You have been depressed for months. Your doctor prescribed an antidepressant. It helped a little —or perhaps not at all. You tried a second medication and waited another six or eight weeks. Still depressed.
Now what?
Traditionally, depression that has failed to respond adequately to two appropriate antidepressant trials has been called treatment-resistant depression. I have never particularly liked that term. Increasingly, clinicians and researchers use the phrase difficult-to-treat depression, which I think better describes what we actually encounter in clinical practice.
“Treatment resistant” sounds ominously final. Difficult to treat means something different: we haven’t yet found the right treatment—or the right combination of treatments.
First, Make Sure We Are Treating the Right Problem
When two medications have failed, my first question isn’t necessarily, “Which antidepressant should we try next?”
It is: Why isn’t this depression getting better?
The diagnosis deserves another look. Is this unipolar major depression, or could there be a bipolar component? Are anxiety, ADHD, substance use, trauma, chronic insomnia, medical illness, medications, or difficult life circumstances contributing to the picture? Was the medication taken at an adequate dose for an adequate period?
Depression is a syndrome, not a single biological disease. Two people who meet diagnostic criteria for major depressive disorder may have remarkably different illnesses. Their treatment should reflect that complexity.
The Problem With Simply Trying Another SSRI
SSRIs—including medications such as sertraline, escitalopram and fluoxetine—are useful and generally well-tolerated antidepressants. But they aren’t magic bullets.
Large studies have shown that only about one-third of patients achieve remission with an initial antidepressant treatment. That means partial response or nonresponse is hardly unusual.
One easy mistake is to keep moving sideways: SSRI number one doesn’t work, so we try SSRI number two. Then number three. Then perhaps number four.
Sometimes that works. But after repeated failures, we need to think more broadly.
In my clinical experience, augmentation is extraordinarily common. Rather than discarding a medication that is providing partial benefit, we can sometimes add another medication with a different pharmacologic action.
Augmentation Opens Many Possibilities
One important strategy is adding a low dose of an atypical antipsychotic medication. Even that name has become somewhat misleading. Several drugs in this category are FDA-approved as adjunctive treatments for major depressive disorder and are routinely used in patients who are not psychotic.
Other augmentation strategies may involve lithium, thyroid hormone, or antidepressants from different pharmacologic classes. The choice depends upon the patient’s symptoms, previous responses, side effects, medical history and other medications.
The point is not simply to add more drugs. It is to develop a rational treatment strategy based upon what has and has not worked.
Newer Medications Work Differently
For decades, antidepressant development focused heavily on serotonin, norepinephrine and dopamine. That landscape is changing.
Auvelity, FDA-approved for major depressive disorder in 2022, combines dextromethorphan with bupropion (Wellbutrin). Its pharmacology includes NMDA receptor antagonism and sigma-1 receptor activity, representing a substantially different approach from conventional SSRIs.
Ketamine and esketamine have also changed our understanding of what an antidepressant can be. Their effects on glutamatergic signaling have helped move the field beyond the traditional monoamine model of depression.
These treatments are not appropriate for everyone, but they demonstrate an important point: failure to respond to SSRIs does not mean that a person’s depression cannot respond to treatment.
Treatment Doesn’t Have to Come From a Bottle
Transcranial Magnetic Stimulation (TMS) is an FDA-cleared, noninvasive treatment for major depressive disorder. Magnetic pulses stimulate targeted brain regions involved in mood regulation. It has become an important option for patients who have not obtained sufficient benefit from medications or who cannot tolerate medication side effects.
Psychotherapy remains equally important. For some patients, it should be part of treatment from the beginning; for others, it may ultimately prove more important than another medication trial.
Cognitive Behavioral Therapy (CBT) can be particularly useful for identifying and modifying patterns of thought and behavior that perpetuate depression. Other forms of psychotherapy may address relationships, loss, trauma, personality patterns, chronic conflicts and the psychological meaning of the depression itself.
And there is another intriguing frontier: psychedelic-assisted psychotherapy. Compounds such as psilocybin are being actively studied for depression, including difficult-to-treat forms. The early research is interesting, but psychedelic-assisted psychotherapy with psilocybin is not currently an FDA-approved treatment for depression. Research should not be confused with established clinical practice.
Two Failed Medications Are Not the End of Treatment
Perhaps the most important message is that unsuccessful treatment is information.
If the first medication doesn’t work, we learn something. If the second doesn’t work, we learn more. At that point, simply repeating essentially the same strategy may make less sense than reconsidering the diagnosis and broadening the therapeutic approach.
Modern psychiatry offers considerably more than a succession of SSRIs: augmentation strategies, different antidepressant mechanisms, psychotherapy, CBT, TMS, ketamine-related treatments and emerging therapies.
The question after two unsuccessful medications shouldn’t be, “What is left?”
There is quite a lot left.
The better question is: “What have we learned so far, and what treatment strategy makes the most sense from here?”