The effects of major depressive disorder (MDD) on neurocognitive function remain poorly understood. Results from published studies vary widely in terms of methodological factors, and very little is known about the effects of depression severity and other clinical characteristics on neurocognitive function. The purpose of this review was to synthesize prior research findings regarding neurocognitive functioning in patients with MDD and varying levels of depression severity and to provide recommendations for future directions. Overall, this review suggests that MDD has been inconsistently associated with neurocognitive functioning and there is limited understanding regarding the relationship between depression severity and neurocognitive sequelae. There was much heterogeneity on depression severity-related factors across studies assessing neurocognitive function in MDD, as well as substantial variability in the consideration of depression severity among studies, which suggests a need to further explore this important issue.

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clinicaltrials.gov Identifier: NCT00076258.

Objective Currently, no valid measures inform treatment selection for depressed patients. Whether C-reactive protein (CRP) in particular and two other acute phase reactants (inflammatory markers) could differentiate between patients responding to either of two treatments with different mechanisms of action was assessed. Method Subjects included Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants randomly assigned to either escitalopram plus placebo (SSRI monotherapy, n=51) or bupropion plus escitalopram combination (bupropion-SSRI combination, n=55) with baseline plasma samples. CRP, serum amyloid P component, and alpha-2-macroglobulin were measured using the Bioplex Pro™ human acute-phase 4-plex panel. We conducted mixed model analyses of depressive symptom (Quick Inventory of Depressive Symptomatology Self-Report) and side-effect burden (Frequency, Intensity, and Burden of Side-Effects Rating Scale) obtained weekly or every other week over the 12-week acute-phase of CO-MED trial to evaluate the relationship between these outcomes and baseline CRP and other acute-phase reactants. Results The treatment arms did not differ in depressive symptom or side effect outcomes. Most participants (69.8%, 74/106) had baseline CRP levels greater than 1 mg/L (indicative of systemic inflammatory activity). Higher baseline CRP levels were associated lower depression severity (correlation coefficient=−0.63) with bupropion-SSRI combination but not with SSRI monotherapy (correlation coefficient=0.40). The overall remission rate was 41.5%. The estimated remission rate with CRP threshold based assignment (SSRI monotherapy for <1 mg/L and Bupropion-SSRI for ≥1 mg/L) was 53.1%, with a number needed to treat of 8.6. Side effect burden was unrelated to any baseline inflammatory marker. Conclusions Baseline CRP levels relate differentially to antidepressant treatment outcomes in persons with major depressive disorder.

Depression is associated with significant functional impairment and reduced quality of life. Disruptions occur both globally as well as in specific functional areas such as work, interpersonal relationships and cognitive function. From both a clinical and research perspective, much focus has been given to the resolution of symptoms associated with depression, while relatively little attention has been given to functional improvements. Definitions of remission in depression are most frequently based on achieving a cut-off score on clinical rating scales of depressive symptoms. Research in this area has sparsely included psychosocial function or health-related quality of life as a primary outcome measure in clinical trials. However, the need to fully understand the impact of depression and its treatments on functioning is great, given the existing evidence of the profound effect that depression has on function. Even mild depressive symptoms and subsyndromal depression result in functional impairment and reduced quality of life, and untreated residual depressive symptomatology can result in an increased likelihood for relapse of the fully symptomatic disorder (i.e. major depressive disorder). Therefore, clinicians and researchers alike need to broaden the focus of treatment to encompass not only the specific symptoms of depression, but the functional consequences as well. Many tools have been developed to assess function and quality of life, both globally as well as within specific domains. In addition, the effect of residual symptoms associated with functional impairment (i.e. insomnia, fatigue, pain [somatic] symptoms and cognition) in depression, even independently of depressive symptoms, warrants evaluation and monitoring. Recommendations for evaluating functional outcomes include: (i) adequately assessing functional impairment; (ii) identifying and/or developing treatment plans that will target symptoms associated with functional impairments; and (iii) monitoring functional impairments and associated symptoms throughout the course of treatment. The development of treatments that specifically target improvements in functional impairments is needed, and may require the use of novel treatment strategies.

Exercise is an efficacious treatment for Major Depressive Disorder (MDD) and has independently been shown to have anti-inflammatory effects in non depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a Selective Serotonin Reuptake Inhibitor (SSRI) were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight (KKW), or 4 KKW for 12 weeks. Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for Interferon-γ (IFN-γ), Interleukin 1-β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α). Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12 week exercise period (p = 0.0023). In addition, a significant positive correlation between change in IL-1β and change in depression symptom scores was observed (p=0.0441). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level. Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1β to positive depression treatment outcomes.

The use of augmentation strategies among patients with major depression is increasing because rates of complete remission with standard antidepressant monotherapy are quite low. Clinical and neurobiological data suggest that exercise may be a good candidate for use as an augmentation treatment for depression. This pilot study examined the use of exercise to augment antidepressant medication in patients with major depression. Seventeen patients with incomplete remission of depressive symptoms began a 12-week exercise program while continuing their antidepressant medication (unchanged in type or dose). Individual exercise prescriptions were calculated based on an exercise dose consistent with currently recommended public health guidelines. The exercise consisted of both supervised and home-based sessions. The 17-item Hamilton Rating Scale for Depression (HRSD17) and the Inventory of Depressive Symptomatology-Self-Report (IDS-SR30) were used to assess symptoms of depression on a weekly basis. Intent-to-treat analyses yielded significant decreases on both the HRSD17 (5.8 points, p < 0.008) and IDS-SR30 (13.9 points, p < 0.002). For patients who completed the study (n = 8), HRSD17 scores decreased by 10.4 points and IDS-SR30 scores decreased by 18.8 points. This study provides preliminary evidence for exercise as an effective augmentation treatment for antidepressant medication. This is a lower-cost augmentation strategy that has numerous health benefits and may further reduce depressive symptoms in partial responders to antidepressant treatment. Practical tips on how practitioners can use exercise to enhance antidepressant treatment are discussed. Longer-term use of exercise is also likely to confer additional health benefits for this population.

ClinicalTrials.gov identifier: NCT02508493.