A Randomized Controlled Trial of Community-Delivered Heated Hatha Yoga for Moderate-to-Severe Depression.

Objective: To evaluate feasibility, acceptability, and preliminary efficacy of heated yoga to treat moderate-to-severe depression.Design: An 8-week randomized controlled trial (RCT) of heated yoga versus waitlist control was conducted from March 2017 to August 2019.Methods: Participants in the yoga condition were asked to attend heated yoga classes at 2 community heated yoga studios at least twice weekly. We assessed acceptability and feasibility using exit interview and attendance data, respectively. The primary intervention efficacy outcome variable was change in the Inventory of Depressive Symptomatology-Clinician Rated (IDS-CR) score from baseline to post-intervention (week 8).Results: We randomized 80 participants and included 65 (mean [± SD] age 32.7 [± 11.7] years; 81.5% female) in the analyses (yoga n = 33, waitlist n = 32). The mean IDS-CR score at baseline was 35.6 (± 7.9) for the full sample, 36.9 (± 8.8) for yoga participants, and 34.4 (± 6.7) for waitlist participants. Participants attended an average of 10.3 (± 7.1) total classes over the 8-week intervention period. Yoga participants had a significantly greater pre- to post-intervention reduction in IDS-CR scores than waitlist participants (Cohen d = 1.04, P < .001). More yoga participants (59.3%; n = 16) than waitlist participants (6.3%; n = 2) evidenced larger treatment responses (IDS-CR ≥ 50% decrease in symptoms). Participants rated the heated yoga and its aftereffects positively in exit interviews.Conclusions: Approximately 1 heated yoga session per week (mean of 10.3 classes over 8 weeks) was associated with significantly greater reduction in depression symptoms than a waitlist control. Participants rated heated yoga positively. Taken together, results suggest feasibility, acceptability, and preliminary efficacy for patients with depression and warrant further research using active control conditions.Trial Registration: ClinicalTrials.gov identifier: NCT02607514.

Individuals with depression exhibiting a pro-inflammatory phenotype receiving omega-3 polyunsaturated fatty acids experience improved motivation-related cognitive function: Preliminary results from a randomized controlled trial.

Cognitive impairment related to major depressive disorder (MDD) is highly prevalent, debilitating and is lacking in effective treatments; dysregulated inflammatory physiology is a putative mechanism and may represent a therapeutic target. In depressed individuals exhibiting a pro-inflammatory phenotype who were enrolled in a 12-week randomized placebo-controlled trial of 3 doses of omega-3 polyunsaturated fatty acids (ω-3-FA), we examined: (i) the relationship between dysregulated inflammatory physiology and baseline cognitive impairment; (ii) improvement in cognitive impairment following treatment; and (iii) the association between baseline inflammatory biomarkers and change in cognitive impairment for those receiving treatment. We randomized 61 unmedicated adults aged 45.50 years (75% female) with DSM-5 MDD, body mass index >25 kg/m2, and C-reactive protein (CRP) ≥3.0 mg/L to three doses of ω-3-FA (1, 2, or 4 g daily) or matching placebo. Analyses focused on 45 study completers who had inflammatory biomarkers assessed [circulating CRP, interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) as well as lipopolysaccharide (LPS)-stimulated concentrations of IL-6 and TNFα in peripheral blood mononuclear cells (PBMC)] and on the highest dose ω-3-FA (4 g daily; n = 11) compared to placebo (n = 10). Impairment in motivational symptoms (e.g., alertness, energy, enthusiasm) and higher-order cognitive functions (e.g., word-finding, memory) were assessed by a validated self-report measure. Among all 45 participants at baseline, lower concentrations of IL-6 in LPS-stimulated PBMC were associated with greater impairment in higher-order cognitive functions (r = -0.35, p = .02). Based on hierarchical linear modeling, individuals receiving 4 g/day of ω-3-FA reported significant improvement in motivational symptoms compared to placebo (B = -0.07, p = .03); in the 4 g/day group, lower baseline concentrations of TNFα in LPS-stimulated PBMC were associated with significant improvement in motivational symptoms (Ρ = .71, p = .02) following treatment. In this exploratory clinical trial, daily supplementation with 4 g of ω-3-FA improves motivational symptoms in depressed individuals exhibiting an inflammatory phenotype.

Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators.

Chronic inflammation has been implicated in the pathophysiology of major depressive disorder (MDD). Activating the resolution of inflammation through ω-3 fatty acid supplementation may prove to be a successful therapeutic strategy for the treatment of MDD. Patients with MDD, body mass index >25 kg/m2, and plasma high-sensitivity C-reactive protein ≥3 µg/mL (n = 61) were enrolled in a 12-week randomized trial consisting of 4 parallel arms: EPA 1, 2, and 4 g/d, and placebo. The supplement contained EPA and DHA in a 3.9:1 ratio. Depression symptoms were assessed using the IDS-C30 scale. Plasma fatty acids and pro-resolving lipid mediators (SPMs) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. The response rate (≥50% reduction in IDS-30 score) was higher in the 4 g/d EPA arm than placebo (Cohen d = 0.53). In the 4 g/d EPA arm, responders had significantly greater increases in 18-hydroxyeicosapentaenoic acid (18-HEPE) and 13-hydroxydocosahexaenoic acid (13-HDHA) than non-responders (p < 0.05). Within the 4 g/d EPA arm, the increase in 18-HEPE was significantly associated with reductions in plasma hs-CRP concentrations (p < 0.05) and IDS-C30 scores (p < 0.01). In summary, response rates were greater among patients with MDD randomized to EPA 4 g/d supplementation and in those who showed a greater ability to activate the synthesis of 18-HEPE. The inverse association of 18-HEPE with both systemic inflammation and symptoms of depression highlights the activation of the resolution of inflammation as a likely mechanism in the treatment of MDD with ω-3 fatty acid supplementation.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

A Patient With Electroconvulsive Therapy-resistant Major Depressive Disorder With a Full Response to Heated Yoga: A Case Report.

Depression remains difficult to treat as a result of less than optimal efficacy and troublesome side effects of antidepressants. The authors present the case of a patient with treatment-resistant depression with melancholic features who had previously been unresponsive to electroconvulsive therapy (ECT) plus an antidepressant regimen but whose condition fully remitted with the addition of a standardized form of heated hatha yoga (HY; Bikram yoga) practiced in a room heated to 105°F. The patient was a 28-year-old woman who underwent 8 weeks of HY as part of a randomized controlled trial of HY for depression while continuing her antidepressant treatment. The patient was asked to attend a minimum of 2 weekly, 90-minute HY classes. After 8 weeks (12 classes in total), the patient no longer met the criteria for a major depressive episode with melancholic features, per Mini-International Neuropsychiatric Interview (MINI) criteria. Her depressive symptoms had improved dramatically, with Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C30), and Hamilton Depression Rating Scale (HAM-D28) scores decreasing from 28 at baseline to 3, and from 28 at baseline to 4, respectively, indicating remission. This patient's ECT-resistant depression remitted with the addition of HY to her antidepressant regimen. Because of her youth and athleticism, this patient was likely well suited to this rigorous form of yoga. Further research is needed to explore HY as a potential intervention for treatment-resistant depression.

Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation.

BACKGROUND: Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients. METHODS: In a 2-site study, 61 MDD patients with body mass index >25 kg/m2 and serum high-sensitivity C-reactive protein ≥3 µg/mL were enrolled in a 12-week randomized trial comparing EPA 1, 2, and 4 g/d to placebo. Plasma EPA (mol%) and SPMs (pg/mL) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. RESULTS: Plasma EPA and SPM concentrations did not change in the placebo group during 12 weeks of treatment. Plasma EPA and EPA-derived metabolites increased significantly and dose-dependently in all EPA supplementation arms. The increase in 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of RvE1-3, was significantly greater with the 4 g/d EPA dose than the other doses from week 4 to 12. RvE1 was undetected in all treatment groups, while RvE2 was detected in half of the subjects both at baseline and after treatment, with dose-dependent increases. RvE3 was detected only after supplementation, dose-dependently. A significant reduction in plasma arachidonic acid (AA), relative to baseline, was observed in all EPA arms. This was in contrast with an increase in AA-derived SPM lipoxin B4 (LXB4) in the 4 g/d arm. CONCLUSIONS: Our results show a robust effect of EPA 4 g/d supplementation in increasing plasma EPA and 18-HEPE levels, associated with improved conversion to RvE2-3, and LXB4 levels.

Community-Delivered Heated Hatha Yoga as a Treatment for Depressive Symptoms: An Uncontrolled Pilot Study.

Objectives: There are no known studies of concurrent exposure to high temperature and yoga for the treatment of depression. This study explored acceptability and feasibility of heated (Bikram) yoga as a treatment for individuals with depressive symptoms. Design: An 8-week, open-label pilot study of heated yoga for depressive symptoms. Subjects: 28 medically healthy adults (71.4% female, mean age 36 [standard deviation 13.57]) with at least mild depressive symptoms (Hamilton Rating Scale for Depression [HRSD-17] score ≥10) who attended at least one yoga class and subsequent assessment visit. Intervention: Participants were asked to attend at least twice weekly community held Bikram Yoga classes. Assessments were performed at screening and weeks 1, 3, 5, and 8. Hypotheses were tested using a modified-intent-to-treat approach, including participants who attended at least one yoga class and subsequent assessment visit (N = 28). Results: Almost half of our subjects completed the 8-week intervention, and close to a third attended three quarters or more of the prescribed 16 classes over 8 weeks. Multilevel modeling revealed significant improvements over time in both clinician-rated HRSD-17 (p = 0.003; dGLMM = 1.43) and self-reported Beck Depression Inventory (BDI; p < 0.001, dGLMM = 1.31) depressive symptoms, as well as the four secondary outcomes: hopelessness (p = 0.024, dGLMM = 0.57), anxiety (p < 0.001, dGLMM = 0.78), cognitive/physical functioning (p < 0.001, dGLMM = 1.34), and quality of life (p = 0.007, dGLMM = 1.29). Of 23 participants with data through week 3 or later, 12 (52.2%) were treatment responders (≥50% reduction in HRSD-17 score), and 13 (56.5%) attained remission (HRSD score ≤7). More frequent attendance was significantly associated with improvement in self-rated depression symptoms, hopelessness, and quality of life. Conclusions: The acceptability and feasibility of heated yoga in this particular sample with this protocol warrants further attention. The heated yoga was associated with reduced depressive symptoms, and other improved related mental health symptoms, including anxiety, hopelessness, and quality of life.

Effects of transcranial photobiomodulation with near-infrared light on sexual dysfunction.

OBJECTIVES: Transcranial photobiomodulation (t-PBM) consists of the delivery of near-infrared (NIR) or red light to the scalp designed to penetrate to subjacent cortical areas of the brain. NIR t-PBM has recently emerged as a potential therapy for brain disorders. This study assessed the efficacy of repeated sessions of NIR t-PBM on sexual dysfunction. METHODS: We performed a secondary analysis of a double-blind clinical trial on t-PBM for major depressive disorder (MDD). Twenty individuals received NIR t-PBM (n = 9) or sham therapy (n = 11) twice a week for 8 weeks. Sexual desire, arousal, and orgasm were assessed using the Systematic Assessment for Treatment-Emergent Effects-Specific Inquiry (SAFTEE-SI). RESULTS: The mean improvement in sexual function (decrease in SAFTEE sex total score) in subjects receiving t-PBM in NIR-mode was significantly greater than in subjects receiving sham-mode in the whole sample (NIR [n = 9] -2.55 ± 1.88 vs. sham [n = 11] -0.45 ± 1.21; z = 2.548, P = 0.011]) and in the completers (NIR [n = 5] -3.4 ± 1.95 vs. sham [n = 7] -0.14 ± 1.21; z = 2.576, P = 0.010]). CONCLUSION: This exploratory study with a small sample size indicates that repeated sessions of NIR t-PBM may be associated with therapeutic effects on sexual dysfunction. The latter appeared unrelated to the antidepressant effect of t-PBM in our cohort. Lasers Surg. Med. 51:127-135, 2019. © 2018 Wiley Periodicals, Inc.

Transcranial Photobiomodulation for the Treatment of Major Depressive Disorder. The ELATED-2 Pilot Trial.

Objective: Our objective was to test the antidepressant effect of transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light in subjects suffering from major depressive disorder (MDD). Background: t-PBM with NIR light is a new treatment for MDD. NIR light is absorbed by mitochondria; it boosts cerebral metabolism, promotes neuroplasticity, and modulates endogenous opioids, while decreasing inflammation and oxidative stress. Materials and methods: We conducted a double-blind, sham-controlled study on the safety and efficacy [change in Hamilton Depression Rating Scale (HAM-D17) total score at end-point] of adjunct t-PBM NIR [823 nm; continuous wave (CW); 28.7 × 2 cm2; 36.2 mW/cm2; up to 65.2 J/cm2; 20-30 min/session], delivered to dorsolateral prefrontal cortex, bilaterally and simultaneously, twice a week, for 8 weeks, in subjects with MDD. Baseline observation carried forward (BOCF), last observation carried forward (LOCF), and completers analyses were performed. Results: The effect size for the antidepressant effect of t-PBM, based on change in HAM-D17 total score at end-point, was 0.90, 0.75, and 1.5 (Cohen's d), respectively for BOCF (n = 21), LOCF (n = 19), and completers (n = 13). Further, t-PBM was fairly well tolerated, with no serious adverse events. Conclusions: t-PBM with NIR light demonstrated antidepressant properties with a medium to large effect size in patients with MDD. Replication is warranted, especially in consideration of the small sample size.

Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial.

Background There is concern that selective serotonin reuptake inhibitors ( SSRI s) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results We studied 737 patients taking SSRI s in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1:1 to 737 patients not taking SSRI s. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in ROCKET AF . Over a mean 1.6 years of follow-up, the rate of major/ nonmajor clinically relevant bleeding was 18.57 events/100 patient-years for SSRI users versus 16.84 events/100 patient-years for matched comparators, adjusted hazard ratio ( aHR ) of 1.16 (95% confidence interval [CI], 0.95-1.43). The aHR s were similar in patients taking rivaroxaban ( aHR 1.11 [95% CI, 0.82-1.51]) and those taking warfarin ( aHR 1.21 [95% CI, 0.91-1.60]). For the rarer outcome of major bleeding, the aHR for SSRI users versus those not taking SSRI s was 1.13 (95% CI, 0.62-2.06) for rivaroxaban; for warfarin, the aHR was higher, at 1.58 (95% CI , 0.96-2.60) but not statistically significantly elevated. Conclusions We found no significant increase in bleeding risk when SSRI s were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with SSRI s added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that SSRI s can be safely added to anticoagulants in patients with atrial fibrillation . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00403767.

A randomized controlled dosing study of Iyengar yoga and coherent breathing for the treatment of major depressive disorder: Impact on suicidal ideation and safety findings.

BACKGROUND: Yoga interventions offer promise for the treatment of major depressive disorder (MDD), yet their safety and potential impact on suicidal ideation (SI) have not been well documented. This study evaluated the safety of a randomized controlled dose-finding trial of Iyengar yoga plus coherent breathing for individuals with MDD, as well as the potential effects of the intervention on SI without intent. METHODS: Participants with Beck Depression Inventory-II (BDI-II) scores ≥14 and a diagnosis of MDD (using DSM-IV criteria) were randomized to either a low dose group (LDG) or high dose group (HDG) and received a 12-week manualized intervention. The LDG included two 90-min yoga classes plus three 30-min homework sessions weekly. The HDG offered three 90-min classes plus four 30-min homework sessions weekly. RESULTS: Thirty-two individuals with MDD were randomized, of which 30 completed the protocol. At screening, SI without intent was endorsed on the BDI-II by 9 participants; after completing the intervention, 8 out of 9 reported resolution of SI. There were 17 adverse events possibly-related and 15 definitely-related to the intervention. The most common protocol-related adverse event was musculoskeletal pain, which resolved over the course of the study. CONCLUSIONS: The Iyengar yoga plus coherent breathing intervention was associated with the resolution of SI in 8 out of 9 participants, with mild side effects that were primarily musculoskeletal in nature. This preliminary evidence suggests that this intervention may reduce SI without intent and be safe for use in those with MDD.

The Effects of Tai Chi on Sleep Quality in Chinese American Patients With Major Depressive Disorder: A Pilot Study.

OBJECTIVE: This pilot study evaluated the effects of Tai Chi training on sleep quality (primary outcomes), and depression and social functioning levels (secondary outcomes) among patients with depression. PARTICIPANTS: Sixteen depressed Chinese patients. METHODS: Participants received 1-hr Tai Chi training sessions 2 times per week for 10 weeks. Patients' subjective sleep quality ratings, objective sleep quality measurements, and depression and social functioning levels were measured before, during, and after the intervention. RESULTS: Sleep quality and depression outcomes improved significantly. Patients reported improved Pittsburgh Sleep Quality Index (PSQI) scores (9.6 ± 3.3 to 6.6 ± 5.2, p = 0.016), and cardiopulmonary coupling (CPC) analysis of electrocardiogram (ECG) showed decreased stable sleep onset latency (75.7 ± 100.6 to 20.9 ± 18.0, p = 0.014), increased stable sleep percentages (31.5 ± 18.7 to 46.3 ± 16.9, p = 0.016), and decreased unstable sleep percentages (45.3 ± 20.1 to 30.6 ± 16.5, p = 0.003). Patients also reported decreased Hamilton Rating Scale for Depression (HAM-D-17; 20.1 ± 3.7 to 7.8 ± 5.9, p < 0.001) and Beck Depression Inventory (BDI) scores (22.3 ± 9.1 to 11.1 ± 10.6, p = 0.006). Significant correlations were found between the changes in subjective sleep assessments ΔPSQI and ΔHAM-D-17 (r = 0.6, p = 0.014), and ΔPSQI and ΔBDI (r = 0.62, p = 0.010). Correlations between changes in objective sleep measurements and changes in depression symptoms were low and not significant. CONCLUSIONS: Tai Chi training improved sleep quality and mood symptoms among depressed patients.

A Randomized Controlled Pilot Study on Mindfulness-Based Cognitive Therapy for Unipolar Depression in Patients With Chronic Pain.

OBJECTIVE: Chronic pain is a disabling illness, often comorbid with depression. We performed a randomized controlled pilot study on mindfulness-based cognitive therapy (MBCT) targeting depression in a chronic pain population. METHOD: Participants with chronic pain lasting ≥ 3 months; DSM-IV major depressive disorder (MDD), dysthymic disorder, or depressive disorder not otherwise specified; and a 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) score ≥ 6 were randomly assigned to MBCT (n = 26) or waitlist (n = 14). We adapted the original MBCT intervention for depression relapse prevention by modifying the psychoeducation and cognitive-behavioral therapy elements to an actively depressed chronic pain population. We analyzed an intent-to-treat (ITT) and a per-protocol sample; the per-protocol sample included participants in the MBCT group who completed at least 4 of 8 sessions. Changes in scores on the QIDS-C16 and 17-item Hamilton Depression Rating Sale (HDRS17) were the primary outcome measures. Pain, quality of life, and anxiety were secondary outcome measures. Data collection took place between January 2012 and July 2013. RESULTS: Nineteen participants (73%) completed the MBCT program. No significant adverse events were reported in either treatment group. ITT analysis (n = 40) revealed no significant differences. Repeated-measures analyses of variance for the per-protocol sample (n = 33) revealed a significant treatment × time interaction (F1,31 = 4.67, P = .039, η²p = 0.13) for QIDS-C16 score, driven by a significant decrease in the MBCT group (t18 = 5.15, P < .001, d = >1.6), but not in the control group (t13 = 2.01, P = .066). The HDRS17 scores did not differ significantly between groups. The study ended before the projected sample size was obtained, which might have prevented effect detection in some outcome measures. CONCLUSIONS: MBCT shows potential as a treatment for depression in individuals with chronic pain, but larger controlled trials are needed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01473615.

Double-blind, proof-of-concept (POC) trial of Low-Field Magnetic Stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD).

BACKGROUND: Low-Field Magnetic Stimulation (LFMS) is a novel, non-invasive, sub-threshold neuromodulation technique, shown in preliminary studies to have immediate mood elevating effects in both unipolar and bipolar depressed patients. OBJECTIVE: We aimed to assess the antidepressant augmentation effects at 48 h of LFMS administered on two consecutive days compared to sham treatment in treatment resistant depression (TRD) subjects, using the Sequential Parallel Comparison Design (SPCD). METHODS: Eighty-four eligible subjects with TRD were randomly assigned to double-blind treatment with LFMS 20 min/day for four days, sham treatment 20 min/day for four days, or sham treatment 20 min/day for 2 days followed by LFMS treatment 20 min/day for two days, using the pre-randomization version of the SPCD (randomization 1:1:1). The SPCD analyses used a repeated measures linear modeling approach with maximum likelihood estimation to use all available data, and using a 60-40 weighting of Stage 1 vs. 2 responses, with the primary outcome being measured after 2 and 4 days. RESULTS: Both primary and secondary outcome measures consistently showed no differences between LFMS-treated patients and those treated with sham, with the exception of a slight, non-significantly greater improvement than sham in the visual analogue scale (VAS) sad mood on LFMS-treated patients. LFMS treatment was relatively well tolerated. CONCLUSIONS: We did not observe a significantly greater, rapid efficacy of LFMS compared to sham therapy. Future studies need to examine the possible therapeutic effects of more intensive forms of LFMS, as other forms of neurostimulation typically require longer duration of exposure.

Reduced orbitofrontal-thalamic functional connectivity related to suicidal ideation in patients with major depressive disorder.

Despite recent developments in neuroimaging, alterations of brain functional connectivity in major depressive disorder (MDD) patients with suicidal ideation are poorly understood. This study investigated specific changes of suicidal ideation in functional connectivity of MDD patients. Whole brain functional connectivity in 46 patients with MDD (23 with suicidal ideation and 23 without) and 36 age- and gender- matched healthy controls were compared using resting-state functional Magnetic Resonance Imaging (fMRI) analyzed with network-based statistics (NBS) and graph-theoretical methods. Decreased functional connectivity in a characterized sub-network was observed in patients with MDD and suicidal ideation (FDR-adjusted p < 0.05). The sub-network included the regions of the fronto-thalamic circuits in the left hemisphere. The network measures of the left superior frontal gyrus, pars orbitalis (r = -0.40, p = 0.009), left thalamus (r = -0.41, p = 0.009), and right thalamus (r = -0.51, p = -0.002) were shown, through graph theoretical analysis, to be significantly negatively correlated with severity of suicidal ideation. The reduced functional connectivity in left orbitofrontal-both thalamic regions with suicidal ideation in MDD were inversely proportional to the severity of suicidality independent from depression severity. These findings suggest problems with decision-making and information integration in MDD patients with suicidal ideation.

A Pilot, Randomized Controlled Study of Tai Chi With Passive and Active Controls in the Treatment of Depressed Chinese Americans.

OBJECTIVE: This pilot, randomized clinical trial investigates the effectiveness of tai chi as the primary treatment for Chinese Americans with major depressive disorder (MDD). METHODS: 67 Chinese Americans with DSM-IV MDD and no treatment for depression were recruited between March 2012 and April 2013 and randomized (1:1:1) into a tai chi intervention, an education program, or a waitlisted group for 12 weeks. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS17); positive response for this outcome was defined as a decrease in total score of 50% or more, and remission was defined as HDRS17 ≤ 7. RESULTS: Participants (N = 67) were 72% female with a mean age of 54 ± 13 years. No serious adverse events were reported. After the end of the 12-week intervention, response rates were 25%, 21%, and 56%, and remission rates were 10%, 21%, and 50% for the waitlisted, education, and tai chi intervention groups, respectively. The tai chi group showed improved treatment response when compared to both the waitlisted group (odds ratio [OR] = 2.11; 95% CI, 1.01-4.46) and to the education group (OR = 8.90; 95% CI, 1.17-67.70). Tai chi intervention showed significantly improved remission rate over the waitlisted group (OR = 3.01; 95% CI, 1.25-7.10), and a trend of improved remission compared to the education group (OR = 4.40; 95% CI, 0.78-24.17). CONCLUSIONS: As the primary treatment, tai chi improved treatment outcomes for Chinese Americans with MDD over both passive and active control groups. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01619631.

Tissue Type-Specific Bioenergetic Abnormalities in Adults with Major Depression.

Brain bioenergetic abnormalities have been observed frequently in adults with major depressive disorder (MDD); however, results have been inconsistent regarding whether decreased or increased metabolism was observed. Phosphorus-31 magnetic resonance spectroscopy (31P MRS) allows for the quantification of bioenergetic molecules, containing high-energy phosphates, over the whole brain as well as measuring the differences between gray matter and white matter. We recruited 50 subjects with a current diagnosis of MDD, not currently treated with psychotropic medication, between ages of 18 and 65 (mean±SD age: 43.4±13.6; 46% female) and 30 healthy volunteers, matched for age and gender (39.0±12.5 years of age; 36.6% female). All subjects received a T1 MP-FLASH scan for tissue segmentation followed by 31P MRS, chemical shift imaging scan with 84 voxels of data collected over the entire brain utilizing a dual-tuned, proton-phosphorus coil to minimize subject movement. Phosphocreatine and inorganic phosphate (Pi) varied in opposite directions across gray matter and white matter when MDD subjects were compared with controls. This finding suggests alterations in high-energy phosphate metabolism and regulation of oxidative phosphorylation in MDD patients. In addition, within the MDD group, gray matter Pi, a regulator of oxidative phosphorylation, correlated positively with severity of depression. These data support a model that includes changes in brain bioenergetic function in subjects with major depression.

Demonstrating test-retest reliability of electrophysiological measures for healthy adults in a multisite study of biomarkers of antidepressant treatment response.

Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test-retest reliability for the three electrophysiological measures selected for a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty-nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes-open and eyes-closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60-100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference-free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low-resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test-retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good-to-excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response.

Major depressive disorder.

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses.

OBJECTIVE: There is burgeoning interest in augmentation strategies for improving inadequate response to antidepressants. The adjunctive use of standardized pharmaceutical-grade nutrients, known as nutraceuticals, has the potential to modulate several neurochemical pathways implicated in depression. While many studies have been conducted in this area, to date no specialized systematic review (or meta-analysis) has been conducted. METHOD: A systematic search of PubMed, CINAHL, Cochrane Library, and Web of Science was conducted up to December 2015 for clinical trials using adjunctive nutrients for depression. Where sufficient data were available, a random-effects model analyzed the standard mean difference between treatment and placebo in the change from baseline to endpoint, combining the effect size data. Funnel plot and heterogeneity analyses were also performed. RESULTS: Primarily positive results were found for replicated studies testing S-adenosylmethionine (SAMe), methylfolate, omega-3 (primarily EPA or ethyl-EPA), and vitamin D, with positive isolated studies for creatine, folinic acid, and an amino acid combination. Mixed results were found for zinc, folic acid, vitamin C, and tryptophan, with nonsignificant results for inositol. No major adverse effects were noted in the studies (aside from minor digestive disturbance). A meta-analysis of adjunctive omega-3 versus placebo revealed a significant and moderate to strong effect in favor of omega-3. Conversely, a meta-analysis of folic acid revealed a nonsignificant difference from placebo. Marked study heterogeneity was found in a Higgins test for both omega-3 and folic acid studies; funnel plots also revealed asymmetry (reflecting potential study bias). CONCLUSIONS: Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.