tianeptine combination for partial or non-response to selective serotonin re-uptake inhibitor...

Regular Article

Tianeptine combination for partial or non-response toselective serotonin re-uptake inhibitor monotherapyYoung Sup Woo, MD,1 Won-Myong Bahk, MD,1* Jong-Hyun Jeong, MD,2

Seung-Hwan Lee, MD,4 Hyeung-Mo Sung, MD,5 Chi-Un Pae, MD,3 Bon-Hoon Koo, MD6

and Won Kim, MD4

1Department of Psychiatry, Yeouido St Mary’s Hospital, 2Department of Psychiatry, St Vincent’s Hospital, 3Department ofPsychiatry, Bucheon St Mary’s Hospital, The Catholic University of Korea, 4Department of Neuropsychiatry, College ofMedicine, Inje University, Seoul, 5Department of Psychiatry, Pochon Cha University, Gumi and 6Department of Psychiatry,College of Medicine, Yeungnam University, Daegu, Korea

Aims: The goal of this study was to assess the efficacyand tolerability of tianeptine in combination withselective serotonin re-uptake inhibitor (SSRI) inpartial responders or non-responders to SSRImonotherapy.

Methods: In this prospective, open-label, 6-weekstudy, 150 patients with major depressive disorderwho had previously not responded or partiallyresponded to SSRI monotherapy were recruited.Tianeptine was given in combination with an SSRIfor 6 weeks.

Results: Significant improvements were observed inthe mean scores of the Hamilton Depression RatingScale (HDRS), Montgomery–Åsberg DepressionRating Scale (MADRS), and Clinical GlobalImpression–Severity (CGI-S). The change in the

mean HDRS, MADRS, and CGI-S scores was signifi-cant from week 1. The response rates were 64.7%(HDRS) and 68.7% (MADRS), and the remissionrates were 34.0% (HDRS) and 42.0% (MADRS) atweek 6. Thirty-six patients (24.0%) reported adverseevents that were determined by the investigator to berelated to one of the study drugs. The tianeptine andSSRI combination was generally well-tolerated.

Conclusions: A combination strategy with tianeptinemay be an effective and well-tolerated tool forpatients who have failed to adequately respond toSSRI monotherapy.

Key words: combination, major depressive disorder,tianeptine, treatment resistance.

DESPITE THE ADVANCES in pharmacologicagents used for the treatment of depression in

the last several decades, a large percentage of patientswith major depressive disorder (MDD) fail torespond to treatment with antidepressants. It is esti-mated that approximately 50% of the patients whoreceive first-time treatment for MDD respondadequately to antidepressants, and as many as 30%

of those treated for MDD do not benefit from a seriesof treatment trials.1,2 In the Sequenced TreatmentAlternatives to Relieve Depression (STAR*D) study,the relative efficacy and tolerability of various treat-ments for adult outpatients with non-psychotic MDDwas evaluated, and only 28–33% of patients achievedremission to open-label monotherapy with citalo-pram.3 Moreover, remission should be the goal oftreatment because failure to achieve remission isassociated with greater relapse rate, poorer functionaloutcome, and a worsening of long-term prognosis.Full and persistent remission, however, is uncom-mon in acute depression trials.4 In managing partialor non-response to antidepressant treatment, variousalternatives have been proposed,5–7 such as optimiza-

*Correspondence: Won-Myong, Bahk, MD, Department of Psychiatry,Yeouido St Mary’s Hospital, College of Medicine, The CatholicUniversity of Korea, 62 Yeouido-Dong, Youngdeungpo-Gu, Seoul150-713, Korea. Email: [email protected] 27 January 2012; revised 26 April 2012; accepted 30 May2012.

Psychiatry and Clinical Neurosciences 2013; 67: 219–227 doi:10.1111/pcn.12042

219© 2013 The AuthorsPsychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology

tion of the posologic regimen, switching of the anti-depressant or the addition of a new drug, which maybe another antidepressant or a medication belongingto a different class, such as lithium, buspirone,pindolol, or thyroid hormone.

Despite these data, there is no consensus on thetreatment of treatment-resistant depression (TRD).8

Hence, the choice of one or another of these alterna-tives depends on anecdotal experience and clinicianknowledge.9,10 Although the number of publishedstudies that have focused on combination treatmenthas increased markedly, the efficacy of combinationtreatment has not been established based on con-trolled trials.11,12

Tianeptine is an antidepressant in clinical use thathas drawn much attention because the effects of thiscompound argue against traditional monoaminergichypotheses of depression. Tianeptine enhances thesynaptic uptake of serotonin with minimal effects onnorepinephrine and dopamine uptake.13,14 Tianept-ine monotherapy has antidepressant and anxiolyticactivities and good tolerability.15–17 The involvementof glutamate in the mechanism of action of tianept-ine is consistent with a well-developed pre-clinicalliterature demonstrating the key role of glutamate inthe altered neuroplasticity that underlies the symp-toms of depression.18 But there have been no reportsfocusing on the combination of tianeptine with selec-tive serotonin re-uptake inhibitors (SSRI). Therefore,the aim of the present study was to assess the efficacyand tolerability of tianeptine as a combination strat-egy in patients who had not responded or partiallyresponded to treatment with SSRI over a 6-weekperiod.

METHODS

Study design

This was an open-label, prospective, multicenter,6-week study that included 150 patients diagnosedwith MDD according to DSM-IV-TR criteria who didnot respond or partially responded to SSRI mono-therapy. The study was conducted at 11 centers inKorea. Partial or non-response was defined as adecrease in the score on the 17-item HamiltonDepression Rating Scale (HDRS) to <50% over aperiod of 6 weeks of treatment, according to the cri-teria of Hirschfeld et al.7 Study participants were maleand female patients �20 and �65 years of age. Atbaseline, all patients were required to have a HDRS

total score �14 and had to be prescribed a SSRI andcompliant with the prescription at a dose recom-mended for the treatment of depression. Among theexclusion criteria were pregnancy or lactation, amedical condition that could interfere with everydaylife activities, and psychotic symptoms or a previousdiagnosis of bipolar disorder, schizophrenia, or otherpsychotic disorder. Other reasons for study exclusionincluded the following: current primary DSM-IV TRAxis I diagnosis other than MDD; lack of responseduring the current or a past episode of depression totwo or more antidepressant medications at clinicallyappropriate doses for a minimum of 6 weeks; andserious suicidal risk. All patients gave informedconsent before participation in the study.

Medication

The dose of tianeptine as an adjunct treatment wasrecommended at 25–37.5 mg/day. This recom-mended dose was determined by the package insert.19

During the study period, the initial SSRI dose waskept constant. Patients were not allowed to take otherantidepressants, mood stabilizers, or antipsychoticsduring the study. Benzodiazepines and hypnoticswere permitted at the discretion of the investigator.

Efficacy and safety assessments

Evaluation of antidepressant efficacy was carried outwith the HDRS, Montgomery–Åsberg DepressionRating Scale (MADRS), and the Clinical GlobalImpressions–Severity Scale (CGI-S) in weeks 1, 2, 4,and 6. Before beginning the treatment with tianept-ine (baseline visit, week 0), the HDRS and CGI-Swere applied. The primary efficacy assessment wasdefined as mean change from baseline to week 6 onthe HDRS total score. Additional efficacy measuresincluded response and remission rates, and the meanchange in MADRS and CGI-S scores. Response wasdefined as a decrease in the HDRS or MADRS totalscore �50%. Remission was defined as absoluteHDRS score �7 or absolute MADRS score <10. Inan analysis of the adverse events, only treatment-emergent signs and symptoms were considered.

Statistical analysis

Data were analyzed on an intent-to-treat (ITT) group,and the last-observation-carried-forward (LOCF)method was applied for endpoint analysis. The data

220 Y. S. Woo et al. Psychiatry and Clinical Neurosciences 2013; 67: 219–227

© 2013 The AuthorsPsychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology

included all patients who provided a baseline and atleast one post-baseline data measurement. Allpatients who received at least one dose of the studymedication were included in the safety analysis.Quantitative data are expressed as mean � SD, andcategorical variables are described as absolute andrelative frequencies. For analysis of quantitative vari-ables, Student’s t-test was used. For analysis of cat-egorical variables, the chi-squared test was used.

For subgroup analysis, the patients were catego-rized based on the mean daily dose of tianeptine asfollows: low (<37.5 mg/day) and high (�37.5 mg/day). A subgroup analysis using repeated measures ofanalysis of covariance (RM-ANCOVA) with meandaily dose groups as a between-subject factor andtime as a within-subject factor was performed todetermine whether or not there was an interactionbetween the mean daily doses of tianeptine in pre-dicting the response. RM-ANCOVA was conductedwith baseline measures, and other baseline variablesthat had significant difference between high- andlow-dose groups were entered as covariates. Tofurther determine whether or not there was an inter-action between the mean daily dose groups and otherbaseline variables that showed significant differencebetween the high- and low-dose groups, we also per-formed logistic regression using these variables as

predictors and response and remission as dependentvariables. To compare the risk of adverse eventsbetween the mean daily dose groups, chi-squaredtests were performed. The statistical significance cri-terion was set at P < 0.05. All statistical tests weretwo-tailed with a significance level of 0.05.

Ethics

The study was conducted according to the Declara-tion of Helsinki and Good Clinical Practices. Writteninformed consent was obtained from all subjects afterthe subjects were given an extensive explanation ofthe nature and procedures of the study. The studyprotocol was approved by the Institutional Review orEthics Committees at each study site.

RESULTS

Patients and medications

The subject demographic and clinical characteristicsare listed in Table 1. The initial mean dose of tianep-tine was 26.2 � 5.7 mg/day, and the mean doseof tianeptine during the study period was29.7 � 7.7 mg/day. Nearly one-half of the patients(49.3%; n = 74) were treated with escitalopram and

Table 1. Baseline demographic and clinical characteristics

Total patients(n = 150)

Low-dose group†

(n = 110)High-dose group†

(n = 40)

PMean (n) SD (%) Mean (n) SD (%) Mean (n) SD (%)

Age 46.8 15.0 45.8 15.5 49.4 13.2 0.198Gender Male 57 38.0 35 31.8 22 55.0 0.010**

Female 93 62.0 75 68.2 18 45.0Baseline HDRS score 22.4 5.1 22.2 5.3 23.0 4.7 0.411Baseline MADRS score 27.1 7.3 26.3 7.3 29.5 6.5 0.015**Baseline CGI-S 4.6 0.8 4.5 0.8 4.6 0.8 0.514Combined SSRI ESC 74 49.3 52 47.3 22 55.0 0.063

FLO 9 6.0 6 5.5 3 7.5PRX 63 42.0 51 46.4 12 30.0SET 4 2.7 1 0.9 3 7.5

Baseline concomitantmedication

BDZ 80 53.3 61 55.5 19 47.5 0.388HYP 22 14.7 12 10.9 10 25.0 0.031**

**P < 0.05. †Mean daily dose of tianeptine: low-dose group, <37.5 mg/day; high-dose group, �37.5 mg/day. BDZ,benzodiazepine; CGI-S, Clinical Global Impression–Severity; ESC, escitalopram; FLO, fluoxetine; HDRS, HamiltonDepression Rating Scale; HYP, hypnotics; MADRS, Montgomery–Åsberg Depression Rating Scale; PRX, paroxetine;SET, sertraline; SSRI, selective serotonin re-uptake inhibitor.

Psychiatry and Clinical Neurosciences 2013; 67: 219–227 Tianeptine for SSRI non-response 221


tianeptine and 42.0% of the patients (n = 63) weretreated with paroxetine and tianeptine. The propor-tion of patients treated with benzodiazepines duringthe study period was 74.0% (n = 111). Thirty-fourpatients (22.7%) were prescribed hypnotics duringthe study.

One hundred and ten patients (73.3%) wereincluded in the low-dose group and 40 patients(26.7%) were included in the high-dose group. Theproportion of male patients was 55.0% (n = 22) inthe high-dose group and 31.8% (n = 35) in the low-dose group (P = 0.010). The proportion of patientsgiven antidepressants combined with tianeptine wasdifferent between the high- and low-dose groups, butthe difference did not reach statistical significance(P = 0.063). The baseline HDRS total score was notsignificantly different between the high- and low-dose groups (P = 0.411), but the baseline MADRStotal score was significantly higher (P = 0.015) in thehigh-dose group (29.5 � 6.5) than in the low-dosegroup (26.3 � 7.3). The other characteristics weresimilar between the low- and high-dose groups.

Efficacy

The mean HDRS score at baseline was 22.4 � 5.1,decreasing to 10.3 � 5.7 in week 6 (mean decrease,54.0%; P < 0.001). The mean MADRS scoredecreased from 27.1 � 7.3 at baseline to 12.7 � 7.5(53.1%, P < 0.001) until the endpoint at week 6(Fig. 1). The percentage of responders at week 6 was64.0% (HDRS) and 68.7% (MADRS). The percentageof patients in remission at week 6 was 34.0% (HDRS)and 42.0% (MADRS; Table 2). Every item of HDRSand MADRS was significantly improved from base-line to week 6.

In the subgroup analysis, there was no significantgroup difference and interaction on HDRS (F =

0.147, P = 0.702 for group difference, F = 1.651,P = 0.165 for interaction). There was no significantgroup difference on MADRS (F = 0.505, P = 0.479),but the interaction was significant (F = 3.611,P = 0.008 for interaction) based on RM-ANCOVA. Asshown in Tables 2,3, however, the response andremission rates were significantly different betweenthe two groups at the same visit. In week 2, the HDRSresponse rate was 24.5% (n = 27) in the low-dosegroup and 45.0% (n = 18) in the high-dose group(P = 0.016). The response rate was significantlyhigher in the high-dose group (75.0%; n = 30) thanthe low-dose group (44.5%; n = 49) in week 4(P = 0.001) and in week 6 (82.5%, n = 33 vs. 63.6%,n = 70; P = 0.028) for MADRS. The HDRS remissionrate in week 6 was also significantly higher (P =

Table 2. Percentage of patients classified as remitters (HDRS score � 7 or MADRS score < 10)

Total Low dose†

HDRS response MADRS response

High dose† P Total Low dose† High dose† P

Week 1 0.0 0.0 0.0 1.000 4.0 5.5 0.0 0.343Week 2 5.3 5.5 5.0 1.000 9.3 11.8 2.5 0.114Week 4 22.7 21.8 25.0 0.681 23.3 21.8 27.5 0.467Week 6 34.0 28.2 50.0 0.013** 42.0 39.1 50.0 0.231

**P < 0.05. †Mean daily dose of tianeptine: low-dose group, <37.5 mg/day; high-dose group, �37.5 mg/day. HDRS,Hamilton Depression Rating Scale; MADRS, Montgomery–Åsberg Depression Rating Scale.

30

25

20

15

10

5

0Baseline Week 1 Week 2 Week 4 Week 6

22.4

27.1

18.4

14.712.2

10.3

22.8

18.9

14.912.7

Figure 1. ( ) HDRS and ( ) MADRS scores of patients withSSRI-resistant MDD treated with tianeptine combined with anSSRI for 6 weeks. HDRS Hamilton Depression Rating Scale;MADRS, Montgomery–Åsberg Depression Rating Scale; MDD,major depressive disorder; SSRI, selective serotonin re-uptakeinhibitor.



0.013) in the high-dose group (50.0%; n = 20) thanthe low-dose group (28.2%; n = 31).

Based on logistic regression analysis, the high-dosegroup had a fourfold increased probability of HDRSremission (relative risk [RR], 3.981; 95% confidenceinterval [CI]:, 1.701–9.315; P = 0.001) at the studyendpoint. Logistic regression failed to identify a sig-nificant association between MADRS remission andthe tianeptine dose group (RR, 2.278; 95%CI: 0.929–5.586; P = 0.072) at the study endpoint. A high base-line MADRS total score significantly predicted a lowremission rate in week 6 (RR, 0.871; 95%CI: 0.819–0.925; P < 0.001).

Adverse events and safety

The tianeptine combination with SSRI was well-tolerated throughout the 6-week study period. Therewere 23 dropouts during the study (15.3%). Twopatients (1.3%) were withdrawn from the study dueto adverse events (one case of headache and one caseof nausea), five for insufficient responses, 10 whowere lost to follow up, and six for personal reasonsunrelated to the study. The dropout rate was notdifferent between the high- and low-dose groups orbetween the SSRI and tianeptine combinations.

The adverse events reported during the 6 weeks ofthe study are listed in Table 4. Thirty-six patients(24.0%) reported 97 adverse events. All events wereof mild or moderate severity. The adverse events thatwere reported during the study period were not sig-nificantly different between the two groups. Twenty-four patients (21.8%) reported adverse events in thelow-dose group, and 12 patients (30.0%) reportedadverse events in the high-dose group (c2 = 1.077,d.f. = 1, P = 0.299). Sedation was the adverse event

most frequently reported (7.3%), followed bynausea/vomiting (5.3%), and headaches (5.3%).

DISCUSSIONA combination strategy should be considered as thefirst choice in patients who do not respond to initialantidepressant monotherapy.20 The combination/augmentation strategy can introduce the increasedcomplexity of polypharmacy to the treatmentregimen, which can increase the side-effect burdenand complicate adherence. Compared to the strategyof substituting an antidepressant with another anti-depressant from a different pharmacologic family

Table 3. Percentage of patients classified as responders (�50% total score)

HDRS response MADRS response

Total Low dose† High dose† P Total Low dose† High dose† P

Week 1 5.3 4.5 7.5 0.476 2.0 2.7 0.0 0.565Week 2 30.0 24.5 45.0 0.016** 24.7 23.6 27.5 0.627Week 4 50.0 49.1 52.5 0.712 52.7 44.5 75.0 0.001**Week 6 64.0 61.8 70.0 0.356 68.7 63.6 82.5 0.028**

**P < 0.05. †Mean daily dose of tianeptine: low-dose group, <37.5 mg/day; high-dose group, �37.5 mg/day. HDRS,Hamilton Depression Rating Scale; MADRS, Montgomery–Åsberg Depression Rating Scale.

Table 4. Adverse events during the study period(�1%)

Total(n)

Lowdose (n)

Highdose (N)

Sedation 11 9 2Nausea/vomiting 8 5 3Headache 8 3 5Dry mouth 6 3 3Dizziness 4 2 2Palpitation 4 2 2Increased dream activity 3 2 1Tremor 3 3 0Loose stool 2 2 0Dyspepsia 2 2 0Fatigue 2 2 0Myalgia 2 1 1Constipation 2 2 0Sexual dysfunction 2 2 0Flushing 2 1 1



in cases of TRD, however, the combination/augmentation strategy offers a series of potentialadvantages. The advantages of combination strategyinclude avoiding withdrawal symptoms, rapid onsetof action, and continuation of the drug that produceda partial response.21 Nevertheless, the possibility ofincreased cost, poorer patient compliance, and drug–drug interactions should be considered.21

The best-studied combination strategies are SSRIwith tricyclic antidepressant,22–24 SSRI with mirtazap-ine,25,26 and SSRI with bupropion.27,28 In general, theresponse rate of combination strategies is 50–60%,but the response rate varies according to the drugused.29 The remission rate of bupropion or buspironeaugmentation in patients with MDD who failed to gointo remission despite citalopram therapy wasapproximately 30% based on the STAR*D trial.30 Thepresent results confirm these data, with approxi-mately 65% of patients responding to tianeptinecombination treatment and approximately 40% ofpatients in remission. The present results suggest thatthe addition of tianeptine to the treatment of MDDpatients who did not respond or partially respondedto SSRI monotherapy is an effective strategy. More-over, the high-dose group had a fourfold increasedprobability of HDRS remission and more thantwofold increased probability of MADRS remission atthe study endpoint, although the difference did notreach statistical significance in MADRS remission.

Early studies suggested that acute and sustained useof tianeptine decreased the extracellular level of sero-tonin.31,32 At that time, this finding was hypothesizedto be the consequence of a serotonin re-uptakeenhancement. Moreover, Kuroda et al. reported thattianeptine also reduced both the number of trans-porter sites and their mRNA levels in the rat dorsalraphe nucleus.33 But because tianeptine has a lowaffinity for serotonin transporter, any facilitatoryinfluence of tianeptine on serotonin re-uptakeappears to be indirect. Further, the validity of olderdata has been contested on the basis of technicallimitations that could not be circumvented at thattime.18,34 More recent work indicates that actions oftianeptine as an antidepressant are independent ofmodulating serotonin levels.35,36 Instead, the primarymode of action of tianeptine is to influence theexpression of synaptic plasticity13,37,38 via the modu-lation of glutamatergic neurotransmission.39,40

There is growing evidence that the glutamatergicsystem plays an important role in the neurobiologyand treatment of MDD.41–43 Musazzi et al. recently

reported that depolarization-dependent release ofglutamate is selectively upregulated by acute stressrelative to GABA release, and that chronic treatmentwith antidepressants (desipramine, fluoxetine or ven-lafaxine) completely abolished the stress-inducedupregulation of glutamate release, suggesting thatthis may be a relevant component of the therapeuticaction of antidepressants.44 Hence, the combinationof tianeptine with SSRI can be therapeuticallysynergistic.

There was no significant difference in tolerabilitybetween the low- and high-dose groups. The goodtolerability of tianeptine in combination with SSRIcan be explained by pharmacokinetic properties.Tianeptine does not undergo cytochrome P450-dependent biotransformation to a significantextent;45 and increased tianeptine concentrationcaused by co-use of these drugs is unlikely to be aproblem because tianeptine has a wide therapeuticmargin.46 Because tolerability and drug interactionsare a concern in combination treatment, the favor-able tolerability profile and low risk of drug interac-tions associated with tianeptine could be of benefit incombination strategies for TRD patients.

The results herein confirmed the tolerability oftianeptine, as demonstrated by the low number ofdiscontinuations for adverse events and the numberof patients with adverse events, which is consistentwith a previous study that reported a premature ter-mination of treatment rate of 4.8% during 3 monthsdue to adverse events.47

The clinical antidepressant efficacy of tianeptine(25–50 mg/day) has been demonstrated againstplacebo in patients 18–60 years of age with MDD.48,49

The manufacturer-recommended dosage of tianept-ine in patients with depression, however, is 37.5 mg/day and dose titration is not required. The fact thatthe high-dose group had a higher response andremission rate and no difference in tolerability whencompared to the low-dose group supports the pre-scription guidelines of the manufacturer.

The present results should be interpreted withcaution in view of important limitations. The resultsof open studies are questionable based on the meth-odology used. Without the use of placebo, it isimpossible to separate an augmented drug responsefrom a clinical response due to continued use of theSSRI. Given, however, that the present sample con-sisted of patients resistant to SSRI monotherapy, it isreasonable to assume that the placebo response ratewould be much lower.50,51 Moreover, the use of



placebo in such a patient group would also be ques-tionable ethically given that the risk of suicidalbehaviors is markedly higher.52

Patients included in the present study failed torespond to one adequate trial of SSRI and thesepatients can be categorized as stage 1 on the Thase–Rush TRD staging method.53 Patients who met thewidely accepted definition of TRD (failure of anadequate trial of at least two distinctly different classesof antidepressants, Thase–Rush TRD stage 2)53 wereexcluded from the present study. Hence, the presentresults cannot be generalized to every TRD stage.

We did not evaluate laboratory findings andelectrocardiogram results. Tianeptine has the poten-tial to cause hepatotoxicity through inhibition ofmitochondrial beta oxidation enzymes.54 Hepatoxic-ity, however, appears rarely and has been reported inonly three patients in France since the drug was intro-duced in 1988.55–57 Moreover, heart rate, blood pres-sure, cardiac conduction, and ventricular functionwere not altered in several long-term trials involvingtianeptine.58

Conclusion

A combination strategy with tianeptine and SSRI is apotentially useful tool in patients prescribed SSRImonotherapy with TRD. Nevertheless, additionalcontrolled, randomized studies are needed todetermine the efficacy of tianeptine combined withan SSRI for partial or non-responders to SSRImonotherapy.

ACKNOWLEDGMENTThe authors had no conflicts of interest in conductingthis study or preparing the manuscript.

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tianeptine combination for partial or non-response to selective serotonin re-uptake inhibitor...

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