The Inflamed Mind: A Radical New Approach to Depression

August 2019

BOOK REVIEWS: The Inflamed Mind: A Radical New Approach to Depression

Aug
2019
Vol. 31. No. 3
Richard Balon, MD

Departments of Psychiatry and Behavioral Neurosciences and Anesthesiology
Wayne State University School of Medicine
Detroit, Michigan, USA

Edward Bullmore, Professor of Psychiatry at the University of Cambridge, argues at the end of his book that our treatment of depression is in crisis, as no new treatments have been developed over the last 30 years. There are also far fewer new drugs for depression in the research and development pipeline than there were 30 years ago. He notes that the old business model of antidepressant drug discovery collapsed in 2010. Big pharmaceutical companies are exiting the whole area of mental health. Dr. Bullmore cites a conversation he had with his boss at GlaxoSmithKline (GSK). He asked his boss whether GSK would ever reinvest in depression and psychiatry. His boss answered, “I’d never say never. But if we were going to… go back there… it would have… to be completely different. What we’re not going to do is stop, wait a bit, and then start doing exactly the same thing we did before all over again. So don’t ask me for tens of millions to jump back into old-school phase 2 because that’s not going to happen any time soon. First, you’ve got to be able to tell me how it’s going to be different next time” (p 196).

Available treatments—mainly selective serotonin reuptake inhibitors (SSRIs)—have been considered panacea. However, “There can be no more talks of panacea. We will need to leave behind the idea that depression is all one thing, in much the same way we no longer think of cancer as one multiheaded monster disease but as a collection of thousands of different kinds of diseases” (p 196). The new generation of antidepressants will probably be personalized and hopefully accompanied by biomarkers used to guide our treatment.

The main focus of Dr. Bullmore’s book is to introduce the idea of one such new treatment pathway and a new concept of depression that explains this new treatment approach. Dr. Bullmore skillfully argues that depression is not a disease of the mind. He rejects the Cartesian dualism, which is “the foundational bedrock of Western scientific medicine” (p 10). For him, depression is a disease of an “inflamed brain” or “inflamed mind” responding to inflammation signals from the rest of the body. He argues that the blood-brain barrier is not impenetrable and that cytokines can send signals about inflammation to the brain. And what does the “inflamed mind” or inflammation-informed mind look like? Very much like a “depressed brain.”

However, Dr. Bullmore also recognizes the fact that although depression is associated with biomarkers of inflammation, it does not prove that the relationship between inflammation and depression is causal. Thus, we need to have a better understanding of this relationship. This relationship could also be circular rather than linear (p 156).

The text moves from an explanation of neuroimmunology, the way the immune system guards our organism from attacks from the outside, what happens in various immunologic diseases (eg, rheumatoid arthritis), to suggestions that drugs targeted against cytokines (anticytokines) could have potent antidepressant effects (especially for patients with inflammatory diseases). Another fascinating fact is that there is an anti-inflammatory reflex mediated by the vagus nerve: vagus nerve sensory fibers have cytokine receptors, and when a change of inflammatory status (high cytokines) is detected, the vagus nerve sends a signal to the spleen, reflectively acting on macrophages and thus decreasing cytokines. The vagus is acting homeostatically. Interestingly, electrical stimulation of the vagus reduces blood cytokine levels with subsequent fewer painful joint symptoms in rheumatoid arthritis. As we know, vagal nerve stimulation is approved for resistant depression (though the effect is weak at the best).

This book is filled with numerous examples of the undisputable link between depression and inflammation. For instance, one study found “children who were not depressed, but were slightly inflamed at the age of nine, were significantly more likely to be depressed 10 years later as 18-year olds” (p 12), “depressed patients who are also inflamed are less likely to respond well to treatment with conventional antidepressant drugs” (p 18), and some individuals become depressed when given interferons. Inflammation can also reduce the amount of serotonin released into synapses and basically counteracts SSRIs. Some patients with so-called treatment-resistant depression who do not respond well to antidepressants are particularly likely to be inflamed (p 143). On the other hand, some anti-inflammatory medications such as what Humera has for rheumatoid arthritis (an antitumor- necrosis factor [TNF] drugs) can cause an immediate high during infusion administration and should be explored for possible treatment of depression. Dr. Bullmore recommends that “natural immune reaction could be leveraged as a biological machine for discovering and manufacturing drugs. Instead of using robots to screen vast numbers of candidate drugs that might or might not work, mice could be used quickly to make antibodies that would certainly and selectively disable human TNF” (p 64). He also argues for repurposing various old drugs and examining their possible antidepressant effects.

At times, the author admits that there are some “holes” or a lack of supporting facts available for his theory. For instance, there is no solid evidence that some antiinflammatory drugs, such as aspirin, have antidepressant effects. I also found the argument that some anti-inflammatory drugs prescribed for pain relief may have an antidepressant effect weak, as the confounding variable of pain has not been excluded. Nevertheless, the theory of “mind” or “brain inflammation” being behind depression and the possibility of giving up the Cartesian dualism of mind and brain is fascinating and worth exploring, as is the possible development of anti-inflammatory drugs linked to biomarkers, such as C-reactive protein, as new antidepressants.

At the end, Dr. Bullmore also entertains the idea of inflammation’s involvement in Alzheimer’s disease dementia, and even schizophrenia.

This small book is an easy read and an entertaining and thoughtprovoking treatise. Only time will tell us whether its prediction will be realized. Right now, it is great bedtime reading that gives us hope that we may be able to move from the standstill of depression treatment development to a totally new realm of novel efficacious treatments for depression.

CORRESPONDENCE

Richard Balon, MD
Wayne State University
Detroit, Michigan, USA

REFERENCES

By Edward Bullmore; New York, New York; Picador (Macmillan Publishing Group, LLC); 2019; ISBN 978-1-250-31814-5; pp 240; $28 (hardcover).