Rethinking Treatment-Resistant Depression: New Hope Ahead?

Treatment-resistant depression (TRD) remains a significant challenge for psychiatrists and family physicians alike, defying multiple standard treatments and complicating patient care. However, despite its clinical importance, a universally accepted definition is still lacking, making it difficult to determine its prevalence and adding uncertainty to treatment decisions.

A type of major depressive disorder, TRD fails to improve after multiple standard treatments. However, the lack of a consensus definition makes it difficult to determine its true prevalence and complicates clinical decision-making.

The lack of a clear definition exists because “we don’t have the science. We have a lot of good science, but it’s only the science of our day,” Philip Muskin, MD, professor of psychiatry at Columbia University Irving Medical Center in New York City, told Medscape Medical News.

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most widely used definition of TRD — an inadequate response to at least two antidepressants, despite adequate treatment duration and adherence.

TRD is particularly challenging to manage due to a complex interplay of biological and psychosocial factors that sustain the condition.

Biologically, dysfunction in neurotransmitter systems may blunt the efficacy of standard antidepressants, whereas neuroinflammation has been implicated in TRD. Additionally, genetic predisposition can increase susceptibility to TRD and contribute to poor response to conventional treatments.

Psychosocial factors also play a significant role. Chronic stress can keep the body’s stress-response system in a prolonged state of activation, leading to inflammation and hormonal imbalances that exacerbate depression. Over time, persistent stress may erode the brain’s resilience mechanisms, making it more difficult for treatments to restore normal function.

Furthermore, early life trauma and social isolation have been strongly associated with TRD, further complicating recovery.

It’s estimated that about 30% of individuals with depression meet the current FDA/EMA definition of TRD.

However, a significant percentage of these patients may actually be “pseudo-resistant” due to inadequate antidepressant trials or nonadherence to treatment. Optimizing dosage, managing side effects, and improving adherence can, in some cases, convert “nonresponders” into responders.

Antidepressants can be highly effective for some individuals, but they come with side effects and require a strong commitment to consistent use, said Muskin. 

He also pointed out that there is a small subset of patients who deny their illness. “Denial is part of the illness itself. I’ve worked with patients who were internally conflicted about getting better — where their illness held a certain psychological space, creating resistance to recovery,” Muskin explained.

For other patients, the ‘sick role’ can serve as a psychological refuge, relieving them of certain responsibilities. However, it’s important to emphasize that these patients are in the minority and that “the vast majority of patients are desperate to recover,” he added.

Despite the challenges of TRD, several current treatments have been shown to be effective.

One recent novel addition to the treatment toolbox for TRD is esketamine nasal spray (Spravato), which has been shown to rapidly relieve depressive symptoms when combined with an oral antidepressant, in patients who failed to improve with multiple prior treatments.

In the ESCAPE-TRD study, which included 675 adults with TRD, esketamine was associated with significantly increased rates of both depression and functional remission compared with extended-release quetiapine.

Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada, said he’s seen the benefits of the glutamate-targeting agent in his clinical practice.

“I had a lot of patients in my practice who were not in remission, had a low quality of life and poor functioning and they had so-called difficult-to-treat depression. Then I gave them a glutamate drug and their depression is in full remission and they now have their lives back,” McIntyre told Medscape Medical News.

As a result, McIntyre said, TRD, which is a moniker that’s been around for almost 50 years, will likely need to be revisited and redefined at some point.

“If a patient exhibits an inadequate response to selective serotonin reuptake inhibitors (SSRIs) but benefits from esketamine, we do not call the patient ‘treatment-resistant’. We would say they’re on the wrong medication,” McIntyre added.

“My personal view is we should be using language which is used in other areas. For example, it might be more helpful to say SSRI-resistant. That would not imply their resistance to other mechanisms. That would be no different than saying that a patient who has pneumonia may be resistant to penicillin, but they may not be resistant to another antibiotic,” McIntyre said.

Some second-generation antipsychotics have also proven to be effective as adjunctive treatment for TRD including aripiprazole, brexpiprazole, cariprazine, and quetiapine XR, as well as the combination of olanzapine and fluoxetine.

When medications alone aren’t enough, neurostimulation may help some patients.

Repetitive transcranial magnetic stimulation and intermittent theta-burst stimulation (iTBS) are FDA-approved for individuals with TRD.

Electroconvulsive therapy (ECT) is the oldest neurostimulation treatment and is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting noninferiority to acute intravenous ketamine.

Vagus nerve stimulation is FDA-approved for use in adults with TRD who fail four or more medications, ECT, or both.

Manual-based psychotherapies have been shown to enhance and sustain the benefits of antidepressant treatments in TRD, leading to more durable recovery but are not established as efficacious on their own in TRD.

Several novel therapies not yet approved in the United Staes have shown considerable promise in TRD.

They include intravenous ketamine, which has been found to rapidly improve depressive symptoms and suicidal ideation in adults with TRD. In one small study more than half of patients with TRD achieved remission (Montgomery-Asberg depression rating scale score < 10) after three infusions of ketamine over 11 days.

An extended-release oral tablet formulation of ketamine has also shown promise for TRD in a phase 2 proof-of-concept study.

Psychedelics like psilocybin, the active compound in “magic mushrooms”, and methylenedioxymethamphetamine, the psychoactive drug often referred to as ecstasy, are being studied in controlled therapeutic settings for TRD and posttraumatic stress disorder.

In a phase 2 study, a single dose of psilocybin, along with psychotherapy, led to significant reductions in core symptoms of TRD for at least 3 weeks, even in patients with long-term depression.

Psychedelics significantly alter the brain’s connectivity patterns, but the full narrative of their effects has yet to be fully explored, Muskin noted.

“Some people — not all — will have a profound experience and get completely better and some actually get worse, so there is the full gamut of human experiences. Nothing in medicine works 100%,” he said.

“Unfortunately,” he added, “there is already a cottage industry providing psilocybin and a microdosing trend, which worries me. There’s no question that some people find it a benefit. Could it be of harm? You bet.”

Other investigational treatments for TRD include lithium, thyroid hormone, buspirone, L-methylfolate, S-adenosylmethionine, and various anti-inflammatory agents such as cyclooxygenase-2 inhibitors, minocycline, statins, and tumor necrosis factor–alpha antagonists, as well as zuranolone and the dextromethorphan-bupropion combination.

Digital therapeutics are also being developed as an aid to mental health treatment.

Last year, the FDA approved the first prescription app for the adjunctive treatment of major depression. The smartphone-based Rejoyn app, is intended for adults aged 22 years or older who don’t fully respond to antidepressants and are under the care of a clinician.

When it comes to TRD, said Muskin, the bottom line is that comes to TRD, “every once in a while, you find the right combination of treatments and the patient gets better, and that might include traditional treatments, it might include other drugs that are not typically used for depression, it may include some integrative medicine treatments.”

“For some people, the ‘treatment,’ is to help them cope with their illness because it’s not curable but we try to get people back to regular mood,” Muskin said.

Muskin had no relevant disclosures. McIntyre had received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, and Neurocrine.