Antidepressants Ineffective? Don't Believe It! (Part 1)

A recent study in JAMA (the Journal of the American Medical Association) appeared to show that antidepressants do not work well in patients whose depression is mild to moderate, which is the majority of patients. The authors combined the results of six studies (three evaluated Paxil and three evaluated the old tricyclic imipramine) and found that there was little difference between active drug and placebo in patients with less severe depression. However, there was a large benefit of the active drug in patients with very severe depression.

The study made news--see, for example, this piece in the New York Times. But do the results really mean that antidepressants are ineffective? I don't think so. In order to understand the implications of the study, you have to understand how clinical trials are conducted, and how radically they differ from usual care.

First, let's look at what happens if you were to seek care through the usual treatment system. You have become increasingly morose after your 401K tanked in the current recession. For weeks, you have been unable to sleep well, you are wracked with anxiety and panic, you have no energy, nothing is enjoyable, and you have been questioning whether life is worth living. You go to a psychiatrist, who diagnoses you with major depression and anxiety and prescribes you a combination of Zoloft (an antidepressant) and Klonopin (an antianxiety medication.) She tells you that your symptoms are an understandable response to a difficult situation, and that in her experience the Zoloft/Klonopin combo is almost certain to help over the next few weeks. And indeed, you get better.

Suppose, instead, that you sought treatment through a research study that was advertised on the radio. Your ears perked up when you heard that treatment was free, and that you would be paid a small stipend to attend sessions. You go to your first appointment and you are surprised to find that this is not a university, but a private clinical research company. The majority of clinical trials now occur in such for-profit enterprises, because drug companies have found that they can exert more control over the research conducted at such companies than they can at universities.

You meet first with a research assistant, who asks you a few screening questions, then you meet with a psychiatrist. Unbeknownst to you, the psychiatrist will get paid several thousand dollars for each patient he enrolls in the study. The drug company, which designed the study, has given the psychiatrist a long list of inclusion and exclusion criteria. For example, you are ineligible if you have bipolar disorder, suicidal ideation, panic disorder, obsessive compulsive disorder, substance abuse within the last 6 months, or an unstable medical condition. There are so many exclusion criteria that only about 10% of depressed patients in a typical clinic would be eligible for such studies (see here for more background).

The screening psychiatrist will interview you with a goal of getting you into the study, and will typically try to "undiagnose" you of any conditions that might otherwise exclude you. For example, the anxieties that you have had are very similar to panic attacks, but this is a matter of clinical judgment. After asking several questions, your psychiatrist convinces himself that you do not have panic disorder, but rather, you have anxiety that often accompanies depression. You admit to drinking a little more than normal as a way of coping, but after careful questioning, your psychiatrist opines that your drinking pattern is not quite severe enough to be labeled "alcohol abuse."

And so on. After an hour or so, your psychiatrist tells you that you are eligible to enter the study....

(To be continued. Tune in next week to follow the adventures of our patient who learns about the peculiar world of the placebo-controlled clinical trial).