The Report Card on Antidepressants

March 4, 2008— -- A study released last week reported that depressed patients put on antidepressants get better at only a slightly higher rate than those treated with a placebo, which is essentially a sugar pill. This is, of course, a potentially concerning finding for people like me, who prescribe antidepressants, and for those of you readers who take them.

The results, reported in the open-access journal PLoS Medicine, come from a combined analysis of 35 studies with more than 5,000 patients, evaluating four of the newer antidepressants -- fluoxetine (Prozac), venlafaxine (Effexor), nefazodone (Serzone) and paroxetine (Paxil).

The new twist is that this report includes data from many studies that were conducted by the drug companies and filed with the Food and Drug Administration but never published in academic journals.

What the PLoS study found is that, on average, patients taking medication had a substantial response as measured by a depression rating scale. Whereas they started with a score of roughly 26 (on a 54-point scale, where higher means more depressed), they dropped after six weeks of treatment to about 16.

But the patients taking placebos also, on average, had a strong response, dropping to about 18.

However, the placebo picture was a bit more complicated. Unlike the antidepressant response, which did not vary based on how initially depressed patients were, the placebo response was strongest in the least-depressed folks, dropping off in those whose illness was more severe.

So here's take-home message No. 1: Antidepressants showed a significant advantage over placebos for the severely depressed patients but not for the mildly and moderately depressed patients.

Maybe that's not really so surprising.

Dear Old Dad

I had a mild depressive episode myself once while I was working in the Peace Corps in West Africa. It occurred in the context of such challenges as acclimating to a new language (Wolof) and culture (Senegalese), getting a well-digging project started and romantic turmoil.

The most memorable symptom was what psychiatrists call anhedonia, an inability to feel pleasure. Nothing felt fulfilling or satisfying. Occasionally, there was some lift from something like a conversation, but when it ended it felt like having a trap door opened beneath me so that I was plunged back into an abyss of emptiness and meaninglessness.

Thankfully, there was nothing dangerous about how I felt, and I did not seek professional help. After about six to eight weeks of this, my father, with whom I am close, arrived for a visit. Upon seeing him, my symptoms disappeared entirely, never to return.

Now, my father is a psychiatrist, but he did not treat me, except to dinner.

It is well established that mild and moderate depression can respond to psychotherapy alone, without medication. For example, Michael Thase, a psychiatrist at the Western Psychiatric Institute, and his colleagues found in a 1997 study that the advantage of antidepressants added to psychotherapy only came when depression was more severe.

While psychotherapy is sometimes conducted using a formal method -- in the Thase study it was interpersonal therapy or cognitive-behavioral therapy -- it can more broadly be thought of as any form of communication, typically talking, that helps.

My father talking with me, and just being with me, helped.

It is not unusual for a depressed patient of mine to come into my office sad and weepy, and leave after an hour feeling buoyed up. There is a sense of relief that comes from being with someone who understands and a sense of hope that comes from being with someone you feel has the power to make things better.

These are important aspects of what happens in psychotherapy, and they are also likely important aspects of the placebo effect. Patients who receive placebos are being seen by medical staff and are getting some of that relief and some of that hope.

Flipping Brain Switches

Sometimes people fail to realize that what medication does and what psychological factors do both have an impact on the brain. Dr. Helen Mayberg, now at Emory University, studies brain circuits in depression. She used a neuroimaging method to study metabolism across brain regions in patients who responded to Prozac and in those who responded to a placebo.

She found that among the placebo responders were a number of specific regions with metabolic increases and others with metabolic decreases. These same changes were also seen in the Prozac responders, suggesting that this is what the brain needs to do to feel better, regardless of how it gets there.

But that's not the whole story. Because there were also some changes unique to the Prozac responder brains, Mayberg and her colleagues speculate that these other changes might be important in maintaining longer-term response and preventing depression.

Indeed, to return to the PLoS study with which we started: It would be interesting to know what happened after the six weeks that most of the individual treatment studies lasted. Were the patients who responded to antidepressants more likely to stay well longer than those with a placebo response?

A recent study by Dr. Arif Khan and colleagues at the Northwest Clinical Research Center in Bellevue, Wash., addresses exactly this question. They analyzed eight antidepressant studies in which drug and placebo were continued in responders for at least four months. The result: Placebo responders were more likely to suffer a recurrence of depression than antidepressant responders.

And now for take-home message No. 2: There still might be some advantage to antidepressants even for mild and moderate depression.

Dr. James Potash is an associate professor of psychiatry and co-director of the Mood Disorders Program at the Johns Hopkins School of Medicine in Baltimore. If you have questions or comments, please e-mail at moods@jhu.edu. To participate in our genetic and clinical studies, call 877-MOODS-JH.