There's feeling sad or anxious, and then there's “major depression”.

Doctors define major depression – AKA clinical depression – as a constant sense of hopelessness and despair that makes it hard to work, study, sleep, eat, and enjoy friends and activities.

Major depression affects about one in 20 Americans over 18, and one in four or five adults will suffer an episode.

It appears to afflict almost twice as many women, partly because they undergo greater hormonal changes and home/work stresses, but also because men are less likely to disclose their suffering.

In addition, as we reported back in 2008, research shows that “Women's Mood-Control System May Differ from Men's” … a difference with implications for their risk for depression and their responses to antidepressant drugs.

Sadly, about half of patients who suffer from major depression don't respond to treatment with the most commonly prescribed antidepressant drugs … see “Prozac & Co. May Not Stem Suicide” and “Depression Drugs Debunked...Again”.

Most antidepressant drugs – such as Prozac, Zoloft, and Paxil – are “selective serotonin reuptake inhibitors” or SSRIs.

Last summer, we reported on a study showing that curcumin – the antioxidant pigments that makes turmeric orange – helps people with “atypical” depression, which does not respond as well to SSRI drugs … see “Turmeric Targets Stubborn Depression”.

Curcumin and omega-3s alike help redress the effects of a drastic imbalance in the “standard American diet” that promotes depression and the inflammation believed to exacerbate it … see “Brains on Fire: How Fish Fats Help Deter Depression” and “Omega Ratio Matters to Mood”.

Now, the results of a Dutch clinical trial suggest that diets high in omega-3-rich fatty fish can also make SSRI antidepressants work better for patients with atypical depression.

Fatty fish improved drug-resistant patients' response to antidepressants
The new research comes from doctors at several psychiatric medical centers in the Netherlands (Mocking RJ et al. 2014).

They were looking at the relationship between depression and fatty acids (such as omega-3s from fish), and various hormones, including the stress hormone cortisol.

According to lead researcher Roel Mocking, M.D., “We were looking for biological alterations that could explain antidepressant non-response …”. (ECNP 2014)

They recruited 121 people for a six-week clinical trial: 70 patients with major depression disorder (MDD) and 51 healthy controls.

The scientists measured the fatty acid and cortisol levels in all 121 participants at the outset of the trial, and continuously during the six-week study period.

They gave the depressed patients 20mg of an SSRI drug daily for six weeks, and in those who did not respond to the SSRIs, the dose was gradually increased up to 50mg per day.

They found that the depression patients who didn't respond to the SSRI drug also tended to have abnormal fatty acid metabolism.

So the researchers categorized the patients into four groups, according to their fatty fish intake.

And they found that those who ate the least fish tended to respond badly to anti-depressants, whereas those who ate the most fish responded the best to anti-depressant drugs.

Specifically, the participants who ate fatty fish at least once a week had a 75 percent chance of responding to antidepressants, while those who never ate fatty fish had only a 23 percent chance of success.

Fatty fish is rich in two essential omega-3 fatty acids: DHA and EPA. 

DHA is critical to brain function, and the body uses omega-3 DHA and EPA to end the kinds of unnecessary, unhealthful inflammation believed to promote depression in general and drive cases of stubborn, atypical depression. 

Dr. Mocking said that his group intended to see whether omega-3s might boost the performance of drugs for other mental disorders, such as post-traumatic stress disorder and schizophrenia.

We should note that this study only shows an association between higher blood levels of omega-3 fatty acids and improved response to anti-depressant drugs, so it can't prove a cause-effect relationship.

Anti-inflammatory drugs appear to boost SSRI benefits, too
Coincidentally, a new study adds evidence that inflammation drives depression.

This finding suggests that inflammation-curbing drugs, foods (like fish), or natural agents (like curcumin) can help. (For example, see “Curry's Color Boosts Mood”.)

Likewise, synthetic over-the-counter painkillers and prescription anti-inflammatory drugs may also enhance the treatment of people suffering from depression ... but, unlike natural counterparts like curcumin, these drugs can cause adverse side effects.

Researchers at Denmark's Aarhus University just published the largest ever meta-analysis (evidence review), in the psychiatric Journal of the American Medical Association (Köhler O et al. 2014).

The review examined 14 international studies involving 6,262 patients who either suffered from depression or had individual symptoms of depression.

“The meta-analysis supports this correlation [between inflammation and depression] and also demonstrates that anti-inflammatory medication in combination with antidepressants can have an effect on the treatment of depression,” said lead author Ole Köhler, M.D. (AU 2014).

The Danish study suggests that physicians can be much more certain that anti-inflammatory drugs or natural agents can enhance treatment with SSRI-type antidepressants.

(Aspirin triggers the same anti-inflammatory agents that the body makes from omega-3 DHA in seafood … see “Aspirin Mimics a Fishy Omega-3”.)

“However”, as Dr. Köhler noted, “these effects must always be weighed against the possible side effects of the anti-inflammatory drugs. We still need to clarify which patients will benefit from the medicine and the dose-sizes required.” (AU 2014)

Some studies suggest that the choice of antidepressant medication can be guided by a blood sample that measures whether there is an inflammatory condition in the body.

Köhler emphasized that it's not safe to conclude that the presence of inflammation in a patient is the sole or primary explanation for their depression.

Instead, as he said, “The analysis should be seen as a significant milestone and this could be a landmark for what future research projects and treatment need to focus on.” (AU 2014)

  • Aarhus University (AU). Analgesics and Antiinflammatory Drugs May Have an Impact on Depression. October, 21, 2014. Accessed at
  • Assies J, Mocking RJ, Lok A, Ruhé HG, Pouwer F, Schene AH. Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular disease comorbidity. Acta Psychiatr Scand. 2014 Sep;130(3):163-80. doi: 10.1111/acps.12265. Epub 2014 Mar 21.
  • Assies J, Pouwer F, Lok A, Mocking RJ, Bockting CL, Visser I, Abeling NG, Duran M, Schene AH. Plasma and erythrocyte fatty acid patterns in patients with recurrent depression: a matched case-control study. PLoS One. 2010 May 14;5(5):e10635. doi: 10.1371/journal.pone.0010635.
  • European College of Neuropsychopharmacology (ECNP). New research shows fish intake associated with boost to antidepressant response. October 18, 2014. Accessed at 
  • Köhler O et al. Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects: A Systematic Review and Meta-analysis of Randomized Clinical Trials. Accessed at
  • Mocking RJ et al. Longitudinal interplay between paroxetine response, cortisol and fatty acid metabolism in major depressive disorder. Eur Neuropsychopharmacol. 2014;24aSuppl 2):S396. Accessed at
  • Mocking RJ, Assies J, Bot M, Jansen EH, Schene AH, Pouwer F. Biological effects of add-on eicosapentaenoic acid supplementation in diabetes mellitus and co-morbid depression: a randomized controlled trial. PLoS One. 2012;7(11):e49431. doi: 10.1371/journal.pone.0049431. Epub 2012 Nov 28.
  • Mocking RJ, Ruhé HG, Assies J, Lok A, Koeter MW, Visser I, Bockting CL, Schene AH. Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression.