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.

CNS Response has built a database of EEGs belonging to about 2,500 patients, from which it's possible to match certain abnormal brain patterns to improvement on a specific drug or combination. When a new patient submits an EEG, CNS Response compares it with their database to suggest personalized medication options (the company's technology is currently in clinical trials). Occasionally the recommendations are surprising. "I had a woman with alcohol dependence and anxiety along with low-level depression," says Mark Schiller, MD, an associate clinical professor of psychiatry at UCSF and the company's director of medical affairs. "The database showed she might respond to a combination of a mood stabilizing drug and a stimulant. Now she's much less anxious and more active. Without this test, I would not normally have tried these types of medications."

Diagnostic scanning is still very experimental, but Nobel Prize–winning neuroscientist Eric Kandel, MD, believes it's promising for gauging what kinds of psychotherapy would be most effective. "It's an important methodology for all aspects of psychiatric illness, and it's a major step forward," says Kandel, University Professor at Columbia.

Drugs: Beyond Prozac

Many new drugs are being investigated. One surprising candidate (except perhaps to certain club-hoppers) is ketamine, an anesthetic that's also sold on the street illegally under names such as Special K. In a recent trial, it snapped people out of depression almost instantly, unlike available medications that often take weeks to work. "We administered very low doses of ketamine intravenously and saw antidepressant effects in as early as two hours," says Husseini Manji, MD, director of the mood and anxiety disorders program at the National Institute of Mental Health. And these were patients who had tried, on average, six antidepressants without success; some even failed to improve with ECT. "By 24 hours, about 70 percent had responded to the ketamine and 35 percent met criteria for remission," says Manji. "It's remarkable that the drug works so well in this difficult-to-treat group, and one dose kept people well for a week."

Ketamine acts on receptors to a different neurotransmitter (glutamate) than current antidepressants do. The problem is that it affects parts of the brain not related to depression; the drug can also cause hallucinations (usually in higher doses—the reason people snort the powder or inject it to get high). "But if we can tweak it and make it in pill form," says Manji, "we might have a great medication that works fast and is easy to use."

Even more exciting to Manji, who thinks "we've been just scratching the surface by focusing on neurotransmitters," is the development of antidepressants based on molecules that travel inside nerve cells to adjust them. "This is a bit far off. But there was a study using the breast cancer drug tamoxifen to treat mania, mainly because it works inside the nerve cell, and it showed a remarkable and very rapid effect."

What all this research means for anyone who bumps up against depression is that soon there will be more options. For many people, psychotherapy and antidepressant medications—new and old—might be enough. If not, the next step could be a treatment using magnetic fields followed, if necessary, by ECT, Lisanby says. "And DBS has the potential of offering hope to people who are not responding to what medical science has to offer today." In the meantime, if you're having no luck with current treatments, check clinicaltrials.gov for the latest research as well as studies you might want to join.

Tim Jarvis is a freelance journalist living in Miami.


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