PHILADELPHIA –- Examining data obtained from a University of Pennsylvania and Vanderbilt University psychology study, researchers at these universities and Northwestern University have reported the first placebo-controlled evidence that antidepressant medications—particularly selective serotonin reuptake inhibitors, or SSRIs—can substantially change patients’ personalities. The personality changes also appeared to be linked to long-term improvements in mood.

The findings counter the common assumption that personality changes during SSRI treatment occur only as a byproduct of alleviating depressive symptoms. In this study, the advantage of paroxetine over placebo in changing personality appears far more drastic than its advantage over placebo in alleviating depression.

“Investigating how SSRIs affect personality characteristics like neuroticism and extraversion may thus lead toward a more refined understanding of the mechanisms of SSRIs,” said Robert DeRubeis, professor in the Department of Psychology in Penn’s School of Arts and Sciences. “SSRIs perhaps can be viewed as personality-normalizing agents, potentially useful in treating many disorders associated with high neuroticism and low extraversion.”

Among responders to paroxetine, those for whom neuroticism changed the most during treatment were also those least likely to relapse. It would appear that change in neuroticism—or in a phenomenon related to self-reported neuroticism—served to reduce vulnerability to relapse.

Earlier reports from the collaboration have indicated that cognitive therapy prevented relapses into depression more effectively than did medication treatment overall. In the current study, patients treated with cognitive therapy were shown to have undergone somewhat greater personality change than those patients taking a placebo, but these effects did not appear to explain the lower relapse rates in the cognitive therapy group. Rather, as earlier published reports from this collaboration have indicated, the changes that appear to be responsible for this effect are related to the learning of new skills rather than to changes in personality. Specifically, it was the ability and the tendency of patients to apply the methods of cognitive therapy once treatment was completed that was related to better long-term effects.

The study is published in the December issue of Archives of General Psychiatry. Research was supported by the National Institute of Mental Health and GlaxoSmithKline.

Researchers randomly assigned 240 participants with major depressive disorder, or MMD, to take a placebo for eight weeks, paroxetine for 16 weeks or receive cognitive therapy for 16 weeks. Their personalities and depressive symptoms were assessed before, during and after treatment. After treatment with paroxetine or with cognitive therapy, responders were followed for a year to assess depression relapse.

As typical in similar trials, patients taking paroxetine experienced moderately greater depression improvement than those receiving placebo. In contrast, changes in neuroticism and in extraversion were far greater for patients taking paroxetine, relative to those receiving placebo, with cognitive therapy in between. Patients taking paroxetine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients.

“Our findings lead us to propose a new model of antidepressant mechanism,” said lead author Tony Z. Tang of Northwestern University. “Our data suggests that modern antidepressants work partly by correcting key personality risk factors of depression."

Not only is high neuroticism a key risk factor of depression, but studies also have found substantial overlap in the genes associated with high neuroticism and the genes associated with depression. Also, both neuroticism and extraversion are associated with the brain's serotonin system, which is targeted by these popular antidepressants.

Neuroticism refers to a tendency to experience negative emotions and emotional instability, whereas extraversion refers not only to socially outgoing behavior but also to dominance and a tendency to experience positive emotions.

The study was conducted by Tang and Benjamin Schalet of the Northwestern University; DeRubeis amd Jay Amsterdam of the University of Pennsylvania; and Steven D. Hollon and Richard Shelton of Vanderbilt University.

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