Search

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. 222 unmedicated adults with MDD randomized to receive sertraline (n=110) or placebo (n=112) in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study completed demographic and clinical assessments, and pre-treatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on Week-8 depression levels (Fs≥9.67,ps≤0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower Week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pre-treatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pre-treatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment. Trial Registration: NCT01407094; http://clinicaltrials.gov/show/NCT01407094

PURPOSE OF REVIEW: To update clinicians on the field of psychoneuroimmunology with respect to depression. RECENT FINDINGS: A significant subset of patients with depression may have illness to which dysfunction of the immune system, typically viewed as inflammation, makes a significant contribution. Normal sickness behavior may sometimes manifest abnormally as mood episodes. Early evidence suggests that interventions that reduce inflammation may improve symptoms in these patients and that they may also respond differently to standard pharmacotherapy. SUMMARY: Treatment of patients with depression should consider inflammatory status, as part of medical and psychiatric health. Recommendations for healthy diet and exercise are important for all patients but may be more important for patients who have clinical evidence of inflammation. Methods of identifying patients in the inflammatory subgroup and treating them with therapy targeted specifically at the immune system are still experimental but likely to impact care for depression in the future.

Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory processes have been implicated in the pathophysiology of depression. It is now well established that dysregulation of both the innate and adaptive immune systems occur in depressed patients and hinder favorable prognosis, including antidepressant responses. In this review, we describe how the immune system regulates mood and the potential causes of the dysregulated inflammatory responses in depressed patients. However, the proportion of never-treated major depressive disorder (MDD) patients who exhibit inflammation remains to be clarified, as the heterogeneity in inflammation findings may stem in part from examining MDD patients with varied interventions. Inflammation is likely a critical disease modifier, promoting susceptibility to depression. Controlling inflammation might provide an overall therapeutic benefit, regardless of whether it is secondary to early life trauma, a more acute stress response, microbiome alterations, a genetic diathesis, or a combination of these and other factors.

Biological Psychiatry, 3 (6), ISSN:0006-3223, ISSN:1873-2402

Background Personality dysfunction represents one of the only predictors of differential response between active treatments for depression to have replicated. We examine whether depressed patients with higher neuroticism scores, a marker of personality dysfunction, show differences compared with depressed patients with lower scores in the functioning of two brain regions associated with treatment response, the anterior cingulate and anterior insula cortices. Methods Functional magnetic resonance imaging data during an emotional Stroop task were collected from 135 adults with major depressive disorder at four academic medical centers participating in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) study. Secondary analyses were conducted including a sample of 28 healthy subjects. Results In whole-brain analyses, higher neuroticism among adults with depression was associated with increased activity in and connectivity with the right anterior insula cortex to incongruent compared with congruent emotional stimuli (all k ≥ 281, all p p Conclusions This study provides convergent evidence for the importance of the right anterior insula cortex as a brain-based marker of clinically meaningful individual differences in neuroticism among adults with depression. This is a critical next step in linking personality dysfunction, a replicated clinical predictor of differential antidepressant treatment response, with differences in underlying brain function.

Objective Because there is overlap between somatic symptoms of depression and symptoms of chronic kidney disease (CKD), it is unclear if self-reported depression rating scales can be used accurately in predialysis CKD patients, especially if CKD and other comorbidities are symptomatic. We assessed the performance of two depression scales — the Beck Depression Inventory (BDI) and the Quick Inventory of Depression Symptomatology (QIDS-SR 16 ) — by CKD stage, diagnosis of diabetes and total medical comorbidity burden — using item response theory (IRT) in a sample of 272 predialysis CKD patients. Methods We performed IRT by low versus high CKD stage, diabetes versus no diabetes and high (>3 diagnoses) versus low medical comorbidity burden. Results IRT models of each rating scale were affected in a limited way by CKD stage, diabetes and medical comorbidity burden. Sleep disturbances on the QIDS-SR 16 were more discriminatory for depression in diabetics and those with high comorbidity burden. Pessimism and guilt from the BDI compared to QIDS-SR 16 were more discriminatory of depression in the high CKD and high comorbidity groups, respectively. Conclusions Overall item differences were modest, and chronic disease severity by CKD stage, diabetes mellitus or other medical comorbidities did not appreciably contribute to differences in scale performance.

Background: The prognostic utility of self-administered depression scales in chronic kidney disease (CKD) independent of a clinician-based major depressive disorder (MDD) diagnosis is neither clearly established nor are the optimal cutoff scores for predicting outcomes. The overlap between symptoms of depression and chronic disease raises the question of whether a cutoff score on a depression scale can be substituted for a time-consuming diagnostic interview to prognosticate risk. Methods: The 16-item Quick Inventory of Depression Symptomatology-Self Report scale (QIDS-SR16) was administered to 266 consecutive outpatients with non-dialysis CKD, followed prospectively for 12 months for an apriori composite outcome of death or dialysis or hospitalization. Association of QIDS-SR16 best cutoff score, determined by receiver/responder operating characteristics curves, with outcomes was investigated using survival analysis. The effect modification of an interview-based clinician MDD diagnosis on this association was ascertained. Results: There were 126 composite events. A QIDS-SR16 cutoff ≥8 had the best prognostic accuracy, hazards ratio (HR) = 1.77, 95% CI 1.24-2.53, p = 0.002. This cutoff remained significantly associated with outcomes even after controlling for comorbidities, estimated glomerular filtration rate, hemoglobin and serum albumin, adjusted HR (aHR) = 1.80, 95% CI 1.23-2.62, p = 0.002, and performed similarly to a clinician-based MDD diagnosis (aHR = 1.72, 95% CI 1.14-2.68). Adjustment for MDD conferred the association of QIDS-SR16 with outcomes no longer significant. Conclusions: QIDS-SR16 cutoff ≥8 adds to the prognostic information available to practicing nephrologists during routine clinic visits from comorbidities and laboratory data. This cutoff score performs similar to a clinician diagnosis of MDD and provides a feasible and time-saving alternative to an interview-based MDD diagnosis for determining prognosis in CKD patients.

Activation of the kynurenine pathway (KP), an important downstream effect of inflammation, is a driver of depression and neurodegeneration. Damage from the end product of KP activation, quinolinic acid, may be responsible specifically for impairment in hippocampally mediated memory function, among its effects. We hypothesized that associative memory – the ability to recall relationships between items – would be sensitive to KP activation because it is heavily dependent on the hippocampus. We tested a sample of N ​= ​80 adults with unmedicated depression using a face-name task which assesses the ability to recognize, as well as to recall correct pairings, of faces and names. Plasma samples were analyzed for KP metabolites – tryptophan (TRP), kynurenine (KYN), quinolinic acid (QUIN) and kynurenic acid (KYNA). Using linear models we examined whether the KYN/TRP and QUIN/KYNA ratios predicted performance of recognition memory and associative memory, accounting for item type and the number of learning exposures to items (1 vs. 3). We found that for rearranged items viewed three times, associative memory performance was inversely related to the QUIN/KYNA ratio (p ​= ​0.01, p ​= ​0.001 adjusted for age, gender and race/ethnicity). Recognition memory was not associated with KP activation. The results support our hypothesis that KP activation most sensitively impacts hippocampally mediated memory function., Highlights • Systemic inflammation is associated with activation of the kynurenine pathway in depressed adults. • Kynurenine pathway activation predicts impaired performance of associative memory in a face-name task. • Recognition memory is, however, was not affected by kynurenine pathway activation.

To further the identification and treatment of patients with mood disorders having an immune component, we must identify the specific nature of immune processes associated with mood. We analyzed peripheral blood RNA sequencing data from the Depression Genes and Networks (DGN) Study using Weighted Gene Co-expression Network Analysis (WGCNA) from 441 adult subjects with a past or current diagnosis of Major Depressive Disorder. After filtering, 5778 genes were clustered in 19 modules. Overall, modules had weak clinical correlation; one module containing 63 genes showed the best correlation with scores on the 9-item Public–Health Questionnaire (PHQ-9) (r = 0.1, p = 0.03). This module was significantly enriched for the Gene Ontology Biological Process Type I Interferon Signaling (adjusted p? 0.001) and other pathways of anti-viral immunity. This module significantly overlapped with a module of 74 genes derived from 325 subjects from the DGN healthy control sample; it did not correlate significantly with any clinical trait in those subjects. One module of 52 genes from the depressed sample, containing primarily immunoglobulin chain genes, had no corresponding module in the healthy sample. This module, however, did not correlate significantly with any clinical trait. These findings replicate the previously published association of Interferon pathways with depression in this sample. Replication in an independent sample is necessary to validate the role of antiviral immunity in depression.

In the last decade, many studies have used automated processes to analyze magnetic resonance imaging (MRI) data such as cortical thickness, which is one indicator of neuronal health. Due to the convenience of image processing software (e.g., FreeSurfer), standard practice is to rely on automated results without performing visual inspection of intermediate processing. In this work, structural MRIs of 40 healthy controls who were scanned twice were used to determine the test-retest reliability of FreeSurfer-derived cortical measures in four groups of subjects-those 25 that passed visual inspection (approved), those 15 that failed visual inspection (disapproved), a combined group, and a subset of 10 subjects (Travel) whose test and retest scans occurred at different sites. Test-retest correlation (TRC), intraclass correlation coefficient (ICC), and percent difference (PD) were used to measure the reliability in the Destrieux and Desikan-Killiany (DK) atlases. In the approved subjects, reliability of cortical thickness/surface area/volume (DK atlas only) were: TRC (0.82/0.88/0.88), ICC (0.81/0.87/0.88), PD (0.86/1.19/1.39), which represent a significant improvement over these measures when disapproved subjects are included. Travel subjects' results show that cortical thickness reliability is more sensitive to site differences than the cortical surface area and volume. To determine the effect of visual inspection on sample size required for studies of MRI-derived cortical thickness, the number of subjects required to show group differences was calculated. Significant differences observed across imaging sites, between visually approved/disapproved subjects, and across regions with different sizes suggest that these measures should be used with caution.

To determine whether depressed or anxious patients experience greater affective change than mentally healthy individuals following influenza vaccination.Participants (n=112) completed the Positive and Negative Affect Schedule (PANAS) before influenza vaccination and 1-2days post-vaccination (M=32.3h). Pre- and post-vaccination PANAS scores were compared using two-tailed, paired-samples t-tests. Change in positive affect between participants with depression or anxiety and those without was compared using two-way ANOVA. Follow up positive affect was further examined using multiple linear regression.Positive affect decreased following vaccination (M=2.18, 95% CI [1.07, 3.29], t(111)=3.89, p0.001) for all participants and was more pronounced for those with anxiety or depression (F(1, 110)=7.51, p=0.009). Similarly, predicted follow up affect score was higher for those without a mental health conditions (β=3.67, 95% CI [1.18, 6.16], t(103)=2.92, p=0.004).These data suggest that influenza vaccine has a greater effect on affect in patients with depression and anxiety than in mentally healthy individuals. This effect was focused on positive affect, suggesting that influenza vaccine induced inflammation may be best suited to examine alterations in positive affect and positive valence systems.

Background Non-adherence to antidepressant treatment is not routinely measured in practical clinical trials. It has not been related to outcomes in a large sample of adults with chronic and/or recurrent major depressive disorder (MDD) or any sample treated with antidepressant combinations. Methods Adult outpatients with chronic and/or recurrent MDD were randomized to 12 weeks of treatment with bupropion-SR plus escitalopram, venlafaxine-XR plus mirtazapine, or escitalopram plus placebo. We compared non-adherence (the frequency with which daily medications were not taken) and specifically the frequency of temporarily stopping and/or skipping medication, or reducing or increasing the dose across treatments in 567 participants using a self-report questionnaire collected at each visit. We tested the association between non-adherence, and both treatment type and outcomes. Results A non-adherence rate under 10% was reported by 77.9%, 70.9%, and 71.6% of participants during weeks 1-4, 5-12, and 1-12, respectively. Antidepressant combinations were associated with a higher non-adherence rate than monotherapy during weeks 1-4 and 1-12. During weeks 1-4, 24.1% stopped/skipped doses and 6.1% reduced the dose. During weeks 5-12, 34.7% stopped/skipped doses and 9.4% reduced the dose. Across 12 weeks, 43.2% stopped/skipped doses, and 12.9% reduced the dose. Stopping/skipping doses during all time frames and dose decreases during weeks 1-12 occurred most frequently with combination treatments. Non-adherence was unrelated to symptom remission, response, or symptom change. Conclusions With closely monitored treatment, non-adherence is low and unrelated to depressive symptom outcome. Nonadherence is highest with antidepressant combinations. Specific non-adherent events are most often sporadic.

OBJECTIVE Obesity and major depressive disorder often co-occur. However, differences between obese and normal-weight depressed patients and the moderating effect of obesity on antidepressant treatment outcome are not well studied. METHODS Adults (n = 662) with major depressive disorder in the Combining Medications to Enhance Depression Outcomes study were randomized to treatment with escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine for a 12-week primary treatment phase and 16-week follow-up. Body mass index (BMI) was calculated at baseline and categorized according to World Health Organization criteria: normal or low weight (NW), overweight, Obese I and Obese II+. A repeated-effects model, unadjusted and adjusted for baseline variables, assessed outcomes. RESULTS Obesity was common (46.2%), only 25.5% were NW. Higher BMI was associated with greater medical illness (p < .001), social phobia (p = .003), and bulimia (p = .026). Lower BMI was associated with more frequent post-traumatic stress disorder (p = .002) and drug abuse (p < .001). Treatment outcomes did not differ including Week 12 remission rates (NW 36%, overweight 40%, Obese I 43%, Obese II+ 37%; p = .69). Lower BMI was associated with more frequent (p = .024 [unadjusted] and .053 [adjusted]) and more severe (p = .008 [unadjusted] and .053 [adjusted]) adverse effects. CONCLUSIONS BMI was related to clinical presentation and prevalence of comorbidities, but not antidepressant outcomes. Lower BMI classes had more psychiatric comorbidities, potentially obscuring the relationship between BMI and antidepressant effects. Trial Registration ClinicalTrials.gov identifier: NCT00590863.

Menopausal status and use of hormonal contraception or menopausal hormone therapy (HT) may affect treatment response to selective serotonin reuptake inhibitors (SSRIs). This report evaluates whether menopausal status and use of hormonal contraceptives or menopausal HT affect outcome in women treated with citalopram.In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 896 premenopausal and 544 postmenopausal women were treated with citalopram for 12-14 weeks. Baseline demographic and clinical characteristics were used in adjusted analysis of the effect of menopausal status and use of hormonal contraceptives or menopausal HT on outcomes. Remission was defined as final Hamilton Rating Scale for Depression-17 (HRSD(17)) ≤7 or Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR(16)) score ≤5 and response as ≥50% decrease from the baseline QIDS-SR(16) score.Premenopausal and postmenopausal women differed in multiple clinical and demographic baseline variables but did not differ in response or remission rates. Premenopausal women taking hormonal contraceptives had significantly greater unadjusted remission rates on the HRSD(17) and the QIDS-SR(16) than women not taking contraception. Response and remission rates were not different between postmenopausal women taking vs. not taking HT. Adjusted results showed no significant difference in any outcome measure across menopause status in women who were not taking contraception/HT. There were no significant differences in adjusted results across HT status in premenopausal or postmenopausal women.In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome.

Introduction Measurement of symptoms domains and their response to treatment in relative isolation from diagnosed mental disorders has gained new urgency, as reflected by the National Institute of Mental Health's introduction of the Research Domain Criteria (RDoC). The Snaith Hamilton Pleasure Scale (SHAPS) and the Motivation and Energy Inventory (MEI) are two scales measuring positive valence symptoms. We evaluated the effect of exercise on positive valence symptoms of Major Depressive Disorder (MDD). Methods Subjects in the Treatment with Exercise Augmentation for Depression (TREAD) study completed self-reported SHAPS and MEI during 12 weeks of exercise augmentation for depression. We evaluated the effect of exercise on SHAPS and MEI scores, and whether the changes were related to overall MDD severity measured with the Quick Inventory of Depression Symptomatology (QIDS). Results SHAPS and MEI scores significantly improved with exercise. MEI score change had larger effect size and greater correlation with change in QIDS score. MEI also showed significant moderator and mediator effects of exercise in MDD. Limitations Generalizability to other treatments is limited. This study lacked other bio-behavioral markers that would enhance understanding of the relationship of RDoC and the measures used. Conclusions Positive valence symptoms improve with exercise treatment for depression, and this change correlates well with overall outcome. Motivation and energy may be more clinically relevant to outcome of exercise treatment than anhedonia.

This study aimed to determine if current comorbid psychiatric disorders differ in adults with cocaine use disorder, other stimulant (primarily methamphetamine) use disorder, or both, and identify demographic and clinical characteristics in those with increasing numbers of comorbid disorders. Baseline data from a randomized controlled trial beginning in residential settings (N=302) was used. Mood disorders were present in 33.6%, and anxiety disorders in 29.6%, with no differences among stimulant use disorder groups. Panic disorder was more frequently present with other stimulant use disorder. Those with two or more comorbid psychiatric disorders were more often female, White, had more symptoms of depression, greater propensity and risk for suicidal behavior, lower functioning in psychiatric and family domains, lower quality of life, more symptoms with stimulant abstinence and greater likelihood of marijuana dependence. Those with one or more comorbid disorders had more medical disorder burden, lower cognitive and physical functioning, greater pain, and higher rates of other drug dependence. With current comorbid psychiatric disorders, the morbidity of stimulant use disorders increases. Use of validated assessments near treatment entry, and a treatment plan targeting not only substance use and comorbid psychiatric disorders, but functional impairments, medical disorder burden and pain, may be useful.

Remission rates for Major Depressive Disorder (MDD) are low and unpredictable for any given antidepressant. No biological or clinical marker has demonstrated sufficient ability to match individuals to efficacious treatment. Biosignatures developed from the systematic exploration of multiple biological markers, which optimize treatment selection for individuals (moderators) and provide early indication of ultimate treatment response (mediators) are needed. The rationale and design of a multi-site, placebo-controlled randomized clinical trial of sertraline examining moderators and mediators of treatment response is described. The target sample is 300 participants with early onset (≤30 years) recurrent MDD. Non-responders to an 8-week trial are switched double blind to either bupropion (for sertraline non-responders) or sertraline (for placebo non-responders) for an additional 8 weeks. Clinical moderators include anxious depression, early trauma, gender, melancholic and atypical depression, anger attacks, Axis II disorder, hypersomnia/fatigue, and chronicity of depression. Biological moderator and mediators include cerebral cortical thickness, task-based fMRI (reward and emotion conflict), resting connectivity, diffusion tensor imaging (DTI), arterial spin labeling (ASL), electroencephalograpy (EEG), cortical evoked potentials, and behavioral/cognitive tasks evaluated at baseline and week 1, except DTI, assessed only at baseline. The study is designed to standardize assessment of biomarkers across multiple sites as well as institute replicable quality control methods, and to use advanced data analytic methods to integrate these markers. A Differential Depression Treatment Response Index (DTRI) will be developed. The data, including biological samples (DNA, RNA, and plasma collected before and during treatment), will become available in a public scientific repository. Clinical trial registration Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC). Identifier: NCT01407094. URL: http://clinicaltrials.gov/show/NCT01407094.

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.

Major depressive disorder is one of the leading causes of disability in the world. Effective treatment guidelines have been developed and disseminated; however, unlike other fields of medicine, psychiatry has been slow to adapt and utilize these empirically validated treatment strategies. Measurement-based care (MBC) provides a simple way to use the established clinical treatment guidelines to provide optimal personalized evidence-based medical care. MBC is simple and easy to implement. At the core of MBC is the longitudinal measurement of symptom severity, adherence to treatment, medication tolerability, and patient safety. For a variety of reasons, published antidepressant treatment guidelines have not been adopted by most prescribing physicians. MBC offers a solution to many of the concerns that have led to the lack of integration of evidence-based clinical practice guidelines into standard care. MBC offers physicians the opportunity to provide optimal personalized evidence-based medical care to patien...

Major depressive disorder (MDD) and metabolic syndrome (MetS) are both widespread and cause enormous morbidity. The presence of one syndrome approximately doubles the risk of the other. Standard antidepressant treatments lead to remission in less than a third of the patients; a majority of patients experience treatment resistance at some point during their illness.

The prediction of treatment response in many neuropsychiatric disorders would be facilitated by easily accessible biomarkers. Using flow cytometry, we herein demonstrate correlations between early reductions of p11 levels in Natural Killer (NK) cells and monocytes and antidepressant response to citalopram in patients with major depressive disorder (MDD).

861 Background: Previous studies have demonstrated that KRAS mutations were associated with higher rates of depression in patients with metastatic colorectal cancer (CRC). The objective of this study was to evaluate the feasibility of extracting EMR data to examine the association between KRAS mutations and positive screening test for depression in CRC patients. Methods: Retrospective review of stage I to IV CRC patients seen between 2011 and 2015 at an academic, NCI-Designated Comprehensive Cancer Center was performed. At each clinic visit, depression was assessed using the Patient Health Questionnaire-2 (PHQ-2), which is part of the institution’s universal Distress Screening tool. PHQ-2 score of 2 and above was considered positive screening test for depression. PHQ-2 and KRAS mutation data were extracted from the EMR via the Clinical Data Exchange Network bioinformatics tool and confirmed by retrospective chart review. Chi-square test was used to assess the association between KRAS mutation and depression. Multiple imputation was used to impute the missing values. Results: Of the 484 CRC patients, KRAS status was known in 45 cases: 22 (49%) were KRAS mutated and 23 (51%) were KRAS wild type. PHQ-2 score was 0 in 42 cases (93.3%), 1 in 2 cases (4.4%), and ≥2 in 1 case (2.3%). The rate of positive PHQ-2 for KRAS mutated vs wild type was 4% vs 0% (p = 0.36). The result based on 50 imputed datasets suggests a trend towards an association between KRAS mutation and depression (p = 0.09). Conclusions: This study did not demonstrate an association between KRAS mutation and depression in patients with colorectal cancer, probably due to a high proportion of missing data. Bioinformatics studies that extract and analyze EMR data are a feasible and effective platform to assess the association of genomic data with clinical outcomes. Additional validated algorithms and data are needed to further optimize such studies.

Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error- (discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures.A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals.Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms.The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures of treatment response.

BACKGROUND: Major depressive disorder (MDD) is a debilitating disorder characterized by widespread brain abnormalities. The literature is mixed as to whether or not white matter abnormalities are associated with MDD. This study sought to examine fractional anisotropy (FA) in white matter tracts in individuals with MDD using diffusion tensor imaging (DTI). METHODS: 139 participants with MDD and 39 healthy controls (HC) in a multisite study were included. DTI scans were acquired in 64 directions and FA was determined in the brain using four methods: region of interest (ROI), tract-based spatial statistics (TBSS), and diffusion tractography. Diffusion connectometry was used to identify white matter pathways associated with MDD. RESULTS: There were no significant differences when comparing FA in MDD and HC groups using any method. In the MDD group, there was a significant relationship between depression severity and FA in the right medial orbitofrontal cortex, and between age of onset of MDD and FA in the right caudal anterior cingulate cortex using the ROI method. There was a significant relationship between age of onset and connectivity in the thalamocortical radiation, inferior longitudinal fasciculus, and cerebellar tracts using diffusion connectometry. CONCLUSIONS: The lack of group differences in FA and connectometry analysis may result from the clinically heterogenous nature of MDD. However, the relationship between FA and depression severity may suggest a state biomarker of depression that should be investigated as a potential indicator of response. Age of onset may also be a significant clinical feature to pursue when studying white matter tracts. Language: en

BackgroundDepression is characterized by poor executive function, but – counterintuitively – in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study.MethodOne hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials).ResultsConsistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = −0.28, p = 0.007).ConclusionsExecutive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression.

Importance Major depressive disorder (MDD) is prevalent among patients with chronic kidney disease (CKD) and is associated with morbidity and mortality. The efficacy and adverse events of selective serotonin reuptake inhibitors in these patients are unknown. Objective To determine whether treatment with sertraline improves depressive symptoms in patients with CKD and MDD. Design, Setting, and Participants The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) was a randomized, double-blind, placebo-controlled trial involving 201 patients with stage 3, 4, or 5 non–dialysis-dependent CKD, who were enrolled at 3 US medical centers. The Mini Neuropsychiatric Interview was used to establish MDD. The first participant was randomized in March 2010 and the last clinic visit occurred in November 2016. Interventions After a 1-week placebo run-in, participants were randomized to sertraline (n = 102) for 12 weeks at an initial dose of 50 mg/d (escalated to a maximum dose of 200 mg/d based on tolerability and response) or matching placebo (n = 99). Main Outcomes and Measures The primary outcome was improvement in depressive symptom severity from baseline to 12 weeks determined by the 16-item Quick Inventory of Depression Symptomatology–Clinician Rated (QIDS-C 16 ) (score range, 0-27; minimal clinically important difference, 2 points). Secondary outcomes included improvement in quality of life (Kidney Disease Quality of Life Survey–Short Form; score range, 0-100; higher scores indicate more favorable quality of life) and adverse events. Results There were 201 patients (mean [SD] age, 58.2 [13.2] years; 27% female) randomized. The primary analysis included 193 patients who had at least 1 outcome assessment after randomization. The mean (SD) baseline QIDS-C 16 score was 14.0 (2.4) in the sertraline group (n = 97) and 14.1 (2.4) in the placebo group (n = 96). The median participation time was 12.0 weeks and the median achieved dose was 150 mg/d, which was not significantly different between the groups. The QIDS-C 16 score changed by −4.1 in the sertraline group and by −4.2 in the placebo group (between-group difference, 0.1 [95% CI, −1.1 to 1.3]; P = .82). There was no significant between-group difference in change in patient-reported overall health on the Kidney Disease Quality of Life Survey (median score, 0 in the sertraline group vs 0 in the placebo group; between-group difference, 0 [95% CI, −10.0 to 0]; P = .61). Nausea or vomiting occurred more frequently in the sertraline vs placebo group (22.7% vs 10.4%, respectively; between-group difference, 12.3% [95% CI, 1.9% to 22.6%], P = .03), as well as diarrhea (13.4% vs 3.1%; between-group difference, 10.3% [95% CI, 2.7% to 17.9%], P = .02). Conclusions and Relevance Among patients with non–dialysis-dependent CKD and MDD, treatment with sertraline compared with placebo for 12 weeks did not significantly improve depressive symptoms. These findings do not support the use of sertraline to treat MDD in patients with non–dialysis-dependent CKD. Trial Registration clinicaltrials.gov Identifier:NCT00946998

114 Background: Previous studies have demonstrated a higher rate of depression in cancer patients harboring KRAS mutations. We evaluated the feasibility of using secondary Electronic Medical Record (EMR) data to examine the association of KRAS mutations with depression in NSCLC patients. Methods: We identified cases with NSCLC from an institutional Cancer Registry. Tumor molecular profiles were obtained as standard of care. Depression was assessed using the Patient Health Questionnaire-2 (PHQ-2), which is part of the institution’s universal Distress Screening tool completed at the time of clinic visit. PHQ-2 score of 2 and above was considered positive for depression. Data was extracted from EMR via Clinical Data Exchange Network bioinformatics tool and confirmed by chart review. Results: Of the 692 NSCLC patients, KRAS status was known in 174 cases: 40 (23%) were KRAS mutated and 134 (77%) were KRAS wild type. 101 (58%) had stage 4 NSCLC. PHQ-2 score was 0 in 146 (83.9%), 1 in 7 (4%), 2 in 19 (10.9%), and > 2 in 2 (1.1%). The rate of positive PHQ-2 for KRAS mutated vs wild type was 15% vs 11% (p = NS). Conclusions: This study in patients with NSCLC did not demonstrate an association between KRAS mutation and depression. Bioinformatics studies harnessing EMR data are a feasible platform to assess the association of genomic data with clinical outcomes and validated algorithms are needed.

Sickness behavior is a universal response to inflammation, including neurovegetative and affect components. Based on the theory that depression is physiologically related to sickness, we hypothesized that patients with depression and anxiety should have a more pronounced change in affect after receiving a mild immune stimulus. We assessed 112 adults before and after (mean 32.3 h) receiving inactivated influenza vaccine, collecting a brief mental and physical health history, mood state on the Positive and Negative Affect Schedule (PANAS), and two measures of interoceptive sensitivity: the Body Awareness Questionnaire (BAQ), and the Body Vigilance Scale (BVS). Pre- and post-vaccination PANAS scores were compared using two-tailed, paired-samples t-tests. Change in positive affect (PA) between participants with and without depression and/or anxiety was compared using two-way ANOVA. A multiple linear regression model assessed whether clinical or demographic factors affected change in affect. PA decreased following vaccination (p

In the last decade, many studies have used automated processes to analyze magnetic resonance imaging (MRI) data such as cortical thickness, which is one indicator of neuronal health. Due to the convenience of image processing software (e.g., FreeSurfer), standard practice is to rely on automated results without performing visual inspection of intermediate processing. In this work, structural MRIs of 40 healthy controls who were scanned twice were used to determine the test–retest reliability of FreeSurfer-derived cortical measures in four groups of subjects—those 25 that passed visual inspection (approved), those 15 that failed visual inspection (disapproved), a combined group, and a subset of 10 subjects (Travel) whose test and retest scans occurred at different sites. Test–retest correlation (TRC), intraclass correlation coefficient (ICC), and percent difference (PD) were used to measure the reliability in the Destrieux and Desikan–Killiany (DK) atlases. In the approved subjects, reliability of cortical thickness/surface area/volume (DK atlas only) were: TRC (0.82/0.88/0.88), ICC (0.81/0.87/0.88), PD (0.86/1.19/1.39), which represent a significant improvement over these measures when disapproved subjects are included. Travel subjects’ results show that cortical thickness reliability is more sensitive to site differences than the cortical surface area and volume. To determine the effect of visual inspection on sample size required for studies of MRI-derived cortical thickness, the number of subjects required to show group differences was calculated. Significant differences observed across imaging sites, between visually approved/disapproved subjects, and across regions with different sizes suggest that these measures should be used with caution.

Background Brain Derived Neurotrophic Factor (BDNF) has potential as a biomarker of depression treatment because serum BDNF in depressed human subjects is decreased and normalizes with treatment. The relationship between serum BDNF and exercise treatment of depression is not known. The Treatment with Exercise Augmentation for Depression (TREAD) study examined dosed exercise augmentation treatment of partial responders to antidepressants. Serum BDNF in TREAD subjects was analyzed to understand its relationship with exercise training. Methods Subjects were randomized to high (16 kcal/kg/week or KKW) or low (4 KKW) energy expenditure exercise over 12 weeks. Actual kcal/week expended and IDS-C scores were collected weekly. One hundred four subjects in TREAD provided baseline blood samples; a subset of 70 subjects also provided week 12 samples. Serum BDNF was determined using ELISA. Correlations were examined between change in BDNF and 1) mean kcal/week expended, and 2) change in IDS-C score. Mixed-effects ANOVA examined the effect of baseline BDNF on outcome. Results Resting serum BDNF was stable and did not correlate with energy expenditure (p = 0.15) or IDS-C improvement (p = 0.89). Subjects entering the study with higher BDNF improved more rapidly on the IDS-C (p = 0.003). Limitations Serum may not be the most sensitive blood fraction in which to measure BDNF change. Pre-treatment with medication may mask exercise effect on BDNF. Conclusions These results suggest that change in serum BDNF does not reflect efficacy of exercise augmentation treatment of MDD. Instead BDNF may function as an augmentation moderator. Pre-treatments that raise BDNF may improve the efficacy of exercise treatment of MDD.

Evidence suggests that inflammation may characterize a biologically distinct subgroup of patients with Major Depressive Disorder (MDD) and comorbid medical illness. In Chronic Kidney Disease (CKD) depression is common and increases morbidity and mortality. We examined baseline immune function in 27 adults with non-dialysis, stage 3–5 CKD and MDD, enrolled in the CKD Antidepressant Sertraline Trial (CAST), using RNA Sequencing of whole blood. Subjects completed the Quick Inventory of Depression Symptomatology (QIDS) to quantify depression severity. We analyzed co-expression of hyper-variable genes, performing hierarchical cluster analysis according to correlation with QIDS score. Subjects empirically divided into two clusters: (1) 18 subjects in whom depression severity inversely correlated with expression of interferon signaling genes (correlation coefficient 0.95), and (2) 9 subjects without correlation to the interferon cluster but whose depression was significantly correlated with ribosomal gene expression (cc = 0.83) (both p 0.001). Using a significance threshold of p 0.001, we analyzed genes within each group for correlation with clinical parameters. In group 2, STAT3 pathway expression was associated with fatigue and expression of interferon and insulin like growth factor signaling genes were correlated with mental and physical function, respectively. Our results suggest the existence of different depression immune phenotypes; further exploration of these types will provide an opportunity to develop personalized depression treatment in patients with comorbid depression and CKD.

Given the role of sleep in the development and treatment of major depressive disorder (MDD), it is becoming increasingly clear that elucidation of the biological mechanisms underlying sleep disturbances in MDD is crucial to improve treatment outcomes. Sleep disturbances are varied and can present as insomnia and/or hypersomnia. Though research has examined the biological underpinnings of insomnia in MDD, little is known about the role of biomarkers in hypersomnia associated with MDD. This paper examines biomarkers associated with changes in hypersomnia and insomnia and as predictors of improvements in sleep quality following exercise augmentation in persons with MDD. Subjects with non-remitted MDD were randomized to augmentation with one of two doses of aerobic exercise: 16 kilocalories per kilogram of body weight per week (KKW) or 4 KKW for 12 weeks. The four sleep-related items on the clinician-rated Inventory of Depressive Symptomatology (sleep onset insomnia, mid-nocturnal insomnia, early morning insomnia and hypersomnia) assessed self-reported sleep quality. Inflammatory cytokines (tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6) and brain-derived neurotrophic factor (BDNF) were assessed in blood samples collected before and following the 12-week intervention. Reduction in hypersomnia was correlated with reductions in BDNF (ρ=0.26, P=0.029) and IL-1β (ρ=0.37, P=0.002). Changes in these biomarkers were not associated with changes in insomnia; however, lower baseline levels of IL-1β were predictive of greater improvements in insomnia (F=3.87, P=0.050). In conclusion, improvement in hypersomnia is related to reductions in inflammatory markers and BDNF in persons with non-remitted MDD. Distinct biological mechanisms may explain reductions in insomnia.

Longitudinal investigation of the neural correlates of reward processing in depression may represent an important step in defining effective biomarkers for antidepressant treatment outcome prediction, but the reliability of reward-related activation is not well understood. Thirty-seven healthy control participants were scanned using fMRI while performing a reward-related guessing task on two occasions, approximately one week apart. Two main contrasts were examined: right ventral striatum (VS) activation fMRI BOLD signal related to signed prediction errors (PE) and reward expectancy (RE). We also examined bilateral visual cortex activation coupled to outcome anticipation. Significant VS PE-related activity was observed at the first testing session, but at the second testing session, VS PE-related activation was significantly reduced. Conversely, significant VS RE-related activity was observed at time 2 but not time 1. Increases in VS RE-related activity from time 1 to time 2 were significantly associated with decreases in VS PE-related activity from time 1 to time 2 across participants. Intraclass correlations (ICCs) in VS were very low. By contrast, visual cortex activation had much larger ICCs, particularly in individuals with high quality data. Dynamic changes in brain activation are widely predicted, and failure to account for these changes could lead to inaccurate evaluations of the reliability of functional MRI signals. Conventional measures of reliability cannot distinguish between changes specified by algorithmic models of neural function and noisy signal. Here, we provide evidence for the former possibility: reward-related VS activations follow the pattern predicted by temporal difference models of reward learning but have low ICCs.

Gene delivery of CD40 Ligand (CD40L) has shown promise in murine models of melanoma and adenocarcinoma; however, its potential for thoracic malignancies such as malignant mesothelioma remains unclear. In this study, we investigated the hypothesis that CD40L gene therapy would be effective in local and distant tumor suppression in mesothelioma using an immunocompetent murine model. Using a recombinant adenovirus encoding murine CD40L (AdCD40L), we demonstrated no suppression of in vitro cell growth for the AC29 (mesothelioma) cell line. However, inoculation of immunocompetent CBA/J mice with AC29 cells treated ex vivo with AdCD40L resulted in significant suppression of tumor formation in vivo when compared with controls (P0.001). Intratumoral inoculation of AdCD40L into previously established AC29 tumors yielded similar antitumor results and was associated with increased recruitment of intratumoral CD8+ T cells. Adoptive transfer of CD8+ T cells from AdCD40L-treated tumor bearing mice conferred protection to naive mice given an AC29 tumor challenge. Finally, in mice with two synchronous tumors, treatment of one of the tumors with AdCD40L resulted in a regression of both tumors. These findings demonstrate the development of tumor specific CD8+ T cells by AdCD40L and support the further development of AdCD40L for the treatment of malignant mesothelioma.