The first effective antidepressants (monoamine oxidase inhibitors and tricyclic antidepressants) relied on their ability to augment serotonin and noradrenaline levels at the synapse. Forty years later, the same biological model led to the supremacy of the serotonergic hypothesis to explain not only the pathophysiology of depressive illness, but also the neuropharmacological basis for obsessive compulsive disorder, phobias, posttraumatic stress disorder, and even generalized anxiety disorder. It could be argued that the blinkered view of depression as a solely serotonergic phenomenon has not only restrained and limited research into other potential systems, but has also slowed down the discovery of putative antidepressant drugs. While some might argue that the hypothalamic-pituitary-adrenal (HPA) axis explains an individual’s sensitivity to depression, there are others who equally claim that the most likely explanations are to be found in the neuropsychopharmacology of the immune system or even through reductions in hippocampal volume. There is a richness of possibilities regarding the mechanisms for antidepressant activity embracing theoretical, pharmacological and clinical data. However, the methods by which putative antidepressants are assessed and their clinical efficacy demonstrated are not always robust. That current clinical comparisons of antidepressants rarely show major differences in efficacy between existing molecules could be taken as an indication that “all drugs are the same” or perhaps, more insightfully, as an indication that the ubiquitous Hamilton depression (HAM-D) rating scales are not sensitive to inter-drug differences, even though pronounced pharmacodynamic differences between molecules are easily demonstrated. Any advances in the development of new antidepressants will have to find not only original compounds but also unique psychometric tests by which the drugs can be assessed in a sensitive, reliable, and valid manner.

The effect of depression on the hippocampus has become the focus of a number of structural and functional neuroimaging studies. In the past two decades, advances in neuroimaging techniques now allow the examination of subtle changes in both regional structure and function that are associated with the pathophysiology of depression. Many studies using 3-dimensional magnetic resonance imaging (MRI) volumetric measurement have reported decreases in hippocampal volume among depressed subjects compared with controls, whereas other studies have not found any volume loss. Differences among studies have been discussed. In some studies, the volume loss appears to have functional significance including an association with memory loss. Furthermore, we have found a trend towards loss of 5-HT2A receptors in the hippocampus using positron emission tomography (PET) to detect regional changes in [18F]altanserin binding. Functional imaging extends the sensitivity and specificity of structural imaging and will lead to a better understanding of affective disorders.

Neuronal plasticity or remodeling is most often discussed with regard to cellular and behavioral models of learning and memory. However, neuronal plasticity is a fundamental process by which the brain acquires information and makes the appropriate adaptive responses in future-related settings. Dysfunction of these fundamental processes could thereby contribute to the pathophysiology of mood disorders, and recovery could occur by induction of the appropriate plasticity or remodeling. These possibilities are supported by preclinical and clinical studies demonstrating that there are structural alterations that occur in response to stress and in patients with mood disorders. Moreover, antidepressant treatment may oppose these effects by regulation of signal transduction and gene expression pathways linked to neuronal plasticity. These findings comprise a novel conceptual framework for future studies of the etiology of mood disorders and for the development of novel therapeutic interventions.

Stress-induced structural and cellular alterations in the hippocampus can contribute to the pathophysiology of depression. The reversal of these alterations may be a mechanism by which antidepressants achieve their therapeutic effect. The aim of the present study was therefore to investigate  the effect of tianeptine on stress-induced structural changes and alterations in cerebral metabolites. To this end, psychosocially stressed male tree shrews were treated with tianeptine. A combination of in vivo and postmortem methods was used to evaluate the antidepressant treatment on the preservation of neuronal plasticity. It was found that all stress-induced effects were prevented by the administration of tianeptine. It is concluded that these findings provide experimental evidence for recent theories that impairment of neuronal viability and neuroplasticity might be important causal factors in mood disorders, suggesting tianeptine as a potential stimulator of neural resilience.

The hippocampal formation, a structure involved in declarative, spatial and contextual memory, undergoes atrophy in depressive illness along with impairment in cognitive function. Animal model studies have shown that the hippocampus is a particularly sensitive and vulnerable brain region that responds to stress and stress hormones. Studies on models of stress and glucocorticoid actions reveal that the hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes remodeling of dendrites in the CA3 region, a region that is particularly important in memory processing. Both forms of structural remodeling of the hippocampus are mediated by adrenal steroids working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, head trauma, and ischemia, and alterations of calcium homeostasis that accompany age-related cognitive impairment. Tianeptine (tianeptine) is an effective antidepressant that prevents and even reverses the actions of stress and glucocorticoids on dendritic remodeling in an animal model of chronic stress. Multiple neurotransmitter systems contribute to dendritic remodeling, including EAA, serotonin, and gamma-aminobutyric acid (GABA), working synergistically with glucocorticoids. This review summarizes findings on neurochemical targets of adrenal steroid actions that may explain their role in the remodeling process. In studying these actions, we hope to better understand the molecular and cellular targets of action of tianeptine in relation to its role in influencing structural plasticity of the hippocampus.

A meta-analysis was performed to compare the efficacy of tianeptine and selective serotonin reuptake inhibitors (SSRI) in the short-term treatment of depression. Consecutive selection and inclusion processes allowed five studies to be selected: two studies on tianeptine versus fluoxetine, two studies on tianeptine versus paroxetine, and one study on tianeptine versus sertraline. A total of 1348 patients were included in the five studies; 681 subjects received an SSRI and 667 tianeptine.

A strict step-by-step methodology was applied in order to legitimize this meta-analysis and to interpret the results. Considering all the patients or those with a Montgomery–Åsberg Depression Rating Scale (MADRS) inclusion score greater than 28, none of the assessed parameters (MADRS total score and responder rate) revealed any significant difference between the two treatment groups. Further analysis based on clinical global impression (CGI) items found no significant difference, except for CGI item 3 (therapeutic index), where a tendency (P=0.06 or 0.07 depending on the methodology) was found in favor of tianeptine. All in all, this study confirmed that tianeptine is at least as effective as SSRI, with a trend for a better acceptability profile in the treatment of depressed patients.