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The Efficacy, Tolerability, and Safety of Contemporary Antidepressants

George I. Papakostas, MD

Published: March 31, 2010

The Efficacy, Tolerability, and Safety of Contemporary Antidepressants

A wide variety of antidepressants are available today for treating major depressive disorder. However, like all medical therapies, antidepressants have several limitations that clinicians should consider when choosing treatments for their patients. This article reviews the efficacy, tolerability, and safety of the newer (ie, posttricyclic era) antidepressants. Specifically, overall efficacy and efficacy in relation to specific depressive symptoms and patient subpopulations, as well as in relation to various psychiatric and medical comorbidities, are addressed, along with tolerability profiles with respect to common side effects, including nausea, fatigue, insomnia, somnolence, sexual dysfunction, and weight gain. Finally, the safety profile of these agents is summarized.

(J Clin Psychiatry 2010;71[suppl E1]:e03)

From the Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston.

This article is derived from the roundtable discussion "International Consensus Group on Depression," which was held on September 1, 2009, in Tokyo, Japan, and supported by an educational grant from GlaxoSmithKline.

Dr Papakostas has served as an advisor/consultant for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Evotec, Inflabloc, Jazz, Shire, Titan, Otsuka, Pfizer, Pierre Fabre, Wyeth, and Pamlab; has received grant/research support from the National Institute of Mental Health, Pamlab, Pfizer, Forest, Precision Human Biolaboratories, and Bristol-Myers Squibb; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Evotec, Inflabloc, Jazz, Shire, Otsuka, Pierre Fabre, Pfizer, Pamlab, Titan, Wyeth, and Lundbeck.

Corresponding author: George I. Papakostas, MD, Massachusetts General Hospital, 15 Parkman St WACC #812, Boston, MA 01224 (

A wide variety of antidepressants have proven efficacy in the acute and long-term treatment of patients with major depressive disorder (MDD). However, like all medical treatments, antidepressants have limitations in terms of their efficacy, as well as in tolerability and safety, which clinicians should always keep in mind when selecting among available therapies for their patients. Specifically, antidepressants can be evaluated for overall efficacy (ie, their ability to resolve an episode of MDD), symptom-specific efficacy (their ability to resolve specific symptoms of MDD), and comorbidity-specific efficacy (their ability to resolve other Axis I disorders often found comorbid with MDD or their ability to treat MDD in patients with specific Axis III disorders). In addition, tolerability profiles differ among antidepressants, and treatment with some agents may be more likely to result in unpleasant or uncomfortable side effects than others. These side effects, in turn, may adversely impact treatment adherence and, thereby, unfavorably influence short-term as well as long-term outcome. Furthermore, select rare side effects experienced during antidepressant therapy may even place patients at increased risk of morbidity or mortality. These and other safety concerns associated with antidepressant therapy must be recognized by clinicians and disclosed to patients, and clinicians should vigorously monitor patients for their emergence. This article reviews the efficacy, tolerability, and safety of newer (ie, posttricyclic era) antidepressants.

For Clinical Use

  • Modern antidepressants are generally comparable in overall efficacy for treating major depressive disorder, but some may exhibit superior efficacy in relation to specific clusters of symptoms or patient subpopulations.
  • It is important to consider the presence of psychiatric and medical comorbidity when recommending antidepressants for patients.
  • Clinicians should understand the differing tolerability profiles of antidepressants, since poor tolerability can affect treatment adherence and, ultimately, patient outcomes.
  • Finally, it is important for clinicians to understand the safety profiles of available antidepressants, to communicate an accurate risk/benefit ratio of antidepressant treatment to patients, and to monitor for the emergence of adverse events during the course of therapy.

Efficacy of Antidepressants

Overall Efficacy

Overall efficacy in the treatment of MDD is defined as the ability to achieve syndromal remission as well as the full resolution of depressive symptoms. The overall efficacy of common, first-line antidepressants in treating MDD has repeatedly been established with the use of double-blind, randomized, placebo-controlled trials. A recent meta-analysis,1 for instance, examined 182 trials, published between 1980 and 2007, which focused on the treatment of adults with MDD (N = 36,385). In that study, approximately 54% of patients treated with an antidepressant experienced a clinical response (defined as a 50% or greater improvement in depressive symptoms), compared with about 37% of patients treated with placebo. While this analysis specifically addressed overall efficacy following a single therapy, naturalistic studies2,3 have also examined the effectiveness of sequential treatments in MDD. For instance, the results of a naturalistic study2 that retrospectively reviewed the charts of 115 adult patients with MDD enrolled at either of 2 academically affiliated depression specialty clinics reported that approximately 20% of patients experienced remission following each sequential treatment, with an estimated 50% of patients achieving remission at the time of the assessment. Similarly, in the prospective Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial,3 patients with MDD (N = 3,671) who did not experience remission after a single antidepressant therapy went on to receive either adjunctive therapy with an antidepressant (ie, combination) or nonantidepressant agent (ie, augmentation), or were switched to a different antidepressant altogether. With each successive therapy, an additional percentage of patients achieved remission such that, after as many as 4 treatment trials, approximately two-thirds from the original sample had achieved syndromal remission.

Time to improvement. While the proportion of patients who experience clinical response or remission following treatment is one measure of overall efficacy, another is the duration of time from the onset of therapy required in order for patients to experience either clinical response or remission. Typically, approximately 4 weeks of antidepressant therapy are required for the average MDD patient to achieve a clinical response, while longer treatment durations are needed for such patients to achieve syndromal remission. As a result of this often characteristic delay in symptom improvement during antidepressant therapy, discontinuing an agent prior to 4 weeks’ time due to lack of efficacy can be premature, depriving a patient of a potentially effective treatment. In contrast, however, continuing an ineffective treatment for more than 6 to 8 weeks may unnecessarily delay recovery, since only a small minority of patients who have not experienced significant symptom improvement by 8 weeks will do so after 8 weeks.4,5

Residual symptoms. Another factor to consider when evaluating the overall efficacy of antidepressants in the treatment of MDD is the presence of residual depressive symptoms among patients who have achieved syndromal remission. In fact, it has been well documented that as many as 50% of MDD remitters may continue to experience cognitive depressive symptoms such as apathy and forgetfulness; physical depressive symptoms such as fatigue, sedation, and sleep disturbance; and emotional depressive symptoms such as guilt.4,6,7 In turn, the presence of residual symptoms among MDD remitters has been linked to an increased risk of depressive relapse, continued functional impairment, and increased risk of morbidity and mortality related to medical (Axis III disorder) comorbidity.8 Therefore, clinicians should assess for and, if present, target residual symptoms among MDD remitters.

Relative efficacy among antidepressants. Relative efficacy is defined as the relative ability of 2 antidepressant agents to resolve MDD symptoms. Overall, it appears that the relative efficacy of antidepressants in MDD is comparable. For instance, numerous meta-analyses have demonstrated equivalent efficacy when comparing the selective serotonin reuptake inhibitors (SSRIs) with other agents, including the tricyclic antidepressants (TCAs),9 the serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine10 and milnacipran,11 the norepinephrine-dopamine reuptake inhibitor (NDRI) bupropion, the serotonin receptor antagonists trazodone and nefazodone,12 the serotonin-norepinephrine receptor antagonist mirtazapine,13 the monoamine oxidase inhibitor (MAOI) moclobemide,14 the norepinephrine reuptake inhibitor reboxetine,15 and the serotonin reuptake enhancer tianeptine16 for MDD. However, certain medications may prove to be exceptions to this general finding.

In fact, there is a relatively large literature suggesting that treatment with the SNRI venlafaxine may result in numerically and statistically greater remission rates than with some SSRIs.17-19 For example, one such analysis derived from a relatively large dataset involving 34 randomized, double-blind studies (N = 7,812) comparing venlafaxine with fluoxetine, paroxetine, sertraline, or citalopram reported a 6% advantage in remission rates in favor of venlafaxine.18 More recently, a meta-analysis19 of 39 published and unpublished, randomized, controlled studies (N = 8,659) of venlafaxine versus an SSRI for MDD reported a 7% advantage in response rates for venlafaxine treatment. This meta-analysis, which included studies involving the use of a number of antidepressants other than venlafaxine, suggested that the slight superiority of venlafaxine over the SSRIs in terms of overall efficacy (response, remission) previously reported may also extend to other antidepressants that have a serotonergic-noradrenergic mechanism of action, although the relative efficacy advantage reported was a mere 4% difference in response rates.

Most importantly, although the consensus of these reports points toward an advantage for venlafaxine versus the SSRIs in overall efficacy, whether this difference is clinically relevant has yet to be established. Additionally, the apparent advantage of antidepressants that have a serotonergic-noradrenergic mechanism of action over the SSRIs may not apply to all individual SSRI agents. For instance, pooled results20 from 4 randomized, double-blind studies comparing escitalopram with either venlafaxine extended release (XR) or duloxetine (SNRIs) in moderate-to-severe MDD showed a small but statistically significant greater reduction (1.7 points) in the primary efficacy parameter (Montgomery-Asberg Depression Rating Scale [MADRS] scores) for patients receiving escitalopram rather than an SNRI (P < .01). In fact, 2 meta-analyses21,22 comparing escitalopram with older SSRIs (fluoxetine, paroxetine, sertraline, and citalopram) have also shown a small but statistically significant advantage for escitalopram, with a treatment difference of about 1 MADRS point (P < .01 for both). However, again, whether the difference in overall efficacy in favor of escitalopram reported in these analyses is clinically relevant has yet to be established.

Symptom-Specific or Subpopulation-Specific Efficacy

Symptom-specific efficacy is defined as the ability of a treatment to resolve a specific depressive symptom (eg, insomnia, hypersomnia, fatigue) or symptom-cluster (eg, lethargy, anxiety, sleep disturbance), while subpopulation-specific efficacy is defined as the ability of a therapy to bring about symptomatic remission (symptom resolution) in specific subpopulations of patients (eg, patients with severe, anxious, or atypical depression). As discussed previously, antidepressants have comparable overall efficacy rates, although some exceptions (of yet to be established clinical relevance) have been noted. However, there is a growing literature suggesting differences in the relative efficacy of antidepressants in resolving specific symptoms of depression or in bringing about remission in select subpopulations of depressed patients.

Perhaps the best example published to date suggesting symptom-specific differences in efficacy among antidepressants stems from a pooled analysis23 of 6 double-blind, randomized clinical trials comparing the NDRI bupropion with an SSRI for MDD. Although equivalent overall remission rates were reported between the treatment groups, patients receiving bupropion demonstrated a significantly greater improvement in hypersomnia scores than patients receiving an SSRI (P < .0001). Patients receiving bupropion also demonstrated a greater improvement in fatigue scores than those receiving SSRIs (P = .0078). In fact, of patients whose depression remitted with either treatment, fewer patients who received bupropion experienced residual hypersomnia (20.5% versus 32.1%, P = .0014) or residual fatigue (19.5% versus 30.2%, P = .0020) than those who received an SSRI. Another example of differences in symptom-specific efficacy stems from a pooled analysis of randomized clinical trials comparing mirtazapine, an agent with considerable affinity for the histamine receptors (antagonist), with an SSRI for MDD. Although equivalent remission rates between the 2 groups were reported in that study, there was a greater resolution of insomnia among mirtazapine-treated than SSRI-treated patients.24

A classic example of differential subpopulation-specific efficacy is the case of atypical MDD, characterized by the presence of symptoms including mood reactivity, rejection sensitivity, leaden paralysis, hypersomnia, and increased appetite, where the advantage of the MAOIs over the TCAs has been repeatedly demonstrated.25 Other, more recent, cases of differential subpopulation-specific efficacy during antidepressant therapy have also been reported. For example, a meta-analysis10 of randomized, controlled trials showed that duloxetine, while comparable to the SSRIs in overall efficacy, was significantly more effective in treating severe depression (P = .046). In addition, a meta-analysis26 focusing on the use of venlafaxine versus SSRIs for MDD also showed an enhanced efficacy advantage for venlafaxine in severe MDD (in other words, there was an advantage of venlafaxine versus the SSRIs in remission rates that was numerically and statistically greater for severe MDD than for the overall MDD population). Similar data are also available for the SSRI escitalopram when compared with the older SSRIs (fluoxetine, sertraline, paroxetine, citalopram),22 as well as the SNRIs venlafaxine and duloxetine.20

Subpopulations other than severe MDD have also demonstrated varying responsiveness to antidepressants. In one analysis, for instance, remission rates reported for venlafaxine were far greater than with SSRI therapy among postmenopausal women with MDD who were not taking hormone replacement27 than for depressed women overall. In addition, in a separate analysis, while comparable remission rates were reported among bupropion-treated and SSRI-treated patients with MDD, response rates were higher among SSRI-treated than bupropion-treated patients with anxious MDD.28

Although in many cases these findings appear to be quite robust, it is important to keep in mind that they remain preliminary, since (1) they would need to be prospectively confirmed (ie, with the use of a study that, a priori, has been designed to test these hypotheses); (2) their clinical relevance would need to be established; and (3) a careful risk-benefit assessment would be required in order to determine whether any specific efficacy advantages are offset by losses in tolerability.

Comorbidity-Specific Efficacy

It has been well recognized that many patients with MDD also present with comorbid Axis I or Axis III disorders.29 For instance, more than 60% of patients (N = 1,376) with MDD enrolled in the STAR*D trial29 also presented with at least 1 concurrent Axis I disorder, while as many as 20% presented with 3 or more comorbid conditions. Axis I comorbid disorders that occurred in 10% or more of the STAR*D sample included social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, bulimia nervosa, alcohol abuse/dependence, obsessive-compulsive disorder, and panic disorder. In addition to contributing to an increase in subjective patient suffering and functional impairment, the presence of comorbid psychiatric and medical disorders in patients with MDD has also been associated with an increase in the severity of depressive symptoms, greater chronicity, and lower remission rates following treatment.4 Comorbidity-specific efficacy with respect to Axis I disorders refers to the ability of an antidepressant therapy to alleviate comorbid psychiatric disorders in patients with MDD, while comorbidity-specific efficacy with respect to Axis III disorders refers to the ability of an antidepressant to resolve MDD in patients who also present with a specific medical illness (eg, cardiovascular or cerebrovascular illness, malignancy, diabetes mellitus, Parkinson’s disorder, or HIV).

The presence of concurrent psychiatric and/or medical disorders can influence treatment decisions in patients with MDD, and clinical management of such patients may require a modified treatment approach. For example, not all antidepressants have proven efficacy in the treatment of various anxiety, eating, and attentional disorders, and the presence of such disorders would argue for choosing an antidepressant with a broader indication over one that is solely indicated for MDD (Table 1).30 Alternatively, if an antidepressant with a more narrow indication is chosen (ie, one that only focuses on MDD), clinicians may wish to supplement therapy for such patients with treatments that target the concurrent disorder (eg, adjunctive benzodiazepines, certain anticonvulsants, buspirone, or cognitive-behavioral psychotherapy [CBT] for various anxiety disorders31,32 adjunctive psychotherapy including CBT and interpersonal therapy [IPT] for comorbid eating disorders33; or adjunctive psychostimulants, atomoxetine, modafinil, or guanfacine for comorbid attention-deficit/hyperactivity disorder [ADHD]). However, it is important to point out that there is a paucity of studies establishing the superiority of such tailored treatment strategies versus more standard treatment approaches for this patient population. Clearly, additional research is needed to help direct clinicians when treating depressed patients who also present with comorbid psychiatric diagnoses.

Table 1

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A similar issue exists with respect to the treatment of MDD in patients who also present with chronic, severe, and/or unstable medical disorders, a population that is typically excluded from participating in standard Phase III antidepressant registration trials. As a result, not all antidepressant agents have been tested or proven efficacious in such patients. In fact, among all classes of antidepressants available to date, the SSRIs appear to have the broadest spectrum of efficacy in treating MDD in populations with comorbid medical illnesses and, as a result, are very popular first-line treatment choices for such patients (Table 2).30 However, it should be pointed out that there is a paucity of studies establishing the superiority of an SSRI versus an agent of a different class for the treatment of MDD in this select patient population.

Table 2

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Tolerability of Antidepressants

While modern antidepressants appear, for the most part, to possess comparable overall efficacy, many appear to differ in substantial ways from each other with respect to their tolerability profiles. Tolerability-related side effects can add to patient suffering and distress, contribute to a delay or failure in attaining an effective or optimal antidepressant dose, and contribute to poor patient treatment adherence or even noncompliance. For instance, it has been reported that as many as 50% of patients prescribed an antidepressant discontinue their treatment within a 6-month period; patients worried about side effects were 3 times more likely to discontinue treatment than patients without such concerns.34 As a result, the tolerability profile of a given therapy remains a key consideration when selecting treatments for MDD.35

Patients receiving antidepressant therapy can experience any combination of a multitude of potential side effects during the course of treatment. Of these, sexual dysfunction, insomnia, somnolence, fatigue, weight gain, and nausea appear to be the most bothersome.36 Therefore, in the following sections, we will focus on comparing antidepressants in terms of the relative prevalence of these side effects. When reviewing tolerability profiles, the SSRIs will be used as the reference compound since most studies comparing antidepressants for MDD involve the use of an SSRI (with the exception of weight gain, where the reference used is placebo, due to the requirement for data from long-term trials). A summary of these findings is reported in Table 3.37,38 In addition, in light of the superior tolerability profile of almost all modern antidepressants when compared with the older TCAs, the review will only focus on comparing post-TCA era agents. Finally, while not a side effect of treatment per se, the issue of antidepressant withdrawal syndrome will also be discussed in this section.

Table 3

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Nausea is commonly cited as a reason for the early discontinuation of antidepressants. One meta-analysis39 reported the prevalence of nausea during SSRI versus placebo therapy at 21% versus 14%, respectively. In addition, reports suggest SSRI therapy is associated with higher rates of nausea than mirtazapine,13 moclobemide,14 reboxetine,15 or bupropion39 therapy, while the incidence of nausea during treatment with an SSRI and trazadone,40-42 nefazadone,43,44 or duloxetine 45-47 appears comparable. However, treatment with the SNRI venlafaxine appears to result in a higher rate of nausea than SSRI therapy.48-50 The extended-release formulations of venlafaxine and paroxetine are associated with lower rates of nausea than their immediate-release formulations.51


Insomnia often emerges early on during SSRI therapy and can persist for the full duration of treatment.36 One pooled analysis39 of randomized, double-blind clinical trials in MDD reported insomnia rates of 16% versus 7% among SSRI and placebo-treated patients, respectively. In addition, insomnia rates reported during treatment with bupropion,39 moclobemide,14 duloxetine,45,52,53 and venlafaxine49,54,55 appear to be comparable to those reported during SSRI therapy. Finally, lower rates of insomnia have been reported during treatment with mirtazapine,13 trazadone,41 and nefazodone,56,57 and higher rates during treatment with reboxetine, than with SSRI therapy.15

Somnolence and Fatigue

Similar to insomnia, somnolence and fatigue can present early on during SSRI therapy and, left untreated, can persist throughout the entire course of treatment. The prevalence of somnolence and fatigue during treatment with an SSRI has been estimated at 12%, compared with 5% for placebo.39 Somnolence and fatigue rates reported during SSRI treatment are significantly higher than those seen during therapy with reboxetine15 and bupropion,23,39 agents that act on norepinephrine and dopamine—the wakefulness-promoting agents in the brain. Treatment with moclobemide,14 nefazodone,43,56 venlafaxine,50,58 and duloxetine45,53,59 appears to result in somnolence and fatigue rates that are equivalent to those reported during SSRI therapy, while mirtazapine13 and trazodone41 are more likely to result in treatment-emergent somnolence and fatigue than SSRI therapy.

Sexual Dysfunction

While sexual dysfunction is one of the most common and bothersome antidepressant side effects, it also appears to be one of the most underreported.60 As a result, physicians need to specifically inquire about the emergence of sexual dysfunction (including problems in desire, arousal, and orgasm) during antidepressant therapy, rather than rely on spontaneous reporting by patients. To date, numerous randomized, double-blind studies that employed a scale that specifically elicited for the emergence of sexual dysfunction during antidepressant treatment have been conducted. Treatment with an SSRI has been repeatedly shown to result in significantly higher rates of sexual dysfunction than placebo,61,62 bupropion,61,63,64 reboxetine,65-67 moclobemide,68 or nefazodone43 therapy. However, studies involving the use of mirtazapine are mixed, with some reports69,70 demonstrating lower rates of sexual dysfunction than with SSRIs and other studies71,72 showing no difference between the 2 treatment groups. Duloxetine45,52,59 appears to result in rates of sexual dysfunction similar to those of the SSRIs and, although few data regarding venlafaxine and sexual dysfunction are available, one randomized, controlled trial55 found no difference in sexual dysfunction between venlafaxine and an SSRI.

Weight Gain

Weight gain in antidepressant trials is most often reported either as change in weight from baseline or as the proportion of patients who gain 7% or more of their body weight during the course of treatment. Owing to its often insidious onset and progressive nature, long-term, placebo-controlled clinical trials are required in order to adequately study treatment-emergent weight gain. Unfortunately, to date only a subset of long-term placebo-controlled studies have reported statistics on weight change. Of these, 2 trials73,74 have shown that treatment with mirtazapine is associated with significantly greater weight gain compared to placebo. That long-term mirtazapine therapy is associated with clinically significant weight gain is also suggested by the results of a large, naturalistic study that involved treatment with an antidepressant for 1 year (Figure 1).38

Figure 1

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In contrast to data focusing on mirtazapine, placebo-controlled studies examining the effects of long-term treatment with an SSRI on patient weight report mixed results. For instance, while long-term weight gain during treatment with fluoxetine75-77 and escitalopram78 appears to be equivalent to that with placebo, paroxetine appears to be associated with a significantly greater rate of weight gain than placebo,46,79 sertraline, or fluoxetine.80 The potential for long-term weight gain during treatment with duloxetine appears to be dose-related: at 40 mg/d, its effect on weight gain is similar to that of placebo,79 while at higher doses duloxetine therapy appears to be associated with greater weight gain than placebo therapy.45,46 The results of a long-term relapse prevention study81 suggest that weight gain with venlafaxine is comparable to that of placebo. Similarly, a long-term study82 of bupropion reported treatment-related weight gain to be comparable to that of placebo, while a pooled analysis83 of long-term trials found patients treated with nefazodone were less likely to experience a clinically significant increase in body weight than SSRI-treated patients (8.3% versus 17.9%, respectively, P = .003).

Antidepressant Withdrawal Syndrome

Abruptly withdrawing certain antidepressants can result in the emergence of a number of adverse effects, including dizziness, vertigo, nausea, increased anxiety, worsening irritability, and vivid dreams.58 Such discontinuation-emergent symptoms predominantly appear to occur following the abrupt withdrawal of antidepressants that inhibit the reuptake of serotonin (eg, SSRIs, SNRIs, and certain "serotonergic" TCAs, including clomipramine).84 As a result, these symptoms can complicate switching from an agent with significant serotonin reuptake potential to one with no serotonergic activity (eg, bupropion, reboxetine, maprotiline, and certain TCAs with low affinity for the serotonin transporter).

Discontinuation symptoms appear to be related not only to the mechanism of action of the antidepressant used (ie, its potential to inhibit the reuptake of serotonin), but also to the half-life of each agent. Specifically, it has been repeatedly demonstrated that shorter plasma half-life is associated with an increased risk of emergence of, as well as increased severity of, discontinuation symptoms.85 For instance, paroxetine, an agent with a relatively short half-life, is associated with significantly more discontinuation symptoms than escitalopram,86 sertraline, fluoxetine,87 or agomelatine,88 while venlafaxine, another agent with a relatively short half-life, also appears to be associated with higher rates of discontinuation symptoms than escitalopram89 and sertraline.58

Few systematic data exist on managing discontinuation symptoms. A slow taper appears to be the best step in preventing or minimizing these effects, particularly at the end of the taper, when most discontinuation symptoms manifest. Anecdotal evidence suggests that the use of a single 20 mg dose of fluoxetine, an agent with a very long half-life that appears to be associated with relatively few discontinuation symptoms,87 may help mitigate withdrawal symptoms when tapering patients off paroxetine, venlafaxine, or other SSRIs. In addition to the paucity of data, a limitation of this strategy is the risk of serotonin syndrome.

Safety of Antidepressants

In contrast to tolerability-related side effects, safety-related adverse events are, by definition, rare (otherwise they would have been detected during the drug development process). The safety profile of all modern antidepressants is much more favorable compared to that of earlier agents, including the MAOIs (which involve the risk of hypertensive crises and serotonin syndrome) and TCAs (which carry the risk of potentially fatal arrhythmias and seizure). However, a number of rare and potentially serious reactions, which vary from agent to agent, have also been reported with all post-TCA agents (Table 4).37 Relatively well-quantified safety risks with modern antidepressants include an increased risk of suicidal ideation and/or suicide gestures—but not suicide mortality—during the treatment of children, adolescents, and young adults (early 20s) with SSRIs90 and an increased risk of seizure (versus other antidepressants) associated with bupropion therapy at daily doses greater than 300 mg.91 Other examples of very rare but potentially serious adverse events during antidepressant therapy are numerous, although not as thoroughly studied. As a result, disclosing the relative risks and benefits of antidepressant agents to patients and vigorously monitoring for the emergence of adverse events following the initiation of pharmacotherapy are vital.

Table 4

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Major depressive disorder is a prevalent illness associated with significant patient suffering and functional impairment, as well as an increased risk of morbidity and mortality. The mainstay of treatment for moderate to severe MDD involves the use of antidepressants, either as monotherapy or in combination with certain forms of psychotherapy such as CBT and IPT. In addition, the presence of comorbid psychiatric and medical disorders in MDD patients appears to be the rule rather than the exception and can contribute to a poorer prognosis. As a result, for such patients, clinicians should consider tailoring their treatment approach in favor of treatments with a broader indication (in the case of psychiatric comorbidity) or treatments proven effective in resolving depression specifically in patient populations presenting with medical comorbidity.

In addition to efficacy in the treatment of concurrent psychiatric disorders or efficacy in treating depression in patients with medical illnesses, many other factors should be considered when choosing an antidepressant, including (1) the overall efficacy of the compound, (2) the efficacy of the compound in relation to particular symptoms or symptom clusters, and (3) the patient’s treatment history (whether a patient has failed to experience sufficient symptom improvement following treatment with a particular antidepressant during the current major depressive episode, or whether a patient experienced intolerable or potentially serious adverse events during treatment with a given compound in the past). In addition, the tolerability profiles of the antidepressant should be considered when making treatment choices, along with the patient’s personal preferences, in order to enhance the therapeutic alliance with the patient. Most importantly, patients should be educated about the potential safety risks associated with antidepressant therapy and then vigorously monitored for the possible emergence of serious adverse events following the initiation of treatment, including the potential emergence and/or worsening of suicidal ideation/gestures in children, adolescents, and young adults (those younger than 25).


Dr Kanba: Sometimes I have heard the term activation syndrome being used. However, I am not aware of any formal definition of activation syndrome in the literature. Is the term well recognized in the United States?

Dr Papakostas: This is a rather vague clinical term that may include a number of adverse events, including insomnia, psychomotor agitation, akathisia, restlessness, anxiety, irritability, the emergence or worsening of suicidal ideation, or the emergence of an abnormal mood elevation (either hypomania or mania). However, it is important to keep in mind that a formal clinical syndrome encompassing a number of these symptoms does not appear to be the case. In other words, developing antidepressant-induced insomnia, psychomotor agitation, or akathisia does not appear to predict the emergence of an abnormal mood elevation or the emergence or worsening of suicidal ideation or gestures following the initiation of therapy for MDD.

Professor Nutt: Is this a particular concern in Japan?

Dr Kanba: Yes. General practitioners as well as psychiatrists are now apprehensive to use SSRIs or SNRIs because of their concern about the presence of a potential activation syndrome.92,93

Dr Papakostas: What is their fear?

Dr Kanba: That the emergence of certain side effects, such as akathisia, irritability, or insomnia, would herald the emergence of more serious adverse events, including suicidality, agitation, etc. The mass media in Japan have disseminated the notion that such a syndrome exists and is particularly associated with newer antidepressants, hence encouraging the use of older agents by general practitioners.

Dr Papakostas: We know that the emergence and/or worsening of suicidal ideation and/or gestures during antidepressant therapy can, in some instances, be an issue during the course of treatment of children, adolescents, and adults younger than 25 years of age.94 The question is whether it is possible to identify, a priori, which patients will develop these side effects. Studies95,96 have examined various symptoms such as akathisia and insomnia, and, to date, they have not shown that developing these early "activation-type" symptoms is statistically correlated with a higher likelihood of developing or worsening of suicidal ideation or suicidal gestures. In addition, there is no evidence to suggest class differences with respect to the emergence and/or worsening of suicidal ideation and/or gestures during antidepressant therapy.

So from that standpoint, it is equally reasonable for one to recommend newer as well as older antidepressants for patients with MDD. A more pragmatic concern is whether the emergence of insomnia, anxiety, irritability, or other "activation-type" side effects predict poorer tolerability or poorer treatment outcome, and whether treating these can improve outcome.

Dr Kanba: Recently, the potential for antidepressant-increased aggression and homicidality has also been raised in Japan. How well has this potential adverse event been studied?

Dr Papakostas: The question of the potential emergence or worsening of homicidality during antidepressant therapy for MDD has not been adequately studied. One limitation involves the paucity of scales specifically designed and validated as a measure of homicidal ideation in depression, as well as the limited employment of validated scales that measure irritability, hostility, and aggression in standard registration trials. However, considering what evidence does exist on this topic, the risk of depression going untreated far outweighs the risk associated with the potential (albeit quite rare) emergence or worsening of irritability, hostility, or aggression associated with antidepressant therapy. In addition, I do not see any evidence for this being a major influencing factor in differential treatment selection since there is no evidence to conclusively suggest that the risks of such adverse events are higher with one therapy than another. In general, in parallel with being vigilant regarding the potential risks, whether well recognized or not, of antidepressant therapy or psychotherapy, it is also important for us to keep in mind the potential adverse outcomes associated with not treating MDD, including an increased risk of functional impairment, morbidity, mortality, and suicide.

Dr Sakamoto: According to some, the incidence of activation syndrome is 20%-40%. However, to me, that percentage seems too high. My colleagues and I researched the incidence of activation syndrome and found a prevalence rate of about 4%.97

Dr Papakostas: The question is, how is activation syndrome defined, and what does it mean in terms of treatment outcome and selection? Certainly, rates of insomnia alone in MDD trials have been reported 3-fold higher than 4%. In contrast, the emergence of mania and/or hypomania in a well-characterized MDD sample is much less common than that.

Dr Gelenberg: I want to address the supposed superiority, albeit small, in effect size of the SNRIs and escitalopram. Regarding the SNRIs versus the SSRIs, a very large prospective study98 that compared venlafaxine XR with fluoxetine in both acute and continuation therapy found no difference in efficacy on primary or secondary outcome measures, and both agents were well tolerated.

Additionally, escitalopram is one of the few SSRIs still under patent in the United States and is used quite frequently. When viewing all data, including unpublished data, escitalopram’s apparent modestly superior efficacy is not clear. I do not think, at least with our current clinical methodology, that we can show a difference, although some patients may selectively improve on one medication versus another.

Dr Papakostas: I agree. If one looks at overall efficacy, meta-analyses that appear to be comprehensive suggest a small numerical advantage in remission rates for some medications over others. But this advantage may not be clinically meaningful.

However, differences in overall efficacy seem to be magnified for certain symptoms or in certain populations, including for lethargic symptoms in severe depression, or in postmenopausal women not on hormone replacement therapy, for instance. Hence, when I think about potential efficacy differences, the question for me is more about subpopulations. In other words, does a slight difference in overall efficacy herald a larger one in subpopulations of patients, or for specific depressive symptoms? And we have seen that difference with venlafaxine, escitalopram, and duloxetine datasets with respect to severity, or with bupropion with respect to lethargy, for example. Also, does comorbidity make a difference? That may be where clinically meaningful differences in efficacy lie.

Dr Karamustafalıoğlu: Do you think clinicians should be advised to use higher doses of antidepressants for depression with comorbid anxiety?

Dr Papakostas: I am not sure, but it would be a good subject to investigate. Patients with depression and moderate to severe anxiety in the STAR*D trial99 did not do as well on antidepressant monotherapy as patients without anxiety. If those results can be replicated, the question then becomes how to improve outcomes for these patients. Is the first step to increase the dose, or to add psychotherapy or an agent that works as a first-line treatment for anxiety? The systematic way to answer these types of questions is to first identify a population that does not do as well, and then focus on finding ways to improve outcomes for that population.

Dr Karamustafalıoğlu: I have a comment about the withdrawal syndrome that can occur after stopping antidepressants. Fluvoxamine has a shorter half-life than paroxetine, but I do not see withdrawal effects as commonly with fluvoxamine as I do with paroxetine, so it seems that something more than the half-life is involved.

Professor Nutt: Some studies have shown withdrawal symptoms after abrupt discontinuation from fluvoxamine, such as the Black et al100 study on panic disorder. A possible kinetic explanation for a greater number of withdrawal symptoms with paroxetine is that it inhibits its own metabolism,99 so as dosage levels fall, the CYP2D6 mechanism is activated and accelerates the drop in blood drug levels.

Dr Terao: What do you think about omega-3 fatty acids? Evidence supports their antidepressant effects, but no reports say that omega-3 fatty acids induce activation syndrome.

Dr Papakostas: I think that the main question at this time pertaining to the use of omega-3 fatty acids in MDD is efficacy. Studies of the omega-3 fatty acids as adjunctive therapy for antidepressant nonresponders have been uniformly positive, but the results of monotherapy studies are inconsistent.101 In order to compare the tolerability profile of omega-3 fatty acids with standard antidepressants, including for activation-type events, direct, head-to-head studies are needed. Such have not been conducted to date.

Dr Terao: Because of the serious worry in Japan about the use of SSRIs in children and adolescents, do you think it would be useful to administer omega-3 fatty acids to these patients?

Dr Papakostas: If we truly establish that omega-3 fatty acids work for these patients and that they are safe, then yes, that strategy could have advantages. We need more research.

Drug Names: atomoxetine (Strattera), bupropion (Aplenzin, Wellbutrin, and others), buspirone (BuSpar and others), citalopram (Celexa and others), clomipramine (Anafranil and others), desvenlafaxine (Pristiq), duloxetine (Cymbalta), escitalopram (Lexapro and others), fluoxetine (Prozac and others), fluvoxamine (Luvox and others), guanfacine (Intuniv, Tenex, and others), milnacipran (Savella), mirtazapine (Remeron and others), modafinil (Provigil), paroxetine (Paxil and others), sertraline (Zoloft and others), venlafaxine (Effexor and others).

Disclosure of off-label usage: The author has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration−approved labeling has been presented in this article.


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