Scientists believe they have identified a metabolic signature that may help determine response to antidepressant treatment in patients with major depressive disorder (MDD).
Using „pharmacometabolomics,“ they identified several biochemical changes in patients who respond to the selective serotonin reuptake inhibitor (SSRI) sertraline.
Of note, these changes occur in the tryptophan pathway connected to the pineal gland that controls sleep, suggesting a further link between sleep, depression, and treatment outcomes, the researchers say.
The study was published online July 17 in PLoS One.
„Metabolomics is a powerful and emerging tool that allows you to measure thousands of chemicals in the blood,“ Rima Kaddurah-Daouk, PhD, associate professor of psychiatry and behavioral sciences at Duke University in Durham, North Carolina, and head of the Pharmacometabolomics Research Network, told Medscape Medical News.
„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,“ she said.
In prior studies, the Duke team used metabolomics tools to map biochemical pathways implicated in MDD. They found several metabolites on the tryptophan metabolic pathway that may play a role in response to antidepressant therapy.
Building on this earlier work, the team has now analyzed levels of specific metabolites within the methoxyindole and kynurenine (KYN) branches of the tryptophan pathway and correlated changes in the metabolites with treatment response.
They randomly assigned 75 outpatients with MDD to sertraline or placebo in the double-blind 4-week trial. After 1 week and 4 weeks of taking the SSRI or placebo, the researchers measured response to treatment using the 17-item Hamilton Rating Scale for Depression and analyzed blood samples using a targeted metabolomic platform they created.
They saw several changes in the methoxyindole branch of the tryptophan pathway in patients who responded to the SSRI.
Specifically, patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, and an increase in 5-methoxytryptophol (5-MTPOL) and melatonin (MEL) levels. „These changes were not seen in the patients showing poor response to sertraline,“ the researchers report.
They also observed significant differences in the ratios between several metabolites in the tryptophan pathway in responders vs nonresponders.
„We have identified at least 1 pathway by which patients get better on antidepressant therapy,“ said Dr. Kaddurah-Daouk.
Toward a Blood Test
Neither KYN nor the other metabolites within the KYN branch of the tryptophan pathway were significantly altered in the group taking sertraline.
In the placebo group, more favorable response was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL ratios.
The researchers point out that it is noteworthy that responders to placebo did not show a reduction in 5-MTPM, suggesting that a decrease in this metabolite might be a specific effect that is related to sertraline.
Overall, this research suggests that serotonin metabolism in the pineal gland „is involved in mechanisms of recovery from a depressed state,“ said Dr. Kaddurah-Daouk.
„It looks like there might be many more chemicals similar to melatonin we are not even aware of that are produced in the pineal gland that controls the sleep cycle, which we know is perturbed in people who are depressed,“ she added.
„The ultimate goal,“ she said, „is to be able to get a blood sample, profile the patient before they take their medication to determine if they will respond to an antidepressant and which antidepressant, or maybe a different type of treatment would be better.“
„The really exciting development over the last 5 years is the knowledge that the way we respond to medication is not only our genetic makeup, it is also our metabolic makeup, as well as environmental influences, like what you eat, your social interactions, how active you are,“ she said.
Commenting on the study for Medscape Medical News, Scott Russo, PhD, from Mount Sinai School of Medicine in New York City, said, „Figuring out ways that we can predict who will respond and how effectively they will respond to an antidepressant is a huge area of interest.“
„These data are impressive; it’s a good paper,“ he said, „but they only looked at 1 type of drug. For this to be something very useful, I would like to see something that would predict response to an SSRI vs an NRI [norepinephrine reuptake inhibitor] or vs a tricyclic, because those are the major classes of drugs that psychiatrists would be working with.“
„In addition, the sample size is pretty small, and they probably don’t reflect the heterogeneity of depression; does this only predict treatment response in a particular type of person who has a deficit in serotonergic pathways, or could it be used more generally for other subtypes of depression as well? These are things the researchers acknowledge in terms of weaknesses,“ Dr. Russo said.
The research was supported by the National Institute of General Medical Sciences and Pfizer. Dr. Kaddurah-Daouk and several of the study authors hold patents in the metabolomics field. A full list of author disclosures can be found in the article. Dr. Russo has disclosed no relevant financial relationships.