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How do these drugs work? // How are drug trials conducted? // How are trial results interpreted? // How can we learn more about depression itself?

Antidepressants: Somber Questions

By Anita Slomski // Photographs by Tina Tyrell // Spring 2012
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Antidepressants opener-SQ

Tina Tyrell

More than one in 10 Americans takes one or more antidepressant medications, and for that large chunk of the population, recent events surely have been unsettling. Three books published in 2010 were uniformly damning of the No. 1 type of medication taken by people ages 18 to 44, though each author takes aim at antidepressants from a different angle. Clinical psychologist Irving Kirsch lays out evidence that antidepressants simply don’t work in The Emperor’s New Drugs: Exploding the Antidepressant Myth—he argues that they’re no more effective than the dummy pills used in clinical trials. Journalist Robert Whitaker, in Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America, makes a more harrowing claim—that chronic use of antidepressants and other psychotropic drugs has created legions of mentally disabled people who are far worse off as a result of treatment. And psychiatrist Daniel Carlat, in Unhinged: The Trouble With Psychiatry—A Doctor’s Revelations About a Profession in Crisis, charges that psychiatrists have engaged in “a binge of drug prescribing” because they can earn half again as much by adjusting medications as they would be paid for talk therapy. “The income differential is a powerful incentive to drop therapy from our repertoire of skills, and psychiatrists have generally followed the money,” Carlat writes.

One hallmark of depression is extreme self-doubt, and the furor the books have caused seems to have led many patients to question their treatment. In the wake of their publication, a number of people under the care of depression researcher Madhukar H. Trivedi abruptly stopped taking antidepressants. Some of those patients then relapsed, again suffering major depression, says Trivedi, professor of psychiatry and director of the Mood Disorders Research Program and Clinic at the University of Texas Southwestern Medical Center at Dallas. But others who quit the drugs have done just fine, Trivedi says.

That’s how it is with antidepressants. Physicians who prescribe them have no doubt that the drugs are essential for the treatment of many patients, particularly those who are most seriously ill. Yet uncertainty about how antidepressants work and whom they can help has increasingly fueled the notion that they may be useless or even dangerous. To improve the understanding of who is most likely to respond to the drugs in this rather broad class, Trivedi has launched a study that he hopes will identify a treatment response “signature.” Four hundred volunteers, randomly assigned to take an antidepressant or a placebo, will receive a battery of tests—functional and conventional magnetic resonance imaging, electrophysiology, and behavioral and cognitive assessments—at the start of the study and again after eight weeks. “We hope this trial will begin to give us biological and clinical signatures of people who are likely to do well versus those who won’t respond to antidepressants, as well as help us determine whether there are unique biological characteristics of those who report improvement with placebo alone,” says Trivedi, who expects results in mid-2014.

Such work could help explain why no current therapy, including psychotherapy without drugs, is consistently effective. “It’s important to ask whether and how well antidepressants work, just as we debate the effectiveness of mammography, prostate cancer screening and surgery for back pain,” says Andrew A. Nierenberg, co-director of the Bipolar Clinic and Research Program and associate director of the Depression Clinical and Research Program at Massachusetts General Hospital. But it’s crucial, says Nierenberg, for those on both sides of the antidepressant question to remain scientifically objective, for the sake of individuals suffering from depression. “People’s lives are at stake when they become needlessly frightened of antidepressants and stop taking them,” he says.

The first antidepressant was actually a tuberculosis drug, iproniazid, created in 1951 by Hoffmann-La Roche. But physicians noticed that many TB patients who were also depressed improved when they took iproniazid: It increased levels of serotonin and norepinephrine, chemicals called neurotransmitters that relay messages among the brain’s 100 billion neurons. Research in animals at about the same time found that a drug that reduced serotonin, norepinephrine and another neurotransmitter, dopamine, made the animals lethargic and apathetic. Noting how psychotropic drugs changed levels of neurotransmitters, other researchers began to hypothesize that abnormal amounts of neurotransmitters caused schizophrenia and other mental disorders. Even then, the evidence was inconclusive, with some studies finding a direct correlation between depression and low levels of serotonin, norepinephrine and dopamine, while others saw no connection. Nevertheless, the idea that chemical imbalances caused depression had taken hold, and creating drugs to restore neurotransmitter health seemed the most promising treatment.

Many of today’s antidepressants indeed increase the levels of neurotransmitters that neurons release into synapses—the spaces between neurons—causing neurons to fire and carry electrical impulses. After a neurotransmitter attaches to receptors on the receiving neurons, transporter pumps suck up and recycle the used chemicals to terminate the signal. Selective serotonin reuptake inhibitors, or SSRIs, are antidepressants that interrupt the transporter pumps so that serotonin remains in the synapses longer than it normally would. That’s supposed to compensate for low levels of the neurotransmitter in people with depression, and the best-known antidepressants—Prozac, Paxil, Zoloft, Celexa and Lexapro—are all SSRIs. Another class of antidepressants—serotonin and norepinephrine reuptake inhibitors, or SNRIs (Effexor and Cymbalta)—work by allowing both serotonin and norepinephrine to flood synapses. And yet another class enhances the release of norepinephrine and dopamine.

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Depression: Running Away from the Blues

Is exercise superior to drugs for treating depression?

Video: Jerrold F. Rosenbaum

Massachusetts General Hospital chief of psychiatry Jerrold F. Rosenbaum discusses the ups and downs of antidepressants.


1. “What Did STAR*D Teach Us? Results From a Large-Scale, Practical, Clinical Trial for Patients With Depression,” by Bradley N. Gaynes et al., Psychiatric Services, Nov. 1, 2009. In summarizing the results of the landmark trial that challenged many psychiatrists’ views about the effectiveness of antidepressants, the authors call for recruiting more real-world patients in clinical trials of antidepressants and using remission as a goal of therapy.

2. “Assessing the ‘True’ Effect of Active Antidepressant Therapy v. Placebo in Major Depressive Disorder: Use of a Mixture Model,” by Michael E. Thase et al., The British Journal of Psychiatry, December 2011. Using statistical modeling, the authors found that antidepressants that fail to show much effectiveness in clinical trials actually do provide a substantial benefit to a subgroup of trial participants—leading the authors to argue that evaluating data only from the group of subjects as a whole may lead to wrong conclusions.

3. “Effect of Exercise Training on Depressive Symptoms Among Patients With a Chronic Illness: A Systematic Review and Meta-Analysis of Randomized Controlled Trials,” by Matthew P. Herring et al., Archives of Internal Medicine, Jan. 23, 2012. In a meta-analysis of 90 studies of the chronically ill, the authors found that exercise training significantly reduced depressive symptoms.

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