To investigate the potential role of neurotrophins in the pathophysiology of depression and their potential as a therapeutic target
Depression is a chronic, debilitating psychiatric disorder characterized by feelings of sadness and despair. The incidence of depressive illness is growing across the developed (and increasingly in the developing) world and is a major cause of mortality worldwide. According to the World Health Organisation, by the year 2020, depression will be second only to heart disease as the leading cause of disability worldwide. The World Health Organisation estimates the total economic cost of depression in Europe to be 128 billion euro annually while the economic burden in the United States is estimated at $80 billion annually. These direct and indirect costs are associated with sick leave and productivity losses, outpatient care, hospitalisation, pharmacological treatment and mortality.
Although it is more than sixty years since the development of the first treatments for this debilitating mental illness, the precise mechanism of therapeutic action of antidepressant drugs is currently not clearly understood. This is due to the involvement of such a variety of intracellular pathways and signalling transduction cascades in the pathophysiology and treatment of depression.
The hippocampus is implicated as one of most important brain structures involved in depression. Chronic stress and resultant depression can lead to atrophy or loss of hippocampal neurons. There are numerous reports demonstrating that the volume of the hippocampus is decreased in depressed subjects. The hippocampus also shares anatomical connections with the amygdala and prefrontal cortex, two very important brain areas implicated in mood and cognition. Early childhood events and adult stress have been shown to induce neurodegenerative alterations in the brain, such as a reduction in size of the hippocampus and the pre-frontal cortex.
The neurotrophin hypothesis of depression:
The plasticity hypothesis was proposed in 1997 and demonstrated a role for neurotrophic factors in stress actions. They found that a single or repeated exposure to stress rapidly decreased the expression of brain-derived neurotrophic factor (BDNF). As previously mentioned, BDNF effects on the nervous system are vast and include outgrowth of neurites, differentiation, synaptic connectivity, neuronal repair, neuronal transmission and protection against stress-induced neuronal damage.
Studies at the clinical level of chronic stress and depression have shown decreased BDNF expression in the hippocampus and cerebral cortex and a resultant decrease in neurogenesis. Decreased BDNF in depressed patients perhaps underpin the atrophy and resultant decrease in brain volumes of certain limbic structures, including the prefrontal cortex, hippocampus and the amygdala that have been observed in depressed patients.
The neurotrophin hypothesis of depression is based on a downregulation of central brain-derived neurotrophic factor (BDNF) and a reduction in BDNF associated neuronal survival activities underlying the pathogenesis of depression eventually this may result in a breakdown and deregulation of neuronal networks involved in the regulation of mood. This implicates Brain Derived Neurotrophic Factor as a link between stress, neurogenesis and hippocampal atrophy in depression.
In my studies, a decrease in BDNF expression was observed in the hippocampus of depressed induced pre-clinical models, and this decrease was prevented by chronic desipramine treatment.