Depression is frequently treated with a mix of drugs, particularly antidepressants, and psychotherapy treatments like cognitive behavioural therapy (CBT). Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), require four to six weeks to take effect.

Treatment-resistant depression can now be treated with ketamine, a hallucinogen and dissociative anesthetic. In the spring of 2019, the Food and Drug Administration (FDA) authorized Ketamine, also known as esketamine, for treatment-resistant depression.

Before the FDA authorized ketamine, it had been used off-label to treat this sort of depression for years. Antidepressants such as fluoxetine (Prozac), venlafaxine (Effexor), and sertraline do not target the same brain functions as ketamine (Zoloft). Rather, it inhibits the N-methyl-D-aspartate (NMDA) receptor.

Researchers are still unsure why some depressed people respond to ketamine while others do not. Despite this, this medicine has been used for "off-label" usage in people with treatment-resistant depression, pain management, and palliative care without FDA authorization.