Major depressive disorder (MDD) is a highly prevalent and debilitating illness in the modern world. In the 1960s, the theory that low serotonin (5-HT) was a primary cause of MDD emerged due to the efficacy of 5-HT restoring drugs in treating depression. The 5-HT deficiency hypothesis of depression has since been criticized through studies not being able to directly tie low serotonin to MDD. The discovery of the antidepressant efficacy of the glutamatergic stimulant ketamine led to a reevaluation of depression pathophysiology. Modern perspectives view depression as an issue of disrupted neurocircuitry resulting from stress induced atrophy of certain limbic and cortical brain regions, such as the hippocampus and PFC, and hypertrophy in the fear evaluating amygdala, the reward evaluating nucleus accumbens, and the orbitofrontal cortex. Depression may be treated by potentiating neuroplasticity, that when combined with psychotherapy, helps individuals relearn negative emotional associations and restores dysfunctional neurocircuitry. The functioning of the serotonergic system may be viewed as a vulnerability factor in developing depression due to its involvement in stress, as well as a treatment target which indirectly primes neuroplasticity. Other neurotransmitter systems similarly represent depressive risk factors and antidepressant targets, namely the noradrenergic and dopaminergic systems. Serotonergic antidepressants such as SSRIs see high rates of prescription due to their minimal side effects. They demonstrate slower efficacy than ketamine, whose dissociative side effects and potential for abuse are unideal, demanding further research of its mechanism to find safer and more effective antidepressant targets.