Are Antidepressant Drugs That Combine Serotonergic and Noradrenergic Mechanisms of Action More Effective Than the Selective Serotonin Reuptake Inhibitors in Treating Major Depressive Disorder? A Meta-analysis of Studies of Newer Agents

Harvard University, Cambridge, Massachusetts, United States
Biological Psychiatry (Impact Factor: 10.26). 01/2008; 62(11):1217-27. DOI: 10.1016/j.biopsych.2007.03.027
Source: PubMed


Recent studies suggest that the treatment of major depressive disorder (MDD) with newer antidepressant drugs that simultaneously enhance norepinephrine and serotonin neurotransmission might result in higher response and remission rates than the selective serotonin reuptake inhibitors (SSRIs). The goal of our work was to compare response rates among patients with MDD treated with either of these two broad categories of antidepressant drugs.
Medline/Pubmed, EMBase, clinical trial registries, program syllabi from major psychiatric meetings held since 1995, and documents from relevant pharmaceutical companies were searched for double-blind, randomized trials comparing a newer serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran, mirtazapine, mianserin, or moclobemide) with an SSRI for MDD.
Ninety-three trials (n = 17,036) were combined using a random-effects model. Treatment with serotonergic + noradrenergic antidepressant drugs was more likely to result in clinical response than the SSRIs (risk ratio [RR] = 1.059; response rates 63.6% versus 59.3%; p = .003). There was no evidence for heterogeneity among studies combined (p = 1.0). Excluding each individual agent did not significantly alter the pooled RR. With the exception of duloxetine (.985), RRs for response for each individual serotonergic + noradrenergic antidepressant drug were within the 95% confidence interval of the pooled RR (1.019-1.101).
Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one indicator of clinical significance, nearly 24 patients would need to be treated with dual-action antidepressant drugs instead of SSRIs in order to obtain one additional responder. This difference falls well below the mark of NNT = 10 suggested by the United Kingdom's National Institute of Clinical Excellence but nonetheless might be of public health relevance given the large number of depressed patients treated with SSRI /serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant drugs. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms.

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    • "Remarkably, though part of the historical criteria for atypical depression arose from the observation of a fair response to monoamine oxidase inhibitors vs. the tricyclic antidepressants available at the time (Stewart et al., 1993; West and Dally, 1959), because of their poor benefit/risk ratio, modern clinicians tend to use newer antidepressants for all outpatients, regardless of the presence of atypical features, especially upon patient failure to respond to SSRIs (Nierenberg et al., 1998; Schultz, 1999). Such an attitude is exemplified by the spreading use of the serotonin norepinephrine reuptake inhibitor (SNRI) duloxetine even for atypical cases of SSRI-TRD, although this drug displays a negligible efficacy advantage vs. the SSRIs, at least for less severe manifestations of depression, as documented by an 8-week, flexible-dose open-label study carried on 20 MDD patients, including a subset of atypical cases (Papakostas et al., 2007; Shelton et al., 2007). A subsequent study failed to demonstrate any difference in therapeutic outcome (50% were responders) compared to non-atypical depressed (Stewart et al., 2008), in contrast to a 12-week, open-label, multi-centric investigation , that had concordant results with the STARnD wisdom indicating the presence of atypical features as one of the factors associated with the reduced response toward duloxetine in MDD (Howland et al., 2008). "
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    ABSTRACT: The efficacy, safety, and tolerability of combined bupropion versus placebo using duloxetine as active reference drug, in patients with a DSM-IV diagnosis of major depression with atypical features and a history of treatment resistance, were evaluated in this preliminary six-week study. Patients (n=46) had a baseline Hamilton Depression Scale (HAM-D) ≥14 and were randomly assigned to 150/300 mg/day bupropion vs. placebo, which was added to 60 to 120 mg/day duloxetine depending on baseline depression severity. Atypical features of depression were assessed using the additional eight-item module of the Structured Interview Guide for the HAM-D with the Atypical Depression Supplement. By week 6, only five (21.7%) patients receiving duloxetine+placebo vs. six (26.1%) patients on the bupropion combination achieved response. No significant difference in final HAM-D scores between the two groups was observed between those patients achieving response. The presence of a higher number of atypical features significantly predicted non-response, with the relevant binary logistic regression model correctly classifying 17 out 22 (77.3%) of non-responders [Exp(B)=0.294; p=.016] vs. 17 out 23 (73.9%) [Exp(B)=0.353; p=.028] non-responder cases in the “+placebo” and “+bupropion” groups, respectively. In those patients receiving bupropion, treatment-emergent adverse events leading to withdrawal were more common among those receiving lower doses of the combination drug, and no life-threating dangers were noted. Additional studies, including an adequate course of duloxetine trial, are nonetheless aimed to allow a firm conclusion about the usefulness of the combination of duloxetine and bupropion for treatment-resistant cases of major depression with atypical features.
    European Neuropsychopharmacology 08/2014; DOI:10.1016/j.euroneuro.2014.04.004 · 4.37 Impact Factor
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    • "Vilazodone compared with placebo also significantly improved overall anxiety symptoms on the basis of HAMA scores. It is possible that the combined property of serotonin reuptake inhibition and 5-HT1A partial agonism of vilazodone leads to a broader antidepressant efficacy with enhanced anxiolytic efficacy in MDD patients compared with serotonin reuptake inhibition alone (Blier and Ward, 2003; Sussman, 2003; Papakostas et al., 2007). "
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    ABSTRACT: Vilazodone is a potent selective serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder in adults. To assess the efficacy of vilazodone across a range of symptoms and severities of depression, data from two phase III, 8-week, randomized, double-blind, placebo-controlled trials were pooled for analysis. Overall improvement in depressive symptoms measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the 17-item Hamilton Depression Rating Scale was statistically significant (P<0.05) for vilazodone treatment compared with placebo as early as Week 1 and continued throughout double-blind treatment. Vilazodone treatment compared with placebo showed significant improvement on all 10 individual MADRS symptom items at end of treatment (P<0.01). Rates of response and remission were significantly greater in the vilazodone group relative to the placebo group, with numbers needed to treat ranging from eight to nine for response and 12-17 for remission. Between-group treatment differences in MADRS and the other outcome measures were similar among all depression subgroups, with no consistent pattern associated with depression severity. These findings support the efficacy of vilazodone across a broad range of depressive symptoms and severities for the treatment of major depressive disorder.
    International clinical psychopharmacology 11/2013; 29(2). DOI:10.1097/YIC.0000000000000016 · 2.46 Impact Factor
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    • "Major depressive disorder (MDD) has a devastating effect not only on symptomatic individuals but also on society as a whole, through high medical costs and loss of productivity (Murray and Lopez, 1996; Collins et al, 2011). Despite the enormous societal burden, recent history has seen relatively little progress in treatment efficacy, with the most common non-invasive treatments continuing to demonstrate relatively low response and remission rates (Papakostas et al, 2007; Imel et al, 2008; Gartlehner et al, 2011; Spielmans et al, 2011). There have been calls for personalized treatment approaches to improve response rates (Collins et al, 2011; Kapur et al, 2012). "
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    ABSTRACT: Despite its high toll on society, there has been little recent improvement in treatment efficacy for major depressive disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting-state functional connectivity predicted response to treatment with repetitive transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty-five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting-state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal, and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased subgenual cingulate cortex-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.Neuropsychopharmacology advance online publication, 23 October 2013; doi:10.1038/npp.2013.222.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2013; 39(2). DOI:10.1038/npp.2013.222 · 7.05 Impact Factor
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