Serotonin and Neuroleptic Malignant Syndromes Linked to Venlafaxine Overdose and Amantadine Withdrawal

DECEMBER 17, 2007
Ella H. Bowman, MD, W. Jeffrey Brown, MS, RPh, and Angela T. Corea, MD

Ella H. Bowman, MD

Assistant Professor of Clinical Medicine
Division of General Internal Medicine and Geriatrics
Indiana University School of Medicine

W. Jeffrey Brown, MS, RPh

Clinical Pharmacy Specialist
Internal Medicine Department
St. Vincent Hospital

Angela T. Corea, MD

Internal Medicine Department
St. Vincent Hospital

Indianapolis, Ind

Serotonin syndrome and neuroleptic malignant syndrome are potentially life-threatening dysautonomias associated with the use of agents that affect neurotransmission mediated by serotonin and dopamine, respectively.1,2 The 2 syndromes can be difficult to diagnose and differentiate, because they share common symptoms with each other and with many other disorders. Patients with either syndrome may present with confusion, agitation, muscle rigidity, hypertension, and hyperthermia. If severe cases are untreated, rhabdomyolysis, seizure, coma, and death can occur.

Case Presentation

A 45-year-old man with a long history of major depression with psychotic features, along with well-controlled essential hypertension, was hospitalized after an intentional overdose of venlafaxine HCl (Effexor). The patient had reportedly taken 30 capsules of venlafaxine 150-mg extended-release approximately 8 hours before being found with seizurelike activity and agitation, which was followed by a period of unresponsiveness. The patient had no history of seizure. In the emergency department he was noted to be lethargic, and he complained of nausea.

His preadmission medications included duloxetine (Cymbalta), verapamil HCl (Calan), ziprasidone (Geodon), amantadine HCl (Symmetrel), and hydrochlorothiazide (Ezide, HydroDIURIL, Hydro-Par). The venlafaxine prescription had been discontinued several weeks before this new event.

On arrival, the man was awake and alert but profoundly diaphoretic. Neurologic examination revealed myoclonus of both legs and pill-rolling tremor of the arms; he was hyperreflexic throughout. Signs of mild tardive dyskinesia included repetitive blinking of the eyes and lip smacking. Laboratory findings were remarkable for an elevated creatine kinase (CK) level (315 U/L). Heart rate was 132 beats/min, and blood pressure (BP) was 127/65 mm Hg. A urine drug screen was negative for coingestants or illicit substances.

No specific treatment was initiated in the emergency department. A presumptive diagnosis of serotonin syndrome was made, and the patient was admitted for observation and supportive care. Verapamil therapy was continued to treat his hypertension, but the hydrochlorothiazide, duloxetine, ziprasidone, and amantadine therapies were withheld.

On hospital day 2, the patient was still extremely diaphoretic and tremulous. He was also disoriented and confused. His pulse decreased to 110 beats/min, his BP rose to 148/88 mm Hg, and he remained afebrile. The CK level increased to 899 U/L. Examination revealed mild cogwheel rigidity of the arms, ongoing myoclonus, and hyperreflexivity. Intravenous fluids were started at this time, because of his poor oral intake, degree of disorientation, and potential for dehydration.

On hospital day 3, the patient's temperature increased to 100.5?F, BP rose to 155/82 mm Hg, and CK level increased to 1461 U/L. Hyperreflexia, diaphoresis, tremors, rigidity, myoclonus, and confusion were worse than on the previous day. The pupils were noted to be markedly dilated, and he developed total mutism. A presumptive diagnosis of neuroleptic malignant syndrome secondary to amantadine withdrawal was made, and oral amantadine, 100 mg twice daily, was resumed.

On day 4, the CK concentration decreased to 596 U/L, and the patient was less tremulous and diaphoretic. Hyperreflexia and myoclonus decreased. Temperature decreased to 99.3?F, pulse to 68 beats/min, and BP to 145/80 mm Hg. The patient's confusion began to resolve. He became minimally responsive and was only able to answer questions with a yes or a no.

On day 5, the patient was markedly improved, with most of the neurologic symptoms of serotonin syndrome and neuroleptic malignant syndrome resolved. BP remained slightly elevated as did the CK level (319 U/L). The patient was told to resume taking duloxetine and verapamil and to continue taking amantadine, and he was discharged to an inpatient mental health center for ongoing treatment of his depression.


Serotonin syndrome and neuroleptic malignant syndrome can be challenging to diagnose because of overlapping signs and symptoms, which also overlap with less-common disorders, such as anticholinergic poisoning and malignant hyperthermia.2 Nevertheless, several obvious, and many subtle, differences can be used to differentiate between the 2 conditions (Table).

Serotonin syndrome

The serotonin syndrome, which results from a hyperserotonergic state, is characterized by a triad of features1:

  • Altered mental status
  • Hyperactivity
  • Neuromuscular disorders.

The syndrome usually results from an interaction between a combination of medications that include serotonergic activity and less frequently from a single drug overdose. In a study of 469 patients admitted to a hospital after a selective serotonin reuptake inhibitor overdose, 14% of these patients were diagnosed with serotonin syndrome.3

Common manifestations of the serotonin syndrome include agitation, delirium, mydriasis, diaphoresis, hyperpyrexia, fluctuating BP, tremor, rigidity, hyperreflexia, and myoclonus. Elevations of CK concentration and leukocytosis occur in some patients. Onset of signs and symptoms typically occurs within hours or days of exposure to the offending agents and resolve within 24 to 72 hours of withdrawing the drug and starting therapy in most cases.

There does not appear to be a gender predilection for serotonin syndrome, and it has occurred in all age-groups and ethnicities. No valid epidemiologic studies of long-term complications have been conducted,1 likely because the majority of physicians are unaware of the diagnosis. 4 Most patients who survive serotonin syndrome do not suffer long-lasting effects.1

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a rare condition that occurs most often in patients receiving high-potency, typical neuroleptic agents. In a study of 78,700 patients treated with neuroleptic medications, the incidence rate of the syndrome was 0.02%.5

Patients treated for an extended period of time with dopaminergic agents, including amantadine, have also developed the syndrome upon abrupt discontinuation of these drugs.6-8

Neuroleptic malignant syndrome has also been associated with atypical antipsychotic agents, including clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel).9 The syndrome is characterized by the following features2:

  • Autonomic dysfunction
  • Elevations in CK and white blood cell count
  • Fever
  • Hyperthermia
  • Mental status changes
  • Severe muscle rigidity
  • Tremor.

Common signs and symptoms include significant "lead-pipe" muscle rigidity, hyperpyrexia, tremor, diaphoresis, tachycardia, leukocytosis, elevation of serum CK, and confusion without agitation or frank stupor. The onset tends to be gradual; manifestations may present within a few days or weeks of initiating treatment or of increasing the dosage of a neuroleptic or dopamine receptor blocking agent. However, neuroleptic malignant syndrome has also occurred after a single dose or after prolonged treatment.

The average duration of the syndrome ranges from several days to weeks. Most patients who survive the acute episode have no lasting effects. However, some patients have persistent central nervous system impairment, peripheral neuropathy, or worsening of a psychiatric illness.10 In a study of 4831 neuroleptic-treated patients, 8 developed neuroleptic malignant syndrome, 1 of whom had persistent clinical sequelae (extrapyramidal and cerebellar symptoms) at 3 years after the initial episode.11

Most patients are between the ages of 20 and 50 years, presumably because this is the age range in which the use of neuroleptic agents peaks.2 However, the disorder has been reported in all age-groups. The incidence in men is nearly twice as high as in women.2 Associated mortality rate has been reported to be as high as 38%, but current literature suggests the rate ranges between 10% and 14%.5,12

Features common to both syndromes

The symptoms of both serotonin syndrome and neuroleptic malignant syndrome can be mild, moderate, or severe. Severe complications of both syndromes include rhabdomyolysis, renal failure, respiratory failure, seizure, venous thromboembolism, myocardial infarction, and death. Diagnosis is based on a thorough medication history, physical examination, and the exclusion of other conditions.


Treatment is primarily supportive, in addition to the immediate discontinuation of the offending agent(s) or, in the case of a withdrawal reaction from dopamine agonists, prompt resumption of an appropriate agent. In severe cases, pharmacotherapy specific for the disorder may be necessary. Serotonin syndrome may be treated with the serotonin antagonist cyproheptadine and with benzodiazepines (eg, Valium, Xanax).1 The use of dantrolene sodium (Dantrium) for the treatment of patients with serotonin syndrome is controversial and cannot be recommended at the present time.1 Severe cases of neuroleptic malignant syndrome are treated with benzodiazepines, dantrolene, or dopamine agonists, such as amantadine or bromocriptine mesylate (Parlodel).2


Our case is unique in that the patient presented with serotonin syndrome and soon progressed to a neuroleptic malignant syndrome that resulted in a confusing constellation of symptoms. A careful review of his medications, the changes in the quality of his symptoms, and the time course of events aided in distinguishing between serotonin syndrome and neuroleptic malignant syndrome. His temperature did not rise until the third day of hospitalization, presumably because hyperthermia is less common with serotonin syndrome than with neuroleptic malignant syndrome. Similarly, the elevation in CK peaked later in the course of treatment.

The patient never developed the classic "lead-pipe" rigidity usually observed with neuroleptic malignant syndrome; we postulate that the severe hyperreflexivity from the serotonin syndrome masked or prevented the development of this sign. His mental status rapidly progressed from agitation to normal to global confusion without agitation, and then to complete mutism—again, consistent with the time course of the syndromes.

Our experience shows that many patients are treated with medications that can cause serotonin syndrome or neuroleptic malignant syndrome. A significant percentage of such patients are treated with more than 1 of these agents, thereby increasing their risk of developing one or both disorders. It is important for physicians who work with such patients to familiarize themselves with the differential diagnosis and treatment of these 2 syndromes, and to be vigilant to the signs and symptoms when they do arise.


  1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005; 352:1112-1120.
  2. Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv. 1998;49:1163-1172.
  3. Isbister GK, Bowe SJ, Dawson A, et al. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277-285.
  4. Mackay FJ, Dunn NR, Mann RD. Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract. 1999;49:871-874.
  5. Spivak B, Maline DI, Kozyrev VN, et al. Frequency of neuroleptic malignant syndrome in a large psychiatric hospital in Moscow. Eur Psychiatry. 2000;15:330-333.
  6. Stotz M, Thummler D, Schurch M, et al. Fulminant neuroleptic malignant syndrome after perioperative withdrawal of antiParkinsonian medication. Br J Anaesth. 2004;93:868-871.
  7. Brown CS, Wittkowsky AK, Bryant SG. Neuroleptic-induced catatonia after abrupt withdrawal of amantadine during neuroleptic therapy. Pharmacotherapy. 1986;6:193-195.
  8. Wilson JA, Farquhar DL, Primrose WR, et al. Long term amantadine treatment. The danger of withdrawal. Scott Med J. 1987;32:135.
  9. Ananth J, Parameswaran S, Gunatilake S, et al. Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry. 2004;65:464-470.
  10. Adityanjee M, Sajatovic M, Munshi K. Neuropsychiatric sequelae of neuroleptic malignant syndrome. Clin Neuropharmacol. 2005;28: 197-204.
  11. Montoya A, Ocampo M, Torres-Ruiz A. Neuroleptic malignant syndrome in Mexico. Can J Clin Pharmacol. 2003;10:111-113.
  12. Panagariya A, Sharma B, Singh R, et al. The neuroleptic malignant syndrome: a report of 14 cases from North India. Neurol India. 2007; 55:166-168.

Copyright© MD Magazine 2006-2020 Intellisphere, LLC. All Rights Reserved.