Rethinking Treatment-Resistant Depression as Treatment Nonresponse

In the September 2025 issue of Psychiatric Times, Dr. John J. Miller challenged psychiatry to rethink the term “treatment-resistant depression.” He argues that the issue isn’t that patients are resistant—it’s that some treatments have not yet produced a response.

Reframing the label to “treatment nonresponse” reduces shame, supports neuroplastic change, and highlights the importance of psychotherapy, lifestyle, and whole-person evaluation within a biopsychosocial model.

A Shift in Language, A Shift in Healing

In Dr. Miller’s article, “Treatment Resistance: It’s Complicated,” he brings to attention something subtle but significant: the words we use in psychiatry matter. When medications don’t work, it’s not the patient who is resistant—it’s the treatment that hasn’t yet met their needs.

At NeuroPain Health, we see this reflected every day. Many patients come to us after trying multiple antidepressants, believing their brain is “resistant.” Yet, as Dr. Miller writes, “It is erroneous to label a patient as treatment resistant based on 2 failed trials of a medication.” The issue is rarely resistance—it’s that the treatment provided hasn’t yet matched the person’s needs.

By shifting our words from treatment-resistant to treatment nonresponsive, we shift the mindset from defeat to curiosity—and that change alone can influence neuroplasticity, motivation, and hope.

From (Patient) “Resistance” to (Medication) “Nonresponse”

The word resistant implies that the person is fighting the treatment. In truth, it’s often the treatment that isn’t the right fit.

Reframing the label to treatment nonresponse to a given solution (medication) centers the problem on the method/medication, not the person. This simple shift matters because language directly impacts healing potential. Hope, safety, and engagement—all key drivers of neural rewiring—rise when a patient feels understood rather than labeled.

For many individuals, hearing they have “treatment-resistant depression” can feel like the moment hope slips away. After two medications, they’re told their depression is “resistant,” a word that can land like a verdict, and even an identity or life sentence.

That sense of finality can reinforce feelings of failure and shut down the very neuroplastic pathways needed for healing. In contrast, describing a treatment as “nonresponsive” keeps the door open—it communicates that the brain’s capacity for change remains intact, and that we simply need a different approach.

What Two “Failures” Can Actually Mean

In psychiatry, “treatment-resistant depression” usually refers to an inadequate response to two antidepressants of adequate dose and duration. But that threshold can also be a gateway—an invitation to explore approaches that act on different brain systems and mechanisms.

This is the point when care can become more personalized. Some individuals may benefit from ketamine-assisted therapy, transcranial magnetic stimulation, or other neuromodulatory treatments that engage neuroplastic pathways more directly. For others, meaningful change begins by addressing the biological, psychological, and lifestyle factors that influence mood and recovery.

Exercise, nutrition, sleep, and stress regulation each play measurable roles in mood stability and neural health. Improving metabolic health, restoring circadian rhythm, and incorporating structured movement can shift neurotransmitter balance and support antidepressant response. Likewise, deepening therapy, integrating mindfulness or somatic work, and building social connection can all strengthen the brain’s adaptability.

These methods—whether pharmacologic, behavioral, or lifestyle-based—work together to create a critical window for therapeutic change. They allow new habits, emotions, and thought patterns to take hold within a more regulated nervous system.

So rather than viewing two “failures” as an endpoint, we can see them as a signpost—a moment to widen perspective and consider options that honor the full complexity of the brain and body.

The Other Levers of Healing: A Biopsychosocial Model

When symptoms persist, a stronger prescription is not always the solution. Dr. Miller emphasizes that non-medication factors are often equally significant.

Psychiatry is most effective when it follows a biopsychosocial model, examining biological, psychological, and social factors together. Each aspect offers a lever for healing and a chance to re-engage neuroplastic change:

• Accurate diagnosis: Depression can mask trauma, anxiety, or thyroid imbalance.

• Adherence and dosage: Missed doses or subtherapeutic levels can mimic nonresponse.

• Substance use: Even occasional alcohol or cannabis use can disrupt mood regulation.

• Medical contributors: Inflammation, pain, or hormonal imbalance may sustain symptoms.

• Psychosocial stressors: Relationship strain, grief, and financial pressure can perpetuate low mood.

• Lifestyle variables: Sleep, exercise, nutrition, and relaxation each influence neurotransmitter balance.

• Support systems: Healing deepens with connection, therapy, and community involvement.

Dr. Miller also notes that nonmedication treatments remain underutilized, despite evidence that psychotherapy should often be the first-line treatment for mild depression, PTSD, OCD, adjustment disorders, and certain personality patterns.

He advocates for a thorough medical and psychosocial evaluation for every new patient—one that includes lab testing, medication review, and substance screening—followed by education on lifestyle factors that influence recovery. Discussing results in a nonjudgmental way encourages openness and trust, two essential ingredients for progress.

This model—addressing the biological, psychological, and social levers together—creates the conditions where both brain and behavior can change.

The Brain is Not Resistant!

In fact, it’s highly neuroplastic, and the language we use directly impacts the thoughts and beliefs it generates.

“I am a person who is resistant to solutions for my depression” tells the brain there’s no hope.

“The two things I’ve tried so far have not yielded a better response, but I have a comprehensive list of other lifestyle and medical factors to try” tells the brain there’s hope, and many more options.

Depression is a dynamic pattern of neural signaling shaped by experience, environment, and stress. Those patterns can change.

Replacing treatment-resistant depression with treatment nonresponse invites collaboration rather than blame. It reminds both patient and provider that healing is an evolving process—one supported by biology, guided by psychology, and sustained through social connection.

Every small shift—an extra hour of sleep, a deeper therapy session, a new sense of calm—signals the brain to rewire toward safety and balance.

Language Matters.

Language can either close doors or open them.

By describing depression as nonresponsive to certain solutions instead of resistant, we honor the brain’s adaptability. We replace finality with flexibility.

Healing is never linear, but it is always possible when approached through curiosity, compassion, and a whole-person model of care.