A “First Do No Harm” Approach to Antidepressant Augmentation

September 1, 2008

I was dismayed by the article by Dr Antonuccio and colleagues (“Common Augmentation Strategies for Depression,” Psychiatric Times, March 2008, page 21), in which they warned us against using augmentation strategies for treatment-resistant depression in the face of a lack of studies that show the efficacy of such strategies. They argued that this is not evidence-based medicine. Far be it from me to be a proponent of “contrary to evidence-based medicine.” I certainly agree that evidence-based controlled studies of each and every reasonable augmentation strategy would be wonderful.

I was dismayed by the article by Dr Antonuccio and colleagues (“Common Augmentation Strategies for Depression,” Psychiatric Times, March 2008, page 21), in which they warned us against using augmentation strategies for treatment-resistant depression in the face of a lack of studies that show the efficacy of such strategies. They argued that this is not evidence-based medicine. Far be it from me to be a proponent of “contrary to evidence-based medicine.” I certainly agree that evidence-based controlled studies of each and every reasonable augmentation strategy would be wonderful.

However, a large percentage of drug studies are funded by pharmaceutical companies. In a few notable cases, such as with Abilify (aripiprazole; manufactured by Bristol-Myers Squibb) and Risperdal (risperidone; manufactured by Janssen), the manufacturers saw their products as potentially useful for augmentation of antidepressants, and they performed the appropriate studies. Unfortunately, there is little reason to suspect that most pharmaceutical companies will spend money to establish that the addition of another medication to their own ineffective antidepressant might confer the efficacy so badly needed by treatment-resistant patients. Thus, we cannot count on all the worthwhile controlled studies of augmentations to antidepressants to be done. For the most part, we are on our own.

Still, it is not time to despair. In my view, evidence-based also includes scientific evidence about the nature of the illness being treated, its pathophysiology, and a thorough, scientific knowledge of the pharmacology of medications being considered. When knowledge of the presentation, history, and previous medication trials is combined with a judicious weighing of risks versus benefits, it is the duty of a psychiatrist to pursue augmentation strategies that bring a tolerable quality of life to his or her patient. I tend to see evidence-based medicine as the rallying cry of insurance companies who refuse to pay for innovative treatment. It would be a shame if we allow it to also become a barrier to intelligent, creative use of our knowledge of pathophysiology and psychopharmacology.

Scott D. Mendelson, MD, PhD

Roseburg, Ore

Dr Antonuccio and colleagues respond:

We would like to thank Dr Mendelson for his thoughtful comments about our article. He seems to agree with us that the evidence for augmentation leaves much to be desired, but he also cautions against restricting the clinician’s ability to be in­novative in exploring potentially effective augmentations through a “ju­­­di­­cious weighing of risk versus benefits.” He also points out that there is little incentive for pharmaceutical companies to spend money on studies about how to effectively augment their own ineffective antidepressants.

We believe that pharmaceutical companies may have an incentive to promote the treatment of patients with 2 drugs rather than 1 when antidepressants are only partially effective-particularly if they have anti­depressant medications and common augmenting agents, such as second-generation antipsychotics, on the market. However, we agree with Dr Mendelson that we cannot count on these funding sources to support sufficient, high-quality studies to inform clinicians about what might be the best strategy for augmenting partially effective antidepressants.

We would like to point out that it is difficult, if not impossible, to weigh risk and benefit in the absence of scientific data on safety or efficacy for many common augmentations, as revealed by our analysis. Certainly, an innovative clinician may find an adequate solution for an individual patient through trial and error. However, this will always fail to give more general guidance to clinicians facing the next patient. Unfortunately, there have been many problematic instances in medicine of widespread implementation of misguided procedures that did not survive subsequent scientific scrutiny. While we have respect for experienced clinicians, we also urge clinicians to employ caution, carefully track the results of “one case experimentation,” and remember the imperative to “first do no harm.”

David Antonuccio, PhD, Craig A. Yury, MA, and Jeremy Matuszak

Reno, Nev

Marcia Valenstein, MD

Ann Arbor, Mich