Opioid System for Depression

By: Yuichi Fukunaga

 

Targeting the Endogenous Opioid System for Depression

Major depressive disorder (MDD) is one of the most prevalent psychopathologies in the United States: the lifetime prevalence is approximately 12% for men and 20% for women (Kessler et al., 2003). Clinical depression is characterized by persistent depressive moods, and MDD patients exhibit symptoms that include, but are not limited to, sleep disturbances, loss of appetite, constipation, and anhedonia (Belmaker & Agam, 2008). The estimated lost productive time is 5.6 hours per week, and the estimated lost annual labor is $44 billion among workers diagnosed with depression in the United States (Stewart et al., 2003). The detrimental effect and economic burden of depression have fostered intensive research for a better treatment for depression. However, to this day, there is no established treatment in which patients exhibit consistent responses (Belmaker & Agam, 2008). An estimated 10-30 percent of MDD patients show no response to standard antidepressant medications (Al-Harbi, 2012), and multiple trials of different prescriptions are needed to find an effective treatment. It is therefore instrumental to advance our understanding of the mechanism and effective treatment of MDD. To highlight a promising pharmacological approach, this review spotlights the use of tianeptine, an opioid-receptor agonist, to target the endogenous opioid system for MDD treatment.

The endogenous opioid system recently emerged as a promising candidate for pharmacological intervention with MDD. The endogenous opioid system is a peptide neurotransmitter system composed of three neuropeptide families: the beta-endorphins, the enkephalins, and the dynorphins. Furthermore, the opioid system is composed of three metabotropic receptors: mu (MOR), delta (DOR), and kappa (KOR) receptors (Emery & Akil, 2020). The effects of these G-protein-coupled receptors vary in mood and hedonic continuum: MOR agonists produce euphoria and stress-coping effects; KOR agonists produce dysphoria and negative affect; and DOR agonists produce anxiolytic and positive affect (Valentino & Volkow, 2018).  These euphoric and stress-relieving effects partially contribute to the addictive nature of opioids. The comorbidity between mood disorders, especially depression, and opioid use or misuse is high, and their relationship is bidirectional (Emery & Akil, 2020). As the expression of opioid receptors is scattered across the brain, with high concentrations in regions associated with pain, affect, and reward, the opioid system regulates affective state and emotional responses to both positive and negative experiences (Akil et al., 2018). These preliminary reports allude to the endogenous opioid system as a promising candidate target for alleviating depressive symptoms. It is therefore worth investigating the use of opioid receptor targeting agents for depression treatment.

Tianeptine is an antidepressant agent that targets the endogenous opioid system, selectively binding to MOR and DOR as a full agonist (Gassaway et al., 2014). Compared to tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), which are commonly prescribed antidepressants for MDD patients, tianeptine shows increased tolerability, reduced incidence and less severity of side effects, and more rapid therapeutic benefits observed after one week (Akil et al., 2018). Tianeptine increases serotonin reuptake in the brain while decreasing stress-induced atrophy of neural dendrites (Wagstaff et al., 2001) and normalizing dysregulated glutamatergic neurotransmission (Kasper & McEwen, 2008). However, the molecular mechanisms of these advantageous effects of tianeptine remain unclear. The primary metabolite of tianeptine, in a MOR-dependent manner, has been reported to produce acute and chronic antidepressant-like effects and opiate-like effects (i.e. reward, analgesia) without the development of any tolerance or dependence in mice (Samuels et al., 2017). Hence, the activation of the MOR may account for tianeptine’s pharmacotherapeutic effects on depression. Furthermore, tianeptine may be established as a non-addictive opioid receptor agonist that manifests few side effects of withdrawal or tolerance.

MDD is a psychological disorder that severely impairs the diagnosed individual's life. It is therefore instrumental to pursue a better intervention approach to prevent the onset and relapse of MDD. Tianeptine is a promising non-addictive antidepressant that could be effective for patients with depression who have not yet found suitable treatment. The opioid-receptor agonist has been approved in more than 60 countries to treat depression and anxiety but not in the United States (Bailey et al., 2018). According to a recent warning by the U.S. Food and Drug Administration, tianeptine is an unsafe food additive with serious adverse events reported (Office of the Commissioner, 2022). Further clinical studies are needed to elucidate the safety and efficacy of tianeptine in treating depression and anxiety. As our better understanding of the effect of tianeptine explicates the neurobiological mechanisms of major depressive disorders, the non-adverse qualities of tianeptine may be further validated. Establishing tianeptine as an approved antidepressant will provide an alternative option for MDD patients who have not yet met an effective treatment. 

 

 

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