The serotonin syndrome, also referred to as the toxic serotonin syndrome (TSS) is a symptom complex caused by an increase in the biologic activity of serotonin. It most often occurs in patients being treated concurrently with 2 or more drugs that increase brainstem serotonin activity or stimulate serotonin receptors. It is associated with several of the medications used to treat depression or other psychiatric conditions, and it has been noticed more often since the introduction of the selective serotonin reuptake inhibitors (SSRI).


Criteria for the diagnosis of the serotonin syndrome:

(1) 3 or more of the following are present:

(1a) confusion, hypomania or other mental status change

(1b) agitation, restlessness (akathisia)

(1c) frightened, diaphoretic hyperarousal state

(1d) myoclonus

(1e) hyperreflexia

(1f) diaphoresis

(1g) shivering, may be uncontrollable

(1h) tremor

(1i) diarrhea

(1j) incoordination

(1k) oculogyric crisis

(1l) fever

(2) onset of symptoms coincident with the addition or increase in a drug with serotonergic activity

(3) a neuroleptic (antipsychotic agent) was not started or increased in dosage prior to the onset of symptoms

(4) other etiologies (infectious, metabolic, drug abuse, withdrawal syndrome, poisoning) have been excluded


Agents potentially causing the serotonin syndrome (after Table 2, Mills, 1995):

(1) increase in serotonin synthesis

(1a) L-tryptophan

(2) decrease in serotonin metabolism, resulting in accumulation to toxic levels

(2a) mono-amine oxidase (MAO) inhibitors (isocarboxazid, phenelzine, selegiline, tranylcypromine)

(3) increase serotonin release

(3a) amphetamines

(3b) cocaine

(3c) fenfluramine

(3d) reserpine (initially)

(4) inhibition of serotonin uptake

(4a) tricyclic antidepressants (TCA): amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline

(4b) selective serotonin reuptake inhibitors (SSRI): fluvoxamine, fluoxetine, paroxetine, nefazodone, sertaline, trazodone

(4c) amphetamines

(4d) cocaine

(4e) dextromethorphan

(4f) meperidine

(4g) venlafaxine

(5) direct serotonin receptor agonists

(5a) buspirone

(5b) LSD

(5c) sumatriptan

(6) nonspecific increase in serotonin activity

(6a) lithium

(6b) electroconvulsive therapy

(7) dopamine agonists

(7a) amantadine

(7b) bromocriptine

(7c) bupropion

(7d) levodopa


Differential diagnosis:

(1) neuroleptic malignant syndrome – This shows muscle rigidity.

(2) anticholinergic syndrome



(1) discontinue medication(s) with serotonergic activity

(2) supportive care

(3) consider administration of a nonselective serotonin receptor antagonist (methysergide, cyproheptadine or propranolol)


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