Four years ago, my colleagues and I published an article titled “Why isn't bupropion the most frequently prescribed antidepressant?” The goal of that article was not to advocate bupropion as the preferred agent for treating depression, but rather to stimulate discussion about how psychiatrists choose an antidepressant as well as to highlight the gap between results of efficacy studies and clinical decision making in real-world practice.

The argument in support of bupropion being the preferred antidepressant was based on three premises: all antidepressants are equally effective; adverse effects (AEs) of greatest concern to patients who take antidepressants are weight gain and sexual dysfunction; and bupropion does not cause either of these AEs. Acceptance of these three premises suggested the title of that article.

Although many reviews of the antidepressant literature, including the revised American Psychiatric Association Practice Guideline for the Treatment of Major Depressive Disorder, conclude that antidepressants are equally effective in general, several experts in the treatment of depression have suggested that medications with >1 mechanism of action may be more effective than agents that have more selective neurotransmitter effects. In a meta-analysis of eight studies comparing the remission rates in patients treated with the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine or selective serotonin reuptake inhibitors (SSRIs), Thase and colleagues demonstrated that venlafaxine was more effective than SSRIs in achieving remission in depressed patients. However, these conclusions were tentative as most of the included studies were comparisons of venlafaxine and fluoxetine; only one study included sertraline, and there were no studies of citalopram included in the review. In addition, patients who had previously failed treatment with an SSRI were not excluded, and, although patients who fail with one SSRI may respond to subsequent treatment with another SSRI, the inclusion of SSRI failures may favor venlafaxine in comparisons with SSRIs. Lastly, all of the studies included in the meta-analysis were funded by the manufacturer of venlafaxine.

Despite significant progress in the development of antidepressant therapies, tolerability remains an important factor associated with the selection of appropriate antidepressant treatment. Side effects commonly reported by depressed patients taking antidepressants include weight gain, sexual dysfunction, and gastrointestinal effects. Tolerability issues associated with antidepressants can negatively impact treatment outcomes for patients with major depressive disorder. In addition, a drug's tolerability profile substantially influences a physician's choice of specific antidepressant therapy. Despite the availability of many antidepressants, empirical clinical evidence to guide physicians in making the best choice is limited and not always clear. Thus, it is key for clinicians to understand the short- and long-term outcomes and side effect profiles of the available antidepressants.

Treatment with the newer generation antidepressants is considered generally effective for most patients with major depressive disorder when taken in accordance with treatment guidelines. However, multiple clinical studies have demonstrated that rates of patient adherence to antidepressants are inadequate, specifically with regard to long-term maintenance treatment. Tolerability issues associated with antidepressants can increase the risk for patient nonadherence and result in subsequent relapse of depressive symptoms. Comorbid symptoms of anxiety also influence psychiatrists' choice of antidepressants for patients with depression. Physicians can improve long-term patient outcomes for patients with major depressive disorder by considering the possibility of drug-drug interactions before prescribing a specific antidepressant.

In medically complex patients with multiple comorbid illnesses who require concomitant medications, selecting the optimal antidepressant (ie, low risk of adverse effects and/or pharmacokinetic interactions) for an individual patient is critical for positive long-term patient outcomes. The serotonin-norepinephrine reuptake inhibitors (SNRIs) are increasingly being used as first-line treatment for major depressive disorder (MDD) and may prove beneficial for treatment of medically complex patients. Thus, it is key for clinicians to evaluate the differences in the pharmacokinetic and tolerability profiles of the SNRI class of antidepressants, evaluating differences both within the class and compared with other antidepressants used to treat MDD.