Switch to a different antidepressant


Switching treatment also may be effective and should take into consideration clinical judgment and patient preference. When switching after failure to achieve response with one therapy, patients may achieve remission with an alternative agent—sometimes even with a medication from the same drug class as the original agent.47,57,58

Data from STAR*D suggest that switching and augmenting are equally efficacious strategies, but that individuals who are tolerating their antidepressant, or showing a partial response, may be more likely than others to benefit from augmentation rather than switching.59

Recently approved antidepressants


In recent years, 3 new agents have been approved by the FDA for the treatment of MDD, including levomilnacipran, vilazodone, and vortioxetine.


Levomilnacipran is a unique dual neurotransmitter reuptake inhibitor of serotonin and norepinephrine.60 Levomilnacipran has a 15-fold selectivity for norepinephrine vs serotonin reuptake inhibition compared with other agents such as duloxetine and venlafaxine.61,62 It is the only antidepressant with an FDA label indicating effectiveness in improving both depression and impaired functioning.60

In multiple short-term (8-10 weeks of treatment) clinical trials, levomilnacipran was found to be more effective than placebo in reducing depression, as measured by the MADRS, and improving functional impairment, as measured by the SDS.63-67

Of 2 long-term (24 or 48 weeks of treatment) studies, only 1 was placebo-controlled, and levomilnacipran was found not to be significantly superior to placebo in preventing relapse. Notably, this trial may not have reached statistical significance, as a relatively low percentage of patients experienced relapse in either arm.68,69

The most common adverse events associated with levo­milnacipran treatment are nausea, headache, dry mouth, hyperhidrosis, and constipation. Other events of note include urinary hesitancy, erectile dysfunction, and elevated pulse and blood pressure. Levomilnacipran has not been associated with weight gain/loss, hepatotoxicity, or clinically significant QTc prolongation.60

Vilazodone is a multimodal antidepressant that inhibits the serotonin transporter (SERT) and is a partial agonist of 5-HT1A receptors. This dual mechanism of action is believed to shorten the time to response, decrease the side effects frequently associated with serotonin reuptake inhibition (eg, sexual dysfunction), and provide increased efficacy in the treatment of comorbid anxiety symptoms.70

The safety and efficacy of vilazodone were established in 2 randomized, double-blind, placebo-controlled phase 3 trials in adults with MDD. In the first study, by Rickels et al, 410 patients with MDD were randomized to vilazodone (titrated from 10 mg to 40 mg once per day over 2 weeks) or placebo. After 8 weeks of treatment, patients receiving vilazodone experienced significant improvement in total MADRS and HAM-D17 scores.71 In the second study by Khan et al, 481 patients with MDD were randomized to receive vilazodone (titrated to 40 mg/day) or placebo for 8 weeks. Patients receiving active treatment experienced significant improvement in MADRS (vs placebo). However, remission rates were not significantly different based on MADRS or HAM-D17.72

In a post hoc analysis of pooled data from both studies, significant antidepressant effect was observed after 1 week of treatment with vilazodone compared with placebo, suggesting a rapid onset of action. Changes in sexual function over the 8-week treatment period were assessed in both studies, as measured by the Arizona Sexual Experiences Questionnaire or the Changes in Sexual Function Questionnaire, and were minimal and generally similar to placebo.70 The most frequently reported adverse effects occurring with significantly greater incidence (P<.05) in vilazodone-treated patients included diarrhea, nausea, dizziness, insomnia, vomiting, and abnormal dreams. Titration of vilazodone dose over 2 weeks was shown to minimize gastrointestinal adverse events.70

Significant improvements in depression-related anxiety were noted in the two phase 3 studies, based on the Hamilton Rating Scale for Anxiety (HAM-A) total score and the Clinical Global Impressions-Severity Scale (CGI-S). These findings were confirmed by a phase 4 study by Croft et al.73,74

In addition, in a post hoc analysis of the phase 4 trial, treatment with vilazodone 40 mg/day was found to significantly improve remission rates compared with placebo as early as week 6 of double-blind treatment, as measured by MADRS (Figure 3).73


Click to enlarge image.

Limitations of this post hoc analysis include that it was based on data from a clinical trial that was not designed or statistically powered to evaluate remission, no active comparators were included, and exposure to the full therapeutic dose was limited to only 6 weeks, thereby making it difficult to compare with other antidepressant studies with longer exposure times.73


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