Old Wine, New Bottles

Human nature, essentially changeable, unstable as the dust, can endure no restraint; if it binds itself it soon beings to tear madly at its bonds, until it rends everything asunder, the wall, the bonds and its very self.

Franz Kafka, "The Great Wall of China" (trans. Edwin and Willa Muir)

"I have a new antidepressant for you...Seroquel XR." These encouraging drug rep's words were directed at a colleague in the office next door (happily I escaped). How did medications initially indicated for schizophrenia successfully migrate to bipolar disorder and now depression? The answer involves both the very porous psychiatric diagnostic system and the slack standards for FDA approval.

Last year, when Abilify was approved for "adjunctive" treatment of depression, patients who saw some commercials started asking for it. The advent of direct-to-consumer advertising on television a few years back allowed pharmaceutical companies to go around physicians at will, and this affected psychiatry more than other specialties due to diagnostic ambiguities. Now that Seroquel XR is indicated for acute treatment of bipolar depression, a number of patients will overlook the bipolar part and will start asking for Seroquel for depression, and a certain fraction of doctors will comply. In fact, Seroquel is widely used "off-label" for both anxiety and insomnia; the maker could probably obtain those indications too if it were worth the company's while.

I think the atypical-antipsychotics-for-bipolar-disorder-and-depression phenomenon represents the confluence of no fewer than five factors. The least interesting is the perennial and understandable drive of pharmaceutical companies to make as much money as possible by accumulating indications. Second, the drug companies are not required to conduct head-to-head trials of prospective drugs with drugs already known to be effective; they need only to demonstrate superiority over placebo. The result is that "new" treatments are not necessarily advances over already available treatments; they are merely different (the "me too" drug).

Third, in recent years the profession has undergone a crisis of confidence in both the safety and the effectiveness of standard antidepressants, particularly for bipolar depression, which is often resistant even to standard mood stabilizers like lithium and valproic acid. Fourth, and related to this, treatment-resistant depression remains a huge problem in general; depression is increasingly recognized as a major source of disability worldwide, and the bad news is that a significant number of patients do not get better even with aggressive treatment.

Why else has a treatment like electroconvulsive therapy, marred as it by stigma and side effects, remained a quite viable treatment for seventy years now? Severe depression can be grim indeed, and ECT still treats it better than anything else. So in the treatment of depression there is very much an effectiveness vacuum; patients urgently want help, and psychiatrists urgently want to help them, so anything at hand that can be shown to be better than sugar pills for depression is likely to be used, even if side effects--such as the high cost, weight gain, and other metabolic issues of atypical antipsychotics--can be alarming. Neither patient nor psychiatrist wants to hear, or to say, "There is nothing more I can do."

Fifth, atypical antipsychotics are both more convenient and, in a purely subjective sense, better tolerated than many alternatives. The standard mood stabilizers--lithium and the anticonvulsants--require monitoring of blood levels other laboratory tests, whereas atypical antipsychotics (unless one counts the lipid profiles that ought to be done to monitor metabolic side effects) do not. This can be an issue of compliance as well as convenience. And while the objective side effects can be dismaying, many patients are subjectively surprisingly tolerant of substantial weight gain (which only adds to the problem of course).

So while I'm thoroughly tired of the phrase "perfect storm," we have one here: a high potential for profit, malleable diagnostic boundaries, and a widespread eagerness to help and be helped with respect to a prevalent illness scourge. Helpful interventions might include ending televised direct-to-consumer drug advertising, requiring higher standards for FDA approval, devising antidepressants that are actually better than the ones we have now (I'm told people are working on that, but breath-holding is not advised), and when it comes to prescribing decisions, knowing when enough is enough.