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Mechanisms of Depression

Though the exact mechanisms of depression are unknown, evidence suggests that social, psychological, and biological correlates all play a significant role in the mechanism of depression.

The exact mechanisms of depression are unknown. This may be a consequence of our limited understanding of neurobiology of brain functioning. Another factor may be that depression is a heterogeneous disorder that may have a common phenomenology but has variable presentations and different etiologies.1 Evidence suggests that social, psychological, and biological correlates all play a significant role in the mechanism of depression. Genetic factors contribute about 30% to 40% of an individual’s susceptibility to depression.2 The remaining 60% to 70% of susceptibility are environmental factors specific to the individual3, such as adverse events in childhood, recent stressors, or traumatic events, etc.4,5

Neuroplasticity Theory

The neuroplasticity theory, which is gathering increasing evidence, demonstrates that patients with major depressive disorder (MDD) have altered neuronal and structural plasticity.6 Brain-imaging studies demonstrated cortical and limbic atrophy with decreased volume in the prefrontal cortex and hippocampus are related to the duration of illness in patients with depression.7,8  Neuroplasticity may be regulated by neurotropic factors such as brain derived neurotropic factor (BDNF). Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has been linked to the viability of neurons in brain circuits that regulate emotion, memory, learning, sleep and appetite.9 The neurotrophin hypothesis of depression is based on the theory that stress decreases BDNF expression and contributes to neuronal atrophy and lack of neuroplasticity important for brain function.10

HPA Axis Suppression

An average 50% of patients with depression secrete excessive amounts of cortisol.11 Abnormalities with the HPA axis in patients with depression include increased average cortisol levels, diminished suppression of cortisol when given dexamethasone, increased adrenal gland volume, increased waking salivary cortisol, diminished expression of peripheral glucocorticoid receptors, and increased CRF in cerebral spinal fluid.12,13

Neurochemical Changes

Serotonin (5-HT) is the most researched monoamine in the context of depression, possibly due to the use of selective serotonin reuptake inhibitors (SSRIs) to treat depression.11 Patients with depression have decreased endocrine responses to 5-HT, especially through presynaptic 5-HT neurons.12 The role of noradrenaline and dopamine is less understood in depression, but substantial evidence exists that they also play a role in depression. Pharmacological agents that target both of these neurotransmitters have demonstrated antidepressants effects.14

There is growing evidence that glutamate, the most prolific neurotransmitter plays a critical role in regulating a number of important brain functions including mood, emotional regulation, cognition, and neuroplasticity. Abnormal glutamate signaling has been seen in depression and pharmacological agents that modulate glutamate have antidepressant properties. This is a growing area of interest for developing new treatment for depression.15

 The main inhibitory neurotransmitter in the brain is g-aminobutyric acid (GABA).12 Several studies have demonstrated lower levels of GABA, both in the CSF and plasma.12 While data is developing regarding the role of depleted GABA in depression, to date medications that potentiate GABA are not beneficial as antidepressants.12   


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