Case and Commentary
Nov 2004

Heads or Tails: Randomized Placebo-Controlled Trials, Commentary 2

Karen Kreiner, MD
Virtual Mentor. 2004;6(11):484-485. doi: 10.1001/virtualmentor.2004.6.11.ccas2-0411.

Case

Upon inspecting his schedule for the day, psychiatrist David Kimball was surprised to learn that his first patient of the morning was Geoffrey Allen. Geoff had been in for an appointment less than 2 weeks ago to discuss his response to a monoamine oxidase inhibitor (MAOI) as treatment for chronic depression. At the time, it seemed as though the medication was working, a relief for both Geoff and Dr. Kimball after several years of searching for the right way to manage Geoff's illness.

Geoff had been referred to Dr. Kimball's practice by Student Health during his freshman year. After discussing Geoff's symptoms of insomnia, lethargy, and weight loss as well as learning of a family history of depressive disorders, Dr. Kimball prescribed the first of what would be a long list of medications. Through the course of his magna cum laude degree in political science and now into his doctoral dissertation, Geoff had tried several tricyclic antidepressants, selective serotonin reuptake inhibitors, and second generation antidepressants. While he would have periods of stability ranging from a few weeks to a few months as in the case of fluoxetine, eventually either the medication stopped working or the side effects became too bothersome.

At his last appointment, Dr. Kimball had been pleased with Geoff's clinical response to the MAOI, even though a brief physical exam revealed the presence of mild orthostatic hypotension. When queried, Geoff himself said he felt better than he had in months with the exception of the fact that he and his girlfriend were less than thrilled about the side effects. In response, Dr. Kimball adjusted the prescription and reminded Geoff not to hesitate to schedule another appointment if things changed.

"Well, you're always reminding me to come see you if something comes up," Geoff said, when Dr. Kimball asked about the purpose of Geoff's visit, "and there's something I need to talk about. I'm starting to feel tired again, like I have no energy, and my motivation to do things is slipping." Geoff went on to describe an elevation in his depressive symptoms as well as a growing dissatisfaction with the MAOI side effects. Then, he mentioned a recent conversation with one of his cousins—also with a history of depression—and her enthusiastic description of her participation in a clinical trial for Licol, a new lithium-based antidepressant. Dr. Kimball was familiar with Licol and thus far it showed great promise for the treatment of atypical depression, especially in younger adults. However, ongoing clinical trials for the medication utilized double-blind placebo controls. In addition, data was not yet available concerning the follow-up treatment of patients who withdrew from the trials. "So I'm thinking I might like to try something like that," Geoff continued. "Something new maybe, since I've tried so many older drugs. And I might be able to help make a difference. I mean, what, have I got to lose? I'd really like to participate in the trial—how do I sign up?"

Commentary 2

This case presents a common clinical dilemma physicians face when treating patients who have depression that is difficult to manage or refractory to available treatments. This high-functioning patient has tried numerous antidepressants in a clinically sound way, yet, while he has a temporary response to treatment, he has been unable to achieve either effective long-term maintenance or a tolerable degree of treatment side effects. In clinical psychiatry, both of these problems are common. In an effort to control his symptoms and address his challenging medical history, the patient now wants to try an investigational drug which has shown some promise in a controlled clinical setting.

The most desirable way for the psychiatrist to handle this situation is to enter into a dialogue with the patient to carefully go over each of the potential treatment options and ensure that the patient understands the risks and benefits of each one. First, if Geoff is willing to consider it, the psychiatrist could entertain the possibility of increasing the current dose of monoamine oxidase inhibitor (MAOI). MAOIs work by inhibiting the monoamine oxidase enzymes that metabolize serotonin, a neurotransmitter linked to mood disorders. By slowing the breakdown of serotonin, MAOIs can be effective pharmaceutical agents for the treatment of depression. Increasing the MAOI dose could lead to more severe side effects—but MAIOs also have a strong history of clinical utility—and for Geoff to make a truly informed decision, greater dialogue would need to take place between him and Dr. Kimball.

If Geoff is unwilling to consider increasing his current MAOI dose, another MAOI should be offered since he responded so well initially to the first one. Several different MAOIs have been approved for use in the treatment of depression, and it is important to consider all of the possibilities. Furthermore, the psychiatrist should also make sure that Geoff has tried all appropriate antidepressants as well as considered the use of mood stabilizers like lithium or lamotrigine. Lamotrigine was originally used as an anticonvulsant medication but was recently approved by the FDA for use in the treatment of depression; it is particularly effective in patients like Geoff who have failed to respond to more traditional antidepressants or mood stabilizers. Finally, additional atypical antipsychotics like olanzapine may be useful.

If Geoff still wants to enroll in the research trial after adequately considering all of his nonexperimental options, he should be informed that he has a 50 percent chance of getting the placebo pill, in which case his condition could truly deteriorate. However, if he does get the investigational drug and responds, he will most likely be unable to continue the drug when the study ends. In the event of a successful clinical outcome, some drug companies will continue to supply the drug on a compassionate basis, but this is highly variable and cannot be guaranteed. More likely, Geoff will experience an ensuing drop in function due to the lack of medication, and that can be traumatic for many patients. According to the AMA Code of Medical Ethics,the physician should assist in trying to secure an ongoing supply of the drug until it is approved and reaches the open market, if there is a clear medical benefit [1]. Geoff should be aware of the hardship he may have to endure: to feel well during the trial therapy and then become depressed again because he loses access to an effective yet still-investigational medication.

Patients who have the capability to make decisions about their care always have the right to choose; we, as doctors, support the autonomy of the patient. If Geoff does decide to enter the study, it is the psychiatrist's responsibility to ensure that he is fully informed prior to making that decision. Unfortunately, for many treatment-resistant patients, research studies are their only hope of getting some relief from their disease. In terms of human suffering, depression exacts a high toll.

References

  1. Opinion 2.071 Subject selection for clinical trials. American Medical Association. Code of Medical Ethics 2008-2009 Edition. Chicago, IL: American Medical Association; 2008:35.

Citation

Virtual Mentor. 2004;6(11):484-485.

DOI

10.1001/virtualmentor.2004.6.11.ccas2-0411.

The people and events in this case are fictional. Resemblance to real events or to names of people, living or dead, is entirely coincidental. The viewpoints expressed on this site are those of the authors and do not necessarily reflect the views and policies of the AMA.