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.

A preliminary descriptive report of the longevity of the effects of Swedish Massage therapy for subjects with Generalized Anxiety Disorder.

OBJECTIVE: Generalized Anxiety Disorder (GAD) is a prevalent and costly disorder, and many patients may prefer non-traditional treatment. A proof-of-concept study demonstrated the efficacy of Swedish Massage Therapy (SMT) as a monotherapy for treatment of GAD. Subjects were followed-up 6-12 months after study completion to evaluate post-treatment outcome. METHODS: Subjects were enrolled into a randomized, single-masked clinical trial between March of 2012 and May of 2013. Forty-seven untreated subjects with DSM-IV diagnosis of GAD were randomly assigned to 6 weeks of twice-a-week light touch (LT) followed by 6 weeks of twice-a-week SMT, or 12 weeks of twice-a-week SMT. The primary outcome measure was reduction in Hamilton Anxiety Rating Scale (HAM-A) scores after six weeks of SMT versus LT. Qualifying participants received a follow-up survey to investigate whether the benefits of SMT for GAD were sustained. RESULTS: 28 of 40 subjects completed at least 12 sessions of SMT and were sent the follow-up survey. Of the 19 subjects with follow-up, nine (47%) reported no return of GAD symptoms up to 1 year after study completion. There were no differences between those randomized to 12 weeks SMT and those receiving 6 weeks LT followed by 6 weeks SMT. Of those reporting a return of some symptoms, 50% associated symptom return with a stressful life event. INTERPRETATION: In this first monotherapy trial of SMT for the treatment of GAD, follow-up results suggest that the beneficial effects of SMT may last up to 1 year after end of treatment.

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.

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.

Six versus twelve weeks of Swedish massage therapy for generalized anxiety disorder: Preliminary findings.

Acute treatment of Generalized Anxiety Disorder often requires 3 months or more of care in order to optimize response. As part of an exploratory grant we have previously demonstrated that six weeks of twice-weekly Swedish Massage Therapy (SMT) was more effective than an active control in decreasing Hamilton Anxiety Rating Scale Scores (HAM-A). An additional goal of this project was to determine if an additional six weeks of twice-weekly SMT led to greater clinical and statistical benefit. We found that HAM-A scores did continue to decrease with an additional six weeks of therapy but that the greatest benefit occurred during the first versus the second 12 sessions (-9.91 vs.-3.09, t = 2.21; df = 10; p = 0.052). These preliminary findings suggest that the majority of benefit in symptom reduction occurs in the first six weeks and that six weeks of twice-weekly SMT may be sufficient for the majority of patients.

Inflammation and Negative Symptoms of Schizophrenia: Implications for Reward Processing and Motivational Deficits.

Negative symptoms of schizophrenia are debilitating and chronic in nature, are difficult to treat, and contribute to poor functional outcomes. Motivational deficits are a core negative symptom and may involve alterations in reward processing, which involve subcortical regions such as the basal ganglia. More specifically, dopamine-rich regions like the ventral striatum, have been implicated in these reward-processing deficits. Inflammation is one mechanism that may underlie negative symptoms, and specifically motivational deficits, via the effects of inflammatory cytokines on the basal ganglia. Previous work has demonstrated that inflammatory stimuli decrease neural activity in the ventral striatum and decrease connectivity in reward-relevant neural circuitry. The immune system has been shown to be involved in the pathophysiology of schizophrenia, and inflammatory cytokines have been shown to be altered in patients with the disorder. This paper reviews the literature on associations between inflammatory markers and negative symptoms of schizophrenia as well as the role of anti-inflammatory drugs to target negative symptoms. We also review the literature on the role of inflammation and reward processing deficits in both healthy controls and individuals with depression. We use the literature on inflammation and depression as a basis for a model that explores potential mechanisms responsible for inflammation modulating certain aspects of negative symptoms in patients with schizophrenia. This approach may offer novel targets to treat these symptoms of the disorder that are significant barriers to functional recovery and do not respond well to available antipsychotic medications.

The prevalence and impact of psychiatric symptoms in an undiagnosed diseases clinical program.

In 2008, the NIH launched an undiagnosed diseases program to investigate difficult to diagnose, and typically, multi-system diseases. The objective of this study was to evaluate the presence of psychiatric symptoms or psychiatric diagnoses in a cohort of patients seeking care at the Emory Special Diagnostic Service clinic. We hypothesized that psychiatric symptoms would be prevalent and associated with trauma exposure, and a decreased quality of life and functioning. This is a cross-sectional, retrospective analysis of 247 patients seen between February 7, 2014 and May 31, 2017. The sources for data included the Emory Health History Questionnaire (HHQ) that had the work and social adjustment and quality of life enjoyment and satisfaction questionnaire-short form (QLSQ) embedded in it; medical records, and the comprehensive standardized special diagnostic clinic forms. Primary outcomes were presence of any psychiatric symptom, based on report of the symptom on the HHQ or medical record, or presence of a confirmed preexisting psychiatric disorder. Seventy-two percent of patients had at least one psychiatric symptom while 24.3% of patients had a pre-existing psychiatric diagnosis. Patients with any psychiatric symptom had significantly diminished Q-LES-Q scores (45.27 ± 18.63) versus patients with no psychiatric symptoms (62.01 ± 21.57, t = 5.60, df = 225, p<0.0001) and they had significantly greater functional disability. Patients with a psychiatric disorder also had significantly diminished Q-LES-Q scores (45.16 ± 17.28) versus those without a psychiatric diagnosis (51.85 ± 21.54, t = 2.11, df = 225, p = 0.036) but did not have significantly increased functional impairment. Both patients with psychiatric symptoms and ones with psychiatric disorders had an increased prevalence of trauma. Psychiatric symptoms are prevalent in patients evaluated for undiagnosed disorders. The presence of any psychiatric symptom, with or without a formal psychiatric diagnosis, significantly decreases quality of life and functioning. This suggests that assessment for psychiatric symptoms should be part of the evaluation of individuals with undiagnosed disorders and may have important diagnostic and treatment implications.

Current Role of Herbal and Natural Preparations.

Depression remains difficult to manage, despite the many registered treatments available. For many depressed individuals, particularly those who have not responded to and/or had adverse effects from standard therapies, herbal and natural medications represent a potentially valuable alternative. This chapter will review several natural remedies used in the treatment of depression. Specific remedies covered include St. John's wort (SJW), S-adenosyl-L-methionine (SAMe), omega-3 fatty acids, rhodiola, and others. We will begin by providing some historical and social context about these remedies. Then we will review efficacy and safety data, as well as biological mechanisms of action of these therapies. Finally, we will discuss the limitations of the current state of knowledge and provide suggestions for a productive research agenda focused on natural remedies. While many questions about these treatments remain unanswered and much work needs to be done before we determine their place in the psychiatric armamentarium, we believe that this chapter will give psychiatrists a good perspective on the pros and cons of herbal and natural antidepressants as part of the pharmacological armamentarium and sensible guidelines on how and when they should be used.

Massage Therapy for Psychiatric Disorders.

This article reviews the current state of knowledge of the role of massage therapy in the treatment of common psychiatric disorders and symptoms. It briefly discusses the prevalence of psychiatric disorders and the popularity of complementary and integrative treatments in the general population. The authors touch on the growing literature describing the biology and neurobiology of massage therapy. The impact of massage as both a therapy for major psychiatric disorders and a treatment for psychiatric symptoms is reviewed, and how massage therapists conceptualize and treat their patients with psychiatric complaints is discussed. If psychiatrists are going to partner with massage therapists, they need to understand how massage therapists' perspectives differ from those of traditional practitioners of allopathic medicine. A model of how psychiatrists and other mental health professionals can work with massage therapists to care for patients is proposed, followed by a summary of the article's key points.

Massage therapy decreases cancer-related fatigue: Results from a randomized early phase trial.

BACKGROUND: Cancer-related fatigue (CRF) is a prevalent and debilitating symptom experienced by cancer survivors, yet treatment options for CRF are limited. In this study, we evaluated the efficacy of weekly Swedish massage therapy (SMT) versus an active control condition (light touch [LT]) and waitlist control (WLC) on persistent CRF in breast cancer survivors. METHODS: This early phase, randomized, single-masked, 6-week investigation of SMT, LT, and WLC enrolled 66 female stage 0-III breast cancer survivors (age range, 32-72 years) who had received surgery plus radiation and/or chemotherapy/chemoprevention with CRF (Brief Fatigue Inventory > 25). The primary outcome was the Multidimensional Fatigue Inventory (MFI), with the National Institutes of Health PROMIS Fatigue scale secondary. RESULTS: Mean baseline MFI scores for 57 evaluable subjects were 62.95 for SMT, 55.00 for LT, and 60.41 for WLC. SMT resulted in a mean (standard deviation) 6-week reduction in MFI total scores of -16.50 (6.37) (n = 20) versus -8.06 (6.50) for LT (n = 20) and an increase of 5.88 (6.48) points for WLC (n = 17) (treatment-by-time P < .0001). The mean baseline PROMIS Fatigue scores were SMT, 22.25; LT, 22.05; and WLC, 23.24. The mean (standard deviation) reduction in PROMIS Fatigue scores was -5.49 (2.53) points for SMT versus -3.24 (2.57) points for LT and -0.06 (1.88) points for WLC (treatment-by-time P = .0008). Higher credibility, expectancy, and preference for SMT than for LT did not account for these results. CONCLUSION: SMT produced clinically significant relief of CRF. This finding suggests that 6 weeks of a safe, widely accepted manual intervention causes a significant reduction in fatigue, a debilitating sequela for cancer survivors. Cancer 2018;124:546-54. © 2017 American Cancer Society.

Impact of Ixekizumab Treatment on Depressive Symptoms and Systemic Inflammation in Patients with Moderate-to-Severe Psoriasis: An Integrated Analysis of Three Phase 3 Clinical Studies.

BACKGROUND: Depression is a common comorbidity in psoriasis, and both conditions are associated with systemic inflammation. The efficacy of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, was evaluated in patients with moderate-to-severe plaque psoriasis (psoriasis) and depressive symptoms that were at least moderately severe. METHODS: Data were integrated from 3 randomized, double-blind, controlled phase 3 trials. At baseline and week 12, depressive symptoms and inflammation were assessed by the 16-item Quick Inventory of Depressive Symptomology - Self-Report (QIDS-SR16) and by a high-sensitivity assay of serum C-reactive protein (hsCRP), respectively. A subgroup of patients with at least moderately severe depressive symptoms at baseline (QIDS-SR16 total score ≥11) was analyzed. Improvement in psoriasis was assessed by the Psoriasis Area and Severity Index (PASI). RESULTS: Approximately 10% of the overall psoriasis population had at least moderately severe depressive symptoms at baseline. At week 12, comorbid patients treated with ixekizumab had significantly greater improvements in their QIDS-SR16 total score (ixekizumab 80 mg every 2 weeks [Q2W], -7.1; ixekizumab 80 mg every 4 weeks [Q4W], -6.1) vs. placebo (-3.4) (p < 0.001, both comparisons) and higher rates of remission of depressive symptoms (ixekizumab Q2W, 45.2%; ixekizumab Q4W, 33.6%) vs. placebo (17.8%) (p ≤ 0.01, both comparisons). Patients treated with ixekizumab also had significant reductions in hsCRP and PASI compared to placebo. Etanercept treatment was not associated with significant improvements in depressive symptoms compared to placebo. CONCLUSIONS: In this comorbid population, 12 weeks of ixekizumab therapy resulted in remission of depression for approximately 40% of patients and improved systemic inflammation as indicated by hsCRP.

Acute Swedish Massage Monotherapy Successfully Remediates Symptoms of Generalized Anxiety Disorder: A Proof-of-Concept, Randomized Controlled Study.

OBJECTIVE: Generalized anxiety disorder (GAD) is a prevalent and costly disorder for which many patients may prefer nontraditional treatment. A proof-of-concept study of was conducted to evaluate the acute effects of Swedish massage therapy (SMT) as a monotherapy for the treatment of subjects with GAD. METHODS: A randomized, single-masked, clinical trial was conducted between March 2012 and May 2013 at the Mood and Anxiety Disorders Program of Emory University. Forty-seven currently untreated subjects with a DSM-IV diagnosis of GAD were randomly assigned to twice-weekly SMT versus a light touch control condition for 6 weeks. The primary outcome measure was reduction in Hamilton Anxiety Rating Scale (HARS) scores after 6 weeks of treatment for SMT versus light touch, as determined by mixed model repeated-measures analysis of 40 evaluable subjects. RESULTS: Mean HARS baseline scores were 20.05 (SD = 3.34) for SMT and 19.58 (SD = 4.90) for light touch. At week 6, the difference in mean (standard error of the mean [SEM]) HARS score reduction was 3.26 points (SMT: -11.67 [1.09]; light touch: -8.41 [1.01]; t106 = -2.19; P = .030; effect size = -0.69). Treatment group differences were significant (P < .05) starting at the end of week 3. CONCLUSION: This first monotherapy trial suggests that a complementary and alternative manual therapy, SMT, is an effective acute treatment for GAD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01337713.

Parental type 2 diabetes in patients with non-affective psychosis.

OBJECTIVE: People with schizophrenia have an increased risk of diabetes that may be independent of antipsychotics. Previous studies have explored the prevalence of a family history of type 2 diabetes (DM2) in schizophrenia. We hypothesized that parental DM2 is increased in probands with non-affective psychosis (NAP) compared to controls, and parental DM2 predicts comorbid diabetes in NAP, after controlling for potential confounders. METHOD: N=217 patients with NAP and N=67 controls were interviewed for a history of parental DM2. NAP was investigated as a predictor of parental DM2 in binary logistic regression models, controlling for age, sex, race, smoking, body mass index, socioeconomic status, and parental psychiatric history. RESULTS: There was an increased prevalence of DM2 in the mother (30.0% vs 13.8%, p=0.013) and in either the mother or father (44.5% vs 24.6%, p=0.006) in patients with NAP versus controls. After accounting for potential confounders, NAP was associated with significant increased odds of parental DM2 (OR=2.80, 95% CI 1.08-7.23, p=0.034). Parental DM2 was also associated with increased odds of comorbid DM2 in NAP (OR=3.67, 95% CI 1.58-8.56, p=0.003). CONCLUSIONS: We replicated an association of an increased prevalence of parental DM2 in patients with NAP. Parental DM2 was also an independent predictor of comorbid DM2 in these patients. These associations may be due to shared environmental or genetic risk factors, or gene by environment interactions. Given risks of incident diabetes with antipsychotic treatment, screening for parental DM2 status is germane to the clinical care of patients with NAP.

Psychiatry Departments Under Constrained Funding Mechanisms or What Is a Chairperson to Do?

OBJECTIVE: The authors surveyed academic departments of psychiatry to examine what effect decreases in funding levels may be having. METHODS: An internet survey of all departments of psychiatry was conducted at US medical schools. The response rate was 43 of 120 programs. Both large more research intensive and smaller more clinical departments responded. RESULTS: Majorities of departments reported that funding decreases negatively impacted faculty recruitment, research, faculty retention, and teaching programs. Approximately, one-third reported laying-off non-tenured faculty members and almost half, staff members. Graduate Medical Education (GME) funding was also a challenge. Departments reported responding by attempting to develop alternative funding sources. Few departments in the sample were doing significant fund raising. CONCLUSIONS: Academic departments find themselves stressed financially and are constricting some functions that are thought important. They are, in general, not able to replace lost funding. The research enterprise appears to be disproportionately affected and results in problems recruiting faculty. GME programs thus far seem less affected. Overall, funding issues appear to be causing serious issues that will have long-term consequences.