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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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The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study.
Ellegaard, PK, Licht, RW, Nielsen, RE, Dean, OM, Berk, M, Poulsen, HE, Mohebbi, M, Nielsen, CT
Journal of affective disorders. 2019;:1043-1051
Abstract
OBJECTIVE To investigate the efficacy of adjunctive N-acetylcysteine (NAC) for the treatment of acute bipolar depression. METHOD A randomized, double-blind, multicentre, placebo-controlled trial including adult subjects diagnosed with bipolar disorder, currently experiencing a depressive episode. Participants were treated with 3 g/day NAC or placebo as an adjunctive to standard treatment for 20 weeks, followed by a 4-week washout where the blinding was maintained. The primary outcome was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) score over the 20-week treatment phase. Linear Mixed Effects Repeated Measures (LMERM) was used for analysing the primary outcome. RESULTS A total of 80 subjects were included. The mean MADRS score at baseline was 30.1 and 28.8 in participants randomized to NAC and placebo, respectively. Regarding the primary outcome measure, the between-group difference (NAC vs. placebo) was 0.5, which was statistically non-significant (95% CI: -7.0-5.9;p = 0.88). All findings regarding secondary outcomes were statistically or clinically insignificant. LIMITATIONS The study had a placebo response rate of 55.6% - high placebo response rates are associated with failure to separate from placebo. CONCLUSIONS Based on our primary outcome measure, we could not confirm previous studies showing a therapeutic effect of adjunctive NAC treatment on acute bipolar depression. Further studies with larger samples are needed to elucidate if specific subgroups could benefit from adjunctive NAC treatment.
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Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial<sup/>.
Sarris, J, Byrne, GJ, Bousman, C, Stough, C, Murphy, J, MacDonald, P, Adams, L, Nazareth, S, Oliver, G, Cribb, L, et al
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2018;(10):1126-1136
Abstract
There has been increasing interest in nutraceutical augmentation strategies to boost the efficacy of antidepressants. This study assessed whether S-adenosylmethionine (SAMe), a methyl donor that occurs naturally in the body, may be of such benefit. We conducted an 8-week, double-blind RCT in which 107 treatment non-remittent outpatients with DSM-5 diagnosed Major Depressive Disorder (MDD) were randomized to either SAMe or placebo adjunctively to antidepressants. One-carbon cycle nutrients, pertinent single nucleotide polymorphisms (SNPs), and BDNF were also analysed as potential moderators of response. A linear mixed-effects model revealed a significant overall reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score across time, however there was no significant between-group difference observed (p = 0.51). Response rates at Week 8 were 54.3% in the SAMe group and 50.0% in the placebo group, with remission rates 43.5% for SAMe and 38.3% for placebo (all results NS). No effect of SAMe was found on any secondary outcome. Differential response to SAMe was not modified by a range of key genotypes (e.g. COMT), nor reflected in a change of homocysteine, red cell folate, or BDNF. Use of SAMe elicited no significant adverse effects beyond placebo, however it was implicated in one case of serotonin syndrome-like symptoms. This study concludes that 800 mg/day of SAMe is not an effective adjunctive treatment in MDD, and no obvious biomarker reflected any differential response to treatment. Due to such a distinctly high placebo-response (despite rigorous screening), future studies should employ a placebo run-in period and other strategies to minimize placebo response.
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Electrocardiogram Alterations Associated With Psychotropic Drug Use and CACNA1C Gene Variants in Three Independent Samples.
Fabbri, C, Boriani, G, Diemberger, I, Filippi, MG, Ravegnini, G, Hrelia, P, Minarini, A, Albani, D, Forloni, G, Angelini, S, et al
Basic & clinical pharmacology & toxicology. 2017;(5):482-490
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Abstract
Several antipsychotics and antidepressants have been associated with QTc prolongation or other electrocardiogram (ECG) alterations, but their impact is still debated and other risk factors are known to affect QTc. We investigated the effect of antidepressants and antipsychotics on QTc and other ECG intervals/waves in three samples. Two discovery samples (cross-sectional sample n = 145 and prospective sample n = 68, naturalistic treatment) and a replication prospective sample (Clinical Antipsychotic Trials of Intervention Effectiveness, n = 515, randomized treatment) were analysed. In both prospective samples, baseline/follow-up changes in ECG parameters were analysed in relation to the number of psychotropic drugs stratified according to their known cardiovascular risk. In the cross-sectional sample, ECG parameters were compared among drugs with different risk profile. The possible effect of single nucleotide polymorphisms (SNPs) in the CACNA1C gene on QTc was also investigated. There was no evidence of mean QTc prolongation or increased risk of clinically relevant QTc prolongation (≥20 msec.) in association with psychotropic drugs stratified according to their known cardiovascular risk. The prescription of drugs with cardiovascular risk was less common in older individuals or individuals with cardiovascular comorbidities. Other factors (gender, baseline QTc, renal function) affected QTc. rs1006737 and SNPs in linkage disequilibrium with it modulated QTc duration/changes in all samples. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not observed. A number of factors other than psychotropic drugs may influence QTc. CACNA1C rs1006737 may modulate QTc in patients treated with psychotropic drugs.
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Acceptance of Antidepressant Treatment by Patients on Hemodialysis and Their Renal Providers.
Pena-Polanco, JE, Mor, MK, Tohme, FA, Fine, MJ, Palevsky, PM, Weisbord, SD
Clinical journal of the American Society of Nephrology : CJASN. 2017;(2):298-303
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Abstract
BACKGROUND AND OBJECTIVES Depression is common in patients receiving chronic hemodialysis but seems to be ineffectively treated. We investigated the acceptance of antidepressant treatment by patients on chronic hemodialysis and their renal providers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS As part of a clinical trial of symptom management in patients on chronic hemodialysis conducted from 2009 to 2011, we assessed depression monthly using the Patient Health Questionnaire 9. For depressed patients (Patient Health Questionnaire 9 score ≥10), trained nurses generated treatment recommendations and helped implement therapy if patients and providers accepted the recommendations. We assessed patients' acceptance of recommendations, reasons for refusal, and provider willingness to implement antidepressant therapy. We analyzed data at the level of the monthly assessment. RESULTS Of 101 patients followed for ≤12 months, 39 met criteria for depression (Patient Health Questionnaire 9 score ≥10 on one or more assessments). These 39 patients had depression on 147 of 373 (39%) monthly assessments. At 103 of these 147 (70%) assessments, patients were receiving antidepressant therapy, and at 51 of 70 (70%) assessments, patients did not accept nurses' recommendations to intensify treatment. At 44 assessments, patients with depression were not receiving antidepressant therapy, and in 40 (91%) instances, they did not accept recommendations to start treatment. The primary reason that patients refused the recommendations was attribution of their depression to an acute event, chronic illness, or dialysis (57%). In 11 of 18 (61%) instances in which patients accepted the recommendation, renal providers were unwilling to provide treatment. CONCLUSIONS Patients on chronic hemodialysis with depression are frequently not interested in modifying or initiating antidepressant treatment, commonly attributing their depression to a recent acute event, chronic illness, or dialysis. Renal providers are often unwilling to modify or initiate antidepressant therapy. Future efforts to improve depression management will need to address these patient- and provider-level obstacles to providing such care.
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Depression, metabolic control, and antidepressant medication in young patients with type 1 diabetes.
Plener, PL, Molz, E, Berger, G, Schober, E, Mönkemöller, K, Denzer, C, Goldbeck, L, Holl, RW
Pediatric diabetes. 2015;(1):58-66
Abstract
OBJECTIVE Recent literature suggests an association between type 1 diabetes (T1D) and depression. So far, most studies explored this link in adult populations, with few data being available on diabetes and depression from minors and young adults. This study aimed to look for associations between symptoms of depression/antidepressant treatment and metabolic outcomes of T1D. METHODS We conducted an observational study using the German diabetes database (Diabetes-Patienten-Verlaufsdokumentation--DPV) and searched for patients up to the age of 25 yr, with depressive symptoms and/or receiving antidepressant medication. RESULTS Of 53 986 T1D patients below the age of 25 yr, antidepressant medication and/or depressive symptoms were reported in 419 (0.78%). After adjustment for age, gender, diabetes duration and center heterogeneity, minors and young adults with depressive symptoms showed worse outcome parameters such as a higher rate of severe hypoglycemia (0.56 vs. 0.20/patient year, p = 0.005) and more episodes of diabetic ketoacidosis (0.20 vs. 0.07/patient year, p < 0.001). Hemoglobin A1c (HbA1c) was higher in the depression group (74.50 vs. 67.58 mmol/mol, p < 0.001) and young patients with T1D and depression showed longer duration of inpatient treatment (7.04 vs. 3.10 hospital days/patient year, p < 0.001) and more frequent admissions to hospital care (0.63 vs. 0.32/patient year, p < 0.001). Antidepressant medication was recorded in 52.3% of the depressed patients, with selective serotonin reuptake inhibitors (SSRIs) being the most widely described class of antidepressants (29.1%). CONCLUSIONS Our findings demonstrate an adverse treatment outcome for young patients with T1D and comorbid depressive symptoms underlining an urgent need for collaborative mental and somatic health care for patients with T1D and depression.
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Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation.
Bedson, E, Bell, D, Carr, D, Carter, B, Hughes, D, Jorgensen, A, Lewis, H, Lloyd, K, McCaddon, A, Moat, S, et al
Health technology assessment (Winchester, England). 2014;(48):vii-viii, 1-159
Abstract
BACKGROUND Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak. OBJECTIVES (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism. DESIGN FolATED (Folate Augmentation of Treatment - Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost-utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a 'small' effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453. SETTINGS Clinical - Three centres in Wales - North East Wales, North West Wales and Swansea. Trial management - North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis - University Hospital of Wales, Cardiff. Genetic analysis - University of Liverpool. PARTICIPANTS Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research. INTERVENTIONS Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners. MAIN OUTCOME MEASURES Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by 'area under curve' (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health - BDI-II (primary), Clinical Global Impression (CGI), Montgomery-Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health - UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale - 5 Dimensions (EQ-5D); Biochemistry - serum folate, B12, homocysteine; Adherence - Morisky Questionnaire; Economics - resource use. RESULTS Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from -12.7 to 7.0 days] and saved a mean of just £48 (95% CI from -£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from -5.2% to -0.8%). CONCLUSIONS The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM. TRIAL REGISTRATION Current Controlled Trials ISRCTN37558856. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.
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Desvenlafaxine compared with placebo for treatment of menopausal vasomotor symptoms: a 12-week, multicenter, parallel-group, randomized, double-blind, placebo-controlled efficacy trial.
Pinkerton, JV, Constantine, G, Hwang, E, Cheng, RF, ,
Menopause (New York, N.Y.). 2013;(1):28-37
Abstract
OBJECTIVE The aim of this study was to assess the 12-week efficacy of desvenlafaxine in treating moderate to severe vasomotor symptoms and the clinical relevance of improvements in postmenopausal women experiencing 50 or more moderate to severe hot flashes per week. METHODS Participants were randomized to placebo or desvenlafaxine 100 mg/day in the 12-week efficacy substudy of a year-long, multicenter, parallel-group, double-blind study. Coprimary outcomes were changes from baseline in the daily number and severity of hot flashes on weeks 4 and 12. The percentage of women achieving the minimal clinically important difference (MCID) in the number of hot flashes on week 12 was determined. RESULTS The efficacy substudy modified intent-to-treat population included 365 women (desvenlafaxine, n = 184; placebo, n = 181). Desvenlafaxine 100 mg/day significantly reduced the number and severity of hot flashes versus placebo on week 4 (P < 0.001) and week 12 (P < 0.001). On week 12, desvenlafaxine reduced the number of moderate and severe hot flashes by 7.3 (62%) per day (placebo, -4.5 [38%] per day) and the severity score by 0.59 (25%) per day (placebo, -0.28 [12%] per day). MCID-a reduction of 5.35 moderate and severe hot flashes per day-was achieved by 64% of desvenlafaxine-treated women (placebo, 41%; P < 0.001). In all, 17.2% (67/390) of participants discontinued, 10.0% (20/200) of participants taking desvenlafaxine and 3.7% (7/190) of participants taking placebo discontinued because of adverse events (P = 0.016), and 2.5% (5/200) of participants taking desvenlafaxine and 8.4% (16/190) of participants taking placebo discontinued because of lack of efficacy (P = 0.012). CONCLUSIONS Postmenopausal women with moderate to severe hot flashes who are treated with desvenlafaxine achieve rapid symptom reduction that is clinically relevant based on MCID.
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A randomized controlled trial of an HIV/AIDS Symptom Management Manual for depressive symptoms.
Eller, LS, Kirksey, KM, Nicholas, PK, Corless, IB, Holzemer, WL, Wantland, DJ, Willard, SS, Robinson, L, Hamilton, MJ, Sefcik, EF, et al
AIDS care. 2013;(4):391-9
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Abstract Depressive symptoms are highly prevalent, underdiagnosed, and undertreated in people living with HIV/AIDS (PLWH), and are associated with poorer health outcomes. This randomized controlled trial examined the effects of the HIV/AIDS Symptom Management Manual self-care symptom management strategies compared with a nutrition manual on depressive symptoms in an international sample of PLWH. The sample consisted of a sub-group (N=222) of participants in a larger study symptom management study who reported depressive symptoms. Depressive symptoms of the intervention (n=124) and control (n=98) groups were compared over three months: baseline, one-month, and two-months. Use and effectiveness of specific strategies were examined. Depressive symptom frequency at baseline varied significantly by country (χ (2) 12.9; p=0.04). Within the intervention group there were significant differences across time in depressive symptom frequency [F(2, 207) = 3.27, p=0.05], intensity [F(2, 91) = 4.6, p=0.01], and impact [F(2, 252) = 2.92, p= 0.05), and these were significantly lower at one month but not at two months, suggesting that self-care strategies are effective in reducing depressive symptoms, however effects may be short term. Most used and most effective self-care strategies were distraction techniques and prayer. This study suggests that people living with HIV can be taught and will employ self-care strategies for management of depressive symptoms and that these strategies are effective in reducing these symptoms. Self-care strategies are noninvasive, have no side-effects, and can be readily taught as an adjunct to other forms of treatment. Studies are needed to identify the most effective self-care strategies and quantify optimum dose and frequency of use as a basis for evidence-based practice.
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Common genetic variation in the indoleamine-2,3-dioxygenase genes and antidepressant treatment outcome in major depressive disorder.
Cutler, JA, Rush, AJ, McMahon, FJ, Laje, G
Journal of psychopharmacology (Oxford, England). 2012;(3):360-7
Abstract
The essential amino acid tryptophan is the precursor to serotonin, but it can also be metabolized into kynurenine through indoleamine-2,3-dioxygenase (IDO). Increased immune activation has long been associated with symptoms of depression and has been shown to upregulate the expression of IDO. The presence of additional IDO directs more tryptophan down the kynurenine pathway, leaving less available for synthesis of serotonin and its metabolites. Kynurenine can be metabolized through a series of enzymes to quinolinic acid, a potent N-methyl-D-aspartate receptor agonist with demonstrated neurotoxic effects. We tested the hypothesis that IDO plays a role in outcome of treatment with the selective serotonin reuptake inhibitor, citalopram. Patients consisted of 1953 participants enrolled in the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D). Genotypes corresponding to 94 single nucleotide polymorphisms (SNPs) in the genes IDO1 and IDO2, which encode IDO and IDO2, were extracted from a larger genome-wide set and analyzed using single marker tests to look for association with previously defined response, remission and QIDS-C score change phenotypes, with adequate correction for racial stratification and multiple testing. One SNP, rs2929115, showed evidence of association with citalopram response (OR = 0.64, p = 0.0005) after experiment-wide correction for multiple testing. Another closely associated marker, rs2929116 (OR = 0.64, p = 0.0006) had an experiment-wide significant result. Both implicated SNPs are located between 26 kb and 28 kb downstream of IDO2. We conclude that common genetic variation in IDO1 and IDO2 may play a role in antidepressant treatment outcome. These results are modest in a genome-wide context and need to be replicated in an independent sample.