Focus on Your Health: Antidepressants

On September 14, 2004, a special panel convened by the Food and Drug Administration voted to add a "black box" warning to the labeling of a popular family of antidepressant drugs. The label cautioned potential users that the drugs, known as selective serotonin reuptake inhibitors, or S.S.R.I.'s, were likely to increase the risk of suicidal thoughts and actions in adolescent patients. The decision was the culmination of a year of international scrutiny, a decade of work by some activists, and several tragic teen suicides alleged to be connected with the drugs.

Until that time, the antidepressants were riding high as one of the pharmaceutical industry's best sellers, with over 11 million S.S.R.I. prescriptions in 2002 alone. [1] Since the debut of the first S.S.R.I., Prozac, in 1987, many child psychiatrists had turned increasingly to the drugs as effective and valuable tools in treating teenage depression and other mental illness - and many still do.

What roles do S.S.R.I. drugs play in the treatment of adolescent depression? How should drugs be incorporated with other forms of psychotherapy in treating mental illness in teens? As the Next Generation set out with questions like these to examine the controversy behind the S.S.R.I. drugs and their connection with teen depression, we discovered that for several of America's leading child psychiatrists, fighting teen depression is a deeper and more complex problem than anything that could fit inside the headlines of a national newspaper or the confines of a black box. How do psychiatrists go about healing the minds of depressed teens?

One of the first things one learns about the S.S.R.I. drugs is that there is very little information that researchers know for certain about their effects on teenagers. Of the various S.S.R.I.'s on the market, the data showing the effectiveness for adolescent depression is strongest for Prozac (fluoxetine), the only antidepressant ever explicitly approved (and purposefully tested) for use in patients under 18. In studies using Prozac, medication was nearly 30% more likely than placebo to result in "significant clinical improvement" [2] - a waning of some of the symptoms of depression, including irritability, sadness, and boredom. But many of the other trials, often "unpublished," that exist for the other members of the family of S.S.R.I. drugs are of inconsistent quality and varying results. Many of them offer slight but substantial evidence that the drugs, when compared to placebo, can increase a patient's risk of suicide. A group of Columbia University researchers, commissioned by the FDA to gather data for the September 2004 hearings, analyzed the sporadic existing S.S.R.I. studies and concluded that depressed teens treated with antidepressants were 1.78 times more likely to engage in suicidal acts than those given placebos. [3] Yet despite this aggregate estimation, several trials, as with Prozac, spoke to the efficacy of the various drugs in alleviating the symptoms of adolescent depression.

For Dr. David Brent, Academic Chief and Professor of Child and Adolescent Psychiatry and the Endowed Chair in Suicide Studies at the University of Pittsburgh School of Medicine, interpreting the data on the antidepressants is a matter of understanding the risks and benefits involved with teen suicide. He agrees with the FDA's basic finding on the drugs but adds an important qualifier. "The risk of emergent suicidality (suicidal thoughts and/or actions) in children and adolescents receiving S.S.R.I.'s is real," he says, "but small." [4] S.S.R.I. detractors should remember, he writes, that the adolescent suicide rate has been dropping for a decade, and evidence suggests that "increases in the number of prescriptions for S.S.R.I.s for adolescents are associated with a decrease in adolescent suicide." [5] For Brent, it is incumbent upon "the FDA, families, and clinicians" to weigh the costs and benefits of the S.S.R.I. drugs and "find the right balance between the risk of suicidality and another, greater risk: the risk that lies in doing nothing." [6]

At the very least, it would seem the great uncertainty about the antidepressants requires patients, parents, and clinicians to weigh the possible costs and possible benefits for each patient. However, treating teen depression entails complexities far beyond just weighing the risks and benefits of antidepressant drugs. The contradictory data on S.S.R.I.'s only underscores the uncertain and challenging nature of the problem. As Dr. Robert Freedman, Chair of Psychiatry and Pharmacology at the University of Colorado Health Sciences Center, explains, complexity is the name of the game: "The S.S.R.I. drugs typically reduce suicide incidents and are effective in this," he says, "but there are of course many complications - it's not simple."

"When it comes to what exactly causes depression or how exactly to best treat it, the short answer is that we don't know," says Dr. John March, Professor of Psychiatry and Chief of Child and Adolescent Psychiatry at Duke University Medical Center. "It's a mix of genetic vulnerabilities and environmental triggers, and the proportion varies for each individual. This mixture means that depression is heterogeneous - kids who look the same will not have the same pathology."

It also means that a given patient's response to a given treatment can be unpredictable. An S.S.R.I. which alleviates the symptoms of one teen might trigger suicidal thoughts in another. The effects the drugs have on individual patients are highly variable. "Sometimes, when people begin to get better," says Freedman, "not all their symptoms will remit at the same time. We often see suicides occurring because a depressed person with intentions to commit suicide had previously lacked the energy to do so. Sometimes, after going on an S.S.R.I. drug, that patient's energy levels will shoot up, but the intention to commit suicide is slower to remit, leading to an apparent connection between the treatment and suicide. The paradox is that people seem to get better and then commit suicide."

Do the possibilities of relief for the many offered by the S.S.R.I.'s outweigh the risks they pose to the few? In keeping the drugs on the market, despite the black box, the FDA has seemed to answer that question in the affirmative. But when it comes to individual cases, are "tradeoffs" and "risk-benefit calculations" all that psychiatrists have to offer their patients?

A resounding 'no' is the answer I received from several psychiatrists, who offered detailed perspectives of the mindset and the method needed to heal a depressed teen. Variable trial results do not imply that good psychiatrists are uncertain about their methods of treatment. Over and over I was reminded that good treatment begins and ends with recognizing depression as a disease to be cured, not a temporary condition to be whisked away or an mindset easily erased with a bottle of pills.

"Historically, psychiatry has used a storybook model," says March. "That model is now on the wane thanks to scientific research, which supports a model for medication and psychosocial treatment that's similar to what's used in other areas of medicine. For example, treating a patient with a psychiatric disease with cognitive behavior therapy is analogous to rehabilitating an ACL ligament repair. And like non-psychiatric medicine, we're using combined treatments - targeted medicine and psycho-social intervention - much like we would when treating diabetes or obesity. The main point is that the story is not driving the illness; it is the illness driving the story."

In this light, merely handing a depressed teen a bottle of antidepressants, on the one hand, or ignoring the possibility that pills could help, on the other, are two sides of the same coin: a failure to understand depression as an illness to be treated with the best medicine that science can provide. And even when highly effective, antidepressants are at most only a part of this picture.

"There are always three key steps when we begin treatment," Freedman explains. "We get the medication going. If treated, the typical bout of depression lasts about six weeks. Untreated, it can extend to as long as a year. And with the drugs comes a focus on safety and very close monitoring - we want to make sure that the drugs are not creating more of a danger than existed before."

But antidepressants cannot do the job alone, Freedman emphasizes. "We also begin therapy. The drugs can relieve depression, but they do not offer a plan for life. How do you get back into school? How do you undo some of the serious problems in which you may have found yourself? How can you get your self-esteem back?"

A discussion of "self-esteem" would seem a long way from a discussion of risks, benefits, drug trials and efficacy rates. But as I quickly learned from the clinicians I spoke with, antidepressants are uniquely tied to the soul, and the treatment of depression is not a simple risk-benefit calculus. Ending depression is taking back control of life. It is healing and curing, not merely treating. It requires human connections, and a desire for a fundamental fix - ingredients not found in a jar of pills or a medical textbook.

"It would be presumptive on my part to assume what the risks and benefits are for a given patient," Brent says. "Many people don't want to be influenced by that and want to know that it's their own decision. With any chronic disease, as depression is, you want people to own the management of the disease themselves. You might not always be their doctor, so there it is important to empower patients and families in their own care."

Chris Catizone is an Associate Editor of the Next Generation and a member of the Harvard College Class of 2006. Special thanks to Rosa Nguyen for artwork.