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Research on antidepressant therapy during the past 2 decades has largely focused on 2 classes of antidepressants: the selective serotonin reuptake inhibitors (SSRIs) and the norepinephrine serotonin reuptake inhibitors (SNRIs). Because all but 1 of the SSRIs and the original (immediate-release) formulation of the SNRI venlafaxine have become available as generic medications, the therapeutic landscape has changed dramatically: it is a tall order to develop a novel medication that is as safe, well-tolerated, and easy to prescribe as these now inexpensive antidepressants.

Research now focuses on treatment strategies that may: (1) enhance existing first-line standards, or (2) provide alternate choices for patients who do not respond to or cannot tolerate the SSRIs and SNRIs. In keeping with this view, the findings of posters presented by Olin and colleagues[1] and Culpepper and colleagues[2] are of particular interest.

What's Wrong With Current Antidepressants?

Olin and colleagues[1] summarized the results of a survey of 1066 psychiatrists conducted at the 2007 APA meeting. According to this survey, about one-third of the respondents considered current antidepressants to be only "somewhat effective" and ranked sexual dysfunction, weight gain, and inadequate efficacy as the primary roadblocks to successful treatment.

Culpepper and colleagues[2] reported on the results of an online national survey conducted by Harris Interactive. Participants included 505 people with self-declared depression who were either currently taking antidepressants (n = 435) or had taken antidepressants within the past 2 years (n = 70). Of note, nearly half (46%) of the respondents reported weight gain as a side effect, along with 44% and 38% of respondents reporting sexual dysfunction and sleep disturbance. Although almost half of the respondents described themselves as "extremely/very satisfied" with their antidepressants, even among this group 50% would consider switching antidepressants if an alternative medication was available with fewer side effects.
Studies Look at Quality of Evidence, Relative Efficacy, and Predicting Who Will Respond to Treatment
Before turning attention to research on new treatment strategies, several posters pertaining to existing standard therapies warrant consideration. First, there is a background of dissatisfaction with the quality of the evidence that supports the efficacy of the existing first-line standards. One source of tension stems from meta-analytic work that has called into question the efficacy of the newer antidepressants, as reflected by the recently published papers of Kirsch and colleagues[3] and Turner and colleagues.[4] These papers, which were widely covered in the lay press, indicated that the apparent effects of antidepressants in placebo (PBO) controlled studies have been exaggerated by the so-called file-drawer effect (ie, selective publication of positive studies) and that, when the unpublished randomized controlled trials (RCTs) are taken into account, average drug vs PBO differences only approach a magnitude that can be considered to be clinically significant in severe depression. Of direct relevance to this contentious debate is the poster that I presented with Sidney Kennedy.[5] Using the data from all of the PBO-controlled studies conducted by the manufacturers of the SSRI escitalopram, we aimed to determine whether the relatively modest average drug vs PBO difference (4.7 points on the Montgomery-Åsberg Depression Rating Scale [MADRS]) actually represented a small benefit for most patients or a large difference for a subset of more severely depressed patients. To test this out, we first subtracted 4.7 points from the final score of all of the patients in the PBO group (ie, a "handicap" based on the average effect). Although this equated the groups in terms of average score, the distribution of final scores was still statistically significant, with more low scores in the group receiving active medication. To test what kind of an effect best explained this difference in outcome, we next ran a series of simulations in which the magnitude of the "handicap" and the proportion of PBO-treated patients receiving the handicap were systematically varied. The difference in the distributions was best explained by a 12-point difference among one-half of the PBO-treated patients. Thus, by focusing on the grouped data, a very large specific difference among about one-half of the patients had been obscured.

Second, controversy continues about the relative efficacy of various antidepressant classes and, within classes, specific antidepressant options. Kennedy and colleagues[6] presented the results of a meta-analysis of 16 studies comparing escitalopram with other active standards, including other SSRIs (12 studies) and SNRIs (4 studies). Overall, they found a small, but statistically significant advantage for escitalopram at week 8, corresponding to about a 1-point difference in MADRS scores and a 4% difference in remission rate. These effects held true in subgroup comparisons vs the SSRIs and SNRIs alone. In a separate report of the 4 studies that compared escitalopram with other comparators (citalopram, paroxetine, and duloxetine) across 24 weeks of therapy, Wade and colleagues[7] reported a significant advantage in remission rates favoring escitalopram (71%) over the comparators (65%), perhaps largely because of a significantly lower rate of attrition (16% vs 24%).

Third, the inability to predict which patients are more or less likely to respond to particular therapies continues to be an important limitation of current therapies. Patient care would of course be enhanced if the patients who were unlikely to benefit from an initial course of SSRI therapy could be prospectively identified and rapidly switched to alternate therapies. Cook and colleagues[8] reported intriguing results using frontal quantitative electroencephalography (fq EEG) as a potential biomarker of SSRI response. In this trial, changes in fqEEG after only 1 week of therapy with escitalopram (10 mg/day) were tested as a potential means to guide the decision to: remain on escitalopram (n = 73), switch to the norepinephrine dopamine reuptake inhibitor (NDRI) bupropion (300 mg/day; n = 73), or augment escitalopram with the NDRI (n = 73), all for 7 more weeks of therapy. Among those randomly assigned to remain on the SSRI, the fqEEG predictor accurately predicted subsequent favorable outcome (67% vs 28%). The converse pattern held for those switched to bupropion (28% vs 53%). Curiously, the pattern did not predict response to augmentation with the NDRI (33% vs 28%).
The search for other potential biomarkers of differential treatment response led Houston and colleagues[9] to study polymorphisms of the catecholamine metabolic enzyme (COMT) and the serotonin 2A receptor as potential moderators of response to the SNRI duloxetine. They found a strong association for COMT polymorphisms and no association with the serotonin receptor. Remission rates for the 3 COMT (rs165599) genotypes were as follows: (AA) 61%, (AG) 46%, and (GG) 38%.

Antidepressant Augmentation

With respect to finding alternate treatments for the patients who do not benefit from the SSRIs, the findings of a series of posters provided further evidence about the utility and safety of augmentation of antidepressants with the atypical antipsychotics aripiprazole,[10-14] quetiapine,[15] and olanzapine combined with fluoxetine.[16] Augmentation therapy with atypical antipsychotics tends to be rapidly effective and, at least with respect to aripiprazole, appears to be as effective for patients with anxious or atypical features and those who were partial responders to antidepressant therapy as it is for the remainder of patients.[11]
The antidepressant effects of quetiapine alone also have been tested in patients with major depressive disorder (MDD)[17,18] and generalized anxiety disorder (GAD).[19,20] Results of these PBO-controlled studies documented clinically and statistically significant effects in both disorders. Of importance, whereas the efficacy data for quetiapine monotherapy of bipolar depression established 300 mg daily as the effective dose, results of these studies indicated that doses as low as 50 mg daily have significant effects on depressive and anxious symptoms, with a relatively early onset of benefits. Although it is likely that the entire class of atypical antipsychotics has some effect on depressive symptoms, particular interest in quetiapine is partly fueled by evidence that the N-desalkyl- metabolite, also known as norquetiapine, inhibits norepinephrine reuptake.[21] Quetiapine monotherapy is currently being reviewed by the US FDA for indications for treatment of MDD and GAD. Issues of cost and tolerability, especially in comparison with first line therapies such as the SSRIs, are likely to be given serious consideration in these deliberations.

New Selective Norepinephrine Reuptake Inhibitor

The only new antidepressant to be introduced in the United States in 2008 is desvenlafaxine succinate (DVS), which was the topic of a number of posters.[22-28] DVS, which has been released as an extended release formulation of the primary active metabolite of venlafaxine, becomes the fourth member of the SNRI class worldwide. The main differences of DVS in comparison to the parent drug are dosing and metabolism, with a lower recommended dose (ie, 50 mg daily vs 75-225 mg daily because of the greater bioavailability of the succinate salt) and simpler pharmacokinetics (ie, a longer elimination half-life and no active metabolite). Of note, unlike the parent drug, a meta-analysis of PBO-controlled studies found no hint of a dose-response relationship in efficacy across a broad range of doses (50- 400 mg daily), with a strong dose-response effect on indices of tolerability.[28] Specifically, attrition related to side effects ranged from 4% on 50 mg daily to 18% on 400 mg daily. It remains to be seen if dosing simplicity and an improved pharmacokinetic profile will result in more widespread use of DVS than venlafaxine XR. At 50 mg daily, DVS is associated with relatively low rates of 2 of the problems associated with higher-dose venlafaxine therapy: discontinuation emergent symptoms[23] and treatment-emergent high blood pressure.[22] As the patent on the latter drug is expected to expire in 2010, the drugs will be comparably priced for several years, which should afford ample opportunity to compare them before it is necessary to make decisions based on perceived cost effectiveness.
In terms of other novel therapies, Rickels and colleagues[29] reported on a double blind, PBO-controlled study of vilazodone, an investigational antidepressant the is both an SSRI and a partial agonist of serotonin 1A receptors. In this relatively large (N = 410) 8 week study, vilazodone (40 mg/day) was superior to placebo on both the MADRS and HAM-D and was generally well tolerated, with no greater effect on sexual dysfunction, as measured by the ASEX scale, than PBO. Further RCTs are needed both to confirm the efficacy and safety of vilozodone vs PBO, and to compare it to existing standards.

This activity is supported in part by an unrestricted educational grant from Bristol-Myers Squibb/Otsuka.


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