No discussion of treatment resistance would be complete without at least acknowledging the possible role played by hormesis.22,23 Formerly called the Arndt-Schulz Law, the hormetic dose-response model is thought to describe the biphasic relationship between dose and response--low-dose stimulation and high-dose inhibition, or vice versa. It is a little-known fact that there is not always a simple linear relationship between the dose of a drug and the clinical response: it is not always the case that the higher the dose, the more effective the drug. Because of this hormetic effect, higher doses--beyond a certain point--may actually be less effective (and not because the drug becomes less well tolerated). In fact, it is estimated that about 50% of drugs prescribed by physicians (including the psychotropic medications prescribed by psychiatrists) demonstrate the so-called hormetic effect (E. Calabrese, written communication, September 2006).
With respect to the mechanism underlying hormesis, Calabrese hypothesizes that hormesis occurs as a result of "modest overcompensation" by the body in the face of threatened disruption to homeostasis. In other words, any stressor that threatens to disrupt the body's homeostatic equilibrium may prompt activations of the body's regulatory systems in an effort to return the body to homeostatic balance. For example, a low-dose stressor (such as mild to moderate exercise) will stimulate the hypothalamic-pituitary-adrenal stress axis and the autonomic nervous system, initially energizing the body and resulting in feelings of increased well-being; but prolonged or excessive exercise will ultimately deplete the body's energetic and nutrient reserves and lead to compromise in functioning, fatigue, and dysphoria.
One of the most impressive and most often cited clinical trials on the efficacy of omega-3 fatty acids in the treatment of unipolar depression may provide a good example of the hormetic effect.18 In this elegantly designed 12-week, double-blind, placebo-controlled study, patients receiving ethyl-EPA were divided into 3 dosage groups (1, 2, and 4 g/d). All the participants had experienced persistent depression despite treatment with standard antidepressants at adequate dosages. The findings from this study showed that the patients receiving 1 g of EPA per day had the best outcome (with more than half achieving a 50% reduction on Hamilton Depression Rating Scale scores). Interestingly, the authors of the study found that the group receiving 2 g/d "showed little evidence of efficacy."22 Obviously, there are many ways to interpret this surprising finding, but one possible explanation involves the hormetic (biphasic) effect of low-dose stimulation and high-dose inhibition.
We must, therefore, always take into consideration the potential impact of hormesis on dosing. If a patient with depression taking 20 mg of fluoxetine(Drug information on fluoxetine) is responding only minimally to treatment, we almost always assume a linear relationship between dose and response and so go higher in our dosing, increasing perhaps to 30 mg, 40 mg, or more in pursuit of the desired antidepressant effect (sometimes stopping only after the drug's side effects become so unmanageable that the patient can no longer tolerate the drug). Indeed, because of a patient's genetic uniqueness and biochemical individuality, a particular patient may experience only mild improvement on a regimen of 20 mg of fluoxetine but significant improvement on a regimen of 10 mg, this latter dose offering obviously the optimal antidepressant effect. Again, it is the hormetic effect of the drug that accounts for this biphasic response of lower-dose (10 mg of fluoxetine) stimulation and higher-dose (20 mg of fluoxetine) inhibition, that is, lower-dose effectiveness and higher-dose ineffectiveness. In essence, more is not necessarily better!
Most remarkable of all is Calabrese's finding that when hormesis is involved, "synergy" occurs with respect not to response but to dose. When combinations of drugs demonstrate the hormetic effect, clinical effectiveness may occur much more easily than anticipated--because of hormesis. This is clearly an instance of the earlier-referenced holism, "the whole is greater than the sum of its parts." Inasmuch as combination/ augmentation strategies figure prominently in our repertoire of strategies for treatment resistance, it is therefore imperative that we appreciate the potential synergistic impact of the hormetic effect on drug combinations.
I began this article by suggesting that if we are to be more broadly effective in our work with patients, then we need to consider adopting a more holistic perspective, one that takes into account the collective and synergistic impact of the many different factors involved in regulating mental health. In addition to considering the levels of neurotransmitters in our patients' brains, it is crucial that we look at additional factors--those that tell a story about the patient (namely, other regulatory systems in the body, comorbid disease states, and individual genetic make-up and biochemical uniqueness) and those that tell a story about the drugs themselves (namely, their potential to demonstrate the hormetic effect).
I conclude, therefore, with the reminder that when we use augmentation/ combination strategies for treatment resistance, we must never lose sight of the big picture, that is, we must be ever attuned to the complicated, often unexpected synergy that exists between confounding factors presented by the patient and confounding factors in the medication regimens we prescribe. By the same token, if we are to stand a chance of improving on the one-third rule, then we must remain acutely aware of the complex relationships between the different drugs in our psychopharmacologic armamentarium.Dr Stark is clinical instructor in psychiatry, department of continuing education, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and adjunct faculty, Center for Psychoanalytic Studies, Massachusetts General Hospital, Harvard Medical School, Boston. She is also the author of several books on resistance and the modes of therapeutic action.She reports that she has no conflicts of interest concerning the subject matter of this article.