Dr. Knutson and Colleagues Reply

To the Editor: We thank Richard Balon, M.D., for reemphasizing some important questions that we touched on in our report (i.e., “Is everyone equally affected by antidepressant treatment?” “Are these changes permanent?”), but we would like to clarify some of the other issues he raises. An active placebo condition might have provided useful additional data, but we should note that neither our subjects nor those of Dr. Gelfin and colleagues could reliably determine whether they had received an active or placebo compound. While the study we reported cannot address all of these issues, future studies may.

A conceptual ambiguity underlying one of the questions concerns us (i.e., “Could it be that serotonergic antidepressants just help ‘normal’ and other people tolerate stress better?”). This question implies that sensitivity to stress is not relevant to personality. In fact, susceptibility to stress comprises a central facet of one of the most prominent trait dimensions commonly measured by psychologists (i.e., neuroticism or negative affect) (1). This trait has clinical relevance in that it can confer vulnerability to a host of affective disorders (2). Framing personality as a unitary entity rather than as a collection of traits obscures our finding that only one aspect of personality was altered by selective serotonin reuptake inhibitor (SSRI) administration. Indeed, this selective effect led us to conclude that agents such as SSRIs might help elucidate biological substrates for some personality variables.

As Dr. Balon implies, our procedures differed from those of Dr. Gelfin and colleagues in a number of ways. These differences may have contributed to an apparent inconsistency of findings. First, we administered SSRI and placebo concurrently to different groups (by means of a double-blind procedure), rather than sequentially to the same subjects. Second, we mainly used psychometric measures developed for normal rather than clinical samples, which may have reduced our susceptibility to floor effects. Third, we also observed changes in objectively coded interpersonal behavior. Fourth, we measured plasma SSRI levels, which afforded some control for compliance or idiosyncratic malabsorption of the drug. Fifth, we tested a larger number of subjects, which may have boosted our statistical power to detect an effect.

Kramer originally observed personality changes in the patients he saw in clinical practice but not in “normal” volunteers. Although behavioral scientists can rarely make definite conclusions, we believe that we have taken the first step toward a testable hypothesis and stand by our original statement: serotonergic mechanisms may selectively modulate an aspect of personality characterized by negative affective experience.