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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    • "On the other hand, a particular arrangement of indications identified with diminished positive affect respond poorly to serotonergic antidepressants (Chantal and Mike, 2011). Therapeutic agents which particularly enhance noradrenaline activity are powerful antidepressants, and there is proof that those acting at the same time on 5-HT and noradrenaline neurotransmission may have antidepressant activity better than selective serotonin reuptake inhibitors (Papakostas et al., 2007) V. vinifera juice has dual action on amine neurotransmitters, that is mean to say that it increases both noradrenaline and 5- HT levels in brain tissue, so it can be newer dual-acting antidepressant agent with superior efficacy and broader pharmacologic spectrum. "
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    ABSTRACT: The advantageous effects of Vitis vinifera juice on depressive model mice were examined utilizing a blend of behavioral evaluations and biogenic amine neurotransmitter estimations. During the behavioral evaluations, immobility time on the forced swimming test and tail suspension test were measured in unstressed and immobilization-induced stressed mice. V. vinifera juice (4 mL/kg and 8 mL/kg) and fluoxetine (20 mg/kg) produced a significant decrease in immobility time of both unstressed and stressed mice when compared with their respective saline-treated control groups in both paradigms. Neurotransmitters were measured using high-performance liquid chromatography with electrochemical detector. V. vinifera juice raised the levels of both serotonin (p<0.001) and noradrenalin (p<0.001) in brain tissue. These outcomes give significant mechanistic insights into the protective effect of V. vinifera juice against depressive disorders. Our results showed that V. vinifera juice could relieve depressive manifestations in the rodent model of depression.
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    • "Unlike TCAs, SNRIs have minimal or no pharmacological action at adrenergic ( 1, 2 , and ), histamine (H 1 ), muscarinic, dopamine, or postsynaptic serotonin receptors (Bymaster et al., 2001;Millan et al., 2001;Owens et al., 1997;Sánchez &amp; Hyttel, 1999;Vaishnavi et al., 2004). There is some evidence that suggests SNRIs may be more effective for the treatment of MDD as compared to SSRIs; however, these differences are relatively modest (Papakostas, Thase, Fava, Nelson, &amp; Shelton, 2007;Stahl, Grady, Moret, &amp; Briley, 2005). The clinical tolerability and the prevalence of sexual dysfunction of SNRIs are comparable with other antidepressant drug treatments (Clayton et al., 2002;Stahl, Grady, Moret, &amp; Briley, 2005). "
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    ABSTRACT: Major depressive disorder (MDD) is a chronic, recurring, and debilitating mental illness that is the most common mood disorder in the United States. It has been almost 50 years since the monoamine hypothesis of depression was articulated, and just over 50 years since the first pharmacological treatment for MDD was discovered. Several monoamine-based pharmacological drug classes have been developed and approved for the treatment of MDD; however, remission rates are low (often less than 60%) and there is a delayed onset before remission of depressive symptoms is achieved. As a result of a "proof-of-concept" study in 2000 with the noncompetitive NMDA antagonist ketamine, a number of studies have examined the glutamatergic systems as viable targets for the treatment of MDD. This review will provide a brief history on the development of clinically available antidepressant drugs, and then review the possible role of glutamatergic systems in the pathophysiology of MDD. Specifically, the glutamatergic review will focus on the N-methyl-D-aspartate (NMDA) receptor and the efficacy of drugs that target the NMDA receptor for the treatment of MDD. The noncompetitive NMDA receptor antagonist ketamine, which has consistently produced rapid and sustained antidepressant effects in MDD patients in a number of clinical studies, has shown the most promise as a novel glutamatergic-based treatment for MDD. However, compounds that target other glutamatergic mechanisms, such as GLYX-13 (a glycine-site partial agonist at NMDA receptors) appear promising in early clinical trials. Thus, the clinical findings to date are encouraging and support the continued search for and the development of novel compounds that target glutamatergic mechanisms. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
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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.
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