Researchers report they have used PET brain imaging (positron emission tomography) to learn more about the relationship between two commonplace factors in the human brain that may have a role in causing depression or vulnerability to it.

The two factors are serotonin transporters (SERTs), specialized proteins that transport the neurotransmitter serotonin between brain cells; and various types of fatty molecules called PUFAs (polyunsaturated fatty acids).

The study, appearing in the Journal of Affective Disorders, found a relationship between one of those PUFAs, called arachidonic acid; levels of serotonin transport in key brain areas; and the severity of depression symptoms.

Led by 2007 BBRF Young Investigator M. Elizabeth Sublette, M.D., Ph.D., and 2008 BBRF Distinguished Investigator and Scientific Council member J. John Mann, M.D., both of Columbia University, the team recruited 21 adults experiencing an episode of major depressive disorder. To qualify for the study, subjects had to be free of medications that affect both the serotonin neurotransmitter system and the biochemical system that generates arachidonic acid, for at least 2 weeks.

Weeks before the PET scans were performed, each participant’s plasma was analyzed for levels of three PUFAs: DHA and EPA, which are omega-3 fatty acids; and AA or arachidonic acid, which is an omega-6 fatty acid. (Fatty acid classifications are based on their chemical structure.)

The PET scans were designed to measure the availability of SERTs in six brain areas associated in past research with depression pathology. In the healthy brain, SERTs must be widely available to remove serotonin molecules from the spaces between “sending” and “receiving” neurons, once they have transmitted a message. The serotonin is taken up by SERTs and recycled back inside the “sending” cell, in anticipation of the next message to be propagated.

Low availability of SERTs has been linked in many studies not only with depression but also with the depression experienced by people with bipolar disorder. The most commonly prescribed antidepressants, called SSRIs (serotonin reuptake inhibitors), specifically block SERTs, enabling serotonin to remain available in the synapses between neurons for a longer period, thus promoting signaling between cells.

PUFA fatty acids, obtained from food and found throughout the brain and body, are key building blocks of cell walls; but they also play vital roles in other cellular processes, including in the immune system—sometimes taking part in its activation and at other times inhibiting it, depending on the biological context. Various attempts have been made to alter PUFA levels in the blood—omega-3 supplementation, for example—as a way of reducing depression symptoms. Results have been inconclusive, but for years PUFA levels have been a consistent subject of interest among depression researchers.

Drs. Sublette, Mann and colleagues including Gregory Sullivan, M.D., a 2004 BBRF Young Investigator, discovered in their study that only one of the PUFAs they measured—AA, or arachidonic acid—had a potential impact on the availability of SERTs across the six brain areas that were imaged via PET scan. Specifically, they found that greater SERT availability in neurons correlated with lower AA levels in subjects, as measured in their plasma prior to the scans.

This result led the team to hypothesize that AA may affect the severity of depression through its impact on the availability of SERTs in the brain. The nature of the observed correlation was complex, with extreme levels of AA affecting both SERTs and depression severity differently than moderate AA levels.

The team hopes that their approach will be replicated in larger samples of patients with major depression. If it is, the finding may shed light on new nutritional approaches to address major depression, which affects millions every year. The team says future studies might examine whether the relationship between AA, serotonin, and depression severity can help to explain why PUFA supplements may have therapeutic effects in the treatment of major depression.