics are included in the prescription, because some of atypical antipsychotics are 5-HT 1A receptor agonist by themselves (Odagaki, 2009). …”