To the Editor:  

The study and management of mental illness is a high priority in public health. The World Health Organization (WHO) opines the following^1,2: 

 

Researchers studying mood disorder have struggled to find a reproducible biologic marker with specificity and sensitivity. Several decades ago, the treatment of patients who had Mycobacterium tuberculosis infection with iproniazid phosphate, a monoamine oxidase inhibitor (MAOI), provided an observation that many patients, even the most regressed, improved.³ According to a 1957 article about this drug in The New York Times,³ “Following therapy, which began in 1951, it was noted that tuberculosis patients experienced improved good spirits and appetite and gained weight. In one case, the drug apparently led to their `dancing in the wards' at Sea View Hospital on Staten Island.” 

The recognition of the effectiveness of MAOIs empirically created the basis of the biogenic amine theory of depression.⁴ A biogenic amine is a biogenic substance with an amine group. Within the group of biogenic amines, there are catecholamines known as dopamine, norepinephrine, and epinephrine, in addition to histamine and the indolamine serotonin. 

Substantial imaging and histologic evidence places neuroplasticity at the center of mood disorder pathologic mechanisms.^5-8 Tianeptine offers an entry into the study of neuroplasticity for advancements in the definition and treatment of the heterogeneous group of mood disorder illnesses. 

Tianeptine is an established, effective, and rapid-acting antidepressant approved in many countries.^9-27 However, tianeptine is not available in the United States. Tianeptine has no affinity for neurotransmitter receptors, and its use does not involve a central nervous system effect to inhibit uptake of serotonin or norepinephrine.²⁸ Nor does tianeptine inhibit monoamine oxidase A or monoamine oxidase B in the central nervous system.²⁸ Tianeptine enhances the reuptake of 5-hydroxytryptamine (ie, serotonin) and reduces the number of transporter sites and messenger ribonucleic acid (mRNA) levels in the dorsal raphe nucleus.²⁸ 

A large body of evidence from positron emission tomography, single photon emission computed tomography, and magnetic resonance imaging studies demonstrates changes in brain function and volume—as measured by blood flow, metabolism, and structure—in patients with mood disorder.⁵ Areas of brain pathology have included the medial prefrontal cortex, the medial and caudolateral orbitalfrontal cortex, the amygdala, the hippocampus, the ventromedial parts of basal ganglia, and the anterior cingulate.⁵ 

In 1999, Rajkowska et al⁶ published one of the first histologic studies in human beings showing morphometric evidence of neuronal and glial cell changes in the histopathologic mechanisms of major depressive disorder (MDD). The authors indicated that they were encouraged to conduct this study by functional abnormalities consistently found in imaging of the left dorsolateral prefrontal cortex and left orbitofrontal cortex. In the study,⁶ 12 patients with a retrospective diagnosis of MDD without psychosis were compared to 12 normal controls. The study demonstrated diminished neuronal size and cortical thickness (most prominently in the rostral orbitofrontal region), marked diminished glial density, and moderately diminished neuronal size without significant loss of cortical thickness in the left caudal orbitofrontal region and dorsolateral prefrontal cortical region.⁶ 

McEwen⁷ demonstrated that the hippocampus undergoes stress-related volume loss. Within the hippocampal dentate gyrus, new neurons may develop in adult mammals. Neuroendocrine and genetic factors regulate development of the new hippocampal dentate gyrus neurons. In addition to reduced neurogenesis of hippocampal neuronal cells with stress, there is also morphologically demonstrated retraction of apical dendrites of cornu ammonis 3 (CA3) pyramidal cells. Tianeptine prevents changes in hippocampal volume and preserves cell proliferation.⁷ 

Sheline et al⁸ demonstrated hippocampal volume loss in medically healthy women with recurrent MDD. In the study, 24 women aged 23 to 86 years with a history of recurrent MDD without medical comorbidity were compared to 24 normal controls.⁸ The investigators found no relationship between age and hippocampal volume loss. They also found a direct relationship of total lifetime depression duration with bilateral hippocampal volume loss and smaller amygdala core nuclei volume. Furthermore, women with recurrent MDD that was in remission had verbal memory loss.⁸ This memory loss implies that MDD—especially recurrent MDD, even if in remission—can be an organic brain disease. The American Psychiatric Association's position is that the aim of treatment in mood disorder is total remission, to provide the least impairment and reduced risk of recurrence.⁸ 

Hippocampal function is crucial in verbal memory. It has been suggested that the amygdala, which comprises several nuclei, enables long-term memory but does not store memory.²⁹ Of the nuclei within the amygdala, the basolateral complex affects long-term memory through its numerous projections. Memory is promoted by stress or excitement. Tianeptine, but not fluoxetine, inhibits stress-induced hypertrophy and reduces extracellular glutamate in the basolateral nucleus of the amygdala.^29,30 

In the search for a model to study and explain mood disorder, maladaptive neuroplastic changes offer a cogent disease model that is reproducible. However, these neuroplastic changes fail as a biologic marker because of the lack of clinical availability and the overlap with other diseases, such as anxiety disorder. Variability in reestablishing normal neuroplasticity implies that mood and anxiety disorders may present with permanent brain disease.