THE OREGON STATE DRUG REVIEW© AN EVIDENCE BASED DRUG THERAPY RESOURCE http://pharmacy.oregonstate.edu/drug-policy/newsletter February 2021 Volume 11 Issue 2 © Copyright 2021 Oregon State University. All Rights Reserved Antidepressant Review Kathy Sentena, Pharm.D., Oregon State University Drug Use Research and Management Group Depression is the second leading cause of disability in the Antidepressant Adverse Events United States (US), following cardiovascular disease, and the Minimizing adverse events can increase adherence and leading cause of disability worldwide.1 There have been many treatment success of antidepressant therapy. Common recent challenges which has resulted in rising incidences of antidepressant adverse reactions are sexual dysfunction, depression. Examples of these include Coronavirus Disease- anticholinergic effects, drowsiness, insomnia/agitation, 2019 (COVID-19), loss of employer-provided health insurance, orthostatic hypotension, QTc prolongation, gastrointestinal the opioid pandemic, job termination and isolation. The Centers adverse reactions and weight gain.8 Antidepressants with a for Disease Control and Prevention (CDC) has reported moderate to high risk of certain adverse reactions are increases in mental health challenges, with 40% of adults in the presented in Table 1. Antidepressants in Table 2 are US reporting issues with mental health or substance abuse.2 associated with less risk of common adverse reactions to Depressive disorders were approximately four times higher in help providers select the most appropriate therapy. Boxed April-June of 2020 compared to the same time period in 2019.2 warnings are part of the prescribing information for all Populations that have seen the largest increase in depressive antidepressants due to the risk of suicidal thoughts and disorders are younger adults, racial/ethnic minorities, essential behaviors in pediatric and young adult populations and workers and unpaid adult caregivers. The most recent report therefore, these populations should be monitored more from the CDC on state specific rates found Oregon to be ranked closely. the highest in the country in depression rates.3 In Medicaid patients served by the Oregon Health Plan (OHP) there were over 133,000 patients with antidepressant claims in the second Table 1. Antidepressants Associated with Moderate to High quarter of 2020.4 Persons with mental health disorders are at Levels of Certain Adverse Reactions*8,9 least 10 times as likely to commit suicide or have a suicide Antidepressant Adverse Reaction Level of Risk attempt, emphasizing the importance of appropriate Citalopram QTc Prolongation Moderate managment.5 The combination of non-pharmacologic strategies, Citalopram Sexual High like behavioral counseling, with antidepressants can be Dysfunction Escitalopram Sexual Moderate important tools in optimizing patient care. This newsletter will Fluoxetine Dysfunction focus on initiating, tapering, and switching antidepressants with Paroxetine a brief update on the use of esketamine. Sertraline Mirtazapine Drowsiness High Antidepressants Mirtazapine Weight gain High Providers are familiar with the classes of antidepressants that Venlafaxine Sexual Moderate are available, which include: selective serotonin reuptake Dysfunction inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors Trazodone Drowsiness High (SNRIs), atypical agents (bupropion and mirtazapine), serotonin Trazodone Orthostatic Moderate modulators, tricyclic antidepressants and monoamine oxidase Hypotension inhibitors (MAOIs). Classes of antidepressants are differentiated Trazodone GI adverse Moderate by their mechanisms of action, which corresponds to differing reactions adverse event profiles. Food and Drug Administration (FDA) Vilazodone GI adverse High indications for antidepressants include depression, anxiety reactions Vortioxetine GI adverse Moderate disorders and pain conditions. The National Institute for Health reactions and Care Excellence (NICE) and American Psychiatric Key: * Other antidepressants may be associated with these Association (APA) recommend second-generation adverse reactions but at slight or low risk. antidepressants (SSRIs, SNRIs, or atypical agents) for initial treatment.6,7 There is a lack of evidence from high quality systematic reviews that one second-generation antidepressant is superior to another; therefore, treatment selection should be based on adverse events, patient specific characteristics, tolerability and cost. OREGON STATE DRUG REVIEW Page 2 Table 2. Antidepressant Recommendations for Minimization of Table 3. Key Strategies for Switching Antidepressants10 Certain Adverse Reactions8 Strategies Explanation Recommended Examples Adverse Reaction to Antidepressants with the Least Risk Classes be Avoided Abrupt Stop the initial - SSRI to SSRI+ Citalopram to Sexual Dysfunction Bupropion switch therapy and - SSRI to SNRI sertraline 25 Mirtazapine start the new - SNRI to SSRI mg/day Duloxetine one at a low - SNRI to Vortioxetine dose mirtazapine+ Nefazodone Cross- Gradually - SSRI to SSRI+ Sertraline 50 Drowsiness SSRIs tapering* increase the - SSRI to mg daily to SNRIs dose of the mirtazapine mirtazapine 15 Bupropion new therapy - mirtazapine to mg daily while SSRI Vilazodone decreasing the - SNRI to Vortioxetine existing mirtazapine+ Anticholinergic SSRIs^ therapy - Switching to or SNRIs from bupropion Serotonin modulators* Bupropion Taper and Taper high - High dose SSRI Taper Orthostatic Atypical agents† switch dose to new SSRI paroxetine by hypotension SNRIs antidepressant 25% every 4 QTc Prolongation SNRIs to a low dose to 6 weeks to Atypical agents† before starting 10 mg daily Nefazodone new therapy and then start Vilazodone sertraline 25 vortioxetine mg daily Weight gain Bupropion Taper and Gradually - Fluoxetine (4-7 Taper and Fluoxetine switch taper dose, day washout) to stop SNRIs with stop current venlafaxine or fluoxetine. washout medication duloxetine After washout Serotonin modulators* and allow for start Abbreviations: SNRIs – serotonin-norepinephrine reuptake inhibitors; SSRIs – selective serotonin reuptake inhibitors washout venlafaxine Key: * Nefazodone, trazodone, vilazodone, vortioxetine; † Bupropion, 37.5 mg/day mirtazapine; ^ Paroxetine is not recommended if anticholinergic adverse Abbreviations: SNRIs – serotonin-norepinephrine reuptake inhibitors; reactions are to be avoided SSRIs – selective serotonin reuptake inhibitors Key: * Not recommended with fluoxetine, which should be stopped and the new SSRI should be started after a 7-day washout; + Abrupt switch or Switching Antidepressants cross-tapering can be used Antidepressant therapy should be tried for a minimum of 4 weeks after dose optimization to determine success of therapy. When switching or discontinuing antidepressants there is a Remission of depressive symptoms with the use of an initial risk of discontinuation syndrome. Tapering antidepressants antidepressant treatment only occurs in around one-third of over 6-8 weeks is recommended to avoid this syndrome; patients, thus necessitating switching to a different however, it can still occur. Discontinuation syndrome can 10 antidepressant. There is limited evidence to guide changing last up to 2 weeks and is due to the effects of decreasing antidepressants but in general, if two therapies from the same levels of serotonin and down regulation of receptors. class have not been effective, it is recommended to try an Discontinuation syndrome presents as gastrointestinal flu- option from a different class. Suggested guidance for switching like symptoms, irritability, insomnia, dizziness, vivid dreams antidepressants depends on the class, half-life and specific drug and paresthesias.11 The syndrome is most often seen when characteristics (Table 3). Caution is warranted due to lack of switching from a serotonergic antidepressant to a data on switching the following therapies: vortioxetine, nonserotonergic treatment (e.g., switching from venlafaxine 10 vilazodone, desvenlafaxine, or levomilnacipran. or paroxetine to buproprion) and with therapies with a shorter half-life.10 Discontinuation syndromes can be treated by increasing the dose of the serotonergic agent, repeating the taper at a slower rate or switching the patient to an SSRI with a longer half-life.11 Oregon DUR Board Newsletter Produced by OSU COLLEGE of PHARMACY DRUG USE RESEARCH & MANAGEMENT Managing Editor: Kathy Sentena [email protected] OREGON STATE DRUG REVIEW Page 3 Esketamine Figure 1. Comparative Antidepressant Monthly Cost for Esketamine is a non-competitive N-methyl-D-aspartate (NMDA) Select Agents receptor blocker initially approved for treatment-resistant $480 depression.12 Esketamine must be given under the supervision $500 $450 of a provider and is only available through a Risk Evaluation $405 $400 and Mitigation Strategy (REMs) Program. It is indicated for use $350 $288 along with an oral antidepressant. Esketamine is associated $300 with nausea, vomiting, dissociation, sedation, and misuse. $250 Blood pressure should also be monitored as elevations have $200 been seen for up to 4 hours. Esketamine, 56 or 84 mg, is given $150 as a nasal spray twice weekly for the first month and then once $100 weekly or every other week as maintenance therapy.12 The cost $50 $2 $1 $2 for esketamine for a 30-day supply (given once weekly) is $0 $1585.13 Esketamine received an expanded indication for major depressive disorder with suicidality in July of 2020.12 Two, four- * Prices based on