Antidepressants restore well-being to many people, but sometimes at the cost of such side effects as weight gain or loss of interest in sex. And these side effects can be just part of the frustration. As Robin Marantz Henig wrote in "Lifting the Black Cloud," in the March issue of Scientific American, the drugs that have long dominated the market—the selective serotonin reuptake inhibitors (SSRIs) and the serotonin and norepinephrine reuptake inhibitors (SNRIs)—"do not help everyone and eventually fail in more than a third of users. A pill that seems to be working today might well stop helping tomorrow. And the drugs can take several weeks to start having a marked effect." Equally disturbing, some major pharmaceutical houses, such as GlaxoSmithKline, are pulling back from developing psychiatric medicines.

But not everyone is abandoning the effort, she noted. Researchers in government and small biotech firms are trying to pick up some of the slack and are searching for agents that work in new ways.

For instance, some investigators, such as Ronald Duman of Yale University, are focusing on finding compounds that will kick in more quickly in our bodies. Duman and his colleagues are trying to learn lessons from ketamine, an anesthetic and painkiller that is also sold illicitly under the name "Special K." The group has shown in rats that ketamine rapidly causes neurons to make new contacts with one another and, apparently by so doing, produces antidepressant effects. Based on an understanding of the molecular basis of those changes, the researchers are now looking for safer agents that operate in a similar way.

Meanwhile, Maura Furey of the National Institute of Mental Health and her colleagues are following up on the discovery that intravenous delivery of scopolamine, a motion-sickness drug, relieves depressive symptoms in people within days. They are trying to find a practical drug-delivery approach; so far skin patches and oral agents do not work well as mood-lifters.

Other teams are attempting to identify agents that ease depression by acting on molecules or processes different from those targeted by existing medicines. Some evidence suggests, for example, that neurogenesis (the production of new neurons) in the hippocampus—a brain region involved in learning and memory—may ease depression. Indeed, induction of such growth is thought to be one way that SSRIs alter mood. With that idea in mind, Neuralstem, in Rockville, Md., has identified a compound that is particularly effective at prompting neurogenesis. The substance is now beginning early tests in humans.

Even gene therapy is under consideration. One approach, meant to increase neurons' responsiveness to the neurotransmitter serotonin, is being tested in monkeys. If all goes well, the tests could justify trials in humans.

For more detail and to learn about other investigations into better antidepressants, see Henig's full article.