Clinical and Neurobiological Effects of Tianeptine and Paroxetine in Major Depression

Abstract

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.

Pharmacological and Nonpharmacological Factors Influencing Hypothalamic–Pituitary–Adrenocortical Axis Reactivity in Acutely Depressed Psychiatric In-patients, Measured by the Dex-CRH Test

“…We could not show an association of presence or absence of antidepressant treatment, the type of antidepressant treatment or of the number of previous ineffective antidepressant treatment attempts before hospitalization and the results of the Dex-CRH test, indicating that the reported normalizing effect of antidepressant treatment on the Dex-CRH test is actually dependent on clinical improvement and not just a pharmacological side effect Holsboer-Trachsler et al, 1991;Nickel et al, 2003). On the other hand, the fact of relapsing under an established prophylactic psychopharmacotherapy enhances the ACTH as well as cortisol response.…”

“…The data of 67 patients were already included in Zobel et al (2001) and of 41 patients in Nickel et al (2003). Comorbid anxiety, somatoform or substance abuse, eating or personality disorders were recorded but did not present an exclusion criterion.…”

“…Changes in HPA-axis reactivity in this test are correlated with changes in depressive symptomatology. Normalization of the Dex-CRH test was shown to anticipate or parallel response to antidepressant treatment Heuser et al, 1996;Holsboer-Trachsler et al, 1991;Nickel et al, 2003), and hyperactivity of the HPA-axis in the Dex-CRH test in remitted patient may predict relapse within the next 6 months (Zobel et al, 1999(Zobel et al, , 2001.…”

Reduction of Hypothalamic Vasopressinergic Hyperdrive Contributes to Clinically Relevant Behavioral and Neuroendocrine Effects of Chronic Paroxetine Treatment in a Psychopathological Rat Model

“…In patients suffering from major depression, the aberrant outcome in the DEX/CRH test can be normalized by effective antidepressant drug treatment (Holsboer, 2000;Zobel et al, 1999Zobel et al, , 2001). Correspondingly, like in patients suffering from major depression (Nickel et al, 2003), paroxetine treatment attenuated the CRH-stimulated hypersecretion of both ACTH and corticosterone seen in the vehicle-treated HAB rats. Basal ACTH and corticosterone levels between 1830 and 1930 h also significantly differed between paroxetine-treated and control HAB rats.…”

Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine

“…The efficacy of tianeptine has been established against placebo and reference antidepressants of different classes, mainly tricyclics and SSRIs. [32][33][34][35][36][37][38][39][40] In addition, tianeptine alleviates anxious symptoms associated with depression, 34,39,41-46 a property not associated with sedative effects. 47 The alleviation of inner tension is also more rapid than fluoxetine effects.…”