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Symptom dimensions have not yet been comprehensively tested as predictors of the substantial heterogeneity in outcomes of antidepressant treatment in major depressive disorder. We tested nine symptom dimensions derived from a previously published factor analysis of depression rating scales as predictors of outcome in 811 adults with moderate to severe depression treated with flexibly dosed escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP). The effects of symptom dimensions were tested in mixed-effect regression models that controlled for overall initial depression severity, age, sex and recruitment centre. Significant results were tested for replicability in 3637 adult out-patients with non-psychotic major depression treated with citalopram in level I of Sequenced Treatment Alternatives to Relieve Depression (STAR*D). The interest-activity symptom dimension (reflecting low interest, reduced activity, indecisiveness and lack of enjoyment) at baseline strongly predicted poor treatment outcome in GENDEP, irrespective of overall depression severity, antidepressant type and outcome measure used. The prediction of poor treatment outcome by the interest-activity dimension was robustly replicated in STAR*D, independent of a comprehensive list of baseline covariates. Loss of interest, diminished activity and inability to make decisions predict poor outcome of antidepressant treatment even after adjustment for overall depression severity and other clinical covariates. The prominence of such symptoms may require additional treatment strategies and should be accounted for in future investigations of antidepressant response.

Most knowledge regarding the effects of antidepressant drugs is at the receptor level, distal from the nervous system effects that mediate their clinical efficacy. Using functional magnetic resonance imaging (fMRI), this study investigated the effects of escitalopram, a selective serotonin reuptake inhibitor (SSRI), on resting-state brain function in patients with major depressive disorder (MDD). Fourteen first-episode drug-naive MDD patients completed two fMRI scans before and after 8 weeks of escitalopram therapy. Scans were also acquired in 14 matched healthy subjects. Data were analyzed using the regional homogeneity (ReHo) approach. Compared to controls, MDD patients before treatment demonstrated decreased ReHo in the frontal (right superior frontal gyrus), temporal (left middle and right inferior temporal gyri), parietal (right precuneus) and occipital (left superior occipital gyrus and right cuneus) cortices, and increased ReHo in the left dorsal medial prefrontal gyrus and left anterior lobe of the cerebellum. Compared to the unmedicated state, ReHo in the patients after treatment was decreased in the left dorsal medial prefrontal gyrus, the right insula and the bilateral thalamus, and increased in the right superior frontal gyrus. Compared to controls, patients after treatment displayed a ReHo decrease in the right precuneus and a ReHo increase in the left anterior lobe of the cerebellum. Successful treatment with escitalopram may be associated with modulation of resting-state brain activity in regions within the fronto-limbic circuit. This study provides new insight into the effects of antidepressants on functional brain systems in MDD.

To improve the 'personalized-medicine' approach to the treatment of depression, we need to identify biomarkers that, assessed before starting treatment, predict future response to antidepressants ('predictors'), as well as biomarkers that are targeted by antidepressants and change longitudinally during the treatment ('targets'). In this study, we tested the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-7, IL-8, IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-α), and neuroplasticity (brain-derived neurotrophic factor (BDNF), p11 and VGF), in healthy controls (n=34) and depressed patients (n=74), before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study. Non-responders had higher baseline mRNA levels of IL-1β (+33%), MIF (+48%), and TNF-α (+39%). Antidepressants reduced the levels of IL-1β (-6%) and MIF (-24%), and increased the levels of GR (+5%) and p11 (+8%), but these changes were not associated with treatment response. In contrast, successful antidepressant response was associated with a reduction in the levels of IL-6 (-9%) and of FKBP5 (-11%), and with an increase in the levels of BDNF (+48%) and VGF (+20%)-that is, response was associated with changes in genes that did not predict, at the baseline, the response. Our findings indicate a dissociation between 'predictors' and 'targets' of antidepressant responders. Indeed, while higher levels of proinflammatory cytokines predict lack of future response to antidepressants, changes in inflammation associated with antidepressant response are not reflected by all cytokines at the same time. In contrast, modulation of the GR complex and of neuroplasticity is needed to observe a therapeutic antidepressant effect.

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.

Electronic medical records (EMR) provide a unique opportunity for efficient, large-scale clinical investigation in psychiatry. However, such studies will require development of tools to define treatment outcome. Natural language processing (NLP) was applied to classify notes from 127 504 patients with a billing diagnosis of major depressive disorder, drawn from out-patient psychiatry practices affiliated with multiple, large New England hospitals. Classifications were compared with results using billing data (ICD-9 codes) alone and to a clinical gold standard based on chart review by a panel of senior clinicians. These cross-sectional classifications were then used to define longitudinal treatment outcomes, which were compared with a clinician-rated gold standard. Models incorporating NLP were superior to those relying on billing data alone for classifying current mood state (area under receiver operating characteristic curve of 0.85-0.88 v. 0.54-0.55). When these cross-sectional visits were integrated to define longitudinal outcomes and incorporate treatment data, 15% of the cohort remitted with a single antidepressant treatment, while 13% were identified as failing to remit despite at least two antidepressant trials. Non-remitting patients were more likely to be non-Caucasian (p<0.001). The application of bioinformatics tools such as NLP should enable accurate and efficient determination of longitudinal outcomes, enabling existing EMR data to be applied to clinical research, including biomarker investigations. Continued development will be required to better address moderators of outcome such as adherence and co-morbidity.

Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.

Meta-analyses, published in 2008–2010, have confirmed abnormally low serum brain-derived neurotrophic factor (BDNF) concentrations in depressed patients and normalization of this by antidepressant treatment. These findings are believed to reflect peripheral manifestations of the neurotrophin hypothesis , which states that depression is secondary to an altered expression of BDNF in the brain. Since the publication of these meta-analyses, the field has seen a huge increase in studies on these topics. This motivated us to update the evidence on the aforementioned associations and, in addition, to compile the data on serum BDNF concentrations in relation to the symptom severity of depression. Using a manifold of data as compared with earlier meta-analyses, we find low serum BDNF concentrations in 2384 antidepressant-free depressed patients relative to 2982 healthy controls and to 1249 antidepressant-treated depressed patients (Cohen’s d =−0.71 and −0.56, P -values <0.0000001). When publication bias is accounted for, these effect-sizes become substantially smaller ( d =−0.47 and −0.34, respectively, P -values<0.0001). We detect between-study heterogeneity in outcomes for which only year of publication and sample size are significant moderators, with more recent papers and larger samples sizes in general being associated with smaller between-group differences. Finally, the aggregated data negate consistent associations between serum BDNF concentrations and the symptom severity of depression. Our findings corroborate the claim that altered serum BDNF concentrations are peripheral manifestations of depression. However, here we highlight that the evidence for this claim is slimmer as was initially thought and amidst a lot of noise.

The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18-65) with TRD and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) increase neurogenesis in the dentate gyrus (DG) of rodents and nonhuman primates. We determined whether SSRIs or TCAs increase neural progenitor (NPCs) and dividing cells in the human DG in major depressive disorder (MDD). Whole frozen hippocampi from untreated subjects with MDD ( N =5), antidepressant-treated MDD (MDDT, N =7), and controls (C, N =7) were fixed, sectioned, and immunostained for NPCs and dividing cell markers (nestin and Ki-67, respectively), NeuN and GFAP, in single and double labeling. NPC and dividing cell numbers in the DG were estimated by stereology. Clinical data were obtained by psychological autopsy, and by toxicological and neuropathological examination performed on all subjects. NPCs decreased with age ( p =0.034). Females had more NPCs than males ( p =0.023). Correcting for age and sex, MDDT receiving SSRIs had more NPCs than untreated MDD ( p ⩽0.001) and controls ( p ⩽0.001), NPCs were not different in SSRI- and TCA-treated MDDT ( p =0.169). Dividing cell number, unaffected by age or sex, was greater in MDDT receiving TCAs than in untreated MDD ( p ⩽0.001), SSRI-treated MDD ( p =0.001), and controls ( p ⩽0.001). The increase of NPCs and dividing cells in MDDT was localized to the rostral DG. MDDT had a larger DG volume compared with untreated MDD or controls ( p =0.009). Antidepressants increase NPC number in the anterior human DG. Whether this finding is critical or necessary for the antidepressants effect remains to be determined.