M irtazapine is a tetracyclic antidepressant with specific effects on the noradrenergic and serotonergic sys- tems. It is an antagonist of central presynaptic α 2 -adrener- gic receptors, and a potent antagonist of postsynaptic 5-hy- droxytryptamine (5-HT) 2 and 3 serotonin receptors, lead- ing to an increase of norepinephrine and serotonin activity, especially at the 5-HT 1A level. However, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin. In addition to mirtazapine’s action on the serotonergic sys- tem, it has a high affinity to the histamine 1 (H 1 ) receptors, causing a sedative effect and improving sleep in patients receiving this drug. 1 Mirtazapine has a faster onset of action in contrast with other selective serotonin-reuptake inhibitors, and is usually accepted as being safe, even when taken in overdose, be- cause of its low incidence of adverse effects, mainly drowsiness, sedation, increased appetite, and weight gain. 2 The serotonin syndrome (SS) is a rare and potentially severe adverse drug reaction identified in humans in 1982 by Insel et al. 3 It is characterized by a triad of clinical man- ifestations: altered mental status, autonomic dysfunction, and neuromuscular abnormalities. The most frequent sero- tonin receptor involved in SS pathogenesis is 5-HT 1 , main- ly the 5-HT 1A subtype. The syndrome usually develops with ≥2 drugs that increase serotonin neurotransmission, although cases with single-agent involvement have been reported. 4 We report a patient who developed severe SS associated with mirtazapine monotherapy. Case Report A 75-year-old man was admitted to our hospital with impaired con- sciousness. His past medical history included chronic obstructive pul- monary disease and major depression diagnosed 3 months earlier. His medications included salbutamol 100 μg 4 times daily, ipratropium bro- mide 0.02 mg 4 times daily, and nimodipine 30 mg/d, which he had tak- en for a number of years. Mirtazapine 15 mg/d had been started 8 days The Annals of Pharmacotherapy ■ 2002 April, Volume 36 ■ 641 Severe Serotonin Syndrome Induced by Mirtazapine Monotherapy José L Hernández, Francisco J Ramos, Jon Infante, Mariano Rebollo, and Jesús González-Macías www.theannals.com Author information provided at the end of the text. OBJECTIVE: To document a case of serotonin syndrome (SS) associated with mirtazapine monotherapy, review the previously reported cases of SS associated with this tetracyclic antidepressant, and discuss the possible pathogenic mechanisms leading to this serious adverse drug reaction. CASE SUMMARY: A 75-year-old man developed agitation, confusion, incoordination, and gait disturbance because of progressive rigidity. Mirtazapine had been started 8 days earlier to control major depression. Physical examination revealed diaphoresis, low- grade fever, hypertension, tachycardia, bilateral cogwheel rigidity, hyperreflexia, tremor, and myoclonus, symptoms and signs that are consistent with severe SS. DISCUSSION: A review of the cases of SS with implication of mirtazapine as the cause was performed. The possible pathogenic mechanisms leading to this adverse reaction in this patient are also discussed, and pathophysiologic hypotheses are formulated. CONCLUSIONS: Although mirtazapine offers clinicians a combination of strong efficacy and good safety, we suggest bearing SS in mind when prescribing this drug, especially in frail, elderly patients with underlying chronic conditions. In these patients, it might be more adequate to start mirtazapine therapy at a lower dose (<15 mg/d). KEY WORDS: mirtazapine, serotonin syndrome. Ann Pharmacother 2002;36:641-3. by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from