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Bacteria, Serotonin, and Depression: A Possible New Approach to Treating Mood Disorders

 

April 30, 2007

Norman Sussman, MD, DFAPA

 

Editor, Primary Psychiatry and Psychiatry Weekly, Professor of Psychiatry, New York University School of Medicine

 

There is growing interest in a suspected cause of some cases of depression: infection and inflammatory response. New research findings that add to our understanding of the interrelationship of immunology and depression, and the reasons that some currently used antidepressants work, may fundamentally change the way that mood disorders and drug therapies are conceptualized.

There are several unambiguous examples of psychiatric illness being the result of an inflammatory or immune reaction.  Considerable evidence already exists about the Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), a disorder in which Streptoccal infection triggers an autoimmune response. The antibodies that form against the invading bacteria mistakenly recognize and “attack” certain parts of the brain, causing psychiatric symptoms.

Another notable example of immune-mediated depression is the response of some patients to treatment with Interferon α, who become profoundly depressed and suicidal. Interestingly, onset of depressive symptoms has been shown to be prevented by treatment with antidepressants that work on the serotonin system.

The involvement of immune activation and depressive-like “sickness behavior” symptoms has been suspected for many years. Evidence specifically suggests that patients with major depression exhibit changes in cytokine activity and inflammation. Immune-mediated psychological and neuroendocrine changes were observed following vaccination with live attenuated rubella virus. A subgroup of vulnerable subjects showed a significant virus-induced increase in depressed mood up to 10 weeks following their vaccination. In a related animal study, the investigators also showed that immune activation with a variety of immune challenges induced a “depressive-like syndrome in rodents: anhedonia, anorexia, body weight loess, and reduced exploratory, and social behavior.” Chronic treatment with TCAs or SSRIs attenuated many of the behavioral effects.

A team of English investigators have, for the first time, shown a possible link between administration of a vaccine, peripheral immune activation, psychological and behavioral changes, and the brain serotonin system. The researchers used antigens derived from the bacterium Mycobacterium vaccae, a generally benign and ubiquitous agent found in dirt. After vaccination, they found that the subsequent immune activation was temporally associated with increases in serotonin metabolism within the ventromedial prefrontal cortex. Treatment with the vaccine seemed to alter behavior in mice similarly as is typically seen with antidepressants. This research was initiated following observations that human cancer patients being treated with the bacteria Mycobacterium vaccae unexpectedly reported increases in their quality of life.

The identification of serotonin neurons in the dorsal raphe nucleus that are uniquely responsive to peripheral immune activation raises the possibility that one day there will be a vaccine designed to modulate the immune response which in turn will the prevent the onset or attenuate the symptoms of major depression and other psychiatric disorders.