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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 8, November 2012—Guest Commentator: Chi-Un Pae, MD, PhD, The Catholic University of Korea College of Medicine; Duke University Medical Center


Early Switch Strategy in Patients with Major Depressive Disorder: A Double-Blind, Randomized Study

Romera I, Pérez V, Menchón JM, et al.
J Clin Psychopharmacol. 2012;32(4):479-486.

Objective: Antidepressant switch is a commonly used strategy in the absence of an adequate response, but optimum timing is not well established. We compared the efficacy of an early and a conventional antidepressant switch strategy in patients with major depressive disorder.

Methods: Patients with no or minimal improvement (30 mm overall pain visual analog scale [VAS]). Patients not achieving 30% reduction in Hamilton Depression Rating Scale (HAM-D) after 4 weeks of escitalopram (10 mg/day) were randomized to duloxetine 60–120 mg/day (early switch) or continued on escitalopram (conventional switch), with non-responders at week 8 switching to duloxetine. Endpoints were time to confirmed response and remission, VAS pain severity, and Sheehan disability scale (SDS). Switch strategies were compared using Kaplan-Meier, logistic regression, and repeated measures analyses.

Results: No differences between early and conventional switching were found in time to confirmed response after randomization (3.9 vs. 4.1 weeks, P=0.511) or remission (6.0 vs. 8.0 weeks, P=0.238). Significantly lower VAS mean pain levels for overall pain, headache, back pain, shoulder pain, interference with daily activities, and time being awake in pain were found for patients in the early switching group. Time to achieving normal functioning (SDS total score <6) was shorter in the early switching group (P=0.042). Safety results were comparable between switch strategies.

Conclusions: In MDD patients with moderate to severe painful physical symptoms not improving after 4 weeks of treatment with escitalopram, an earlier switch to duloxetine may lead to better pain and functional outcomes.

Clinical Commentary
Although depressed mood and lack of interest are the key symptoms of MDD, it also has a number of somatic and psychological symptoms that negatively affect the clinical course. In fact, patients with residual symptoms showed greater chance of relapse and experienced a recurrence more than 3 times faster than those with full recovery. Painful physical symptoms are also highly associated with residual symptoms. Currently, existing data also suggest a negative impact of painful physical symptoms on various treatment outcome measures including antidepressant efficacy, medical cost, daily productivity, quality of life, and treatment compliance. Hence, timely and early control of painful physical symptoms should be considered an important target for MDD treatment. The study preliminarily proposes that early switch to a different antidepressant leads to better clinical outcomes in MDD patients with moderate to severe pain, when the initial antidepressant shows inadequate response within 4 weeks.


Antidepressant Combination for Major Depression in Incomplete Responders: A Systematic Review

Lopes Rocha F, Fuzikawa C, Riera R, et al
J Affect Disord. 2012. Jul 24. [Epub ahead of print]

Background: Antidepressant combination has been suggested as a strategy to increase treatment efficacy. The objective of this study was to perform a systematic review and meta-analysis of studies that assessed the effect of antidepressant combination for major depression in patients with incomplete response to an initial antidepressant.

Methods: Studies were retrieved from PubMed (1966-February 2012), Cochrane Library (February 2012), Embase (1980-February 2012), PsycINFO (1980-February 2012), Lilacs (1982-February 2012), clinical trials registry, thesis database (, and secondary references. Included studies had an open-label phase in which an initial antidepressant was used for the treatment of major depression and a double-blind phase for the incomplete responders that compared monotherapy with the first antidepressant versus the association of a second antidepressant to the first one.

Results: Out of the 4,884 studies retrieved, only five satisfied the inclusion criteria. The total number of patients included was 483. Only two small trials reported benefits of adding a second antidepressant to the initial antidepressant. Dropouts due to side effects were not reported in three studies. Meta-analysis was not performed due to the small number of studies, the inconsistency in the direction of effect, and the possible instability of effect size. Only limited kinds of combination, involving mianserin, mirtazapine, and desipramine were studied. Some properties of the first two drugs such as the anxiolytic, sedative, and orexigenic effects, can mimic depression improvement. Limitations: Publication bias cannot be ruled out. Only one study included a monotherapy arm with the antidepressant used for augmentation of the first antidepressant.

Conclusions: The practice of using a combination of antidepressants for major depression in incomplete responders is not warranted by the literature.

Clinical Commentary
According to a number of clinical trials and meta-analyses, approximately 30% of major depressive disorder (MDD) patients do not achieve remission after multiple treatment trials. For MDD patients with initial treatment failure, augmentation, combination, and switching strategies are available in clinical practice. Combination of different antidepressants may be beneficial for such patients, since this strategy may offer synergistic effects while counteracting existing tolerability issues from primary antidepressant. However, there are sparse data to support combination strategy due to small sample sizes and methodological pitfalls. The present meta-analysis by Lopes Rocha and colleagues confirms a lack of clear data supporting combination strategy as routine practice for MDD patients with initial treatment failure, and calls well-controlled, adequately-powered, short- and long-term studies to evaluate the efficacy and tolerability of antidepressant combinations.


Omega-3 Fatty Acids for the Treatment of Depression: Systematic Review and Meta-Analysis

Bloch MH, Hannestad J.
Mol Psychiatry. 2011; Sep 20. doi: 10.1038/mp.2011.100. [Epub ahead of print]

Objective: We conducted a meta-analysis of randomized, placebo-controlled trials of omega-3 fatty acid (FA) treatment of major depressive disorder (MDD) in order to determine efficacy and to examine sources of heterogeneity between trials.

Methods: PubMed (1965-May 2010) was searched for randomized, placebo-controlled trials of omega-3 FAs for MDD. Our primary outcome measure was standardized mean difference in a clinical measure of depression severity. In stratified meta-analysis, we examined the effects of trial duration, trial methodological quality, baseline depression severity, diagnostic indication, dose of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in omega-3 preparations, and whether omega-3 FA was given as monotherapy or augmentation.

Results: In 13 randomized, placebo-controlled trials examining the efficacy of omega-3 FAs involving 731 participants, meta-analysis demonstrated no significant benefit of omega-3 FA treatment compared with placebo (standard mean difference [SMD]=0.11, 95% confidence interval [CI]: -0.04, 0.26). Meta-analysis demonstrated significant heterogeneity and publication bias. Nearly all evidence of omega-3 benefit was removed after adjusting for publication bias using the trim-and-fill method (SMD=0.01, 95% CI: -0.13, 0.15). Secondary analyses suggested a trend toward increased efficacy of omega-3 FAs in trials of lower methodological quality, trials of shorter duration, trials which utilized completers rather than intention-to-treat analysis, and trials in which study participants had greater baseline depression severity.

Conclusion: Current published trials suggest a small, non-significant benefit of omega-3 FAs for major depression. Nearly all of the treatment efficacy observed in the published literature may be attributable to publication bias.

Clinical Commentary
The utility of omega-3 fatty acids for treating MDD is of considerable interest as one of promising complimentary medicines, particularly for MDD patients who have partial response or tolerability issues with modern antidepressants. Despite the fact that preexisting meta-analyses have reported positive outcomes for omega-3 fatty acid treatment for MDD, the meta-analysis by Bloch and Hannestad found no significant benefit of omega-3 fatty acids for MDD. However, caution must be undertaken when interpreting these findings. Omega-3 fatty acids have been found to demonstrate greater effects in patients with MDD diagnosed formally with proper diagnostic criteria than in those without formal diagnosis. Hence, a conclusive remark on the exact role of omega-3 fatty acids in the use of MDD treatment as adjunct or monotherapy should be delayed until clear and sufficient evidence from many adequately-powered and well-designed clinical trials are available.


A Double-Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant Therapy Among Depressed Outpatients with Inadequate Response to Prior Antidepressant Therapy (ADAPT-A Study)

Fava M, Mischoulon D, Iosifescu D, et al
Psychother Psychosom. 2012;81(2):87-97.

Background: We assessed the efficacy of low-dose aripiprazole added to antidepressant therapy (ADT) in major depressive disorder (MDD) patients with inadequate response to prior ADT.

Methods: As per the sequential parallel comparison design, 225 MDD subjects were randomized to adjunctive treatment with aripiprazole 2 mg/day or placebo across two 30-day phases, with a 2:3:3 randomization ratio to drug/drug (aripiprazole 2 mg/day in phase 1; 5 mg/day in phase 2), placebo/placebo (placebo in both phases), and placebo/drug (placebo in phase 1; aripiprazole 2 mg/day in phase 2). Eligible subjects were patients whose MDD was independently deemed 'valid' with SAFER criteria. Subjects had been receiving ADT for ≥8 weeks, and had inadequate response to ≥1 and <4 adequate ADTs in the current episode, as defined by the Antidepressant Treatment Response Questionnaire.

Results: The pooled, weighted response difference between aripiprazole 2 mg/day and placebo in the two phases was 5.6% (P=0.18; NS). The aripiprazole 2 mg/day-placebo difference on the Montgomery-Asberg Depression Rating Scale pooled across the two phases was -1.51 (P=0.065; NS). Other secondary endpoint analyses showed nonsignificant pooled differences favoring aripiprazole over placebo. Of the 225 randomized subjects in phase 1, 2 dropped out in both arms; of the 138 phase 1 placebo nonresponders in phase 2, 9 dropped out on aripiprazole and 5 on placebo. There were only minimal differences in adverse event rates between treatments, except for constipation, weight gain, and dry mouth, more common on aripiprazole.

Conclusion: This study provides clear support for the tolerability of low-dose aripiprazole as an ADT-augmenting agent, with marginal efficacy.

Clinical Commentary
Aripiprazole, quetiapine XR, and olanzapine/fluoxetine (combination agent) have been approved and widely used for treating patients with MDD worldwide. Among such agents, aripiprazole has been approved first  and its use has dramatically increased in MDD treatment; however, selection of proper starting and target doses for the individual patient is challenging in clinical practice due to risk of developing akathisia and inadequate efficacy in the use of aripiprazole for MDD. The results herein offer clear support for the tolerability of aripiprazole 2 mg/day as an augmenting agent, with limited efficacy; clinicians may have to increase the dose of aripiprazole up to 5–15 mg/day based on the individual patient’s response and tolerability. Pharmacokinetic differences in different ethnicities should also be considered in selection of starting and target dose of aripiprazole; slight differences in dosing pattern of aripiprazole were observed in clinical trials conducted in Asian countries.


Effects of S-Adenosylmethionine Augmentation of Serotonin Reuptake Inhibitor Antidepressants on Cognitive Symptoms of Major Depressive Disorder

Levkovitz Y, Alpert JE, Brintz CE, et al
J Affect Disord. 2012;136(3):1174-1178.

Background: Major depressive disorder (MDD) is often accompanied by significant cognitive impairment, and there are limited interventions specific to this particular symptom. S-adenosyl methionine (SAMe), a naturally occurring molecule which serves as a major methyl-donor in human cellular metabolism, is required for the synthesis and maintenance of several neurotransmitters that have been implicated in the pathophysiology and treatment of cognitive dysfunction in MDD.

Methods: This study is a secondary analysis of a clinical trial involving the use of adjunctive SAMe for MDD. Forty-six serotonin reuptake inhibitor (SRI) non-responders with MDD enrolled in a 6-week, double-blind, randomized trial of adjunctive oral SAMe were administered the self-rated cognitive and physical symptoms questionnaire (CPFQ), a validated measure of cognitive as well as physical symptoms of MDD, before and after treatment.

Results: There was a greater improvement in the ability to recall information (P=0.04) and a trend toward statistical significance for greater improvement in word-finding (P=0.09) for patients who received adjunctive SAMe than placebo. None of the remaining five items reached statistical significance.

Conclusion: These preliminary data suggest that SAMe can improve memory-related cognitive symptoms in depressed patients, and warrant replication.

Clinical Commentary
S-adenosylmethionine (SAMe) is a natural compound that is found in almost every tissue and fluid in the body. SAMe has a major role in the immune system and cell metabolism as well as involvement in the life cycles of major neurotransmitters (e.g., serotonin) which are implicated in the development of MDD. Existing data suggest that augmentation with SAMe is tolerable for MDD patients and may boost the antidepressant effect in treating these patients. The data herein present a potential utility of SAMe in the treatment of MDD-related cognitive decline without safety or tolerability issues, although more replication studies are needed to confirm such findings. In fact, cognitive impairment is common in MDD patients, especially in the geriatric population. Hence, SAMe may be another viable option for treating cognitive dysfunction in MDD patients. In addition, SAMe may be beneficial in the treatment of MDD patients with minimal cognitive impairment.

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