WORKPLACE SECRETS

THE QUEST FOR A CURE

New drugs and therapies join the battle against depression

MARK NICHOLS December 1 1997
WORKPLACE SECRETS

THE QUEST FOR A CURE

New drugs and therapies join the battle against depression

MARK NICHOLS December 1 1997

THE QUEST FOR A CURE

New drugs and therapies join the battle against depression

MARK NICHOLS

Every few weeks, several teenage girls arrive at Halifax’s Queen Elizabeth II Health Sciences Centre to take part in a study that may someday ease the crippling misery of depression. For two nights, the girls, a different group each time, bunk down in a sleep laboratory with tiny electrodes attached to their heads. Through the night, electronic equipment monitors their brain activity as they pass through the various stages of sleep, including the periods of rapid eye movement (REM) when dreaming occurs. Half of the roughly 80 girls who will take part in the study have no family history of depression. The others do—their mothers have had major depression and researchers know that these girls have a 30-per-cent chance of being victims, too. Dr. Stan Kutcher, a Dalhousie University psychiatrist who is involved in the study, wants to see whether a feature of sleep in depressed adults—they reach the REM stage faster than others—shows up in the kids. If it does, doctors for the first time would have a way of predicting depression and starting treatment early. Kutcher has been working with troubled youngsters most of this life. “It’s a tremendous feeling to be able to help kids get better,” he says. “It’s a privilege to be let into their lives.”

A pioneer in studying and treating adolescent depression, Kutcher is part of an army of medical researchers whose efforts are bringing new drugs, new therapies and new ways of thinking to bear in the war on the debilitating disorder. One of the biggest breakthroughs came in capsule form when Indianapolis’s Eli Lilly and Co. introduced a product called Prozac almost 10 years ago. The first of a new class of drugs that can alleviate depression without the same nasty side-effects of many older antidepressants, it profoundly improved the quality of life for millions of people. Thanks to Prozac and drugs like it, says Dr. Sid Kennedy, head of the mood disorders program at Toronto’s Clarke Institute of Psychiatry, “depressed people are able to live normal, productive lives in

a way that wouldn’t have been possible 10 years ago.” Now, drugs that are potentially even better are undergoing tests, while researchers study the intricate universe of the brain in search of clues that could someday banish depression entirely. “Things are really moving quickly,” says Dr. Trevor Young, a neuroscientist at McMaster University in Hamilton. “We’re really getting close to understanding the biochemical changes that occur in depressed brains.” And doctors are coming closer to the time when they may be able to start treatment, in some cases, even before depression takes hold. After the Dalhousie researchers finish their current series of tests early next year, they will keep track of their young subjects for five years to see whether their REM sleep patterns pinpoint which of them will become depressed. If they do, then doctors in the future may be able to test children from families with a history of depression, and identify potential victims. One possibility, says Kutcher, would be to begin treating those children with antidepressants even before the first bout of depression occurred—in the hope that it never will.

Underpinning the new wave of research is a quiet revolution that has transformed thinking about depression over the past two decades. As recently as in the 1960s, when Sigmund Freud’s psychoanalytic philosophy was still pervasive, depression and most other forms of mental illness were regarded as the consequences of emotional turmoil in childhood. Now, scientists have clear evidence that inherited flaws in the brain’s biochemistry are to blame for many mental problems, including manic-depressive illness—with its violent swings between depressive lows and manic highs—and, according to some experts, recurring severe depression. Beyond that, many experts think that damaging events in childhood—sexual or physical abuse, poisoned parental relationships and other blows to the child’s psyche—may cause depression later by disrupting development of crucial chemical pathways in the brain. “Losses early in life,” says Dr. Jane Garland, director of the mood and anxiety clinic at the British Columbia Children’s Hospital in Vancouver, “can raise the brain’s level of stress hormones that are associated with depression.”

When the dark curtain of depression descends, today’s victims have access to quick and effective treatment. Short-term “talk therapies” now in use can help haul a patient out of depression in as little as four months—as opposed to years on a psychoanalyst’s couch. The purpose of such therapy, says Dr. Marie Corral, a psychiatrist at the British Columbia Women’s Hospital in Vancouver, is “to deal with the skewed thinking that develops when a person has been depressed for a long time.” The most widely used methods: interpersonal therapy, which focuses on specific people-related problems, and cognitive therapy, which tries to counter the feelings of worthlessness and hopelessness that plague depressed people. ‘We try to show the patient that much of this thinking may be unfounded,” says Zindel Segal, a Toronto psychologist.

But along with the new approaches to dealing with depression, a treatment introduced nearly 60 years ago that has earned a grim public image—electroconvulsive therapy (ECT)—is still a mainstay. Popularly known as shock treatment, it remains “one of our most potent forms of therapy” for severely depressed patients who do not respond to other treatment, says Dr. David Goldbloom, chief of staff at Toronto’s Clarke Institute. ECT is routinely used every year on thousands of depressed Canadians, including older patients who cannot tolerate some of the side-effects of drug therapies.

ECT’s bad reputation owes much to the 1975 movie One Flew over the Cuckoo’s Nest, in which staff members of a mental institution punish a rebellious patient, played by Jack Nicholson, with repeated ECT sessions. Patients did endure painful ordeals in the early days of ECT when larger electrical shocks were used to induce a limb-shaking seizure in unanesthetized patients. Electroconvulsive treatment is gentler now. Doctors administer a muscle relaxant and a general anesthetic before subjecting the patient’s brain to the amount of current needed to light a 60-watt bulb for one second.

ECT’s aftereffects can include painful headaches lasting half an hour or so, and some memory loss. ECT does its job, they add, by altering the brain’s electrical and chemical activity. The

therapy has some bitter opponents, who claim that it can cause lasting memory loss and impair other brain functions, such as concentration. “ECT damages people’s brains—that’s really the whole point of it,” says Wendy Funk, a 41-year-old Cranbrook, B.C., housewife. Funk says that after receiving electroconvulsive therapy for depression in 1989 and 1990, she lost virtually all memory—she could not recall even her own name or that she was married and had two children.

Meanwhile, for the approximately 70 per cent of patients who respond to them, Prozac and the family of drugs it spawned—Paxil, Zoloft, Luvox and Serzone—are making life far more bearable. Collectively, the drugs are known as SSRIs (for selective serotonin reuptake inhibitors) because they increase the brain’s supply of the chemical messenger serotonin.

The SSRIs have foes: the Internet bristles with accusations that the drugs can cause panic attacks, aggressive behavior and suicidal tendencies. But most doctors have nothing but praise for the drugs. It’s not that they are better than their predecessors at relieving depression—most physicians say they are not.

But SSRIs are easier to live with than some older antidepressants, which often caused dry mouth, daytime sleepiness, constipation, vision problems and other unpleasant side-effects. “The SSRIs are better tolerated,” says Dr. Russell Joffe, dean of health sciences at McMaster University, “and it is much harder to overdose on them than the older drugs”—a vital consideration in treating people who may be at risk from suicide. The SSRIs can have side-effects of their own, including insomnia and a diminished interest in sex that sometimes persuade patients to stop taking them. ‘You just don’t get sexually aroused,” says Giselle, a 41-year-old Manitoba resident who requested anonymity. “There’s just nothing there.”

Another problem with the SSRIs is that patients usually have to take them for three weeks or more before they start to work. The reason: when an SSRI increases the flow of serotonin in the brain, the thermostat-like mechanism that normally controls the flow of the chemical shuts down—and then takes three to six weeks to adapt and allow serotonin to flow again. “If you have a severely depressed patient who may be thinking about suicide,” says Dr. Pierre Blier, a professor of psychiatry at Montreal’s McGill University, “telling

him he may have to wait that long for relief isn’t good enough.”

After studying the problem exhaustively, Blier and another McGill psychiatrist, Dr. Claude deMontigny, proposed in 1993 that the SSRIs would probably take effect more rapidly if used in conjunction with another drug that could block the brain mechanism causing the delay. Such a drug, a hypertension medication called Pindolol, existed. And the following year, a Spanish physician tried the combination—and found that it worked. Since then, studies have shown that the PindololSSRI combination can cut the waiting time for SSRIs to take effect to about 10 days. Working with that knowledge, several major drug companies now are trying to develop a new generation of fast-acting SSRIs.

Meanwhile, efforts to lay bare the roots of depression are being pursued by a number of Canadian research teams:

• While most antidepressants concentrate on two of the brain’s chemical messengers—serotonin and noradrenaline—a research team at the University of Alberta in Edmonton headed by neurochemist Glen Baker is studying a substance called GABA. Another of the brain’s neurotransmitters, GABA appears to play a role in quelling the panic attacks that often accompany depression. GABA (for gamma-aminobutyric acid) seems to work in the brain by preventing selected nerve cells from sending signals down the line. To find out more, Baker’s team is studying the action of two older antidepressants that are used to treat panic, imipramine and phenelzine. They want to find out whether the drugs work by increasing GABA activity in the brain. A possible payoff: a new class of drugs that could some day stem panic by boosting the flow of GABA in the brain.

• At McMaster, Young’s team is focusing on manic-depressive illness in an effort to discover which brain chemicals are involved.

§ One approach to the puzzle involves dosing rats—which have many 1 of the same genes as humans—with antidepressants or mood staS bilizers and examining tissue samples to see which genes are acti£ vated. Eventually, Young hopes to learn more about the signalling 1 process inside the brain that can go awry and lead to depression or ë mania. He also wants to identify which defective chemical pathI ways make that happen. “Once we know more about these things,”

Most doctors praise the Prozac-like drugs

says Young, “we may be able to correct the problems with drugs.” • In Toronto, a Clarke Institute team co-headed by psychiatrists Sid Kennedy and Franco Vaccarino is using high-tech imaging equipment to look at brain functioning before and after treatment with antidepressants. Images produced by a PET scan machine show that, in depressed people, some parts of the brain’s pre-frontal region—an area associated with emotion—are less active than normal. Surprisingly, when antidepressant drugs start acting on the brain, those areas become even less active. Kennedy thinks that may be because in depression, the brain deliberately dampens down pre-frontal activity to cope with high levels of stress, and antidepressants may help the process by reducing activity even further. Kennedy hopes next to study brains in people who had remained well on antidepressants for at least a year, and thinks “we may find that by then activity in the prefrontal areas has returned to something normal”—meaning that the brain’s overstressed condition has been corrected.

The best antidepressants can banish depression—but they do not necessarily protect patients from relapses. Susan Boning, who organizes volunteer services for the Society for Depression and Manic Depression of Manitoba at its Winnipeg headquarters, had been taking Prozac for two years when she felt her mood “dipping” last March. Her condition worsened to the point where she made what she calls “a suicidal gesture” by drinking half a bottle of rum and passing out on her living-room floor. Boning, 37, has stopped taking Prozac and has turned to three other drugs, including Serzone. Boning’s experience, like countless others, shows that while medical science is making rapid progress in treating depression, for many in the remorseless grip of the disease it is still not fast enough. □