Psychiatry and Clinical Neurosciences

Volume 67, Issue 4

Regular Article

Free Access

Tianeptine combination for partial or non‐response to selective serotonin re‐uptake inhibitor monotherapy

Young Sup Woo MD

Department of Psychiatry, Yeouido St Mary's Hospital, Seoul, Korea

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Won‐Myong Bahk MD

Corresponding Author

Department of Psychiatry, Yeouido St Mary's Hospital, Seoul, Korea

Correspondence: Won‐Myong, Bahk, MD, Department of Psychiatry, Yeouido St Mary's Hospital, College of Medicine, The Catholic University of Korea, 62 Yeouido‐Dong, Youngdeungpo‐Gu, Seoul 150‐713, Korea. Email:

wmbahk@catholic.ac.kr

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Jong‐Hyun Jeong MD

Department of Psychiatry, St Vincent's Hospital, The Catholic University of Korea, Seoul, Korea

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Seung‐Hwan Lee MD

Department of Neuropsychiatry, College of Medicine, Inje University, Seoul, Korea

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Hyeung‐Mo Sung MD

Department of Psychiatry, Pochon Cha University, Gumi, Korea

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Chi‐Un Pae MD

Department of Psychiatry, Bucheon St Mary's Hospital, The Catholic University of Korea, Seoul, Korea

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Bon‐Hoon Koo MD

Department of Psychiatry, College of Medicine, Yeungnam University, Daegu, Korea

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Won Kim MD

Department of Neuropsychiatry, College of Medicine, Inje University, Seoul, Korea

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Young Sup Woo MD

Department of Psychiatry, Yeouido St Mary's Hospital, Seoul, Korea

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Won‐Myong Bahk MD

Corresponding Author

Department of Psychiatry, Yeouido St Mary's Hospital, Seoul, Korea

wmbahk@catholic.ac.kr

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Jong‐Hyun Jeong MD

Department of Psychiatry, St Vincent's Hospital, The Catholic University of Korea, Seoul, Korea

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Seung‐Hwan Lee MD

Department of Neuropsychiatry, College of Medicine, Inje University, Seoul, Korea

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Hyeung‐Mo Sung MD

Department of Psychiatry, Pochon Cha University, Gumi, Korea

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Chi‐Un Pae MD

Department of Psychiatry, Bucheon St Mary's Hospital, The Catholic University of Korea, Seoul, Korea

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Bon‐Hoon Koo MD

Department of Psychiatry, College of Medicine, Yeungnam University, Daegu, Korea

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Won Kim MD

Department of Neuropsychiatry, College of Medicine, Inje University, Seoul, Korea

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First published: 20 May 2013

https://doi.org/10.1111/pcn.12042

Cited by: 4

Aims

The goal of this study was to assess the efficacy and tolerability of tianeptine in combination with selective serotonin re‐uptake inhibitor (SSRI) in partial responders or non‐responders to SSRI monotherapy.

Methods

In this prospective, open‐label, 6‐week study, 150 patients with major depressive disorder who had previously not responded or partially responded to SSRI monotherapy were recruited. Tianeptine was given in combination with an SSRI for 6 weeks.

Results

Significant improvements were observed in the mean scores of the Hamilton Depression Rating Scale (HDRS), Montgomery–Åsberg Depression Rating Scale (MADRS), and Clinical Global Impression–Severity (CGI‐S). The change in the mean HDRS, MADRS, and CGI‐S scores was significant from week 1. The response rates were 64.7% (HDRS) and 68.7% (MADRS), and the remission rates were 34.0% (HDRS) and 42.0% (MADRS) at week 6. Thirty‐six patients (24.0%) reported adverse events that were determined by the investigator to be related to one of the study drugs. The tianeptine and SSRI combination was generally well‐tolerated.

Conclusions

A combination strategy with tianeptine may be an effective and well‐tolerated tool for patients who have failed to adequately respond to SSRI monotherapy.

DESPITE THE ADVANCES in pharmacologic agents used for the treatment of depression in the last several decades, a large percentage of patients with major depressive disorder (MDD) fail to respond to treatment with antidepressants. It is estimated that approximately 50% of the patients who receive first‐time treatment for MDD respond adequately to antidepressants, and as many as 30% of those treated for MDD do not benefit from a series of treatment trials.1, 2 In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the relative efficacy and tolerability of various treatments for adult outpatients with non‐psychotic MDD was evaluated, and only 28–33% of patients achieved remission to open‐label monotherapy with citalopram.3 Moreover, remission should be the goal of treatment because failure to achieve remission is associated with greater relapse rate, poorer functional outcome, and a worsening of long‐term prognosis. Full and persistent remission, however, is uncommon in acute depression trials.4 In managing partial or non‐response to antidepressant treatment, various alternatives have been proposed,5-7 such as optimization of the posologic regimen, switching of the antidepressant or the addition of a new drug, which may be another antidepressant or a medication belonging to a different class, such as lithium, buspirone, pindolol, or thyroid hormone.

Despite these data, there is no consensus on the treatment of treatment‐resistant depression (TRD).8 Hence, the choice of one or another of these alternatives depends on anecdotal experience and clinician knowledge.9, 10 Although the number of published studies that have focused on combination treatment has increased markedly, the efficacy of combination treatment has not been established based on controlled trials.11, 12

Tianeptine is an antidepressant in clinical use that has drawn much attention because the effects of this compound argue against traditional monoaminergic hypotheses of depression. Tianeptine enhances the synaptic uptake of serotonin with minimal effects on norepinephrine and dopamine uptake.13, 14 Tianeptine monotherapy has antidepressant and anxiolytic activities and good tolerability.15-17 The involvement of glutamate in the mechanism of action of tianeptine is consistent with a well‐developed pre‐clinical literature demonstrating the key role of glutamate in the altered neuroplasticity that underlies the symptoms of depression.18 But there have been no reports focusing on the combination of tianeptine with selective serotonin re‐uptake inhibitors (SSRI). Therefore, the aim of the present study was to assess the efficacy and tolerability of tianeptine as a combination strategy in patients who had not responded or partially responded to treatment with SSRI over a 6‐week period.

Methods

Study design

This was an open‐label, prospective, multicenter, 6‐week study that included 150 patients diagnosed with MDD according to DSM‐IV‐TR criteria who did not respond or partially responded to SSRI monotherapy. The study was conducted at 11 centers in Korea. Partial or non‐response was defined as a decrease in the score on the 17‐item Hamilton Depression Rating Scale (HDRS) to <50% over a period of 6 weeks of treatment, according to the criteria of Hirschfeld et al.7 Study participants were male and female patients ≥20 and ≤65 years of age. At baseline, all patients were required to have a HDRS total score ≥14 and had to be prescribed a SSRI and compliant with the prescription at a dose recommended for the treatment of depression. Among the exclusion criteria were pregnancy or lactation, a medical condition that could interfere with everyday life activities, and psychotic symptoms or a previous diagnosis of bipolar disorder, schizophrenia, or other psychotic disorder. Other reasons for study exclusion included the following: current primary DSM‐IV TR Axis I diagnosis other than MDD; lack of response during the current or a past episode of depression to two or more antidepressant medications at clinically appropriate doses for a minimum of 6 weeks; and serious suicidal risk. All patients gave informed consent before participation in the study.

Medication

The dose of tianeptine as an adjunct treatment was recommended at 25–37.5 mg/day. This recommended dose was determined by the package insert.19 During the study period, the initial SSRI dose was kept constant. Patients were not allowed to take other antidepressants, mood stabilizers, or antipsychotics during the study. Benzodiazepines and hypnotics were permitted at the discretion of the investigator.

Efficacy and safety assessments

Evaluation of antidepressant efficacy was carried out with the HDRS, Montgomery–Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions–Severity Scale (CGI‐S) in weeks 1, 2, 4, and 6. Before beginning the treatment with tianeptine (baseline visit, week 0), the HDRS and CGI‐S were applied. The primary efficacy assessment was defined as mean change from baseline to week 6 on the HDRS total score. Additional efficacy measures included response and remission rates, and the mean change in MADRS and CGI‐S scores. Response was defined as a decrease in the HDRS or MADRS total score ≥50%. Remission was defined as absolute HDRS score ≤7 or absolute MADRS score <10. In an 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 included all patients who provided a baseline and at least one post‐baseline data measurement. All patients who received at least one dose of the study medication were included in the safety analysis. Quantitative data are expressed as mean ± SD, and categorical variables are described as absolute and relative frequencies. For analysis of quantitative variables, Student's t‐test was used. For analysis of categorical variables, the chi‐squared test was used.

For subgroup analysis, the patients were categorized based on the mean daily dose of tianeptine as follows: low (<37.5 mg/day) and high (≥37.5 mg/day). A subgroup analysis using repeated measures of analysis of covariance (RM‐ANCOVA) with mean daily dose groups as a between‐subject factor and time as a within‐subject factor was performed to determine whether or not there was an interaction between the mean daily doses of tianeptine in predicting the response. RM‐ANCOVA was conducted with baseline measures, and other baseline variables that had significant difference between high‐ and low‐dose groups were entered as covariates. To further determine whether or not there was an interaction between the mean daily dose groups and other baseline variables that showed significant difference between the high‐ and low‐dose groups, we also performed logistic regression using these variables as predictors and response and remission as dependent variables. To compare the risk of adverse events between the mean daily dose groups, chi‐squared tests were performed. The statistical significance criterion was set at P < 0.05. All statistical tests were two‐tailed with a significance level of 0.05.

Ethics

The study was conducted according to the Declaration of Helsinki and Good Clinical Practices. Written informed consent was obtained from all subjects after the subjects were given an extensive explanation of the nature and procedures of the study. The study protocol was approved by the Institutional Review or Ethics Committees at each study site.

Results

Patients and medications

The subject demographic and clinical characteristics are listed in Table 1. The initial mean dose of tianeptine was 26.2 ± 5.7 mg/day, and the mean dose of tianeptine during the study period was 29.7 ± 7.7 mg/day. Nearly one‐half of the patients (49.3%; n = 74) were treated with escitalopram and tianeptine and 42.0% of the patients (n = 63) were treated with paroxetine and tianeptine. The proportion of patients treated with benzodiazepines during the study period was 74.0% (n = 111). Thirty‐four patients (22.7%) were prescribed hypnotics during the study.

Table 1. Baseline demographic and clinical characteristics

		Total patients (n = 150)		Low‐dose groupa (n = 110)		High‐dose groupa (n = 40)		P
		Mean (n)	SD (%)	Mean (n)	SD (%)	Mean (n)	SD (%)	P
Age		46.8	15.0	45.8	15.5	49.4	13.2	0.198
Gender	Male	57	38.0	35	31.8	22	55.0	0.010**
Gender	Female	93	62.0	75	68.2	18	45.0	0.010**
Baseline HDRS score		22.4	5.1	22.2	5.3	23.0	4.7	0.411
Baseline 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	0.514
Combined SSRI	ESC	74	49.3	52	47.3	22	55.0	0.063
	FLO	9	6.0	6	5.5	3	7.5
	PRX	63	42.0	51	46.4	12	30.0
	SET	4	2.7	1	0.9	3	7.5
Baseline concomitant medication	BDZ	80	53.3	61	55.5	19	47.5	0.388
Baseline concomitant medication	HYP	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, Hamilton Depression Rating Scale; HYP, hypnotics; MADRS, Montgomery–Åsberg Depression Rating Scale; PRX, paroxetine; SET, sertraline; SSRI, selective serotonin re‐uptake inhibitor.

One hundred and ten patients (73.3%) were included in the low‐dose group and 40 patients (26.7%) were included in the high‐dose group. The proportion of male patients was 55.0% (n = 22) in the high‐dose group and 31.8% (n = 35) in the low‐dose group (P = 0.010). The proportion of patients given antidepressants combined with tianeptine was different between the high‐ and low‐dose groups, but the difference did not reach statistical significance (P = 0.063). The baseline HDRS total score was not significantly different between the high‐ and low‐dose groups (P = 0.411), but the baseline MADRS total score was significantly higher (P = 0.015) in the high‐dose group (29.5 ± 6.5) than in the low‐dose group (26.3 ± 7.3). The other characteristics were similar 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 score decreased 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 was 64.0% (HDRS) and 68.7% (MADRS). The percentage of patients in remission at week 6 was 34.0% (HDRS) and 42.0% (MADRS; Table 2). Every item of HDRS and MADRS was significantly improved from baseline to week 6.

**Figure 1**
Open in figure viewer PowerPoint

() HDRS and () MADRS scores of patients with SSRI‐resistant MDD treated with tianeptine combined with an SSRI for 6 weeks. HDRS Hamilton Depression Rating Scale; MADRS, Montgomery–Åsberg Depression Rating Scale; MDD, major depressive disorder; SSRI, selective serotonin re‐uptake inhibitor.

Caption
() HDRS and () MADRS scores of patients with SSRI‐resistant MDD treated with tianeptine combined with an SSRI for 6 weeks. HDRS Hamilton Depression Rating Scale; MADRS, Montgomery–Åsberg Depression Rating Scale; MDD, major depressive disorder; SSRI, selective serotonin re‐uptake inhibitor.

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

	Total	Low dosea	HDRS response			MADRS response
	Total	Low dosea	High dosea	P	Total	Low dosea	High dosea	P
Week 1	0.0	0.0	0.0	1.000	4.0	5.5	0.0	0.343
Week 2	5.3	5.5	5.0	1.000	9.3	11.8	2.5	0.114
Week 4	22.7	21.8	25.0	0.681	23.3	21.8	27.5	0.467
Week 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.

In the subgroup analysis, there was no significant group 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 significant group 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. As shown in Tables 2, 3, however, the response and remission rates were significantly different between the two groups at the same visit. In week 2, the HDRS response rate was 24.5% (n = 27) in the low‐dose group and 45.0% (n = 18) in the high‐dose group (P = 0.016). The response rate was significantly higher in the high‐dose group (75.0%; n = 30) than the 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 remission rate in week 6 was also significantly higher (P = 0.013) in the high‐dose group (50.0%; n = 20) than the low‐dose group (28.2%; n = 31).

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

	HDRS response				MADRS response
	Total	Low dosea	High dosea	P	Total	Low dosea	High dosea	P
Week 1	5.3	4.5	7.5	0.476	2.0	2.7	0.0	0.565
Week 2	30.0	24.5	45.0	0.016**	24.7	23.6	27.5	0.627
Week 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.

Based on logistic regression analysis, the high‐dose group had a fourfold increased probability of HDRS remission (relative risk [RR], 3.981; 95% confidence interval [CI]:, 1.701–9.315; P = 0.001) at the study endpoint. Logistic regression failed to identify a significant association between MADRS remission and the tianeptine dose group (RR, 2.278; 95%CI: 0.929–5.586; P = 0.072) at the study endpoint. A high baseline MADRS total score significantly predicted a low remission 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. There were 23 dropouts during the study (15.3%). Two patients (1.3%) were withdrawn from the study due to adverse events (one case of headache and one case of nausea), five for insufficient responses, 10 who were lost to follow up, and six for personal reasons unrelated to the study. The dropout rate was not different between the high‐ and low‐dose groups or between the SSRI and tianeptine combinations.

The adverse events reported during the 6 weeks of the study are listed in Table 4. Thirty‐six patients (24.0%) reported 97 adverse events. All events were of mild or moderate severity. The adverse events that were reported during the study period were not significantly different between the two groups. Twenty‐four patients (21.8%) reported adverse events in the low‐dose group, and 12 patients (30.0%) reported adverse events in the high‐dose group (χ² = 1.077, d.f. = 1, P = 0.299). Sedation was the adverse event most frequently reported (7.3%), followed by nausea/vomiting (5.3%), and headaches (5.3%).

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

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

Discussion

A combination strategy should be considered as the first choice in patients who do not respond to initial antidepressant monotherapy.20 The combination/augmentation strategy can introduce the increased complexity of polypharmacy to the treatment regimen, which can increase the side‐effect burden and complicate adherence. Compared to the strategy of substituting an antidepressant with another antidepressant from a different pharmacologic family in cases of TRD, however, the combination/augmentation strategy offers a series of potential advantages. The advantages of combination strategy include avoiding withdrawal symptoms, rapid onset of action, and continuation of the drug that produced a partial response.21 Nevertheless, the possibility of increased cost, poorer patient compliance, and drug–drug interactions should be considered.21

The best‐studied combination strategies are SSRI with tricyclic antidepressant,22-24 SSRI with mirtazapine,25, 26 and SSRI with bupropion.27, 28 In general, the response rate of combination strategies is 50–60%, but the response rate varies according to the drug used.29 The remission rate of bupropion or buspirone augmentation in patients with MDD who failed to go into remission despite citalopram therapy was approximately 30% based on the STAR*D trial.30 The present results confirm these data, with approximately 65% of patients responding to tianeptine combination treatment and approximately 40% of patients in remission. The present results suggest that the addition of tianeptine to the treatment of MDD patients who did not respond or partially responded to SSRI monotherapy is an effective strategy. Moreover, the high‐dose group had a fourfold increased probability of HDRS remission and more than twofold increased probability of MADRS remission at the study endpoint, although the difference did not reach statistical significance in MADRS remission.

Early studies suggested that acute and sustained use of tianeptine decreased the extracellular level of serotonin.31, 32 At that time, this finding was hypothesized to be the consequence of a serotonin re‐uptake enhancement. Moreover, Kuroda et al. reported that tianeptine also reduced both the number of transporter sites and their mRNA levels in the rat dorsal raphe nucleus.33 But because tianeptine has a low affinity for serotonin transporter, any facilitatory influence of tianeptine on serotonin re‐uptake appears to be indirect. Further, the validity of older data has been contested on the basis of technical limitations that could not be circumvented at that time.18, 34 More recent work indicates that actions of tianeptine as an antidepressant are independent of modulating serotonin levels.35, 36 Instead, the primary mode of action of tianeptine is to influence the expression of synaptic plasticity13, 37, 38 via the modulation of glutamatergic neurotransmission.39, 40

There is growing evidence that the glutamatergic system plays an important role in the neurobiology and treatment of MDD.41-43 Musazzi et al. recently reported that depolarization‐dependent release of glutamate is selectively upregulated by acute stress relative to GABA release, and that chronic treatment with antidepressants (desipramine, fluoxetine or venlafaxine) completely abolished the stress‐induced upregulation of glutamate release, suggesting that this may be a relevant component of the therapeutic action of antidepressants.44 Hence, the combination of tianeptine with SSRI can be therapeutically synergistic.

There was no significant difference in tolerability between the low‐ and high‐dose groups. The good tolerability of tianeptine in combination with SSRI can be explained by pharmacokinetic properties. Tianeptine does not undergo cytochrome P450‐dependent biotransformation to a significant extent;45 and increased tianeptine concentration caused by co‐use of these drugs is unlikely to be a problem because tianeptine has a wide therapeutic margin.46 Because tolerability and drug interactions are a concern in combination treatment, the favorable tolerability profile and low risk of drug interactions associated with tianeptine could be of benefit in combination strategies for TRD patients.

The results herein confirmed the tolerability of tianeptine, as demonstrated by the low number of discontinuations for adverse events and the number of patients with adverse events, which is consistent with a previous study that reported a premature termination of treatment rate of 4.8% during 3 months due to adverse events.47

The clinical antidepressant efficacy of tianeptine (25–50 mg/day) has been demonstrated against placebo in patients 18–60 years of age with MDD.48, 49 The manufacturer‐recommended dosage of tianeptine in patients with depression, however, is 37.5 mg/day and dose titration is not required. The fact that the high‐dose group had a higher response and remission rate and no difference in tolerability when compared to the low‐dose group supports the prescription guidelines of the manufacturer.

The present results should be interpreted with caution in view of important limitations. The results of open studies are questionable based on the methodology used. Without the use of placebo, it is impossible to separate an augmented drug response from a clinical response due to continued use of the SSRI. Given, however, that the present sample consisted of patients resistant to SSRI monotherapy, it is reasonable to assume that the placebo response rate would be much lower.50, 51 Moreover, the use of placebo in such a patient group would also be questionable ethically given that the risk of suicidal behaviors is markedly higher.52

Patients included in the present study failed to respond to one adequate trial of SSRI and these patients can be categorized as stage 1 on the Thase–Rush TRD staging method.53 Patients who met the widely accepted definition of TRD (failure of an adequate trial of at least two distinctly different classes of antidepressants, Thase–Rush TRD stage 2)53 were excluded from the present study. Hence, the present results cannot be generalized to every TRD stage.

We did not evaluate laboratory findings and electrocardiogram results. Tianeptine has the potential to cause hepatotoxicity through inhibition of mitochondrial beta oxidation enzymes.54 Hepatoxicity, however, appears rarely and has been reported in only three patients in France since the drug was introduced in 1988.55-57 Moreover, heart rate, blood pressure, cardiac conduction, and ventricular function were not altered in several long‐term trials involving tianeptine.58

Conclusion

A combination strategy with tianeptine and SSRI is a potentially useful tool in patients prescribed SSRI monotherapy with TRD. Nevertheless, additional controlled, randomized studies are needed to determine the efficacy of tianeptine combined with an SSRI for partial or non‐responders to SSRI monotherapy.

Acknowledgment

The authors had no conflicts of interest in conducting this study or preparing the manuscript.

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Citing Literature

Number of times cited: 4

Małgorzata Szafarz, Agnieszka Wencel, Krzysztof Pociecha, Filip A. Fedak, Piotr Wlaź and Elżbieta Wyska, Pharmacokinetic study of tianeptine and its active metabolite MC5 in rats following different routes of administration using a novel liquid chromatography tandem mass spectrometry analytical method, Naunyn-Schmiedeberg's Archives of Pharmacology, 391, 2, (185), (2018).
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Benjamin Adam Samuels, Katherine M Nautiyal, Andrew C Kruegel, Marjorie R Levinstein, Valerie M Magalong, Madalee M Gassaway, Steven G Grinnell, Jaena Han, Michael A Ansonoff, John E Pintar, Jonathan A Javitch, Dalibor Sames and René Hen, The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor, Neuropsychopharmacology, 42, 10, (2052), (2017).
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Soo Min Hwang, Sae Hee Lim, Dong Ju Oh, Sung Kyun Kim, Hak Hyun Jung and Gi Jung Im, Effect of Tianeptine on Depressed Tinnitus Patients, Journal of Audiology & Otology, 20, 2, (90), (2016).
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M M Gassaway, M-L Rives, A C Kruegel, J A Javitch and D Sames, The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist, Translational Psychiatry, 4, 7, (e411), (2014).
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Volume67, Issue4

May 2013

Pages 219-227

Psychiatry and Clinical Neurosciences

Tianeptine combination for partial or non‐response to selective serotonin re‐uptake inhibitor monotherapy

Abstract