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	Serotonin Syndrome Mon 30th Sep 2002 Associate Professor Chris Alderman (School of Pharmacy & Medical Sciences, University of South Australia and Director of Pharmacy, Repatriation General Hospital) recently presented a very informative discussion to the pharmacists at HPS on antidepressant use in Australia and in particular the adverse reaction known as serotonin syndrome. Anti-depressant use has changed dramatically in the past decade. In 1990 Prozac was launched onto the American market and since then a myriad of new agents have been released. Newer agents are released onto the market quicker and the uptake of these agents by prescribers is also rising, however older drugs are still being used at roughly the same rate. This means more patients are being diagnosed and treated with these new agents. If we look at the treatment options available in the 1980’s compared to 2002 the amount of growth in this area becomes apparent. MID 1980’s TCA’s (8) Nonselective MAOI’s (2) Psychotherapy ECT 2002 TCA’s (7) Nonselective MAOI (1) ECT Psychotherapy Augmented therapy (Lithium, liothyronine, pindolol) Plus Selective MAOI (moclobemide) SSRI’s (fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine) SNRI’s (venlafaxine, nefazadine) 5HT receptor modulators (mirtazapine) NARI’s Looking at the older drugs vs the newer drugs there appears to be no robust evidence for efficacy differences. The older drugs are well known, prescribers are familiar with their adverse reaction profile and know what to expect and how to treat it. Whilst the newer agents may have better usefulness in certain situations we are still building up an understanding of their adverse reaction profile. Serotonin syndrome is an example of the uncertainty surrounding the safety and tolerability of the newer agents. However the syndrome itself is not new; the first report was made in 1960 as a reaction between tryptophan and the MAOI phenelzine, and since then over 200 reports have been published in journals worldwide. The syndrome is still regarded with some scepticism and the main reason for this is the non-specific/symptoms that are associated with it. An excellent reference to "Serotonin States" in Therapeutic Guidelines Psychotropic 2000 lists the distinguishing features between SSRI discontinuation syndrome, adverse effects, depression symptoms and serotonin syndrome. Another problem is that while the number of reports is increasing the quality of the reports are variable. The landmark paper on this subject was published in 1991 - Sternbach H. The Serotonin Syndrome, American J Pyschiatry, 1991;148:705-13 This paper gives suggested diagnostic criteria for serotonin syndrome. A. Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen, at least three of the following clinical features are present: 1. mental status changes ( confusion, hypomania) 2. agitation 3. myoclonus 4. hyper reflexia 5. diaphoresis ( profuse perspiration) 6. shivering 7. tremor 8. diarrhoea 9. incoordination 10. fever B. Other etiologies (eg infectious, metabolic, substance abuse or withdrawal) have been ruled out. C. A neuroleptic had not been started or increased in dosage prior to the onset of the signs or symptoms listed above. It is important to note that studies have shown that approximately 75% of cases present with 24 hours of the increase or addition of a serotonergic agent. Clinical circumstances leading to serotonin syndrome include: - overdose - multiple agent overdose - supratherapeutic doses - paediatric presentation - breast milk penetration - drug interactions The drugs implicated include: - TCA’S - MAOI’s - Lithium - Carbamazepine - Neuroleptics - Moclobemide and selegiline - SSRI’s - Nefazodone - Venlafaxine - Mirtazapine - Buspirone - Anti-retrovirals (affect the metabolism of serotonin agent) - Pethidine - Dextromethorphan - Fentanyl - Tramadol - Triptan antimigraine drugs - MDMA(ecstasy), cocaine, LSD - Bupropion Why does it happen? - poorly understood by prescribers and pharmacists - inappropriate dosing - lack of evidence-based practice - pharmacokinetic interactions (eg SSRI’s profoundly inhibit the metabolic clearance of TCA’s, so a small dose of TCA added to a SSRI will in fact give the response of a much higher dose) - non-specific signs - Inappropriate washout periods ( guideline are given but the period required is dependent on the individual patient circumstances eg young fit patient compared to an older frail patient and community setting compared to hospital). Mechanism It is thought to occur as a result of overstimulation of the 5HT1A receptor and may also involve the 5HT2 and 5HT3 receptors. There appears to be an overlap with the neuroleptic malignant syndrome and longer acting agents are associated with a poorer prognosis. Management - discontinuation of the offending agents - supportive care - IV fluids - Chlorpromazine (antiserotonic agent) - Dantrolene ( muscle relaxant) - Cyproheptadine ( antiserotonic agent) In summary the serotonin syndrome is a self –limiting condition that resolves quickly when the offending serotonergic agents are removed, although fatalities can occur, so early recognition and treatment is vital. Whilst the exact incidence is unknown it is probably more common than appreciated and could continue to rise as more agents enter the market. Increased awareness by prescribers and pharmacists of the potential for this to occur when increasing doses or using combination therapy will help to prevent this potentially life threatening event from occurring. Jenny Pink Clinical Pharmacist     back