Metabolites derived from omega-3 fatty acids could help reduce depression: dream or reality?
I am a senior postdoctoral neuroscientist at the Stress, Psychiatry, and Immunology (SPI) Lab, the team that brings you InSPIre the Mind. While I have been working in the field of mental health, for now, more than 10 years, and have previously contributed to this online platform with blogs on neuroinflammation and mental health, it’s only recently that I started to become fascinated by the role of nutrition, and particularly by the so-called omega-3 polyunsaturated fatty acids (or PUFAs), in the context of mental health pathologies.
You may have already heard about omega-3 PUFAs. The most commonly known omega-3 PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These are often found in the everyday diet, for example in fish oil, such as the one derived from salmon, herring, sardines, or mackerel, as well as in nuts and seeds. While a lot has already been said about these nutritional compounds, and their anti-inflammatory and potentially anti-depressant properties, there is still little knowledge on how they work exactly in the brain to support good mental health. Considering this, I decided to conduct some investigations and assessed the effects of administering high doses of EPA and DHA, first in patients and then in lab-grown neurones, to help clarify how they reduce inflammation and depression.
Omega-3 metabolites in patients
First, I assessed twenty-two patients with major depression who received either 3 grams of EPA or 1.4 grams of DHA daily for twelve weeks, and then measured metabolites of EPA and DHA in their blood before and after the omega-3 PUFA treatment, along with a score of their depressive symptoms. Do you wonder what we found? Well, results showed that when omega-3 PUFAs are given to patients with depression they are metabolized into smaller molecules called metabolites, or more precisely lipid mediators and that the levels of these in the blood were associated with an improvement in depressive symptoms. Interesting, is it not? This is the first study ever published to report such findings. But, how do these lipid mediators act in the brain?
Omega-3 metabolites in lab-grown neurones
In order to answer this question, I used human brain cells derived from the hippocampus, a part of the brain known to regulate the production of new neurones — a process called neurogenesis — which is involved in many cognitive functions, such as memory and learning, which are relevant for depression.
Subsequently, I exposed these cells to several chemical inflammatory messengers called cytokines — we have been using this experimental model for years as it perfectly mimics inflammation in the brain of depressed patients. Using this experimental model, I was able to show that treating human hippocampal cells with EPA or DHA, before being exposed to inflammatory cytokines prevented the reduction in the number of newly generated neurones, or neurogenesis, which was previously observed in cells exposed to cytokines alone. Further investigation confirmed these effects were mediated by the formation of the same metabolites previously detected in the blood of depressed patients receiving omega-3 PUFAs, namely hydroxyeicosapentaenoic acid (HEPE), hydroxydocosahexaenoic acid (HDHA), epoxyeicosatetraenoic acid (EpETE), and epoxydocosapentaenoic acid (EpDPA).
This was the first time we detected these metabolites in human hippocampal neurones! Further investigation showed that treatment with an inhibitor of the enzyme involved in the synthesis of these metabolites can increase their availability, therefore suggesting a possible way by which future treatments could be optimized in order to increase the activity of these metabolites.
So, what did we learn?
This study, now published in the journal of Molecular Psychiatry, has provided exciting new insight into how omega-3 fatty acids bring about anti-inflammatory effects that improve depression. For some time, we have known that omega-3 PUFAs can induce anti-depressant and anti-inflammatory effects but, without further understanding of how this happens in the human brain, it has been difficult to develop treatments. This study has helped shine a light on the mechanisms involved in this relationship which can inform the development of potential new treatments for depression using omega-3 PUFAs.
The metabolites that I have identified are broken down in the body relatively quickly, which means they may only be available for a relatively short time. By testing the effect of inhibitors of the enzymes involved in the metabolism of omega-3 PUFA I was able to show that we can greatly improve how long they can have an effect in the body and ultimately, increase their efficacy. This is very important for the development of new treatments and means that patients could be given higher doses of EPA and DHA together with these enzyme inhibitors to increase the amount of these important compounds in their blood over time.
What would be the next step?
For sure, the evidence generated here suggests that the metabolites produced by the breakdown of EPA and DHA in the body could be targeted as a mechanism to reduce depression and inflammation. But, remember, there is a need to ensure that their effects are prolonged in order for this approach to be successful! The development of novel drugs able to target the enzyme involved in the synthesis of EPA- and DHA-derived metabolites could be a valid therapeutic option and could be used for inflammation-associated brain disorders, such as depression, where at least a sub-group of patients often have chronic levels of inflammation. There is an ever-growing interest in the links between the immune system, inflammation, and depression but in order to develop new treatments in this area, we need to better understand the mechanisms behind these relationships. By identifying and measuring the exact lipid mediators that are involved, identifying the enzyme that prolongs their effects and finding the same lipid mediators in depressed patients treated with omega-3 PUFA, and demonstrating improvements in symptoms, this study has provided vital information to help shape clinical trials for future therapeutic approaches with omega-3 fatty acids. However, it is important to highlight that this research has not shown that by simply increasing omega-3 fatty acids in our diets or through taking nutritional supplements we can reduce inflammation or depression! The mechanisms behind the associations between depression and omega-3 PUFA are complicated and require further research and clinical trials to fully understand how they work and inform future therapeutic approaches.
But for now, I believe this is enough food for thought!
Header image source: Whitney E. RD