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1.
L-theanine in the adjunctive treatment of generalized anxiety disorder: A double-blind, randomised, placebo-controlled trial.
Sarris, J, Byrne, GJ, Cribb, L, Oliver, G, Murphy, J, Macdonald, P, Nazareth, S, Karamacoska, D, Galea, S, Short, A, et al
Journal of psychiatric research. 2019;:31-37
Abstract
Partial or non-response to antidepressants in Generalized Anxiety Disorder (GAD) is common in clinical settings, and adjunctive biological interventions may be required. Adjunctive herbal and nutraceutical treatments are a novel and promising treatment option. L-theanine is a non-protein amino acid derived most-commonly from tea (Camellia sinensis) leaves, which may be beneficial in the treatment of anxiety and sleep disturbance as suggested by preliminary evidence. We conducted a 10-week study (consisting of an 8-week double-blind placebo-controlled period, and 1-week pre-study and 2-week post-study single-blinded observational periods) involving 46 participants with a DSM-5 diagnosis of GAD. Participants received adjunctive L-theanine (450-900 mg) or matching placebo with their current stable antidepressant treatment, and were assessed on anxiety, sleep quality, and cognition outcomes. Results revealed that adjunctive L-theanine did not outperform placebo for anxiety reduction on the HAMA (p = 0.73) nor insomnia severity on the Insomnia Severity Index (ISI; p = 0.35). However, LT treated participants reported greater self-reported sleep satisfaction than placebo (ISI item 4; p = 0.015). Further, a separation in favour of L-theanine was noted on the ISI in those with non-clinical levels of insomnia symptoms (ISI ≤ 14; p = 0.007). No significant cognitive effects (trail making time and the modified emotional Stroop) were revealed. While this preliminary study did not support the efficacy of L-theanine in the treatment of anxiety symptoms in GAD, further studies to explore the application of L-theanine in sleep disturbance are warranted.
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2.
Nutraceuticals for major depressive disorder- more is not merrier: An 8-week double-blind, randomised, controlled trial.
Sarris, J, Byrne, GJ, Stough, C, Bousman, C, Mischoulon, D, Murphy, J, Macdonald, P, Adams, L, Nazareth, S, Oliver, G, et al
Journal of affective disorders. 2019;:1007-1015
Abstract
BACKGROUND One of the most pressing questions in "Nutritional Psychiatry" is whether using combinations of different nutraceuticals with putative antidepressant activity may provide an enhanced synergistic antidepressant effect. METHODS A phase II/III, Australian multi-site, 8-week, double-blind, RCT involving 158 outpatients with a DSM-5 diagnosis of MDD. The intervention consisted of a nutraceutical combination: S-adenosyl methionine; Folinic acid; Omega-3 fatty acids; 5-HTP, Zinc picolinate, and relevant co-factors versus placebo. The primary outcome was change in MADRS score. Hypothesis-driven analyses of potential moderators of response involving key SNPs, and BDNF were also conducted. RESULTS Placebo was superior to the nutraceutical combination in reducing MADRS score (differential reduction -1.75 points), however a mixed linear model revealed a non-significant Group X Time interaction (p = 0.33). Response rates were 40% for the active intervention and 51% for the placebo; remission rates were 34% and 43% for active and placebo groups, respectively. No significant differences were found between groups on any other secondary depression, anxiety, psychosocial, or sleep outcome measures. Key SNPs and BDNF did not significantly moderate response. No significant differences occurred between groups for total adverse effects, aside from more nausea in the active group. LIMITATIONS Very high placebo response rates suggest a placebo run-in design may have been valuable. INTERPRETATION The adoption of a nutraceutical 'shotgun' approach to treating MDD was not supported, and appeared to be less effective than adding placebo to treatment as usual.
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3.
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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4.
Adjunctive N-acetylcysteine in depression: exploration of interleukin-6, C-reactive protein and brain-derived neurotrophic factor.
Hasebe, K, Gray, L, Bortolasci, C, Panizzutti, B, Mohebbi, M, Kidnapillai, S, Spolding, B, Walder, K, Berk, M, Malhi, G, et al
Acta neuropsychiatrica. 2017;(6):337-346
Abstract
OBJECTIVE This study aimed to explore effects of adjunctive N-acetylcysteine (NAC) treatment on inflammatory and neurogenesis markers in unipolar depression. METHODS We embarked on a 12-week clinical trial of NAC (2000 mg/day compared with placebo) as an adjunctive treatment for unipolar depression. A follow-up visit was conducted 4 weeks following the completion of treatment. We collected serum samples at baseline and the end of the treatment phase (week 12) to determine changes in interleukin-6 (IL6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following NAC treatment. RESULTS NAC treatment significantly improved depressive symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial. Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response. However, we found no significant changes in IL6, CRP and BDNF levels following NAC treatment. CONCLUSION Overall, this suggests that our results failed to support the hypothesis that IL6, CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression. IL6 may be a useful marker for future exploration of treatment response.
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5.
Increased plasma levels of competing amino acids, rather than lowered plasma tryptophan levels, are associated with a non-response to treatment in major depression.
Ormstad, H, Dahl, J, Verkerk, R, Andreassen, OA, Maes, M
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2016;(8):1286-96
Abstract
Lowered plasma tryptophan (TRP) and TRP/competing amino acid (CAA) ratio may be involved in the pathophysiology of major depression (MDD). Increased cortisol and immune-inflammatory mediators in MDD may affect the availability of TRP to the brain. We investigated whether baseline or post-treatment TRP, CAAs and TRP/CAA ratio are associated with a treatment response in MDD and whether these effects may be mediated by cortisol or immune biomarkers. We included 50 medication-free MDD patients with a depressive episode (DSM diagnosis) and assessed symptom severity with the Inventory of Depressive Symptomatology (IDS) before and after treatment as usual for 12 weeks (endpoint). Plasma levels of TRP, CAAs, the ratio, cortisol, CRP and 6 selected cytokines were assayed. The primary outcome was a 50% reduction in the IDS, while the secondary was a remission of the depressive episode. In IDS non-responders, CAAs increased and the TRP/CAA ratio decreased, while in IDS responders CAAs decreased and the TRP/CAA ratio increased from baseline to endpoint. In patients who were still depressed at endpoint TRP and CAAs levels had increased from baseline, while in remitted patients no such effects were found. Increases in CAAs were inversely correlated with changes in interleukin-1 receptor antagonist levels. The results show that increased CAA levels from baseline to endpoint are associated with a non-response to treatment in MDD patients. This suggests that the mechanism underpinning the CAA-related treatment resistance may be related to changes in immune pathways. CAA levels and amino acid metabolism may be new drug targets in depression.
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6.
Investigation of the efficacy of adjunctive therapy with bioavailability-boosted curcuminoids in major depressive disorder.
Panahi, Y, Badeli, R, Karami, GR, Sahebkar, A
Phytotherapy research : PTR. 2015;(1):17-21
Abstract
Current medications have limited efficacy in controlling the symptoms of major depressive disorder (MDD), and are associated with several adverse events on long-term use. Curcuminoids are extremely safe and multifunctional phytopharmaceuticals that have been shown to alleviate depressive symptoms in a variety of experimental models. The present study aimed to investigate the efficacy of curcuminoids as an add-on to standard antidepressants in patients with MDD. One hundred and eleven subjects were assigned to standard antidepressive therapy plus curcuminoids-piperine combination (1000-10 mg/day; n=61) or standard antidepressive therapy alone (n=50) for a period of 6 weeks. Efficacy measures were changes in the psychological status on the basis of the Hospital Anxiety and Depression Scale (HADS) and Beck Depression Inventory II (BDI-II). The BDI-II and HADS total and subscale scores were reduced by the end of trial in both study groups. There were significantly greater reductions in total HADS score and subscales of anxiety and depression in the curcuminoids versus control group (p<0.001). Likewise, reductions in BDI-II total score and scores of somatic and cognitive subscales were found to be greater in the curcuminoids compared with control group (p<0.001). Co-administration of curcuminoids with piperine may be used as a safe and effective add-on to standard antidepressants in patients with MDD.
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7.
Comparison of adjunctive use of aripiprazole with bupropion or selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors: analysis of patients beginning adjunctive treatment in a 52-week, open-label study.
Clayton, AH, Baker, RA, Sheehan, JJ, Cain, ZJ, Forbes, RA, Marler, SV, Marcus, R, Berman, RM, Thase, ME
BMC research notes. 2014;:459
Abstract
BACKGROUND This post hoc analysis assessed the safety, tolerability and effectiveness of long-term treatment with aripiprazole adjunctive to either bupropion or selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD). METHODS Data from de novo patients (did not participate in 2 previous studies) in a 52-week, open-label safety study of adjunctive aripiprazole after documented inadequate response to 1-4 antidepressant treatments (ADTs; SSRI, SNRI, or bupropion) were analyzed post hoc. Assessments included safety and tolerability, sexual functioning (Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI]) and Clinical Global Impressions-Severity (CGI-S). RESULTS Forty-seven patients received bupropion plus aripiprazole and 245 received an SSRI/SNRI plus aripiprazole; 19 (40.4%) and 78 (31.8%), respectively, completed 52 weeks of treatment, and 46 and 242, respectively, received ≥1 dose of study medication (safety sample). Median time to discontinuation (any reason) was 184.0 days. Overall, 97.8% of patients in the bupropion group and 93.8% in the SSRI/SNRI group experienced ≥1 adverse event. The most common treatment-emergent adverse events were fatigue (26.1%) and somnolence (21.7%) with bupropion and fatigue (23.6%) and akathisia (23.6%) with an SSRI/SNRI. Mean change in body weight at week 52 (observed cases) was +3.1 kg for bupropion and +2.4 kg for an SSRI/SNRI. Treatment-emergent, potentially clinically relevant abnormalities in fasting glucose occurred in 8.3% of patients with bupropion and 17.4% with an SSRI/SNRI; for abnormalities in fasting total cholesterol, the incidence was 25.0% and 34.7%, respectively. Mean (SE) change from baseline in fasting glucose was 1.4 (1.9) mg/dL with bupropion and 2.7 (1.5) mg/dL with an SSRI/SNRI. Baseline MGH-SFI item scores indicated less severe impairment with bupropion versus an SSRI/SNRI; in both groups most MGH-SFI items exhibited improvement at week 52. Mean CGI-S improvement at week 52 (last observation carried forward) was -1.4 with bupropion and -1.5 with an SSRI/SNRI (efficacy sample). CONCLUSIONS There were no unexpected AEs with long-term adjunctive aripiprazole therapy when added to either bupropion or SSRIs/SNRIs, and symptom improvement was similar between ADT groups. Sexual functioning in patients with MDD on antidepressants was also modestly improved after adding aripiprazole. TRIAL REGISTRATION ClinicalTrials.gov: NCT00095745 (November 9, 2004).
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8.
Selected factors determining a way of coping with stress in type 2 diabetic patients.
Sobol-Pacyniak, AB, Szymczak, W, Kwarta, P, Loba, J, Pietras, T
BioMed research international. 2014;:587823
Abstract
OBJECTIVES The aim of the study was to examine factors which determine stress coping styles in type 2 diabetic (T2D) patients, with regard to selected demographic variables, clinical diabetes-related variables and selected psychical variables (anxiety level and assessment of depressive disorders). METHODS 50 T2D patients, aged 59.9 ± 10.2 years were assessed by Coping Inventory for Stressful Situations (CISS), Spielberger State-Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI). In the statistical analysis simple and multivariable logistic regression models were used. RESULTS Variables significantly increasing the selection risk of stress coping style different from preferred task-oriented strategy in a simple logistic regression model are: hypoglycemia within three months prior to the research: odds ratio (OR) = 6.86 (95% confidence interval (CI) 1.25-37.61), taking antidepressants or neuroleptics: OR =15.42 (95% CI 2.42-98.33), severe depression in Beck's scale: OR = 84.00 (95% CI 6.51-1083.65), high state-anxiety level: OR = 9.60 (95% CI 1.08-85.16), and high trait-anxiety level: OR = 18.40 (95%CI 2.96-114.31), but in a multivariable model, diagnosed depression is the strongest factor: OR = 32.38 (95% CI 4.94-212.13). CONCLUSIONS In T2D patients, the strategy to cope with stress appears to be mostly influenced by psychical predisposition.
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9.
Hippocampal N-acetylaspartate and morning cortisol levels in drug-naive, first-episode patients with major depressive disorder: effects of treatment.
Wang, Y, Jia, Y, Chen, X, Ling, X, Liu, S, Xu, G, Huang, L
Journal of psychopharmacology (Oxford, England). 2012;(11):1463-70
Abstract
An excess of glucocorticoids has been associated with hippocampal pathology in major depressive disorder (MDD). However, the relationships between depression, hippocampal structure and function, and cortisol levels are unclear, and the effects of antidepressant treatment on the measures are not well studied. For this study, 26 first-episode, treatment-naive, non-late-life adult depressed patients and 13 healthy controls were enrolled. Subjects underwent proton magnetic resonance spectroscopy ((1)H MRS) to obtain metabolite levels from the bilateral hippocampus. Patients with MDD were treated with serotonergic-noradrenergic reuptake inhibitor duloxetine for 12 weeks. After the 12-week period, all subjects with MDD underwent (1)H MRS again. Morning serum cortisol levels also were measured both before and after antidepressant treatment. Comparison of baseline values indicated that there were no significant differences in any of the metabolite ratios (N-acetyl aspartate/creatine (NAA/Cr) and choline (Cho)/Cr) in the bilateral hippocampus. After treatment, NAA/Cr ratios increased significantly in the right hippocampus compared with pre-treatment values. There was no correlation between morning serum cortisol levels and bilateral hippocampal NAA/Cr or Cho/Cr in patients with MDD. These findings suggest that there are unaltered hippocampal metabolites in the early stage of MDD. Antidepressant treatment may affect hippocampal NAA levels in patients with MDD. In addition, the results do not support cortisol-mediated hippocampal neurotoxicity as the major etiological mechanism.
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10.
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.