Stablon®: A novel approach to enhancing mood and memory
Depression is a complex disorder that affects millions around the world. Even in the 21st century, the roots of this increasingly common malady are not fully understood and are still the subject of intensive medical research. Ever since the finding a few decades ago that conventional antidepressants act by raising neurotransmitter levels, (i.e., serotonin, norepinephrine, and dopamine), the prevailing view has been that depression is caused by insufficient activity of these brain chemicals. Yet in spite of the wide range of antidepressant drugs on the market, the disorder remains difficult to treat, with up to 30 percent of patients not obtaining significant relief from these agents, (1) or discontinuing treatment altogether due to troublesome and dangerous side effects.
Could it be that a monoamine neurotransmitter deficit does not sufficiently explain the complete physiological picture of depression? The answer is yes: the etiology of mood disorders is much more complicated than previously thought, and monoamine deficiency is only a partial explanation. One drug that has contributed greatly to our understanding of the complexity of depression is Stablon® (tianeptine), a novel antidepressant with unique pharmacological properties, unrelated to tricyclics, monoamine oxidase inhibitors, or selective serotonin reuptake inhibitors (SSRI’s). Tianeptine has been clinically proven to be effective in treating depression and associated anxiety and cognitive deficits, without the debilitating side effects characteristic of conventional antidepressants. Let’s take a look at this intriguing compound and its many applications.
Depression leads to altered neuroplasticity and changes in the brain
Recent theories suggest that depressive disorders may be associated not only with an imbalance of neurotransmitters, but also with impairment of a fundamental property of the brain known as neuroplasticity. (1-4) Neuroplasticity is the ability of the brain to reorganize neural circuitry in response to new experiences. The brain has the remarkable ability to form new neural connections throughout life in order to adapt to new situations, such as learning, sensory stimulation or injury. For example, the brain can ‘rewire’ itself to compensate for lost function after damage caused by a stroke, or in the process of learning and retaining data in memory. But as studies have shown, in response to stress and depression, this adaptive capacity is hindered and instead, the brain undergoes structural and functional alterations in three regions that are highly involved in emotional and cognitive processing: the hippocampus, prefrontal cortex, and amygdala. (1-3) The hippocampus is the brain’s primary memory center and the prefrontal cortex is involved in complex cognitive functions, such as planning, decision-making, and behavioral flexibility; both of these areas undergo significant reductions in size. (1, 2) In addition, the activity of the amygdala, which plays a key role in the processing of emotions, is increased in depression. (2) It appears that changes in the amygdala precipitate changes in other brain regions, including the hippocampus and prefrontal cortex. (1, 2) Researchers believe that the impairment of neuroplasticity in these brain regions and consequent changes in brain structure and function lead to the disturbances in cognition, learning, memory and emotions exhibited in depression. (1, 2, 5)
Tianeptine reverses damaging changes to the brain due to stress and depression
It has been shown that stress is linked to depression and produces similar alterations, (1) including impairments in learning and memory. In fact, in animal studies, stress paradigms have been used as to simulate depression in order to investigate the efficacy of potential new treatments. In these stress-based models, tianeptine has been shown to exert antidepressant effects by preventing both structural and functional changes in the hippocampus, prefrontal cortex and amygdala, (1, 5) and restoring neuroplasticity. (6) How is that accomplished? By normalizing the activity of a key neurotransmitter unrelated to the monoamines, as we will see below.
Key role of glutamate in tianeptine’s mechanism of action
Although we now know that tianeptine’s mechanism of action is independent of influencing monoamine neurotransmitter levels, early studies proposed that the drug acted by enhancing serotonin reuptake. (1, 2) But that theory has been challenged by more recent work indicating that tianeptine acts independently of the serotonin pathway (1-3) and instead modulates the activity of glutamate, (1-3, 5) the primary excitatory neurotransmitter of the central nervous system and an essential participant in many forms of neuroplasticity, including learning and memory. (1) Both stress and depression have been linked with alterations (generally increases) in the activity of the glutamate pathway, (1, 2) and the deleterious changes in neuroplasticity and brain structure and function that underlie stress and depression may be due to over-activity of this neurotransmitter. (1, 2) In animal studies, tianeptine has been shown to normalize stress-induced changes in glutamate neurotransmission (1, 2) and reverse structural changes in the brain (1, 2, 5) and impaired neuroplasticity. (2, 6)
In a nutshell, then, by normalizing glutamate transmission, tianeptine reverses damaging changes to the brain and restores normal neuroplasticity, and so exerts its anti-stress, antidepressant, and pro-cognitive effects.
Clinical studies on tianeptine
The efficacy of tianeptine in animal models of depression has led to dozens of clinical trials evaluating its antidepressant effects in humans. Tianeptine at doses of 25 to 50 mg/day (the usual dose is 37.5 mg/day, i.e., 12.5 mg three times a day) has been investigated in major depression, bipolar disorder, dysthymia, (3,7) treatment-resistant depression, (6) and recurrent depression. (8)
A compelling body of evidence demonstrates that tianeptine is at least as effective as conventional antidepressants including the tricyclics amitriptyline, clomipramine, and imipramine, (7) and the SSRI’s fluoxetine (Prozac®), (7; 9-11) paroxetine (Paxil®), (7; 11-13) and sertraline (®), (7, 11, 14) if not superior. It displays a remarkably low rate of adverse effects such as sleep disturbances and weight changes. In addition, it does not lead to sexual dysfunction or cardiovascular problems characteristic of some other antidepressants; remarkably, it improves these conditions in patients with mood disorders.
A study of patients with depression and erectile dysfunction (ED) showed that tianeptine ameliorates symptoms of both conditions, (15) and trials on those with mood disorders and concurrent heart disease demonstrated that the medication is safe, well tolerated and effective in reducing depressive and cardiac symptoms. (16-18) In addition, tianeptine is superior to some conventional antidepressants (i.e., tricyclics) in that it does not cause memory problems; (1, 3) in fact, as we will see below, tianeptine exerts pro-cognitive effects. Nor does the medication cause the impairment in functioning (3) or sedation (1, 5) characteristic of some other drugs.
A study evaluating the effects of two antidepressants on car driving performance found that tianeptine had no adverse effect on driving, in contrast to mianserin, which clearly impaired performance. (19) Besides heart disease and ED, tianeptine has also been successfully used to treat depressive symptoms in patients with Parkinson’s disease, (3, 20) post-traumatic stress disorder, (21, 22) alcohol addiction, (3, 7, 23) and in the elderly. (3, 7, 24, 25) And as an added benefit, tianeptine also reduces the symptoms of anxiety that often accompany depression, (1-3; 5, 12, 25, 26) without the need for an additional anti-anxiety medication. (1, 2)
Tianeptine: Antidepressant and cognitive-enhancer
In addition to its impressive track record in safely treating depression and accompanying disorders, tianeptine is also a potent cognitive enhancer, protecting against stress-induced deficits in learning and memory. (1, 2) In an animal model of depression based on stress, rats administered tianeptine exhibited intact hippocampus-dependent memory despite being exposed to a fear-provoking stressor, such as an animal intruder. (2) And in humans, the drug improves measures of short term memory, learning, reaction time and attention in patients with depression. (27) It appears that tianeptine enables the brain to store information more efficiently, preventing its retrieval from being disrupted by stress. (2) Even under non-stress conditions, tianeptine enhances learning and memory in animals, as shown by improved performance on discrimination tasks. (2) An interesting area for future research would be the determination of the medication’s pro-cognitive effects in humans without depression.
The study of tianeptine has contributed greatly to our understanding of the complexity of depression, with the realization that the development of the disorder stems from much more than a monoamine neurotransmitter deficit.
Tianeptine prevents and reverses depression-induced changes in the brain and there is little doubt that patients who have not gained adequate relief with conventional anti-depressants will benefit from a medication with a glutamate-based mode of action. But tianeptine is much more than just an antidepressant ─ it’s a remarkably versatile therapy that counteracts the adverse effects of chronic stress, enhances learning and memory, and calms anxiety ─ all this with a favorable tolerability profile.
Although Stablon® (the brand name for tianeptine) is marketed as a prescription drug in many areas of the world, it is not available in the USA (to the detriment of many who have not been served by conventional antidepressants), but thankfully, it may be obtained from IAS.
Tianeptine may be a major breakthrough in the treatment of depression.
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