Serotonin Syndrome How to Avoid, Identify, &

Serotonin syndrome How to avoid, identify, & As the list of serotonergic agents grows, recognizing hyperthermic states and potentially dangerous drug combinations is critical to our patients’ safety. 14 Current VOL. 2, NO. 5 / MAY 2003 p SYCHIATRY Current p SYCHIATRY treat dangerous drug interactions Harvey Sternbach, MD Clinical professor of psychiatry UCLA Neuropsychiatric Institute Los Angeles, CA romptly identifying serotonin syndrome and acting decisively can keep side effects at the mild end of the spec- Ptrum. Symptoms of this potentially dangerous syndrome range from minimal in patients starting selective serotonin reuptake inhibitors (SSRIs) to fatal in those combining monoamine oxidase inhibitors (MAOIs) with serotonergic agents. This article presents the latest evidence on how to: • reduce the risk of serotonin syndrome • recognize its symptoms • and treat patients with mild to life- threatening symptoms. WHAT IS SEROTONIN SYNDROME? Serotonin syndrome is characterized by changes in autonomic, neuromotor, and cognitive-behavioral function (Table 1) triggered by increased serotonergic stimulation. It typically results from pharmacodynamic and/or pharmacokinetic interactions between drugs that increase serotonin activity.1,2 continued VOL. 2, NO. 5 / MAY 2003 15 Serotonin Table 1 activity or reduced ability to How to recognize serotonin syndrome secrete endothelium-derived nitric oxide may diminish the System Clinical signs and symptoms ability to metabolize serotonin.2 Autonomic Diaphoresis, hyperthermia, hypertension, tachycardia, pupillary dilatation, nausea, POTENTIALLY DANGEROUS diarrhea, shivering COMBINATIONS Neuromotor Hyperreflexia, myoclonus, restlessness, MAOIs. Serotonin syndrome tremor, incoordination, rigidity, clonus, has been reported as a result of teeth chattering, trismus, seizures interactions between MAOIs— Cognitive-behavioral Confusion, agitation, anxiety, hypomania, including selegiline and insomnia, hallucinations, headache reversible MAO-A inhibitors (RIMAs)—and various serotonergic compounds. These The syndrome was first identified in animal reports have included fatalities,4 some of which studies, followed by case reports in humans. The were preceded by severe hyperthermia with com- first review—with suggested diagnostic criteria— plications such as disseminated intravascular was published in 1991.1 coagulation, rhabdomyolysis, and renal failure. Since then, case reports have described sero- Some cases resulted from overdoses, but others tonin syndrome with many drug combinations, did not. including nonpsychotropics and illicit drugs. Most disturbingly, some cases occurred after Using an irreversible MAOI with a serotonergic patients had undergone agent is the most toxic reported the traditional 2-week combination, but any drug or com- washout from the MAOI and then bination that increases serotonin Some fatal MAOI- took a serotonergic agent.5-7 In one can, in theory, cause serotonin syn- serotonergic instance,8 a patient who had discon- drome (Table 2). A clinical scale3 is interactions occur tinued fluoxetine for 6 weeks devel- being developed to define and iden- after the usual oped serotonin syndrome after starting tify this potentially dangerous state, 2-week washout tranylcypromine. These cases remind but no consensus has emerged on us to be vigilant when switching diagnostic criteria. patients from irreversible MAOIs to Pathophysiology. Serotonin syndrome’s symptoms serotonergic antidepressants or vice and signs appear to result from stimulation of versa—even when recommended wash-out times specific central and peripheral serotonin recep- are observed—and not to combine these agents tors, especially 5HT1a and 5HT2. Others—such acutely. as 5HT3 and 5HT4—may also be involved in Selegiline is a relatively selective MAO-B inhibitor causing GI symptoms and may affect dopaminer- when used at 5 to 10 mg/d to treat Parkinson’s dis- gic transmission. ease, though it loses MAO-B selectivity when Damaged vascular or pulmonary endotheli- used at higher dosages to treat depression. In a um, atherosclerosis, hypertension, or hypercho- study9 of 4,568 patients with Parkinson’s disease lesterolemia may increase the risk for serotonin who received selegiline (in dosages selective for syndrome. In patients with these common med- MAO-B) plus an antidepressant: ical conditions, reduced endothelial MAO-A • 11 (0.24%) experienced symptoms “possi- continued on page 19 16 Current VOL. 2, NO. 5 / MAY 2003 p SYCHIATRY Current p SYCHIATRY continued from page 16 bly” consistent with Table 2 serotonin syndrome Serotonergic agents and their actions • 2 others (0.04%) experienced serious Actions Agents serotonin syndrome Inhibit serotonin Fluoxetine, sertraline, citalopram, symptoms.9 reuptake escitalopram, paroxetine, clomipramine, Serotonin syndrome has venlafaxine, fluvoxamine, tramadol, been reported when MAO- trazodone, nefazodone, tricyclic B-selective doses of selegiline antidepressants, amphetamine, cocaine, were combined with meperi- dextromethorphan, meperidine, St. John’s wort dine10 and nortriptyline.11 Increases serotonin Tryptophan This underscores the need synthesis for caution when combining Inhibit serotonin Phenelzine, tranylcypromine, isocarboxazid, these agents, especially if metabolism selegiline (deprenyl), linezolid, moclobemide transdermal selegiline— Increase serotonin MDMA (“Ecstasy”), amphetamine, cocaine, which would not be MAO- release fenfluramine B-selective—becomes avail- Increase serotonin Lithium, ECT able for treating depression. activity Moclobemide is a RIMA used Serotonin receptor Buspirone, sumatriptan and other “triptans” in treating depression and agonists used for migraine anxiety, with a purported reduced risk of drug and food interactions compared with other MAOIs. Moclobemide is not approved in inhibition. Cases of potential serotonin syndrome the United States, but some patients obtain it have been reported with linezolid plus paroxe- elsewhere. tine17 or sertraline.18 Patients in each case were Joffe and Bakish reported on safely combin- medically ill and taking several other medica- ing moclobemide with SSRIs,12 and a review of tions, which complicates interpretation of these MAOIs—including RIMAs—indicated that reports. Nonetheless, physicians should be aware moclobemide was involved in only 9 of 226 cases of the potential risk of serotonin syndrome if this of adverse effects and 3 of 105 cases of defined antibiotic is combined with serotonergic agents. serotonin syndrome.13 Most moclobemide-SSRI Atypical antipsychotics. Original diagnostic crite- interactions—including fatalities—involved ria for serotonin syndrome excluded the addition overdoses in suicide attempts, although toxic of, or increase in, an antipsychotic prior to the symptoms have been reported with clomipramine syndrome’s onset.1 However, serotonin syndrome or meperidine taken at normal dosages.14,15 has been reported with combinations of risperi- In one study,16 18 healthy controls received done with paroxetine,19 olanzapine with mirtaza- fluoxetine, 20 to 40 mg/d, for 23 days, then were pine and tramadol,20 and olanzapine with lithium given moclobemide, up to 600 mg/d, or placebo and citalopram.21 The 5HT2 antagonist effect of and observed for adverse effects. No indication of these atypical antipsychotics may have led indi- serotonin syndrome was observed. rectly to overactivation of 5HT1a receptors and Linezolid is an oxazolidinone antibiotic with rela- serotonin syndrome. In each case, neuroleptic tively weak, nonspecific, but reversible MAO malignant syndrome was ruled out. VOL. 2, NO. 5 / MAY 2003 19 Serotonin syndrome Table 3 Signs and symptoms that differentiate 5 hyperthermic states Hyperthermic state Symptoms/signs Lab findings Cause Serotonin Typically rapid onset with Nonspecific Increased syndrome hyperreflexia, tremors, serotonergic tone myoclonus, diaphoresis, confusion, agitation, or shivering; muscular rigidity not invariably present Neuroleptic Variable rapidity of onset; Elevated CPK, Blockade of dopamine malignant severe muscular rigidity, leukocytosis receptors or abrupt syndrome diaphoresis, delirium, withdrawal of a fluctuating blood pressure, dopamine agonist tachycardia, extrapyramidal symptoms Lethal catatonia Muscular rigidity, Nonspecific Evidence of pre-existing diaphoresis, delirium, psychosis (bipolar alternating extreme disorder, schizophrenia) excitement and stupor, tremors, hypertension Anticholinergic Hot, dry skin, pupillary Nonspecific Agents that block central toxicity dilatation, tachycardia, and peripheral constipation, urinary muscarinic cholinergic retention, confusion, receptors hallucinations, muscular relaxation Malignant Rapid onset, severe Elevated CPK, Inherited disorder hyperthermia muscular rigidity, potassium, with onset after exposure ischemia, hypotension magnesium; to anesthetic agents DIC; acidosis; that block the rhabdomyolysis neuromuscular junction CPK: creatine phosphokinase DIC: disseminated intravascular coagulation Tramadol is an analgesic with opioid and sero- nists used in treating migraine. Gardner and tonin-reuptake inhibiting properties that is Lynd24 concluded that most patients tolerate metabolized by the cytochrome P (CYP)-450 iso- sumatriptan with SSRIs or lithium. They felt enzyme 2D6. Serotonin syndrome has been they could not ensure the safety of sumatriptan reported from interactions between tramadol and with MAOIs, however, because sumatriptan sertraline22 and fluoxetine.23 Possible causes elimination depends

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