Paul Melançon, 57, tried dozens of antidepressants across multiple drug classes — first alone, then in combinations that his doctors hoped might work better. None provided lasting relief from his severe, recurrent depression. At best, a medication helped only briefly before losing its effects. At worst, the side effects proved too severe to tolerate before the drug had a chance to work.
That cycle of trial and disappointment eventually pushed the Atlanta-based singer-songwriter to the Peruvian Amazon. There, he drank the psychedelic plant medicine ayahuasca, which he had read — and some studies show — may help when other treatments fail.
For a few weeks afterward, he felt something rare: relief. As that feeling faded, he reluctantly started another antidepressant, expecting little. But this time, it worked.
“I had a pretty good stretch on it — about three years,” Melançon says. “I didn’t have many side effects, and I was pretty level.”
He believes — and research supports — that the ayahuasca altered something in his brain to make it more responsive to medication.
But the relief didn’t last. When that antidepressant stopped working, he went back to cycling through treatments. Today, a combination of medications keeps him more stable, but not well. “It’s an improvement over where I was [before], but it’s not great,” he says.
For the many people like Melançon, who’ve tried multiple antidepressants without success, “This is not the end of the road. There is so much more we can do,” says Sarah H. Lisanby, MD, founding dean and foundation professor at the John Shufeldt School of Medicine and Medical Engineering at Arizona State University.
The key is understanding a few critical points:
- Failure of one treatment doesn’t predict the outcome of the next.
- Managing depression often requires a complex, long-term approach.
- Even after many setbacks, you still have options.
What Is Treatment-Resistant Depression?
Depression is described as treatment-resistant when it doesn’t get better after at least two trials of antidepressants taken at the right dose and for long enough to allow them to work. “As many as half of patients with depression fall into that group,” says John Krystal, MD, professor of psychiatry, neuroscience, and psychology at Yale School of Medicine.
“Treatment-Resistant” Is Not “Untreatable”
“I don’t think there is such a thing as ‘untreatable’ depression,” Krystal says. “There are many ways to add different medications to the standard antidepressant to try to improve response. Just because a person hasn’t responded to a particular medication or a group of medications doesn’t mean they aren’t going to respond [to something else].”
Newer treatments that fall outside the standard antidepressant paradigm, such as esketamine (Spravato) and transcranial magnetic stimulation, are giving people with treatment-resistant depression much better chances, Krystal says. While previous research found that not getting better after one year of treatment put the odds of improvement over the next four years at about 20%, “with these newer interventions, expectations for response can be very high – in the 70%-80% range,” he says.
Without treatment, just like with cancer or heart disease, "depression can lead to preventable death," Lisanby says. “Depression can kill – with suicide.”
After Antidepressants — What’s Next?
If you’ve tried a few courses of antidepressants without much luck, your doctor might first check whether you are also receiving some type of psychotherapy. Although many medical treatments exist for depression, it is not a condition that can always be treated with medication alone.
Talk therapy
“Depression is mostly an environmental disorder,” Krystal says. “For most people, major life issues trigger their depression so psychotherapy is important.”
In online forums such as Reddit, people who describe their treatment as a “success” often point to cognitive behavioral therapy (CBT), added to medical treatments and lifestyle changes, as the strategy that finally made all the difference. Some describe CBT and antidepressants as interdependent. “I still use CBT skills, but antidepressants allow them to work,” one Reddit user says.
Medication add-ons
Next, doctors might add another medication to your regimen. Though depression is not a psychotic disorder, antipsychotic medications can improve some people’s response to antidepressants.
Melançon’s current regimen, which he’s in the process of changing, includes an antidepressant plus an antipsychotic. He agrees, it made the antidepressant work better, but with a caveat. “I don’t have big lows, which is good, but I also don’t have big highs. I’m flat, ” Melançon says.
Advanced therapies
When standard medications and psychotherapy aren’t enough, people may move on to esketamine or one of several types of neuromodulation — electrical stimulation used to change or reset the abnormal nerve activity causing or worsening the depression.
There are a few types of neuromodulation.
Transcranial magnetic stimulation. In transcranial magnetic stimulation (TMS), a magnetic field directed at the brain is rapidly switched on and off, causing tiny electric pulses. “The electrical current that’s induced in the brain stimulates neurons in the circuitry related to depression,” Lisanby says. “With repeated stimulation, this change can make those circuits more effective.”
During the procedure, you feel a tapping on your head, but no pain. Some people have a headache afterward. The treatment happens over several sessions.
Electroconvulsive therapy (ECT). This treatment happens under general anesthesia. Small electrical currents go through the brain to cause a seizure. It’s believed that the treatment changes brain chemistry in a way that quickly improves depression and some other mental health conditions.
“It has a high response and remission rate,” Lisanby says. “It can be highly effective, even in severe depression. It works when everything doesn’t.” When people are in a suicidal crisis, she says, “within a few treatments, that impulse to kill themselves has been relieved.”
ECT’s reputation, however, often precedes it. In the early days of ECT, which has been used since the late 1930s, people received high doses of electricity to the whole brain without anesthesia, which was extremely painful and caused injuries.
Today, patients receive lower doses of electricity targeted toward the most relevant parts of the brain while trying to avoid parts of the brain related to memory. Memory loss has been a well-known side effect of ECT. Modern ECT can still cause memory loss, usually around events in the days, weeks, or months before the treatment. Most people get their memory back within a few months after treatment ends.
Vagus nerve stimulation (VNS). This therapy works through a device implanted just under the skin of the chest. It sends electrical pulses to areas of the brain that affect mood. It’s been called a “pacemaker for the brain.” It’s approved for people who have not benefited from at least four courses of antidepressants, electroconvulsive therapy, or both. It’s important to note that it may take up to a year to see the full effects, and insurance coverage is not a given, Lisanby says.
Ketamine and esketamine. Melançon has just gotten insurance coverage for ketamine, which he’ll start soon.
Ketamine is an anesthetic that’s been in use for more than 50 years, and it is the “k” in the party drug “Special K.” It has been used for sedation, pain relief, and to stop suicidal crises. More recently, it has shown major benefits for people with treatment-resistant depression, often providing relief within hours or days.
Because ketamine, in some doses and formulations, can cause a dissociative experience, or a “trip,” its effects on depression are often compared to those of psychedelics such as ayahuasca, psilocybin, and lysergic acid diethylamide (LSD).
That’s what got Melançon interested in it. “Ayahuasca was the only thing that created high moments for me, moments where I really felt good, so I’m very interested in psychedelics as a depression treatment. So ketamine is something I’ve been wanting to try for a while now.”
Esketamine is an FDA-approved nasal spray formulation of ketamine. You take it yourself under the supervision of a healthcare provider at a healthcare office that is certified to administer it, or you may receive an IV infusion of ketamine. Some clinics offer ketamine-assisted psychotherapy that integrates the two treatments.
Krystal, whose research led to the discovery of ketamine’s antidepressant effects, stresses that people who don’t benefit from standard antidepressants, TMS, or ECT can still benefit from ketamine. Likewise, those who don’t find relief from ketamine may still respond to TMS or ECT.
Getting Through the Day-to-Day
While you work through treatment options to find a regimen that helps you, you’ve still got to get through the day-to-day.
Habits that keep you resilient are important, Krystal says. It's key that you:
- Stay in psychotherapy to maintain coping skills.
- Get proper sleep, as poor sleep worsens depression.
- Exercise, as it has measurable antidepressant effects.
- Eat a healthy diet to support brain function.
- Stay connected to others, as isolation can worsen symptoms.
It may seem like tired advice that you’ve heard too many times, but these are all part of your treatment, Krystal says, even if they are difficult to do.
Melançon’s approach is even simpler. He avoids thinking too far ahead. “I try to just deal with things day to day,” he says.
He also leans on something many people say is critical: an understanding partner, one who has reasonable expectations of him.
A Chronic Condition, Not a One-Time Fix
For many people, treatment-resistant depression is not something you cure. It’s something you manage long-term, such as diabetes or high blood pressure. Ongoing success depends on staying on top of treatment. Successful treatment is likely to involve a multipronged approach, such as psychotherapy and a combination of medications, rather than a single strategy.
A Reddit user defined treatment success as feeling excited about an upcoming job opportunity, finding his anxiety to be manageable, and not having suicidal thoughts in over a year. Getting to this point and staying there was the result of psychotherapy, exercise, journaling, meditation, past participation in a psychedelic psilocybin trial, and ongoing commitment to staying well.
Recovery may not look like you thought it would. For some, it means relief from symptoms. But for others, it’s regaining function and feeling good despite some symptoms or flares. It’s finding the right combination of treatments and management strategies; changing course every time it’s needed; and knowing there is always another course.
“Even when you’re in the depths of depression, when you’re on the brink of wanting to end your life because you’re in such misery...there is hope available,” Lisanby says.
Melançon’s hope is the way he felt after his psychedelic retreat in Peru. He remembers what it’s like to feel good and is hopeful he can get back there again. “That’s the feeling I’m chasing.”
Show Sources
SOURCES:
Frontiers in Psychiatry: “The therapeutic potential of ayahuasca in depression, generalized anxiety, and substance use disorders: modulation of the depressive burden in a longitudinal study.”
Cleveland Clinic: “Treatment-Resistant Depression,” “Vagus Nerve Stimulation.”
Patient Preference and Adherence: “Treatment-resistant depression: therapeutic trends, challenges, and future directions.”
Reddit: “Any success stories from people who had debilitating depression and/or anxiety?”
CMAJ: “Neuromodulation for treatment-refractory major depressive disorder.”
Mayo Clinic: “Transcranial magnetic stimulation,” “Electroconvulsive Therapy,” “Vagus Nerve Stimulation.”
The American Journal of Psychiatry: “A Brief History of Electroconvulsive Therapy.”
Frontiers in Human Neuroscience: “Ketamine: 50 Years of Modulating the Mind.”
Harvard Medical School: “Ketamine for treatment-resistant depression: When and where is it safe?”
