Interaction Between Monoamine Oxidase B Inhibitors and Selective Serotonin Reuptake Inhibitors

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REVIEW

Interaction between Monoamine Oxidase B Inhibitors and Selective Serotonin Reuptake Inhibitors

Abdullah Aboukarr and Mirella Giudice

ABSTRACT RÉSUMÉ Background: Monoamine oxidase B (MAO-B) inhibitors are used to Contexte : Les inhibiteurs de la monoamine oxydase B (MAO-B) sont treat the motor symptoms of Parkinson disease. Depression is commonly employés dans le traitement des symptômes moteurs de la maladie associated with Parkinson disease, and selective serotonin reuptake de Parkinson, maladie à laquelle la dépression est souvent associée et inhibitors (SSRIs) are often used for its management. Tertiary sources fréquemment traitée à l’aide d’inhibiteurs sélectifs de la recapture de la warn that the combination of MAO-B inhibitors and SSRIs can result in sérotonine (ISRS). Des sources tertiaires mettent en garde contre la increased serotonergic effects, leading to serotonin syndrome. combinaison d’inhibiteurs de la MAO-B et d’ISRS car elle peut mener à une augmentation des effets sérotoninergiques, dégénérant en un Objective: To explore the mechanism, clinical significance, and manage - syndrome sérotoninergique. ment of this potential drug interaction through a review of the supporting evidence. Objectif : Chercher à connaître le mécanisme, la signification clinique et la prise en charge de cette potentielle interaction médicamenteuse en Data Sources: PubMed, MEDLINE (1946 forward), Embase (1947 procédant à une revue des preuves à l’appui. forward), PsycINFO (1806 forward), and International Pharmaceutical Abstracts (1970 forward) were searched on February 4, 2017. Sources des données : Les bases de données PubMed, MEDLINE (depuis 1946), Embase (depuis 1947), PscyINFO (depuis 1806), et Study Selection and Data Extraction: Studies and case reports describ - International Pharmaceutical Abstracts (depuis 1970) ont été interrogées ing aspects of the potential interaction between MAO-B inhibitors and le 4 février 2017. SSRIs in patients with Parkinson disease and published in English were identified by both title and abstract. Sélection des études et extraction des données : Des études et des observations cliniques, publiées en anglais, portant sur des aspects de la Data Synthesis: The search identified 8 studies evaluating the potential potentielle interaction entre les inhibiteurs de la MAO-B et les ISRS chez interaction between SSRIs and the MAO-B inhibitors selegiline and les patients atteints de la maladie de Parkinson ont été repérées par une rasagiline. The largest, a retrospective cohort study of 1504 patients with recherche ciblant les titres et les résumés. Parkinson disease, found no cases of serotonin syndrome with coadmin - Synthèse des données : La recherche a permis de trouver 8 études istration of rasagiline and an SSRI. A survey of 63 investigators in the analysant la potentielle interaction entre les ISRS et deux inhibiteurs de Parkinson Study Group identified 11 potential cases of serotonin la MAO-B : la sélégiline et la rasagiline. La plus importante d’entre elles, syndrome among 4568 patients treated with the combination of selegiline une étude de cohorte rétrospective sur 1504 patients atteints de la maladie and antidepressants (including SSRIs). In addition, 17 case reports de Parkinson, n’a relevé aucun cas de syndrome sérotoninergique en describing the onset of serotonin syndrome with coadministration of présence d’une prise concomitante de rasagiline et d’un ISRS. Une an SSRI and either selegiline or rasagiline were identified. Following enquête auprès de 63 chercheurs dans le Parkinson Study Group a permis discontinuation or dose reduction of one or both of the agents, the de relever 11 potentiels cas de syndrome sérotoninergique chez 4568 symptoms of serotonin syndrome gradually resolved in most cases, with patients traités avec une combinaison de sélégiline et d’antidépresseurs none being fatal. (notamment des ISRS). De plus, 17 observations cliniques qui décrivaient Conclusions: According to the literature, serotonin syndrome occurs un début de syndrome sérotoninergique en présence d’une prise rarely, and the combination of SSRI and MAO-B inhibitor is well concomitante d’un ISRS et de sélégiline ou de rasagiline ont été recensées. tolerated. Therefore, SSRIs and MAO-B inhibitors can be coadministered, Suivant la réduction de la posologie ou l’interruption d’un ou des deux provided that their recommended doses are not exceeded and the SSRI médicaments, les symptômes du syndrome sérotoninergique se sont dose is kept at the lower end of the therapeutic range. Among the SSRIs, graduellement résolus dans la plupart des cas, et il n’y a eu aucune citalopram and sertraline may be preferred. mortalité. Keywords: Parkinson disease, serotonin syndrome, selegiline, rasagiline, Conclusions : Selon la documentation, le syndrome sérotoninergique est selective serotonin reuptake inhibitor, drug interactions rare et la combinaison d’ISRS et d’inhibiteurs de la MAO-B est bien

196 CJHP – Vol. 71, No. 3 – May–June 2018 JCPH – Vol. 71, n o 3 – mai–juin 2018 This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact CJHP at [email protected]

Can J Hosp Pharm. 2018;71(3):196-207 tolérée. Ainsi, les deux types d’inhibiteurs peuvent être administrés conjointement pourvu que l’on ne dépasse pas la posologie recommandée et que la dose d’ISRS demeure dans le bas de l’intervalle thérapeutique. Parmi les ISRS, il peut être préférable d’employer le citalopram ou la sertraline. Mots clés : maladie de Parkinson, syndrome sérotoninergique, sélégiline, rasagiline, inhibiteur sélectif de la recapture de la sérotonine, interaction médicamenteuse

INTRODUCTION incoordination, and fever. 12 Despite their widespread use, the Sternbach criteria have some limitations. They can be nonspecific, he monoamine oxidase B (MAO-B) inhibitors selegiline and because of heavy reliance on mental status changes. Furthermore, Trasagiline are among the agents used to treat the motor the inclusion of incoordination (ataxia), a cerebellar feature, is 1 symptoms of Parkinson disease. Depression is commonly controversial, because serotonin toxicity is not known to affect associated with Parkinson disease, with up to 50% of patients the cerebellum. Any patient who is agitated or confused may also 1,2 being affected. The treatment of depression in patients with appear ataxic or uncoordinated. Lastly, the Sternbach criteria were Parkinson disease should be individualized, with particular developed on the basis of a series of published cases; therefore, 1,3 emphasis on concomitant therapy. Although selective serotonin any clinical features not identified as features of serotonin reuptake inhibitors (SSRIs) are often used to manage the syndrome by the authors of the original cases may have been 2 symptoms of depression associated with Parkinson disease, these missed. 9,13 drugs have the potential to worsen the motor symptoms of the In 2003, Dunkley and others 13 undertook to improve the 3-5 disease (tremor, restless legs, and periodic limb movement). Sternbach criteria, and developed the Hunter serotonin toxicity Furthermore, a potential interaction between SSRIs and criteria (HSTC). According to these criteria, a diagnosis of 6-8 MAO-B inhibitors can lead to serotonin syndrome. This review serotonin syndrome requires the presence of a serotonergic agent explores the mechanism of, supporting evidence for, clinical and one of the following conditions: significance of, and management of potential serotonin syndrome • clonus with concomitant use of MAO-B inhibitors and SSRIs. • inducible clonus AND agitation or diaphoresis • ocular clonus AND agitation or diaphoresis DIAGNOSTIC CRITERIA FOR SEROTONIN • tremor AND hyperreflexia SYNDROME • hypertonicity AND temperature > 38°C AND ocular clonus Serotonin syndrome is a measure of central nervous system or inducible clonus (CNS) hyperexcitability in relation to an excess of serotonin. This The HSTC are currently the most accurate criteria for hyperexcitability can manifest in multiple ways, and ultimately diagnosing serotonin syndrome, being both more sensitive and 12-14 there is no true “gold standard” for the diagnosis of serotonin more specific than the Sternbach criteria. Nonetheless, the syndrome. Published diagnostic criteria have attempted to identify HSTC have their shortcomings. They are based solely on cases of symptoms or symptom combinations that best capture the nature SSRI overdose, making them potentially nongeneralizable to cases of CNS hyperexcitability related to an excess of serotonin. 9 of serotonin syndrome involving therapeutic doses. In addition, Serotonin syndrome can manifest as symptoms that range a subset of cases used to derive the criteria were also used for 9 from mild to life-threatening. Initially, the patient may present validation, leading to a potential overestimate of validity. Lastly, with akathisia and tremor, followed by mental status changes and clonus or hyperreflexia may not be elicited in patients with severe inducible clonus. The clonus can become sustained, and may then serotonin syndrome who have peripheral neuropathy or muscle evolve to muscular rigidity or hypertonicity. Hyperthermia is a rigidity, which can cloud the clinical diagnosis of serotonin 9,10 symptom that manifests later; it can be life-threatening. 10 Most syndrome. cases of serotonin syndrome present within 24 h of a dose increase MECHANISM OF DRUG INTERACTION or initiation of a new serotonergic agent. 11 Sternbach 12 first suggested diagnostic criteria for serotonin MAO exists as 2 isoforms, MAO-A and MAO-B. Inhibition syndrome in 1991. The Sternbach criteria require at least 3 of the of MAO-A reduces the metabolism of both serotonin and following clinical features, coincident with adding or increasing noradrenaline, whereas inhibition of MAO-B does not affect the the dose of a serotonergic agent: mental status changes, agitation, metabolism of these neurotransmitters, unless sufficient doses (as myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, described below) are used. 15 Inhibition of MAO-B, the major

CJHP – Vol. 71, No. 3 – May–June 2018 JCPH – Vol. 71, n o 3 – mai–juin 2018 197 This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact CJHP at [email protected] isoform in the human brain, prevents the breakdown of extracel - blocking the reuptake of serotonin from synapses. 5 Serotonin lular levels of dopamine in the striatum. The resulting increase in receptors are classified into 7 families, which are designated

dopaminergic activity in the striatum may explain the mechanism 5-HT 1 to 5-HT 7, with specific families having multiple subtypes. by which MAO-B inhibitors exert their beneficial effects in The development of serotonin syndrome has not been attributed Parkinson disease. 16,17 Inhibition of MAO can also be reversible to one specific receptor; however, evidence suggests that agonism

or irreversible; irreversible inhibitors can lead to longer-lasting of the 5-HT 2A subtype may play a considerable role. The 5-HT 1A toxic reactions caused by MAO inhibition, including serotonin subtype may also be implicated in the development of serotonin syndrome. 15 Selegiline and rasagiline, both irreversible MAO-B syndrome through a pharmacodynamic interaction in which inhibitors, are selective for MAO-B at therapeutic doses of 10 mg increased synaptic concentrations of serotonin can saturate all daily and 1 mg daily, respectively, for patients with Parkinson receptor subtypes. 10 disease. At higher doses, they lose selectivity and inhibit both MAO-A inhibitors can augment the serotonergic effects MAO-B and MAO-A. 15 Higher doses of MAO-B inhibitors alone of SSRIs by preventing the breakdown of serotonin. 6,19 have resulted in serotonin syndrome. 17,18 Consequently, serotonin syndrome has been reported with Serotonin syndrome results from increased serotonergic concomitant use of SSRIs and nonselective MAO inhibitors activity in the CNS. The SSRIs increase serotonin activity by (e.g., phenelzine, tranylcypromine), as well as with selective

Table 1. Recommendations for Management of the Interaction between MAO-B Inhibitors and SSRIs from Tertiary Sources Reference Recommendation Selegiline product monograph 16 Concomitant use of selegiline and fluoxetine should be avoided. Administration should be separated by a washout period of at least 5 weeks after discontinuing fluoxetine and starting an MAO inhibitor, and at least 2 weeks after discontinuing an MAO inhibitor and starting fluoxetine. Rasagiline product monograph 17 Concomitant use of rasagiline and SSRIs should be avoided. Administration should be separated by a washout period of at least 2 weeks after discontinuing rasagiline and starting an SSRI, and at least 2 weeks after discontinuing most SSRIs (5 weeks after discontinuing fluoxetine) and starting rasagiline. Selegiline product label 27 Concomitant use of selegiline and SSRIs should be avoided. Administration should be separated by a washout period of at least 2 weeks after discontinuing selegiline and starting an SSRI, and at least 5 weeks after discontinuing fluoxetine and starting selegiline. Rasagiline product label 28 Concomitant use of rasagiline and SSRIs is not recommended. Administration should be separated by a washout period of at least 2 weeks after discontinuing rasagiline and starting an SSRI, and at least 5 weeks after discontinuing fluoxetine and starting rasagiline. Lexi-Interactions database: SSRIs Concomitant use is contraindicated. Administration should be separated by a washout period of at least and MAO inhibitors 6 1–2 weeks, and 5 weeks for fluoxetine, depending on the half-life of the agent being discontinued. Supporting literature for the interaction includes Suchowersky, 29 Suchowersky and DeVries, 30 and Panisset et al. 31 Interaction Checking (MicroMedex Concomitant use is contraindicated. database): SSRIs and MAO inhibitors 7 Selegiline: Administration should be separated by a washout period of at least 2 weeks after discontinuing selegiline and starting an SSRI, and at least 2 weeks after discontinuing most SSRIs Supporting literature for the interaction (5 weeks after discontinuing fluoxetine, and 1 week after discontinuing sertraline) and starting selegiline. includes Suchowersky 29 and Rasagiline: Administration should be separated by a washout period of at least 2 weeks after Suchowersky and DeVries 30 discontinuing rasagiline and starting an SSRI, and at least 2 weeks after discontinuing most SSRIs (5 weeks after discontinuing fluoxetine) and starting rasagiline. Medscape Drug Interaction Checker: Selegiline: Concomitant use of selegiline and SSRIs is contraindicated. SSRIs and MAO inhibitors 8 Rasagiline: Concomitant use of rasagiline and SSRIs should be avoided. Administration should be separated by a washout period of at least 14 days ( ≥ 5 weeks after discontinuing fluoxetine). Stockley’s Drug Interactions 20 : This reference refers to the manufacturers’ recommendations regarding management of the drug MAO-B inhibitors + SSRIs or SNRIs interaction. Supporting literature for the interaction includes Laine et al., 32 Suchowersky, 29 Suchowersky and DeVries, 30 Ritter and Alexander, 33 Kurlan and Dimitsopulos, 34 Jermain et al., 35 Montastruc et al., 36 Waters 37 and Toyama and Iacono 38 UpToDate : Management of nonmotor MAO-B inhibitors should be prescribed only at recommended doses. Caution is advised when combining symptoms in Parkinson disease 4 MAO-B inhibitors and SSRIs because of the risk of serotonin syndrome. Physician Guide: Non-motor Symptoms The interaction between MAO-B inhibitors and SSRIs is theoretical and may not be clinically relevant. of Parkinson’s Disease 2 Selegiline has been combined with SSRIs for many years with only infrequent reports of serotonin syndrome; data on rasagiline are limited. However, patients must be warned of this theoretical interaction as it commonly flagged by pharmacy management software. MAO-B = monoamine oxidase B, SNRI = serotonin and norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor.

198 CJHP – Vol. 71, No. 3 – May–June 2018 JCPH – Vol. 71, n o 3 – mai–juin 2018 This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact CJHP at [email protected] MAO-A inhibitors (e.g., moclobemide). 6,20 According to references Based on the Canadian Network for Mood and Anxiety reporting these interactions, patients have experienced symptoms Treatments (CANMAT) 2016 Clinical Guidelines for the such as agitation, confusion, myoclonus, rigidity, nausea, and Management of Adults with Major Depressive Disorder, 39 SSRIs insomnia; some cases were fatal. 6,20 MAO-B inhibitors have also vary in their overall potential for drug–drug interactions: been implicated in the development of serotonin syndrome, as citalopram and escitalopram have minimal or low potential; discussed below (see “Summary of Evidence”). sertraline has moderate potential; and fluoxetine, fluvoxamine, and paroxetine have high potential. Selegiline is also classified as RECOMMENDATIONS FROM TERTIARY REFERENCES having a higher potential for drug–drug interactions relative to other antidepressants; rasagiline is not classified. 39 Selegiline is The product monographs for escitalopram, paroxetine, metabolized primarily via the cytochrome P450 isozymes fluoxetine, sertraline, citalopram, and fluvoxamine all recommend CYP2B6, CYP2C9, CYP3A4, and CYP2A6, whereas rasagiline avoiding their concurrent use with selective and nonselective is metabolized via CYP1A2. 40,41 MAO inhibitors and separating administration of these drugs by a washout period ranging from 2 to 5 weeks. 21-26 The product SUMMARY OF EVIDENCE monograph for sertraline reports serious, sometimes fatal reactions with concomitant use of selegiline. 24 Various drug interaction ref - A search of PubMed, MEDLINE (1946 forward), Embase erences and the product monographs and labels for selegiline and (1947 forward), PsycINFO (1806 forward), and International rasagiline (Table 1) reiterate these recommendations. 2,4,6-8,16,17,20,27,28 Pharmaceutical Abstracts (1970 forward) was conducted on

Table 2 (part 1 of 2). Studies Examining the Interaction between Selegiline or Rasagiline and SSRIs Study Design Population Interventions and Outcomes Duration of Therapy Hilli et al. (2009) 42 Open, sequential-setting 12 healthy male volunteers Rasagiline 1 mg/day + • Combination was generally well study escitalopram 10 mg/day tolerated, with 91% of adverse events OR classified as mild or moderate. One Rasagiline 1 mg/day patient had severe headache and another had severe tiredness. Duration: 7 days • No cases of serotonin syndrome. • Slight but significant decrease in heart rate with concomitant escitalopram and rasagiline (mean 56 beats/min) versus rasagiline alone (mean 58 beats/min; p = 0.0047) and baseline (mean 60 beats/min; p = 0.0097). Laine et al. (1997) 32 Part 1: Randomized, 18 healthy male volunteers; Part 1 • Combination therapy was well tolerated. double-blind, parallel mean age 24 years Group A: citalopram The most frequent adverse events were study (citalopram) and 20 mg/day for 14 days, headache, dry mouth, sweating, 25 years (placebo) with selegiline 10 mg/day nausea, and sleep disturbances. Part 2: Open-label, added for days 11–14 Reported adverse events were similar in crossover study both groups, both before and after Group B: Placebo for initiating selegiline. 14 days, with selegiline • No cases of serotonin syndrome. 10 mg/day added for • Lack of clinically relevant interaction. days 11–14 Part 2 After a 5-week washout period, patients from group A were crossed over to selegiline 10 mg/day for 4 days Panisset et al. Multicentre, retrospective 1504 patients with PD; Group 1: rasagiline + • No cases of serotonin syndrome in (2014) 31 cohort study mean age 67.0 years; antidepressant (74.5% any group. 58.8% male SSRIs*; 10.0% were using > 1 antidepressant) Duration: 50.5–53.5 weeks Group 2: antidepressant only (77.0% SSRIs*; 16.6% were using > 1 antidepressant) Duration: 51.7–80.9 weeks Group 3: rasagiline continued on page 200

CJHP – Vol. 71, No. 3 – May–June 2018 JCPH – Vol. 71, n o 3 – mai–juin 2018 199 This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact CJHP at [email protected] Table 2 (part 2 of 2). Studies Examining the Interaction between Selegiline or Rasagiline and SSRIs Study Design Population Interventions and Outcomes Duration of Therapy Richard et al. Survey of investigators 4568 patients with PD Selegiline + antidepressant • 11 patients (0.24%) experienced (1997) 43 from Parkinson Study (including SSRIs); doses symptoms possibly related to serotonin Group not stated syndrome; 2 patients (0.04%) experienced symptoms judged to be serious. • See Table 3 for details about SSRI cases for which detailed information was available. Ritter and Alexander Retrospective chart 28 male patients with PD; Selegiline + antidepressant • One possible case of serotonin (1997) 33 review mean age 68 years (7/40† SSRIs) syndrome involving selegiline 10 mg/day and fluoxetine 20 mg/day. Rihmer et al. Observational study 8 patients with PD; Selegiline 5–10 mg/day + • No cases of serotonin syndrome. (2000) 44 mean age 74.1 years, citalopram 20 mg/day • No other adverse events. 75% male Duration: 8 weeks Waters (1994) 37 Retrospective chart 23 patients with PD; Selegiline 5–10 mg/day + • No cases of serotonin syndrome. review mean age 64.6 years, fluoxetine 5-40 mg/day • One patient experienced worsened 56.5% male parkinsonian tremor, both with Duration: 1 month – fluoxetine alone and with the ongoing combination of fluoxetine and selegiline.‡ Toyama and Iacono Case series 16 patients with PD Selegiline 5–10 mg/day + • No cases of serotonin syndrome. (1994) 38 SSRI (sertraline • No other adverse events. 25–100 mg/day or paroxetine 10–40 mg/day) with or without trazodone 25–150 mg/day Duration: 2–30 weeks (mean 10 weeks) PD = Parkinson disease, SSRI = selective serotonin reuptake inhibitor. *Mean SSRI doses in antidepressant + rasagaline group and antidepressant-only group, respectively: citalopram 23.7 and 26.0 mg, escitalopram 13.8 and 14.2 mg, fluoxetine 24.1 and 27.2 mg, paroxetine 22.3 and 22.9 mg, and sertraline 78.0 and 85.0 mg. †There were a total of 40 selegiline–antidepressant combinations, because some patients were treated with more than 1 trial of different antidepressants. ‡Tremor improved after discontinuation of fluoxetine.

February 4, 2017, using the MeSH (Medical Subject Heading) approved by the US Food and Drug Administration (FDA) in term “drug interaction” and combined keywords “selegiline and 1989 and has therefore been available much longer than rasagiline, SSRI,” “rasagiline and SSRI”, “fluoxetine and selegiline”, “fluvox - which was approved by the FDA in 2006. 45 amine and selegiline”, “sertraline and selegiline”, “paroxetine and Two studies involved healthy patients, so their results may selegiline”, citalopram and selegiline”, “escitalopram and not be applicable to patients with Parkinson disease. 32,42 In one of selegiline”, “fluoxetine and rasagiline”, “fluvoxamine and these studies, 42 which involved rasagiline and escitalopram, the rasagiline”, “sertraline and rasagiline”, “paroxetine and rasagiline”, area under the curve (AUC) for rasagiline increased by 42% citalopram and rasagiline”, and “escitalopram and rasagiline”. (p < 0.0001) and oral clearance decreased by 35% ( p < 0.001) Studies and case reports were identified by both title and abstract. after 7 days of combination therapy, relative to rasagiline Duplicate citations, identified by author, journal, and date of treatment alone. The elimination half-life, peak plasma concen - publication, were excluded. Only studies and case reports tration ( Cmax ), and time from drug intake to peak concentration published in English were considered. 42 (tmax ) of rasagiline were not significantly affected by escitalopram. In the other study, 32 which involved selegiline and citalopram, the Studies AUC of selegiline decreased by 29% with concomitant

Eight relevant studies were identified (3 retrospective studies, citalopram, relative to selegiline alone; Cmax and tmax were 1 observational study, 1 open sequential-setting study, 1 case not significantly affected. Citalopram pharmacokinetics were series, 1 survey study, and 1 randomized controlled trial) that unaffected, and the authors reported a lack of clinically relevant evaluated the potential for an interaction between SSRIs and the pharmacokinetic interaction. 32 MAO-B inhibitors selegiline and rasagiline (Table 2). 31-33,37,38,42-44 The largest study, involving rasagiline, 31 was a multicentre, Most of the studies had a small sample size, and most evaluated retrospective cohort study, in which the authors systematically selegiline; this finding was unsurprising, given that selegiline was evaluated the incidence of serotonin syndrome among patients

200 CJHP – Vol. 71, No. 3 – May–June 2018 JCPH – Vol. 71, n o 3 – mai–juin 2018 This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact CJHP at [email protected] taking rasagiline plus an antidepressant. Study centres were and one of these cases was already published (in 2 reports). 29,30 All selected from individual neurology practices with medical records 5 patients had used an SSRI (see “PSG cases” in Table 3 for further for 50 or more patients with Parkinson disease who had received details). 29,30,43 Because details were unavailable for the remaining rasagiline, 50 or more patients with Parkinson disease who had 6 patients, it is unknown whether they were taking an SSRI received an antidepressant, and 50 or more patients with or another antidepressant. 43 In addition to their survey of the Parkinson disease who had received the combination of rasagiline Parkinson Study Group investigators, the authors obtained a and an antidepressant. Serotonin syndrome was defined using the summary of all possible cases of drug interactions with concomi - HSTC, which to date are the most sensitive and specific criteria tant use of selegiline and an antidepressant that had been submit - for diagnosing serotonin syndrome. 31 Out of 1507 patients ted to the FDA between 1989 and 1996. Fifty-seven cases were initially considered, all with Parkinson disease, 471 were taking identified, of which 27 involved an SSRI. From these 27 cases, rasagiline in combination with an antidepressant (351 or 74.5% only 2 were stated as having possibly fulfilled the Sternbach criteria using SSRIs), 511 were taking rasagiline without an antidepressant for serotonin syndrome (see “FDA cases” in Table 3 for further (3 of whom did not meet the eligibility criteria and were later ex - details). 43 Lastly, the authors conducted a MEDLINE search and cluded from analysis), and 525 were taking antidepressants (404 reviewed bibliographies for published cases of adverse events as - or 77.0% using SSRIs) without rasagiline. The mean SSRI doses sociated with concomitant use of selegiline and an antidepressant. in the antidepressant + rasagiline group and the antidepressant- Six cases were identified, 5 of which (including one of the cases only group were, respectively, citalopram 23.7 and 26.0 mg, identified by the Parkinson Study Group survey) involved an SSRI escitalopram 13.8 and 14.2 mg, fluoxetine 24.1 and 27.2 mg, (see “published cases” in Table 3 for further details). 43 paroxetine 22.3 and 22.9 mg, and sertraline 78.0 and 85.0 mg, Apart from these 11 potential cases of serotonin syndrome which fall mainly at the lower end of the therapeutic ranges of (4 cases from the survey [excluding the published case], 2 cases these drugs. Of the 1419 patients (94.3%) with known outcomes, submitted to the FDA, and 5 cases from the MEDLINE search none experienced serotonin syndrome. The authors stated that [including the case identified in the survey]), a retrospective chart the lack of serotonin syndrome cases suggests a rarer-than- review of 28 patients with Parkinson disease identified 1 possible expected incidence of the syndrome, which was below the study’s case of serotonin syndrome. 33 The patient in question experienced detection threshold. 31 They further stated that future studies increased nervousness, anxiety, tremor, and confusion less than should increase the sample size to assess the true incidence of 1 week after starting fluoxetine 20 mg/day (in addition to serotonin syndrome with concomitant use of rasagiline and selegiline 10 mg/day). Although the authors stated that the antidepressants. 31 This study had both strengths and limitations. reaction was consistent with serotonin syndrome, it was not One major strength was the independent, systematic review of possible to establish a firm diagnosis. Soon after stopping each case according to the HSTC, which ensured that cases of fluoxetine, the patient’s symptoms improved, but they had not serotonin syndrome that might not have been properly recognized completely resolved 3 weeks later. 33 during a medical encounter were reassessed against robust criteria Overall, the combination of SSRI and MAO-B inhibitor was for this syndrome. Conversely, a major limitation was the well tolerated in these studies, with 12 possible cases of serotonin retrospective study design, which meant that roughly 20% of syndrome (1 additional case from the retrospective chart review). medical records were unavailable for ascertainment of serotonin One additional patient experienced worsening of a parkinsonian syndrome. Furthermore, there was limited access to the medical tremor, which was attributed to fluoxetine. 37 The evaluated doses records of deceased patients, because of the requirement for of selegiline and rasagiline were both within the recommended informed consent at several study centres, which potentially range for Parkinson disease, and the doses of SSRIs were generally prevented the capture of further cases of serotonin syndrome. A at the lower end of the therapeutic range for depression. From final limitation was the potential dismissal of symptoms of these studies, it appears that selegiline or rasagiline can be used serotonin syndrome as features of the underlying disease. As such, with an SSRI, provided that the recommended doses of both practitioners might not have documented unusual findings as agents are not exceeded and, ideally, the SSRI dose is kept at the symptoms of serotonin syndrome, giving rise to false negatives. 31 lower end of the therapeutic range. However, further studies using A survey of 63 investigators in the Parkinson Study Group larger sample sizes would be welcome to determine the true utilized a standardized questionnaire to identify patients treated incidence of this drug interaction. with the combination of selegiline and antidepressants. 43 Forty- seven investigators responded, which allowed identification of a Case Reports total of 4568 patients who were taking this combination. Of these Although the largest study found no evidence of a clinically patients, 11 (0.24%) experienced symptoms “possibly consistent” relevant interaction between MAO-B inhibitors and SSRIs, 31 and with serotonin syndrome, with 2 patients having symptoms that only 12 possible cases of serotonin syndrome were identified in were considered serious. Details were provided for only 5 patients, other studies, 6 further case reports have described the onset of

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204 CJHP – Vol. 71, No. 3 – May–June 2018 JCPH – Vol. 71, n o 3 – mai–juin 2018 This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact CJHP at [email protected] possible serotonin syndrome with coadministration of an SSRI hyperthermia. 10,14 The authors did not report the patient’s and either selegiline or rasagiline. 34,47-51 Table 3 describes these temperature. For this reason, it was not possible to confirm the cases, in addition to the 11 cases identified by the Parkinson Study cause of the seizure as serotonin syndrome. Group (including the survey, literature search, and review of FDA- Cyproheptadine has been proposed as an off-label treatment reported cases). 29,30,34-36,43,46-51 For one published case identified by for serotonin syndrome. It is a histamine-1 receptor antagonist the Parkinson Study Group, we noted discrepancies between their with additional nonspecific binding at the 5-HT 1A and 5-HT 2A description 43 and the reports of the original authors. 29,30 As such, receptors. It is recommended as an antidote for serotonin the authors’ original description 29,30 has been included in Table 3. syndrome, 10 despite a lack of evidence for its efficacy. The The onset of serotonin syndrome varied from days to weeks suggested dosage is 12 mg initially, followed by 2 mg every 2 h, following a dose increase (1 case only) or initiation of the new or 4–8 mg every 6 h until symptoms are controlled. Because of serotonergic agent (most reports). This finding is inconsistent with its anticholinergic activity, it causes sedation. 10,14,52 In only one of the statement by Mason and others 11 that most cases of serotonin the identified cases was cyproheptadine reported as having been syndrome manifest within 24 h after a dose change or initiation used to manage serotonin syndrome. 49 The dosing in this case of a serotonergic agent; however, the observations of those authors differed somewhat from the previously proposed dosing: it was were based on only 41 patients. Although most of these patients prescribed as 4 mg orally every 2–4 h, with up to 30 mg per day. had underlying diseases, none had Parkinson disease. 11 In The patient’s vital signs stabilized, and her symptoms had addition, selegiline was not implicated in any of the cases, improved by the next day. 49 rasagiline had not yet been approved, 45 and a substantial propor - Four cases of serotonin syndrome 47-50 were reported after tion of the patients (26%) experienced serotonin syndrome after publication of the HSTC in 2003, and we determined that 2 of 48,49 more than 24 h, with the longest period of symptom onset being them met these criteria. Fulfillment of the HSTC in these 36 days. 11 Therefore, serotonin syndrome cannot be ruled out on 2 cases is noteworthy because it may indicate that the HSTC are the basis of timeframe alone, and a specific timeframe is not a emerging as a new standard for diagnosis. It may also suggest that requirement to fulfill the HSTC. 13 the HSTC can be applied to cases of serotonin syndrome The most commonly implicated MAO-B inhibitor and SSRI occurring in patients who receive therapeutic doses, despite the were selegiline and fluoxetine, respectively, likely because of their criteria being based solely on cases of SSRI overdose. Of these 48 lengthier market approval and the relatively longer half-life of 2 cases, Duval and others used the HSTC for their diagnosis of 49 fluoxetine. This longer half-life is important because changes in serotonin syndrome, whereas Sanyal and others used the plasma concentration will not be fully observed for several weeks. Sternbach criteria. Conversely, we determined that all 4 of the 47-50 Similarly, when fluoxetine is discontinued, plasma concentrations cases published after 2003 met the Sternbach criteria, which drop slowly, and the drug remains in the body for several weeks. 23 would suggest that these criteria are still being used to diagnose In these case reports, the doses of the MAO-B inhibitor were serotonin syndrome. Of the 2 cases that we deemed as not within the recommended range for Parkinson disease, and the meeting the HSTC criteria, the case reported by Suphanklang 47 doses of the SSRI were at the lower end of the therapeutic range and others would not be classified as serotonin syndrome, on for depression. 16,17,21-24 the basis of information available in the abstract; the full article Following discontinuation or dose reduction of one or both could not be obtained for examination. In the other case, Hébant and others 50 diagnosed serotonin syndrome with the Sternbach serotonergic agents, symptoms of serotonin syndrome gradually criteria and made no mention of the HSTC. resolved in most cases; no cases were fatal. In 2 cases, the patients Three further case reports (describing 2 individual patients) also experienced worsened symptoms of Parkinson disease. In did not explicitly mention serotonin syndrome, but described the the first case, worsening of tremor persisted despite sertraline occurrence of mania with concomitant use of selegiline and discontinuation. 43 In the second case, worsening of tremor also fluoxetine. In the first case (described in 2 separate articles), 29,30 persisted, but no mention was made of whether the SSRI was the authors thought the prolonged mania resulted from concomi - discontinued; notably, however, the dose of selegiline had been tant use of fluoxetine and selegiline, because both medications are reduced. 43 It is interesting to note the similarities between the known to induce mania when used alone. In the other case, the motor symptoms of Parkinson disease, specifically resting tremor patient experienced a second manic episode 2 months after and rigidity, and the motor symptoms of serotonin syndrome. 1,2 discontinuing selegiline. At that point, the authors did not further Both of these cases were published before development of the clarify the patient’s psychiatric diagnosis. 34 Mania alone does not HSTC, which include both tremor and hypertonicity as clinical fit the Sternbach criteria 12 or the HSTC. 13 features of serotonin syndrome. 13 Therefore, a mild form of serotonin syndrome might have been considered, had the HSTC CLINICAL MANAGEMENT been available at the time of the event in these 2 cases. In the case presented by Montastruc and others, 36 the patient The benefits of MAO-B inhibitor and SSRI in combination experienced a tonic–clonic seizure. Seizures are more severe in the treatment of depression related to Parkinson disease complications of serotonin syndrome, often associated with generally outweigh the risks; therefore, either selegiline or

CJHP – Vol. 71, No. 3 – May–June 2018 JCPH – Vol. 71, n o 3 – mai–juin 2018 205 This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact CJHP at [email protected] rasagiline can be used cautiously with an SSRI, if their 6. Selective serotonin reuptake inhibitors / MAO inhibitors. In: Lexi-Interactions recommended doses are not exceeded (i.e., total daily doses of up [database on internet]. Hudson (OH): Lexi-Comp, Inc; 2007 [cited 2017 Feb 4]. Available from: http://online.lexi.com/lco/action/home/switch. to 10 mg and 1 mg for selegiline and rasagiline, respectively) and Subscription required to access content. doses of SSRI are kept at the lower end of the therapeutic range. 7. Selective serotonin reuptake inhibitors / MAO inhibitors. In: Interaction When adding an SSRI to either selegiline or rasagiline, the SSRI checking [database on internet]. Ann Arbor (MI): Truven Health Analytics; 2016 [cited 2017 Jan 28]. Available from: www.micromedexsolutions.com. should be initiated at the lowest possible dose and titrated slowly. Subscription required to access content. The use of other serotonergic agents should be avoided; drugs that 8. Selective serotonin reuptake inhibitors / MAO inhibitors. In: Medscape drug can decrease the metabolism of either MAO-B inhibitors or SSRIs interaction checker [database on internet]. New York (NY): Medscape, LLC; 1994 [cited 2017 Feb 4]. Available from: http://reference.medscape.com/ should also be avoided. Among the SSRIs, citalopram and sertra - drug-interactionchecker line may be preferred because of their demonstrated efficacy and 9. Werneke U, Jamshidi F, Taylor DM, Ott M. Conundrums in neurology: tolerability as antidepressants in Parkinson disease. 2,4,5 Sertraline diagnosing serotonin syndrome—a meta-analysis of cases. BMC Neurol. 2016;16(1):97. is the SSRI that appears to have the least potential for inducing 10. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005; parkinsonism, 4 whereas citalopram has an overall low potential 352(11):1112-20. for drug interactions. 39 Proper patient monitoring is imperative. 11. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome presentation of 2 cases and review of the literature. Medicine . 2000;79(4):201-9. According to case reports, the onset of the interaction is variable, 12. Sternbach H. The serotonin syndrome. Am J Psychiatry . 1991;148(6):705-13. ranging from a few days to weeks after initiation of the new agent. 13. Dunkley EJC, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Therefore, clinicians must remain vigilant for this interaction at serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J Med . 2003;96(9):635-42. all times. As a cautionary measure, the patient and/or caregiver 14. Boyer EW. Serotonin syndrome (serotonin toxicity). In: Post TW, editor. should be advised of the signs and symptoms of serotonin UpToDate . Waltham (MA): UpToDate; 2014. syndrome, despite the low risk. 15. Finberg JPM. Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: focus on modulation of CNS monoamine neurotransmitter release. Pharmacol Ther. 2014;143(2):133-52. CONCLUSION 16. Teva-Selegiline [product monograph]. In: Drug product database . Ottawa (ON): Health Canada; 2017 [updated 2015 Jul 14; cited 2017 Oct 22]. To date, the only report to estimate the incidence of Available from: https://health-products.canada.ca/dpd-bdpp/index-eng.jsp. serotonin syndrome with the coadministration of an MAO-B Also available in paper copy from the publisher. inhibitor and antidepressants (including SSRIs) is the Parkinson 17. Azilect [product monograph]. In: Drug product database. Ottawa (ON): Health Canada; 2017 [updated 2014 Nov 20; cited 2017 Oct 22]. Available 43 Study Group survey. In that survey, the authors found an from: https://health-products.canada.ca/dpd-bdpp/index-eng.jsp. Also incidence of 0.24%, although these were not cases of serotonin available in paper copy from the publisher. syndrome retroactively assessed using the Sternbach criteria, and 18. Fernandes C, Reddy P, Kessel B. Rasagiline-induced serotonin syndrome [letter]. Mov Disord . 2011;26(4):766-7. the survey report predated the development of the HSTC. 19. McKie J. What is serotonin syndrome and which medicines cause it? NHS Furthermore, the large retrospective study that used a preset Med Q&As. 2016;:219.4. Also available from: https://www.sps.nhs.uk/ definition of serotonin syndrome based on the HSTC did not articles/what-is-serotonin-syndrome-and-which-medicines-cause-it-2/ 31 20. Preston CL, editor. Stockley’s drug interactions. London (UK): Pharmaceutical identify any cases of serotonin syndrome. The clinical data Press; 2015. supporting this potential interaction are therefore based on case 21. Cipralex [product monograph]. In: CPS . Ottawa (ON): Canadian Pharma - reports alone. Given that the benefits of this combination in cists Association; [updated 2016 Jun 9; cited 2017 Feb 3]. Available from: www.e-therapeutics.ca. Subscription required to access content; also available treating depression related to Parkinson disease generally outweigh in paper copy from the publisher. the risks, either selegiline or rasagiline can be used cautiously with 22. Paxil [product monograph]. In: CPS . Ottawa (ON): Canadian Pharmacists an SSRI, provided that their recommended doses are not exceeded Association; [updated 2014 Nov 13; cited 2017 Feb 3]. Available from: www.e-therapeutics.ca. Subscription required to access content; also available and the doses of SSRIs are kept at the lower end of the therapeutic in paper copy from the publisher. range. 23. Prozac [product monograph]. In: CPS . Ottawa (ON): Canadian Pharmacists Association; [updated 2016 Jul 7; cited 2017 Feb 3]. Available from: www. References e-therapeutics.ca. Subscription required to access content; also available in 1. Grimes D, Gordon J, Snelgrove B, Lim-Carter I, Fon E, Martin W, et al. paper copy from the publisher. Canadian guidelines on Parkinson’s disease. Can J Neurol Sci. 2012;39 24. Zoloft [product monograph]. In: CPS . Ottawa (ON): Canadian Pharmacists (4 Suppl 4):S1-30. Association; [updated 2016 Jul 8; cited 2017 Feb 3]. Available from: www. 2. Postuma R, Rios Romenets S, Rakheja R. Physician guide: non-motor e-therapeutics.ca. Subscription required to access content; also available in symptoms of Parkinson’s disease. Montréal (QC): McGill University Health paper copy from the publisher. 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206 CJHP – Vol. 71, No. 3 – May–June 2018 JCPH – Vol. 71, n o 3 – mai–juin 2018 This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact CJHP at [email protected]

27. Eldepryl® [label]. Tampa (FL): Somerset Pharmaceuticals, Inc; 2008 Jan 45. Orange book: approved drug products with therapeutic equivalence evaluations. [cited 2017 Oct 22]. Available from: https://www.accessdata.fda.gov/ Silver Spring (MD): US Food and Drug Administration; 2018 [cited 2018 drugsatfda_docs/label/2008/020647s006s007lbl.pdf May 19]. Available from: https://www.accessdata.fda.gov/scripts/cder/ob/ 28. Azilect® [label]. Overland Park (KS) Teva Neuroscience, Inc; 2014 May 46. Garcia Monco JC, Padierna A, Beldarrain MG. Selegiline, fluoxetine, and [cited 2017 Oct 22]. Available from: https://www.accessdata.fda.gov/ depress-ion in Parkinson’s disease. Mov Disord . 1995;10(3):352. drugsatfda_docs/label/2014/021641s016s017lbl.pdf 47. Suphanklang J, Santimaleeworagun W, Supasyndh O. Combination of 29. Suchowersky O. Possible interactions between deprenyl and prozac. 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Jermain DM, Hughes PL, Follender AB. Potential fluoxetine–selegiline lexi.com/lco/action/home/switch. Subscription required to access content. interaction [letter]. Ann Pharmacother. 1992;26(10):1300. 36. Montastruc JL, Chamontin B, Senard JM, Tran MA, Rascol O, Llau ME, et al. Pseudophaeochromocytoma in parkinsonian patient treated with fluoxetine plus selegiline [letter]. Lancet. 1993;341(8844):555. 37. Waters CH. Fluoxetine and selegiline—lack of significant interaction. Can J Neurol Sci. 1994;21(3):259-61. 38. Toyama SC, Iacono RP. Is it safe to combine a selective serotonin reuptake Abdullah Aboukarr, PharmD, was, at the time this review was inhibitor with selegiline? Ann Pharmacother. 1994;28(3):405-6. performed, a PharmD student in the Leslie Dan Faculty of Pharmacy, 39. Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al.; University of Toronto, Toronto, Ontario. He is now with Medical Affairs, CANMAT Depression Working Group. Canadian Network for Mood and Purdue Pharma (Canada), Pickering, Ontario. Anxiety Treatments (CANMAT) 2016 clinical guidelines for the manage - Mirella Giudice, BScPharm, is with the Ottawa Valley Regional Drug ment of adults with major depressive disorder: section 3. Pharmacological Information Service, The Ottawa Hospital, Ottawa, Ontario. treatments. Can J Psychiatry . 2016;61(9):540-60. 40. Selegiline. In: Lexi-drugs online [database on internet]. Hudson (OH): Competing interests: This manuscript was undertaken when Abdullah Lexicomp, Inc; 2016 [updated 2017 Apr 4; cited 2017 Apr 12]. Available Aboukarr was a fourth-year PharmD student with a placement at the from: http://online.lexi.com. Subscription required to access content. Ottawa Valley Regional Drug Information Service, for which Mirella 41. Rasagiline. In: Lexi-drugs online [database on internet]. Hudson (OH): Giudice was the preceptor. Dr Aboukarr now works as a medical Lexicomp, Inc; 2016 [updated 2017 Apr 4; cited 2017 Apr 12]. Available information/pharmacovigilance officer with Purdue Pharma (Canada), from: http://online.lexi.com. Subscription required to access content. which does not market or manufacture any of the products mentioned 42. Hilli J, Korhonen T, Laine K. Lack of clinically significant interactions in this article, or any competing products. No other competing interests between concomitantly administered rasagiline and escitalopram. Progr were declared. Neuropsychopharmacol Biol Psychiatry. 2009;33(8):1526-32. Address correspondence to: 43. Richard IH, Kurlan R, Tanner C, Factor S, Hubble J, Suchowersky O, et al.; Dr Abdullah Aboukarr Parkinson Study Group. Serotonin syndrome and the combined use of Purdue Pharma (Canada) deprenyl and an antidepressant in Parkinson’s disease. Neurology. 1997; 575 Granite Court 48(4):1070-6. Pickering ON L1W 3W8 44. Rihmer A, Satori M, Pestality P. Selegiline-citalopram combination in patients e-mail: [email protected] with Parkinson’s disease and major depression. Int J Psychiatry Clin Pract. 2000;4(2):123-5. Funding: None received.

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