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    1 Comment for this article
    The Wrong Placebo was Used
    Pesach Lichtenberg, M.D. | Herzog Hospital, and the Medical School of the Hebrew University of Jerusalem
    The fascinating work by Tang et al (1) has a flaw which undermines its central claim, to wit, that “Paroxetine appears to have a specific pharmacological effect on personality that is distinct from its effect on depression.” The basis for their conclusion is their finding that paroxetine treatment has a far greater effect upon neuroticism and extraversion than upon depression. The study includes a control group receiving placebo, which forms the basis for determining paroxetine’s effectiveness. While the paper does not specify what the study participants were told, one may assume that expected to receive an anti-depressant, not an anti-neuroticism pill or pro-extraversion pill. Therefore, the implied suggestion was that their depression, and only their depression, would be helped. The participants could have had no expectation that the pill would have an effect upon their personality. Therefore, in this study, the antidepressant effect of paroxetine was being compared with a placebo effect, while the effect upon personality was being compared with no treatment at all. It is no surprise that on these unequal terms, the anti-depressant effects appeared much weaker. Were this study properly carried out, the participants would have to be told that the medication they were to receive could have an effect on depression, neuroticism, and extraversion. The relative effect of paroxetine upon personality, thus measured against the appropriate placebo, would likely be slighter than that found in the study as performed. Too often placebos are treated simply as inert pills. However, the specificity of placebo effects is well documented (2-4), and depends upon the expectations aroused in the patient. How the placebo is integrated into the design of a study can have far reaching implications. Pesach Lichtenberg, MD Herzog Hospital POB 3900 Jerusalem 91035 Israel
    I have no relevant conflicts of interest to declare.
    1. Tang TZ, DeRubeis RJ, Hollon SD, Amsterdam J, Shelton R, Schalet B. Personality change during depression treatment: a placebo-controlled trial. Arch Gen Psychiatry. 2009;66:1322-30.
    2. Colloca L, Lopiano L, Lanotte M, Benedetti F. Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol 2004;3:679-84.
    3. Oken BS. Placebo effects: clinical aspects and neurobiology. Brain. 2008;131:2812-23
    4. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry. 2008;65:220-31.
    Original Article
    December 2009

    Personality Change During Depression Treatment: A Placebo-Controlled Trial

    Author Affiliations

    Author Affiliations: Northwestern University, Evanston, Illinois (Dr Tang and Mr Schalet); University of Pennsylvania, Philadelphia (Drs DeRubeis and Amsterdam); and Vanderbilt University, Nashville, Tennessee (Drs Hollon and Shelton).

    Arch Gen Psychiatry. 2009;66(12):1322-1330. doi:10.1001/archgenpsychiatry.2009.166

    Context  High neuroticism is a personality risk factor that reflects much of the genetic vulnerability to major depressive disorder (MDD), and low extraversion may increase risk as well. Both have been linked to the serotonin system.

    Objectives  To test whether patients with MDD taking selective serotonin reuptake inhibitors (SSRIs) report greater changes in neuroticism and extraversion than patients receiving inert placebo, and to examine the state effect hypothesis that self-reported personality change during SSRI treatment is merely a change of depression-related measurement bias.

    Design  A placebo-controlled trial.

    Setting  Research clinics.

    Patients  Adult patients with moderate to severe MDD randomized to receive paroxetine (n = 120), placebo (n = 60), or cognitive therapy (n = 60).

    Outcome Measures  NEO Five-Factor Inventory and Hamilton Rating Scale for Depression.

    Results  Patients who took paroxetine reported greater personality change than placebo patients, even after controlling for depression improvement (neuroticism, P < .001; extraversion, P = .002). The advantage of paroxetine over placebo in antidepressant efficacy was no longer significant after controlling for change in neuroticism (P = .46) or extraversion (P = .14). Patients taking paroxetine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement. Although placebo patients exhibited substantial depression improvement (Hamilton Rating Scale for Depression score, −1.2 SD, P < .001), they reported little change on neuroticism (−0.18 SD, P = .08) or extraversion (0.08 SD, P = .50). Cognitive therapy produced greater personality change than placebo (P ≤ .01); but its advantage on neuroticism was no longer significant after controlling for depression (P = .14). Neuroticism reduction during treatment predicted lower relapse rates among paroxetine responders (P = .003) but not among cognitive therapy responders (P = .86).

    Conclusions  Paroxetine appears to have a specific pharmacological effect on personality that is distinct from its effect on depression. If replicated, this pattern would disconfirm the state effect hypothesis and instead support the notion that SSRIs' effects on personality go beyond and perhaps contribute to their antidepressant effects.