Impact of Supplementation and Nutritional Interventions on Pathogenic Processes of Mood Disorders: A Review of the Evidence.

This narrative review was conducted using searches of the PubMed/Medline and Google Scholar databases from inception to November 2019. Clinical trials and relevant articles were identified by cross-referencing major depressive disorder (and/or variants) with the following terms: folate, homocysteine, S-adenosylmethionine (SAMe), L-acetylcarnitine, alpha-lipoic acid, N-acetylcysteine, L-tryptophan, zinc, magnesium, vitamin D, omega-3 fatty acids, coenzyme Q10, and inositol. Manual reviews of references were also performed using article reference lists. Abnormal levels of folate, homocysteine, and SAMe have been shown to be associated with a higher risk of depression. Numerous studies have demonstrated antidepressant activity with L-methylfolate and SAMe supplementation in individuals with depression. Additionally, the amino acids L-acetylcarnitine, alpha-lipoic acid, N-acetylcysteine, and L-tryptophan have been implicated in the development of depression and shown to exert antidepressant effects. Other agents with evidence for improving depressive symptoms include zinc, magnesium, omega-3 fatty acids, and coenzyme Q10. Potential biases and differences in study designs within and amongst the studies and reviews selected may confound results. Augmentation of antidepressant medications with various supplements targeting nutritional and physiological factors can potentiate antidepressant effects. Medical foods, particularly L-methylfolate, and other supplements may play a role in managing depression in patients with inadequate response to antidepressant therapies.

Overcoming Challenges to Treat Inadequate Response in Major Depressive Disorder.

​​ ​​ When a patient with major depressive disorder experiences inadequate response to an antidepressant, clinicians should employ measurement-based care strategies to improve outcomes. Evidence suggests that adjunctive therapies, such as the FDA-approved atypical antipsychotics, are efficacious when the initial treatment is well tolerated but not improving symptoms. Clinicians should consult guidelines, peer-reviewed journals, CME programs, and other sources to stay up-to-date with current and emerging treatments in this area. They should also be familiar with the available options for psychotherapy, neurostimulation, supplements, and exercise for patients who prefer alternative therapies. ​​.

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.

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.

Association between physician beliefs regarding assigned treatment and clinical response: re-analysis of data from the Hypericum Depression Trial Study Group.

BACKGROUND: We have previously shown an association between patient belief and treatment response in the Hypericum Depression Trial Study Group's 2002 study. We re-examined these data to determine whether clinical improvement was associated with physician belief about assigned therapy. METHODS: Three hundred and forty adults with major depression and baseline scores ≥20 on the 17-item Hamilton Depression Scale (HDRS-17) were randomized to Hypericum 900-1500mg/day, sertraline 50-100mg/day, or placebo for 8 weeks. At week 8, physicians guessed their patients' treatment. We analyzed 277 subjects with at least one post-baseline visit and physician guess data. We examined association between guess and improvement in HDRS-17 and whether treatment assignment moderated the effect of belief on remission (final HDRS-17 score <8). RESULTS: Patient and doctor guesses agreed at 53% for sertraline, 68% for Hypericum, and 52% for placebo (kappa=0.37). Doctors guessed placebo correctly (38%) more than sertraline (18%) or Hypericum (19%) (p=0.001). Adverse event scores were significantly greater among subjects for which the clinicians guessed Hypericum (p<0.001) or sertraline (p=0.005) compared to placebo. Significant improvements in HDRS-17 score were found when comparing the Hypericum-guess (p<0.001) or the sertraline-guess group (p<0.001) against the placebo-guess group. Remission rates were significantly greater for subjects whose clinicians guessed sertraline (p<0.001) or Hypericum (p<0.001) versus placebo. CONCLUSION: Doctors tended to guess placebo more easily than Hypericum or sertraline, and their guesses tended to favor active therapies when improvement was more robust. Results show association but not causation, and merit more careful investigation.

Folates and S-adenosylmethionine for major depressive disorder.

Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased significantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, efficacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.

Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder.

OBJECTIVE: To characterize the impact of S-adenosyl methionine (SAMe) on homocysteine and potential risk of adverse cardiovascular effects by examining plasma levels of SAMe, S-adenosyl homocysteine (SAH), total homocysteine (tHCY), methionine (MET), and 5-methyltetrahydrofolate (5-MTHF) in 35 of 73 patients from a 6-week randomized double-blind, placebo-controlled trial of SAMe augmentation in serotonin reuptake inhibitor partial responders with DSM-IV major depressive disorder (MDD), published in 2010. METHOD: Subjects were randomized from June 4, 2004, until August 8, 2008, to adjunctive placebo or SAMe 800-1600 mg/d for 6 weeks. Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm (by paired t test) and between treatment arms (by independent samples t test). Univariate analysis of variance and Fisher Protected Least Significant Difference were carried out to compare posttreatment levels of each one-carbon cycle intermediate. Secondary outcome measures included associations between clinical improvement and change in plasma intermediate levels, examined by linear regression (for change in Hamilton Depression Rating Scale scores) and logistic regression (for response or remission). RESULTS: We found significant differences in pretreatment plasma levels of tHCY (P = .03) between the SAMe and placebo arms. Following 6 weeks of treatment, plasma SAMe (P = .002) and SAH (P < .0001) levels increased significantly in the SAMe arm; no intermediates in the placebo group changed significantly. Posttreatment plasma SAMe (P = .0035), SAH (P < .0001), and tHCY (P = .0016) levels differed significantly between the SAMe and placebo groups. No significant associations were found between plasma intermediate levels and clinical improvement, response, or remission. CONCLUSIONS: Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects, the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected. Our findings, however, have some significant limitations and should be interpreted with caution. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00093847.

Association between patient beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum Depression Trial Study Group.

OBJECTIVE: To reanalyze data from a 2002 study by the Hypericum Depression Trial Study Group to determine whether patients who believed they were receiving active therapy rather than placebo obtained greater improvement, independent of treatment. METHOD: Three hundred forty adults with major depressive disorder (according to the Structured Clinical Interview for DSM-IV) and baseline scores of ≥ 20 on the 17-item Hamilton Depression Rating Scale (HDRS-17) were randomized to Hypericum perforatum 900-1,500 mg/d, sertraline 50-100 mg/d, or placebo and were asked to guess their assigned treatment after 8 weeks. This reanalysis of data was performed from October 1, 2009, to April 15, 2011. The intent-to-treat sample included 207 subjects (mean age = 44 years) who had (1) at least 1 postbaseline visit; (2) adherence data based on serum levels of hyperforin, sertraline, and desmethylsertraline; and (3) guess data. Univariate factorial analysis of variance was used to determine whether treatment assignment affected clinical improvement according to HDRS-17 score and whether this effect was moderated by patient guess of sertraline, Hypericum, or placebo. Analysis of covariance was used to determine whether side effects mediated improvement in the context of patient guess and assigned treatment. χ2 analyses compared response rates (≥ 50% decrease in HDRS-17 score) between the guess groups and between the treatment groups within each guess group. RESULTS: Assigned treatment had no significant effect on clinical improvement (P = .65), but patient guess was significantly associated with improvement (P < .001), and treatment and guess interacted significantly (P = .005). Among subjects who guessed placebo, clinical improvement was small and did not differ significantly across treatments. Among subjects who guessed Hypericum, improvement was large and did not differ significantly across treatments. Among subjects who guessed sertraline, those who received placebo or sertraline had large improvements, but those who received Hypericum had significantly less improvement (P < .001). Similar findings were obtained for response rates. CONCLUSIONS: Patient beliefs regarding treatment may have a stronger association with clinical outcome than the actual medication received, and the strength of this association may depend upon the particular combination of treatment guessed and treatment received.

Complementary and alternative medicine for major depressive disorder: a meta-analysis of patient characteristics, placebo-response rates, and treatment outcomes relative to standard antidepressants.

OBJECTIVE: To compare patient characteristics, placebo-response rates, and outcome differences in active treatment compared to placebo in randomized controlled trials (RCTs) of complementary and alternative medicine (CAM) and standard antidepressants for major depressive disorder (MDD). DATA SOURCES: Eligible studies were first identified using searches of PubMed/MEDLINE, restricted to English, by cross-referencing the search term placebo with each of the antidepressants (those that had received letters of approval by the US, Canadian, or EU drug regulatory agencies for the treatment of MDD) and selected CAM agents. These searches were limited to articles published between January 1, 1980, and September 15, 2009 (inclusive). Reference lists from identified studies were also searched for studies eligible for inclusion. STUDY SELECTION: We selected RCTs for MDD that included validated diagnostic assessment and baseline/outcome measures of illness severity. Assessment was limited to widely used CAM agents most frequently studied in RCTs with pill placebo: St John's wort, omega-3 fatty acids, and S-adenosyl-L-methionine (SAMe). DATA SYNTHESIS: Of eligible publications, 173 reported results of 1 trial, and 5 included > 1 trial, representing a total of 185 RCTs. Patient variables, including illness severity, were similar across CAM and antidepressant RCTs, except for a higher proportion of women in CAM studies (P = .0003). Random-effects meta-analysis indicated that both antidepressant and CAM monotherapy resulted in superior response rates compared with placebo. Placebo-response rates were significantly lower for patients enrolled in CAM versus antidepressant RCTs (P = .002). Meta-regression analyses yielded no significant differences in the relative risk of prematurely discontinuing therapy due to any reason between active treatment and placebo for antidepressant and CAM RCTs, although discontinuation due to adverse events was higher in antidepressant RCTs compared to CAM RCTs (P = .007). CONCLUSIONS: Participants in CAM trials were more likely to be female and to have a lower placebo-response rate compared to those in standard antidepressant trials for MDD. Trials of standard antidepressants and CAM therapies were composed of patients with similar depression severity.

Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder.

Despite the increasingly large array of antidepressants available to treat major depressive disorder, patients continue to experience relatively modest response and remission rates. In addition, patients may experience adverse side effects from pharmacotherapy that not only hinder treatment compliance and adherence but, in some cases, may also contribute to increased disability, patient suffering, morbidity, and mortality. In order to enhance treatment efficacy and tolerability, patients and clinicians have become increasingly interested in nonpharmaceutical supplements for treating depression. One of the best-studied of these supplements is S-adenosyl-L-methionine (SAM-e), a naturally occurring molecule present in all living cells and a major methyl group donor in the human body. Controlled trials have found SAM-e to be more efficacious than placebo and equal in efficacy to the tricyclic antidepressants for treating major depressive disorder (MDD) when administered parenterally (either intravenously or intramuscularly). Less evidence supports the use of oral SAM-e, although some trials have demonstrated its efficacy as well. In addition, there is a paucity of evidence examining whether oral forms of SAM-e can be safe, well tolerated, and efficacious when used as adjunctive treatment for antidepressant nonresponders with MDD. Although preliminary data suggest SAM-e may be useful as an adjunctive therapy to antidepressants, controlled studies are needed to confirm or refute these preliminary findings.

Timing of clinical improvement and symptom resolution in the treatment of major depressive disorder. A replication of findings with the use of a double-blind, placebo-controlled trial of Hypericum perforatum versus fluoxetine.

BACKGROUND: Our objective was to assess for the relationship between timing of clinical improvement and resolution of depressive symptoms during the treatment of major depressive disorder (MDD). Thirty-nine MDD outpatients who responded following a 12-week, double-blind study comparing Hypericum perforatum, fluoxetine or placebo were included in the analysis. METHODS: Onset of clinical improvement was defined as a 25% decrease in 17-item Hamilton Depression Scale (HDRS-17) scores that was not followed by a subsequent worsening of symptoms. Controlling for baseline symptom severity, we then assessed for the relationship between timing of clinical improvement and depressive symptom severity at endpoint. RESULTS: Among responders, earlier clinical improvement predicted lower HDRS-17 scores at week 12 (p = 0013). This was also true of responders who received active treatment (n = 29, p = 0.0113) but not placebo responders (n = 10; p > 0.05). Finally, patients with an early onset of clinical improvement (occurring during the first 2 weeks) had lower week 12 HDRS-17 scores than patients with a late onset of clinical improvement (p = 0.0404). CONCLUSION: In the present work, earlier as well as early clinical improvement during treatment is predictive of greater symptom resolution at endpoint among responders. This was replicated among patients who received active treatment (either hypericum or fluoxetine) but not placebo.

S-adenosyl-methionine in depression: a comprehensive review of the literature.

As many as 29% to 46% of patients with major depressive disorder (MDD) show only partial or no response to an adequate course of an antidepressant. The current practice is to increase the dose, switch to another antidepressant, or to combine the initial antidepressant with an antidepressant of a different class or a non-antidepressant agent. A growing number of studies have also been directed toward exploring the potential use of augmenting traditional antidepressants with nonpharmaceutic supplements, or even using such supplements as monotherapy for depression. S-adenosyl-methionine (SAMe) is one such compound. Compared with many other nonpharmaceutic supplements, SAMe has been extensively studied, and impressive literature extending back three decades suggests the antidepressant efficacy of SAMe. In the present work, the authors summarize the literature, focusing on the potential role of SAMe and its precursors in the pathophysiology of MDD, followed by a review of studies examining the use of SAMe for the treatment of MDD. Finally, the authors propose a model that would explain the actions of SAMe in the central nervous system.