Evidence-Based Reviews

Serotonin syndrome: How to avoid, identify, & treat dangerous drug interactions

Current Psychiatry. 2003 May;2(5):14-24

References

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Reports have associated the following combinations with serotonin syndrome, perhaps as the result of pharmacodynamic and/or pharmacokinetic interactions:

paroxetine plus dextromethorphan and pseudoephedrine
paroxetine plus nefazodone
fluoxetine plus clomipramine and buspirone
fluvoxamine plus buspirone
fluoxetine plus buspirone
amitriptyline plus meperidine and venlafaxine
venlafaxine and dextroamphetamine
fluoxetine plus clomipramine.

Table 4

Clinical signs that distinguish hyperthermic states

Signs	Possible diagnosis
Prominent muscular rigidity	Neuroleptic malignant syndrome, malignant hyperthermia, catatonia
Myoclonus/hyperreflexia	Serotonin syndrome
Diaphoresis	Serotonin syndrome, neuroleptic malignant syndrome, catatonia
Hot dry skin	Anticholinergic toxicity
Elevated creatine phosphokinase	Neuroleptic malignant syndrome, malignant hyperthermia
Family history of anesthetic-induced hyperthermia	Malignant hyperthermia

HOW TO RECOGNIZE SEROTONIN SYNDROME

Signs and symptoms of serotonin syndrome can overlap with those seen in neuroleptic malignant syndrome, lethal catatonia, malignant hyperthermia, and anticholinergic toxicity (Table 3),^1,36,37 particularly with fever or hyperthermia (>40.5 °C, 105 °F). Fink³⁷ has opined that acute neurotoxic syndromes such as serotonin syndrome and neuroleptic malignant syndrome also meet criteria for catatonia and are therefore subtypes of catatonia. The types of drugs involved and clinical findings can help distinguish the various hyperthermic states (Table 4).

As mentioned above, original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic agent. This exclusion was intended to avoid confusion between serotonin syndrome and neuroleptic malignant syndrome. Co-administering antipsychotic and serotonergic agents requires heightened awareness for both neurotoxic syndromes.

TREATING MILD TO SEVERE CASES

If a patient develops serotonin syndrome, immediately discontinue the suspected agent(s) and observe carefully. In most cases, serotonin syndrome will resolve within 24 hours.

In mild cases, lorazepam, 1 to 2 mg slow IV push every 30 minutes until excessive sedation develops, may help. In moderate to severe cases, agents that block serotonin’s action are recommended,² including:

cyproheptadine (4 mg po every 4 hours as needed, up to 20 mg in 24 hours)
propranolol (1 to 3 mg IV every 5 minutes, up to 0.1 mg/kg).

Case reports attest to these agents’ potential benefit. Other clinicians have reported using mirtazapine,³⁵ nitroglycerin,³⁸ and chlorpromazine.¹

Serotonin syndrome symptoms resolved within minutes when IV nitroglycerin was used in a patient with serotonin syndrome and cardiac ischemia. The authors hypothesized that nitroglycerin, via nitric acid, provided an “off” signal for serotonin, though they did not advocate this as a routine treatment.³⁸

The rationale for using chlorpromazine is its potential to block serotonin receptors. I would avoid the routine use of any antipsychotic agent in this setting, however, to minimize the risk of neuroleptic malignant syndrome.

Severe cases. Intensive care observation and treatment is required for patients with severe serotonin syndrome, including evidence of hyperthermia, DIC, rhabdomyolysis, renal failure, or aspiration. In cases of hyperthermia, supportive measures and standard treatments include muscle relaxants, cooling, and endotracheal intubation.

Severe complications are most likely with interactions between MAOIs and serotonergic agents, especially in overdose. Therefore, using such combinations requires close observation.

Related resources

Di Rosa AE, Morgante L, Spina E et al. Epidemiology and pathoetiology of neurological syndromes with hyperthermia. Funct Neurol 1995;10:111-19.
Radomski, JW, Dursun SM, Reveley MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypothesis 2000;55: 218-24.
Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208-21.

Drug brand names

Almotriptan • Axert
Amitriptyline • Elavil
Buspirone • Buspar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Cyproheptadine • Periactin
Dextroamphetamine • Dexedrine
Dextromethorphan • Delsym
Efavirenz • Sustiva
Escitalopram • Lexapro
Fenfluramine • Pondimin
Fentanyl • Sublimaze
Fluoxetine • Prozac
Fluvoxamine • Luvox
Frovatriptan • Frova
Isocarboxazid • Marplan
Linezolid • Zyvox
Meperidine • Demerol
Mirtazapine • Remeron
Moclobemide • Aurorix
Nortriptyline • Pamelor
Naratriptan, • Amerge
Nefazodone • Serzone
Olanzapine • Zyprexa
Ondansetron • Zofran
Paroxetine • Paxil
Phenelzine • Nardil
Propranolol • Inderal
Risperidone • Risperdal
Ritonavir • Norvir
Rizatriptan • Maxalt
Saquinavir • Invirase
Selegiline • Eldepryl
Sertraline • Zoloft
Sumatriptan • Imitrex
Tramadol • Ultram
Tranylcypromine • Parnate
Trazodone • Desyrel
Venlafaxine • Effexor
Zolmitriptan • Zomig

Disclosure

Dr. Sternbach receives research grants from Otsuka America Pharmaceuticals and Eli Lilly and Co. and owns stock in Merck & Co., Pfizer Inc., and Johnson & Johnson.