CASE REPORT

Serotonin Toxicity Caused by Moclobemide Too Soon After -

Ming-Ling Wu*, Jou-Fang Deng Division of Clinical Toxicology, Department of Medicine, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.

Serotonin toxicity is an iatrogenic complication of serotonergic drug therapy. It is due to an overstimulation of central and peripheral serotonin receptors that lead to neuromuscular, mental and autonomic changes. Moclobemide is a reversible inhibitor of (MAO)-A, selegiline is an irreversible selective inhibitor of MAO-B, and paroxetine is a selec- tive serotonin inhibitor. Combined use of these agents is known to cause serotonin toxicity. A 53-year-old woman had been treated with paroxetine and selegiline. After moclobemide was prescribed in place of paroxetine without a washout period, she quickly developed confusion, agitation, , diaphoresis, tremor, mydriasis, ocular clonus, hyper- reflexia, tachycardia, moderately elevated blood pressure and high fever, symptoms that were consistent with serotonin toxicity. Discontinuation of the drugs, hydration and supportive care were followed by remarkable improvement of baseline status within 3 days. This case demonstrates that serotonin toxicity may occur even with small doses of paroxetine, selegi- line and moclobemide in combination. Physicians managing patients with depression must be aware of the potential for serotonin toxicity and should be able to recognize and treat or, ideally, anticipate and avoid this pharmacodynamically- mediated interaction that may occur between prescribed drugs. [J Chin Med Assoc 2009;72(8):446–449]

Key Words: drug interaction, monoamine oxidase inhibitor, selective serotonin , serotonin toxicity

Introduction significant than MAO-B in this process.1 Serotonergic excess can be caused by drug interactions, overdose of Serotonin toxicity is a drug-induced toxidrome that is a serotonergic drug, or as a complication of therapy. a condition of serotonergic hyperstimulation. It is still Serotonergic drug interactions, particularly when 2 commonly referred to as . How- drugs increase serotonergic transmission through dif- ever, it is not a discrete syndrome, but represents a ferent mechanisms, are a common cause of serotonin spectrum of serotonergic effects.1,2 Serotonin acts cen- toxicity.2 It typically results from the combination trally as a modulator of exciting neurotransmission. of MAO inhibitors (MAOI) with other serotonergic Serotonergic neurons play an integral part in the reg- agents. The 3 important mechanisms, in relation to ulation of wakefulness, affective behavior, food intake, severe serotonin toxicity, are inhibition of reuptake, thermoregulation, , emesis, and sexual behavior. presynaptic release, and MAO inhibition.2 There have In the periphery, serotonin assists in the regulation of been reports of fatalities from moclobemide alone and vascular tone and gastrointestinal motility.3 In humans, in combination with , and serotonin is derived from dietary , which is paroxetine.4 Professor Whyte’s research group at the converted to 5-hydroxytryptophan and then to sero- Hunter Area Toxicology Service (HATS) in tonin. After transport into cells, serotonin is degraded has maintained a prospective clinical database of all mainly by monoamine oxidase (MAO). MAO-A is more poisonings since 1987. The HATS data indicate that

*Correspondence to: Dr Ming-Ling Wu, Division of Clinical Toxicology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, R.O.C. E-mail: [email protected] ● Received: October 7, 2008 ● Accepted: May 5, 2009

446 J Chin Med Assoc • August 2009 • Vol 72 • No 8 © 2009 Elsevier. All rights reserved. Serotonin toxicity by moclobemide-paroxetine-selegiline interaction it is only the higher elevations of serotonin resulting Discussion from MAOI plus serotonin reuptake inhibitor (SRI) combinations that are likely to induce hyperpyrexia and The typical clinical features of serotonin toxicity in death.5 We report a case of serotonin toxicity resulting humans, derived from the HATS data, are: (1) neuro- from the combination of paroxetine, selegiline and muscular hyperactivity: tremor, clonus, myoclonus and moclobemide in therapeutic doses. hyperreflexia and, in the advanced stage, pyramidal rigidity; (2) autonomic hyperactivity: diaphoresis, fever, mydriasis, tachycardia, moderately elevated blood pres- Case Report sure and tachypnea; and (3) altered mental status: ex- citement and agitation, with confusion in the advanced A 53-year-old woman presented to the emergency stages only.5 The diagnosis of serotonin toxicity is made department with fever and consciousness disturbance on a clinical basis. A strong clinical suspicion, known on the day after changing prescriptions. Her past history exposure to serotonergic agents, demonstration of spe- was significant for multiple system atrophy, secondary cific signs and symptoms, and exclusion of other medical Parkinsonism and depression for about 5 years, and and psychiatric conditions are required for diagnosis. neurogenic bladder dysfunction with several episodes This patient’s symptomology included fever, hyper- of urinary tract infection. Her medications included tension, mydriasis, and confusion; therefore, differen- paroxetine 20 mg qd, selegiline 5 mg bid, midodrine tial diagnoses should include toxicity 2.5 mg/1.25 mg bid, biperiden 2 mg tid, and ginkgo- and sympathomimetic toxicity. Neither anticholinergic flavone 40 mg bid. Because of incomplete response to syndrome nor sympathomimetic syndrome have fea- this regimen, the day before admission, moclobemide tures of neuromuscular excitation.6 Our patient had (150 mg tid) had been prescribed in place of paroxe- been on medications with anticholinergic and sympa- tine. The patient took paroxetine in the morning and thomimetic effects for some time without incident. moclobemide after lunch and dinner. A few hours (at She presented with tremor, ocular clonus, diaphoresis, 10 pm) after her second dose of moclobemide, she hyperthermia, confusion, , tachycardia, developed stiffness, ataxia and diaphoresis. Hyperther- tachypnea and mydriasis rapidly after the second dose mia and confusion were also noted 2 hours later. She of a new serotonergic drug in her regimen. The find- was sent to our hospital 8 hours after the second dose ings were consistent with the diagnosis of serotonin of moclobemide. toxicity. In the emergency department, she was confused Serotonin toxicity is a disorder that can be caused by and disoriented. Glasgow coma scale was E1V2M5. the use of drugs or drug combinations that increase Vital signs were: blood pressure, 154/74 mmHg; intrasynaptic serotonin. It most often occurs when 2 pulse, 132 beats/minute; respiratory rate, 20 beats/ or more drugs that increase serotonin availability by minute; body temperature, 39.7°C. Mydriasis, ocular different mechanisms are used simultaneously. It may clonus, diaphoresis, tremor, neck stiffness, limb rigidity, develop after therapeutic use or overdose. In our case, hyperreflexia and positive Babinski’s sign (left side) were there were 3 drugs with the potential to increase sero- also noted. Biochemical and hematological studies were tonin, i.e. paroxetine, moclobemide and selegiline. remarkable, with a leukocyte count of 13,200/mm3 Paroxetine is a selective serotonin reuptake inhib- (neutrophils 82%, lymphocytes 15%) and glucose level itor (SSRI). The effective therapeutic dose range is of 169 mg/dL only. Urinalysis was normal, as were 10–60 mg daily. The half-life is 15–22 hours, and it is cultures of blood and urine. Brain computed tomog- significantly prolonged in older patients. Considerable raphy disclosed mild brain atrophy. Cerebrospinal fluid intersubject variation is observed, as demonstrated by analyses showed normal cell count, protein and glu- the range of half-lives between 3.8 and 65 hours.7 cose, and were negative for microbiological stains and Paroxetine’s potency is the greatest among the SSRIs. cultures. Chest radiography was normal and electro- The metabolites of paroxetine, unlike , are cardiography confirmed sinus tachycardia. Serotonin not active. Paroxetine and fluoxetine show the greatest toxicity was suspected. The patient’s medications were inhibition of CYP2D6. If a patient does not respond discontinued, and she was treated with intravenous to paroxetine, 2 weeks should elapse before beginning fluid and supportive care. The fever persisted for only MAOI therapy.2,3 24 hours, and she achieved complete recovery 3 days Moclobemide, an MAOI, is a reversible competi- later. She had recurrent fever and urinary tract infec- tive selective inhibitor of MAO-A, with a wide spec- tion on the 4th day of hospitalization but recovered trum of activity.8 It is devoid of the with antibiotic management. major problems that discredited the first generation of

J Chin Med Assoc • August 2009 • Vol 72 • No 8 447 M.L. Wu, J.F. Deng irreversible, mixed inhibitors of MAO-A and MAO-B. Our patient took both selegiline and paroxetine However, moclobemide loses selectivity for MAO-A without the development of side effects before the at higher doses. The elimination half-life of moclobe- addition of moclobemide. Because moclobemide is mide is rapid, in the range of 1–3 hours. The drug is safer than the old irreversible MAOI, some studies have almost completely metabolized in the by 2 en- claimed that a washout period is not necessary when zymes, CYP2C19 and CYP2D6.8 Moclobemide does switching therapy from an SSRI to moclobemide.9,14 not precipitate serotonin toxicity in overdose by itself, In vulnerable patients, the combination of selegiline, nor does it produce serotonergic side effects in clinical paroxetine and moclobemide in therapeutic doses use.9 When switching treatment from moclobemide may have the potential to induce moderate serotonin to SSRI, a washout period of 24 hours is sufficient. toxicity, as in our patient. Selegiline, a derivative of , is an To diagnose serotonin toxicity, the clinician must irreversible selective MAO-B inhibitor. Selegiline is retain a high index of suspicion and exclude other used for the treatment of early-stage Parkinson’s dis- medical and psychiatric conditions. Serotonin toxicity ease, depression and senile dementia.10 It leaves those is a serious and sometimes fatal event. For this reason, peripheral mechanisms intact that normally prevent combination therapy of any MAOI, including moclobe- a hypertensive response following reaction. mide, and any potent SSRI should be avoided. If a Dietary restrictions are common for MAOI treatments, patient does not respond to an SSRI, it is prudent but special dietary restrictions for lower doses have been to wait for 2 weeks (5 weeks for fluoxetine) before found to be unnecessary.9 For its selectivity, selegiline beginning MAOI therapy. Serotonin toxicity should has relatively small potential for serotonin toxicity. not be viewed as an idiosyncratic reaction, but rather Selegiline is extensively metabolized to methamphet- as a predictable one with variability in occurrence and , and N-desmethylselegiline.11 In severity among patients. Clinicians who are aware of selegiline overdose, patients may also exhibit clinical the potential for serotonin toxicity should be able to effects similar to those of methamphetamine. In the recognize and treat or, ideally, anticipate and avoid clinical setting, concurrent use of selegiline and par- this pharmacodynamically-mediated interaction that oxetine is not contraindicated. However, concurrent may occur between prescribed drugs. administration of selegiline with may produce profound serotonergic toxicity in vulnerable patients.12,13 References Both moclobemide and paroxetine are substrates and inhibitors of CYP2D6. Major P450 interaction 1. Whyte IM. Serotonin toxicity (syndrome). In: Dart RC, ed. rd both ways may occur with expected substantial eleva- Medical Toxicology, 3 edition. Baltimore: Lippincott, Williams & Wilkins, 2004:103–6. tions in the blood levels of both drugs, thereby greatly 2. Gillman PK. Serotonin Toxicity. 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