A Deep Dive Into The Science of Depression

A Deep Dive Into The Science of Depression

March 4, 2021

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.

mechanisms of depression

The exact mechanisms of depression are unknown. This may be a consequence of our limited understanding of the 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 is contributed by environmental factors specific to the individual, including factors such as adverse events in childhood, recent stressors, or traumatic events.3,4,5

Neuroplasticity Theory

The neuroplasticity theory, which is gathering increasing evidence, indicates that patients with major depressive disorder (MDD) have altered neuronal and structural plasticity.6 Brain-imaging studies demonstrated that 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), which 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 therefore contributes to neuronal atrophy and lack of neuroplasticity important for brain function.10

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

According to one meta-analysis, approximately two thirds of patients with psychotic 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 cerebrospinal 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.12 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, but substantial evidence exists that they also play a role in depression.14 Pharmacological agents that target both of these neurotransmitters have demonstrated antidepressant 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.15 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 treatments 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 cerebrospinal fluid (CSF) and plasma, in patients with depression.12 While data is developing regarding the role of depleted GABA in depression, medications that potentiate GABA have not demonstrated a robust benefit similar to other antidepressants.12    

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