Section 2

Limitations of traditional antidepressants 

Although antidepressants are a mainstay of MDD treatment, they are plagued by poor efficacy, high rates of relapse, and intolerable side effects.40,41 Second-generation antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other agents that selectively target neurotransmitters are the most commonly prescribed pharmacotherapeutics for MDD in the United States (US).42

Multiple studies have examined the efficacy of currently approved agents, with conflicting findings: some report no difference in efficacy between agents and others report a superior efficacy-acceptability ratio with escitalopram and sertraline. However, a 2011 meta-analysis found that statistical differences reflected very small effect-size differences, suggesting no real clinical difference. In addition, the meta-analysis reported no difference in HRQoL between agents.42-44

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As noted earlier, lack of response and failure to achieve remission are common issues in the management of MDD. In the 2011 meta-analysis described above, 37% of patients did not demonstrate treatment response after 6 to 12 weeks of treatment with a second-generation antidepressant and 53% failed to achieve remission.42 In addition, 63% of patients experienced at least 1 adverse event during treatment. Rare but serious adverse events associated with these agents include suicidality, seizures, cardiovascular events, serotonin syndrome, hyponatremia, and hepatotoxicity.42

Strategies for improving therapeutic response in patients with residual MDD symptoms

Several options exist for individuals who have an inadequate clinical response to an antidepressant. The APA recommends that all patients with acute MDD who do not respond to initial therapy within 4 to 8 weeks receive 1 of 3 therapeutic changes2:

  • Increase dose of original antidepressant

  • Augment with an additional agent and/or psychotherapy
Switch to a different antidepressant

  • Increase dose of original antidepressant

While dose-finding studies do not support the initiation of treatment at higher-than-standard doses, the APA and other guidelines recommend dose escalation as an appropriate strategy for nonresponders, especially if the upper-limit dose of the antidepressant has not been reached. The decision to increase dosage should balance medication efficacy, side effects, and patient adherence.6 In addition, clinicians and patients may need to consider health insurance limits on number of pills approved per 30 days, as well as prior authorization requirements. 

Dose increases appear to be most effective among patients who have failed 8 weeks of standard therapy, with effect typically seen after 4 weeks at the increased dose.45 While there is a paucity of evidence on how dose escalation should be implemented, it is clear that higher doses can be associated with increased side effects. In addition, especially for SSRIs, several studies suggest that increasing the dosage does not increase therapeutic response.45,46

Augment with an additional agent and/or 

Another strategy for assisting patients in achieving remission is to augment the originally prescribed antidepressant with an agent designed to enhance efficacy. Such adjunctive therapies may include lithium, second-generation antipsychotics (SGAs), low-dose thyroid hormone (triiodothyronine [T3]), or another antidepressant.47,48 In addition, several agents are available to alleviate specific residual symptoms and may therefore enhance the efficacy of first-line antidepressants. These may include buspirone for anxiety, zolpidem for insomnia, or modafinil for significant fatigue/sleepiness.48-50 In addition, methylphenidate, a psychostimulant, has been shown to enhance response to an antidepressant in the elderly and in patients with significant psychomotor retardation.48 However, methylphenidate is contraindicated in patients over the age of 65, is classified as pregnancy category C, and is associated with significant side effects.51

Table 3 provides a comprehensive list of adjunctive treatments for residual symptoms associated with MDD. As can be seen in the table, a number of these agents are used off-label for the specific residual symptoms listed.

Some studies report that treatment with combination therapy vs monotherapy may increase the likelihood of achieving remission. A study of 61 patients with unipolar depression compared mirtazapine monotherapy or paroxetine monotherapy with mirtazapine/paroxetine combination therapy.53 The rate of remission at 6 weeks among patients receiving combination therapy was twice that of patients receiving monotherapy with either agent, and the combination regimen was found to be well tolerated.53

In a study comparing fluoxetine monotherapy (plus placebo) to mirtazapine/fluoxetine, mirtazapine/venlafaxine, or mirtazapine/bupropion in 105 patients with MDD, each combination regimen was superior to the monotherapy regimen in remission rates. All regimens were generally well tolerated.54

However, these findings must be balanced against those from a much larger study of 665 patients treated for depression in the outpatient setting. Patients were randomized to receive escitalopram/placebo, sustained-release bupropion/escitalopram, or extended-release venlafaxine/mirtazapine.55 At 12 weeks, response rates and remission rates were equivalent among the 3 treatment groups. The authors reported no advantage to combination therapy vs monotherapy, and a greater risk of adverse events was noted with extended-release venlafaxine/mirtazapine.55

This study, however, had several limitations. While the study size was reasonable, it may not represent the universe of outpatients with chronic and/or recurrent major depression. Also, the doses used may not have been sufficient to realize the full potential value of combination therapy. Finally, clinicians were not blinded to treatment.55

In the STAR*D trial, adding cognitive behavioral therapy (CBT) to pharmacotherapy (citalopram) was as effective as adding a second antidepressant (sustained-release bupropion) or switching antidepressant medications.9,29 This finding was confirmed and extended in a recent large effectiveness trial conducted in primary care settings in the United Kingdom, which found that the addition of CBT to pharmacologic treatment as usual doubled rates of response and remission at 6 months.56

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