Understanding Depression Through Biochemical Mapping

Researchers at Duke Medicine have discovered biochemical changes in people taking antidepressants, but only when depression improves. Changes occur within the neurotransmitter pathways of the pineal gland, which is the part of the endocrine system responsible for controlling the body’s sleep cycle.

A new type of science called pharmacometabolomics was used in this study to measure and map chemicals in the blood to determine mechanisms causing disease and find new treatments tailored to a patient’s metabolic profile.

Rima Kaddurah-Daouk, PhD, professor of psychiatry and behavioral sciences at Duke’s Institute for Brain Sciences, said, “Metabolomics is teaching us about the differences in metabolic profiles of patients who respond to medication, and those who do not. This could help us to better target the right therapies for patients suffering from depression who can benefit from treatment with certain antidepressants, and identify, early on, patients who are resistant to treatment and should be placed on different therapies.”

In the United States an average of 6.7 percent of adults in any given year are affected by major depressive disorder, which is characterized by a severely depressed mood for two weeks or more. The most commonly prescribed treatments for major depressive disorder are selective serotonin reuptake inhibitors (SSRI), but these are only effective for some patients. Other people find relief from a placebo while some do not respond to either SSRIs or a placebo. This variability of response creates difficulty for physicians who only have the choice to prescribe one type of SSRI at a time and wait several weeks for the results.

This recent study by the Duke team has begun to identify which patients will respond to SSRI or a placebo based on metabolic profiles. These metabolomic tools have shown several metabolites located in the tryptophan pathways as factors affecting response to antidepressants. The body metabolizes tryptophan in several different ways. One pathway leads to serotonin which then leads to melatonin and a group of similar biochemicals referred to as methoxyindoles that are produced in the pineal gland.

In this study, researchers compared the levels of metabolites in tryptophan pathways with treatment outcomes. Seventy-five participants with major depressive disorder were randomly assigned either a placebo or the antidepressant sertraline, commonly known as Zoloft, in a double-blind trial. Improvement was measured after one week and four weeks of treatment by analyzing blood samples to create a metabolomics platform to measure neurotransmitters.

The researchers found 60 percent of participants responded to antidepressant treatments and 50 percent who received the placebo also responded. However, in the patients who responded to SSRI treatment, metabolic changes in the tryptophan pathways which lead to melatonin and methoxyindoles were observed. These results suggest the metabolism of serotonin in the pineal gland may be a significant component in treatments outcomes and causes of depression.

“This study revealed that the pineal gland is involved in mechanisms of recovery from a depressed state. We have started to map serotonin which is believed to be implicated in depression, but now realize that it may not be serotonin itself that is important in depression recovery. It could be metabolites of serotonin that are produced in the pineal gland that are implicated in sleep cycles,” Kaddurah-Daouk explained.

“Shifting utilization of tryptophan metabolism from kynurenine to production of melatonin and other methoxyindoles seems important for treatment response but some patients do not have this regulation mechanism. We can now start to think about ways to correct this.”

The Duke researchers are the first to define a molecular basis for antidepressants’ several week delay in response. By identifying the metabolic signature of mildly depressed patients who will respond to placebo treatment, researchers can streamline clinical trials of antidepressants. In further research studies, participants may be tested both day and night to discover how circadian cycles, sleep pattern changes, neurotransmitters and hormonal systems are modified for patients who do not respond to SSRI treatment and placebos. This will hopefully lead to more effective treatment options.