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S-Adenosylmethionine (SAMe) monotherapy for depression: an 8-week double-blind, randomised, controlled trial.
Sarris, J, Murphy, J, Stough, C, Mischoulon, D, Bousman, C, MacDonald, P, Adams, L, Nazareth, S, Oliver, G, Cribb, L, et al
Psychopharmacology. 2020;(1):209-218
Abstract
RATIONALE Dysregulation of the one carbon cycle is documented in depression. Thereby, S-adenosylmethionine (SAMe), a one-carbon cycle nutraceutical compound with a favourable side effect profile, has a theoretical rationale for efficacy. However, further controlled studies are required to confirm SAMe's efficacy. OBJECTIVES To test the efficacy of SAMe versus placebo in unmedicated DSM-5 diagnosed (major depressive disorder) (MDD) patients with mild-to-moderate levels of depressive symptoms. METHODS We conducted an 8-week, double-blind, randomised controlled trial testing 800 mg/day of SAMe monotherapy versus placebo in 49 patients with MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] score 14-25) who were not currently taking antidepressants. One-carbon cycle biomarkers, brain-derived neurotropic factor (BDNF), and relevant single nucleotide polymorphisms (SNPs) were analysed as potential treatment moderators. RESULTS A clinically relevant differential reduction from baseline to week 8 of 3.76 points occurred on the primary outcome (MADRS) in favour of SAMe. This however was not significant (p = 0.13) on an adjusted linear mixed model, notwithstanding a medium to large effect size of 0.72. A high placebo response rate of 53% occurred (> 50% reduction on MADRS). Exploratory analyses showed that SAMe was however effective in reducing depression amongst participants with milder depression severity (MADRS ≤ 22, p = 0.045). Response was not moderated by BDNF, SNPs, or one-carbon cycle biomarkers, although increased folate concentrations were correlated with improved symptoms in the SAMe group (r = - 0.57, p = 0.026). The treatment was safe and well tolerated. CONCLUSIONS Although a differential reduction in depression symptoms between groups was observed in favour of SAMe, the results of this pilot study were not statistically significant. TRIAL REGISTRATION ANZCTR-Australian New Zealand Clinical Trials Registry; No.: ACTRN12613001299796; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364900.
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Peripheral tryptophan, serotonin, kynurenine, and their metabolites in major depression: A case-control study.
Colle, R, Masson, P, Verstuyft, C, Fève, B, Werner, E, Boursier-Neyret, C, Walther, B, David, DJ, Boniface, B, Falissard, B, et al
Psychiatry and clinical neurosciences. 2020;(2):112-117
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Abstract
AIM: Tryptophan is the sole precursor of both peripherally and centrally produced serotonin and kynurenine. In depressed patients, tryptophan, serotonin, kynurenine, and their metabolite levels remain unclear. Therefore, peripheral tryptophan and metabolites of serotonin and kynurenine were investigated extensively in 173 patients suffering from a current major depressive episode (MDE) and compared to 214 healthy controls (HC). METHODS Fasting plasma levels of 11 peripheral metabolites were quantified: tryptophan, serotonin pathway (serotonin, its precursor 5-hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid), and kynurenine pathway (kynurenine and six of its metabolites: anthranilic acid, kynurenic acid, nicotinamide, picolinic acid, xanthurenic acid, and 3-hydroxyanthranilic acid). RESULTS Sixty (34.7%) patients were antidepressant-drug free. Tryptophan levels did not differ between MDE patients and HC. Serotonin and its precursor (5-hydroxytryptophan) levels were lower in MDE patients than in HC, whereas, its metabolite (5-hydroxyindoleacetic acid) levels were within the standard range. Kynurenine and four of its metabolites (kynurenic acid, nicotinamide, picolinic acid, and xanthurenic acid) were lower in MDE patients. CONCLUSION Whilst the results of this study demonstrate an association between the metabolites studied and depression, conclusions about causality cannot be made. This study uses the largest ever sample of MDE patients, with an extensive assessment of peripheral tryptophan metabolism in plasma. These findings provide new insights into the peripheral signature of MDE. The reasons for these changes should be further investigated. These results might suggest new antidepressant therapeutic strategies.
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EPA and DHA as markers of nutraceutical treatment response in major depressive disorder.
van der Burg, KP, Cribb, L, Firth, J, Karmacoska, D, Mischoulon, D, Byrne, GJ, Bousman, C, Stough, C, Murphy, J, Oliver, G, et al
European journal of nutrition. 2020;(6):2439-2447
Abstract
PURPOSE Depression clinical trials are increasingly studying biomarkers to predict and monitor response to treatment. Assessment of biomarkers may reveal subsets of patients who are responsive to nutraceutical treatment, which may facilitate a personalized approach to treating depression. METHODS This is a post hoc analysis of an 8-week, double-blind, randomized, controlled trial (n = 158) investigating a combination nutraceutical comprising Omega-3 (EPA 1 g/DHA 656 mg), SAMe, zinc, 5-HTP, folinic acid, and co-factors versus placebo for the treatment of Major Depressive Disorder. The study explored levels of polyunsaturated fatty acids, folate, vitamin B12, zinc, homocysteine, and BDNF as possible predictors and correlates of response to nutraceutical supplementation. RESULTS Concentrations of EPA and DHA in red cell membranes increased in response to treatment and were significantly correlated with a decrease in depressive symptoms during active treatment (p = 0.003 and p = 0.029; respectively). Higher baseline levels of omega-6 fatty acid also correlated with depression reduction in the active treatment group ( p = 0.011). No other biomarkers were associated with a lessening of depressive symptoms. CONCLUSION Changes in fatty acid levels resulting from a nutraceutical combination containing EPA and DHA provide a response biomarker in treating depression.
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Randomized, Double-Blind, Placebo-Controlled Trial of the mGlu2/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder.
Umbricht, D, Niggli, M, Sanwald-Ducray, P, Deptula, D, Moore, R, Grünbauer, W, Boak, L, Fontoura, P
The Journal of clinical psychiatry. 2020;(4)
Abstract
OBJECTIVE To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria. METHODS This randomized, placebo-controlled, double-blind, multicenter phase 2 trial consisted of 4 weeks' screening, 6 weeks' treatment, and 8 weeks' follow-up between September 2011 and June 2014. Individuals with Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 25 and Clinical Global Impressions-Severity of Illness scale score ≥ 4, despite up to 2 adequate trials of an SSRI/SNRI and compliance confirmed by positive SSRI/SNRI blood levels, were randomized to decoglurant 5 mg (n = 101), 15 mg (n = 102), or 30 mg (n = 55) daily or placebo (n = 99) as adjunct to ongoing treatment with 1 SSRI/SNRI. An adaptive design was used with an interim analysis after 30 patients in each group had received 6 weeks' treatment. The primary outcome variable was change in MADRS total score from baseline to end of treatment. Primary assessments were performed by fully blinded centralized raters. RESULTS Of 357 participants, 310 completed 6 weeks' treatment. At 6 weeks, no significant differences between any active treatment arm and placebo in reducing MADRS total score or response or remission rates were observed. Decoglurant exerted no significant effects on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores or on secondary measures of mood and functioning. A relatively high placebo response was observed, which may have constrained the ability to detect treatment effects. No deaths occurred; few patients reported serious adverse events. CONCLUSIONS Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01457677.
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Effect of Multinutrient Supplementation and Food-Related Behavioral Activation Therapy on Prevention of Major Depressive Disorder Among Overweight or Obese Adults With Subsyndromal Depressive Symptoms: The MooDFOOD Randomized Clinical Trial.
Bot, M, Brouwer, IA, Roca, M, Kohls, E, Penninx, BWJH, Watkins, E, van Grootheest, G, Cabout, M, Hegerl, U, Gili, M, et al
JAMA. 2019;(9):858-868
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Abstract
IMPORTANCE Effects of nutritional interventions on the prevention of major depressive disorder (MDD) in overweight adults are unknown. OBJECTIVE To examine the effect of 2 nutritional strategies (multinutrient supplementation, food-related behavioral activation therapy) and their combination for prevention of a new MDD episode in overweight adults with subsyndromal depressive symptoms. DESIGN, SETTING, AND PARTICIPANTS This multicenter 2 × 2 factorial randomized clinical trial included overweight adults (body mass index, 25-40) with elevated depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] scores ≥5) and no MDD episode in the past 6 months from 4 European countries. A total of 1025 adults were randomized (July 30, 2015-October 12, 2016) and followed up for 1 year (October 13, 2017). INTERVENTIONS Daily multinutrient supplements (1412-mg omega-3 fatty acids, 30-μg selenium, 400-μg folic acid, and 20-μg vitamin D3 plus 100-mg calcium) vs placebo and 21 individual or group therapy sessions vs none (blinded to researchers) for 1 year. Participants were allocated to placebo without therapy (n = 257), placebo with therapy (n = 256), supplements without therapy (n = 256), and supplements with therapy (n = 256). MAIN OUTCOME AND MEASURES Cumulative 1-year onset of MDD via the Mini International Neuropsychiatric Interview at 3, 6, and 12 months. Logistic regression using effect-coded variables (-1 indicating control, 1 indicating intervention) evaluated intervention effects both individually and in combination (interaction) on MDD onset. RESULTS Among 1025 participants (mean age, 46.5 years; 772 women [75%]; mean BMI, 31.4), 779 (76%) completed the trial. During the 12-month follow-up, 105 (10%) developed MDD: 25 (9.7%) patients in the placebo without therapy, 26 (10.2%) in the placebo with therapy, 32 (12.5%) in the supplement without therapy, and 22 (8.6%) in the supplement with therapy group. None of the treatment strategies affected MDD onset. The odds ratio (OR) for supplements was 1.06 (95% CI, 0.87-1.29); for therapy, 0.93 (95% CI, 0.76-1.13); and for their combination, 0.93 (95% CI, 0.76-1.14; P for interaction, .48). One person in the supplementation with therapy group, died. Twenty-four patients in each of the placebo groups and 24 patients in the supplementation with therapy group were hospitalized, and 26 patients in the supplementation-only group were hospitalized. CONCLUSIONS AND RELEVANCE Among overweight or obese adults with subsyndromal depressive symptoms, multinutrient supplementation compared with placebo and food-related behavioral activation therapy compared with no therapy did not reduce episodes of major depressive disorder during 1 year. These findings do not support the use of these interventions for prevention of major depressive disorder. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02529423.
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Facilitators and barriers to modifying dietary and hygiene behaviours as adjuvant treatment in patients with depression in primary care: a qualitative study.
Olivan-Blázquez, B, Montero-Marin, J, García-Toro, M, Vicens-Pons, E, Serrano-Ripoll, MJ, Castro-Gracia, A, Sarasa-Bosque, MC, Mendive-Arbeloa, JM, López-Del-Hoyo, Y, Garcia-Campayo, J
BMC psychiatry. 2018;(1):205
Abstract
BACKGROUND Major depression is a highly prevalent condition. Its pathogenesis is related to a wide variety of biological and psychosocial factors and among these is factors related to lifestyle. Lifestyle-based interventions seem to be appropriate strategies as coadjutant treatment. The objective of this study is to explore and identify expectations and experiences of both patients and healthcare professionals that can point to the main barriers and facilitators with regard to the promotion of healthy dietary and hygiene behaviours in patients suffering from major depression. METHODS A qualitative design was used to collect information from a wide range of purposefully and theoretically guided samples of depressed patients and health professionals from Primary Care (PC). Both in-depth interviews and discussion groups were used. A standardized protocol was designed to guide the interviews and groups, including the preparation of a topic list to be addressed, with previously tested, open suggestions that could be of interest. A thematic analysis was performed from grounded theory in order to explore, develop and define until saturation the emergent categories of analysis derived from the individual interview and group data. RESULTS Both patients as well as PC professionals noted a series of central aspects with respect to the implementation of a programme for the acquisition of healthy dietary and hygiene habits for depressive patients, which may be organized around 'personal', 'programmatic', and 'transversal' aspects. As for the personal aspects, categories regarding 'patient history', and 'disposition' were found; the programmatic aspects included categories such as 'presentation and monitoring', and modification of 'cognitive' and 'behavioural' habits; whereas the transversal aspects comprised the possibilities of 'social support' and defining categories of 'objectives'. CONCLUSION The implementation of intervention programmes that combine dietary and hygiene-related factors in patients with depression is complex, given the nature of the disorder itself, and its symptoms such as apathy and feelings of guilt or incompetence. Key issues exist for the success of the intervention, such as the simplicity of guidelines, tailoring through motivational interviewing, prolonged and intense monitoring throughout the different stages of the disorder, and the provision of adequate feedback and social support. PC could be an appropriate level in which to implement these interventions.
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Neuroticism and post-traumatic stress disorder: a prospective investigation.
Breslau, N, Schultz, L
Psychological medicine. 2013;(8):1697-702
Abstract
BACKGROUND Neuroticism has been consistently correlated with the post-traumatic stress disorder (PTSD) response to traumatic events. Interpretation of these findings is limited by the retrospective nature of these findings: neuroticism was measured after the trauma had occurred. The prospective association of neuroticism with PTSD has not been examined (the relationship of neuroticism with PTSD symptoms was examined in a few prospective studies). We evaluate prospectively the relationship of neuroticism, measured at baseline, with the cumulative occurrence of PTSD during the subsequent 10 years, using data from a longitudinal epidemiological study of young adults. METHOD A sample of 1007 young adults randomly selected from the membership of a large health maintenance organization in southeast Michigan was assessed at baseline and followed up at 3, 5 and 10 years later. We conducted a series of multinomial logistic regressions to estimate the relative risk (RR) of exposure to trauma and PTSD by neuroticism at baseline, adjusting for history of major depression (n = 990). RESULTS During the 10-year follow-up, 50.2% of the sample experienced traumatic events and 5.2% developed PTSD. Neuroticism score at baseline increased significantly the RR of PTSD response to trauma. Additional analysis revealed that, among persons with history of major depression at baseline, RR for PTSD associated with neuroticism was equal to the null value of 1, but was increased significantly among those with no history of major depression. CONCLUSIONS The results confirm the role of neuroticism as diathesis in the PTSD response to traumatic experiences.