Neuroleptic Malignant Syndrome vs Serotonin Syndrome: Can They Be Distinguished Without an Underlying Etiology? Roy R. Reeves, DO, PhD; Mark E. Ladner, MD; and Percy Smith, PA The potentially serious complications for patients with neuroleptic malignant syndrome and serotonin syndrome cannot be underplayed by mental health clinicians, patients, and their families. The authors discuss clinical similarities and diagnostic and treatment approaches to the 2 syndromes. euroleptic malignant syn- of symptoms or whether the patient ployment. He had stopped taking his drome (NMS) and sero- was taking different medications that medication (risperidone 3-mg daily) tonin syndrome (SS) are rare could affect both the serotonin and 3 months earlier, because he was Nbut potentially fatal condi- dopamine systems. experiencing adverse effects (AEs) tions associated with the treatment In clinical practice many patients and shortly thereafter hearing voices. of psychotropic medications. Neu- are treated concurrently with both The clinic psychiatrist started him on roleptic malignant syndrome is be- dopamine receptor antagonists and olanzapine 10-mg daily and sertra- lieved to be caused by a reduction in agents that increase serotonin activity. line 50-mg daily. At a follow-up visit dopaminergic activity secondary to Thus, the distinction of NMS and SS a week later, Mr. A showed an im- drug-induced dopaminergic block- may be problematic if these patients provement of his mood and reported age, whereas SS results from an ex- develop symptoms that could be at- that his hallucinations had decreased cess of central nervous system (CNS) tributed to either disorder. This article significantly. serotonin activity, usually because will discuss the clinical similarities of Several days later, Mr. A became of serotonin agonist polypharmacy NMS and SS and the treatment ap- confused and was found wander- or a drug-drug interaction involv- proaches to the 2 syndromes, as well ing around his neighborhood. He ing serotonin agonist drugs.1,2 How- as possible clues that may help to dis- was brought to the hospital by the ever, the clinical presentations of the tinguish one from the other. police. An examination at the hos- 2 syndromes are alike in many ways. pital revealed his being disheveled Neuroleptic malignant syndrome and CASE PRESENTATION and agitated. He was tremulous and SS may be difficult to distinguish if it Mr. A, a 28-year-old man with diaphoretic. His speech was loud and is not known what medications the chronic, undifferentiated schizophre- pressured. His vital signs were the patient was taking before the onset nia since his late teens, was evaluated following: heartbeat rate, 110 bpm; at the psychiatric clinic of the G.V. blood pressure (BP), 98/62; respira- Dr. Reeves is chief of psychiatry, Dr. Ladner is (Sonny) Montgomery VAMC in Jack- tion, 20 breaths/min; and tempera- a staff psychiatrist, and Mr. Smith is a physi- cian assistant, all in Mental Health Service at the son, Mississippi, where he reported ture, 102.6°F. An examination of the G.V. (Sonny) Montgomery VA Medical Center in auditory hallucinations and para- heart, lungs, and abdomen revealed Jackson, Mississippi. Dr. Reeves is a professor of noia. He also reported feeling hope- no additional evidence of pathology. psychiatry and neurology and Dr. Ladner is an as- sistant professor of psychiatry, both at the Univer- less about his future and depressed, Deep-tendon reflexes were diffusely sity of Mississippi School of Medicine in Jackson. because he could not maintain em- increased. Muscle tone in the extrem- 34 • FEDERAL PRACTITIONER • NOVEMBER 2013 ities was increased. No other physical days there, he again complained of injuries or insults, physical illness, abnormalities were detected. auditory hallucinations and depres- dehydration, rapid escalation of anti- Mr. A’s orientation was to per- sion. He was treated cautiously with psychotic dosage, use of high-potency son and year only. He could not ziprasidone and venlafaxine start- antipsychotic agents, and use of intra- recall the events of recent days. ing at low doses, which were then muscular antipsychotic agents.4 De- Laboratory findings included a titrated slowly. He was discharged hydration is a risk factor not only for white blood cell count (WBC) of 2 1/2 weeks later on ziprasidone NMS, but also for further complica- 13,800 cells/mm3 with a mild left 80-mg bid and venlafaxine 150-mg tions of NMS, explained later. shift. The chemistry survey results daily. Neuroleptic malignant syndrome were unremarkable, except for the During subsequent clinic visits, may be a serious disorder. Creati- mild elevation of the blood urea Mr. A maintained an euthymic mood. nine phosphokinase may rise to as nitrogen (BUN) (26 mg/dL)and He still experienced occasional hal- much as 60,000 IU/L. White blood creatinine (1.3 mg/dL) tests. Creat- lucinations and paranoia but was not cell counts are typically in the range inine phosphokinase (CPK) level disturbed by his symptoms. He was of 10,000 to 40,000 cells/mm3, some- was 402 IU/L. Liver function stud- able to procure and maintain em- times with a left shift.5 Possible medi- ies, serum iron level, and thyroid- ployment at a local grocery store, had cal complications are numerous and stimulating hormone results were no further episodes of agitation or can include organ failure, particularly within normal limits. The urine drug confusion, and experienced no AEs renal failure, possibly resulting from screen was negative, and the com- from his current medications. dehydration and from a large amount puted tomography scan of the head of myoglobin produced by rhabdo- and lumbar puncture findings were NEUROLEPTIC MALIGNANT myolysis. Pulmonary aspiration may unremarkable. SYNDROME occur due to dysphagia or obtunda- Determining the exact diagnosis All dopamine-blocking drugs are ca- tion. Respiratory failure may result for Mr. A’s condition was difficult. pable of precipitating NMS. Neuro- from aspiration pneumonia or de- His symptoms not only could have leptic malignant syndrome was first creased chest wall compliance. Deep been considered consistent with described in 1960 during clinical venous thrombosis and pulmonary NMS related to the recently started trials with haloperidol. Since then, embolus may occur secondary to im- olanzapine, but also with SS related NMS has been reported to occur mobility. Problems with electrolyte to the recently initiated sertraline. with all dopamine-blocking agents, imbalance may involve hypokalemia, Both medications were withheld. He including the newer atypical anti- hyponatremia, or hypernatremia. was admitted to an intensive care psychotic agents. The abrupt cessa- Other complications that have oc- unit (ICU) and closely monitored tion of dopaminergic-agonist drugs curred with NMS include myocardial and treated with supportive mea- used to treat Huntington disease and infarction, congestive heart failure, sures. In the ICU he was given intra- Parkinson disease may also produce cardiac arrhythmias, thrombocytope- 3 venous D5W 0.45% NaCl, requiring NMS-like conditions. nia, and disseminated intravascular 5 liters on the first day. He was given A large number of cases of NMS coagulation. Immobility may cause lorazepam as needed for agitation, have been reported, but many fea- pressure ulcers and related complica- receiving a total of 4 mg on the first tures of the syndrome remain contro- tions. These complications may in hospital day and 2 mg each on hos- versial. In a classic case, symptoms of some cases result in the death of the pital days 2 and 3. After 3 days his NMS include fever, autonomic insta- patient.5,6 confusion and agitation resolved, bility (BP instability and tachycardia), According to the Diagnostic and and he was able to communicate rigidity, and mental status changes. Statistical Manual of Mental Disorders, effectively. Laboratory parameters Medical students sometimes use the 4th Edition, Text Revision (DSM-IV- returned to normal ranges, includ- mnemonic FARM to recall this con- TR), the diagnosis of NMS should ing WBC, 8,700 cells/mm3; BUN, stellation of symptoms. Neuroleptic be assigned only to patients who de- 19 mg/dL; creatinine, 0.9 mg/dL; and malignant syndrome is frequently velop severe muscle rigidity and el- CPK, 190 IU/L. misdiagnosed and can be fatal in evated temperature while receiving Intravenous fluids were discon- 5% to 20% of patients if untreated.4 a neuroleptic drug and who display tinued, and Mr. A was transferred Risk factors for NMS include young 2 or more of the following signs and to a psychiatric unit. Within a few age, male gender, preexisting brain symptoms: diaphoresis, dysphagia, NOVEMBER 2013 • FEDERAL PRACTITIONER • 35 Neuroleptic Malignant Syndrome vs Serotonin Syndrome Table. Clues that may help distinguish neuroleptic malignant clinical presentation. The mortality rate of SS is unknown; the disorder syndrome and serotonin syndrome when no precipitating may resolve quickly with removal of 3,5,16,18 agent can be identified the offending agent(s) or may be po- Clinical course tentially fatal.6 Specific risk factors for SS have not been identified beyond Rapid onset and progression: More likely SS serotonin polypharmacy, such as the Rapid resolution: More likely SS potentially fatal combination of a se- Clinical symptoms lective serotonin reuptake inhibitor (SSRI) and a monoamine oxidase in- Gastrointestinal symptoms: More likely SS hibitor (MAOI).3 Shivering: More likely SS A review by Sternbach with sug- gested diagnostic criteria was pub- Clinical signs lished in 1991.11 Sternbach proposed Severe rigidity: More likely NMS criteria that included the occurrence Myoclonus: More likely SS concomitant with the addition of a serotonergic agent to an established Hyperreflexia: More likely SS medication regimen of at least 3 of Laboratory findings the following features: mental status changes (confusion, hypomania), ag- Severely elevated CPK: More likely NMS itation, myoclonus, hyperreflexia, di- Severely elevated WBC: More likely NMS aphoresis, shivering, tremor, diarrhea, Low serum iron levels: More likely NMS incoordination, or fever.