1. The clinical usefilness of Tianeptine on Alcohol dependence

2. Target of antidepressants

3. Antidepressants
TCA
MAOI
SSRI
SNRI
NDRI
NaSSA

4. 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)

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

6. 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

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

8. Serotonin involved
in structural changes

9. Depression and Glutamate

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

11. 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.

12. Tianeptine as a Glutamatergic Modulator

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

14. 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

15. 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

16. 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

17. 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;

18. 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

19. 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.

20. Neuroplasticity and Tianeptine
*National Comorbidity Survey

21. 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

22. 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

23. 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

24. 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.

25. 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

26. 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

27. 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

28. 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

29. 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:

30. 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:

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

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

51. Conclusion