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Increased serotonin platelet uptake after tianeptine administration in depressed patients
BIOL ~ Y C H I A ~ Y
609
Increased Serotonin Platelet Uptake after Tianepfine Administration in Depressed Patients, Genevi/~ve Chamba, Patrick Lemoine, Elisabeth Hacnaire, Nicole Ferry, Claude Quincy, Jean Sassard, C h ~ t ~ Fer~r, Elisabeth Moca/~r, Annie Kamoun, and Bemard Renaad
Tianeptine is a new antidepressant drug reported to enhance serotonin (5-hydro~'t~'ptamine [5-HTD uptake in rat brain. The effect of tianeptine on 5-HT plate&t uptake was studied in i0 depressed patients treated for 28 days. Tianeptine increases V ~ of 5-HT platelet uptake during treatment without inducing any change in K~. As early as 2 hr after the frst administration. V,,,~ increased significantly ( + 23%, a = 0.01L Although of a lesser magnitude. 5-HT platelet uptake remains increased af'ter chronic administration (+ 14% on day 10 and + 13% on day 28). This suggests t ~ t tianeptine affects 5-HT platelet uptake sites, either directly or via an action on modulators of 5-HT uptake. These results, in contrast with the action of other tric3.'clic antidepressants, confirm the original action of tianeptine on 5-HT platelet metabolism.
Introduction Tianeptine {[(chloro-3 methyl-6 dioxo-5,5 dihydro-6. II dibenzo [c,q ti~epine-1,2 yll I) aminol-7 heptanoic acid, sodium salt, Stablon ~} is a new tricyclicagent with a_nfidepressant properties in animal models (Labrid et ~ 1988; Moca6r ct ~ 1988)and in humans (Dcfrance et al 1988; L6o and Deniker 1988; Oli6 et al 1988; Casacchia et al i989). Although fianeptine has a pharmacological profile that includes various c ~ c teristicsof an antidepressant drug (Poignant 1981), its neurochc~cal properties differ c ~ , fianeptine from those of the other tricyclicantidepressants (such as imipramine). m "-u'--" does not inhibit the reuptake of serotonin (5-hydroxytrypt~ine [5-HTD or norepinephrine in the central nervous system (Mennini et al 1987; Kato and Weitsch 1988). In contrast, it has been reported to increase 5-HT uptake in rat brain (Mennini et al 1987; Fattaccini et al 1990) and m rat platelets (Kato and Weitsch !988). Furthermore, in rats, tianeptine induces an increase in plasma (Ortiz et al 1991) and brain (Fattaccini et al 1990) 5hydroxyindolacetic acid (5-HIAA) levels. These results are in agreement with previous
From the Laboratoirede Ncuropharmacologie, Universi0bClaude Bernard et CNRS UMR 105, Fa~lt~ de ~ i c . Lyon. France (GC, BRL Unitd Clinique de Psychiaa'icBiologiquc, H6pitald~ V ~ c r , Bran, France (PL. CF), Service de Biologic, H6pital Ncurologiq~c, Lyon, France (EF, CQ, BR), ~ m e n t de Physio/ogiect ~ o l o g i e Clinique. Univcrsil~Oaude Bernard c t CNRS URA 606. F~'~I~ de Phammcic. Lyon. France (NF. JS). and the Institut de R~hetchcs Intemafionales Servier. Neuilly sur Seine. France {EM, AK). Address rcprimrequeststo Genevieve Clmmba, Ph.D., Laboratoirede N c ~ l o g i ¢ . Univcrsit~Cla~de Bcma~, Facultt de Phatmacie. 8 Avenue Rockefeller,69373 Lyon Ccdex 08, France. Received December l. 1990; revised April 20, 1991. © 1991 Sociely of Biological Psychiatry
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voltammetric data reporting that tianeptine emianees the extracellular levels of 5-HIAA in the rat hippocampus (De Simoni et al 1989). Tianeptine has no affinity for 5-HTI or 5-HT2 cerebral receptors (El Mestikawy et al 1988; Hamon et al 1989) and has no effect in vivo or ex vivo on 3H-imipramine binding (Kato and Weitsch 1988). Nevertheless, the above data support a serotonergic component in the meehanism of action of tianeptine. In humans, only a preliminary study has reported an increase in 5-HT platelet uptake in two depressed patients after tianeptine treatment (Renaud et al 1988). Furthermore, such an increase has been foun,' in elderly patients after a single tianeptine administration (Baccino et al 1989). Our study was performed to evaluate 5-HT platelet uptake in depressed patients receiving tiat~ptine. Serotonin platelet uptake and 5-HT platelet content were determined at different times (days 0, 1, 10, and 28) during a 28-day treatment. Methods
Patietzts and Treatment The protocol was approved by an Ethics Committee (Comit6 d'Ethique de l'Universit6 C. Bernard et des Hospices Civils) and all the patients gave informed consent according to current legal regulations. Th~een inpatients (i ! women, 2 men, 18-69 years old) with major depression or dysthymic dis~raers according to DSM-m criteria (categories 296.22, 296.2, 300.40) were included in the study. All scored at least 20 points on the Montgomery and Asberg Depression Rating Scale (MADRS). One month before the beginning of the study, other ~ i c a t i o n s (antidepressants, neuroleptics, antiplatelet ~ags, nonsteroidial anti-in~ammatory drugs, and salicylate compounds) were stopped; only benzodiazepines were authorized during the treatment. Depressed patients received three tablets of Stablon per day (12.5 mg tianeptine per tablet, at 8:00 AM, 12:00 noon, and 8 : ~ PM) for 28 days. The criteria of assessment of efficacy were scored on days 0, 10, and 28 on Clinical Global Investigation (CGI), MADRS, and Hamilton Anxiety Rating Scale (HARS).
Biochemical Determinations Blood Samples Collection. Blood samples were collected by venopuncture into plastic tubes containing 12 mg sodium EDTA as anticoagulant. Samples collected on day 0 (before treatment), on day l (2 hr after the first tianeptine administration), and on days i0 and 28 (just before, the morning administration)were kept at room temperature and the biochemical determinations started within 2 hr following the puncture. 5-HT Platelet Uptake. 5-HT platelet uptake was determined by a modification of the radiometric method of Kamal et al (1984). Blood was centrifuged (170 g, 15 rain, + 20°C) to obtain platelet-rich plasma (PRP). After 5 min at + 37°C, an aliquot of PRP, containing a defined n~.,nber of platelets (measured in HYCEL HPC 52 platelets counter), was incubated for 30 sec with seven (0. l, 0.2, 0.5, 0.75, 1.0, 1.5, and 2 p,mol/L) concentrations of [3HI5-HT (Amersham France, 550 GBq/mmol), at + 37°C for total uptake or at + 4°C for passive uptake. Solutions were then filtered through cellulose nitrate la~ters (0.45 p.m pore size, Millipore) that were washed with 3 ml cold buffer (10 mmoi/L Tris HCI, 150 mmol/L NaCl, i mmol/L EDTA, pH 6.5). Dried filters were deposited in microvials, Picofluor 15 (Packard) was added, and radioactivity was counted in a liquid
n~ ~vc-w~v
Tianeptine-lnduced Increase in 5-HT Platelet Uptake
61 t
scintillator counter (Packard, Prias, Mod61e Tricarb PLDL Duplicate determirations were made for each assay condition. Active 5-HT uptake is d e f i ~ as the difference between total and passive uptake at different 5-HT concentrations° For each ~ t , t ~ rr~aximM velocity (V,,~) and the affinity constant (K,) of 5-HT uptake were expressed as the mean of the values obtained by using two different graphical ~ s : ~ double recip~c~ plot of Lineweaver-Burk and the linear reg!~sion analysis of Eadie-Hofstee plods. V ~ values were expressed in picomoles of 5-HT accumulated per minute ~ per t ~ platelets and K , values were expressed in micromoles per liter. 5-HT Platelet Content. Blood was firstcentrifuged (170 g, t5 min, + 20~C) to obtain P R P in which plateletswere counted. P R P was then centri~ged (1093 g, 20 rain, + 20°C) to obtain a plateletpelletthat was frozen at -70°C untilanalysis.In order to determine its 5-HT content, the pellet was deproteinized with H ~ O 4 7%, ~ the pH was then adjusted to 5.00 with N a O H 5N. After a finalcentfifugation(1093 g, 20 rain, + 4°C), the clear supemat~nt was used for the determination of 5 - ~ concentration by highperformance liquid chromatography {HPLC) with electrochemical detee:,ionat 0.75 V (Flachaire et al 1990). Results were expressed as nanomoles of 5-HT per 109 p|atelets.
Tianeptine Plasma Concentration. Treatment compliance was assessed by determination of plasma tianeptine concentrations. Blood samples were collected in plastic m ~ containing Li heparinate as an anticoagulant o'~ days I, 10, ~ 28 before ~ 2 hr after the tianeptine administration. Blood was centrifuged {900 g, 15 ~ , + 20°C) ~ plasma was frozen at -20~C until analysis. Concentrations of tianeptine and its ~ metabolite (resulting from a [3-oxidation of the lateral chain of the moIecule) were determined by HPLC with UV detection at 220 am (Nicot et al 1986). Resets were expressed as nanograms of tianeptine per milliliter of plasma.
Statistical Analysis Results of different parameters were analyzed using a two-way ~ y s i s of v m ~ e ( ~ subjects) in order to determine a change in the parameters d u n g the c o ~ o f t ~ t r e a ~ n t a n t i ©t~ati©ti~al i~iehlar'¢ t ~ ¢ t ~ ¢ ll~; i n t h e ea.¢~ f~f a gi~ificant dine effect, a NewmanKeuls test was performed. m s . i t
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Results
Clinical Evaluation Thirteen patients were included in this study but o~y 10 completed the 28-day treatment regimen. Three patients dropped out for lack of efficacy or worsening after 12, 16, and 22 days of treatment. Evaluation of clinical improvement of depression and anxiety was quantified by CGI, HARS, and MADRS scores. Results of three items of the CGI have shown that tianeptine induced an effective improvement of depression as early as day 10, with very few undesirable effects. Evolution of HARS ~ MADRS scores are presented in Figure 1 for the 13 patients. A significant decrease of HARS and MADRS scores was observed as early as day 10. This decrease was ~ain~ined between day 10 and day 28 (p < 0.001).
012
6. Chamba et al
BIOL PSYCHIATRY It~l ; 3 0 : ~ 5 1 7
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MADRSSCORES HARSSCORES
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TREATMENT DURATION (DAYS) Figurc 1. Clinical evolution of MADRS and HARS scores during a tianeptine treatment in depressed patients, Results represent values obtained with 13 patients on days 0 and !0 ~ d 6 patients on day 28 (3 patients dropped out after 12, 16, and 22 days of treatment). The selecuon of subjects and treatment modalities are described in Methods, **a = I%, Newman-Keuls test.
5-HT Platelet Uptake
Vm., of 5-HT uptake and 5 - h " platelet content have been evaluated on plasma patients. Figure 2 shows the time course of ¢.,.,, of 5-HT platelet uptake for the 10 patients who completed the study. Vm.~ of 5-HT uptake was found to be increased during the course of the treatment (Table I, time effect, p = 0.01 l). This increase is higher after the first administration ( + 23%, o~ = 1%) than after IO or 28 days of treatment ( + 14% and + 13%, respectively). No change in K,. was observed at any time.
5-HT Platelet Content Surprisingly, no significant change in 5-HT platelet content was found during tianeptine treatment (Table ! ). Even 2 hr after tianeptine admJ,istration, while 5-HT platelet uptake was significantly increased, 5-HT platelet content remains unchanged.
Tianeptine Plasma Levels For each patient, we confirmed that the plasma level of tianep~ine at steady state (8:00 AM) and 2 hr after ti~eptine tablet administration (10:00 AM) was in the normal range for adult treated depressed patients (internal report, 1991).
Tianeptine-lnduced Increase in 5-HT Plate,et Uptake
alOL PSVCt~A~Y
613
<
TRi~ATMENT
DURATi()N
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Figure 2. Time course of V~.~ of 5-HT platelet u ~ e during a f i ~ m e treat~nt m [0 de~essed patients who completed the study. 5-HT uptake determinations have been determined 2 ~ after the first tianeptine administ2ation on day I and just before fia.~pti~ ~ m i n i s t r a t ~ on days [0 and 28. V=~, was found increased during the treatment: time effect p = O.Oi ~. V~,~ is significantly increased after the first tianeptine administration ~+ 23%. a = | % on day t as compared to vMue on day 0L
Discussion The present study was performed to evaluate the effects of a tianeptine t r e a t n ~ m on 5-HT platelet uptake and contem in depressed patients. After tianeptine treatment, M A D R S and H A R S scores showed rapid and significant decreases as soon as day 10, and this improvement continued on day 28. This confirms previous reports o f the rapid clinical activity of fianeptine (O|i~ et al 1988; Souche et ai
1990). Our present biochemical findings demonstrate for the first time that tianeptine significantly increases the uptake of 5-HT by plalclets o f depressed patients after a single administration ( + 23%, cx = | %). This effect appears to be related to an i n c r e ~ in V=~ without any change in Kin, ~ d suggests an increase in the a v ~ a b i l i t y of u ~ e sites.
Table i. Evolution ~,. 5-HT Parameters during a Ti~eptine Treatment in 10 Depressed Patients ~ Variables
N
Day 0
Day !
Day Z0
Day 28
Time Effect
5-HT uptake V,=~
10
26.1 -" 2.7
5-HT uptake K,,,
i0
0.31 __ 0.04
32.1 __ 2.6 ~!23%) 0.37 ___0.03
29.9 ~ 3.5 ~114%) 0.34 _ 0.04
29.6 ± 3.0 {!13%) 0.35 ± 0.04
p = 0.011 (S) c~ = 1% DI * DO p = 0.042
i 19%)
(110%)
(113%)
5-HT platelet content
10
3.41 ± 0.45
3.27 ± 0.46
3.80 ± 0.44
3.95 ± 0.47
~96%)
~111%~
~116%)
q3iochemicai results mteans "" SEMI) of 5-HT plau:~ parameters are expressed as f o l ~ s : V ~ . m o | c s per minute ~ per iOs p|~tele,.s: K=---nticronmk~s per ~ 5-HT p ~ t e ~ c c ~ t e ~ per |0" ~ s .
parentheses me expressed as percentages of the mean vaJues ~
(NS)
p = 0.175 ¢NS) of 5-HT The v~ues mdicamd m
on day 0. ~ 5-HT uptaXe, an inc~se ~ ~-rved dm'ingme
Ueatn~n'. time effect, p = 0.0] l. On day 1, V~,~ is significandy increased: + 23%, a = |%. N ~ K e , a . t s
test.
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G. Chamba et al
BIOL PSYCHIATRY
Table 2. Plasma Tianeptine Concentrations d u ~ n g a Tianeptine Treatment in 10 Depressed Patients~ Day I 8:00 ND
10:00 224.0 "4"23.5
Oay 10 8:~ 28.6 "" 7.9
10:~ 224.0 - 25.9
~Plasma tiancp~iue kveis (expressed as ng/m] _* SEM, n = I0) were d e ~ c m ~ after t~aneptin¢ administration. ND, not detectable.
Day 28 8:00 24.6 -- 7.4 at 8,'00~
10:00 268.0 "" 43.0
before and at I0.~I0.2 ht
Because there are physiological and ph~acological similarities between 5-HT uptake by platelets and uptake by nerve endings in the c e n ~ nervous system (Stahl and Meltzer 1978; Da Prada et al 1988; Pletscher 1988). it is of interest to compare our data with those obtained in the brain. Our results are in agreement with the stimulation of in ~ivo 5-HT uptake fouad in rat brain (from + I0% to + 33% depending on brain regions analyzed) after acute tianepfine administration (Mennini eta[ 1987; Fattaccini et al 1990). This effect has been reported to be specific for 5-HT since the ~ g does not influence dopamine or norepinephrine uptake (Mennini et al 1987). This i n c ~ s e in 5-HT uptake is consistent with previous reports: 5-HIAA levels were increased in various brain regions after acute tianeptine administration in the rat (Fattaccini et al 1990; Ortiz et al 1991). Under the same conditions, an increase in 5-HIAA levels was also observed in plasma (Ortiz et al 1991). Such results confirm data reported in a voitarnrnetric study, showing a significant increase in the extracellular levels of 5-HIAA in rat hippocampus (De Simoni et al 1989). However, this apparently enhanced 5-HT neurotransmission cannot be attributed to an increase in 5-HT release (Mennini et al 1987). This has been confirmed by in vim) studies showing that tianeptine does not stimulate the outflow of 13H]5-HT from cortical slices of rat brain (Hamon et al 1989). These results are consistent with the unchanged firing rate of serotonergic neurons of dorsal raphe nucleus (Dresse and Scuv~-Moreau 1988) following acute tianeptine administration in the rat. Other electrophysiological studies are necessary to determine the acute mechanism of action of the drug. Howe~¢r, the fact that tianeptine acutely induces increases in 5-HT uptake (as well as in 5-HIAA levels) shows that this d~g m ~ e d l y differs from other tricyclic antidepressant drugs, which reduce these pa. rameters in the same conditions (Hamon 1979; Manias and Taylor 1983). ..... v-,,,...Is also shown in t ~ ~-sent study to increase 5-HT pia,,elet uptake afte~ 10 and 28 days of treatment, although this i~rease is of a lesser magnitude than on day I. This result confirms data reported in a preliminary s~ady performed on two depressed patients (Renaud et al 1988). However, the increases in V,,~ observed in the present study are smaller than those observed in the preliminary re oort ( + 14% versus + 65%, respectively). This difference may be explained by changes in the experimental conditions. Our present results have been obtained on 10 depressed patients and 5-HT platelet uptake has been measured for a 30-sec period using a radiometric technique. In the previous study (Renaud et al 1988), 5-HT uptake was determined during a 15-rain period with unlabeled 5-HT concentrations higher than those used to determine high-affinity uptake of 5 - H T . Our present results are also in agreement with data reported for rat platelets (Kato and Weitsch 1988), showing that a repeated tianeptine treatment induces an increase in Vn~ of 5-HT uptake without any change in Kin. Increased rat plasma 5-HIAA levels have been found under similar conditions (Ortiz et al 1991). As in platelets, chronic tianeptine
Tianeptine-lnduced Increase in 5-HT Platelct Uptake
administration enhances V,,~ of 5-HT uptake in rat brain ex vivo but nc~ in vitro (Merm~ni et al 1987). This is compatible with the hypothesis of an increase in 5-HT ~tw.mansmission. Even after chronic administration, tianeptine has an effect on 5 - ~ uptake ~ t e in effect to 5-HT reuptake inhibitor antidepressants. Although the antide~s~,~:t p r ~ e s of tianeptine might therefore appear surprising, it has been suggested that uptake inhibition may not be the explanation for the clinical activity of 5-HT r e u s e blockers: 5-HT uptake is inhibited from the first day of drug administration while at least 2-3 weeks is needed before the therapeutic effect of these antidepressants is manifested ( ~ i ~ i n et 1984; Kato and Weitsch 1988). Furthermore, it is known that, white imipramine a~vd desme~ylimipramine inhibit 5-HT uptake in vitro and after acute ~miniswati~, these compour:ds may enhance 5-HT uptake after chronic admir, is~tion ( B ~ a c c i a ,.~ al 1983). It has been observed that, in some cases, the t~erapeutic improvement might be related to a stimulation of 5-HT uptake rather than to its inhibition (He~y et ~ 1983: W ~ and Coppen 1985). If we take into account this hypothesis, the fact that t i ~ p t i ~ i ~ e s an increase in 5-HT uptake from the beginning of the treatment might explain the ~pid onset of the antidepressant efficacy of this drug (Figure I). However, studies are n e c e s s ~ to evaluate the. functional state of 5-ttT neurons after chronic tianepti~ ~ministration. Indeed, it is of particular interest to note that dectrophysiological studies have recently shown that different antidepressant compounds (monoamine oxidase inhibitors [MAOIs], tricyclic antidepressant ¢hags, and reuptake blockers) lead to an increase in 5 - ~ neurotransmission via different (and sometimes apparently opposite) effects (Blier et al | 987). Although tianeptine increases 5-HT platelet uptake during treatment, the i n c r e ~ observed after the initial administration ( + 23%) is higher than the increases f o u ~ after chronic administration (about + 14%). This result is likely to be due to differences in tianeptine plasma concenwations observed between blood sam#es collected on day I (2 hr after tianeptine administration, 224.0 ± 23.5 ng/ml) and on days 10 and 28 (just before tianeptine administration, i.e., 12 hr after the last administration, 28.6 - 7.9 and 24.6 ± 7.4 ng/ml, respectively). Because the increase in V~,, of 5-HT uptake is seen as soon as 2 hr after the first administration, it is likely that the ~ g acts on 5-HT platelet uptake sites, either directly or via an. action on modulators of 5 - ~ uptake. This hypothesis is consistent with the increase in rat plasma 5-HIAA levels after the first adminis~tion of tianeptine (Ortiz et al 199|). Furthermore, the increase in 5 - ~ platelet u p ~ e was ~t~,~ ,~f~,~,-t p ~-.. O. 0| J~, ~'.tml'eas --.., ~ . .. .. .. . . ,~t . . ..4,,,.i,,,,, . . f:, t h , . o n t ~ , . ~ ~ . , ~ , ~ , , t lmlpl~qll~ ~and desmethylimipramine increase the 5-HT platelet uptake only after the early inhibiting phase (Barbaccia et ai 1983). Surprisingly, the effect of tianeptine on 5-HT uptake did not result in any change i~: 5-HT platelet content. Such a result is in accordance with the data of Mennini et al (1987) and Fattaccini et al (1990), who reported no increase in rat brain 5-HT after tianeptine treatment. Two mechanisms might explain the lack of increase in 5-HT platelet content during the treatment by tianeptine: (I) an increase in 5-HT r e ! e ~ m y occur, although this is not the case in the rat brain (Mennini et al 1987; Hamon et al 1989), or (2) an oxidation of 5-HT by platelet MAO is another possible mechanism consistent wit,q increases in plasma 5-HIAA levels following acute and chronic tianeptine ad~nistration in the rat (Ortiz et al 1991). In summary, the major finding of this study is that tianepfine is distinguished from the other tricyclic antidepressant compounds by its enhancing action on 5-HT platelet uptake. To our knowledge, tianeptine is the only drug reported to increase 5-HT uptake, •
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BIOL PSYCHIATRY 1991; 3 0 : ~ 6 1 7
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both by platelets and s y r i a , from the beginning of its administration. Fdectmphysiological sp~dies on functional state of 5-HT ~ are necessary to verify if therapeutic activity of tiane~ine is, as for the other antidepressants, associated with an enhanced 5-HT neurotransmission. This research has been suppofledby Institutde ~
latematiom/esSesvier(!. R. I. S.).
References Baccino E. Bressollette L. Mottier D, Moce/~rE. Salvadofi C, ~ A (1989): Tianepline: An antidepressant with ~a original action on platelet 5 - ~ uptake in elderly patients, international Symposium on Serotonin: From Cell Biology to lqmrmacology and Therapeutics, Rorence, p90. Barbaccia ML, Gandolfi O, Chuang DM, Costa E (1983): Modulation of neuronal semtonin uptake by a putative endogenous iigand of m ~ n e r e c o g n i ~ sites. Proc Natl Acad Sci USA 80:5 i 34-5 i 38. Blier, De Montigny C, Chaput Y (1987): M o d i f i e s of the serotonin system by antidelaeSSant treatments: Implications for ~ ~ ~ ~ in major ~ . 3 Clin P s y c ~ . macol (Suppl. 24S-35S). Casacchia M, Sconei V, Vespucci G, Bmncato T (1989): Double blind clinical study of fianeptine, a new 5-HT u ~ e e ~ . International S ~ u m on Semtonin: From Cell Biology to Pharmacology and Therapeutics, Florence, p 92. Curzon G (1988): Serotonergic mechanisms of ~ . Clin Nearophammcol i I(suppl 2):S11$20. Da Prada M, Cesura AM, Launay JM, R~hards olG (1988): Platelets as models for txeunms? Experiemia 44:1 ! 5- ! 26. Defrance R, Marey C, Kamoun A (1988): Antidepressant and anxiolytic activities of ~ . An overview of clinical trials. Clin Ne~op&wmacol I I(suppl 2):$74--$82. De Simoni MG, De Luigi A, Manfridi A, Sokola A (1989): Tianeptine enhancement of semtonin uptake: An in vivo v o l ~ t r i c study. IntemationM Symposium on ~ : From Cell Biology to Pharmacology ~-~ Therapeutics, Florence, p 87. Dresse A, Scuv(~*-MoreauJ (1~8): Electrophysiologica]effects of tianeptine on rat locus coendeus, raphe dorsalis and hipgggam~s activity. Clin Neuropharmacol II(suppl 2):$51--$58. [] Mestikawy S, Gozlan H, Me,nard F, Bourgoin S, ~ M (1988): I n ~ ofthe potential antide~sant f i ~ ~ with central serotonin reeeptt~ in the rat brain. Fhqh International Meeting on Clinical ~ o l o g y and Psychiatry, Tromso, p 31. Fa~cihli CM, Boianos-Jimenez F, Gozian H, Hamon M (1990): Tianeptine stimulates uptake of 5-hydrox~ine in vivo in the rat brain. Neuropharmacology 29:1-8. Flachaire E, Beney C, Berthier A, Selandre J, Quincy C, RenaM B (1990): DeternfiPxtion of reference values for ~ o n i n platelet concentrations of healthy new boats, children, adults, and elderly subjects by HPLC with electrochemical detection. C//n Chem 36:2117-2121. Hamon M (1979): Mechanisms of action of antidepressant drugs. In Passouant P, Oswald I (eds), Pharmacology of the States of Alertness. Oxford: Pergamon, pp 117-128. Hamon M, Bou~HoinS, Gozlen H (1989): Effet de la tianeptine sur la liberation de !a [3H]5 HT et sur les divers types de r~cepteurs s&otoninergiques darts ie systi~me nerveux chez le rat. J Psychimr Biol Ther 32-35 (March). Healy D, Carney PA, Leonard BE (1983): Monoamine-related markers of depression: changes following treatment. J Psychiatr Res 17:251-260. Kamal LA, Le Quan-Bui KH, Meyer P (1984): Decreased uptake of 3H-semtonin and endogenous content of serotonin in blood platelets in hypertensive patients. Hypertension 6:568-573. Kato G, Weitsch AF (1988): N ~ h e m i c a i profile of fianeptine, a new antidepressant drug. Clin Neuropharmacol 1l(suppl 2):$43-$50. Labrid C, Moleyre J, Poignant JC, Malen C, Moca~ E, Kamonn A (1988): Structure-activity
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nt~L P S Y ~ A T ~
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relationship of tricyclic antidepressants, wi~ special reference to t i m ' ~ a e . Ch:n Ne, r ~ . nmcol I l(suppl 2):$21-$31. 1,6o H, Deniker P (1988): Position of tianeptine among anfi~x~ssive c~ h e ~ r ~ . . Clin Neuropharmacol ! i (suppl 2):$97-S 102. Manias B, Taylor DA (1983): Inhibition of vitro amine uptake into rat brain a~er m vi~o ~_mmistration of antidepressants. Fur 3 Pharnuzco195:305-~. Mennini T, Moca~r E, Garmtini S ( |987): Tianeptine, a selective e n ~ c e r of ser~onJn u ~ m rat brain. Naun)~n Schmiedebergs Arch Pharn~col 3 3 6 : 4 7 ~ 2 . Moac~r E, ReRori MC. Kamoun A (1988): Phar,p~cological antideptessive effects a~,,d ~anep~i~induced 5-HT uptake increase. Clin Neuropharmaco! I [(supp| 2~:$32-$42. Nicot G, Lachatre G, Gonnet C, Ma|Jon .L Moca~r E ~|986): Ion paired e x t r a , o n ~ high performance liquid chromatographic determination of t i ~ v . e ~ i~ metabot;tes in human plasma, urine and tissues. J Chronmtogr 381:| 15-126. Oli6 JP. Guelfi JD. Malka R. Du|cire C, Kamoun A. L~o H ¢1988): Traite~nts ~ |ongue G~6e par les antid(:presseurs. La tianeptine: M~Lhodo!ogie d'une ~tude au Iong cours et ~suI~ts pr~liminaires. L'Enc~phale 14:79-84. Ortiz J. Moca~r E. Artigas F (199i): Effects of r&c antideprcss~t d~g tia~pti~ on plasma and p|atelet semtonin in the rat. Eur J Pharmaco/. in press. Pletscher A (1988): Platelets as models: Use and [imitations. Experien~ ~ : | 5 2 - 1 5 4 . Poignant JC (1981): Etude pharmacologique d'un nouve| ~ti~presseur: [a f i ~ i n e , in Pert'is C. Struwe G, Jansson B {eds), Biological P~chiato'. Amsterdam: Elsevier. pp 573-578. Quiikin FM. r,-mun n_u.-_ Ju, .,- Ros D, McGrath Pl (!984): D~ation of anti~pressant drug treatment. Arch Gen P~'chiato" 41:238--245. Renaud B, Moca6r E. Weitsch AF, Kato G. Mennini T, Garattini S ( 1988): Stimulation of ~ o n i n uptake induced by a new antidepressant. Proceedings of ~he ECNP Constituent Meeting. Brussels, Pharmacops)'chiato" 2 ! :66. Royer RJ, Albin H, Barrucand D, Sadvadori-FailIer C. Kamoun A ( 1988): Semtonergic mechanisms of depression. Clin Neuropharmacol ! i (suppI 2):S I-S !O. Souche A. Duclaud L, Zekfi JR. et al (1990): Patients ~ t ~ s un an par |a tiane~ine. Presentation des r~suRats obtenus par i'un des Centres du Sud-Est de la France. L'Enc~pha!e | 6 ]81-187. Stahl SM. Meitzer HY (1978): A .~netic and pharamacolog~c analysis of 5 h y d r o x ~ i n e transport by human platelets and platelet storage ~ u l e s : Comparison with central serotonergic neurons. J Pharmacol Exp Ther 205:i 18-132. Wood K. Coppen A (1985): Platelet transport and receptor sites in depressive illness. In Meltzer HY (ed), P~'chopharmacolo~': Recent Advances a~M Future Prospects. New York: Raven. pp 21-32.
609
Increased Serotonin Platelet Uptake after Tianepfine Administration in Depressed Patients, Genevi/~ve Chamba, Patrick Lemoine, Elisabeth Hacnaire, Nicole Ferry, Claude Quincy, Jean Sassard, C h ~ t ~ Fer~r, Elisabeth Moca/~r, Annie Kamoun, and Bemard Renaad
Tianeptine is a new antidepressant drug reported to enhance serotonin (5-hydro~'t~'ptamine [5-HTD uptake in rat brain. The effect of tianeptine on 5-HT plate&t uptake was studied in i0 depressed patients treated for 28 days. Tianeptine increases V ~ of 5-HT platelet uptake during treatment without inducing any change in K~. As early as 2 hr after the frst administration. V,,,~ increased significantly ( + 23%, a = 0.01L Although of a lesser magnitude. 5-HT platelet uptake remains increased af'ter chronic administration (+ 14% on day 10 and + 13% on day 28). This suggests t ~ t tianeptine affects 5-HT platelet uptake sites, either directly or via an action on modulators of 5-HT uptake. These results, in contrast with the action of other tric3.'clic antidepressants, confirm the original action of tianeptine on 5-HT platelet metabolism.
Introduction Tianeptine {[(chloro-3 methyl-6 dioxo-5,5 dihydro-6. II dibenzo [c,q ti~epine-1,2 yll I) aminol-7 heptanoic acid, sodium salt, Stablon ~} is a new tricyclicagent with a_nfidepressant properties in animal models (Labrid et ~ 1988; Moca6r ct ~ 1988)and in humans (Dcfrance et al 1988; L6o and Deniker 1988; Oli6 et al 1988; Casacchia et al i989). Although fianeptine has a pharmacological profile that includes various c ~ c teristicsof an antidepressant drug (Poignant 1981), its neurochc~cal properties differ c ~ , fianeptine from those of the other tricyclicantidepressants (such as imipramine). m "-u'--" does not inhibit the reuptake of serotonin (5-hydroxytrypt~ine [5-HTD or norepinephrine in the central nervous system (Mennini et al 1987; Kato and Weitsch 1988). In contrast, it has been reported to increase 5-HT uptake in rat brain (Mennini et al 1987; Fattaccini et al 1990) and m rat platelets (Kato and Weitsch !988). Furthermore, in rats, tianeptine induces an increase in plasma (Ortiz et al 1991) and brain (Fattaccini et al 1990) 5hydroxyindolacetic acid (5-HIAA) levels. These results are in agreement with previous
From the Laboratoirede Ncuropharmacologie, Universi0bClaude Bernard et CNRS UMR 105, Fa~lt~ de ~ i c . Lyon. France (GC, BRL Unitd Clinique de Psychiaa'icBiologiquc, H6pitald~ V ~ c r , Bran, France (PL. CF), Service de Biologic, H6pital Ncurologiq~c, Lyon, France (EF, CQ, BR), ~ m e n t de Physio/ogiect ~ o l o g i e Clinique. Univcrsil~Oaude Bernard c t CNRS URA 606. F~'~I~ de Phammcic. Lyon. France (NF. JS). and the Institut de R~hetchcs Intemafionales Servier. Neuilly sur Seine. France {EM, AK). Address rcprimrequeststo Genevieve Clmmba, Ph.D., Laboratoirede N c ~ l o g i ¢ . Univcrsit~Cla~de Bcma~, Facultt de Phatmacie. 8 Avenue Rockefeller,69373 Lyon Ccdex 08, France. Received December l. 1990; revised April 20, 1991. © 1991 Sociely of Biological Psychiatry
(X}06-3223/91/$03.50
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voltammetric data reporting that tianeptine emianees the extracellular levels of 5-HIAA in the rat hippocampus (De Simoni et al 1989). Tianeptine has no affinity for 5-HTI or 5-HT2 cerebral receptors (El Mestikawy et al 1988; Hamon et al 1989) and has no effect in vivo or ex vivo on 3H-imipramine binding (Kato and Weitsch 1988). Nevertheless, the above data support a serotonergic component in the meehanism of action of tianeptine. In humans, only a preliminary study has reported an increase in 5-HT platelet uptake in two depressed patients after tianeptine treatment (Renaud et al 1988). Furthermore, such an increase has been foun,' in elderly patients after a single tianeptine administration (Baccino et al 1989). Our study was performed to evaluate 5-HT platelet uptake in depressed patients receiving tiat~ptine. Serotonin platelet uptake and 5-HT platelet content were determined at different times (days 0, 1, 10, and 28) during a 28-day treatment. Methods
Patietzts and Treatment The protocol was approved by an Ethics Committee (Comit6 d'Ethique de l'Universit6 C. Bernard et des Hospices Civils) and all the patients gave informed consent according to current legal regulations. Th~een inpatients (i ! women, 2 men, 18-69 years old) with major depression or dysthymic dis~raers according to DSM-m criteria (categories 296.22, 296.2, 300.40) were included in the study. All scored at least 20 points on the Montgomery and Asberg Depression Rating Scale (MADRS). One month before the beginning of the study, other ~ i c a t i o n s (antidepressants, neuroleptics, antiplatelet ~ags, nonsteroidial anti-in~ammatory drugs, and salicylate compounds) were stopped; only benzodiazepines were authorized during the treatment. Depressed patients received three tablets of Stablon per day (12.5 mg tianeptine per tablet, at 8:00 AM, 12:00 noon, and 8 : ~ PM) for 28 days. The criteria of assessment of efficacy were scored on days 0, 10, and 28 on Clinical Global Investigation (CGI), MADRS, and Hamilton Anxiety Rating Scale (HARS).
Biochemical Determinations Blood Samples Collection. Blood samples were collected by venopuncture into plastic tubes containing 12 mg sodium EDTA as anticoagulant. Samples collected on day 0 (before treatment), on day l (2 hr after the first tianeptine administration), and on days i0 and 28 (just before, the morning administration)were kept at room temperature and the biochemical determinations started within 2 hr following the puncture. 5-HT Platelet Uptake. 5-HT platelet uptake was determined by a modification of the radiometric method of Kamal et al (1984). Blood was centrifuged (170 g, 15 rain, + 20°C) to obtain platelet-rich plasma (PRP). After 5 min at + 37°C, an aliquot of PRP, containing a defined n~.,nber of platelets (measured in HYCEL HPC 52 platelets counter), was incubated for 30 sec with seven (0. l, 0.2, 0.5, 0.75, 1.0, 1.5, and 2 p,mol/L) concentrations of [3HI5-HT (Amersham France, 550 GBq/mmol), at + 37°C for total uptake or at + 4°C for passive uptake. Solutions were then filtered through cellulose nitrate la~ters (0.45 p.m pore size, Millipore) that were washed with 3 ml cold buffer (10 mmoi/L Tris HCI, 150 mmol/L NaCl, i mmol/L EDTA, pH 6.5). Dried filters were deposited in microvials, Picofluor 15 (Packard) was added, and radioactivity was counted in a liquid
n~ ~vc-w~v
Tianeptine-lnduced Increase in 5-HT Platelet Uptake
61 t
scintillator counter (Packard, Prias, Mod61e Tricarb PLDL Duplicate determirations were made for each assay condition. Active 5-HT uptake is d e f i ~ as the difference between total and passive uptake at different 5-HT concentrations° For each ~ t , t ~ rr~aximM velocity (V,,~) and the affinity constant (K,) of 5-HT uptake were expressed as the mean of the values obtained by using two different graphical ~ s : ~ double recip~c~ plot of Lineweaver-Burk and the linear reg!~sion analysis of Eadie-Hofstee plods. V ~ values were expressed in picomoles of 5-HT accumulated per minute ~ per t ~ platelets and K , values were expressed in micromoles per liter. 5-HT Platelet Content. Blood was firstcentrifuged (170 g, t5 min, + 20~C) to obtain P R P in which plateletswere counted. P R P was then centri~ged (1093 g, 20 rain, + 20°C) to obtain a plateletpelletthat was frozen at -70°C untilanalysis.In order to determine its 5-HT content, the pellet was deproteinized with H ~ O 4 7%, ~ the pH was then adjusted to 5.00 with N a O H 5N. After a finalcentfifugation(1093 g, 20 rain, + 4°C), the clear supemat~nt was used for the determination of 5 - ~ concentration by highperformance liquid chromatography {HPLC) with electrochemical detee:,ionat 0.75 V (Flachaire et al 1990). Results were expressed as nanomoles of 5-HT per 109 p|atelets.
Tianeptine Plasma Concentration. Treatment compliance was assessed by determination of plasma tianeptine concentrations. Blood samples were collected in plastic m ~ containing Li heparinate as an anticoagulant o'~ days I, 10, ~ 28 before ~ 2 hr after the tianeptine administration. Blood was centrifuged {900 g, 15 ~ , + 20°C) ~ plasma was frozen at -20~C until analysis. Concentrations of tianeptine and its ~ metabolite (resulting from a [3-oxidation of the lateral chain of the moIecule) were determined by HPLC with UV detection at 220 am (Nicot et al 1986). Resets were expressed as nanograms of tianeptine per milliliter of plasma.
Statistical Analysis Results of different parameters were analyzed using a two-way ~ y s i s of v m ~ e ( ~ subjects) in order to determine a change in the parameters d u n g the c o ~ o f t ~ t r e a ~ n t a n t i ©t~ati©ti~al i~iehlar'¢ t ~ ¢ t ~ ¢ ll~; i n t h e ea.¢~ f~f a gi~ificant dine effect, a NewmanKeuls test was performed. m s . i t
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Results
Clinical Evaluation Thirteen patients were included in this study but o~y 10 completed the 28-day treatment regimen. Three patients dropped out for lack of efficacy or worsening after 12, 16, and 22 days of treatment. Evaluation of clinical improvement of depression and anxiety was quantified by CGI, HARS, and MADRS scores. Results of three items of the CGI have shown that tianeptine induced an effective improvement of depression as early as day 10, with very few undesirable effects. Evolution of HARS ~ MADRS scores are presented in Figure 1 for the 13 patients. A significant decrease of HARS and MADRS scores was observed as early as day 10. This decrease was ~ain~ined between day 10 and day 28 (p < 0.001).
012
6. Chamba et al
BIOL PSYCHIATRY It~l ; 3 0 : ~ 5 1 7
r~
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i
r7 r'l
O
mn
MADRSSCORES HARSSCORES
t
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TREATMENT DURATION (DAYS) Figurc 1. Clinical evolution of MADRS and HARS scores during a tianeptine treatment in depressed patients, Results represent values obtained with 13 patients on days 0 and !0 ~ d 6 patients on day 28 (3 patients dropped out after 12, 16, and 22 days of treatment). The selecuon of subjects and treatment modalities are described in Methods, **a = I%, Newman-Keuls test.
5-HT Platelet Uptake
Vm., of 5-HT uptake and 5 - h " platelet content have been evaluated on plasma patients. Figure 2 shows the time course of ¢.,.,, of 5-HT platelet uptake for the 10 patients who completed the study. Vm.~ of 5-HT uptake was found to be increased during the course of the treatment (Table I, time effect, p = 0.01 l). This increase is higher after the first administration ( + 23%, o~ = 1%) than after IO or 28 days of treatment ( + 14% and + 13%, respectively). No change in K,. was observed at any time.
5-HT Platelet Content Surprisingly, no significant change in 5-HT platelet content was found during tianeptine treatment (Table ! ). Even 2 hr after tianeptine admJ,istration, while 5-HT platelet uptake was significantly increased, 5-HT platelet content remains unchanged.
Tianeptine Plasma Levels For each patient, we confirmed that the plasma level of tianep~ine at steady state (8:00 AM) and 2 hr after ti~eptine tablet administration (10:00 AM) was in the normal range for adult treated depressed patients (internal report, 1991).
Tianeptine-lnduced Increase in 5-HT Plate,et Uptake
alOL PSVCt~A~Y
613
<
TRi~ATMENT
DURATi()N
~DAYS}
Figure 2. Time course of V~.~ of 5-HT platelet u ~ e during a f i ~ m e treat~nt m [0 de~essed patients who completed the study. 5-HT uptake determinations have been determined 2 ~ after the first tianeptine administ2ation on day I and just before fia.~pti~ ~ m i n i s t r a t ~ on days [0 and 28. V=~, was found increased during the treatment: time effect p = O.Oi ~. V~,~ is significantly increased after the first tianeptine administration ~+ 23%. a = | % on day t as compared to vMue on day 0L
Discussion The present study was performed to evaluate the effects of a tianeptine t r e a t n ~ m on 5-HT platelet uptake and contem in depressed patients. After tianeptine treatment, M A D R S and H A R S scores showed rapid and significant decreases as soon as day 10, and this improvement continued on day 28. This confirms previous reports o f the rapid clinical activity of fianeptine (O|i~ et al 1988; Souche et ai
1990). Our present biochemical findings demonstrate for the first time that tianeptine significantly increases the uptake of 5-HT by plalclets o f depressed patients after a single administration ( + 23%, cx = | %). This effect appears to be related to an i n c r e ~ in V=~ without any change in Kin, ~ d suggests an increase in the a v ~ a b i l i t y of u ~ e sites.
Table i. Evolution ~,. 5-HT Parameters during a Ti~eptine Treatment in 10 Depressed Patients ~ Variables
N
Day 0
Day !
Day Z0
Day 28
Time Effect
5-HT uptake V,=~
10
26.1 -" 2.7
5-HT uptake K,,,
i0
0.31 __ 0.04
32.1 __ 2.6 ~!23%) 0.37 ___0.03
29.9 ~ 3.5 ~114%) 0.34 _ 0.04
29.6 ± 3.0 {!13%) 0.35 ± 0.04
p = 0.011 (S) c~ = 1% DI * DO p = 0.042
i 19%)
(110%)
(113%)
5-HT platelet content
10
3.41 ± 0.45
3.27 ± 0.46
3.80 ± 0.44
3.95 ± 0.47
~96%)
~111%~
~116%)
q3iochemicai results mteans "" SEMI) of 5-HT plau:~ parameters are expressed as f o l ~ s : V ~ . m o | c s per minute ~ per iOs p|~tele,.s: K=---nticronmk~s per ~ 5-HT p ~ t e ~ c c ~ t e ~ per |0" ~ s .
parentheses me expressed as percentages of the mean vaJues ~
(NS)
p = 0.175 ¢NS) of 5-HT The v~ues mdicamd m
on day 0. ~ 5-HT uptaXe, an inc~se ~ ~-rved dm'ingme
Ueatn~n'. time effect, p = 0.0] l. On day 1, V~,~ is significandy increased: + 23%, a = |%. N ~ K e , a . t s
test.
614
G. Chamba et al
BIOL PSYCHIATRY
Table 2. Plasma Tianeptine Concentrations d u ~ n g a Tianeptine Treatment in 10 Depressed Patients~ Day I 8:00 ND
10:00 224.0 "4"23.5
Oay 10 8:~ 28.6 "" 7.9
10:~ 224.0 - 25.9
~Plasma tiancp~iue kveis (expressed as ng/m] _* SEM, n = I0) were d e ~ c m ~ after t~aneptin¢ administration. ND, not detectable.
Day 28 8:00 24.6 -- 7.4 at 8,'00~
10:00 268.0 "" 43.0
before and at I0.~I0.2 ht
Because there are physiological and ph~acological similarities between 5-HT uptake by platelets and uptake by nerve endings in the c e n ~ nervous system (Stahl and Meltzer 1978; Da Prada et al 1988; Pletscher 1988). it is of interest to compare our data with those obtained in the brain. Our results are in agreement with the stimulation of in ~ivo 5-HT uptake fouad in rat brain (from + I0% to + 33% depending on brain regions analyzed) after acute tianepfine administration (Mennini eta[ 1987; Fattaccini et al 1990). This effect has been reported to be specific for 5-HT since the ~ g does not influence dopamine or norepinephrine uptake (Mennini et al 1987). This i n c ~ s e in 5-HT uptake is consistent with previous reports: 5-HIAA levels were increased in various brain regions after acute tianeptine administration in the rat (Fattaccini et al 1990; Ortiz et al 1991). Under the same conditions, an increase in 5-HIAA levels was also observed in plasma (Ortiz et al 1991). Such results confirm data reported in a voitarnrnetric study, showing a significant increase in the extracellular levels of 5-HIAA in rat hippocampus (De Simoni et al 1989). However, this apparently enhanced 5-HT neurotransmission cannot be attributed to an increase in 5-HT release (Mennini et al 1987). This has been confirmed by in vim) studies showing that tianeptine does not stimulate the outflow of 13H]5-HT from cortical slices of rat brain (Hamon et al 1989). These results are consistent with the unchanged firing rate of serotonergic neurons of dorsal raphe nucleus (Dresse and Scuv~-Moreau 1988) following acute tianeptine administration in the rat. Other electrophysiological studies are necessary to determine the acute mechanism of action of the drug. Howe~¢r, the fact that tianeptine acutely induces increases in 5-HT uptake (as well as in 5-HIAA levels) shows that this d~g m ~ e d l y differs from other tricyclic antidepressant drugs, which reduce these pa. rameters in the same conditions (Hamon 1979; Manias and Taylor 1983). ..... v-,,,...Is also shown in t ~ ~-sent study to increase 5-HT pia,,elet uptake afte~ 10 and 28 days of treatment, although this i~rease is of a lesser magnitude than on day I. This result confirms data reported in a preliminary s~ady performed on two depressed patients (Renaud et al 1988). However, the increases in V,,~ observed in the present study are smaller than those observed in the preliminary re oort ( + 14% versus + 65%, respectively). This difference may be explained by changes in the experimental conditions. Our present results have been obtained on 10 depressed patients and 5-HT platelet uptake has been measured for a 30-sec period using a radiometric technique. In the previous study (Renaud et al 1988), 5-HT uptake was determined during a 15-rain period with unlabeled 5-HT concentrations higher than those used to determine high-affinity uptake of 5 - H T . Our present results are also in agreement with data reported for rat platelets (Kato and Weitsch 1988), showing that a repeated tianeptine treatment induces an increase in Vn~ of 5-HT uptake without any change in Kin. Increased rat plasma 5-HIAA levels have been found under similar conditions (Ortiz et al 1991). As in platelets, chronic tianeptine
Tianeptine-lnduced Increase in 5-HT Platelct Uptake
administration enhances V,,~ of 5-HT uptake in rat brain ex vivo but nc~ in vitro (Merm~ni et al 1987). This is compatible with the hypothesis of an increase in 5-HT ~tw.mansmission. Even after chronic administration, tianeptine has an effect on 5 - ~ uptake ~ t e in effect to 5-HT reuptake inhibitor antidepressants. Although the antide~s~,~:t p r ~ e s of tianeptine might therefore appear surprising, it has been suggested that uptake inhibition may not be the explanation for the clinical activity of 5-HT r e u s e blockers: 5-HT uptake is inhibited from the first day of drug administration while at least 2-3 weeks is needed before the therapeutic effect of these antidepressants is manifested ( ~ i ~ i n et 1984; Kato and Weitsch 1988). Furthermore, it is known that, white imipramine a~vd desme~ylimipramine inhibit 5-HT uptake in vitro and after acute ~miniswati~, these compour:ds may enhance 5-HT uptake after chronic admir, is~tion ( B ~ a c c i a ,.~ al 1983). It has been observed that, in some cases, the t~erapeutic improvement might be related to a stimulation of 5-HT uptake rather than to its inhibition (He~y et ~ 1983: W ~ and Coppen 1985). If we take into account this hypothesis, the fact that t i ~ p t i ~ i ~ e s an increase in 5-HT uptake from the beginning of the treatment might explain the ~pid onset of the antidepressant efficacy of this drug (Figure I). However, studies are n e c e s s ~ to evaluate the. functional state of 5-ttT neurons after chronic tianepti~ ~ministration. Indeed, it is of particular interest to note that dectrophysiological studies have recently shown that different antidepressant compounds (monoamine oxidase inhibitors [MAOIs], tricyclic antidepressant ¢hags, and reuptake blockers) lead to an increase in 5 - ~ neurotransmission via different (and sometimes apparently opposite) effects (Blier et al | 987). Although tianeptine increases 5-HT platelet uptake during treatment, the i n c r e ~ observed after the initial administration ( + 23%) is higher than the increases f o u ~ after chronic administration (about + 14%). This result is likely to be due to differences in tianeptine plasma concenwations observed between blood sam#es collected on day I (2 hr after tianeptine administration, 224.0 ± 23.5 ng/ml) and on days 10 and 28 (just before tianeptine administration, i.e., 12 hr after the last administration, 28.6 - 7.9 and 24.6 ± 7.4 ng/ml, respectively). Because the increase in V~,, of 5-HT uptake is seen as soon as 2 hr after the first administration, it is likely that the ~ g acts on 5-HT platelet uptake sites, either directly or via an. action on modulators of 5 - ~ uptake. This hypothesis is consistent with the increase in rat plasma 5-HIAA levels after the first adminis~tion of tianeptine (Ortiz et al 199|). Furthermore, the increase in 5 - ~ platelet u p ~ e was ~t~,~ ,~f~,~,-t p ~-.. O. 0| J~, ~'.tml'eas --.., ~ . .. .. .. . . ,~t . . ..4,,,.i,,,,, . . f:, t h , . o n t ~ , . ~ ~ . , ~ , ~ , , t lmlpl~qll~ ~and desmethylimipramine increase the 5-HT platelet uptake only after the early inhibiting phase (Barbaccia et ai 1983). Surprisingly, the effect of tianeptine on 5-HT uptake did not result in any change i~: 5-HT platelet content. Such a result is in accordance with the data of Mennini et al (1987) and Fattaccini et al (1990), who reported no increase in rat brain 5-HT after tianeptine treatment. Two mechanisms might explain the lack of increase in 5-HT platelet content during the treatment by tianeptine: (I) an increase in 5-HT r e ! e ~ m y occur, although this is not the case in the rat brain (Mennini et al 1987; Hamon et al 1989), or (2) an oxidation of 5-HT by platelet MAO is another possible mechanism consistent wit,q increases in plasma 5-HIAA levels following acute and chronic tianeptine ad~nistration in the rat (Ortiz et al 1991). In summary, the major finding of this study is that tianepfine is distinguished from the other tricyclic antidepressant compounds by its enhancing action on 5-HT platelet uptake. To our knowledge, tianeptine is the only drug reported to increase 5-HT uptake, •
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~. . . . . . . . . . .
•
•
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BIOL PSYCHIATRY 1991; 3 0 : ~ 6 1 7
G. C h a n ~ et al
both by platelets and s y r i a , from the beginning of its administration. Fdectmphysiological sp~dies on functional state of 5-HT ~ are necessary to verify if therapeutic activity of tiane~ine is, as for the other antidepressants, associated with an enhanced 5-HT neurotransmission. This research has been suppofledby Institutde ~
latematiom/esSesvier(!. R. I. S.).
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