Context Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression.Objective To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression.Data Sources PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews.Study Selection Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included. Data ExtractionIndividual patient-level data were obtained from study authors. ResultsMedication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. ConclusionsThe magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

Cognitive therapy can be as effective as medications for the initial treatment of moderate to severe major depression, but this degree of effectiveness may depend on a high level of therapist experience or expertise.

Cognitive therapy has an enduring effect that extends beyond the end of treatment. It seems to be as effective as keeping patients on medication.

About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.Methods: This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures. Results: Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine See related features: Commentary by Dr. Schatzberg (p. 422) and CME course (p. 491)

A recent randomized controlled trial found nearly equivalent response rates for antidepressant medications and cognitive therapy in a sample of moderate-to-severely depressed outpatients. In this article, we seek to identify the variables that were associated with response across both treatments as well as variables that predicted superior response in one treatment over the other. The sample consisted of 180 depressed outpatients: 60 of whom were randomly assigned to cognitive therapy; 120 were assigned to antidepressant medications. Treatment was provided for 16 weeks. Chronic depression, older age, and lower intelligence each predicted relatively poor response across both treatments. Three prescriptive variables were identified: marriage, unemployment, and having experienced a greater number of recent life events predicted superior response to cognitive therapy compared to antidepressant medications. Thus, six markers of treatment outcome were identified, each of which might be expected to carry considerable clinical utility. The three prognostic variables identify subgroups that might benefit from alternative treatment strategies; the three prescriptive variables identify groups who appear to respond particularly well to cognitive therapy.

Major depressive disorder (MDD) is a heterogeneous illness for which there are currently no effective methods to objectively assess severity, endophenotypes, or response to treatment. Increasing evidence suggests that circulating levels of peripheral/serum growth factors and cytokines are altered in patients with MDD, and that antidepressant treatments reverse or normalize these effects. Furthermore, there is a large body of literature demonstrating that MDD is associated with changes in endocrine and metabolic factors. Here we provide a brief overview of the evidence that peripheral growth factors, pro-inflammatory cytokines, endocrine factors, and metabolic markers contribute to the pathophysiology of MDD and antidepressant response. Recent preclinical studies demonstrating that peripheral growth factors and cytokines influence brain function and behavior are also discussed along with their implications for diagnosing and treating patients with MDD. Together, these studies highlight the need to develop a biomarker panel for depression that aims to profile diverse peripheral factors that together provide a biological signature of MDD subtypes as well as treatment response.

The etiology of major depression (MDD), a common and complex disorder, remains obscure. Gene expression profiling was conducted on post-mortem brain tissue samples from Brodmann Area 10 (BA10) in the prefrontal cortex from psychotropic drug-free persons with a history of MDD and age, gender, and post-mortem interval matched normal controls (n=14 pairs of subjects). Microarray analysis was conducted using the Affymetrix Exon 1.0 ST arrays. A list of differential expression changes were determined by dual fold change-probability criteria (|ALR|>0.585 [equivalent to a 1.5-fold difference in either direction], p<0.01), while molecular pathways of interest were evaluated using Gene Set Enrichment Analysis (GSEA) software. The results strongly implicate increased apoptotic stress in the samples from the MDD group. Three anti-apoptotic factors, Y-box binding protein 1 (YBX1), Caspase-1 dominant-negative inhibitor pseudo-ICE (COP1), and the putative apoptosis inhibitor FKGS2 were over-expressed. Gene set analysis suggested up-regulation of a variety of pro- and anti-inflammatory cytokines, including interleukin 1α (IL1α), IL2, IL3, IL5, IL8, IL9, IL10, IL12A, IL13, IL15, IL18, interferon gamma (IFNγ), and lymphotoxin alpha (LTA; TNF super family member 1). The genes showing reduced expression included metallothionein 1M (MT1M), a zinc binding protein with a significant role in the modulation of oxidative stress. The results of this study suggest that post-mortem brain tissue samples from BA10, a region which is involved in reward-related behavior, show evidence of local inflammatory, apoptotic, and oxidative stress in MDD.

Background High neuroticism is a personality risk factor that captures much of the genetic vulnerability to Major Depressive Disorder (MDD), and low extraversion may increase risk as well. Both have been linked to the serotonin system. Objectives To test whether MDD patients in selective serotonin reuptake inhibitors (SSRIs) treatment report greater changes in neuroticism and extraversion than patients receiving inert-placebo; and to examine the state-effect hypothesis, that self-reported personality change during SSRI treatment is merely a change of depression-related measurement bias. Design/Setting Personality was measured during a placebo-controlled trial in research clinics. Patients Adult moderate-to-severe MDD patients randomized to receive paroxetine (n=120), placebo (n=60), or cognitive therapy (CT) (n=60). Outcome Measures NEO Five-Factor Inventory; Hamilton Rating Scale for Depression. Results Paroxetine patients reported greater personality change than did placebo patients, even after controlling for depression improvement (p≤.002). The advantage of paroxetine over placebo in antidepressant efficacy was no longer significant after controlling for change in personality (p≥.14). Paroxetine patients reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement. Although placebo patients exhibited substantial depression improvement (−1.2 SD, p<.001), they reported little change on neuroticism (−0.18 SD, p=.08) or extraversion (0.08 SD, p=.50). CT produced greater personality change than placebo (p≤.01); but its advantage on neuroticism was no longer significant after controlling for depression (p=.14). Neuroticism reduction during treatment predicted lower relapse rates among paroxetine responders (p=.003), but not among CT responders (p=.86). Conclusion Paroxetine appears to have a specific pharmacological effect on personality that is distinct from its effect on depression. If replicated, this pattern would disconfirm the state-effect hypothesis and instead support the notion that SSRIs’ effects on personality go beyond and perhaps contribute to their antidepressant effects.