New Strategies for Treatment-Resistant Depression
The most effective treatments are not traditional antidepressant medications.
Updated January 21, 2025 | Reviewed by Lybi Ma
A new paper in the journal Neuropsychopharmacology indicates that brain stimulation treatments such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) were among the most effective treatments for treatment-resistant depression , usually defined as severe depressive symptoms that have not improved despite treatment with at least two standard interventions. The study investigated the results of 25 different standard treatments in studies that included over 10,000 participants. Also among the top most effective treatments was ketamine . Minocycline, a drug perhaps better known as a treatment for acne, was, to this psychiatrist at least, a bit of a surprise.
Electroconvulsive therapy was arguably the first treatment for serious depression to be developed. The Hungarian psychiatrist, Joseph Ladislav von Meduna published a report in 1935 that artificially induced seizures in patients with severe depression resulted in dramatic improvements for many. Improvements in anesthesia techniques over the ensuing decades have made the treatment much safer and it remains a treatment of choice for certain kinds of serious depression.
Like ECT, transcranial magnetic stimulation (TMS) is also a brain stimulation treatment but delivers much smaller bursts of electrical energy using magnetic pulses. The study also gave high marks to a new version of TMS called theta burst stimulation (TBS), in which the magnetic pulses are delivered at frequencies that mimic the brain's natural electrical rhythms.
Ketamine targets glutamate, one of the brain’s communication chemicals or neurotransmitters, but one that other antidepressants don’t have much effect on.
Minocycline, in addition to the antibiotic effects that make it useful for treating acne, also has neuroprotective effects, defending brain cells from a damaging process called oxidative stress . This toxic process is caused by dangerous molecules generated during many chemical reactions in the body and not sufficiently neutralized by the body’s defenses against them.
By and large, antidepressant medications work by altering levels of brain chemicals called neuroamines. These are the nitrogen-containing molecules that serve as chemical messengers in the brain. Serotonin is probably the most familiar. Since the first of these antidepressants, imipramine was introduced in the 1950s, every subsequent medication developed has been essentially a variation on this theme. While these medications are highly effective for some people with depression, as this post shows, there is a sub-set of depressive disorders in which targeting neuroamine levels simply doesn’t work.
Brain stimulation treatments such as ECT, TMS, and TBS appear to directly stimulate underactive areas of the brain and restore a normal balance of electrical activity to brain function. Ketamine appears also to stimulate brain cells directly, although through chemical rather than electrical effects. The neuroprotective effect of minocycline is also in line with the idea that underactive neurons in certain areas of the brain cause some cases of serious depression. (By the way, lithium, the “magic bullet” for so many people with bipolar disorder , also works through neuroprotective mechanisms.) Minocycline appears to provide a layer of protection that allows these neurons to function normally again.
Understanding how these new treatments treat depression will undoubtedly stimulate more research into the pathological mechanisms of mood disorders and result in even more novel treatments for these debilitating illnesses.
Saelens, J., Gramser, A., Watzal, V. et al. Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis of randomized controlled trials. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-02044-5
For a comprehensive discussion of ECT, TMS and TBS, see: "Brain Stimulation Treatments" in Mondimore, F.M., Bipolar Disorder, A Guide for You and Your Family, 4th ed. (Baltimore, Johns Hopkins University Press) 2020. https://www.amazon.com/Bipolar-Disorder-Guide-Hopkins-Health/dp/1421439…
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Francis Mondimore, M.D., is a psychiatrist with over 30 years of experience treating people with psychiatric disorders. He is an Associate Professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine.
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