ÖSSZEFOGLALÓ KÖZLEMÉNY ACTION OF IS CONNECTED WITH ACCELERATION OF TURNOVER IN THE : A HYPOTHESIS

MARAT G. UZBEKOV Department of Brain Pathology, Research Institute of Psychiatry, Moscow

ÖSSZEFOGLALÓ KÖZLEMÉNY Neuropsychopharmacologia Hungarica 2009, XI/2, 83-87

ÚJ HIPOTÉZIS A TIANEPTIN SUMMARY ANTIDEPRESSZÁNS HATÁSÁRÓL, A Based on the results of our investigation of pa- SZEROTONIN SZINAPSZISBAN TÖRTÉNÕ tients with anxious depression under the treat- FELSZABADULÁS GYORSÍTÁSÁVAL ment with with dif- A szerotonerg antidepresszánsokkal kezelt szo- ferent mechanism of action on serotonin reup- rongásos depressziós betegek vizsgálatának take we, the first time in the literature, propose eredményeibõl kiindulva, az irodalomban elsõ- the hypothesis about neurochemical mechanism ként felvetjük, hogy a tianeptin hatás a szero- of tianeptine action. According to this hypothesis tonin visszavétel serkentésén alapul. Eszerint a tianeptine not only activates serotonin tianeptin nemcsak a szerotonin visszavételt akti- into the synaptic ending but also activates its re- válja a szinapszisban, hanem a felszabadulást is, lease from the ending into the synaptic cleft thus ennélfogva gyorsítja a szerotonin turnovert. Az accelerating serotonin turnover rate in the syn- általunk felvetett fõként a szerotonerg neuro- apse. Proposed mechanism mainly refers the transzmisszió normalizálására irányuló hatás first, acute phase of its action directed to the nor- elsõ, akut fázisára vonatkozik. malization of serotonergic . KULCSSZAVAK: tianptin, neurokémiai hatás- KEYWORDS: tianeptine, neurochemical mecha- mechanizmus, szorongásos depresszió nisms of action, anxious depression

Tianeptine is a serotonin (5-hydroxytryptamine, ” (1999, p. 160) wrote: “Tianeptine 5-HT) reuptake enhancer. It exhibits a mechanism is an example of an agent that allosterically modi- of action totally opposite to selective serotonin fies serotonin reuptake in a manner that is almost reuptake inhibitors (SSRI), such as sertraline, but the opposite to that of the SSRIs. Although this paradoxically both mechanisms of action are asso- might theoretically seem to have the potential to ciated with a therapeutic efficacy in depressive cause depression rather than treat it, tianeptine in disorders, in particular in anxious depressions. In fact appears to be antidepressant.” spite of a numerous experimental and clinical tri- All these prompt us to carry out the compara- als the neurochemical mechanism of tianeptine tive clinical-biochemical investigation of patients action is not enough clear (Ansseau, 1993; Stahl, with anxious depression under the treatment of 1999; Kasper, 2006). Ansseau (1993) had ana- tianeptine and sertraline and on the basis of results lyzed the different effects of tianeptine and dis- of the study develop possible mechanism of tia- cussed the approaches, mainly clinical, which could neptine action. Some clinical and biochemical as- help to understand “the paradoxical activity of pects of this work are described elsewhere (Ma- tianeptine”. But he did not express his views on ximova et al. 2000; Uzbekov et al. 2006). the ways to solve the problem of the neuroche- In this paper we want to stress the attention on mical and therapeutic mechanisms of action of the working hypothesis of the neurochemical mech- this antidepressant. Stahl in his “Essential Psycho- anisms of tianeptine action. Some preliminary as-

Neuropsychopharmacologia Hungarica 2009, XI/2, 83-87 83 ÖSSZEFOGLALÓ KÖZLEMÉNY MARAT G. UZBEKOV pects of this hypothesis were published earlier It was earlier shown that in depressed patients (Uzbekov et al., 2002). the capacity (or activity) of the serotonin reuptake Shortly, in 43 patients with anxious depression mechanisms were decreased (Bellivier et al. 2002; we have revealed significant almost twofold in- Slanley et al. 1982; Stahl, 1985). On the other crease of platelet monoamine oxidase (MAO) ac- hand in our study we have established that in tivity as compared with healthy volunteers. These anxious-depressed patients MAO activity was in- disturbances in systems were ac- creased almost twofold (Uzbekov et al. 2006). The companied by the significant twofold decrease of letter specifies that in this case serotonin is taken serum semicarbazide-sensitive amine oxidase up more actively by the glial cells where MAO is (SSAO) activity, significant increase of the level localized. We can assume that the ratio – serotonin of plasma middle-mass endotoxic molecules affinity for receptors on the presynaptic ending (MMEM) and significant decrease of albumin and the same on the glial cells in patients with functional properties (Uzbekov et al. 2006). There anxious depression changes. The left part of the were found significant changes in blood serum ratio is decreasing and the right part – is increas- concentrations of cortisol, estradiole and testos- ing, i.e. the ratio becomes, for example, 2 to 2 terone (Uzbekov et al. 2003). All these disturbed instead of 3 to 1 (as in norm). On the functional parameters indicate on the pronounced endoge- level it means that in anxious depression serotonin nous intoxication (Uzbekov and Misionzhnik, 2000; is taken up by glial cells in larger quantity where it Uzbekov et al. 2006). chemically inactivated by MAO. Owing to this Anxious depression is characterized by the de- serotonin concentration in the synaptic cleft is crease in serotonergic activity (Kasper, 2001) and reduced and as a result less quantity of serotonin is possibly by the decrease in serotonin concent- returned in the presynaptic ending. All this events ration in the . Twofold increased platelet lead to the disturbances in serotonergic activity MAO activity in anxious patients indirectly sup- and in particular serotonergic neurotransmission. ported this view. It is thought that the platelet The therapeutic effects under tianeptine treat- MAO activity in some instances reflects the simi- ment (37,5 mg/day) is manifested after two weeks lar activity in the brain (Stahl, 1985). of therapy (Maximova et al. 2000; Uzbekov 2006) According to the literature (Avakjan, 1976; that is supported by literature data (Quitkin et al. Hughes, 1972) it is supposed that at normal 1984; Kato and Weitsch, 1988; Ansseau, 1993). condition about 75% of serotonin released in the At that time we have found changes in activity or synaptic cleft undergoes functional inactivation levels of all investigated biochemical parameters. by the reuptake in the presynaptic ending () These changes were not very pronounced although by the reuptake mechanisms (reuptake or they were significant (Uzbekov, 2006). ). Serotonin is accumulated Elucidation of the antidepressive mechanism of in the synaptic vesicles and thus it becomes un- tianeptine action is one of the most difficult prob- available to the action of MAO localized in mito- lems. The analysis of available data has shown the chondria of presynaptic ending. The remaining lack of any information that could explain neuro- serotonin (approximately 25%) undergoes chemi- chemical mechanism of action of this antidepres- cal (irreversible) inactivation by MAO localized sant. It is well known that tianeptine activates in mitochondria of glial cells (astrocytes and/or serotonin reuptake in the presynaptic ending. microglial cells) that close the synaptic cleft and Thus promoting for the more “energetic with- where the is taken up (Hughes, drawal” of serotonin from the synaptic cleft. In 1972; Avakjan, 1976; Whitaker et al. 1983). As spite of all existing theories tianeptine on the clini- serotonin uptake in neuronal and glial cells pro- cal level reveals antidepressive, anxiolytic effects. ceeds through the receptors (or transporters) it is Ansseau writes about this situation in such words: possible to suppose that serotonin affinity for the “The paradoxical finding that both tianeptine and receptors on presynaptic ending (neuron) and on selective 5-HT reuptake inhibitors exhibit antide- glial cells correlates as 3 to 1 (75% and 25%, see pressant activity despite clearly antagonistic me- above). It is necessary to note that receptors for chanisms is rather puzzling” (1993). serotonin on astrocytes differ from those on the We think that the problem of tianeptine action (Hertz and Tamir, 1981). is necessary to consider from the point of view of structural-functional unity of the synapse. Based

84 Neuropsychopharmacologia Hungarica 2009, XI/2, 83-87 ANTIDEPRESSANT ACTION OF TIANEPTINE IS CONNECTED WITH… ÖSSZEFOGLALÓ KÖZLEMÉNY on this thesis the synapse has to be considered as a conclude that under tianeptine action serotonin complex, multiple biological system but not only turnover rate in the synapse is increased that pro- as a structure with “reuptake receptor”. motes the increase in the unit of time serotonin According to our working hypothesis tianep- concentration on postsynaptic receptors. Decreas- tine, enhancing serotonin reuptake, decreases se- ing MAO activity supports serotonin concentra- rotonin level in the synaptic cleft. Simultaneously tion in the synaptic cleft on the minimally allow- with this process in responders we have estab- able level to display its neurotransmitter func- lished that a very high MAO activity starts to tions. decrease. It is possible to suppose that tianeptine Proceeding from the offered neurochemical decreasing affinity of glial receptors for serotonin mechanism of tianeptine action it is possible to reduces activity of glial cells in serotonin uptake. hypothesize of the interrelation between the dyna- That is followed by the inhibition of MAO activ- mics of MAO activity and the clinical status of ity. Our supposition is supported by results of anxious depressed patients. In responders activ- Marinesco et al. (1996) who have found that tia- ation of serotonin turnover rate in the synapse is neptine decreases serotonin availability to MAO accompanied by decrease of MAO activity that which localized in glial cells. Because of that the allows on the minimally allowable serotonin level ratio – serotonin affinity for the receptors on pre- in the synaptic cleft to achieve pronounced thera- synaptic endings and on glial cells changes. The peutic effects. The increase of the parameters of left part of the ratio is increased (neuron) and the functional albumin activity and decrease of right part – decreased (glia), i. e. we have the ratio MMEM level are indicated to the decrease of not 2 to 2 (peak of anxious depression) but, for degree of endogenous intoxication and the im- example, 2,5 to 1,5 (beginning of the remission). provement of homeostasis as a whole (Uzbekov et Under tianeptine action two processes take place al. 2006). in the synaptic region: a) enhancing of serotonin Analysis of our own and literature data make it reuptake in the synaptic ending, and b) inhibition possible to suppose that tianeptine antidepressant of MAO activity that is followed by increase of effects are characterized by two-phase action. serotonin concentration in the synaptic cleft. But In the first, acute phase of its action there take in a whole it is possible to assume that serotonin place the neurochemical processes on the synaptic concentration in the synaptic cleft appeared to be level, i.e. processes that were described as stated dropped because process (a) is more active then above. They lead to a relative normalization of process (b). That is the “paradox“ of the action of serotonergic neurotransmission, moreover tianep- this antidepressant. tine does not induce the decrease of 5-HT1A re- What is the fate of serotonin, which continues ceptors sensitivity for serotonin (Kelly and Leon- to take up in the presynaptic ending? Here it is ard, 1994). necessary to make an assumption. Tianeptine is The second phase of tianeptine action begins, characterized by one more property that has a possibly, after a relative normalization of seroton- principle meaning. Carlsson et al. (1969) had de- ergic neurotransmission. It is connected with such scribed that 4-methyl-alpha-meta-tyramine caused properties of this antidepressant as ability to de- the depletion of serotonin from the intraneuronal crease of degree of endogenous intoxication (Uz- stores. They also had found that tianeptine mark- bekov et al. 2006) and mobilization and activation edly potentiated this type of serotonin depletion. of compensatory and plastic mechanisms of the Later Fattaccini et al. (1990) and Labrid et al. central . Thus, tianeptine reduces (1992) have shown in vivo and in vitro that tianep- stress-induced atrophy of neuronal dendrites (Wag- tine had significantly increased serotonin deple- staff et al. 2001; Watanabe et al. 1992), in stressed tion from its intraneuronal stores. animals tianeptine attenuates the activation of the Based on these data we can make the assump- hypothalamo-pituitary-adrenal axis (Delbende et tion that tianeptine directly or indirectly through al. 1994; Droste et al. 2006), increases neuronal any unknown mechanisms activates serotonin re- electric activity (Pineyro et al. 1995). It was lease from presynaptic ending in the synaptic cleft. shown that tianeptine prevents or reverses stress- Thus, tianeptine enhances not only serotonin associated structural and cellular changes in the reuptake but also it activates its surge from the brain and normalizes disrupted neu- ending into the synaptic cleft. So it is possible to rotransmission. In hippocampus, amygdala and

Neuropsychopharmacologia Hungarica 2009, XI/2, 83-87 85 ÖSSZEFOGLALÓ KÖZLEMÉNY MARAT G. UZBEKOV cortex it prevents stress-induced dendritic atro- hypothesis tianeptine not only activates serotonin phy, improves neurogenesis, reduces apoptosis reuptake but also activates serotonin release in and normalizes metabolite levels (Lucassen et al. synaptic cleft thus accelerating serotonin turnover 2004; Kasper and McEwen, 2008). in the synapse. Proposed mechanism mainly re- The latent period for about 2 weeks, that is nec- fers the first, acute phase of its action directed on essary to reveal tianeptine therapeutic effect, pos- the normalization of serotoninergic neurotrans- sibly is connected with the reorganization of dif- mission. ferent pathologically disturb brain system (Ans- seau, 1993; Hirschfeld, 2001; Uzbekov et al. 2006). ACKNOWLEDGEMENTS The results of our investigations indicate that in- I am grateful to Professor Brian Leonard (Galway, deed as early as in two weeks of tianeptine treat- Ireland) for his consultations. Technical assistance of ment we have revealed the improvement of inves- Lena Skokina is gratefully acknowledged. tigated biochemical parameters; although these Correspondance: changes were not very pronounced they were sig- Marat G Uzbekov nificant (Maximova et al. 2000; Uzbekov et al. Professor, MD, PhD, DScMed 2006). Head, Department of Brain Pathology Research Institute of Psychiatry, In conclusion, we in the first time in the litera- Poteshnaya 3, 107076 Moscow, Russia ture propose the hypothesis about neurochemical E-mail: [email protected] mechanism of tianeptine action. According to our

REFERENCES Fattaccini CM, Bolanos-Jimenez F, Labrid C, Mocaer E, Kamoun A. 1992. Ansseau M, 1993. The paradox of tia- Golzan H, Hamon M. 1990. Tianep- Neurochemical and pharmacologi- neptine. Eur. Psychiatry 8 (suppl 2): tine stimulates uptake of 5-hydr- cal properties of tianeptine, a novel 89-93. oxytryptamine in vivo in the rat antidepressant. Br J Psychiatry Avakjan OM. 1976. Up-to-date data brain. Neuropharmacology 29: 1-8. Suppl 15: 56-60. about the mechanisms of the release Hertz L, Tamir H. 1981. Some proper- Lucassen PJ, Fuchs E, Czeh B. 2004. and reuptake of catecholamines; ties of an astrocyte protein fraction Antidepressant treatment with tia- possibilities and perspectives of that binds serotonin. J. Neurochem neptine reduces apoptosis in the their pharmacological regulation. 37: 1331-1334. hippocampal dentate gyrus and tem- Mendeleev Zh Vsesouznogo Hirschfeld RM. 2001. Clinical impor- poral cortex. Biol Psychiatry 55: Khimicheskogo Obshchestva 21: tance of long-term antidepressant 789-796. 165-171. treatment. Br J Psychiatry 42 Marinesco S, Poncet L, Debilly G, Bellivier F, Roy I, Leboyer M. 2002. (Suppl): S4 – S8. Jouvet M, Cespuglio R. 1996. Ef- Serotonin transporter gene polymor- Hughes J.1972. Evaluation of mecha- fects of tianeptine, sertraline and phisms and affective disorder- nisms controlling the release and in- clomipramine on brain serotonin related phenotypes. Curr Opin Psy- activation of the trans- metabolism: a voltammetric ap- chiatry 15: 49-58. mitter in the rabbit portal vein and proach in the rat. Brain. Res 736: Carlsson A, Corrodi H, Fuxe K, Hokfelt vas deferens. Br. J. Pharma 44: 82-90. T. 1969. Effect of antidepressant 472-491. Maximova NM, Misionzhnik EY, on the depletion of intraneu- Kasper S. 2001. Depression and Anxi- Vertogradova OP, Uzbekov MG. ronal brain 5-hydroxytryptamine ety - Separate or Continuum. World 2000. Therapeutic efficacy and met- stores caused by 4-metyl-alfa-ethil- J Biol Psychiatry 2: 162-163. abolic peculiarities in patients with metatyramine. Eur. J. Pharmacol 5: Kasper S. 2006. Neuroplasticity and the depressive disorder under tianeptine 357-366. treatment of depression. Neuropsy- (TIA) and sertraline (SER) treat- Delbende C, Tranchand Bunel D, chiatric Disease and Treatment 2, ment. Eur Psychiatry 15 (Suppl. 2): Tarozzo G, Grino M, Oliver C, Suppl 2: 15-20. 379S. Mocaer E, Vaudry H. 1994. Effect Kasper S, McEwen BS. 2008. Neuro- Pineyro G, Deveault L, Blier P, Dennis of chronic treatment with the antide- biological and clinical effects of the T, de Montigny C. 1995. Effect of pressant tianeptine on the hypo- antidepressant tianeptine. CNS acute and prolonged tianeptine ad- thalamo-pituitary-adrenal axis. Eur J Drugs 22: 16-26. ministration on the 5-HT trans- Pharmacol 251: 245-251. Kato G, Weitsch AF. 1988. Neuroche- porter: electrophysiological, bio- Droste SK, Schweizer MC, Ulbricht S, mical profile of tianeptine, a new chemical and radioligand binding Reul JM. 2006. Long-term volun- antidepressant . Clin. Neuro- studies in the rat brain. Naunyn tary exercise and the mouse hypo- pharmacology 11 (suppl 2): 43-50. Schmiedebergs Arch Pharmacol thalamic-pituitary-adrenocortical Kelly JP, Leonard BE. 1994. The effect 351: 111-118. axis: impact of concurrent treatment of tianeptine and sertraline in three Quitkin FM, Rabkin JG, Ross D, Mc with antidepressant drug tianeptine. animal models of depression. Grath PJ. 1984. Duration of antide- J Neuroendocrinol 18: 915-925. Neuropharmacology 33: 1011-1016. pressant drug treatment. What is an

86 Neuropsychopharmacologia Hungarica 2009, XI/2, 83-87 ANTIDEPRESSANT ACTION OF TIANEPTINE IS CONNECTED WITH… ÖSSZEFOGLALÓ KÖZLEMÉNY

adequate trial? Arch. Gen. Psychia- chic disorders. Russian Journal of zhov AM, Shikhov SN. 2003. Some try 41: 238-245. Psychiatry ¹ 4: 56-65. aspects of metabolic disturbances in Stahl SM. 1985. Peripheral models for Uzbekov MG, Misionzhnik EY, Maxi- anxious depression. Russian Journal the study of neurotransmitter recep- mova NM, Vertogradova OP. 2006. of Psychiatry ¹ 6: 58-62. tors in man. Psychopharmacol. Bull Biochemical profile in patients with Wagstaff AJ, Ormrod D, Spencer CM. 21: 663-671. anxious depression under the treat- 2001. Tianeptine: a review of its use Stahl SM. 1999. Essential Psychophar- ment with serotonergic antidepres- in depressive disorders. CNS Drugs macology. Neuroscientific Basis sants with different mechanisms of 15: 231-259. and Clinical Applications. Cam- action. Hum Psychopharmacol Clin Watanabe Y, Gould E, Daniels DC, bridge University Press: Cambridge. Exp 21: 109-115. Cameron H, McEwen BS. 1992. Stanley M, Virgilio J, Gershon S. 1982. Uzbekov MG, Maximova NM, Mision- Tianeptine attenuates stress-induced Tritiated imipramine sites are de- zhnik EY, Vertogradova OP. 2002. morphological changes in the hippo- creased in the frontal cortex of sui- About the neurochemical mecha- campus. Eur J Pharmacol 222: 157- cides. Science 216: 1337-1339. nism of tianeptine (coaxil) action in 162. Uzbekov MG, Misionzhnik EY. 2000. anxiety-depressed patients. Social Whitaker PM, Vint CK, Morin R. 1983. Nonspecific syndrome of endoge- and Clinical Psychiatry 12: 43-45. Imipramine labels sites on brain nous intoxication as an integral Uzbekov MG, Misionhznik EY, Maxi- astroglial cells not related to component of patogenesis of psy- mova NM, Vertogradova OP, Ri- serotonin uptake. J. Neurochem 41: 1319-1322.

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