Olanzapine and Neuroleptic Malignant Syndrome: Potential to miss if we rely on extrapyramidal symptoms.
Senior Clinical Pharmacist,Mental Health and Addictions Services
5th year Medical Student,
Faculty of Medical and Health Sciences
University of Auckland
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication largely associated with antipsychotic medications. Patients with NMS can present to the medical ward with fever, muscular rigidity, altered sensorium, autonomic instability and disturbances in blood indices (1). The incidence rates for NMS ranges between 0.01 to 0.02% among people treated with antipsychotic, with symptoms manifesting as early as 24 hours to no later than 30 days of the initiation of medication (2). Selective dopaminergic antagonism is the likely pathophysiological mechanism by which NMS occurs (3). Thus, first-generation antipsychotics (FGA) are commonly associated with NMS, although recent case reports have implicated SGA like olanzapine (3).
A 45 year old man with a well established diagnosis of schizophrenia, managed with 15mg olanzapine at night and mirtazapine 30mg at night, was admitted to the pyschiatric unit with a two week relapse secondary to medication non-adherence. He had only been drinking protein shakes, was sleeping poorly and believed he was invisible. He was visibly dehydrated, responded to auditory and visual halluciantions, had poor self-cares with periods of mutism and echolalia. He received a stat dose of 20mg olanzapine on admission. Shortly after this, he became highly agitated and displayed the following physical features: persistent low-grade hyperthermia at 37.70C, blood pressure 140/71 mm Hg, tachycardia of 140-150bpm, with QTc of 468ms, diaphoresis and CK levels peaking at 2440U/L. His agitated state made neurological examination, including that of extrapyramidal signs, difficult to assess. A provisional diagnosis of NMS, based on Sachdev’s criteria (4), secondary to Olanzapine was made - given the presence of hyperthermia, raised CK, psychomotor agiation tachycardia and diaphoerisis.
Olanzapine was immediately ceased, and diazepam 5mg tds was commenced. Over the course of the next 5 days, the tachycardia reduced to 120bpm, blood pressure returned to 128/76 mm Hg, CK levels dropped to 249U/L, diaphoresis and pyschomotor agitation reduced. Interestingly, his pyschotic symptoms began to resolve as well, despite no administration of antipsychotics. His initial agitation upon admission was attributed to NMS rather than a relapse of schizophrenia. He was discharged on aripiprazole 15mg in the morning and mirtazapine 30mgs at night ; diazepam 2mg three times daily for two weeks. aripiprazole has less risk to cause NMS (5).
In this case, olanzapine, a SGA, was implicated in the development of NMS. Before arriving at the diagnosis of NMS, we considered the possibility of serotonin syndrome (SS) on the grounds that concomitant use of mirtazapine with olanzapine could have increased the risk of developing SS. SS is yet another potentially life-threatening adverse drug reaction caused by excessive serotonergic activity in the central and peripheral nervous system. SS is characterised by a triad of neuron-excitatory features: (a) neuromuscular hyperactivity -- tremor, clonus, myoclonus, hyperreflexia and, in advanced stages, pyramidal rigidity; (b) autonomic hyperactivity -- diaphoresis, fever, tachycardia and tachypnea; (c) altered mental status -- agitation, excitement and, in advanced stages, confusion (6). The overlapping clinical presentations of NMS and SS often leads to diagnostic confusion and challenges in clinical management (7, 8). Our patient had only some features of autonomic hyperactivity and altered mental status, which were not enough to support the diagnosis of SS. Furthermore, SS is caused by medications that can significantly increase serotonin release, inhibit serotonin reuptake or cause direct agonism of the serotonin by coadministration of serotonergic agents such as tramodol, venlafaxine, and mirtazapine (6). Our patient had only been on olanzapine 15 mg and 30 mg mirtazapine in the community, but only developed symptoms until he received a higher dosage of olanzapine in a dehydrated state. In the absence of any new medication that could have increased the serotonergic activity in the brain, the elevated CK and the absence of full range of symptoms consistent with SS, we favoured the diagnosis of NMS.
Diagnosisng NMS, especially in the medical ward setting, is often challenging because of divergent diagnostic systems using varying criteria. Take for instance the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR), (9) requiring the presence of two or more of the following criteria : fever and muscular rigidity (major findings), sweating, tachycardia, altered or generally elevated arterial tension, elevated white blood cell count, altered consciousness, tremor, urinary-fecal incontinence, and elevated CPK (minor findings) (9). It would not be possible to diagnose NMS if a patient did not present with muscle rigidity if one was to use DSM IV TR criteria. DSM-5 (2), on the other hand, no longer uses a categorical or criteria based diagnostic approach for NMS. Instead, it allows for the diagnosis to be made if a patient presents with hyperthermia, rigidity, mental status alteration, CPK elevation, sympathetic nervous system lability and hypermetabolism after exposure to dopamine antagonist or dopamine agonist withdrawal, with a negative examination for infectious, toxic, metabolic and neurologic causes. Criteria by Nirenberg et al (10) and Sachdev (4) offer a compromise by enlisting symptoms and yet allowing the diagnosis of NMS to be made even if a patient does not present with muscle rigidity but does present with others such as fever, raised CPK, autonomic instability and altered consciousness. It is our view that using DSM 5 (2) or Criteria by Nirenberg et al (10) and Sachdev (4) may be better as muscle rigidity may be less common with decreasing usage of FGA globally. In the medical ward setting, a lower threshold for the diagnosis of NMS may be useful so that treatment can commence early for a condition with a reported fatality rate of 10-20% (2)
The role of Olanzapine in the aetiology of NMS needs to be considered in its interesting neurochemical profile and should be examined in light of what is known about the relationship between the two. Olanzapine has a high affinity for serotonin 5HT2a & 2c, dopamine D1-3, muscarinic M1-6 and histamine H1 receptors (6). In an analysis of 26 cases of olanzapine-induced NMS (11), Kogoz et al found six cases that did not meet all of Sachdev’s diagnostic criteria for NMS (4). Our patient also only met Sachdev’s criteria. This review also found a preponderance of men, with an average age of 49 years and majority (16/20) being on a combination of olanzapine and other psychiatric medications (other anti-psychotics, mood-stabilisers and anti-depressants) - findings replicated in another review (3). It does appear, as was the case here, middle aged men on a combination of olanzapine and other psychotropic medication may be at a higher risk of developing NMS, especially in the context of initiation or increasing dosage (3).
It is also noteworthy NMS in patients taking olanzapine seldom presents with discrete signs of extrapyramidal rigidity (3). Prior dehydration and agitation appear to increase the likelihood of development NMS in SGA treated patients (4). Our patient was dehydrated with sustained fasting and developed NMS with no overt signs of rigidity after receiving a higher dosage of olanzapine while he continued to take mirtazapine. Threshold for suspecting NMS should be low in men in forties, treated with a combination of olanzapine and other serotonergic medications, especially while the dosage of the former is being titrated up and if they are dehydrated. Such low threshold for suspicion, especially in the medical ward setting, will enable early treatment to be instituted and adverse outcomes to be lowered.
In summary, our case report supports recent findings implicating an SGA like olanzapine in the development of NMS. With increasing usage of SGA, we propose the diagnostic criteria for NMS ought to be revised with less reliance on muscle rigidity. Whilst there is a significant overlap between the presentation of FGA and SGA related NMS, extrapyramidal signs including rigidity, dystonia and dysphagia may occur less frequently in NMS caused by SGA.
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First Published November 2020