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The Director Discusses:

Treatment-Resistant Depression: The Problem Reconsidered

Photo: John F. Greden, M.D. Clinical Depression does not always respond to our available treatments. Clinicians use the term “treatment resistant depression,” or “TRD,” when an episode does not respond to at least two courses of evidence-based antidepressant medication that were long enough and included the appropriate dose.  This definition applies whether the treatments are medications, psychotherapy, other approaches, or combinations of these.

TRD develops in nearly a third of all people with major depression -- this is a substantial number of people who do not respond to effective, well-known treatments. Major depression itself has been ranked by the National Quality Forum as the #1 “high-impact” Medicare condition, surpassing even such significant disorders as asthma, diabetes, and lung cancer. It has been ranked as the second-most-costly illness in the entire U.S. population.  This is to say nothing of the enormous emotional and physical burdens that those with depression endure, particularly those who cannot achieve wellness after determinedly following treatment regimens that have brought relief to others.

How much each depression subtype contributes to overall burden remains unknown, but TRD creates perhaps the largest and most destructive contribution to health care burdens. We resolutely need to focus on what we can do to prevent TRD’s development, and more promptly treat these more severe episodes should they occur.  Fortunately, promising new avenues for treatment options are generating much-needed optimism.

First, let us recognize that “treatment resistance” does not mean that people with TRD will never improve, or that their depression will never be successfully treated. If you are among the millions of people living with TRD, know that you are not alone and that your illness is the subject of renewed efforts to elucidate and refine new and effective treatments. A new NIMH initiative has prioritized the TRD problem, hopefully mobilizing the most creative minds in our field and ideally creating networking alliances that can be sustained.  The latter is especially important; it is unlikely there will be one treatment solution for TRD.

Prevention of TRD should be our real goal. How might this be done? Detecting the earliest signs of depression and intervening early is crucial. We know that untreated depression, with multiple depressive episodes over long periods, cumulates in brain changes that, in turn, catalyze and fuel treatment resistance.  Earlier screening to identify and treat depression soon after an episode begins needs to be coupled with attainment and maintenance of wellness. Stated differently, preventing the recurrences that characterize untreated depression is essential to conquering this looming public health issue.

Discontinuing treatments prematurely may also contribute to TRD. While it is understandable that people may wish to abandon their treatments once they have improved, because of expense, side effects, stigma, or misinformation, such a course of action is often ominous.  Untreated, this chronic disorder tends to strike again, often in response to unavoidable stresses.  No one person could be expected to conquer all these obstacles alone, but you owe it to yourself to follow your doctor’s guidance and see your treatment through. Progress happens gradually in a way that can be difficult to measure or recognize. You may be closer to that “wellness” goal than you think.

A number of evidence-based treatment strategies may be quite helpful in treating depressions when medication alone has not been able to fully resolve the syndrome.  Treatment that combines psychotherapy and medications has been shown repeatedly to improve outcomes and help in preventing relapse. Should these not work, various brain stimulation therapies, including rTMS (transcranial magnetic stimulation), ECT (electroconvulsive treatment), or VNS (Vagus Nerve Stimulation) may provide relief to people whose symptoms have not improved even after trying an array of traditional therapies.  These “neuromodulation” techniques, which use electrical or magnetic energy to stimulate the brain and alter (or “neuromodulate”) brain activity, offer important treatment options for patients with difficult-to-treat depression.

Peer support services, support groups, the addition of methylfolate, Vitamin D, and possibly omega-3 are additional tools to boost other treatments and provide encouragement and motivation for people with longer-term depressive symptoms. And we can never underestimate the mighty influence of self-care: attending to one’s nutrition, sleep, exercise, and limiting substance misuse.  These can be incredibly effective against difficult-to-treat depression.

For people with loved ones living with TRD, and everyone else?  In many ways, fighting stigma can be one of the most effective things the rest of us can contribute to preventing TRD.  TRD can be difficult and frightening, but it is comparable to other medical conditions such as heart disease, diabetes, and cancer, and it is treatable, so any remaining stigma that might prevent individuals from seeking out and adhering to treatment is simply unjustified.  

Networks of experts are working to conquer this scourge. Aided by families, promoted by education, and supported by new research, together, we will win this fight.


John F. Greden, M.D.

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