Which Drug for Whom?

I came armed basically with one question: Which drug is best for whom? Seated around the table were Maurizio Fava, M.D., director of the depression clinical and research program at MGH, and associate directors Jonathan E. Alpert, Ph.D., M.D., and Andrew A. Nierenberg, M.D., and myself. (Hara Estroff Marano)

I didn't get the answer I wanted. What I got was more interesting.

AAN: Matching patients to antidepressants is opinion-based not data-based.

MF: There are many different positions within our field. Some believe you can predict who is most likely to respond to a drug or who is most likely to have difficulties in tolerating a drug. But the data do not support that anyone has figured this out yet in any systematic way. Then there are the nihilists, who say you can't predict anything so you might as well go by cost, something you can measure. Some people feel that regardless of the prediction factor, some antidepressants are more efficacious, at least for certain subtypes of depression. Their impressions are typically based on their own limited experience and are totally self-fulfilling. If I have a lot of faith in a drug I'll use it a lot, and use it first-line—and have a lot of success. If I don't believe in a drug I'll use it in a limited fashion in more resistant patients and the outcome will be less good.

The most rational approach is to present the patient with a menu of reasonable choices and discuss them. If you talked about 30 antidepressants, the patient would be overwhelmed. Even then the patient will ask, "but doctor, which one would you take if you were depressed?" That's a completely subjective answer.

AAN: There's another aspect. Everybody weighs the risk of side effects differently. We published data showing there's more weight gain with one SSRI [Paxil] than with others and that it causes more sexual dysfunction. There's also a problem with discontinuation reactions—feeling terrible when the drug is stopped. We might weight these more than other groups might. That's one reason why there's great variation in what people prescribe.

JEA: One handle is co-morbid illnesses. Many who present for treatment with depression have other disorders, especially anxiety disorders. The serotonergic drugs such as the SSRIs have been very well studied for the major anxiety disorders: panic, social phobia, generalized anxiety disorder, obsessive-compulsive disorder. For someone who has depression and social phobia, it's a reasonable starting point to use a medication whose effectiveness had been well-documented for both disorders.

Some of the SSRIs have been well studied for eating disorders, so they would be reasonable first choices in someone with an eating disorder too. There's not such good evidence that SSRIs are helpful for ADD, but there's a little evidence that buproprion (Wellbutrin) and the tricyclic desipramine are helpful.

Co-morbid illness provides the illusion of choice—because we have only a little positive data showing that a drug may work and no data comparing one drug versus another. Yes, some studies clearly show that Paxil works better than Wellbutrin for social phobia, but in general we don't know that something is not effective—because it might not have been studied.

MF: Some people take the view that a drug's indication [approved usage] is secondary to the investment of the pharmaceutical company, that if other drugs were studied they would probably have that indication as well. Not all SSRIs have an indication for a particular condition, but we tend to say, if one SSRI has it probably all have it, that it is a class effect.

However, the tricyclics used to be standard treatment for panic disorder, and the tricyclics mostly work on norepinephrine, so it's not necessarily true that you can only work on anxiety disorders by affecting serotonin. The more you know the literature, the more you are not so certain that there is, or should be, a first choice.

HEM: Do the atypical antidepressants give you more leverage with norepinephrine as well as serotonin systems?

AAN: If you're not that sophisticated, you'll think it works that way. But the more one looks into this, the more closely the systems are linked together, and it's hard to change one without changing the others.

MF: No one has linked neurotransmitter systems with the pathophysiology of depression yet in a convincing way. In fact, some people argue that antidepressants work by changing gene expression to promote nerve regeneration, by stimulating brain-derived neurotrophic factor. Wellbutrin is not an uptake inhibitor and it affects primarily norepinephrine, but it works as an antidepressant. Whatever theory you have, something disproves it.