Neuroleptic malignant syndrome associated with quetiapine and venlafaxine use: a case report and discussion

Introduction

We report a case of neuroleptic malignant syndrome (NMS) in a 36-year-old man prescribed quetiapine, venlafaxine and methadone. NMS is a rare but potentially fatal side-effect of all antipsychotic medications characterized by fever and muscle rigidity, and two or more of diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness, mutism, autonomic dysfunction, leukocytosis and elevated creatine kinase. Complications include rhabdomyolysis, renal failure and death. Mortality appears to be reduced with second-generation antipsychotics. Although predominantly associated with antipsychotic use, NMS has been observed with antidepressants and lithium.

Case

A 36-year-old man with a history of opioid dependence and depression presented to the emergency department (ED) in late 2009 with acute onset of confusion and paranoid ideation. His partner had noticed its development over a 24-hour period, during which he had believed there was an intruder in his home and been at times incoherent. He had complained of headache and she had observed facial grimacing and unusual limb movements.

On assessment in the ED he was acutely confused, agitated and intermittently aggressive. There was a marked diaphoresis, with rigidity and choreoathetoid movements noted. The patient’s blood pressure was fluctuant and pulse elevated, with mild pyrexia of 37.5°C recorded. There were no focal neurological deficits. The patient appeared to be responding to perceptual abnormalities and reported auditory and visual hallucinations.

The patient’s partner revealed a history of opioid dependence and hepatitis C infection. He had been engaged with the substitute prescribing programme since 1997 and was receiving methadone 90 mg daily. He had developed depression after being treated for hepatitis C in 2007 with pegylated interferon. At the time of presentation to the ED his antidepressant treatment regime involved venlafaxine 375 mg daily (since February 2009), quetiapine 50 mg nocte (since May 2009) and levothyroxine 50 µg daily (since December 2008). He was not receiving any additional medications. There was no prior history of confusion or psychosis.

He was admitted medically and initially treated empirically with acyclovir and chloramphenicol until an encephalitis could be excluded. Intravenous lorazepam was administered on two occasions for severe agitation. A CT brain was performed and showed no abnormality. Initial bloods showed a raised white cell count (WCC) of 13.5 × 10⁹/l (neutrophils 8.26 × 10⁹/l) but a C-reactive protein (CRP) < 1 mg/l. Gamma-glutamyl transpeptidase (GGT) was 1091 U/l. A urine drug screen confirmed the presence of opioids only. On the post take ward round later that day he was observed to be sweating profusely, agitated and tachycardic. He remained confused and spoke of concerns regarding gangs with knives. Nystagmus and sluggish pupils were noted. Both venlafaxine and quetiapine were held.

He was reviewed by neurology on day 2 and choreiform movements noted in his legs, arms and head. Further lorazepam was required for agitation. Creatine kinase (CK) was 13,928 U/l and a working diagnosis of neuroleptic malignant syndrome was established. A planned lumbar puncture was deferred and management was focused on ensuring adequate hydration and management of agitation with further doses of benzodiazepines as required. Repeat liver function tests (LFTs) showed elevated aspartate transaminase (AST; 290 U/l) and alanine transaminase (ALT; 105 U/l) with a small decline in GGT to 900 U/L. Systolic blood pressure fell to lie between 80 and 100 mmHg and he was intermittently tachycardic to a maximum of 120 bpm. The patient was verbally aggressive toward staff and removed several IV cannulae. He was placed on one-to-one nursing observations.

Urea and electrolytes were normal on day 3 and CK had fallen to 11,461 U/l. A repeat CK later that day showed a further fall to 5877 U/l. He underwent a lumbar puncture under sedation. He remained disruptive and agitated and was moved to a side room. On day 4 he appeared less agitated. CK was 2708 U/l with normal urea and electrolytes, CRP and WCC. Cerebrospinal fluid (CSF) analysis was normal.

On day 5 he was confused and wandering, eventually absconding from the ward. He was returned by the police and was aggressive on his return. He was referred to and assessed by the liaison psychiatry team. On assessment he remained disorientated, believing that he was in prison. Mood appeared labile and speech was largely incoherent. He remained concerned for his safety and believed that he was in danger of being stabbed. Choreoathetoid movements were again noted. He was distracted at interview and appeared to be responding to stimuli. The medical team was advised to continue to hold his psychotropic medications and to use benzodiazepines as required for the management of agitated behaviour while his medical investigations continued. A collateral history from his community addictions team key worker revealed that he had been stable on methadone for several years and that there were no concerns of recent substance misuse.

On day 6 he threw a rubbish bin toward another patient. He was no longer tachycardic. WCC was 7.4 × 10⁹/L, alkaline phosphatase (ALP) 61 U/l, AST 59 U/l, ALT 65 U/l and GGT 657 U/l. He underwent an MRI brain scan under general anaesthetic which was normal. Viral polymerase chain reaction (PCR) was returned as negative and acyclovir and chloramphenicol were discontinued.

He was reviewed on day 7 by psychiatry and was relaxed, coherent and appropriate. There was no evidence of any ongoing psychotic symptoms or abnormal movements. He scored 27/30 on the Mini-Mental State Exam (MMSE). When reviewed on day 11 he remained well. Mood was euthymic and he scored 30/30 on the MMSE. There were no psychotic symptoms. The likely diagnosis of NMS was explained to the patient and both venlafaxine and quetiapine discontinued completely, only to be recommenced in future with marked caution and under strict supervision.

Discussion

We believe that the above case adds to the literature base describing NMS in association with both quetiapine and venlafaxine. It is acknowledged that there exists no universally accepted set of diagnostic criteria for NMS and that there is considerable overlap of features between NMS and serotonin syndrome, allowing for significant diagnostic blurring [Sachdev, 2005]. We believe that in this case the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for NMS were satisfied given the presence of muscle rigidity and elevated temperature accompanied by diaphoresis, altered consciousness, tachycardia, labile blood pressure, leukocytosis and markedly elevated CK [American Psychiatric Association, 2000]. The slow duration of onset and recovery are felt to be more suggestive of a diagnosis of NMS than serotonin syndrome [Susman, 2001]. The recent stability in the patient’s medication regime, the history of opioid dependence and hepatitis C status and the prescription of the second-generation antipsychotic quetiapine are at odds with Sternbach’s criteria for a diagnosis of serotonin syndrome which include a recent change in a potent serotonergic agent, the absence of a history of substance misuse or infectious (or metabolic) disease and the absence of an antipsychotic agent [Sternbach, 1991]. Prominent autonomic instability and the presence of a leukocytosis lend further support to the diagnosis of NMS [Marlowe and Schirgel, 2006].

NMS has been described with all second-generation antipsychotics such as quetiapine, including even the recently licensed preparation asenapine [Singh and Wise, 2010]. It has also been described in several cases of antipsychotics being prescribed in combination with both selective serotonin reuptake inhibitor (SSRI) and serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants, the latter class of which includes venlafaxine [Stevens, 2008]. In their recent comparison of NMS induced by first- and second-generation antipsychotics, Trollor and colleagues noted a high rate of concurrent prescription of serotonergic antidepressants in their sample [Trollor et al. 2012]. When serotonergic antidepressants are used with antipsychotics, it is proposed that serotonergic inhibition of central dopaminergic activity theoretically increases the potential for NMS already associated with the antipsychotic agents [Odagaki, 2009]. There exist reports of NMS occurring in patients prescribed venlafaxine in isolation [Lu et al. 2006].

NMS has generally been associated with high doses of antipsychotic medication as opposed to the low dose in this case although Lazarus and colleagues did conclude that NMS appeared not to be dose dependent [Viejo et al. 2003; Lazarus et al. 1989]. We considered the potential impacts of both hepatitis infection and methadone in the development of NMS in this case but were unable to find any clear associations for either. It does not seem unreasonable to suggest that as a serotonergic enhancer, methadone may be involved in central dopaminergic inhibition similar to that seen with antidepressants and may therefore have played some role in the development of NMS in the above case.