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The Case for Supplements in Treating Depression

A new paper highlights the usefulness of nutrients as adjunctive treatment.

wikimedia commons
Source: wikimedia commons

For decades, psychiatrists have been searching for ways to improve the treatment of major depressive disorder. This disease is a common constellation of symptoms including sad mood and/or decreased interest in normal activities that used to bring pleasure along with other symptoms, such as suicidal thoughts, poor energy, poor concentration and appetite or sleep disturbance. The depressive symptoms last long enough and are disabling enough to prevent normal functioning, affects approximately 6% of the world’s population each year, and is one of the most expensive diseases in the world in terms of lost productivity (1).

Existing initial treatments include psychotherapy and antidepressant medication, both with the possibility of side effects and with a success rate of at least reducing the depression symptoms of about 60%, with only a 30% chance of eliminating the depression. Once you get to resistant depression that hasn’t responded to initial treatments, the options tend to get more expensive and time consuming (such as intensive full day therapy or hospitalization) or you add additional medications that tend to have even more possibility for side effects, such as lithium or certain antipsychotics.

Lifestyle modification like good sleep hygiene, exercise, and eating well can be extremely helpful and likely preventative, but unfortunately since depression tends to rob you of motivation and energy, it’s not always easy to implement these strategies in someone who is already very ill. What is needed is something with low side effect potential that would hopefully treat an underlying nutritional or metabolic deficit that could help the person get better without the need for the more dangerous, expensive, and time consuming treatments…or at least make the person feel better enough so that therapy and lifestyle modification can be implemented more successfully.

Over the years, then, many nutrient supplements have been tested for just this purpose, but the literature ranges from poorly devised trials to case studies to good, solid randomized controlled experiments with careful thought and measurement behind them. Fortunately, Dr. Jerome Sarris from the University of Melbourne along with some of the nutraceutical expert psychiatrists out of Massachusetts General Hospital have now written an excellent paper looking at the major supplement trials over the years to find which ones really have good evidence and those that haven’t panned out (2). This paper is about using supplements for the adjunctive treatment of depression, that means in combination with antidepressants, so just for the purposes of this article, I’m not going to comment on supplements used alone.

In general, supplements used for treatment of depression come in three major categories. First are the “one carbon cycle” supplements that help the body with the folate cycle (3), a biochemical process that helps us take food and make it into DNA, neurotransmitters, and lots of other things we need to make the brain and body work well. The folate cycle is also responsible for recycling components used for these purposes and for the removal of some waste products. Helping the folate cycle move along efficiently, therefore, would theoretically help general health and depression at the same time.

The most common supplements used for this purpose are folate itself, methylfolate (which is a more biologically available form of folate than many people are less efficient at making for genetic reasons), SAMe, and vitamins B12 and B6. The researchers found positive evidence in the form of replicated randomized controlled trials for both SAMe (800-1600mg) and methylfolate (usually in the high dose forms of 7.5 or 15mg). The main downside to these specific supplements is they tend to be on the expensive side, but sometimes insurance will pay for methylfolate if someone has been found to have the genetic variation showing he or she makes it less efficiently. I’ve also seen anecdotal reports of irritability, and SAMe can cause mania in someone with bipolar disorder. There’s also some question if high dose long term supplementation of folic acid could cause cancer (it’s unclear if methylfolate would have the same risk).

A second category of supplement used for the treatment of depression are the omega 3 fatty acids, whose effects I reviewed in my last blog post, Is Fish Oil Beneficial for the Brain? The authors from the newest paper found, just like the authors of prior analyses, that fish oil supplements weighted towards EPA (not DHA or ALA) do have replicated, high quality evidence supporting their use at least short term (meaning 4-8 weeks) for adjunctive treatment of depression, with very little in the way of side effects. Long term use of omega3 supplements has been associated with increased risk of prostate cancer. I tend to err on the side of talking to people about getting more omega3 rich fish in the diet, but short term supplementation of EPA might be a good idea in light of these findings.

The third category of supplement used for the treatment of depression is tryptophan and its various forms, such as 5-HTP. This amino acid is the precursor for serotonin. If used with antidepressants that affect serotonin, it’s theorized that short term tryptophan could make antidepressants work better or faster. However, since it’s unlikely serotonin itself is the real issue with major depressive disorder (the so-called monoamine hypothesis or ‘chemical imbalance’ hypothesis of depression has long been discredited…now major depression is considered a disease of overlong and ineffective stress response combined with genetic vulnerability and neuroinflammation), it’s not surprising to find the overall evidence for tryptophan doesn’t seem to pan out (again, when used in combination with prescription antidepressants). The combination of tryptophan or 5-HTP with prescription antidepressants can also increase the risk for a dangerous possible side effect of many antidepressants called serotonin syndrome.

The final supplements commonly studied for the treatment of depression over the years don’t fit any single category, but all of them tend to help the body along the way with either energy production, reducing inflammation, making neurotransmitters, or helping tone down the stress response system. These supplements include zinc, creatine, vitamin D3, vitamin C, mixed amino acids, and inositol. Of these, surprisingly (or perhaps not so much, as vitamin D deficiency is the single most common vitamin deficiency I see as a psychiatrist), vitamin D3 has data to support supplementation for depression. One study used 1500 IU daily for 8 weeks with fluoxetine, the other 300,000 IU shot open label along with any antidepressant and measured differences after 4 weeks. More data is needed for zinc and creatine, whereas inositol seems to be a real bust.

In my own practice which is primarily people who come to me already on medications for depression, I’ve used neutroceuticals like SAMe or methylfolate when people are still struggling with depression symptoms that prevent effective lifestyle modification as a step before trying something with a worse side effect profile, such as the atypical antipsychotic abilify or lithium. Also I’ll use supplements in people where the situation isn’t urgent (i.e. immediate safety or job security, etc. is not at risk, in which case I’ll use hospitalization, more intensive therapy, and/or stronger prescription meds). I test B12 levels along with vitamin D levels and tend to use those if levels are low or even low normal, not just give everyone B12 shots willy nilly, but if someone doesn’t want to get labs checked or keeps forgetting I’ll often recommend a steady lowish dose of vitamin D, such as 2000IU daily in the wintertime. I practice at 40 degrees north latitude and there is a high percentage of D deficiency here. I don't subscribe to the idea that people need super-high levels...30-35 is fine, but I've also seen extremely low levels (3 is the record in my practice) and people perk up *immediately* with a more intense version of supplementation at that point.

I’ve had a few women try creatine temporarily to try to get the antidepressant to work faster, and in cases such as post-gastric bypass, vegetarians, or people who eat poorly I’ve been known to suggest zinc 25mg daily along with a B complex, and I’ll check iron levels as well (also if there is some clinical indication, such as vegetarian diet, heavy periods, or restless legs which can be a symptom of iron deficiency).

For the more general population and for the long term health of my patients, I tend to push more towards lifestyle modification, good sleep, regular exercise, and eating a variety of whole foods, avoiding processed foods for the most part, rather than supplements on a regular basis. That said, short term supplementation with some of the nutrients listed above could be quite useful for the adjunctive treatment of major depression and perhaps prevent someone getting stuck on more medications with worse side effects.