Photo: Plamen Petkov
Nearly 25 years after the Prozac revolution, scientists are seeking faster, more effective ways to loosen the grip of depression.
Imagine your doctor has just diagnosed you with depression. She sits down to write you a prescription for an antidepressant, but not before she performs a simple blood test that tells her exactly which medication will work best for you. You take a pill in her office, and within two hours your mood is already lighter.

Or suppose you decide to go into therapy—except in addition to seeing a shrink, you also check in with a computer program that leads you through a series of depression-relieving exercises. Or let's say drugs and therapy have failed to relieve your symptoms, so your psychiatrist suggests an alternative treatment. He positions a device on your scalp that's designed to stimulate activity in certain areas of your brain, and after several weeks of sessions, your depression lifts.

Such scenarios may sound far-fetched, but in fact they may not be long out of reach. And they represent a new generation of research that, according to Andrew Leuchter, MD, professor of psychiatry and biobehavioral sciences at UCLA, may offer "treatments that are a marked improvement over what's available now."

Today many people with depression are prescribed drugs (like Prozac and Zoloft) that belong to a family of medications known as selective serotonin reuptake inhibitors (SSRIs). But these drugs have drawbacks. One is that only about 30 percent of patients see improvement from the first SSRI they take; others must try another medication, or two or three, before they find one that does the trick. Leuchter is working to eliminate the trial and error by using biomarkers—signals from our bodies that can indicate whether a treatment will be successful. Right now one of the most promising biomarkers is changes in brain activity. By comparing a brain scan taken immediately before a patient starts an antidepressant to a scan conducted just one week later, Leuchter says he can predict with 74 percent accuracy whether the medication will ultimately make the person well. The future may bring an even speedier shortcut: a blood test that would match a patient with the right drug based on her genetic makeup, before she ever takes a pill.

The other drawback to SSRIs is that they can take up to 12 weeks to make people feel better. That's because the drugs work in part by setting off a chain of neurochemical events that eventually regulates brain levels of glutamate, a neurotransmitter that improves communication between neurons. A drug that targets glutamate levels directly could improve mood much faster. One drug that has been shown to do so is ketamine, which is currently used as an anesthetic.

In one experiment, researchers at the National Institute of Mental Health (NIMH) administered an intravenous dose of ketamine to a group of people with depression. "Less than two hours later, the participants reported feeling better. Within 24 hours, they had achieved the same level of depression relief that people on SSRIs get in approximately six weeks," says Carlos Zarate, MD, a scientist in the Mood and Anxiety Disorders Program at the NIMH and lead researcher on the study. "When it comes to the speed of depression treatment, that's like breaking the sound barrier." However, ketamine can also temporarily distort sensory perception, so Zarate and his colleagues are hoping to create newer versions that would be just as effective but safer.

Computer-assisted therapy (CAT) and a new, painless version of electro-shock therapy
Of course, even the best medications are often not enough to combat severe depression—for which psychotherapy is also an important part of the recommended treatment. The trouble is, many patients never get therapy. "In many communities, there is a shortage of trained therapists," says Jesse Wright, MD, PhD, director of the University of Louisville Depression Center in Kentucky. "And therapy can be expensive. But in the future, a computer may help solve these problems."

In computer-assisted therapy, or CAT, sessions with a human therapist are supplemented with the use of interactive software. The computer might show you a video of a woman who is depressed and demonstrate how her low mood is perpetuated by her excessively negative thoughts. The program would help you identify these types of thoughts in your own life, and lead you through exercises designed to get you thinking more clearly and positively.

Computers may also help doctors screen people at risk for depression, via voice analysis software that gauges a patient's mental state based on nuances of her speech. "Depressed people tend to talk in characteristic ways; their speech is quiet, slow, without a lot of variety or emphasis," explains Alex Pentland, PhD, a professor at MIT who helped develop the software. After analyzing thousands of samples of depressed patients' speech, Pentland and his colleagues created a program that recognizes cues only a very experienced clinician would pick up. He predicts that the software will one day be used to "listen over the shoulder" of healthcare providers on phone calls with patients, issuing an alert when it identifies the warning signs of depression.

For many patients whose depression doesn't respond to medication or therapy, the treatment of last resort was once electroconvulsive therapy (ECT). While effective, ECT can cause serious side effects, including memory loss. But a new generation of brain stimulation therapies is beginning to offer relief from intractable depression with fewer risks. "In the same way that cardiologists use pacemakers to correct abnormal heart rhythms, we're now beginning to use brain stimulators to correct the neural circuitry that's causing the psychiatric disorder," says Sarah Lisanby, MD, director of the Brain Stimulation and Therapeutic Modulation Division at Columbia University Medical Center in New York.

One therapy offered at Lisanby's clinic is transcranial magnetic stimulation (TMS). TMS delivers mild, painless electrical signals to the prefrontal cortex through a plastic-coated wire coil placed on the head. "The treatments stimulate nerve cells in a region of the brain called the prefrontal cortex," says Lisanby. "This area plays an important role in mood regulation, and it's often less active in people who are depressed." Scientists are also exploring how similar but more invasive technologies—such as vagus nerve stimulation and deep brain stimulation—might also be effective in alleviating treatment-resistant depression.

"In the past, our options for people with the most severe forms of the disease were very limited, but we're already able to offer a wider variety of safer choices," says Lisanby. For patients who have lived with the darkness of depression, such treatments will mean a bright new day.

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