One of the challenges in treating patients with MDD is to keep the ultimate goal of treatment in mind. The goal of treatment is neither to reduce symptoms, nor is it to increase productivity in the workplace. The goal is to return the patient to a state of euthymia, achieving remission rather than response. From a patient's perspective, this would be described as getting well, rather than settling for getting better.
Complicating the task of treating patients with MDD to remission is that no laboratory assay currently is available that will identify which neurochemical intervention is most likely to be successful. This lack has been exacerbated by the fact that during the past 5 decades, antidepressants with differing mechanisms of action have been introduced.
In the early history of modern pharmacotherapy for MDD, monoamine oxidase inhibitors (MAOIs) effectively served (and continue to serve) as a classic example of a broad-spectrum antidepressant. The MAOIs involve the noradrenergic, serotonergic, and dopaminergic systems. The MAOIs, however, are not without potential complications (eg, risk of tyramine-containing foods producing a hypertensive crisis, potential drug-drug interactions).
Tricyclic antidepressants (TCAs), tending to be more noradrenergic (except for clomipramine), were introduced at approximately the same time as MAOIs. Although the safety and tolerability profile of TCAs was better than that of MAOIs, TCAs were not the easiest medications to prescribe; therefore, the introduction of fluoxetine in the late 1980s was a revolution in the pharmacotherapeutic treatment of patients with MDD.
Although SSRIs do not have greater efficacy than MAOIs or TCAs, the safety and adverse effect profiles of SSRIs are a major improvement over those two earlier classes of antidepressants. Other antidepressants include bupropion hydrochloride, which is believed to be both noradrenergic and dopaminergic in its mechanism of action; mirtazapine, a dual-acting agent via receptor antagonism; and venlafaxine, an SNRI. Finally, duloxetine hydrochloride, another SNRI, has recently received approval by the US Food and Drug Administration for the treatment of patients with depression.
Essentially then, treatment of patients for MDD has come full circle in that contemporary pharmacotherapy began with the introduction of broad-spectrum antidepressants (eg, MAOIs, clomipramine hydrochloride), moved to selective drugs (eg, TCAs, SSRIs), and is now returning to broad-spectrum medications (eg, mirtazapine, venlafaxine, duloxetine). The introduction of peptidergic-acting drugs (ie, corticotropin-receptor antagonists) is still several years in the future.
Given the current trend toward increased use of broad-spectrum antidepressants, one might reasonably ask whether data exist to support their use. To a certain extent, the answer depends on where in the literature one poses this question. Outpatient studies that have response as their endpoint, do not, in general, differentiate between antidepressant treatment modalities. However, dual-acting agents seem to convey advantages over selective-acting agents in inpatient studies.
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Finally, in inpatient studies that use the more clinically relevant measure of remission as outcome, dual-acting agents seem to confer an advantage. Examples of two studies that compared an SSRI and a dual-acting TCA were conducted by the Danish University Antidepressant Group in Copenhagen.
10,11 In the first, researchers compared clomipramine (a dual-acting TCA) with paroxetine (an SSRI) in inpatients with MDD.
10 The group treated with clomipramine had a higher rate of remission than the group treated with the SSRI. Researchers in the second study compared an SNRI (clomipramine) with an SSRI (citalopram) in a population of inpatients with MDD.
11 There were equal numbers of nonresponders in both groups, more responders (termed partial remission in the study) were observed in the SSRI-treated group, and a higher percentage of patients treated with the SNRI achieved remission, compared with the SSRI-treated group.
Although these Danish studies were individual trials, developing a pooled analysis of data is often of great benefit. Two such pooled analyses compared SNRIs with SSRIs. The smaller analysis (six studies) compared patients with MDD treated with duloxetine with patients with MDD treated with placebo, fluoxetine, and paroxetine.
12 When patients with a Hamilton Depression Scale score of greater than or equal to 19 (n=approximately 960) were included in the post hoc analysis, the SNRI-treated group had a higher remission rate after 8 weeks of treatment than the SSRI-treated group. The SSRI-treated group, however, had a higher remission rate than that of participants who received placebo.
A second larger pooled analysis included 32 studies (n=7549) that compared venlafaxine or venlafaxine extended release to either citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or placebo.
12 This pooled analysis found that higher remission rates were achieved with SNRI treatment than with SSRI treatment. Also rates of remission were higher after 8 weeks of therapy achieved with SSRI treatment, compared with placebo.
The results of these pooled analyses support and extend earlier observations based on single trials of clomipramine compared with SSRIs.
10,11 The advantage to using pooled analyses is that sample sizes become large enough to minimize the chance of incorrectly identifying no difference between two effective treatment approaches.