Juan Rivera, an immigration lawyer in Miami, has faced ongoing challenges with depression that did not respond to traditional antidepressant medications. Now 35, Rivera recalls that during college he gradually lost interest in activities he once enjoyed, such as socializing with friends, and often struggled with low energy and motivation. After trying multiple antidepressants over several years without improvement, he was diagnosed with what clinicians refer to as treatment-resistant depression.

Treatment-resistant depression generally describes a condition in which patients do not experience adequate relief after trying at least two different antidepressant medications over a period of four to six weeks each, according to experts such as Dr. Gerard Sanacora, director of the Yale Depression Research Program. The definition and classification vary, but an estimated 31 percent of individuals receiving treatment for depression in the United States fall into this category.

Various factors may contribute to the difficulty in treating this form of depression. Dr. Debra Kahn, director of the Advanced Psychiatric Therapeutics Clinic at UC Davis Health, highlights that patients with histories of childhood trauma, coexisting anxiety, vitamin deficiencies, thyroid or heart conditions, and sleep disorders may be more susceptible to treatment resistance. Genetic predispositions related to insomnia and certain personality traits have also been linked to poorer responses to antidepressants, revealing the complex interplay of biological and environmental influences.

For patients who do not respond to conventional antidepressants and psychotherapy, additional therapies are often considered. At UC Davis, physicians may prescribe adjunctive medications such as low-dose atypical antipsychotics or lithium. Non-pharmacological options include transcranial magnetic stimulation (TMS), a procedure approved by the U.S. Food and Drug Administration (FDA) in 2008. TMS involves the use of magnetic pulses to stimulate brain regions that regulate mood, showing increased remission rates in studies when combined with antidepressants.

Another emerging treatment is the use of ketamine and its derivative esketamine. The FDA approved Spravato, an intranasal esketamine spray, in 2019 specifically for treatment-resistant depression. Clinical trials have reported significant symptom improvement in over half of patients using esketamine alongside antidepressants compared to placebo controls. Researchers believe ketamine promotes neural connectivity in brain areas involved in mood regulation. Additionally, psychedelic substances like psilocybin and ibogaine are under investigation for their potential therapeutic effects.

Rivera recently began treatment with Spravato and noticed symptom relief shortly after his second session, describing it as lifting a “negative filter” that had clouded his mood and thinking. Nevertheless, experts caution that managing treatment-resistant depression often requires a comprehensive approach. Dr. Kahn emphasizes that no single medication is likely to be a definitive cure, and combining pharmacological therapies with lifestyle changes and social engagement remains essential. Dr. Sanacora adds that encouraging patients to participate in activities outside of medication is a critical component of recovery.