Antidepressant Risk/Benefit: Fish Oil Versus Placebo

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Could fish oil replace antidepressants as a first-line pill for depression?

fish oil

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Could fish oil replace antidepressants as a first-line pill for depression? New data from placebo research invite this consideration (just when the magnitude of antidepressant benefit is again questioned in a reanalysis of the STAR*D).1

The AMA Code of Medical Ethics states that use of a placebo without patients’ knowledge undermines trust. Accordingly, use of a placebo without deception would not be unethical.2 But could that help anyone? Clearly yes, say multiple studies of open-label placebo (OLP)3, due to the brain’s Bayesian approach to symptoms.4

For example: in a 3-week trial in irritable bowel syndrome (IBS), patients receiving OLP were told the pills were inactive (ie, “inert”), like a sugar pill that contained no medication. The 15-minute semi-scripted explanation included mention that the placebo effect is powerful; that the body can automatically respond to taking placebo pills (like Pavlov's dogs who salivated when they heard a bell), and that a positive attitude helps but is not necessary.5

Remarkably, roughly twice as many patients in the OLP group experienced “adequate pain relief” compared with those on the wait list (49% versus 23% at 11 days; 59% versus 35% at 3 weeks). A 2021 study replicated and advanced these findings.6

Rethinking Antidepressants

Antidepressants are better than placebos—by a small margin, with an average effect size of 0.3 across 7 meta-analyses.7 Antidepressant percentage-response rates are also superior to placebo by a small margin, narrowed by placebo response rates around 35% to 40%.8 In other words, placebos are markedly effective in depression (less so in treatment-resistant cases, where the placebo response rate is around 20%9). Thus prescribers must be careful not to undermine antidepressants’ placebo effect by inviting doubt about benefits relative to risks.10

Consider severe withdrawal symptoms on discontinuation, for example: incidence estimates range from 1% to 2%, per a respected academic11, to 50% in an oft-cited survey of patient experience12—an unfortunately broad range. Nevertheless, making clear to patients even a 1% to 2% chance of life-limiting symptoms (cannot take care of family, work, or go to school) could seriously interfere with positive expectations.

This leaves practitioners balancing 2 opposing goals and ethical principles: fully informed consent (autonomy), versus maximizing benefit (beneficence).10 Trying to narrow the divide between psychiatry and its critics, I presented this dilemma in an essay for Mad in America, a website that frequently criticizes psychiatry. Reader Altostrata commented:

There is no conflict between being honest about the marginal efficacy of antidepressants and maximizing the placebo effect. The supposed conflict can easily be resolved by — talking up a placebo! As long as you’re going to fabulate, do it with a relatively harmless drug.

Think about that for a minute, minus the little jab about “fabulating.” Is there a relatively harmless pill that could be offered as an OLP for depression? Better if the pill actually had some evidence for efficacy, as then practitioners would not have to be so careful to avoid deception, as they would with a true OLP.

Internists recommend aspirin as a treatment for some kinds of pain, knowing that most of any positive effect it produces is due to an expectation of benefit they have instilled more than a physiologic action.13 Could we recommend fish oil in like fashion?

Omega-3s for Depression: Not Quite a Placebo

Since 2011, there have been 3 meta-analyses of randomized trials of omega-3s for the treatment of depression. One attributed positive results to publication bias.14 Two found that doses less than 750 to 1000 mg of EPA (in a form that is at least 60% EPA relative to DHA) were not better than placebo.15,16

Antidepressants also have mixed results when unpublished negative results are included.17 Thus prescribers need not change their general description of alternatives when including fish oil. For example (holding one’s hands like scales of judgement): “Option A has a 1-in-3 chance of helping, with no adverse effects and no risks. Option B has about a 1-in-2 chance of helping, but a 1-in-100 to 1-in-50 chance of causing troublesome withdrawal effects when you stop it, such that you would be unable to work, go to school, or support your family. Which would you like to try first?”

A Patient Decision Aid for Depression

These options should be preceded by consideration of a broader array of treatment approaches, as in a patient decision aid (PDA). PDAs are handouts and videos designed to help patients join in shared decision-making. PDAs often read like reports from the Intergovernmental Panel on Climate Change, weakened by the need for complete consensus among authors. For example, Ottawa Hospital hosts a library of over 100 PDAs, including 4 on depression. None mention the risk of antidepressant withdrawal. Imagine a PDA that includes fish oil, such as the Figure. Does yours look like this?

Figure. Main Depression Treatment Options/Issues

Figure. Main Depression Treatment Options/Issues

Concluding Thoughts

MIA reader Altostrata suggested that apparent ethical conflicts between the goals of autonomy and beneficence can easily be resolved by talking up a harmless placebo. Fish oil meets the “harmless” criterion, so could be used as an open-label placebo. Better yet, omega-3s have at least mixed evidence for efficacy greater than placebo. But will patients really consider it as an alternative to a pharmaceutical antidepressant?

That depends on how the risks of antidepressants are presented, which depends on your working estimate of risks such as withdrawal and post-SSRI-sexual dysfunction. Controversy over these sequelae has devolved into for-or-against-antidepressant camps, such that whatever incidence rates I cite (from 1% to 50%), you are likely to think antidepressant risks are either seriously underestimated or dangerously overstated.

Unfortunately, I fear I have not moved the needle at all on antidepressant prescription, an admitted goal. What we really need is more data on the incidence of serious antidepressant risks. In the interim, thank you for considering the line of thought offered here.

Dr Phelps is research editor at the Psychopharmacology Institute; emeritus faculty at Samaritan Mental Health in Corvallis, Oregon; and founder of PsychEducation.org. He is the bipolar disorder section editor for Psychiatric Times® and the author of A Spectrum Approach to Mood Disorders for clinicians and Bipolar, Not So Much for patients and their families.

Acknowledgment: The author would like to thank Altostrata for her thoughtful comment, and Mad in America for presenting his essays on antidepressant withdrawal.

References

1. Pigott HE, Kim T, Xu C, et al. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR* D study’s patient-level data with fidelity to the original research protocol. BMJ Open. 2023;13(7):e063095.

2. Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010;375(9715):686-695.

3. Kaptchuk TJ, Hemond CC, Miller FG. Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice. BMJ. 2020;370:m1668.

4. Ongaro G, Kaptchuk TJ. Symptom perception, placebo effects, and the Bayesian brain. Pain. 2019;160(1):1-4.

5. Kaptchuk TJ, Friedlander E, Kelley JM, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PloS One. 2010;5(12):e15591.

6. Lembo A, Kelley JM, Nee J, et al. Open-label placebo vs double-blind placebo for irritable bowel syndrome: a randomized clinical trial. Pain. 2021;162(9):2428-2435.

7. Munkholm K, Paludan-Müller AS, Boesen K. Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ Open. 2019;9(6):e024886.

8. Furukawa TA, Cipriani A, Atkinson LZ, et al. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry. 2016;3(11):1059-1066.

9. Jones BD, Razza LB, Weissman CR, et al. Magnitude of the placebo response across treatment modalities used for treatment-resistant depression in adults: a systematic review and meta-analysis. JAMA Netw Open. 2021;4(9):e2125531-e2125531.

10. Annoni M, Miller FG. Placebo effects and the ethics of therapeutic communication: a pragmatic perspective. Kennedy Inst Ethics J. 2016;26(1):79-103.

11. Rashad W, Thase ME. Top 10 drug combinations in MDD - interview with Prof. Michael E. Thase. December 1, 2020. Accessed December 18, 2023. https://psychopharmacologyinstitute.com/publication/top-10-drug-combinations-in-mdd-interview-2577

12. Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: are guidelines evidence-based? Addict Behav. 201;97:111-21.

13. Tilburt JC, Emanuel EJ, Kaptchuk TJ, et al. Prescribing “placebo treatments”: results of national survey of US internists and rheumatologists. BMJ. 2008;337:a1938.

14. Bloch MH, Hannestad J. Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Mol Psychiatry. 2012;17(12):1272-1282.

15. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584.

16. Liao Y, Xie B, Zhang H, et al. Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl Psychiatry. 2019;9(1):190.

17. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252-260.

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