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

Papakostas, George I.; Thase, Michael E.; Fava, Maurizio; Nelson, J. Craig; Shelton, Richard C.

doi:10.1016/j.biopsych.2007.03.027

Cited by 269 publications

(163 citation statements)

References 114 publications

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“…3). [115] Clearly, further research into augmentation strategies with NE medications to determine the anxiolytic benefits appears warranted. Figure 3.…”

Section: Treatment Implications Of Ne System Dysregulationmentioning

confidence: 99%

“…The results from a recent meta-analysis in patients with MDD showed that SNRIs have a small but significant advantage in effectiveness compared with SSRI treatments. [115] Along these lines, augmentation treatment with an NRI for patients with partial response to an SSRI is commonly used when treating MDD. [129,130] Several studies have shown that SNRIs that elevate both 5-HT and NE (e.g., venlafaxine and duloxetine) have been shown to be efficacious in treating anxious depression.…”

Section: Duration Of Treatmentmentioning

confidence: 99%

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Current perspectives of the roles of the central norepinephrine system in anxiety and depression

et al. 2010

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Norepinephrine (NE) is a major monoamine neurotransmitter that has widespread effects across multiple brain areas to regulate arousal and stress responses. The underlying function of the NE cortical system is to balance vigilance/scanning behavior with focused attention on novel environmental stimuli and the state of arousal. The central NE system is involved intrinsically with the stress response system, and dysregulation within the NE system has been implicated in the pathogenesis of anxiety and depressive disorders. Central NE activity paradoxically has either anxiogenic or anxiolytic effects, depending on whether the time course of the stress is acute or chronic, whether the stress is predictable or unpredictable, and which underlying brain regions are affected. Under conditions of chronic stress, NE system activity dysregulation of the hypothalamic-pituitary-adrenal system may turn a homeostatic stress response into a pathological stress response. Data suggest that the NE interplay with the serotonin system may exert neurobiological normalization of the pathophysiological state of anxious depression. Accordingly, pharmacological interventions targeting the NE system can result in anxiolytic, rather than anxiogenic, outcomes when used to treat patients with anxiety and depression. Depression and Anxiety 27:339-350, 2010. r r

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“…3). [115] Clearly, further research into augmentation strategies with NE medications to determine the anxiolytic benefits appears warranted. Figure 3.…”

Section: Treatment Implications Of Ne System Dysregulationmentioning

confidence: 99%

Section: Duration Of Treatmentmentioning

confidence: 99%

Current perspectives of the roles of the central norepinephrine system in anxiety and depression

et al. 2010

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“…The superiority of most clinically employed antidepressants over placebos in controlled trials has been modest in adult patients diagnosed with major depression, even lower in juvenile depressed patients, and probably has declined in recent years (Walsh et al, 2002;Baldessarini, 2005;Cipriani et al, 2007;Papakostas et al, 2007;Gartlehner et al, 2008;Kirsch et al, 2008;Tsapakis et al, 2008;Bridge et al, 2009;Wooley et al, 2009;Masi et al, 2010;Pigott et al, 2010;Khin et al, 2011). Evident decline in superiority of drugs over placebos has occurred despite evidence of selective reporting of positive findings of potential commercial interest from therapeutic trials (Ioannidis, 2008;Turner et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, there is little evidence that one antidepressant or pharmacological class of antidepressants is clearly and convincingly more effective than others (Anderson, 2001;Baldessarini, 2005Baldessarini, , 2012Cipriani et al, 2007;Papakostas et al, 2007;Gartlehner et al, 2008;Kirsch et al, 2008;Khin et al, 2011). In part, this lack of clear differentiation may arise from the modest drug-placebo differences in many controlled trials of antidepressants, which, in turn, may reflect broad clinical heterogeneity arising from the current broad concept of 'major depression' (Healy, 1997;Ghaemi, 2008).…”

Section: Introductionmentioning

confidence: 99%

Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review

Undurraga

Baldessarini

2011

Neuropsychopharmacol

212

168

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Antidepressant-placebo response-differences (RDs) in controlled trials have been declining, potentially confounding comparisons among older and newer drugs. For clinically employed antidepressants, we carried out a meta-analytic review of placebo-controlled trials in acute, unipolar, major depressive episodes reported over the past three decades to compare efficacy (drug-placebo RDs) of individual antidepressants and classes, and to consider factors associated with year-of-reporting by bivariate and multivariate regression modeling. Observed drug-placebo differences were moderate and generally similar among specific drugs, but larger among older antidepressants, notably tricyclics, than most newer agents. This outcome parallels selective increases in placebo-associated responses as trial-size has increased in recent years. Study findings generally support moderate efficacy of clinically employed antidepressants for acute major depression, but underscore limitations of meta-analyses of controlled trials for ranking drugs by efficacy. We suggest that efficiency and drug-placebo differences may be improved with fewer sites and subjects, and better quality-control of diagnostic and clinical assessments.

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“…SNRIs show greater efficacy than SSRIs overall, and have a broader therapeutic range (e.g., against neuropathic pain), but their advantages are not dramatic and may be offset by other factors, such as an enhanced risk of hypertension. 3,35,37,38,275 In fact, rather inconveniently, the SSRI escitalopram appears to be equivalent in efficacy to SNRIs-although perhaps reflecting its distinctive multisite interaction with 5-HT transporters. 276,277 By analogy, mirtazapine (which has antagonist properties at ␣ 2 -ARs, 5-HT 2C , and 5-HT 3 receptors) is more effective than selective ␣ 2 -AR or 5-HT 3 antagonists, but it remains unknown how it compares with a selective 5-HT 2C antagonist in the clinic.…”

Section: A Valedictory Caveatmentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

179

123

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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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

Cited by 269 publications

References 114 publications

Current perspectives of the roles of the central norepinephrine system in anxiety and depression

Current perspectives of the roles of the central norepinephrine system in anxiety and depression

Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

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