The clinical usefilness of Tianeptine on Alcohol dependence

Target of antidepressants

Antidepressants TCA MAOI SSRI SNRI NDRI NaSSA

Stahl S M, Essential Psychopharmacology (2000) Monoamine Hypothesis SRI inserted NRI inserted depression lifts depression lifts Stahl S M, Essential Psychopharmacology (2000) ref.추가하였음. Stahl S M, Essential Psychopharmacology (2000)

New Targets Stress-induced disturbances in neurotrophic factors Changes in the post-receptor intracellular machinery 새로운 항우울제의 Potential Target

NEUROPLASTICITY Depression A new approach to the pathophysiology of depression Psychological environment Traumatic life events Somatic diseases Pharmacological agents Genes Number of previous depressive episodes Neurotransmitters Hormones Growth factors Pittman JR: Drug Topics 2002; 7: 43-9 삭제함. Neuroplasticity in the hippocampus, amygdala, cortex Depression

Factors involved in structural changes in depression Serotonin Glucose transporters Depression Trophic factors Apoptosis Glutamate Glucocorticoids Neurogenesis Transcription factors Cellular atrophy etc Hippocampal volume

Serotonin involved in structural changes

Depression and Glutamate

Depression and Glutamatergic system Neuroplasticity Depression Glutamate, the biochemical basis of neuroplasticity and depression Rocher. Cereb Cortex. 2004; 14:224-229.

Glutamate in Animal Model of Depression Extracellular levels of glutamate are increased in the hippocampus and other brain regions (amygdala) in models of depression Glutamate is an important regulator of neuroplasticity. Reznikov et al.European Journal of Neuroscience. 2007;25:3109–3114.

Tianeptine as a Glutamatergic Modulator

Tianeptine = Glutamatergic Modulator International Guidelines for treatment in DEPRESSION “ STABLON has neuroprotective effects that contribute to its antidepressant properties ”

Glutamatergic Modulator Tianeptine = Glutamatergic Modulator Changes in GLT- 1mRNA expression in rats exposed to restrain stress and effect of Tianeptine treatment Tianeptine blocks the stress- Related increase of GLT-1mRNA Expression in CA3. Reagan LP et al, 2004, PNAS Geha PY et al. neuron 2008; 60

Glutamatergic Modulator Whole cell patch clamp technique Tianeptine = Glutamatergic Modulator NMDA currents in CA3 Whole cell patch clamp technique Tianeptine normalize NMDA currents (N-methyl-D-aspartate (NMDA) receptor Mediated excitatory postsynaptic currents) augmented by stress in the CA3 region of hippocampal formation in rats subjected to chronic stress Kole MH et al, 2002, Eur J Neurosci

Glutamatergic Modulator Amygdala Glutamate Efflux & Tianeptine Acute stress increased extracellular glutamate levels in the BLA & CeA. Stress-mediated increases in glutamate efflux in the BLA were inhibited by the antidepressant tianeptine but not by fluoxetine. Reznikov LR et al, 2007, Eur J Neurosci

Tianeptine = Glutamatergic Modulator STABLON has a unique impact on neuroplasticity thanks to a regulatory effect on glutamate. P Svenningsson, P Greengard Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to Tianeptine. Eur J Neuroscience. 2007, Vol 26, pp;3509-3517.

Tianeptine, Pharmacodynamic Receptor Binding Does not bind to or has low affinity for - 5-HT receptors - α1-, α2-, β-adrenoreceptors - GABA, BZ receptors - Cholinergic receptors - Histaminergic receptors Less side effects

Tianeptine, Pharmacodynamic Kinetics Properties 12.5mg single dose Absorption tmax 0.94h Bioavailability 99% Distribution Distribution H/L 0.7h Protein binding 95% Metabolism Conjugation 20-25% Elimination Elimination H/L 2.5h Total plasma CL 14.5 L/h Severe Renal failure or patients aged >70 years : 25mg/day # 2 Compensated cirrhosis : doseage adjustments are not likely to be necessary.

Neuroplasticity and Tianeptine *National Comorbidity Survey

Tianeptine & Gene Expression Expression of genes for neurotrophic factors NGF BDNF Tianeptine reversed the stress effects for these genes. Alfonso J et al. Biol Psychiatry. 2005

Dendritic length in the hippocampus The Effects of STABLON on Neuroplasticity Dendritic length in the hippocampus Hippocampal neurons Magarinos AM et al. Eur J Pharmacol. 1999

Dendritic length and branching in the amygdala The Effects of STABLON on Neuroplasticity Dendritic length and branching in the amygdala Restraint stress Restraint stress Chattarji S. Am Neurosci. 2004

The Effects of STABLON on Neuroplasticity Stress induced dendritic changes Restraint Stress shortening of dendritic length in CA3 region Tianeptine normalize dendritic length, but fluoxetine was not effective.

The Effects of STABLON on Neuroplasticity Hippocampal neurogenesis & Tianeptine BrdU immunohistochemistry Chronic stress cause decreases In BrdU(+) cell suggest decrease in neurogenesis Tianeptine normalize Neugrogenesis achieved not with acute but with chronic treatment Meyer-Rosberg K et al. Eur J Pain 2001; 5

Hippocampal apoptosis & Tianeptine The Effects of STABLON on Neuroplasticity Hippocampal apoptosis & Tianeptine Dominant Subdominant Chronic psychosocial stress increase apoptosis in the hippocampal formation (A) In the temporal cortex Tianeptine treatment significantly decreased the incidence of apoptosis Lucassen PJ et al, 2004, Biol Psychiatry

Apoptosis rate in the temporal cortex The Effects of STABLON on Neuroplasticity Apoptosis rate in the temporal cortex *P<0.05 vs control ###P<0.001 vs control Lucassen PJ et al. Biol Psychiatry. 2004

STABLON restores hippocampal volume The Effects of STABLON on Neuroplasticity STABLON restores hippocampal volume *P<0.05 (versus STABLON) Czeh B et al. Proc Natl Acad Sci U.S.A. 2001

The Effects of STABLON on Neuroplasticity Structural plasticity Hippocampus Dendritic length and branching↑ Neurogenesis rate↑ Hippocampal volume↑ Metabolite concentration↑ Apoptosis↓ Amygdala Dendritic length and branching↑ Cortex Apoptosis↓ McEwen, Olie.Mol Psy. 2005;10:525-537.

Delbende C, et al. Eur J Pharmacol. 1994;251:245-251 The Effects of STABLON on HPA axis Delbende C, et al. Eur J Pharmacol. 1994;251:245-251

(Favre, 1997, Eur Neuropsychopharmacol) Tianeptine: Antidepressant for alcoholism (Favre, 1997, Eur Neuropsychopharmacol)

Comparative effects of antidepressants on the signs of ethanol withdrawal syndrome in rats (Uzbay, Alcohol Alcohol 2008)

Conclusion