Curr Psychiatry Rep (2012) 14:360–369 DOI 10.1007/s11920-012-0283-x

PSYCHIATRY IN PRIMARY CARE (BN GAYNES, SECTION EDITOR)

How Should Primary Care Doctors Select Which Antidepressants to Administer? Gerald Gartlehner & Kylie Thaler & Seth Hill & Richard A. Hansen

Published online: 31 May 2012 # Springer Science+Business Media, LLC 2012

Abstract Clinicians can choose among various secondgeneration antidepressants for treating depressive disorders, such as major depressive disorder, subsyndromal depression, or dysthymia. Systematic reviews indicate that available drugs differ in frequency of administration, costs, and the risks of some adverse events but have similar efficacy for treating major depressive disorder. Furthermore, evidence does not support the choice of one antidepressant over another based on accompanying symptoms, such anxiety, insomnia, or pain. Available studies provide little guidance for clinicians about the benefits of second-generation antidepressants for treating dysthymia and subsyndromal depression. Evidence is also unclear about the comparative risks of serious adverse events, such as suicidality, seizures, fractures, increased bleeding, or serotonin syndrome. This article summarizes the best available evidence regarding comparative benefits and harms of second-generation antidepressants for treating depressive disorders. G. Gartlehner (*) : K. Thaler Department of Evidence-based Medicine and Clinical Epidemiology, Danube University, Karl Dorrek-Straße 30, 3500 Krems, Austria e-mail: [email protected] G. Gartlehner RTI International, Research Triangle Park, Durham, NC, USA S. Hill : R. A. Hansen Harrison School of Pharmacy, Department of Pharmacy Care Systems, Auburn University, Auburn, AL, USA

Keywords Major depressive disorder . Dysthymia . Subsyndromal depression . Second-generation antidepressants . Treating depressive disorders . Primary care

Introduction Depressive Disorders Depressive disorders, such as major depressive disorder (MDD), subsyndromal depression, and dysthymia, are serious, disabling illnesses and the cause of a vast burden of disease [1]. Combined, they affect approximately one in five adults at some point during a lifetime [2]. As of 2005, an estimated 27 million North Americans were treated with antidepressants [3]. The economic burden of depressive disorders in the United States is estimated to be >$83 billion annually [4]; >30 % of these costs are attributable to direct medical expenses. Depression-related workforce productivity losses are projected to be $24 billion annually [5]. MDD is the most commonly diagnosed form of depression. Table 1 outlines core symptoms of depressive disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [1], according to which the diagnosis of MDD requires at least five core symptoms to be present during the same 2-week period. One of these symptoms has to be depressed mood or anhedonia [1]. MDD disease course and treatment are classified into three phases [6]: (1) Acute phase, during which a patient experiences depressive symptom progression and seeks medical attention. The acute phase lasts up to 12 weeks, and the therapeutic goal is to achieve response to treatment and eventually remission. (2) Continuation phase, occurs when patients (4–9 months).

Curr Psychiatry Rep (2012) 14:360–369 Table 1 Core symptoms of depressive disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)] Core Symptoms of Depressive Disorders Depressed mood for most of the day* Anhedonia (loss of interest or pleasure) nearly every day* Change in appetite or weight (>5 % of body weight within a month) Sleep disturbance (insomnia or excessive sleeping) Psychomotor agitation or retardation Fatigue or loss of energy nearly every day Feelings of guilt, worthlessness, or low self-esteem Concentration or memory problems, indecisiveness Recurrent thoughts of death or suicidality *One of these two core symptoms is required for diagnosis of major depression

The therapeutic goal during this period is to prevent relapse and achieve full recovery. Relapse is defined as the return of depressive symptoms during the acute or continuation phases and is considered part of the same depressive episode. (3) Maintenance phase, the final phase, lasts ≥9 to 12 months. In this phase preventing recurrence is the ultimate goal. Recurrence is defined as the return of depressive symptoms as a new, distinct episode. Second-generation Antidepressants Second-generation antidepressants account for the majority of antidepressant prescribing. These drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other drugs with related mechanisms of action that selectively target neurotransmitters. In 2009, second-generation antidepressants accounted for $9.9 billion in sales in the United States, ranking as the fourth topselling therapeutic class of prescription drugs [7]. Many second-generation drugs are available generically, although newer agents such as desvenlafaxine, duloxetine, and escitalopram have remaining patent protection. Drug names, all dosage forms, and usual daily frequency of use are described. Fig. 1 illustrates approval times for second-generation antidepressants by the US Food and Drug Administration (FDA) over the past three decades. Except for fluvoxamine (approved only for treating obsessive–compulsive disorder), all secondgeneration antidepressants are approved for treating MDD [18••]. Table 2 summarizes, by mechanism of action, secondgeneration antidepressants in the United States, listing names, all dosage forms, and usual daily frequency of use. Treatment of Acute-Phase Major Depressive Disorder Pharmacotherapy is the primary choice for treating acutephase depression. The goal is to help patients achieve

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remission and regain functional capacity and QOL (QOL). Pharmaceutical options include first-generation drugs such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and newer drugs referred to here as secondgeneration antidepressants (see above). Although first- and second-generation antidepressants have similar efficacy [8, 9], first-generation agents often are accompanied by side effects that many patients find intolerable. For example, TCAs tend to cause anticholinergic effects, including dry mouth and eyes, urinary hesitancy, and sometimes retention and constipation. In addition, TCAs have a high rate of lethality when overdose occurs. MAOIs can produce a potentially lethal hypertensive crisis if taken along with particular medications or with certain foods or dietary supplements containing excessive amounts of tyramine. Thus, first-generation antidepressants are no longer agents of choice in many circumstances, and second- generation drugs are the current standard of therapy. To assess the comparative benefits and harms of the various newer antidepressants, several systematic reviews were conducted [8, 10–17, 18••]. Most concluded that antidepressants have similar efficacy for treating MDD. A notable exception among these reviews, however, is the Meta-analysis of New Generation Antidepressants (MANGA) study [19]. This study group reported that escitalopram and sertraline have the best efficacy–acceptability ratio compared with other secondgeneration antidepressants. Although the MANGA study received substantial press coverage, scientifically, it has been criticized for methodological shortcomings [20–24]. Specifically, the authors included studies with a high risk of bias and with open-label designs; assumed that a response on the Hamilton Depression Rating Scale (HAM-D) equates to response on the Montgomery Asberg Depression Rating Scale (MADRS) or the Clinical Global Inventory; and overstated the importance of statistically significant differences without considering clinical relevance. Findings of the MANGA study could not be reproduced by a recent comparative effectiveness report funded by the US Agency for Healthcare Research and Quality (AHRQ) [25]. Results of the AHRQ report indicate that current evidence does not warrant the choice of one second-generation antidepressant over another based on greater efficacy of a particular drug. Treatment effects with respect to response, remission, or QOL were similar among secondgeneration drugs approved for treating MDD. This report, however, also stressed that similar efficacy does not mean that second-generation antidepressants can be considered identical drugs. Some differences were apparent with respect to onset of action and adverse event (AE) profiles. Specifically, consistent evidence from multiple trials demonstrates that mirtazapine has a faster onset of action than citalopram, fluoxetine, paroxetine, and sertraline [26–32]. The benefit of a faster onset of mirtazapine, however, must be weighed against possible decreased adherence because of long-term weight gain.

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Fig. 1 Second-generation antidepressant approvals by the US Food and Drug Administration

Table 2 Dosing ranges of second-generation antidepressants for treating adults Generic name

Bupropion

c

Citalopram c Desvenlafaxine

US trade name a

Usual daily dosing range

Frequency

Wellbutrin®

200–450 mg

Wellbutrin SR® Wellbutrin XL® Celexa® Pristiq®

150–400 mg

Three times daily Twice daily

150–450 mg

Once daily

20–40 mg 50 mg

Once daily Once daily

Cymbalta®

40–60 mg b

Once or twice daily

Lexapro® Prozac®

10–20 mg 10–80 mg

Prozac Weekly® Luvox®

90 mg (weekly)

Once daily Once or twice daily Once weekly

f

Duloxetine

e

Escitalopram Fluoxetine c

Fluvoxamine Mirtazapine

c

Nefazodone c Paroxetine c Sertraline c Trazodone c Venlafaxine

c

d

c

50–300 mg

Remer on® Remer on Sol tab® Serzone® Paxil® Paxil CR® Zoloft® Desyrel®

15–45 mg 15–45 mg 200–600 mg 20–60 mg 12.5–75 mg 50–200 mg 150–400 mg

Effexor®

75–375 mg

Effexor XR®

75–225 mg

Once or twice daily Once daily Once daily Twice daily Once daily Once daily Once daily Three times daily Two to three times daily Once daily

Adverse events, in general, are an important tradeoff of treatment regimens with second-generation antidepressants. On average, 63 % of patients in clinical trials experienced at least one AE [25]. Constipation, diarrhea, dizziness, headache, insomnia, nausea, adverse sexual events, and somnolence are commonly and consistently reported. Nausea and vomiting were the most common reasons for discontinuation of treatment in clinical studies [25]. Overall, between 7 % and 15 % of patients discontinued treatment because of intolerable adverse effects [25]. Although second-generation antidepressants have similar AE profiles, some differences in the frequencies of AE exist. For example, amongst all secondgeneration drugs, sertraline has a higher risk of diarrhea, venlafaxine of vomiting and nausea, paroxetine of sexual dysfunction, mirtazapine of weight gain, and trazodone of somnolence. Bupropion has fewer sexual side effects than escitalopram, fluoxetine, paroxetine, and sertraline [33–40]. Although some of these differences are small, they may be clinically relevant and influence the choice of a medication for a specific patient. For example, patients who have a history of nausea or who dread sexual dysfunction might be more adherent to a choice of treatment that takes these factors into consideration. Past treatment experiences may also influence decisions regarding medications to either select or avoid, but no evidence exists to verify these inferences [18••]. The American College of Physicians (ACP) recommends that when clinicians are initially treating patients with acute MDD, they should first select an antidepressant on the basis of AE profiles, cost, and patient preferences [41]. Once an initial medication is selected, the ACP guidelines recommend that clinicians assess the patients’ status, therapeutic response, and adverse effects on a regular basis, beginning 1–2 weeks after initiation of therapy. If patients do not have an adequate response to pharmacotherapy within 6–8 weeks, then clinicians should modify the treatment.

a

CR, SR, XL, and XR are registered trademarks referring to controlled-, sustained-, or extended-release dosage forms, respectively

b

Doses of duloxetine up to 120 mg were studied in clinical trials, although doses >60 mg are not believed to have additional efficacy c

Generic available for some dosage forms

d Could become available generically in 2012 e Could become available generically in 2013 f Could become available generically in 2022

Treating Major Depressive Disorder with Accompanying Symptoms More than 50 % of psychiatrists base their choice of secondgeneration antidepressants on the presence of a symptom cluster [42]. For example, in one study of veterans with depression, those with accompanying anxiety were more

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likely to be prescribed paroxetine and least likely to receive bupropion [43]. In another study, 46 % of psychiatrists reported they would prescribe nefazodone for a patient with accompanying insomnia [44]. Eli Lilly, the makers of duloxetine, elude to several common accompanying symptoms in their “Depression Hurts” advertising campaign, including pain (“I feel these aches and pains”), guilt, insomnia (“my sleep just isn’t right”), anxiety (“I’m so anxious”), and lack of concentration (“I need to focus”) [45]. However, few trials are adequately designed to test the efficacy of the second-generation antidepressants for accompanying symptoms; many analyses of accompanying symptoms in depression trials are based on scores from the individual items in the HAM-D and are therefore susceptible to chance findings due to multiple testing (when looking at 17 individual items, some are likely to be significantly different just based on chance). Very few direct head-to-head comparisons of second-generation antidepressants exist that provide information of their comparative efficacy for accompanying symptoms. In an analysis of the comparative effectiveness of second-generation antidepressants for symptoms that accompany depression, we found head-to-head data for three common symptoms: anxiety, insomnia, and pain [18••]. For anxiety, SSRIs seem to be equivalent to each other; escitalopram, fluoxetine, paroxetine, and sertraline show similar efficacy but confidence intervals are wide. Two studies indicate that venlafaxine is superior to fluoxetine, and one trial showed that it is equivalent to sertraline [46–48]. Furthermore, three individual trials indicate the equivalence, respectively, of sertraline and bupropion, paroxetine and nefazodone, and citalopram and mirtazapine [32, 49, 50]. Insomnia is both an accompanying symptom of depression and a common side effect of depression treatment. Hence, some studies record sleep parameters separately, and some rely on the insomnia items of the HAM-D score (the “sleep disturbance factor”). In general, SSRIs fluoxetine, paroxetine, and sertraline seem to be similar for improving insomnia based on the HAM-D sleep disturbance subscale. Likewise, one trial that employed the Leeds Sleep Evaluation Questionnaire showed that patients taking fluoxetine and mirtazapine had similar improvements in sleep. In contrast, a trial of depressed patients who underwent polysomnographic recording to measure their sleep showed that nefazodone was superior to fluoxetine [51]. Two trials showed trazodone to be better than fluoxetine and venlafaxine for sleep disturbance [52, 53]. Clinicians treating depressed patients with prominent insomnia might consider trazodone or nefazodone therapy, as both have been shown to be superior to other drugs. For depressed patients with pain, only four studies that directly compared second-generation antidepressants could be found [54–57]. These studies were flawed in that they compared higher doses of duloxetine with lower doses of

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paroxetine; however, they indicate no difference between the two agents. No evidence exists to guide practicing clinicians toward any particular second-generation antidepressant for depressed patients with pain. Preventing Relapse and Maintaining Remission For both continuation- and maintenance-phase treatment, patients should remain on the same antidepressant as long as they do not have a relapse or recurrence [41, 58]. The desirable outcome of continuation-phase treatment is preventing relapse, whereas maintenance-phase treatment goals are preventing recurrence of a new distinct episode. In terms of whether continuation- and maintenance-phase treatment is effective, 14 placebo-controlled relapse-prevention trials (representing continuing treatment of 14–72 weeks) and 17 placebo-controlled recurrence-prevention trials (representing 36-100 weeks) support the benefits of various secondgeneration antidepressants when compared with placebo. The benefits of these various antidepressants appear to be generally consistent in placebo-controlled efficacy trials. This observation is consistent with conclusions of two published meta-analyses of placebo-controlled trials [59, 60]. For clinical decision making, the question is whether the choice of one antidepressant is better than another for preventing relapse and recurrence. Seven head-to-head trials and one comparative naturalistic study compared second-generation antidepressants for maintaining response or remission. The seven trials compared escitalopram and desvenlafaxine [61], escitalopram and paroxetine [62], fluoxetine and sertraline [63], fluoxetine and venlafaxine [64], fluvoxamine and sertraline [65, 66], and trazodone and venlafaxine [52]; the naturalistic study compared fluoxetine and venlafaxine [67]. Of these studies, none found statistically significant differences in effectiveness at preventing relapse and maintaining remission between the compared second-generation antidepressants. Whereas no significant differences in maintaining remission were reported, one of these studies reported a significantly shorter time to recurrence with fluoxetine than with venlafaxine during 2 years of maintenance treatment [64]. The naturalistic reported similar rehospitalization rates over 1 year. Overall, it appears that second-generation antidepressants show few differences in terms of efficacy and effectiveness at preventing relapse and maintaining remission. Head-tohead evidence of this conclusion is not robust, and additional evidence could provide new conclusions. Achieving Response in Unresponsive or Recurrent Disease Overall, about 40 % of patients do not adequately respond to 6–12 weeks of treatment with second-generation antidepressants; 53 % do not achieve remission. For unresponsive or recurrent disease, the question of the best next-step treatment

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is an ongoing debate. Six studies assessed differences among alternative antidepressants in patients who either had not responded to or could not tolerate an acute-phase treatment. The strongest study is the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial [68, 69]. This randomized trial compared outcomes of 727 adult outpatients randomly assigned to bupropion-SR, sertraline, or venlafaxineXR after unsuccessful treatment with aggressively managed citalopram. After 14 weeks, approximately one in four of the 727 participants who switched medications after initial treatment failure became symptom free [68]. Furthermore, there were no statistically significant differences in the number of patients achieving remission of depressive symptoms between the three medications, suggesting that all three are appropriate second-step choices for achieving response in unresponsive patients. A second arm of the STAR*D trial compared augmentation strategies of citalopram plus bupropion-SR and citalopram plus buspirone in 565 participants who failed initial treatment with citalopram [69]. No statistically significant differences were observed when comparing these strategies. A secondary analysis of the STAR*D trial found no clear differences between switch and augmentation strategies after accounting for differences in these groups [70]. A smaller study comparing mirtazapine, paroxetine, and venlafaxine also found no statistically significant differences in response or remission rates [71]. Evidence from the STAR*D trial and the Fang et al. study is somewhat contradicted by four head-to-head trials involving patients with treatment-resistant depression. These four studies compared venlafaxine and paroxetine [72], venlafaxine and citalopram [73], fluoxetine and venlafaxine [74], and venlafaxine and conventional antidepressants (including citalopram, fluoxetine, mirtazapine, paroxetine, and sertraline) [75]. Of these four trials, response and remission rates were numerically better with venlafaxine than with comparators. Results were only statistically significant in two of these trials [71, 75] and may be subject to bias and confounding related to their designs. However, these differences leave some doubt as to whether venlafaxine might be slightly more efficacious in unresponsive or recurrent depression. Overall, it appears the evidence is insufficient to determine factors that can reliably predict response or nonresponse in individual patients. One approach to achieving higher acute-phase response rates is to combine one or more antidepressants [76]. However, the benefits of combination treatment are conflicting. Four studies conducted from 2000 to 2011 show that combination therapy has the potential to yield significantly better patient outcomes than monotherapy. Carpenter and colleagues [77] showed this by adding mirtazapine to an SSRI, bupropion, or venlafaxine therapy; Lam and colleagues [78], by combining citalopram and bupropion therapies in patients receiving one of these monotherapies, and Blier and colleagues in two studies

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—one combining mirtazapine and paroxetine [79] and the other analyzing mirtazapine in combination with either fluoxetine, venlafaxine, or bupropion [76]. In each trial, the combination group demonstrated statistically significant higher remission rates when compared with the monotherapy group. Small sample sizes and short follow-up times were noted limitations of these studies. Finally, in 2011, Rush and colleagues [80] conducted the Combining Medications to Enhance Depression Outcomes (CO-MED) study, which randomized 665 MDD patients into three groups: escitalopram plus placebo, escitalopram plus bupropion-SR, or venlafaxineXR plus mirtazapine for 7 months. Findings contradict results of the previous body of literature, showing no significant difference in response and remission rates between combination and monotherapy groups at 12 weeks and at 7 months, and demonstrating a higher side effect burden in the venlafaxineXR plus mirtazapine group at both 12 weeks and 7 months. This larger trial is likely more representative of actual effect sizes than previous studies analyzing smaller samples over shorter time periods. Treating Dysthymia Dysthymia is a chronic depressive condition that affects approximately 1.5 % of the adult population in the US [2]. According to the DSM-IV, the diagnosis of dysthymia requires that depressive symptoms occur on more days than not for at least 2 years [1]. In addition, two or more accompanying symptoms such as poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low selfesteem, poor concentration or difficulty making decisions, and feelings of hopelessness must be present. Evidence regarding the efficacy of antidepressants for treating dysthymia is sparse and limited to placebo-controlled trials on fluoxetine, paroxetine, and sertraline [81–87]. A search in www.clinicaltrials.gov revealed that several trials on newer second-generation antidepressants for treating dysthymia have been completed [e.g., bupropion extended release (XR), citalopram, duloxetine, escitalopram], but results have not been published. In addition to the dearth of available research, studies present conflicting results about the benefits of secondgeneration antidepressants for patients with from dysthymia. Two trials evaluated the efficacy of fluoxetine over 12 weeks [81, 84]. One study, conducted in patients ≥60 years reported numerically greater response rates for patients on fluoxetine than placebo (27 % vs. 20 %) [84]. The difference, however, did not reach statistical significance and must be interpreted cautiously. Likewise, in a large primary-care-based pragmatic randomized controlled trial (RCT), paroxetine was not statistically significantly better than placebo, except in a subgroup of patients >60 years [85, 87]. By contrast, three RCTs reported statistically significantly greater response rates for

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patients treated with fluoxetine or sertraline compared with placebo [84, 85, 87]. All of these results, however, need to be interpreted cautiously because, overall, <2,000 patients have been enrolled in published controlled trials on dysthymia. Treatment of Subsyndromal Depression There is a lack of consensus about the nomenclature of depressive disorders that do not meet criteria for MDD but still substantially impair patient’s functional capacity [88]. Commonly used terms are minor depression, subsyndromal depression, and subthreshold depression. The American Psychiatric Association defines minor depression as the presence of fewer than five core symptoms (see Table 1) for at least 2 weeks, to a degree that adversely affects a patient’s social relationships and usual activities. At least one core symptom must be depressed mood or anhedonia [1]. Subsyndromal depression has been acknowledged as a serious risk factor for MDD [89]. For treating subsyndromal depression, evidence from sound studies to guide clinicians is even more limited than for dysthymia. Overall, available double-blinded RCTs provide data on <500 patients with subsyndromal depression. Two double-blinded placebo-controlled trials assessed the efficacy and tolerability of a single SSRI. In one trial, fluoxetine-treated patients achieved statistically significantly greater improvements on depression scales after 12 weeks than did patients on placebo [90]. The second trial was a large primary-care-based pragmatic study that randomized 656 patients with dysthymia or minor depression to 11 weeks of paroxetine (10–40 mg/day), placebo, or behavioral therapy [85, 87]. In a subgroup of patients ≥60 years, those on paroxetine experienced a greater change in depression scores than those receiving placebo [87]. Paroxetine was not more efficacious than placebo in patients <60 years [85]. The only study that directly compared one secondgeneration antidepressant to another is a nonrandomized, single-blinded trial (n0138) that assessed the comparative efficacy and safety of citalopram and sertraline in patients with late-life subsyndromal depressive disorders [91]. Overall, both treatments improved depressive symptoms, but the groups did not differ significantly at any time point. At the end of the study, remission was achieved by 53 % of patients on citalopram and 42 % on sertraline (P00.25). Likewise, no differences in psychosocial functioning emerged. Risk of Serious Harms Second-generation antidepressants have been associated with rare but serious AEs, such as suicidality (suicidal thoughts and behavior), seizures, cardiovascular events, fractures, increased risk of bleeding, serotonin syndrome, hyponatremia, or hepatotoxicity. For most of these serious AEs, the evidence is

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insufficient to draw conclusions about differences in risks among second-generation antidepressants. An exception is the risk of hepatotoxicity, which appears to be a potential harm specifically during nefazodone treatment [92, 93]. The risk of suicidality during treatment with second-generation antidepressants has been covered prominently in the public press and has been examined by several large studies [94–96]. About one in 166 patients reports suicidal feelings while being treated with a second-generation antidepressant [97]. Suicide, however, is still a rare event (about one in 8,000 psychiatric patients treated with second-generation antidepressants) and thus difficult to detect with statistical significance, even in large observational studies. A recent meta-analysis of observational studies in a combined population of >200,000 patients indicated that with the use of SSRIs, the risk of attempted or completed suicide was decreased among adults odds ratio (OR), 0.57, 95 % confidence interval (CI), 0.47–0.70]. Among people ≥65 years or older, exposure to SSRIs had a protective effect (OR, 0.46, 95 % CI, 0.27–0.79) [98•]. These findings were consistent with an FDA data analysis of >99,000 participants in 372 trials. The FDA pointed out that the risk of suicidality is increased in children and patients 18–24 years of age but not in other adult patients [97]. Results from existing studies do not indicate that any particular drug of interest has an excess risk compared with that of other second-generation antidepressants [95, 96, 98•, 99–102]. All these studies, however, were underpowered to detect a statistically significant difference between two drugs.

Discussion Good evidence indicates that for MDD, the efficacy of second-generation antidepressants does not differ substantially when treating adults. Evidence also does not support the selection of one second-generation antidepressant over another for specific accompanying symptoms. For other depressive disorders, such as dysthymia or subsyndromal depression, the underlying evidence remains insufficient to draw inferences about the benefits of second-generation antidepressants. Despite these conclusions, many questions remain. Given the fact that almost two in five patients do not respond to initial treatment, an important future research agenda item is to focus on making the initial treatment strategy more effective. Potential approaches include looking at ways to better predict treatment response to optimize initial treatment selections (e.g., through genetic analysis). In addition, more evidence is needed regarding the most appropriate duration of antidepressant treatment for maintaining response and remission. Such studies should also evaluate further whether different formulations (i.e., controlled release vs. immediate release) lead to differences in adherence and subsequently to

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differences in relapse or recurrence. Additionally, although most trials maintained the dose used in acute-phase treatment throughout continuation and maintenance treatment, little is known about the effect of drug dose on the risk of relapse or recurrence [18••]. Therefore, what does the available evidence mean to practicing clinicians? Given the difficulty in predicting what medication will be both efficacious for and tolerated by an individual patient, familiarity with a broad spectrum of antidepressants is prudent. Existing efficacy evidence does not warrant choosing one second-generation antidepressant over another as a first-line therapy in patients with acutephase MDD or as a subsequent treatment in patients who do not respond or experience remission. Clinicians need to explore patient preferences about dosing regimens and the level of acceptance that individual patients have for various AEs. Taking these factors into consideration will strengthen informed decision making when choosing an antidepressant and thus improve patient adherence.

Conclusion For treating MDD, evidence does not warrant the choice of one second-generation antidepressant over another based on differences in efficacy or accompanying symptoms. Differences with respect to onset of action and AEs may be taken into consideration for choosing a medication. The evidence is insufficient to draw conclusions about the benefits and harms of second-generation antidepressants for treating dysthymia and subsyndromal depression.

Disclosure Dr. Gartlehner has received research support from Agency for Healthcare Research and Quality (AHRQ). Dr. Thaler has received research support from AHRQ. Mr. Hill has received research support from AHRQ and Foundation for the National Institutes of Health (FNIH). Dr. Hansen has received research support from AHRQ and FNIH, and has served as a consultant for Novartis and Takeda.

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