August 3, 2016

Nutraceuticals for Adjunctive Depression Care

Evidence suggests supplements are effective and safe when used in combination with antidepressants
Systematic review of existing research reveals that certain nutrients enhance the effectiveness of antidepressant medications—good news for clinicians caring for treatment-resistant patients.


Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry. 2016;173(6):575-587.


This study was a systematic search of multiple databases, including PubMed, CINAHL, Cochrane Library, and Web of Science. Included were human clinical trials that identified both specific nutraceuticals and type of trial. Searched nutraceuticals included omega-3 fatty acids, folic acid, vitamin D, and methylfolate. These nutraceuticals were chosen based on their reputation as supportive for brain and neurological function.  
In combination were searched the terms “depression,” “major depressive disorder,” “major depression,” “mood,” “antidepressant,” and “SSRI” along with “adjunct,” “adjunctive,” “adjuvant,” “augmentation,” and “add-on.” Studies were required to have a duration of at least 3 weeks of treatment.  Out of an initial search of 5,287 articles, 40 studies met the full inclusion criteria. Of the 40 studies reviewed for this study, 31 were randomized, double-blind, and placebo-controlled trials.


Subjects of these clinical trials were currently using antidepressant medications and were diagnosed with major depressive disorder or ongoing depression. Depression was defined as current use of antidepressant medication and a moderate or above-threshold level of depressive symptoms according to a validated scale, such as a score greater than 17 on the Hamilton Depression Rating Scale (HAM-D). The majority of studies used the DSM-IV criteria for a diagnosis of major depressive disorder; 29 studies used the HAM-D; and the remaining studies used other well-known scales, such as the Beck Depression Inventory or the Montgomery-Åsberg Depression Rating Scale. The mean sample size for these studies was 63, with a mean age of 44 years.  Close to 70% of the subjects were female. Research subjects were on a variety of antidepressant medications, most commonly SSRIs (eg, fluoxetine), citalopram, and escitalopram.

Key Findings

Overall, 68% of the clinical trials found positive effects for the adjunctive intervention under study. In 6 of the 8 studies omega-3 fatty acids contributed most to the positive effect. Positive results were found for replicated studies testing methylfolate, S-adenosylmethionine (SAMe), vitamin D, and omega-3 fatty acids (primarily in the eicosapentaenoic (EPA) or ethyl-EPA forms). Single studies showed benefit for creatine monohydrate, folinic acid, and general amino acid combinations. Studies showed trends to benefit, but with mixed conclusions, for zinc, folic acid, vitamin C, and tryptophan. None of the studies reported major side effects, aside from occasional stomach upset or nausea. 

Practice Implications

When it comes to depressive illness, modern psychiatry is challenged with treatment-resistant patients. About 70% of patients with mild to moderate depression—the population that accounts for most antidepressant prescriptions—do not respond to antidepressant medications.1  Even more, there is a growing recognition in the field that full remission is either short-lived or absent. The National Institute of Mental Health reports that 25% of those patients who do respond to pharmacotherapy experience tachyphylaxis (diminished response) at some point during treatment.2
Given this, augmentation strategies in depression treatment need to be considered for optimal antidepressant care. While the focus in conventional care involves either switching medications or prescribing add-on drugs, natural medicines may provide another option. A body of research is starting to evaluate natural medicines as helpful, and even modern psychiatry has been creating consensus to look more seriously at nutraceuticals.3 This paper reviewed numerous trials, and chose studies that adhered to rigorous standards of conventional medical paradigms. 
As a naturopathic doctor, I believe this is a useful review elucidating safer, natural means to support mood.
Among all the nutraceuticals studied in these papers, the authors determined that omega-3 fats, SAMe, folic acid and its related forms of methylfolate, and vitamin D were most well-supported for efficacy, with folinic acid and creatine each providing a nonreplicated rigorous study that suggested efficacy.
S-adenosylmethionine (SAMe) is a well-known mood-supportive nutrient. It acts via a number of mechanisms, including supporting dopamine, raising serotonin, enhancing catecholamine methylation, and acting as an anti-inflammatory agent.4 Many countries consider SAMe a prescription medication. Dosage in the reviewed studies ranged from 800 mg to 1,600 mg a day. 
Omega-3 fatty acids are known to support neuronal structure and modulate inflammation. Common dosing of 1 g to 2 g a day showed a modest but significant effect overall, especially when the EPA fraction was greater than docosahexaenoic acid (DHA). 
Vitamin D is a neurosteroid that shows hippocampal, prefrontal cortex, and hypothalamic activity. It may also upregulate the production of dopamine and catecholamines.5 While dosages vary, I generally recommend 2000 IU to 5,000 IU of vitamin D3 per day to achieve a 55 ng/ml to 70 ng/mL blood level of 25-hydroxyvitamin D [25(OH)D].  
Methylfolate, the primary, active form of folate in circulation, is known for its ability to methylate and contributes to the production of neurotransmitters.  This form of folate was used adjunctively in dosages of 15 mg to 30 mg a day.  While the data was stronger for SAMe, vitamin D, and omega-3 fatty acids, methylfolate and folinic acid both showed benefit although the study author stated these should be “tentatively recommended.” 
Creatine is a popular exercise supplement known for its benefit in athletic performance. It is postulated that brain creatine reserves are able to shift brain creatine kinase activity, thereby increasing adenosine triphosphate (ATP) production, perhaps improving brain bioenergetics in depression. Most studies dose 4 g a day, and some include a loading dose of 20 g per day for 1 week. 
Studies with trends to benefit, but mixed conclusions, included zinc, folic acid, vitamin C, and tryptophan. As a naturopathic doctor, I believe this is a useful review elucidating safer, natural means to support mood. There are limitations with these studies and this type of approach, mainly due to the inability to take individual patient information into account to create an individualized nutraceutical plan.  
For example, conclusions were mixed for zinc. However, there may be a greater effect in patients who test low for zinc status.  In the same vein, a very recent study suggests that reduced B vitamins may be more beneficial in depressed individuals who have high homocysteine along with concomitant methylenetetrahydrofolate reductase (MTHFR) polymorphisms.6
While no side effects were noted in this analysis, it is important to consider these with nutraceuticals as well. Creatine and SAMe may not be appropriate in bipolar disorder patients because they may worsen manic episodes, possibly due to methylation effects and ATP, respectively. Vitamin D, in toxic amounts, can alter calcium metabolism and lead to cardiovascular concerns. Omega-3 fatty acids in high amounts may affect coagulation and may increase overall lipid peroxides in the system. 
Although more research is needed, it is heartening to see nutraceuticals considered as options for patients with depression. These natural agents work on multiple pleiotropic mechanisms and may act to heal the underlying issues rather than just treat symptoms. Beyond offering individualized nutraceutical care, naturopathic medicine also has a great deal to offer regarding augmentation strategies for mental health. Sleep, exercise, lifestyle changes, stress reduction, and relaxation are all part of the naturopathic paradigm, and each has been shown to improve symptoms of depression. Using these along with individualized nutrients to both maximize the effectiveness of antidepressant medications and heal the underlying causes of depression may, in time, allow select patients to safely wean off prescription medications.7

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  1. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47-53.
  2. Solomon DA, Leon AC, Mueller TI, et al. Tachyphylaxis in unipolar major depressive disorder. J Clin Psychiatry. 2005;66(3):283-290. 
  3. Sarris J, Logan AC, Akbaraly TN, et al. International Society for Nutritional Psychiatry Research consensus position statement: nutritional medicine in modern psychiatry. World Psychiatry. 2015; 14(3):370-371.
  4. Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008;13(3):216-226.
  5. Shelton RC, Sloan Manning J, Barrentine LW, Tipa EV. Assessing effects of l-methylfolate in depression management: results of a real-world patient experience trial. Prim Care Companion CNS Disord. 2013;15(4). 
  6. Mech AW, Farah A. Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2016;77(5):668-671. 
  7. Bongiorno PB. Holistic Solutions for Anxiety & Depression in Therapy. New York, NY:W.W. Norton; 2015.