AAN: That said, we could probably still agree that the drugs of the newer generation are more tolerable overall, and patients are more likely to take them in the short and long run. By and large we tend not to choose the old generation—the tricyclics and monamine oxidase inhibitors—as first-line drugs. Over time we've seen people have trouble tolerating them. It is also accurate to say that antidepressants don't work if people don't take them. If they're not willing to put up with the side effects, they're not going to take them.
MF: Once you move beyond that point into the newer antidepressants, it's difficult to know which drug to pick. Most comparative studies fail to show a difference in efficacy among the newer drugs.
And with some exceptions, comparative studies are inadequate for using tolerability as a [selection] factor. Regarding sexual dysfunction, studies favor the atypical agents. With weight gain, evidence also favors the atypicals, particularly buproprion and nefazodone (Serzone). But nefazodone bears a warning from the FDA on liver failure. So a drug promoted for sexual function and weight stability could cause you to die of liver failure.
AAN: Even that presents a problem in interpretation. The risk of liver failure with Serzone is one in 350,000 patient years of exposure. Is that a big or little risk? It's a matter of clinical judgment.
MF: The argument regarding tolerability of risk is the same one that makes people hate flying but feel comfortable driving. The risk of a car accident is much higher but is perceived to be very low. The risk of liver failure is very low, but it's fatal, you can't predict it and it's not dose-dependent.
Suggestion is very powerful—for patients and for clinicians. Strong beliefs about your choices can translate into a tremendous placebo effect. If I look directly into your eyes and say "I know exactly what's going to work for you and this is it," as opposed to "well, you have these options and what do you think, we're not sure which one is going to work for you," I'm already downsizing the placebo effect.
AAN: This is interesting for the fact that the drugs work fairly well. The effect size, which shows how something works versus placebo, is as good as many things in medicine. It's not that we don't know anything. It's just that it's much more complicated.
JEA: Residents often come to us for supervision saying "I think I made a mistake, I put someone on Zoloft yesterday and now I think Serzone would have been better." You can make a case that a person has a fighting chance to respond to either one.
When people ask what's the best antidepressant for me, we say the best antidepressant for you is the one you go on to respond to. There's a good chance they'll respond to the first or second one we prescribe, or they'll go on to respond to something else. Even there we don't know whether switching from one SSRI to another or from an SSRI to an atypical antidepressant is better. In the patient who is treatment-naïve, there's a 60 to 70% chance that whatever antidepressant we use, the person will respond.
MF: For that reason, the most important question about drug choice is what to do next, rather than what to do first, if whatever I prescribe first doesn't work.
AAN: And more important than which one first is the relationship you have with the patient. It's not just ok to say "you're taking medicine" and "goodbye" in two minutes. It's necessary to develop a caring, compassionate, genuine relationship, and part of that is also contained within the negotiation. You say, "here are several choices you could take. Here are some of the side effects. What's acceptable to you, what's not?" You treat people with respect. It's almost more the psychotherapeutic quality that happens in the first encounter.
MF: Any good psychopharmacologist keeps an open mind to the needs of the patients and is willing to switch treatment halfway if necessary, to adjust or augment and combine. There's no recipe that can be determined a priori to be best for a patient. It's an interactive process. You have to hear what the patient has to say and adjust the treatment. You don't say, "yes, you can't eat, you can't sleep, and you've lost 13 pounds but this is a great drug so just stick with it."
AAN: We take great pride here in being responsive to feedback. We don't tell the patient who is substantially worse after two weeks of treatment, "just keep doing it." We have to do something different if they can't tolerate it. But we don't spend five minutes with patients; we spend a half hour.
HEM: So is the secret that the drugs are irrelevant?
AAN: As the famous quote says, the secret of patient care is caring for the patient, making sure, once that initial treatment is chosen, and it doesn't matter that much which one is chosen, that it is an interactive tailored process over time.
MF: In order to establish a dynamic relationship you have to be willing to take responsibility for faulty decisions. And for having perhaps caused unwanted untoward side effects. What patients will say once you do that is, "I feel validated. I didn't know this was a side effect." Outcome is related to duration of treatment. If you stop the drug prematurely, you're not going to respond. You get people to stay on an antidepressant by establishing communication. In order to establish that communication, you have to be comfortable taking responsibility.
HEM: Why don't you just have a wonderful relationship with someone, prescribe chocolates and say, "these might put on a little weight but they'll make you happy."
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