Adjunctive Nutraceuticals as depression treatment

(Series: critical commentaries on depression trials. Prior posts: 1, 2, 3, 4)

Antidepressants only marginally outperform placebos (Khan & Brown, 2015) – which has led to a number of novel strategies to try to improve treatment for patients suffering from depressive disorders. Adjunctive Nutraceuticals present one such strategy: providing patients with specific forms of dietary supplements in addition to antidepressants (Wikipedia: Nutraceuticals). This is in line with general dietary supplements: the industry has grown considerably in the last decades, and more than half of the US adult population consume dietary supplements regularly (Wikipedia: Dietary Supplements). Interestingly, meta-analyses have repeatedly failed to find any evidence for positive effects of dietary supplements such as Vitamin C on numerous health outcomes – ranging from the common cold to cancer – in general population samples (Hemilä & Chalker, 2013; Lee, Oh & Myung, 2015).

In a new paper entitled “Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses”, Sarris et al. investigated whether adjunctive nutraceuticals provide significant benefits to patients with Major Depression. They reviewed 40 studies in total: 9 studies on folic acid, folinic acid, methylfolate, or a combination of folic acid and vitamins B6 and B12; 8 on tryptophan (or 5-HTP) and omega-3; 4 on S-adenosylmethionine; 2 on zinc, inositol, vitamin C, and vitamin D; and 1 for creatine, B12, and an amino acid combination. The mean sample size per study was small (n=63), and only 31 of the 40 studies were randomized placebo-controlled trials.

The authors concluded:

Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.

Because such a conclusion of a review and meta-analysis by prominent authors in one of the flagship journals of the field may have have considerable impact not only on researchers and clinicians, but also policy-makers, it should be done with great care. While the study was conducted thoroughly, and while the paper is well-written and features a number of important limitations, the authors’ conclusion does not seem to take these limitations into account. When taking them seriously, there is little evidence that supports the adjunctive use of nutraceuticals.

1) Publication bias
The authors included 40 published studies in their analysis, but did not include unpublished work. This is a concern because prior investigations have established severe levels of publication bias: when clinical trials discover significant differences between the treatment and the placebo group, results are much more often published compared to studies with negative results (Kirsch et al. 2008; Turner et al. 2008). On top of that, the authors themselves mention numerous times in the manuscript that funnel plots showed evidence for publication bias*, but do not use novel meta-analytic techniques aimed at controlling for publication bias. This is especially relevant considering that the included 40 studies featured on average a total of n=63, which means that the actual group sizes were considerably smaller because many studies had 2 subsamples (nutraceutical vs. placebo). Of note, the authors mention that they do not find significant relationships between sample size and effect size, but that may well be due to the very small number of studies included in most of their meta-analysis.

2) Conflicts of interest
The authors mention that industry-funded clinical trials are about 5 times more likely than independent investigations to report positive results (Perlis et al. 2005; see also Sen & Prabhu, 2012), and that only a minority of trials are independent from industry sponsoring. It would be interesting to see whether this also holds in the field of nutraceuticals.

Interestingly, not only are there conflicts of interest regarding the content of the present meta-analysis, seeing that the majority of trials were under industry-sponsorship – on top of that, all but one author report conflicts of interests, to the degree that the section in the paper is nearly twice as long as the introduction (731 words vs. 398 words).

3) Safety concerns and adverse effects
Most of the included trials lasted 4-8 weeks – a standard length for antidepressant trials. Considering that depression is an often chronic condition (cf. McClintock et al. 2010), this is a comparably short timeframe to investigate the efficacy of any form of treatment. And while a few weeks are certainly long enough to pick up on short-term adverse effects such as nausea, genital symptoms or sleep problems, they are not sufficient to investigate moderate or long-term side-effects and adverse consequences that food supplements may have. For antidepressants themselves, for instance, there is considerable evidence that they increase the probability to develop diabetes (Andersohn et al., 2009).

The authors note that there are safety concerns regarding some of the substances such as folic acids that are under suspicion to increase the risk for developing cancer.

Despite the mild nature of the adverse effects reported in the included studies, nutraceuticals are not without risk or serious safety concerns when used at high doses, over long periods of time, and/or when combined with certain medications.

Summary
In sum, evidence of publication bias in 40 studies with very small samples sizes, the severe conflicts of interests, and potential safety concerns raise doubts about the usefulness of adjunctive nutraceuticals, and considerably more evidence should be required before coming to strong conclusions regarding their efficacy.

* Funnel plots visualize the relationship between treatment efficacy and sample size; in case of publication bias, these plots usually show that studies with smaller n report higher levels of treatment efficacy, whereas larger studies have reduced or no efficacy.

References
Andersohn, F., Schade, R., Suissa, S., Garbe, E., 2009. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry 166, 591–598.

Hemilä, H., Chalker, E., 2013. Vitamin C for preventing and treating the common cold. Cochrane database Syst Rev CD000980.

Lee, B., Oh, S.-W., Myung, S.-K., 2015. Efficacy of Vitamin C Supplements in Prevention of Cancer: A Meta-Analysis of Randomized Controlled Trials. Korean J Fam Med 36, 278–85.

McClintock, S.M., Husain, M.M., Greer, T.L., Cullum, C.M., 2010. Association between depression severity and neurocognitive function in major depressive disorder: a review and synthesis. Neuropsychology 24, 9–34.

Khan, A., Brown, W.A., 2015. Antidepressants versus placebo in major depression : an overview. World Psychiatry 14, 294–300.

Kirsch, I., Deacon, B.J., Huedo-Medina, T.B., Scoboria, A., Moore, T.J., Johnson, B.T., 2008. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5, e45.

Perlis, R., Perlis, C., Wu, Y., Hwang, C., Joseph, M., Nierenberg, A.A., 2005. Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Am J Psychiatry 162, 1957–1960.

Sen, S., Prabhu, M., 2012. Reporting bias in industry-supported medication trials presented at the American Psychiatric Association meeting. J Clin Psychopharmacol 32, 2012.

Turner, E.H., Matthews, A.M., Linardatos, E., Tell, R.A., Rosenthal, R., 2008. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 358, 252–60.