Enhancing Anti-Depressant Therapies by Reducing Inflammation

Psychiatrists prescribe many different drugs for the treatment of depression. Do they work well? Overall, today’s drugs are no more effective than the anti-depressant therapies that were introduced over 60 years ago. Some patients respond well; the majority do not. Unfortunately, about one-third of all depressed patients never respond to any therapy. The most common residual symptoms for these unlucky people are insomnia, fatigue, painful physical complaints, problems concentrating, and lack of interest in pleasurable activities. Medical science clearly needs to discover better therapies for this disorder that affects so many people around the world. In order to do this, scientists need to understand what happens in the brain when we become depressed.

Many studies have demonstrated a correlation between increased brain and body inflammation and depression. The problem is that no one knows what comes first—the inflammation, a neurochemical imbalance, or the depressive symptoms. A new study provides evidence that depression begins with widespread inflammation that indirectly alters brain chemistry, leading to depression.

A recent study investigated whether the levels of inflammatory proteins in the blood prior to treatment could predict which depressed patients might respond well to the anti-inflammatory drug minocycline. Minocycline is an anti-inflammatory drug that can easily penetrate the blood-brain barrier. This is in contrast to other more common anti-inflammatory drugs that do not penetrate the blood-brain barrier. Minocycline was given to a group of patients who had been diagnosed with major depressive disorder and who were also considered treatment-resistant to standard anti-depressant therapies. During the study, all of the patients were allowed to stay on their current medications, which included typical antidepressants (selective serotonin reuptake inhibitors, tricyclics, monoamine oxidase inhibitors, noradrenergic and specific serotonin receptor antagonists as well as the more popular serotonin or noradrenaline reuptake inhibitors) or a mood stabilizer or antipsychotic. The study authors also decided to select only those patients who had elevated levels of a particular inflammatory protein in the serum, C-reactive protein. C-reactive protein is produced by the liver; its level rises when there is inflammation in your body. Sixty percent of depressed patients have elevated levels of C-reactive protein.

The current study discovered that minocycline was significantly effective in improving the mood of depressed patients but only in those patients with low-grade inflammation, as defined by relatively low levels of C-reactive protein. The add-on treatment with minocycline was not helpful in patients with high levels of C-reactive protein.

Why is this study important? It suggests that many different anti-depressant therapies fail to work because the patients’ body and brain levels of inflammatory proteins are too high. Why does inflammation reduce the effectiveness of anti-depressants? Inflammatory proteins in the body quickly move into the brain. Once inside the brain, the inflammatory proteins lead to the activation of a key enzyme that alters the metabolism of tryptophan resulting in a reduction of serotonin production and an increase in neurotoxic molecules. In addition, the inflammation results in a reduction in the release of serotonin. These changes in serotonin function contribute to the symptoms of depression.

Obesity is associated with significantly elevated blood and brain levels of inflammatory proteins. Taken together with the results of the current study, the elevation in pro-inflammatory proteins may explain why obese patients do not respond as well to anti-depressant therapies.

A combination approach of weight reduction and anti-inflammatory drugs, such as minocycline, might provide some relief to obese, severely depressed patients.

© Gary L. Wenk, Ph.D., author of Your Brain on Food, 3rd Edition, 2019 (Oxford University Press).