Debating the One-third Rule

Debating the One-third Rule

Dr Stark's article, "Neurotransmitters, Pharmacologic Synergy, and Clinical Strategies" (
Psychiatric Times, October 2006 Special Edition, page 1) offered a refreshing and sober discussion about the difficulties in treating psychiatric illnesses with the therapies that are currently available. The point regarding the error of adopting a "too-narrow focus on imbalanced neurotransmitter levels" without considering the "contributions of other biochemical and physiologic factors to the overall picture" was especially relevant. However, despite the inherent appeal of the holistic model of treatment, the practical adoption of its principles in the treatment of psychiatric patients may remain a guessing game for some time.

One of the difficulties is that to date there is little clinically useful knowledge about the precise ways in which disruptions in the immune system and the brain-end organ endocrine axis cause psychiatric pathology, and even less information about what steps are to be taken to restore homeostasis in the form of mental balance. The issue of emotional and cognitive resilience, which probably involves numerous variables (of which physiological homeostatic regulation may be one), remains poorly understood.

Dr Stark may very well be on the right track when she suggests that homeostatic mechanisms as well as the medications' biochemical actions, including hormesis, combine in certain ways to produce the desired therapeutic effect, or lack thereof, as the case may be. The fly in the ointment is that each patient's clinical condition represents a unique combination of multiple degrees of freedom in an equation that is probably far more complicated than we suspect. Today there is no way to answer the question of why one premenopausal patient with diabetes mellitus and compensated hypothyroidism responds to a 10-mg dose of fluoxetine (Prozac) while another requires 40 mg, and yet another fails to respond to anything but electroconvulsive therapy.

Hormesis and synergy, terms that in principle may apply to the treatment of every patient may, nevertheless, apply in ways that are highly idiosyncratic. Understanding these idiosyncrasies is highly desirable but difficult to investigate in the sort of large, placebo-controlled, double-blind studies on which we have rightly or wrongly relied for learning whether medicines work. Until we have at least a somewhat better appreciation for how the sort of internal physiological variables of which Dr Stark speaks in her article combine with medication effects in individual patients, we may have to continue to rely on the rule of thirds that many of us continue to use in clinical practice with some embarrassment, resignation, and yes, tongue in cheek.

Boris Vatel, MD
Evansville, Ind

Dr Vatel is a staff psychiatrist at Evansville State Hospital in Indiana.

Dr Stark responds:
Dr Vatel's point is indeed well taken, namely, that it's all well and good to conceive of the patient in holistic terms as a synergy of regulatory systems responsible for maintaining overall homeostatic balance—but that to operationalize such an approach is easier said than done.


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