Serotonin Syndrome: Causes and Treatment

Background

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter biosynthesized from the amino acid tryptophan by decarboxylation and hydroxylation. It binds to seven different families of the serotonin receptor (5-HT1 to 5-HT7) and elicits central and peripheral effects that affect mood, behavior, sleep-wake cycle, thermoregulation, pain perception, appetite, vomiting, muscles, and nerves, among others. Serotonin is vasoconstrictive and bronchoconstrictive, promotes platelet aggregation, and is an inflammatory mediator. In the intestine, it is produced in enterochromaffin cells, mediates smooth muscle contraction, and thus influences motility. It is degraded by monoamine oxidase A.

Symptoms

Depending on its course, serotonin syndrome manifests itself very differently in symptoms ranging from mild and subacute to severe and life-threatening. Possible symptoms include (1) behavioral or consciousness changes, (2) neuromuscular symptoms, and (3) autonomic symptoms:

  • Sweating or chills.
  • Rapid pulse, high blood pressure
  • Diarrhea, bowel sounds, nausea, vomiting.
  • Dilation of pupils
  • Coordination disorders, disturbance of the movement sequences
  • Inability to sit quietly
  • Excessive reflex excitability
  • Involuntary muscle twitching and contractions.
  • Increase in body temperature
  • Tremor
  • Confusion, agitation, restlessness, anxiety, hallucinations.

In a severe course, there is a sharp increase in body temperature, convulsions, delirium, coma, acidosis, clotting disorders, disintegration of skeletal muscles and renal failure.

Causes

The cause is increased central and peripheral synaptic serotonin action triggered by drugs, intoxicants, or food supplements. These promote the synthesis or release of serotonin, act as agonists directly at the receptors, inhibit reuptake into the presynaptic neuron, or inhibit degradation. Well-known and well-documented cases have occurred with antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs, SSRNIs), monoamine oxidase inhibitors (MAOIs), and amphetamines. There is an increased risk with the combination of serotonergic agents and with pharmacokinetic interactions, for example via cytochromes P450. In particular, the 5-HT1A– and 5-HT2A receptors are thought to be involved. Serotonin syndrome is not an idiosyncratic reaction but a predictable and dose-dependent adverse effect that begins shortly after ingestion of the appropriate triggers. The symptoms overlap with the adverse effects of serotonergic drugs and represent the end of a continuum. The boundary is drawn differently depending on the author.

Trigger

The following table lists an incomplete selection of possible triggers of the syndrome mentioned in the literature and in drug technical information. Some are controversial as causes (e.g., the triptans, for which see Gillman, 2009) and not all may cause severe serotonin syndrome.

SSRI Citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone
SSNRI Duloxetine, sibutramine, venlafaxine
MAOI Linezolid, moclobemide, selegiline
Tricyclic antidepressants Amitriptyline, clomipramine, imipramine, opipramol, trimipramine
Other psychotropic drugs, neuroleptics Trazodone, buspirone, mirtazapine, flupentixol, ziprasidone, lithium, amphetamines, MDMA
Serotonin agonists Lorcaserin
Analgesics Fentanyl, pentazocine, pethidine (= meperidine), tramadol, tapentadol
Triptans Eletriptan, frovatriptan, naratriptan, oxitriptan, rizatriptan, sumatriptan, zolmitriptan
Antitussives Dextromethorphan
Antiepileptic drugs Carbamazepine, valproate
Antihypertensives Reserpine
Food supplements Tryptophan, S-adenosylmethionine
Phytopharmaceuticals St. John’s wort, ginseng, soy extracts.
Intoxicants Cocaine, LSD, psilocybin

Diagnosis

Mild manifestations are likely to be frequently overlooked because too little is known and symptoms are nonspecific and not associated with medications. Diagnosis is made on the basis of clinical signs and medication history. Specific laboratory tests are not yet available. Possible differential diagnoses include malignant neuroleptic syndrome, carcinoid syndrome, delirium tremens, malignant hyperthermia, poisoning, encephalitis, sepsis, and tetanus.

Treatment

Treatment is medical care and, if severe, hospitalization. Most cases are self-limiting within 1-2 days, provided the precipitating drugs are discontinued. Treatment is based on the nature and intensity of the symptoms. Medications used include medicated charcoal and benzodiazepines; cyproheptadine, beta-blockers, serotonin antagonists, and chlorpromazine abolish the action of serotonin at the receptor.

Prevention

The concomitant use of triggering drugs should be avoided to prevent the development of the syndrome. In practice, such combinations are nevertheless prescribed relatively frequently, for example in psychiatry, and mild to moderate serotonergic adverse effects are accepted (for example, diarrhea, tremor, sleep disturbances). It is important that the professionals involved and the patients are informed about the possible risks and that no additional serotonergic drugs are dispensed. Some combinations, such as MAOIs and SSRIs, are specifically contraindicated and should not be prescribed.