Alternative Treatments May Help Treatment-Resistant Depression

Juan Rivera first noticed his mental health waning in college, when the things he loved — nights out with friends chief among them — stopped feeling fun. “I would be with my friends but not enjoying it fully and just sort of feeling flat,” he told The New York Times. On the worst days, getting out of bed was the most he could manage, he said. After speaking to a psychiatrist about the change, she diagnosed him with depression, later prescribing an antidepressant to treat the condition.

Unfortunately, Rivera says, the medication didn’t work. Now 35, he said that the psychiatrist prescribed various other antidepressants over the years, all of which failed to relieve his symptoms and led to a new diagnosis: treatment-resistant depression. There is no standard definition for the condition that affects roughly 31% of those treated for depression in the United States, said Dr. Gerard Sanacora, director of the Yale Depression Research Program. He says depression is generally deemed treatment-resistant if a person’s symptoms don’t improve by at least 50% after two consecutive periods of treatment with two different antidepressants.

People with certain genetic differences are at greater risk, as are those with a history of childhood trauma, anxiety, certain vitamin deficiencies, thyroid disease, heart disease or sleep apnea, said Dr. Debra Kahn, director of the Advanced Psychiatric Therapeutics Clinic at UC Davis Health. Several of those conditions can mimic or worsen depression symptoms like fatigue, making the underlying illness harder to treat. A patient’s own diminishing hope for improvement after each failed antidepressant can also stand in the way. Still, treatment-resistant doesn’t mean untreatable. Alternative strategies, including other pharmaceuticals, can help.

Talk therapy combined with antidepressants is often a first line of defense, Kahn said, but if that should fail, clinicians might try a low-dose antipsychotic or test for another medical condition that could affect brain health.

Transcranial magnetic stimulation, or TMS, is another relatively new option, having only been cleared by the Food and Drug Administration to treat depression in 2008. Yielding no long-term serious side effects, the procedure uses magnetic pulses to spark the release of mood-lifting chemicals in the brain, including norepinephrine, dopamine and serotonin, she said. A 2023 meta-analysis of 19 clinical trials found that patients on TMS plus an antidepressant were nearly three times as likely to experience remission as those who received an antidepressant with a placebo TMS treatment.

The surgical anesthetic ketamine is also growing in popularity as a depression treatment. The drug is believed to help the brain forge new or stronger connections in the circuitry that governs mood and cognition, Kahn said. A derivative, esketamine, is sold as the FDA-approved nasal spray Spravato. In a 2019 trial, just over half of patients who paired esketamine with an antidepressant saw their symptoms significantly ease, compared to about 31% of those on an antidepressant with a placebo. Spravato is the latest treatment Rivera has tried — and he’s finally reporting some success, saying it’s clearing the “negative filter” that has long tinted his mood.

Still, experts emphasize that no pill or medication can heal depression on its own. “You can take the medicine, but you also have to do the other physical and social interventions that are so important,” Yale’s Dr. Sanacora said. In practice, that means maintaining the ordinary, hard-to-sustain work of living well — getting good nutrition, adequate sleep, moving your body, breathing fresh air and building real connections with other people.