Tianeptine is associated with lower risk of suicidal ideation worsening during the first weeks of treatment onset compared with other antidepressants: A naturalistic study
Introduction
Suicidal behavior is a major public health problem and new therapeutic agents are urgently needed. Depression is the most important treatable risk factor for suicidal behavior and 40–80% of suicide attempts are directly linked to a depressive episode (Greden, 2001). Thus, we can expect antidepressants, which are the most effective treatment for depression (Arroll et al., 2009), to decrease suicide rates. Yet, it has been reported that depressed patients at high suicidal risk (i.e., with current suicidal ideation (SI) or lifetime history of suicide attempt (SA)) respond poorly to antidepressants (Lopez-Castroman et al., 2016, Pompili et al., 2010). Moreover, poor response to antidepressant treatment predicts suicidal risk worsening (i.e., SI emergence or suicidal act) (Courtet et al., 2014).
However, it is not known whether the relationship between suicidal risk worsening and poor response to antidepressant depends on the specific mechanism of action of the molecule used. For instance, tianeptine, an approved antidepressant, is a mu-opioid receptor (MOR) agonist that acts specifically on the opioidergic system (Gassaway et al., 2014). On the one hand, a recent study conducted by Samuels et al. showed that the antidepressant- and opioid-like behavioural effects of tianeptine are mediated by its MOR agonism (Samuels et al., 2017). On the other hand, growing evidence suggests the possibility of acting on suicidal behavior through the opioidergic system (Lalanne et al., 2014, Olié et al., 2013). In addition, very low doses of sublingual buprenorphine (an opioid medication) have been associated with reduced SI in severely suicidal patients (Yovell et al., 2016). Thus, we hypothesized that tianeptine, through its MOR agonist action (Gassaway et al., 2014), may have a specific effect on SI in depressed patients compared with other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). To test this hypothesis, we investigated whether, compared with other antidepressants, tianeptine was associated with: 1) lower risk of SI worsening in the first weeks following antidepressant treatment onset; 2) higher SI decrease, independently of the antidepressant response, at week 6 after treatment onset; and 3) lower depression scores and higher remission rates in suicidal patients with depression at week 6 after treatment onset.
Section snippets
Material and methods
The full methodology is detailed in (Courtet et al., 2014, Lopez-Castroman et al., 2016). Briefly, participants were recruited from primary and psychiatric care clinical settings across France. A list of 3000 practitioners were contacted by mail and asked to participate in a short-term follow-up protocol. By the end of the study, 1186 clinicians (39.5%) had included at least one patient (a maximum of 5 was requested to avoid center effects) during a 3-month interval, patients for whom a new or
Results
The study sample consisted of 4017 patients at baseline and assessed at 6 weeks with a mean age of 47.16 years (SD = 13.90) among whom 64.0% were women. The mean duration of the current major depressive episode (MDE) was 7.38 weeks (SD = 9.03), with a mean age at onset of 39.13 years (SD = 14.21). This was the first MDE for 44.4% (n = 1785) of patients, whereas 14.4% (n = 577) reported at least three previous MDEs. Overall, 18.9% (n = 760) of patients had a lifetime history of suicide attempt.
Discussion
As hypothesized, tianeptine use is associated with lower risk of SI worsening compared with SNRIs and TCAs in the first 6 weeks of antidepressant treatment. However, the differences between tianeptine and SSRIs are no longer significant when adjusted for potential confounding factors. Moreover, compared with tianeptine, only TCAs are associated with lower SI improvement and lower remission rates at the end of the follow-up period. However, these results should be considered with caution due to
Acknowledgements
The present work was supported by a research grant from Servier, who had no involvement in the design, organization, analysis, or preparation for publication of the study. Philip Gorwood has received honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, and Servier. Philippe Courtet has received honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, and Servier. Sébastien Guillaume has received honoraria or research or educational conference grants from
References (18)
- et al.
Sleep architecture parameters as a putative biomarker of suicidal ideation in treatment-resistant depression
J. Affect. Disord.
(2017) - et al.
Is it valid to measure suicidal ideation by depression rating scales?
J. Affect. Disord.
(2012) - et al.
Increased density of mu-opioid receptors in the postmortem brain of suicide victims
Brain Res.
(1995) - et al.
Response to intravenous antidepressant treatment by suicidal vs. nonsuicidal depressed patients
J. Affect. Disord.
(2010) - et al.
Clinical correlates of the worsening or emergence of suicidal ideation during SSRI treatment of depression: an examination of citalopram in the STAR*D study
J. Affect. Disord.
(2009) - et al.
Antidepressants versus placebo for depression in primary care
Cochrane Database Syst. Rev.
(2009) - et al.
Antidepressants and suicidal behavior: are we hurting or helping?
Clin. Neuropsychiatry
(2005) - et al.
Antidepressant dosage and suicidal ideation
JAMA Intern. Med.
(2014) - et al.
The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist
Transl. Psychiatry
(2014)
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