Antidepressants increase brain steroids.

Prozac, Paxil, Zoloft, and similar antidepressants, collectively called selective serotonin reuptake inhibitors (SSRIs), fly off pharmacy shelves even though scientists continue to argue about how the drugs lift a person's mood (SN:9/25/99, p. 196). The prevailing theory holds that the drugs work by inhibiting a protein that mops up the brain chemical serotonin. In the latest challenge to this view, a new study suggests that SSRIs may relieve depression by boosting the efficiency of brain enzymes that make several steroid hormones.

In the past decade, scientists have found that the brain, using the same enzymes employed by the testes and adrenal glands, produces steroids such as allopreguanolone. Moreover, these neurosteroids don't interact only with traditional hormone receptors deep within a cell. They also bind to some of the cell-surface proteins that receive signals from the brain chemicals known as neurotransmitters, which include serotonin.

The initial connection between neurosteroids and mood came when researchers associated brain concentrations of these hormones with symptoms of premenstrual syndrome (PMS), including depression. Since Prozac sometimes helps women who suffer from a severe form of PMS, investigators began to examine whether the SSRIs alter neurosteroid concentrations in the brain. In both rats and people, according to two recent studies, treatment with Prozac indeed seems to boost the concentration of allopreguanolone in the brain or spinal fluid.

To explore how the antidepressants may bring about this change, Lisa D. Griffin and Synthia H. Mellon, both of the University of California, San Francisco, recently did test-tube experiments to determine whether the drugs interact with the enzymes that make allopreguanolone from its steroid precursors. The SSRIs didn't influence the first enzyme in the steroid-production pathway, but they did enable a second enzyme to work with lower concentrations of the steroid's precursors, the two report in Nov. 9 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

"All this work suggests that there's another component of depression and that one should look at neurosteroids and their abnormal synthesis," says Mellon. In fact, she plans to study whether people with depression have subtle mutations in the genes for the hormone-synthesizing enzymes.