The Breakthrough Depression Solution

Integrative medicine for mental health.

The Brain on Fire: Inflammation and Depression

Inflammation and Its Effects on Mood

We have all had the flu or at least know what it feels like.

The miserable collection of symptoms includes lack of energy, difficulty concentrating, sleepiness, loss of appetite, and general malaise.

For most of us these symptoms disappear within a few days. For some, it takes much longer. Although we tend to blame the influenza virus for making us feel miserable, the symptoms are actually a result of our immune system trying to combat the virus.

The symptoms of the flu are brought on by proteins, pro-inflammatory cytokines, our bodies produce in order to fight the flu and other infections.

When the immune system is under attack from physical injury, infections, or toxins, the immune system generates an inflammatory response. Inflammation is a normal physiological process that is now understood to play a major role in many chronic medical illnesses, including cancer, heart disease, diabetes, asthma, and obesity. In each of these cases inflammation causes the release of cytokines. Cytokines, which come in many different classes, including anti- and pro-inflammatory, behave as messengers and signal cells of the immune system.

The effects of pro-inflammatory cytokines can cause a diverse array of physical and psychological symptoms. When this happens it is referred to as sickness behavior.  

Recently, scientists have been able to demonstrate how the symptoms of sickness behavior mirror those of depression. Researchers and health professionals are now beginning to understand the connection between inflammation and depression.

  1. One study found that patients with major depressive disorder had significantly higher levels of the pro-inflammatory cytokine TNF-alpha than their non-depressed counterparts. In addition, patients with depression had low levels of anti-inflammatory cytokines.
  2. Researchers have also found that eight weeks of Zoloft treatment was able to decrease some pro-inflammatory cytokines seen in depressed patients. On Zoloft, the depressed patients also saw an increase in anti-inflammatory cytokines.
  3. A study involving depressed patients classified as non-responders supplemented the patients' standard antidepressant treatment with the addition of aspirin, an anti-inflammatory. More than 50% of these patients responded to this combination treatment. At the end of the study more than 80% of the group responsive to the anti-inflammatory went into remission.

Cytokines, the messengers during inflammation, are also used to treat infections and autoimmune disorders. So-called autoimmune disorders are clear examples of how an unregulated immune system can cause destructive damage to many different organs and tissues. Some of the most common autoimmune diseases include rheumatoid arthritis, multiple sclerosis, thyroid disease, and celiac disease.

Interferons, a form of cytokines which activate the immune system and act as antiviral agents, is a common treatment for hepatitis C infection.  Research and clinical studies have shown that interferon therapy can actually lead to depression in patients who have hepatitis C. It's been reported that between 20% and 30% of patients who have hepatitis C and who receive interferon treatment are at risk for depression.

In one study, nearly a third of patients with chronic hepatitis C who received interferon treatment displayed psychiatric symptoms after four weeks of treatment. Symptoms included mania, hypomania, and depression.  Over the years I have had to admit patients for inpatient psychiatric treatment for depression and suicidal behavior following interferon therapy.

It appears that inflammation and the complicated collection of immune system chemical messengers called cytokines play an important role in brain function and may cause psychological symptoms.

When the brain is aggravated by any source-stress, infections, trauma, stroke, poisons, or nutritional deficiencies-inflammation spurs the release of pro- inflammatory cytokines, which may affect mood. Scientists have proposed many mechanisms as to how this may occur.

One mechanism as to how an unregulated immune system may contribute to depression is quite well understood. Cytokines activate an enzyme, indoleamine 2,3-dioxygenase (IDO), which degrades serotonin resulting in low levels of the neurotransmitter. IDO also degrades the precursor to serotonin, tryptophan. Decreased levels of the neurotransmitter serotonin are likely the contributing factor to the development of depressive symptoms. The inflammatory process' contribution to the constant destruction of serotonin decreases the chances of recovery.

For too many years we have tried to correlate depression with a deficiency of serotonin and related neurotransmitters in the brain. Using medications based on this theory has yielded dismal results, barely better than a placebo.  If we understand the underlying physiological abnormalities contributing to mood disorders, then we are likely to benefit from more effective solutions.

Understanding the connection between depression and inflammation gives researchers and pharmaceutical companies incentive to look for alternative medications to treat depression. In the meantime there are, however, well-researched lifestyle and nutritional interventions that are known to decrease inflammation and improve mood: exercise, stress reduction, nutritional supplements (i.e. omega-3 fatty acids), and optimizing vitamin D levels. Chronic stress is one of the major preventable contributors to inflammation and immune dysregulation.

For each individual the inflammatory response is likely precipitated by a unique and complex interaction of causative agents. Infection, stress, nutritional deficiencies, and sedentary lifestyles are the most common factors. Individual, personalized understanding of inflammation and its contributions to the physiology of mood disorders is a critical, but often neglected component of integrative therapies for depression. By neglecting the underlying cause of depression, recovery is less likely.

James M. Greenblatt, M.D., a dually certified child and adult psychiatrist, is a pioneer in integrative medicine. His latest book is The Breakthrough Depression Solution.

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