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Vitamin D, fish oil and folates may enhance antidepressants

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“Do antidepressants work better when taken with supplements?,” the Mail Online asks.

A new review of existing evidence suggests that, “Omega-3 fish oils, certain amino acids, folate and vitamin D” may boost the beneficial effect of antidepressants, the Mail says.

There was also tentative evidence that S-Adenosyl methionine (SAMe) – a type of amino acid supplement popular in some countries – may boost the effects of antidepressants.

At a glance

  • Evidence was strongest for omega-3 supplements; the evidence of benefits of folate, vitamin D and “SAMes” was arguably less robust.
  • Many of the studies looked at were industry funded, sopublication bias, as highlighted by the current team of researchers, could be a factor.
  • Even over-the-counter supplements can be potentially harmful for some people – for example, omega-3 may not be suitable for men with prostate cancer – so always check with your pharmacist or GP.
  • The research looked at nutraceuticals – nutrient-based supplements produced to pharmaceutical standards. Other brands of supplements may be less effective or less safe to use.

Researchers from Melbourne, Australia, reviewed the evidence about combining antidepressant treatment for depression with “nutraceuticals” – nutrient-based supplements produced to pharmaceutical standards. This means that consumers can be confident about information relating to important issues such as dosage and ingredients. 

The researchers looked at 40 studies, of varying quality, to pool the results where possible and draw conclusions. They found that omega-3 supplements (usually derived from fish oil) had a significant effect, but there were varying results for other nutraceuticals studied.

In some cases, only one or two small studies had been published, making it hard to rely on the results. The researchers also found evidence that more positive studies than expected had been published, suggesting that some negative studies had not been published (publication bias).

The researchers say they have shown that EPA-rich omega-3 oil “may be recommended” as an additional treatment for depression, alongside antidepressants. But they caution that people taking antidepressants should talk to their doctors before starting any supplements.  

Where did the story come from?

The study was carried out by researchers from the University of Melbourne, Swinburne University of Technology, Deakin University, the National Centre of Excellence in Youth Mental Health, and the Florey Institute for Neuroscience and Mental Health, all in Australia, and Harvard Medical School in the US. Information on funding was not provided in the study. 

The study was published in the peer-reviewed journal The American Journal of Psychiatry. Six of the seven authors reported financial interests in the field, mainly research funding and payments for speaking and writing about pharmaceuticals and nutraceuticals.

The Mail Online reported the results of the study uncritically, without considering the strength of the evidence for the different nutrients studied. Of the three nutrients named in its headline, the study only found strong evidence for omega-3.

What kind of research was this?

This study was a systematic review, with meta-analyses performed where there was sufficient evidence to do so. The researchers found enough studies to perform meta-analyses for just two nutrients: omega-3 and folic acid.

Meta-analyses are a good way of pooling results of studies, giving an overall view of whether a treatment works. However, systematic reviews and meta-analyses are only as good as the individual trials that go into them.

What did the research involve?

Researchers searched for any studies in English that looked at the effects of adding one of 14 nutrients known to be involved in nerve cell function to antidepressant treatments. They divided them into groups and summarised the results. For nutrients where they had at least two randomised controlled trials (RCTs), they carried out a meta-analysis.

They included open-label studies (where people knew which treatment they were taking) and uncontrolled studies, where they looked at the effect of adding a nutraceutical treatment to an antidepressant for people who had not responded to an antidepressant, without using a placebo for comparison. People in the studies had to have been diagnosed with a major depressive disorder or have ongoing depression.

For most of the nutrients, they summarised the results from the different studies, stating how many showed a positive effect and how many did not. For folic acid and omega-3 oils, they carried out meta-analyses of the mean difference between treatment and placebo, in the change from start to end of the study.

What were the basic results?

The most reliable evidence came from the meta-analyses:


Eight studies, all RCTs containing 20 to 122 people, looked at the effect of omega-3. Six of the eight studies showed a statistically significant reduction in depression scores for the treatment group, compared to the placebo group. The meta-analysis showed a statistically significant effect size of 0.61 for the difference between the treatment and placebo group (p=0.0009). It is not possible to interpret how clinically important this effect size is, as there was no information about the actual depression scores in the studies.

Folic acid

Four RCTs looked at the effects of folic acid. Two of them showed a reduction in depression scores for people taking folic acid, but one big study showed no significant effect. The meta-analysis showed no statistically significant effect size.

Other nutrients

Other nutrients which the researchers said showed positive effects included:

  • an amino acid based nutrient called S-adenosylmethionine (SAMe) – three small open-label studies found a positive effect; however, the only RCT found no significant effect
  • methylfolate, a type of folate – three small trials (one open-label) found a positive effect; one larger RCT found no significant effect
  • vitamin D – one RCT and one open-label study, both fairly small, found a positive effect

The other nutrients studied either had only one study looking at them, or mixed results. Evaluation of the meta-analyses showed big differences between the study results, and potential publication bias (where studies are published if they are positive, but not if they are negative).

How did the researchers interpret the results?

The researchers were upbeat about the results, especially for omega-3 oils, which they said could now be recommended for use as an add-on treatment alongside antidepressants, on the basis of their results.

They conclude: “several nutraceuticals may hold a potential clinical application to enhance the antidepressant effect of medications” and that groups issuing guidelines for doctors should consider including nutraceuticals.

However, they admit that good-quality, large RCTs are now needed.


Many people with depression benefit from taking antidepressants, but some either don’t find them helpful, or don’t completely recover while taking them. A safe and effective way to boost the effects of antidepressants would therefore be useful.

This study is a useful summary of which nutrients have been tested as an add-on to antidepressants, and an overall indication of what the studies found. It shows that, for most of these nutrients, the evidence comes from small studies of varying quality and length, and that we need bigger, better studies to get a true picture of their effects.

For the nutrients where there was sufficient evidence to carry out a meta-analysis, the difficulty is that the way the results are presented makes it hard to tell how much of an effect the nutrients actually had on people’s depression.

We don’t know whether the difference in the effect of treatment seen with omega-3 supplements amounted to more people getting completely better from depression, or whether some people’s depression scores on questionnaires improved a few points, but not enough to make much difference to their quality of life. The researchers describe the effect as “moderate to strong”.

If you are taking antidepressants and feel they are not making much difference, talk to your doctor. Antidepressants take a while to start working properly, so you may need to wait a little longer. If you’ve been taking them for a while and they don’t help, talk to your GP about trying another type of antidepressant, or a different dose. If you are interested in taking a supplement alongside your antidepressant, talk to your doctor first.

Finally, it’s important to remember that the study was looking at “nutraceuticals” – nutrient-based supplements produced to pharmaceutical standards. If you do decide to try a supplement, make sure it is from a trusted source with a reputation for safety and high quality.

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