For the past several decades, those suffering from depression have been told that by boosting serotonin levels, brain chemicals will re-balance and mood will improve.  It’s no surprise then that more than one in 10 Americans age 12 and older take some form of antidepressant medication designed to increase serotonin levels, offsetting the chemical imbalance. However, new research suggests the link between low levels of serotonin and depression is, at best, a partial answer.

“Chemical imbalance is really an overly simplistic way of thinking,” said Paul B. Hicks, M.D., Ph.D., vice dean and professor of psychiatry and behavioral sciences at the Texas A&M Health Science Center College of Medicine in Temple. “Depression is a very complex problem that we know involves certain parts of the brain, but we don’t have a complete picture. While countless theories have been tested, we still don’t have the final understanding of what changes in the brain with depression and how we should proceed to reverse such changes.”

One theory is the idea that our brains can run low on a neurotransmitter called serotonin. It’s thought that by prescribing a selective serotonin-reuptake inhibitor (or SSRI) antidepressant medication, like Prozac or Zoloft, the imbalance can be medically fixed; bringing serotonin levels back to “normal.”

“This idea is based upon the assumption that serotonin and/or norepinephrine – a neurotransmitter secreted in response to stress – brain levels are low in depression and that antidepressants work by elevating brain neurochemical concentrations,” Hicks said. “It has been valuable in helping to identify all the currently marketed antidepressants.”

SSRIs are designed to boost serotonin levels, helping kick off the production of new brain cells, which in turn is thought to allow depression to “lift.” However, if low serotonin levels were the cause of depression, then increasing levels of serotonin should alleviate the symptoms instantly. Unfortunately, that’s not the case.

“The major problem with this theory is the chronology of the resulting chemical changes in the brain,” Hicks said. “SSRIs release serotonin and increase the amount in the brain almost immediately, while the antidepressant effect can take a few weeks to kick in.”

This time-lapse indicates that there may not be a direct relationship between low levels of serotonin and depression. However, antidepressants are still effective and two-thirds of patients respond to them positively, we just don’t have the entire answer as to why they work, yet.

New hypotheses in depression focus on the role of an excitatory brain chemical produced from glucose, glutamate, which is known to increase brain activity and energy levels.

“Studies link high glutamate levels in the brain with depression and antidepressants are known to decrease these levels,” Hicks said.

In fact, intriguing recent findings show an immediate antidepressant response when ketamine, a drug that blocks glutamate’s actions, is given directly into the blood.

“While brain chemicals, including serotonin and the more prevalent glutamate, seem to play a role in depression, it is also true that specific brain regions appear to mediate the development of depression,” Hicks added.

A brain region called the hippocampus, where stress is mediated and memory consolidation occurs, decreases in size and complexity of chemical connections under the influence of stress and presumably depression.

“We also know that another brain region near the base of the front of the brain, the subgenual cingulate cortex, is overactive in depression and antidepressants decrease its activity when an antidepressant response is seen,” Hicks said.

While serotonin deficiency may not cause depression after all, new research may lead to a more direct and effective treatment than common SSRIs.

“Management of depression is an evolving field and there are many important studies being done to enhance our available treatment options,” Hicks said. “While we don’t have all the answers now, we may have more effective and convenient interventions in the future.”

— Holly Shive

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