Savvy Psychopharmacology Antidepressants: Is a higher dose always better? Aaron N. Tran, PharmD, BCPP, BCPS, and Risa Ishino, PharmD, BCPP, BCPS r. E, age 39, presents to the mental However, based on our review of available health (MH) intake clinic, reporting literature, this recommendation is equivo- M he has had depressed mood almost cally supported for general practice. every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate Selective serotonin reuptake on daily activities, low energy and motiva- inhibitors tion, and feelings of guilt. He is diagnosed The Table1-3 (page 40) summarizes the results Vicki L. Ellingrod, with major depressive disorder and agrees to of 3 studies of high-dose selective serotonin PharmD, FCCP a trial of sertraline, which is titrated up to 100 reuptake inhibitors (SSRIs). Department Editor mg/d. He is also referred to the MH pharmacy Adli et al1 evaluated 3 types of studies— clinic for interim visits. studies of patients with treatment-resistant Four weeks later during a follow-up visit, depression receiving high-dose treatment, Mr. E reports tolerating sertraline, 100 mg/d, comparative dose studies, and studies of with a slight improvement in his mood. He therapeutic drug-monitoring (TDM) of anti- reports that he has started working on his depressants—to assess the effectiveness of previous hobbies again and tries to consis- high-dose antidepressants after a treatment tently eat 2 meals a day. He feels that his sleep failure with a medium dose. They concluded remains unchanged. He would like to enroll that SSRIs exhibit a flat dose-dependency in school again, but is concerned about his pattern, where increasing a dose above the poor concentration. He asks whether a further minimum effective dose (MED) does not increase in his sertraline dose would improve increase efficacy but results in more adverse his symptoms. What would you advise? effects. Because treatment at the MED Escalating antidepressant doses up to, or Practice Points even above, the FDA-approved maximum • Recommending an antidepressant dose escalation assumes a dose-response dose is a strategy for clinicians to consider relationship. for patients who are nonresponders or par- tial responders to treatment. This practice • Compared with other types of assumes that the effectiveness of an anti- antidepressants, tricyclic and tetracyclic antidepressants appear to have more Savvy Psychopharmacology depressant is dependent on the dosage. is produced in partnership evidence supporting a benefit from with the College dose escalation. of Psychiatric Dr. Tran is Clinical Pharmacist Specialist, Mental Health VA Loma and Neurologic Linda Healthcare System, Loma Linda, California. Dr. Ishino is Clinical • Current evidence equivocally supports Pharmacists Pharmacist Specialist, Mental Health VA Loma Linda Healthcare cpnp.org System, Loma Linda, California. dose escalation for selective serotonin reuptake inhibitors. mhc.cpnp.org (journal) Disclosures The authors report no financial relationships with any companies • Consider an individual patient’s pharma- whose products are mentioned in this article, or with manufacturers cogenetic and relevant pharmacokinetic of competing products. factors before initiating a dose escalation. Current Psychiatry doi: 10.12788/cp.0102 Vol. 20, No. 3 39 Savvy Psychopharmacology Table Dose escalation of selective serotonin reuptake inhibitors: 3 studies Study Design Conclusion Adli et al1 Review of 3 types of studies: 1) dose SSRIs exhibit a flat dose-dependency increase studies in treatment-refractory pattern, where an increase in dose above patients, 2) comparative dose studies, and the minimum effective dose does not 3) therapeutic drug monitoring studies increase efficacy but results in more adverse effects Ruhe et al2 Review of 8 randomized controlled trials Evidence for increased efficacy with and 3 systematic analyses that examined SSRI dose escalation was inconclusive, dose escalation of SSRIs, including but dose escalation resulted in more paroxetine, fluoxetine, and sertraline adverse effects Hieronymus Mega-analysis of dose-dependency SSRIs at low doses were superior to et al3 patterns of selected SSRIs, including placebo but inferior to higher doses. The Clinical Point citalopram, paroxetine, and sertraline, in dose-response relationship plateaued adult patients with depression at 20 mg/d for paroxetine, 40 mg/d for Evidence supporting citalopram, and 100 mg/d for sertraline antidepressant SSRIs: selective serotonin reuptake inhibitors dose escalation is inconclusive, but higher doses result inhibits 70% of serotonin reuptake and is received placebo. They further divided the only marginally less effective than medium SSRIs into “low” vs “optimal” doses based in more adverse therapeutic doses, the authors recom- on the dose curves of these agents. For cita- effects mended reserving treatment at higher doses lopram, 10 to 20 mg/d was considered low for patients who have failed other standard vs 40 to 60 mg/d, which was considered treatment options, such as augmentation. optimal. For paroxetine, 10 mg/d was con- Ruhe et al2 evaluated 8 randomized con- sidered low vs other doses as optimal (20, trolled trials and 3 systematic analyses that 30, and 40 mg/d). For sertraline, 50 mg investigated dose escalation of SSRIs, includ- was considered low vs other doses as opti- ing paroxetine, fluoxetine, and sertraline. The mal (100, 200, and 400 mg/d). The authors authors noted that all included studies had concluded that at low doses, these anti- methodological limitations and discussed depressants were superior to placebo but 1 study that showed potential benefit from inferior to higher doses. Interestingly, they dose escalation when dropouts due to suggested that the dose-response relation- adverse effects were excluded from analy- ship plateaued at 20 mg/d for paroxetine, sis. They determined that the evidence for 40 mg/d for citalopram, and 100 mg/d for increased efficacy with dose escalation was sertraline. One of the limitations of the study inconclusive; however, dose escalation un- was a lack of information on the tolerability doubtedly resulted in more adverse effects. of higher vs lower doses. Hieronymus et al3 found a dose- dependency pattern with selected SSRIs— Other antidepressants citalopram, paroxetine, and sertraline—in Adli et al1 found a high-dose study and sev- a mega-analysis of studies of adult patients eral comparative studies that supported a Discuss this article at with depression. All company-funded, dose-response relationship with a reason- www.facebook.com/ acute-phase, placebo-controlled fixed-dose able degree of tolerability for venlafaxine, MDedgePsychiatry trials of these agents were included in this but there were no pertinent studies that analysis. It included a total of 2,859 patients: evaluated mirtazapine. The only fixed-dose 600 patients received citalopram (10 to study found for bupropion did not support 60 mg/d); 1,043 patients received parox- a dose-response relationship.1 etine (10 to 40 mg/d); 481 patients received The authors also concluded that there Current Psychiatry 40 March 2021 sertraline (50 to 400 mg/d); and 735 patients may be evidence supporting high-dose Savvy Psychopharmacology prescribing of tricyclic and tetracyclic antide- pressants (TCAs and TeCAs, respectively). Related Resources • Berney P. Dose-response relationship of recent anti- Despite the lack of clinical data that directly depressants in the short-term treatment of depression. addressed the dose-dependency of TCAs Dialogues Clin Neurosci. 2005;7:249. and TeCAs, the authors supported dose • Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic escalation with amitriptyline, clomipramine, review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive imipramine, desipramine, nortriptyline, and disorder. Am J Psychiatry. 2016;173:174-183. maprotiline, based on the data from compar- Drug Brand Names 1 ative dose and TDM studies. The authors Amitriptyline • Elavil Maprotiline • Ludiomil urged caution in interpreting and applying Bupropion • Wellbutrin Mirtazapine • Remeron Citalopram • Celexa Nortriptyline • Pamelor the results of TDM studies because the phar- Clomipramine • Anafranil Paroxetine • Paxil macodynamic of each medication—such as Desipramine • Norpramin Sertraline • Zoloft Fluoxetine • Prozac Venlafaxine • Effexor being linear, curvilinear, or uncorrelated— Imipramine • Tofranil may vary, which suggests there is a targeted Clinical Point 1 therapeutic dose range. Before initiating Important considerations a dose escalation, Differences in the pharmacokinetic and enzymes, mainly CYP2D6 and CYP2D19, consider a patient’s pharmacogenetic properties of individual have been shown to directly affect anti- pharmacogenetic medications may account for the mixed out- depressants’ serum levels. Depending on and relevant comes found when evaluating antidepres- the patient’s phenotype expression, such pharmacokinetic sant dose-response relationships. Genetic as poor, intermediate, extensive (ie, nor- polymorphisms of cytochrome (CYP) P450 mal), or ultra-metabolizers, use of a specific factors Savvy Psychopharmacology antidepressant at a similar dose may result patients in making an informed decision in therapeutic effectiveness, ineffective- on dose escalation to and beyond the FDA- ness, or toxicity. For antidepressants such approved doses. as TCAs, which have a narrow therapeutic index compared with SSRIs,