Newer Antidepressants Work 2 Ways

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New research shows that the popular, and sometimes controversial, antidepressants known as selective serotonin reuptake inhibitors (SSRIs) boost serotonin levels on two fronts.

The finding could explain why these medications often take weeks to work, the scientists report in the April 7 issue of Neuron. Apparently, SSRIs kick off a two-pronged process that puts serotonin levels back into balance. Serotonin is a brain chemical that scientists believe is in short supply in depressed people.

In addition to boosting serotonin levels, this family of antidepressants apparently also “hijacks” the dopamine signaling system, causing it to affect serotonin levels as well.

The use of SSRIs, especially by children, came into question last fall following reports of increased thoughts of suicide and attempts among young, depressed patients. The U.S. Food and Drug Administration responded by mandating a black box warning on the use of these drugs in children and teenagers.

“We have known about these interrelationships,” said Dr. Fred Quitkin, director of the depression evaluation service at the New York State Psychiatric Institute. “It’s of interest, but no one knows what it means.”

“The brain is so incredibly complicated,” said Dr. Eugenio M. Rothe, director of the child and adolescent psychiatry clinic at Jackson Memorial Hospital in Miami, Fla., and an associate professor of psychiatry at the University of Miami School of Medicine. “More and more things have yet to be discovered. The brain is the final frontier.”

Many of the millions of Americans afflicted with depression have a disorder in the brain’s reward system, explained study author Fu-Ming Zhou, an assistant professor of pharmacology at the University of Tennessee College of Medicine in Memphis. Zhou conducted the study while at the Baylor College of Medicine.

“A large body of research indicates that the dopamine system is the most important player in the reward system,” he added.

Often, however, depression is treated with medications that affect the serotonin system. SSRIs block the reuptake of serotonin back into the nerve terminals.

In a healthy person, serotonin is stored in nerve terminals and then released into the spaces between neurons. Problems occur when the neurotransmitter is sucked back into the terminal, a process called reuptake. “This limits the level or availability of serotonin near the nerve terminals,” Zhou said. “There is a possibility, which remains to be proven, that the local serotonin level near these nerve terminals is abnormally low in depressed patients.”

“When a patient takes an SSRI, the reuptake process is inhibited, leading to increased serotonin levels around the nerve terminal, and also restored or enhanced serotonin signaling,” he continued. “This restored or enhanced signaling is often believed to be the major therapeutic mechanism of SSRIs.”

Apparently, however, SSRIs affect more than just serotonin levels, as Zhou and his colleagues demonstrated in mice.

Dopamine transporters in the brain area involved in reward response normally reuptake dopamine. But because there are so many dopamine transporters, they may also pick up serotonin, albeit at a lower level of efficiency.

“Put simply: serotonin transporters are like a high-power vacuum pump that can suck back serotonin really fast,” Zhou said. “Dopamine transporters may suck back serotonin very slowly, like a large sponge. This sponge is of no significance if the high power vacuum pump is working. When a patient takes SSRI, the pump is inhibited or becomes not functional. Under this condition, the large sponge becomes significant, capable of sucking in significant amounts of serotonin over a long period of time.”

“We believe that these neurochemical changes contribute to the therapeutic mechanisms of SSRIs,” Zhou said.

The fact that the “sponge” is not very efficient may account for why it can take several weeks for the effects of Prozac and other SSRIs to kick in, he added.

The authors also speculated that disrupting normal serotonin levels in children, while neurons are still under development, could result in problems later in life.

Although the study was done in mice, Rothe believes there is a message for humans.

“People taking antidepressants need to have regular doctor visits, and their doctor has to keep a close eye on what’s going on,” he said. “They should fight insurance companies that think that they can go for one visit and get five refills, and not go back for six months.”

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