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Clinical and Neurobiological Effects of Tianeptine and Paroxetine in Major Depression

Nickel, Thomas MD; Sonntag, Annette MD; Schill, Julia MD; Zobel, Astrid W. MD; Ackl, Nibal MD; Brunnauer, Alexander PHD; Murck, Harald MD; Ising, Marcus PHD; Yassouridis, Alexander PHD; Steiger, Axel MD; Zihl, Josef PHD; Holsboer, Florian MD, PHD

Journal of Clinical Psychopharmacology: April 2003 - Volume 23 - Issue 2 - p 155-168
Original Contributions

Selective serotonin reuptake inhibitors (SSRIs) are widely used as effective pharmacological agents to treat depressive disorders. In contrast to the SSRIs, which block the presynaptic serotonin (5-HT) transporter and by this route increase the concentration of serotonin in the synaptic cleft, the antidepressant tianeptine enhances the presynaptic neuronal reuptake of 5-HT and thus decreases serotonergic neurotransmission. Both SSRIs and tianeptine are clinically effective; however, their opposite modes of action challenge the prevailing concepts on the need of enhancement of serotonergic neurotransmission. To better understand the differences between these two opposite pharmacological modes of action, we compared the changes induced by tianeptine and paroxetine on psychopathology, the hypothalamic-pituitary-adrenocortical (HPA) system, and cognitive functions in a double-blind, randomized, controlled trial including 44 depressed inpatients over a period of 42 days. Depressive symptomatology significantly improved in all efficacy measures, with no significant differences between tianeptine and paroxetine. There was a trend toward better response to the SSRI among women. Assessment of the HPA system showed marked hyperactivity before the beginning of treatment, which then normalized in most of the patients, without significant differences between the two antidepressants. Cognitive assessments showed no significant differences between the two drugs investigated. The results of the current study suggest that the initial effect, i.e., enhancement or decrease of 5-HT release, is only indirectly responsible for antidepressant efficacy, and they support the notion that downstream adaptations within and between nerve cells are crucial. The normalization of the HPA system as a common mode of action of different antidepressants seems to be of special interest.

Max Planck Institute of Psychiatry, Munich, Germany

Received August 14, 2001; accepted after revision June 13, 2002.

Address reprint requests to: Thomas Nickel, MD, Max Planck Institute of Psychiatry, Kraepelinstr. 10, 80804 Munich, Germany. Address e-mail to:

© 2003 Lippincott Williams & Wilkins, Inc.