NEW YORK — Juan Rivera, a 35-year-old immigration attorney in Miami, experienced what clinicians refer to as treatment-resistant depression during his college years, when activities he once enjoyed, like spending time with friends, ceased to bring him satisfaction. Despite multiple antidepressant prescriptions over the years, Rivera saw little improvement, a common frustration among those with this form of depression.
Treatment-resistant depression lacks a universally accepted definition, but many experts consider it present when a patient shows less than a 50% improvement after trying two successive antidepressants for four to six weeks each, according to Gerard Sanacora, director of the Yale Depression Research Program. Although the condition can be challenging to manage, it is not insurmountable, with various therapies—often in combination—offering hope for improvement or remission.
Several factors contribute to the difficulty of treating depression effectively. Debra Kahn, director of the Advanced Psychiatric Therapeutics Clinic at UC Davis Health, highlighted that individuals with a history of childhood trauma frequently experience more persistent depressive symptoms. Comorbidities such as anxiety, vitamin deficiencies, thyroid disorders, heart disease, and sleep apnea can also complicate treatment by mimicking or exacerbating depressive symptoms.
Genetic influences are another important consideration. Research from 2025 indicates that genetic predispositions to insomnia and certain personality traits, like neuroticism, may increase the risk of treatment resistance. Patient expectations play a psychological role as well; those who have endured multiple unsuccessful treatments may have diminished hope for future therapies, potentially affecting outcomes, Sanacora noted.
Approximately 31% of people treated for depression in the United States fall into the treatment-resistant category, according to a 2021 study. Advances in treatment options have brought fresh possibilities. Transcranial magnetic stimulation (TMS), when combined with antidepressants, has proven effective; a 2023 meta-analysis found that patients receiving both were nearly three times more likely to achieve remission compared to those on antidepressants with a sham TMS procedure.
Pharmacological innovations have also gained traction. Ketamine, traditionally used as an anesthetic, is emerging as an option for treatment-resistant cases. The U.S. Food and Drug Administration approved an intranasal esketamine spray, Spravato, in 2009. Clinical trials demonstrated that over half of the patients receiving esketamine alongside an antidepressant experienced significant symptom reduction within 28 days, compared to just 3% on antidepressants with placebo.
Kahn explained that ketamine may promote recovery by enhancing the brain’s ability to form new connections in mood-related neural networks. Psychedelic substances such as psilocybin, ibogaine, and 5-MEO-DMT are also under investigation for similar neural effects.
Rivera recently began treatment with intranasal Spravato and reported noticeable improvement after his second session, describing the medication as helping to remove a “negative filter” affecting his mood and thoughts.
Experts emphasize that no single medication is a universal cure for treatment-resistant depression. Kahn stressed the importance of combining medical, psychological, and lifestyle interventions. Sanacora encourages his patients to engage in social activities and maintain physical routines, underscoring the need for a holistic approach alongside medication.
“You can take the medicine, but you also have to do the other physical and social interventions that are so important,” Sanacora said.