Evidence-based Antidepressant Augmentation with Nutraceuticals "Nutraceuticals may provide an effective and safe approach to enhancing antidepressant effects, either by synergistically augmenting a particular activity of an antidepressant medication or by providing a range of additional biological effects" Some nutraceuticals (e.g. ω-3 PUFAs) have been demonstrated to be potentially effective as an adjunct treatment to antidepressant medication in patients with MDD but it is hard to draw a firm conclusion about the efficacy of ω-3 PUFAs. According to the results of the RCTs conducted so far, the antidepressant efficacy of saffron seems to be comparable to (i.e. equal to) the efficacy of classic AD agents, such as imipramine, fluoxetine and citalopram, in patients with MDD. As an add-on to SSRIs it is associated with a significantly greater decrease in depressive symptoms in com-parison with the administration of SSRI + placebo. Moreover, adverse events did not differ significantly between the two groups and the number of drop-outs due to side effects was much lower in the group that received saffron and fluoxetine co-treatment than in the group that received fluoxetine and placebo Results suggested that adjuvant administration of vitamin D (compared to placebo) is effective in the augmentation of SSRI therapy. According to the results of the meta-analysis by Shaffer et al., vitamin D supplementation is found to have a moderate but significant antidepressive effect in depressed individuals - adjuvant administration of vitamin D (compared to placebo) is effective in the augmentation of SSRI therapy Active folate forms (i.e. folinic acid and methylfolate) can be tentatively recommended in the adjuvant treatment of depression Results of preclinical and open-label human studies, in general, support the notion that creatine may have antidepressive effects as a stand-alone or add-on treatment. 1 However, only three placebo-controlled RCTs in humans have been conducted so far (participants in each study were exclusively females). In one of them creatine and SSRI were administered together from the start of the treatment of MDD, while in two others creatine therapy was commenced as an add-on agent only after the stand-alone AD treatment had proven to be ineffective. The results of those three studies are not conclusive as to whether the add-on administration of creatine to AD treatment is effective in the therapy of MDD A meta-analysis demonstrated that the administration of acetyl-L-carnitine (ALC) (vs. placebo) is associated with a significant decrease in depressive symptoms. The effectiveness of ALC as an adjunctive agent to standard ADs has not been tested so far in clinical studies but results of another meta-analysis of three RCTs (two of them included people with dysthymia, while one of them included people with fibromyalgia) indicated that ALC confers a comparable effect to standard ADs in alleviating depressive symptoms The efficacy of curcumin in the treatment of MDD as a stand-alone or as an adjuvant therapy still needs to be explored but some studies are promising including a very recent double-blind, placebo-controlled study demonstrated that adjunctive curcumin is more effective than placebo in the augmentation of standard AD treatment in patients with MDD even after a thorough survey The three placebo-controlled, randomized, double-blind studies conducted so far provided supportive results confirming that supplementation of AD therapy with Zn is effective Preclinical and clinical investigations have provided some reassuring data on the efficacy of magnesium both in the monotherapy and adjunctive therapy of depressive symptoms. Due to the various methodological shortcomings of the studies so far, large-scale, placebo-controlled, double-blind clinical trials in patients with MDD are needed to assess the efficacy of stand-alone and adjunctive Mg supplementation in the treatment of MDD Even though they are few in number, findings of open-label and placebo controlled human studies consistently suggest beneficial effects of DHEA either as monotherapy or as an adjunct to ADs in patients with depression or dysthymia The effects of add-on SAMe to standard AD therapy have indicated that adjunctive SAM treatment is beneficial either in enhancing symptom improvement and/or shortening the onset of the effects of AD treatment. It seems that the beneficial effects of SAM as anadjunct agent are irrespective of the type of co-administered AD (i.e. SAM is effective when it is co-administered both with older and newer kinds of ADs). Caution with regard to mania is required. Though the majority of the results suggest that probiotics have a positive effect on mood symptoms, the numerous methodological drawbacks of the existing 2 studies largely limit the applicability of those results to everyday clinical practice. It is note-worthy that the efficacy of adjunctive therapy with probiotics (viz. their co- administration with standard ADs) has only been sparsely investigated either in high-quality studies (i.e. studies with a double-blind, placebo-controlled design The efficacy of N-acetylcysteine (NAC) as an add-on treatment to ADs in MDD is poorly investigated, so further, well-designed, larger controlled trials are needed to clarify the usefulness of NAC in this indication. Other agents (e.g. inositol, selenium) with an expected antidepressive effect due to their biochemical activities in the CNS or the results of preclinical/epidemiological (observational) investigations have either failed to prove their efficacy in clinical studies as a possible add-on treatment or no high-quality clinical trials have been conducted so far with such agents. There is a lack of firm evidence on the beneficial effects of adjunctive OTC NSAID administration to ADs in the treatment of MDD Authors of a current systematic review concluded that further research is needed to establish whether tryptophan and 5-HTP are valuable agents in the adjuvant treatment of depression Review: Natural health products, dietary minerals and over-the-counter medications as add-on therapies to antidepressants in the treatment of major depressive disorder: a review https://doi.org/10.1016/j.brainresbull.2018.12.015 Creatine as a novel augmentation option: While results have been mixed, creatine as a treatment for people with SSRI-resistant MDD is suggested [1]. Effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy [2]. It targets downstream similar pathways to ketamine [3]. Even a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression [4]. Combined creatine and exercise has synergic effects and is more effective than a single treatment. Dietary supplementation with creatine can improve learning, memory, and mitochondrial function and have important implications for the treatment of diseases affecting memory and energy homeostasis [5]. Supplementation with creatine for 6 weeks is associated with improvement in verbal fluency tests in bipolar disorder [6]. "Oral creatine administration may improve short-term memory and intelligence/reasoning of healthy individuals but its effect on other cognitive domains remains unclear. Findings suggest potential benefit for aging and stressed individuals. Since creatine is safe, future studies should include larger sample sizes. It is imperative that creatine should be tested on 3 patients with dementias or cognitive impairment." [7] [1] https://www.ncbi.nlm.nih.gov/pubmed/26907087 [2] https://www.ncbi.nlm.nih.gov/pubmed/26822799 [3] https://www.ncbi.nlm.nih.gov/pubmed/26660117 [4] https://www.ncbi.nlm.nih.gov/pubmed/27757384 [5] https://www.ncbi.nlm.nih.gov/pubmed/29339557 [6] https://www.ncbi.nlm.nih.gov/pubmed/27890303 [7] https://www.ncbi.nlm.nih.gov/pubmed/29704637 4