All of which leads to an intriguing question. If cell maintenance is the real goal of treatment, are there cleaner, less roundabout ways to achieve it? Could drugs designed specifically to shield or rebuild neurons bring faster, surer relief, while causing fewer side effects? It’s still too soon to say, but the race to find out has already begun.
Scientists have long wondered how drugs like Prozac work their charms. These medicines, known collectively as SSRIs (selective serotonin reuptake inhibitors), raise serotonin levels almost immediately, yet they take several weeks to affect mood. What happens during the interim? Animal studies suggest that the rise in serotonin sets off a series of biochemical events in the hippocampus, a brain structure that plays important roles in memory and emotion. Specifically, the brain starts churning out BDNF (brain-derived neurotrophic factor), a chemical that enables hippocampal neurons to branch out and form new links with their neighbors. The process takes time, but as mice go through it they become more spirited. Placed in a pool surrounded by high walls, for example, they’ll swim vigorously instead of giving up within minutes.
No one has connected the dots quite this neatly in people (few of us would volunteer for experiments that involved brain biopsies and the prospect of drowning). But the animal findings square nicely with recent discoveries about human depression. Brain-imaging studies show that the hippocampus of a depressed person is often abnormally small–and preliminary findings suggest that medication may reverse this shrinkage. Similarly, one autopsy study found that depressed patients on mood-boosting drugs had higher BDNF levels than those who died untreated. The clear implication is that depression involves reversible cellular damage–and that blocking or repairing it is the proper goal of therapy. As Yale neuroscientist Ronald Duman observes, a drug designed specifically to sustain hippocampal cells might work both faster and better than today’s SSRIs.
What sort of treatment might accomplish that? BDNF would seem an obvious candidate, but it has little potential as a drug. It dissolves in the gut if taken orally, and wouldn’t pass from the bloodstream into the brain if injected. It’s more feasible to boost BDNF’s effects by using drugs to slow its removal from the brain. But if depression stems from cell damage, perhaps the most elegant solution is simply to block whatever is causing it. Experts aren’t sure what causes hippocampal atrophy in depressed people, but the suspects include the stress hormones cortisol and corticotropin-releasing factor (CRF). These homegrown chemicals prime the body for fight or flight during times of trauma, but studies suggest they wreak havoc on the hippocampus when constantly elevated. Pfizer, Bristol-Myers Squibb and GlaxoSmithKline are all now testing mood drugs that work in part by blocking the effects of CRF. The race has yet to move from lab to clinic, but the early findings have experts enthralled. “In animals, these drugs have fabulous antidepressant and antianxiety effects and a benign side-effect profile,” says Dr. Charles Nemeroff of the Emory University School of Medicine. “They could replace drugs like Librium and Valium for anxiety, and I suspect they’ll work as well as the current crop of antidepressants, if not better.” Prozac, it seems, has just been a warm-up act.
