Addressing Treatment-Resistant Depression: Walking a Clinical Tightrope

depressed man
depressed man
The heterogeneity of depression as a disease contributes to the challenge in identifying effective treatments.

Treatment-resistant depression (TRD) poses a dire challenge to the field of clinical psychiatry, exposing just how little we know about which depression treatments work for individual clients.

Treatment resistance is experienced by 45% of patients with a major depressive disorder and is defined as nonresponsiveness to at least 2 antidepressant therapies.1 Highly associated with suicidal ideation and suicide attempts, TRD contributes to nearly one-third of patients attempting suicide in their lifetime, a rate more than double that of their treatment-responsive peers.2,3

The Toll of an Untreatable Disease

Gerard knows the difficulties of this disease better than most. A veteran living with depression and suicidal ideation, he has tried almost every treatment modality available to find relief. “I’ve taken most categories of antidepressant medication, undergone transcranial magnetic stimulation, attended multiple IOPs [Intensive Outpatient Programs], and I go to therapy a couple of times a week,” Gerard explains. He said some therapies provided relief for a while and then stopped. Others never really helped, and some even felt actively counterproductive.

For Gerard, his illness meant that work was no longer an option. “My depression amplifies exponentially when I try [to work],” he explains, “which sucks, because I’d like to…I don’t know where I would be if I had to work to keep a roof over my head and food on my plate. Realistically, I’d probably be dead already.”

For those less financially independent, the chronic stress of balancing full-time work with variable levels of cognitive function makes for a precarious situation. Gerard continues, “Part of the problem is that our society isn’t structured to accommodate someone working who has good days and bad days. You can either be scheduled or you can’t, or you’re just flat out expected to show up every day, regardless of illness and symptoms.” Even worse, this chronic stress can also cause structural modifications to the brain that often exacerbate depressive symptoms.4

Gerard knows that his depression and suicidal ideation have probably pushed some friends away, too. The pressure to “get better,” and a patient’s subsequent failure to do so, often puts a strain on friendships. “It’s hard not to be an emotional drain on those around you, even if only passively. …Inevitably [friends] get tired of cancelled plans or hanging out with a zombie.”

Even if friends remain, the stress of TRD can often be compounded by well-meaning colleagues who suggest natural remedies like yoga, long walks in the woods, and herbal supplements as curative measures. While lifestyle changes like exercise, healthy diet, and social engagement can alleviate depressive symptoms for some patients, especially in the short term, it can be emotionally exhausting for patients to field new treatment suggestions from friends and colleagues.

What Works, What Doesn’t

Clinicians must maintain a delicate balance when pursuing treatment options to avoid compounding their patients’ stress. Although new antidepressant treatments are frequently the focus of news, the onslaught of information can be encouraging but also overwhelming for patients like Gerard. Clinical trials and observational studies are ongoing for a number of new treatments for TRD, including serotonergic psychedelics (such as LSD [lysergic acid diethylamide], psilocybin, and ayahuasca), atypical antipsychotics, ketamine, deep brain stimulation, and electroconvulsive therapy.5

In LSD trials, researchers suggest that psychedelic-induced 5-HT2AR signaling creates a state of neural plasticity wherein patients can observe the richer context of their world — in essence, “seeing the forest through the trees”— and allowing them to revise some of their cognitive biases that lead to depressed thought, rumination, and suicidality. Treatment with psychedelic agents has been shown to be associated with reduced depressive symptoms, lower suicidality, and less psychological distress in patients with recurrent depression or TRD.5

This same logic model supports the effectiveness of cognitive-behavioral therapy, intensive short-term dynamic psychotherapy, and interpersonal therapy, all of which have demonstrated effectiveness at decreasing depression in people with TRD.6

Deep brain stimulation, which sends electrical impulses to parts of the brain via implanted electrodes, has also resulted in the significant improvement of depressive symptoms for some patients. In one clinical study, 37% of patients with TRD experienced relief at 1 month, 50% at 6 months, and 48% at 12 months following deep brain stimulation.7 Those response rates were sustained and even increased in a longer follow-up study, with 62.5% of patients experiencing relief after 1 year and 75.0% after 3 years; an average response rate of 64.3% was noted at the last follow-up visit (range, 3-6 years).8

What’s the Catch?

While many of these treatments are promising, it is unclear what will work for each individual patient. Some of this uncertainty comes from the heterogeneity of depression as a disease. Per the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, there are 681 combinations of symptoms that could meet the criteria for major depressive disorder.9 Multiple depressive subtypes exist, such as melancholic and psychotic depression, which may respond differently depending on treatment regimen. The impacts of heritability, chronic stress, and adverse life experiences on treatment success are also not fully understood, which makes individualizing treatment a difficult process.

Short clinical trial times can also mask the success of these interventions, which sometimes take ≥12 months to show significant effects. Yet when a disease poses such a high risk of suicidality, every month waiting to judge a treatment’s effectiveness can put patients at greater risk for a deadly outcome. 

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There are also legal concerns that must be considered when approaching therapy. Though marijuana, psilocybin, and LSD offer promising results for some patients, these drugs occupy a legal gray area. Even with a prescription and physician oversight, the presence of these substances on a drug screen can be grounds for termination of employment. In states where medical or recreational marijuana has been legalized, federal employees and contractors are still subject to federal law and could lose their security clearances and employment due if receiving these treatments for depression.

And of course, every new treatment comes with potential risk. In a recent trial assessing intranasal ketamine for TRD, participants experienced “significant acute cardiovascular, psychotomimetic and neurological side effects…at doses <100 mg ketamine.”10 None of the trial participants were able to finish the course of treatment due to lack of coordination required to self-administer all 10 doses.10 With deep brain stimulation — a treatment requiring a surgical implant with its own incumbent medical risks — adverse events during one clinical trial included hypomania (2.56%), disinhibition (5.13%), and vision/eye movement disorder (5.13%).7

What Other Treatments Are We Ignoring?

In the rush to capitalize on the latest clinical innovations, psychiatry may be overlooking time-tested treatments that can be repurposed for a new audience, particularly trauma-response therapies. Psychotherapist Kelli Cronin, LCSW-C, explains: “I strongly believe body-based psychotherapies and other somatic interventions need more attention and research. Many of these are therapies for trauma resolution, such as Somatic Experiencing®, Sensorimotor PsychotherapyTM, and the Trauma Resiliency Model (TRM).”

Somatic psychotherapies operate by addressing the lasting imprint that trauma leaves on the body and psyche. Cronin explains that somatic psychotherapies can help people with depression if we widen our lens for understanding what constitutes trauma. “A​​ny​ experience that overwhelms a ​person’s capacity to cope…could be considered traumatic. We are starting to understand trauma as a physiological response to stressors, rather than an event itself. With this new understanding, people who are ‘just’ depressed, or ‘just’ anxious may be open to trauma therapies and their potential to shift an overwhelmed nervous system from a chronic state of freeze, fight, or flight (or a combination of these) to a more regulated system that is able to experience more ease.”

Unlike more traditional therapeutic modalities like cognitive-behavioral therapy, somatic therapies are said to have the capacity to heal trauma from a “bottom-up” rather than a “top-down” approach.11 Like deep brain stimulation, transcranial magnetic stimulation, and other new treatments, somatic therapy sidesteps the conscious process of noticing and “reframing” depressive thoughts and focuses on the body’s innate ability to heal itself.

How Do We Keep Our Patients Going?

The road to a definitive treatment protocol for people experiencing depression and suicidal ideation is long and still full of unanswered questions. In the meantime, mental health professionals and patients utilize whatever support is close at hand to make the day-to-day struggle bearable.  An important tactic is the creation of a support system to help patients process suicidal ideation. Cronin provides all of her clients with a phone number to a suicide hotline; she also provides an LGBTQ-affirming hotline, when necessary. She offers to call the hotline with them during their in-person session “to soften their initial fears and unknowns when using a new resource.” Some of her clients will also create a self-care contract (often called a “suicide contract” or “no harm agreement”) as a plan for staying safe until their next therapy appointment.

Sometimes, the little things are what help a person push through until they find the treatment that will finally provide relief. Gerard admits that it has been difficult to find encouragement when numerous treatments have failed to improve his depression, but the acknowledgement of his efforts by friends and clinicians provides reassurance. He wants people to know that he’s not getting better, but it’s not for lack of trying. Gerard also tries to surround himself with “other neuro-atypical people who are going through similar issues” because, if nothing else, he finds it  comforting to have friends who “get it.”


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