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Serotonin syndrome |
Summary
Serotonin syndrome is a toxic state caused mainly by excess serotonin within the central nervous system. It results in a variety of mental, autonomic and neuromuscular changes, which can range in severity from mild to life-threatening. Most cases are self-limiting. Severe serotonin syndrome is nearly always caused by a drug interaction involving two or more 'serotonergic' drugs, at least one of which is usually a selective serotonin reuptake inhibitor or monoamine oxidase inhibitor. Management involves withdrawal of the offending drugs, aggressive supportive care and occasionally serotonin antagonists such as cyproheptadine. Treatment of the condition for which the serotonergic drugs were prescribed should be reviewed.
Key words: selective serotonin reuptake inhibitors, drug interactions, cyproheptadine.
(Aust Prescr 2003;26:62-3)
Introduction
The treatment of depression in Australia has evolved greatly over the lasttwo decades. Tricyclic antidepressant use is decreasing, while the use of selectiveserotonin reuptake inhibitors (SSRIs) is increasing. In 2001, prescriptionsfor SSRIs outnumbered those for tricyclics by two to one.1 Othernew antidepressants with serotonergic properties are also being introduced.Although SSRIs and the other 'atypical' antidepressants are generally regardedas having lower toxicity than tricyclics, minor toxic effects are common, andserious toxicity can occur.
Serotonin syndrome refers to a drug-induced syndrome that is characterisedby mental, autonomic and neuromuscular changes. It is not an idiosyncraticadverse reaction, but a dose-related range of toxic symptoms that are largelyattributable to increasing serotonin concentrations in the central nervoussystem. Serotonin syndrome was first described in 1955, but during the 1990sreports became increasingly common, as the signs, symptoms, and precipitantsbecame more widely recognised. Although severe cases have been reported withan overdose of a single drug, they usually only occur with a combination oftwo or more 'serotonergic' drugs (even when each is at a therapeutic dose),presumably leading to an excessive rise in serotonin concentrations. The trueincidence of serotonin syndrome is unknown, because of a lack of large caseseries, a wide spectrum of symptoms and variations in the definition.
Pathophysiology
Serotonin (5-hydroxytryptamine, 5-HT) is synthesised from the amino acid tryptophan.It has central and peripheral effects and there are at least seven differenttypes of serotonin receptors. Centrally, serotonin acts as a neurotransmitterwith influences on mood, sleep, vomiting and pain perception. Depression isoften associated with low concentrations of serotonin. Peripherally, the primaryeffect of serotonin is on muscles and nerves. The majority of serotonin issynthesised and stored in the enterochromaffin cells of the gut where it causescontraction of gastrointestinal smooth muscle. Serotonin is also stored inplatelets and promotes platelet aggregation. It also acts as an inflammatorymediator.
The pathophysiology of serotonin syndrome remains poorly understood. It isthought to result from stimulation of the 5-HT1A and5-HT2 receptors, and the drug classes implicatedin serotonin syndrome reflect this theory. These include serotonin precursors,serotonin agonists, serotonin releasers, serotonin reuptake inhibitors, monoamineoxidase inhibitors (MAOIs) and some herbal medicines (Table 1).Commonly used migraine medications such as sumatriptan and dihydroergotamineare also regarded as 'serotonergic' drugs. There are isolated case reportsof mild/moderate serotonin syndrome associated with these drugs. Most caseswill involve either an SSRI or an MAOI and at least one other medication. Generally,drugs with two different mechanisms of action on serotonin must be presentfor a severe serotonin syndrome to develop.
Some other drugs may cause serotonin syndrome although how this happens remainsunclear. Drugs with effects on catecholamines, tryptamine and dopamine mayhave secondary effects on serotonin release or reuptake.
Diagnosis
The diagnosis of serotonin syndrome is purely clinical. It is based upon recognisinga varied combination of signs and symptoms in the presence of selected 'serotonergic'medications. The diagnosis should not be made without identifying a cause.Serotonin syndrome most commonly occurs after a dose increase (or overdose)of a potent serotonergic drug or shortly after a second drug is added. Someof the drugs involved have very long half-lives (e.g. fluoxetine) and may havebeen ceased weeks before. There may be a history of recent overdose or useof illicit drugs, particularly ecstasy, amphetamines or cocaine. Herbal medicinesmay be implicated (St John's wort, ginseng, S-adenosyl-methionine).
The clinical features of serotonin syndrome are highly variable, reflectingthe spectrum of toxicity (Table 2). The onset can be dramaticor insidious. The most useful features in the diagnosis of serotonin syndromeare hyperreflexia and clonus (inducible/spontaneous/ocular). However, manypatients taking SSRIs may display one or more of the clinical features withoutgross toxicity.
Investigations are generally unhelpful in the diagnosis of serotonin syndrome,but may assist in treatment and in ruling out a differential diagnosis. Thewhite cell count is often mildly raised and elevations in creatine kinase levelsmay occur.
The differential diagnosis includes neuroleptic malignant syndrome, dystonicreactions, encephalitis, tetanus, thyroid storm and sepsis, as well as poisoningby anticholinergic drugs, amphetamines, cocaine, lithium, MAOIs, salicylatesand strychnine. Serotonin syndrome can also be confused with the withdrawalof antidepressant treatment.2 Serotoninsyndrome and the other agitated deliriums share many clinical features, butclonus, hyperreflexia and flushing are the most specific signs.
Time course/complications
In most cases, serotonin syndrome is a self-limiting condition and will improveon cessation of the offending drugs. Mild to moderate cases usually resolvein 24-72 hours. In severe cases patients require intensive care as thesyndrome may be complicated by severe hyperthermia, rhabdomyolysis, disseminatedintravascular coagulation and/or adult respiratory distress syndrome.
Treatment
Recognising the possibility of serotonin syndrome and diligent supportivecare are the mainstays of treatment. All patients with moderate or severe serotonergicsymptoms should be admitted to hospital. Those with hyperthermia should beadmitted to an intensive care unit. All serotonergic medications should beceased, and care taken that other precipitants are not inadvertently administered.Intravenous hydration is given, to ensure an adequate output of urine. Carefulmonitoring of temperature, pulse, blood pressure and urine output is required.Aggressive cooling techniques may be required for hyperthermia. This may involvecool water sprays, ice packs, and even paralysis and ventilation. Benzodiazepinesmay be used to control seizures and muscle hyperactivity. Specific treatmentof hypertension is usually not required.
Serotonin antagonists have been used in management of moderate to severe serotoninsyndrome. Cyproheptadine is possibly the most promising drug.3 Theinitial dose is 4-8 mg orally. This may be repeated in two hours. If noresponse is seen after 16 mg it should be discontinued. If there is a responsethen it may be continued in divided doses up to 32 mg/day (e.g. up to 8 mgfour times daily). Other drugs that have been suggested include chlorpromazineand propranolol, but these have more contraindications and adverse effects.
After the patient has recovered reconsider the ongoing treatment of the conditionfor which the serotonergic drug was prescribed.
Prevention
The prevention of serotonin syndrome involves awareness of the toxic potentialof serotonergic drugs. The manufacturer's advice about washout periods shouldbe carefully considered when switching antidepressants and patients shouldalso be educated about possible drug interactions.
E-mail: michael.hall@act.gov.au
References
1. Data produced by Drug Utilisation Sub-Committee, PharmaceuticalBenefits Branch, Health Access and Financing Division, Commonwealth Departmentof Health and Ageing, Canberra, 2002.
2.Tiller JWG. Medicinalmishaps: serotonin states. Aust Prescr 1998;21:63.
3. Chan BS, Graudins A, Whyte IM, Dawson AH, BraitbergG, Duggin GG. Serotonin syndrome resulting from drug interactions. Med J Aust1998;169:523-5.
F U R T H E R R E A D I N G
Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-9.
Gillman PK. Serotonin syndrome: history and risk. Fundam Clin Pharmacol 1998;12:482-91.
Conflict of interest: none declared
