For years, researchers have known that women are twice as likely to develop depression as men and they suffer a wider range of symptoms.  But when it came to prescribing effective treatments, researchers couldn't agree if gender mattered. As some small studies suggested, certain drugs worked better in women than men. Could there be significant biological differences in how each gender responded to these medications? A $35 million, federally funded study, was commissioned to answer the controversy, and its just-published results suggest that the answer to both questions is a probable yes.

The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, the largest and most rigorous depression study done to date, enrolled 2,876 men and women (ages 18 to 75) from 41 treatment centers with funding from the National Institute of Mental Health (NIMH). All participants were treated for 12 to 14 weeks with citalopram (popularly known as Celexa), a selective serotonin reuptake inhibitor (SSRI), currently the most popular class of antidepressants on the market.

Even though the women in the study generally had more severe depressive symptoms than the men, they were 33 percent more likely than the male participants to achieve a full remission. "These results are very exciting because they give more confirmation that gender is a factor that should be considered when prescribing treatment for depression," said Dr. Susan Kornstein, professor of psychiatry and obstetrics/gynecology at Virginia Commonwealth University, and one of the study's lead authors. "This is one more big piece of the puzzle as we try to understand sex differences in treatment response." The results were recently published in the online version of the Journal of Psychiatric Research.

In retrospect, she added, the STAR*D results help explain why early drugs developed for depression, such as tricyclics--which were originally tested for effectiveness in men--seemed so much less helpful to women in clinical practice. "People hadn't thought much about gender in terms of treatment options in the early days," she said. "No one thought about treating women differently than men."

In the late 90s, however, Kornstein led a pivotal study comparing the effectiveness of SSRIs to tricyclics among 600 women and men. The results made it clear that women responded better to SSRIs, while men did better on tricyclics. The study also found that it took women significantly longer to get results from tricyclics. Not surprisingly, men taking SSRIs and women taking tricyclics were the most likely to drop out of the study--presumably because the medication was not helping.

However, Kornstein's original study did not directly compare the effectiveness of SSRIs on women versus men. And studies since have come up with conflicting results, Kornstein said, partly because they were not well designed. That's why the decision was made to do this analysis of the STAR*D data. Study participants included a broad range of "real-world patients" who were seeking help for depression, not the typical small groups of research subjects recruited and screened to create a homogenous cohort, Kornstein stressed. Study participants had, on average, suffered from depression for more than 15 years, and included those who had previously attempted suicide and had other medical and psychiatric diagnoses.

Kornstein's earlier study also found that SSRIs were significantly more effective for pre-menopausal women, while menopausal women and men experienced similar results. That seemed to add further evidence that the sex hormone, estrogen, which younger women create in greater abundance than older women, may be one key to SSRI's increased effectiveness in women as a group.

Animal studies have long shown that estrogen helps the brain regulate levels of the neurotransmitter, serotonin, a key brain chemical that affects mood, anxiety and sleep. (When serotonin levels drop, people are more likely to feel helpless and hopeless. Very low levels are associated with suicidal tendencies.) Kornstein says she hopes to further analyze the STAR*D results to determine whether menopausal women taking hormone therapy containing estrogen supplements had a better response to SSRIs than those not taking HT.