Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals.

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. A total of 222 unmedicated adults with MDD randomized to receive sertraline (n = 110) or placebo (n = 112) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study completed demographic and clinical assessments, and pretreatment 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 (HSRD) 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 pretreatment 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. Pretreatment 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.

A COMPREHENSIVE EXAMINATION OF WHITE MATTER TRACTS AND CONNECTOMETRY IN MAJOR DEPRESSIVE DISORDER.

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.

Relationship between obesity and depression: characteristics and treatment outcomes with antidepressant medication.

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.

Kynurenine pathway metabolites selectively associate with impaired associative memory function in depression.

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 â€‹= â€‹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 â€‹= â€‹0.01, p â€‹= â€‹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.

Pilot investigation into the sickness response to influenza vaccination in adults: Effect of depression and anxiety.

OBJECTIVE: To determine whether depressed or anxious patients experience greater affective change than mentally healthy individuals following influenza vaccination. METHODS: 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. RESULTS: Positive affect decreased following vaccination (M=2.18, 95% CI [1.07, 3.29], t(111)=3.89, p<0.001) 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 (ß=3.67, 95% CI [1.18, 6.16], t(103)=2.92, p=0.004). CONCLUSIONS: 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.

Effects of serum Brain Derived Neurotrophic Factor on exercise augmentation treatment of depression.

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.