Voltage-gated sodium (Na+) channels (VGSCs) are responsible for action potential initiation and propagation in most electrically excitable cells which are implicated in a wide range physiological functions including neuronal signalling, muscle contraction, endocrine secretion, cardiac pacemaking, as well as neurotransmitter releases. VGSCs are targets for certain antidepressant drugs such as tricyclic antidepressant and duloxetine. Sodium channel gene mutations are associated with a variety of inherited diseases known as channelopathies such as epilepsy, chronic pain, migraine and cardiac arrhythmia. A common clinical features of many channelopathies are the paroxysmal symptoms, discrete attacks, usually precipitated by a physiologic stress, and most people return to normal or near normal function between attacks similar to depression. It has been demonstrated that sodium channel gene mutations are also associated with increased susceptibility to suicidal attempts, sleep disturbance, dysregulation of diurnal rhythm in corticosterone secretion indicating hypothalamic-pituitary-adrenal axis dysfunction. Neuromodulation of voltage-gated sodium channels plays an important role in regulating neuroplasticity and cellular resilience mediated by cAMP-dependent PKA and PKC that could contribute to pathophysiology of depression. Antidepressant drugs and somatic therapies (e.g., electroconvulsive therapy, and transcranial magnetic stimulation) regulate a number of neurotrophins such as cAMP response element binding protein and brain derived neurotrophic factor which have the potential to increase neuroplasticity and cellular resilience. These findings support the hypothesis that sodium channel dysfunction may be involved in the etiology of depression.