This week brought big news in the mood disorder business. First, the New York Times previewed a study, sponsored by the National Institute of Mental Health, that found Prozac to be remarkably effective in treating adolescent depression. Then New York Attorney General Eliot Spitzer announced that he had filed suit against GlaxoSmithKline, the pharmaceuticals giant. The charge is that the company manipulated or suppressed research data, to make its drug Paxil appear safe and effective in treating depression in children and teenagers, when it is neither.
Which are we to believe? Should doctors prescribe medication for depressed adolescents or hold off?
One answer is that we just don't know—precisely because drug companies manage the information about antidepressants, promulgating positive studies and suppressing evidence of harm or failure. For this reason, the Spitzer lawsuit is a very good thing. It promises to lead, if not through legislation then through the self-protective instincts of corporations, to greater openness about research results. The indictment is a damning document. It suggests that in the drug company's own research, Paxil looked ineffectual in children and adolescents. By releasing results of a single study that showed positive outcomes, GlaxoSmithKline was—this is the gist of the charge—misleading doctors and their patients.
It may just be that Prozac is more effective than Paxil in young patients. But it is also possible that the difference in the research results has less to do with the medication than with the nature of the studies. It turns out that drug companies are shockingly inept at testing their own products.
When independent psychiatrists and psychologists look at data submitted to the Food and Drug Administration—the results of corporations' early studies on their own antidepressants—the medications look only modestly effective. But these findings always strike me as suspect, since the same antidepressants have proven highly useful in treating recalcitrant kinds of depression, such as depression after strokes and post-partum depression. Why would the medications fail only in research on the run-of-the-mill mood disorders?
There are a number of answers to this puzzling question, but mostly it comes down to this: The pharmaceutical companies do shoddy research on the drugs' efficacy. Because the patents on medication have a limited duration, the corporations are always in a rush to bring drugs to market. The companies pressure the subcontractors that perform the studies, demanding that they gather research subjects fast. The recruiters then stretch diagnostic criteria, signing up patients who may not have the disease in question. Studies often include people with a host of shifting complaints, many of which are based less on acute illness than on personality style. The result is a group with poorly defined conditions and high placebo response rates—enough static to drown out whatever effects the medications have on substantial disease.
Drug company studies can have other problems. Sometimes they are conducted before the proper dosage or length of treatment has been established. Inexact dosing leads to low rates of response, or to excessive side effects—and a tendency for subjects to drop out of a study. These and other study design defects tend to make medications appear less effective than they prove in clinical practice or in later research.
In studies of younger patients, these problems are magnified. There is a sense in which all depressed children are "outliers." Whatever it is that causes depression—predisposing genes, stressful environment—you need large doses of it to contract mood disorder early in life. Children's symptom clusters are not always the same as adults'. Children are less able to report on their experience. Their brains develop at different rates. And they are hard to recruit into studies, because parents are often rightly concerned about their participating. So when you test drugs in children, you tend to be addressing small groups that on the relevant variables—brain biology, level of illness, diagnosis—contain heterogeneous members. Some research subjects will have disease based on severe physical pathology; some will simply be misdiagnosed. And no one imagines that antidepressants work in a high percentage of children. Researchers are listening for quiet signals in a system with loud background noise.
Oddly, then, in the "rush to market," drug company studies tend to hide the efficacy of the very medications that the corporations hope to promote. It is the rule, not the exception, for similar medications to fare poorly in drug company trials but to fare well in subsequent (presumably disinterested) government-sponsored research. The NIMH-supervised research on adolescent depression has not been published, which means that it has not undergone its final peer review. But it is known to be well-designed and carefully executed. It is likely to pass with flying colors and emerge, more or less as the Times reported, in the Journal of the American Medical Association. The study's results suggest that antidepressants are highly effective.
The NIMH study compares cognitive psychotherapy and Prozac, alone and in combination, to each other and to placebo. The subjects, 439 teens aged 12 to 17, had moderate to severe depression—a level at which diagnosis tends to be reliable. In the group that took Prozac, the Times reported, 61 percent showed some improvement, compared to 35 percent in the placebo group. Cognitive therapy helped 43 percent but overall was statistically hard to distinguish from placebo. Drug and talk therapies in combination helped 71 percent of subjects.