One of the great pleasures of being editor is that I get to talk to some of the smartest, most interesting and humane people in the world. All I have to do is ask questions.
When it came to tackling the subject of antidepressants, I really hit paydirt. In addition to having my own private seminar with the folks who run the psychopharmacology unit at Massachusetts General Hospital, I had several other productive conversations there. I thought you might particularly want to overhear part of the discussion I had with Jerrold F. Rosenbaum. M.D., who is chief of psychiatry, and John B. Herman, M.D., director of clinical services.
Dr. Herman: "One of the bigger side effects of taking these drugs is shame."
Dr. Rosenbaum: "That's partly a depressive cognition, that I'm weak, I should be able to feel better, I should be able to take care of myself. That's the sinister thing about depression. If you weren't depressed you probably could. You have to get undepressed so you can have that quality back. It's a vicious cycle. The patient refuses treatment because of the belief that they should take care of themselves, yet the goal of treatment is to restore the ability to do that."
Dr. Herman: "That's one of my favorite responses when asked by patients, which is inevitable in the group that doesn't want to take medicine. Before you even pull out the prescription pad, they say, 'will I have to take this for the rest of my life?' My response is, 'you're an optimist'. That gets their attention. Because then you have to explain, you assume it will work. You assume you won't have side effects. And finally, you assume that's my choice."
Me: "Is it your choice?"
Dr. Herman: "The physician helps with the trial. The course is the determination of the patient."
Dr. Rosenbaum: "We can make some prediction who is likely to need indefinite treatment based on their past history. The reality is very few people end up starting on a drug, having it work, and staying on that, for lots of reasons.
"The drug stops working in about half of those who start it, by which I mean, not as well as they want to be anymore. They may be substantially better than when they were first treated. They're not as well as they were when they were very well. 'Roughening' is the word we sometimes use. You can lose benefit, you can have new side effects or late emergent side effects, or you could have a partial loss of benefit."
Side effects are matters for negotiation and trade-off. "Some of the most tearful exchanges in my office," Dr. Herman confided, "have involved women who don't want to gain weight on a drug. The patients are tearful because they're depressed and then they come in undepressed but tearful because they're way overweight."
"That's a stealth side effect", Dr. Rosenbaum interjected, "because it emerges subtly over time and surprises everybody, because you told the patient and told yourself that it doesn't cause weight gain."
One of the most compelling challenges of these drugs is understanding how they work. "What do these agents tell us about depression?" I asked. In a word, nothing.
Dr. Rosenbaum: "We are lucky we have these molecules that when we give them people get better. The fact that we have them is just luck. Originally they were designed for other purposes but produced side effects, and the side effects turn out to be therapeutic elsewhere. It was the antipsychotics that gave us the antidepressants. We started out looking for a better antihistamine and got the antipsychotic thorazine. We looked for a better thorazine and found imipramine, which was a lousy antipsychotic but it turned out people felt better so it begat the antidepressants.
"But it tells us that if you give a molecule that causes the brain to have to adapt to its presence in certain systems, somehow in that adaptation to that molecule we reset, renew or restore something that brings someone back more towards a normal state. We know we're doing something that's complicated. What we're doing looks like a healthy adaptation to stress, that the antidepressants reverse the deleterious impact of stress."
How do they do it? The psychopharmacologists are already into a next generation of hypotheses after the business of regulating serotonin and other receptors. It looks like antidepressants stimulate the growth and branching of neurons in parts of the brain involved in learning, memory, mood, and emotion, areas that atrophy in response to stress. One of the prime architects of this new theory is Ronald S. Duman, Ph.D., of Yale, who reported at a recent scientific meeting that all classes of antidepressants and even electroshock therapy have the regenerative effect on nerve cells.
It's just a theory, supported by increasing amounts of evidence obtained from imaging studies of the brain. "Right now," however, observed, Dr. Rosenbaum, "the issue of understanding depression is not pertinent to selecting an antidepressant."
