Neurotrophins Role in Depression Neurobiology: A Review of Basic and Clinical Evidence

Abstract

Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially in developed countries. Research has devoted much of its attention to this problematic and many drugs have been developed and are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs, which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even in the cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment and remission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapy present a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets, besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated with several structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophic factor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronal atrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed in depressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatment enhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here we review some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiological mechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis.

Neurobiological Background of Affective Disorders

“…In animal models, acute or chronic stress decreased BDNF levels in the hippocampus inclusive the dentate gyrus [52]. Along with this hypothesis, stress is known to reduce the branching of hippocampal dendrites [55].…”

“…Along with this hypothesis, stress is known to reduce the branching of hippocampal dendrites [55]. It additionally increases plasma and adrenal corticosterone levels and application of this hormone induces reduced hippocampal BDNF levels, mimicking stress reaction [52]. The major stress system of the body is the HPA axis, a neuroendocrine system involved in the production of the stress hormone cortisol by adrenal glands.…”

“…In patients with bipolar disorder, reduced hippocampal expression of BDNF has been reported [51] while antidepressants reversed this effect [52]. In blood of depressed patients, including patients with bipolar disorder, BDNF levels have been found to be decreased and correlated to higher depression evaluation scores [53,54].…”

Neuroadaptations of the 5-HT System Induced by Antidepressant Treatments: Old and New Strategies

“…Such neuroadaptive changes are a major argument supporting the monoaminergic hypothesis. However, a growing body of evidence also shows that downstream antidepressant actions include adaptations of signal transduction pathways and gene expression, notably neurotrophic factors and hippocampal neurogenesis [95][96][97], which favour the neurotrophic and neurogenic hypothesis of depression. In the following part of this review, we will describe the neuroadaptive changes seen after 5-HT antidepressant treatment according to this theory.…”

“…Modifications involving cell proliferation and plasticity in some brain limbic structures as the hippocampus, the frontal cortex and the amygdala have been identified in both depressive state and following antidepressant treatments [95][96][97].…”