Illustration: Luba Lukova
It's the year 20 A.P.—two decades After Prozac was approved—and depression is hardly the crippler it once was. But that's for most people. In at least a third of patients, medication doesn't help. It's as if the train has passed them by.

The bright side for those left behind is that researchers have quietly been on the case, investigating fresh approaches to unlocking depression's most stubborn grip. On the brink of a whole new era of treatment, advances range from novel, fast-acting drugs to devices that work like brain pacemakers.

Among the most impressive:

Devices: Probing the Brain

To date, electroconvulsive therapy (ECT)—which uses electricity to produce a brief seizure in the brain that seems to jostle it back to normal—is widely acknowledged as the most effective weapon for treatment-resistant depression in a psychiatrist's arsenal, and often the last resort. Like drugs, however, it doesn't work for everyone and can cause serious side effects such as memory loss. "That's why I'm motivated by my work on magnetic seizure therapy [MST]," says Sarah Lisanby, MD, chief of the division of brain stimulation and therapeutic modulation at Columbia University, who developed the procedure with her team. The idea behind MST is that by using magnetic fields rather than electricity, you can induce a similar brain seizure in a more targeted, less invasive way. "We want to take advantage of the efficacy of ECT but try to make it more available by making it safer."

Perhaps most radical—and exciting for the treatment-resistant depressed—are brain implants that work like pacemakers to keep a lagging neural area up to speed. One pioneer in the field is Helen S. Mayberg, MD, professor of psychiatry and neurology at Emory University School of Medicine in Atlanta. Implanting electrodes in the brain through two holes in the scalp, she's using deep brain stimulation (DBS) to transmit a constant low-voltage current to an area called the subgenual cingulate region, or Brodmann area 25.

This region, says Mayberg, is overactive in treatment-resistant depression. "It regulates your stress responses and is involved in your feeling sad. It interacts with other brain areas that determine if the negative things you're feeling are relevant and what you're going to do about them. That whole choreography goes wrong in people who are depressed. Our theory is, the system gets stuck, and with the DBS we unstick it and give it a different rhythm so it responds more normally."

In fact, Mayberg's DBS had a profound effect in a study published in the journal Neuron: Four out of six patients with otherwise intractable depression went into remission. "Four years later, the four patients still have the stimulator and all continue to be well. This is a whole new model for thinking about the disease," she says, adding that more conclusive studies are four to five years away. "It's really not just being a quart low on serotonin; there's a complexity to brain areas involved in regulating your normal emotional response to your environment."

Scans: Mind Readers

Trial and error, a frustrating aspect of current depression treatment, leaves many patients in misery and at risk for suicide while trying to find something that works. But a number of experts have started looking at brain scans for guidance on which drugs to prescribe. Research out of the University of Cambridge in England showed for the first time that MRIs can help predict how well a patient will respond to antidepressants. Meanwhile, a California company called CNS Response claims success with electroencephalograms (EEGs), which measure electrical activity in the brain.