As a mother of five who sang in a church choir and ran two businesses near Philadelphia, Garrett Aguilar considered herself happy.
But she also knew that depression ran in her family. When she began to show symptoms four years ago, her doctors tried a variety of standard treatments - six months on Prozac, a week on Wellbutrin and a year on Zoloft. Nothing could restore her spirits.
"I just found myself getting deeper and deeper. It got so bad I couldn't get out of bed," said Aguilar, 55, of Berwyn, Pa.
Then a friend mentioned an experimental treatment that sounded almost like science fiction. Called TMS - for transcranial magnetic stimulation - it attacks depression by applying a magnetic field to the brain.
She enrolled in a TMS clinical trial at the University of Pennsylvania School of Medicine - a site for one of two major TMS studies in recent years. The study was funded by a firm seeking federal approval for the first TMS device specifically designed to treat depression.
If approved, it could offer hope to the 4 million people who suffer from depression but fail to respond to standard therapies or can't tolerate the side effects, said Dr. Mark Demitrack, a psychiatrist and medical director of Neuronetics Inc. of Malvern, Pa.
"There's no question that what's out there now just doesn't work for everyone," Demitrack said.
Researchers have been exploring TMS for two decades, using a technique that can sound bizarre to the uninitiated. The test subject sits in a chair while a scientist places a magnet on his head, then sends magnetic pulses through his skull to "light up" various areas of the brain.
As strange as TMS seems, depression can be so debilitating that patients who fail to respond to other treatments are willing to try almost anything.
That's how bad things were for Aguilar by Christmas 2004, when she found she didn't even have the energy to decorate her house for the holidays - a ritual she always enjoyed. "I was at a point where I felt like I had nowhere else to turn," she said.
After participating in the six-week randomized trial, Aguilar agreed to a follow-up round of TMS treatments. "It kind of tickles your scalp," she remembered.
After a few weeks, she began to improve. These days, she takes a low dose of Lexapro, an antidepressant, and hasn't had a TMS session since March 2005. She credits the magnetic therapy with curbing her depression.
"TMS absolutely changed my life," she said. "It might not work for everybody, but it certainly worked for me."
Researchers are still refining their techniques. They know that by placing the device on different areas of the head, they can make fingers twitch or freeze speech in mid-sentence. There is a small risk of seizures.
But in preliminary studies, TMS has stilled imaginary voices in the heads of the mentally ill and shown promise for treating headaches, post-traumatic stress and obsessive-compulsive disorders.
"It sounds like sci-fi, doesn't it? But I think this is big news," said Dr. Sarah H. Lisanby, a TMS researcher who is director of brain stimulation at Columbia University College of Physicians and Surgeons.
Doctors interested in treating depression aim the magnets at the prefrontal cortex. Other researchers target areas controlling speech, memory or the nerve centers that bring on migraine headaches.
Researchers at Ohio State University Medical Center released a study last week showing a hand-held TMS device placed against the back of the head reduced the pain of migraine headaches. There is no risk of seizures because the device sends out only single - and not repeated - magnetic pulses, said Robert Fischell, the Howard County inventor who developed it. A clinical trial is planned for this year and Fischell hopes to win Food & Drug Administration approval and begin selling the device by mid 2007.
Last year, scientists at Yale University reported the benefits of applying TMS to brain areas controlling speech perception in 50 schizophrenic patients who were having auditory hallucinations. When researchers focused the magnetic field on what is known as Wernicke's area, the imaginary voices subsided. Their report was published in Biological Psychiatry.
"You can shut off specific brain functions, things like speech or motor control," said Dr. Eric Wassermann, chief of brain stimulation at the National Institute of Neurological Disorders and Stroke, a branch of the National Institutes of Health.
In 1998, after a small number of TMS test subjects reported seizures from repeated pulses, Wassermann published safety guidelines dealing with the frequency and duration of the magnetic pulses used in TMS research.
There remains a small risk of seizure, a risk also found with several depression medications. But Wassermann considers the technique safe enough to practice on himself. He experimented a few years ago by having a fellow researcher target the speech centers of his brain as he was speaking. A few zaps of TMS stopped him from talking in mid-sentence.
"It was an indescribable feeling," he said.
There are several standard treatment options for depression. Over the years, drugs such as Prozac and Wellbutrin have helped millions cope. Electroconvulsive therapy, also known as ECT or shock therapy, has also been used since the 1940s. In ECT, doctors anesthetize a patient and use electric current to induce a seizure that releases antidepressant neurotransmitters in the brain.
Psychiatrists say that ECT can fog short-term memory. But they also say techniques have improved considerably since the days when the treatment was so harshly portrayed in Ken Kesey's 1962 novel (and subsequent movie), One Flew Over the Cuckoo's Nest.
Last summer, the FDA approved vagus nerve stimulation, a treatment in which surgeons wrap a wire connected to a battery-operated pacemaker around the vagus nerve in the neck. An electrical pulse stimulates the nerve, releasing chemicals that help combat depression.
But medications don't work for everyone, and some patients are reluctant to try treatments that involve surgery and seizures. "They scare the hell out of me," Aguilar said.
Magnetic treatment offers another advantage over ECT: the patient remains awake and alert during the 40-minute process. "They can watch television, listen to an iPod or do whatever they want to do," said Peter Anastasiou, a Neuronetics spokesman.
TMS got its start in 1985 when English scientists wanted to see whether a magnetic field could stimulate nerves and possibly treat neurological disorders.
"We were looking for a way to maybe help people with things like carpal tunnel syndrome or multiple sclerosis," said Reza Jalinous, who was part of the original University of Sheffield team and is now a co-owner of Magstim Co. Limited, a Welch company that sells TMS devices.
These days, a handful of firms sell TMS equipment to researchers in the United States - and to clinicians who use them to treat patients for depression in Canada, Australia and Europe, where the technique is approved.
TMS has also been the focus of dozens of studies, including a $7 million, four-year study that began last year with funding from the National Institute of Mental Health. But U.S. researchers say that the Neuronetics clinical trial is the most thorough.
Waiting for approval
Neuronetic's device is designed with a patented magnetic coil that passes a magnetic field into the prefrontal cortex, "tickling" it and easing depression, company officials say. The firm applied for FDA approval in mid-April. The agency could grant approval in the next few months or conduct an in-depth review that could take much longer.
"It won't be good for everything, but it will be good for depression and probably for a few other things," said Dr. John O'Reardon, a psychiatrist at the University of Pennsylvania who treated Aguilar in the clinical trial but has no financial interest in Neuronetics. He has been using TMS in research for six years.
Anastasiou declined to disclose the cost of the clinical trial or the expected price tag for its Neuro- Star TMS Therapy System because, he said, FDA rules prohibit those discussions of unapproved products.
In the clinical trial, 301 patients at 23 sites in the United States, Canada and Australia were randomly selected to receive either magnetic stimulation or a pla- cebo treatment in which a plate blocked the magnetic field.
The volunteers were not paid and to qualify they had to be unresponsive to other depression treatments. Treatments were given Monday through Friday, up to 40 minutes a day for up to six weeks. Patients were monitored for six months, Demitrack said.
After the randomized trial was completed, all patients were allowed to receive real TSM treatments as part of an "open label" study.
In the randomized trial, 25 percent of those given TMS improved noticeably, compared with 12 percent in the placebo group, Demitrack said. In the open label study, in which patients knew they were getting TMS, about 45 percent responded.
Considering that patients in the trial had been unresponsive to other therapies, the results were impressive, according to Dr. Mark George, a TMS researcher at Medical University of South Carolina and principal investigator on the separate NIMH study.
"They showed it was safe and that it made people well," George said.
But other experts say it might be too early to design treatments that target specific areas of the brain because so little is known about its workings.
"We might be treating one signal of a disease, one side effect of it, but not the disease itself," Wassermann said.
Many of depression's biological underpinnings remain a mystery, and targeting a specific area could prove ineffective, said Dr. Ralph Hoffman, the Yale psychiatrist who did the work with schizophrenics who heard voices.
"There's little that's known about the physiology of depression. It's a real limitation," Hoffman said.
Demitrack agreed that some biological roots of depression remain elusive. But he said that shouldn't stop doctors from using a new type of treatment for depression when drugs and psychotherapy don't work.
"The question is, do we know enough about the biology, the symptoms and causes of depression to test and use a new therapy? I think the answer to that is yes," he said. "The problem is that depression has multiple biological underpinnings, so there's no one therapy that will work in everybody, and I don't think TMS will work for everybody either."