Introduction
The prevalence of depression varies widely
between societies. In developed countries it can be as high as 9.6%, second only to hypertension as the most common chronic condition encountered in general medical practice.1 In India, a meta-analysis of epidemiologic studies done in rural and urban areas since 1960, reported a median prevalence of 3.4% for mood disorders.2 Surveys suggest that most cases of depression are either unrecognized or inappropriately treated, and that this leads to a social burden on the family, loss of productivity, functional decline, and increased mortality.1
This article reviews some of the new insights into the pathophysiology of depression, particularly neuroplasticity, the problems with conventional antidepressive drug treatment, and the need to target neuropalsticity rather than neurotransmitters with agents such as tianeptine.
Pathophysiology of depression
The exact aetiology of depression is unclear. However, advancing age, disease such as atherosclerosis or infection, alterations in endocrine and immune status, elevated levels of psychological stress faced by individuals in modern societies, and genetic susceptibility are believed to be involved.3 It is postulated that these factors cause depression by mediating three types of molecules in the brain (Fig. 1).
Neurotransmitters
 The neurotransmitters that have received the most attention are the monoamines norepinephrine, serotonin, and dopamine. These molecules project broadly through the brain and regulate multiple behavioural neural circuits. While the role of dopamine in motivation and norepinephrine in arousal are established, the role of serotonin is less clear. Some evidence suggests decreased activity of the serotonin receptor systems in depression. Thus treatment with specific serotonin reuptake inhibitors (SSRI) that increase synaptic serotonin ameliorates depressive symptoms at least in the short term. On the other hand, treatment with tianeptine is clinically as effective, despite having the opposite action of increasing the reuptake of serotonin, and reducing the level of synpatic serotonin.4
Recent observations point of an interaction between different neurotransmitters, rather than the predominance of any one in causing the symptoms of depression. For example, normally, there is an inverse relationship between the concentration of serotonin and norepinephrine in the cerebrospinal fluid, which is reversed in depression.5 This suggests that it may not be the static levels of individual neurotransmitters but their dynamic interaction with each other that is the crux of depression.
Neuropeptides
Neuropeptides such as corticotrophin releasing hormone (CRH), adrenocorticotrophic hormone (ACTH), and cortisol are released in response to stress. In comparison to healthy persons, CRH levels in the cerebrospinal fluid are elevated in depressed patients.6 Since CRH affects so many parts of the brain that control stress, arousal, and depression, its dysregulation may be part of the pathophysiology of the disorder. Other neuropeptides released from the hypothalamus such as gamma aminobutyric acid (GABA) influence arousal, and hypocretin, sleep/wake cycles. The diurnal variation in the concentration of these neuropeptides in the CSF is lost in depressed patients, suggesting their role in depression.4
Neuroplasticity and neurotrophic factors
It was once believed that the formation of new neurons and synaptic connections occurred only during the prenatal period, suggesting that only young brains were ‘plastic’, and that the process of neurogenesis after birth largely ceased. Because of this, it was thought that damage to a part of the brain led to permanent loss of function controlled by that area. Today it is recognized that the brain forms new neurons and neural connections throughout life, and this has been demonstrated even in a 72-year-old adult. This phenomenon is called ‘neuroplasticity’ and includes formation of new neurons that contribute to performance, sprouting of dendrites that communicate with other neurons, and the strengthening of these connections.7
One of the most consistent findings in depression is the loss of neuroplasticity reflected in the decreased size of the hippocampus in comparison to controls. Some evidence suggests that this loss of plasticity and neuronal death may be caused by CRH and cortisol which are elevated in both chronic stess and depression. Alternatively, the level of brain-derived-neurotrophic factor (BNDF), which is thought to enhance neuroplasticity and the number of neurons within the hippocampus, may be low.4
Problems with conventional neurotransmitter reuptake inhibiting drugs in the treatment of depression
Conventional antidepressant drugs act by inhibiting the reuptake of one or more neurotransmitters at synpatic junctions in the brain. Although in use for several years, their actual clinical benefit over placebo in the treatment of major depression has been questioned.8 While many trials do find antidepressants that block neurotransmitter reuptake to be superior to placebo, many do not, including some of the largest and most well-known landmark trials such as the Medical Research Council trial and the early National Institute of Mental health trial. Recently, a meta-analysis of placebo controlled trials of SSRI found significant differences in the levels of symptoms, but these were so small that the effects were deemed unlikely to be clinically important.8 When continuous measures on the Hamilton scale are considered the overall mean difference is no more than 1.7.9
Other factors which argue against the mode of action of these drugs targeting the real cause of depression is that there is no linear relationship between the severity of depression and antidepressive effectiveness. After initiating treatment, symptoms improve only after a time lag of up to 3 weeks (Fig. 2), and in longitudinal studies, the long-term outcome is reported to be very poor,9 with more than 50% of patients suffering a relapse within 6 months after successful treatment of a depressive episode.10
The Neuroplasticity Theory of Depression
The suspect efficacy, and particularly poor long term outcome of conventional antidepressants8 may be because these agents treat the biochemical effect, which is decreased synaptic neurotransmitter concentration, rather than its cause, which is fewer neurons and synaptic connections due to loss of neuroplasticity in depression.
The recent evidence on neuroplasticity suggests an alternative mechanism to the purely neurotransmitter theory of depression (Fig. 3).
In susceptible individuals, chronic stress increases the levels of neurotoxic peptides such as CRH, cortisol, and GABA which decrease the mass of neurons and synaptic connections particularly in the hippocampus. This loss of ‘plasticity’ is the primary cause of depression.11 The fewer than normal neurons and synaptic connections results in low levels of neurotransmitters such as serotonin, in neural circuits that express mood.
The fact that serotonin levels are low in depression may therefore be the consequence of loss of neuropalsticity rather than a primary cause of depression.
Hypothetically, if depression is associated with reduced hippocampus size and neuronal atrophy, then treatment to increase neuroplasticity can alleviate depression with potential long-term benefit.11 This has found support in the demonstration that preventing neuroplasticity in mice by irradiation completely negates the beneficial behavioural effects of antidepressants. This suggests that any clinical benefit with an antidepressant must necessarily be mediated by at least some stimulation of neurogenesis in the hippocampus.12
The antidepressive efficacy and action of tianeptine on neuroplasticity
Tianeptine is an antidepressant drug, which resembles conventional tricyclic agents in structure, but has an opposite action on brain neurotransmitters. Whereas conventional antidepressants inhibit reuptake and increase neurotransmitter concentration in the synapse, tianeptine enhances serotonin reuptake by about 15%, leading to reduced serotonin levels in the synaptic cleft.13 Despite this diametrically opposite mode of action between tianeptine and conventional antidepresant drugs, a meta-analysis of all randomized controlled trials with tianeptine versus SSRI showed equivalent short-term efficacy in relieving symptoms of major depression.14
This paradox was one of the main reasons for the reassessment of the neurotransmitter theory of depression during the past decade. Increasingly the evidence suggests that tianeptine primarily relieves the symptoms of depression by enhancing neurogenesis in those areas of the brain, which express mood (Fig. 4).
In animal models of depression, tianeptine has been shown to prevent neuron death caused by psychological stress in the hippocampus, dentate gyrus, and temporal cortex,15 together with an increase in hippocampus volume,16 and unlike SSRI, it prevents stress induced dentrite atrophy.17
Apart from prevention, the treatment effect of tianeptine on neuroplasticity has also been demonstrated. In the same animal model, hippocampus neuron atrophy caused by corticosterone was reversed by treatment with tianeptine.17 These actions of tianeptine on neuroplasticity in the hippocampus appear to be mediated by its preventive action on chronic stress related decline of key brain metabolites (N-acetyl-aspartate, creatine, phosphocreatine, and choline-containing compounds), and rate of proliferation of precursor cells.16
Clinical implications of antidepressive treatment with tianeptine
Long term efficacy and prevention of relapse/recurrence of major depression
A critical clinical implication of the neuroplasticity theory of depression is related to relapse and recurrence of major depression. This is because the antidepressive efficacy of tianeptine is due to restoration of neuroplasticity. By comparison, conventional agents treat the effect of loss of plasticity which is low synaptic neurotransmitter levels. Tianeptine is therefore expected, at least in theory, to have a comparatively lower rate of relapse and recurrence.
Although there is no direct comparative evidence, long-term randomized placebo controlled studies of comparable design, with tianeptine,18 sertraline,19 and paroxetine20 on patients with major depression have been reported. In these studies, the frequency of recurrence/relapse rate after successful treatment of the depressive episode and discontinuation of active treatment was about 25% less with tianeptine.
Anxiolytic action of tianeptine
The frequency of coexisting anxiety in major depression is as high as 74%, being directly proportional to the severity of depression.21 Although patients are primarily treated with an antideperssant, a short course of benzodiazepines is usually prescribed. However, it is frequently necessary to prolong their use or increse their dose.21 This exposes patients to the risk of dependence and amnestic side effects.
Uniquely, tianeptine has an Anxiolytic action comparable to alprazolam without causing daytime sedation.22 This complements its antidepressive action, and decreases the need for benzodiazepine co-prescription. The anxiolytic effect may be a reflection of the lower concentration of serotonin in the synaptic cleft due to its reuptake with tianeptine.
Patient tolerability
In clinical studies, tianeptine is not associated with sedation, loss of attention, or memory that are frequently observed with commonly used antidepressants. It has no adverse cardiovascular effects or influence on body weight, and may have an advantage over SSRI in not causing sexual dysfunction.23
Conclusion
Although depression is a common disease with serious morbidity, most patients are inadequately treated over the long term. Until recently, the neurotransmitter theory of depression was widely accepted as the pathophysiologic basis for depression. Recent evidence suggests that the cause of depression is chronic psychological stress related loss of plasticity in the areas of the brain that regulate mood, particularly the hippocampus. The changes in brain neurotransmitters observed in depression are a consequence of this loss in plasticity. Drugs that primarily target the restoration of neuroplasticity rather than neurotransmitters could be more useful in the long-term management of depression. Tianeptine is as effective and acceptable as conventional drugs in the treatment of depression, with a complementary anxiolytic effect. However, its primary action is to restore neuroplasticity, and the evidence suggests that because of this it may reduce to a greater extent the long-term risk of relapse and recurrence of depression.
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