Anti-inflammatory effects may also boost antidepressants’ efficacy 09/26/2019
Depression is a growing domestic and global disaster.
More than 20 million Americans, including more than 3 million aged 12 to 17, suffer from major depression.
In 2017, the condition led more than 47,000 Americans to commit suicide, and some 1.4 million adults to attempt it.
Along with homicide, suicide is the leading cause of death in Americans aged 10 to 14 years, among whom the suicide rate rose by 56% between 2007 (0.9%) and 2017 (2.5%).
And the World Health Organization offers these global statistics:
- More women are affected by depression than men.
- Depression is now the leading cause of disability, worldwide.
- Nearly 800,000 people commit suicide — the second leading cause of death in 15-29-year-olds — every year.
Those sobering facts lend urgency to the quest for safe, effective ways to treat depression and reduce the risk for it.
Several recent clinical trials found that diet can play major preventive and therapeutic roles, as we reported in Healthy Diets May Help Deflect Anxiety & Depression and as two mental health pros agreed in Top 5 Foods for Boosting Mood.
There’s also substantial evidence that diets rich in fish reduce the risk for depression and that omega-3 fish oil can significantly boost the efficacy of antidepressant drugs and bring independent benefits. For more on that, see Brains on Fire: How Fish Fats Help Deter Depression, Fish May Deter Depression in Women, Fish Oil Rivals Antidepressants in Clinical Trial, and Omega-3 Mood Benefits Get More Backing.
Back in 2006, an expert psychiatric panel that reviewed the evidence concerning omega-3 fish oil and depression concluded that omega-3s can help: see Top Psych Panel Says Omega-3s Deter Depression, Bipolar Disorder.
Likewise, omega-3 fish oil was the nutritional supplement found most effective against depression in a recent review of the clinical evidence.
Coincidentally, the results of a recent rodent study affirm prior evidence suggesting why seafood source omega-3s would enhance the efficacy of prescription antidepressants such as Zoloft and Prozac.
Let’s look at the findings of the recent evidence review, and the illuminating results of that animal study.
New evidence review affirms omega-3s’ mood-supporting powers
The goal of the largest-ever review of the clinical evidence was to gauge the efficacy of various forms and doses of commonly used nutritional supplements in people with different mental disorders.
In addition to the Australian scientists who led the study, the evidence-review team included university-based researchers from Britain, Canada, and Belgium (Firth J et al. 2019).
Lead author Dr. Joseph Firth of Australia’s Western Sydney University explained the background to their review: “While there has been a longstanding interest in the use of nutrient supplements in the treatment of mental illness, the topic is often quite polarizing, and surrounded by either over-hyped claims or undue cynicism.”
The study authors examined 33 meta-analyses (reviews) of randomized control clinical trials that collected data from 10,951 people with mental health disorders, including depression, stress and anxiety disorders, bipolar disorder, personality disorders, schizophrenia and attention-deficit/hyperactivity disorder (ADHD).
Although most of the nutritional supplements assessed did not significantly improve mental health, the researchers found strong evidence that certain supplements add considerable benefit to conventional treatments for some disorders.
They also found that all the nutrient supplements studied in the trials were safe when used at recommended doses, and that there was no evidence either of serious adverse effects or of contraindications with psychiatric medications.
These were their findings, in brief:
- The strongest evidence was found for omega-3 supplements as an add-on treatment for major depression, which reduced symptoms beyond the effects of antidepressants alone.
- Some evidence suggested that omega-3 supplements may yield small benefits for ADHD patients.
- Emerging evidence suggests that the amino acid N-acetylcysteine can be a useful adjunct to standard therapies for mood disorders and schizophrenia.
- High doses of a form of supplemental folate (vitamin B9) called methylfolate may be effective as an add-on treatment for major depression and schizophrenia, while supplements containing the synthetic form of folate — called folic acid — were deemed ineffective.
- No strong evidence showed that supplemental omega-3s improve schizophrenia or other mental health conditions, other than as an adjunct to conventional treatments for major depression. (That conclusion is surprising: see Can Fish Oil Help Prevent Teen Psychosis? and Omega-3s Curbed Psychosis in Clinical Trial).
- The review found no compelling evidence that other supplemental vitamins or minerals improve any mental disorder.
Rodent study helps explain omega-3s’ ability to boost antidepressants’ benefits
Major depression is commonly treated with selective serotonin reuptake inhibitors (SSRIs) such as Prozac — which don't work for about one in three patients.
Prior research shows that controlling inflammation and increasing brain "neuroplasticity" can help patients who don’t respond to SSRI-type drugs.
Seafood source omega-3s — EPA and DHA — play essential roles in controlling inflammation: see Fish Oil Linked to Lower Inflammation, Aspirin Mimics a Fishy Omega-3, and Pain May be Relieved by Omega-3 Byproducts.
That may explain growing evidence that supplemental omega-3s (especially EPA) can enhance the efficacy of antidepressant drugs — particularly in drug-resistant depression patients — and allow doctors to reduce doses of SSRI drugs in some patients.
Antidepressants and omega-3s also promote formation of new connections between brain cells (neurons) — which underlies and enhances a key brain property known as neuroplasticity: see New Insight into Anti-Aging Brain Benefits of Omega-3s and MIT Report Shows Omega-3s Boost Brain Networks Critical to Memory Capacity.
Antidepressants and omega-3s both help control levels of brain inflammation — a fact that led Italian scientists to look for an optimum balance between neuroplasticity and inflammation.
Now, the results of rodent studies from Italy suggest that omega-3s' anti-inflammatory (and neuroplasticity-promoting) effects may explain their ability to enhance the efficacy of SSRI drugs.
Those results — which could guide research designed to make SSRIs more effective for all patients, at minimum doses — were presented earlier this month in Copenhagen, at the European College of Neuropsychopharmacology Congress (Golia MT et al. 2019; Branchi I et al 2019; Poggini el al 2019).
Study #1: Prozac’s effects on brain inflammation depended on the environment
The scientists placed mice in a stressful environment for three weeks, which produced inflammation in the animals’ brains.
They then fed the mice the SSRI-type antidepressant Prozac (fluoxetine), which boosted the neuroplasticity of their brains, and reduced brain levels of inflammation.
Conversely, when the mice were placed in a relaxing environment that reduced brain inflammation, feeding them Prozac boosted the activity of genes associated with inflammation.
This doesn’t mean that Prozac caused excessive brain inflammation in relaxed mice, just that the drug tended to affect the animals “working” genes in ways that could promote slightly higher brain inflammation.
Study #2: Inflammation “sweet spot” for antidepressant efficacy
In a second study, the researchers divided the mice into two groups, treating some with a chemical (lipopolysaccharide) that increases inflammation, while giving the others ibuprofen (Advil), which reduces inflammation.
They then measured markers of brain neuroplasticity in the mice, to see whether changes in inflammation raised (a good thing) or lowered (a bad thing) those markers.
As study co-author Dr. Silvia Poggini said, “We found that neural plasticity in the brain was high as long as we were able to keep inflammation under control. But inflammation levels that were either too high or too low reduced neuroplasticity …”.
And when the mice were tested for depression-related responses, their behavior reflected the balance between neuroplasticity and inflammation induced in them by exposure to either a pro-inflammatory (lipopolysaccharide) or anti-inflammatory (ibuprofen) drug.
Importantly, these findings supported the outcomes of the first study, thereby confirming the existence of a “sweet spot” where inflammation and neuroplasticity achieve a balance point at which SSRI-type drugs work best.
It’s also important to note that while ibuprofen (Advil) is a potent anti-inflammatory drug, omega-3 EPA and DHA are simply the essential raw materials the body needs to make the chemical messengers (resolvins and protectins) it uses to end excessive or chronic, unnecessary inflammation.
This distinction explains why omega-3 fish oil has never been shown to impair inflammation — a key component of the body’s immune response to injury or infection — when it’s actually needed.
Lead researcher Professor Igor Branchi made this observation: “The work shows that neuroplasticity and inflammation are interdependent, and that to provide the right conditions for the antidepressant to work, inflammation needs to be tightly controlled. More generally, this work shows us that SSRI antidepressants are not one-size-fits-all drugs, and that we should look at other options for improving drug response.”
Professor Carmine M. Pariante of King's College London offered this comment on the study, in which he was not involved: “We have known for some time that depressed patients with increased inflammation do not respond to antidepressant treatment, but this study finally proposes the biological mechanisms underpinning these effects.”
In other words, the results of this mouse study could have very big implications for improving the efficacy of antidepressants in people suffering from major depression — which may mean adding omega-3s to the prescription.
- Alboni S, van Dijk RM, Poggini S, Milior G, Perrotta M, Drenth T, Brunello N, Wolfer DP, Limatola C, Amrein I, Cirulli F, Maggi L, Branchi I. Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment (2015) https://www.ncbi.nlm.nih.gov/pubmed/26645631
- Alboni S, et Al, Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment (2016). https://moh-it.pure.elsevier.com/en/publications/fluoxetine-treatment-affects-the-inflammatory-response-and-microg
- Branchi I: Interplay between inflammation and neuroplasticity in promoting antidepressant treatment https://2019.ecnp.eu/programme/Programme#!abstractdetails/0000374170
- Firth J, Teasdale SB, Allott K, Siskind D, Marx W, Cotter J, Veronese N, Schuch F, Smith L, Solmi M, Carvalho AF, Vancampfort D, Berk M, Stubbs B, Sarris J. The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials. World Psychiatry. 2019 Oct;18(3):308-324. doi: 10.1002/wps.20672.
- Golia MT et al. Interplay between inflammation and neural plasticity: Both immune activation and suppression impair LTP and BDNF expression (July 2019). https://www.ncbi.nlm.nih.gov/pubmed/31279682
- Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007 Jul;68(7):1056-61.
- Nunes B, Pinho C, Sousa C, Melo AR, Bandarra N, Silva MC. [Relevance of Omega-3 and Omega-6 / Omega-3 Ratio in Preventing Cognitive Impairment]. Acta Med Port. 2017 Mar 31;30(3):213-223. doi: 10.20344/amp.7970. Epub 2017 Mar 31. Portuguese.
- Poggini el al: The interaction between inflammation and neural plasticity controls the efficacy of serotoninergic antidepressants https://2019.ecnp.eu/programme/Programme#!abstractdetails/0000396360
- Schefft C, Kilarski LL, Bschor T, Köhler S. Efficacy of adding nutritional supplements in unipolar depression: A systematic review and meta-analysis. Eur Neuropsychopharmacol. 2017 Nov;27(11):1090-1109. doi: 10.1016/j.euroneuro.2017.07.004. Epub 2017 Oct 5. Review.
- Sheppard KW, Cheatham CL. Executive functions and the ω-6-to-ω-3 fatty acid ratio: a cross-sectional study. Am J Clin Nutr. 2017 Jan;105(1):32-41. doi: 10.3945/ajcn.116.141390. Epub 2016 Nov 16.
- Sheppard KW, Cheatham CL. Omega-6 to omega-3 fatty acid ratio and higher-order cognitive functions in 7- to 9-y-olds: a cross-sectional study. Am J Clin Nutr. 2013 Sep;98(3):659-67. doi: 10.3945/ajcn.113.058719. Epub 2013 Jul 3.
- Sheppard KW, Cheatham CL. Omega-6/omega-3 fatty acid intake of children and older adults in the U.S.: dietary intake in comparison to current dietary recommendations and the Healthy Eating Index. Lipids Health Dis. 2018 Mar 9;17(1):43. doi: 10.1186/s12944-018-0693-9.