Treatment Resistance: It’s Complicated

Rafal Rutkowski/AdobeStock

One of the most rewarding experiences in practicing psychiatry is seeing a patient at follow-up who tells you they are “back to their old self.” Depending on the psychiatric practice setting this can be common or happen only occasionally. Individuals with more serious psychiatric conditions—such as schizophrenia, bipolar disorder, recurrent major depressive disorder, and severe obsessive compulsive disorder—are often diagnosed as treatment resistant after many unsuccessful medication trials, ideally alongside other appropriate treatments. The definition of treatment resistance can vary significantly, even for the same diagnosis. Experts in a particular field typically reach a consensus on a definition, which is often fluid, in order to establish a common language for treatment guidelines, determine eligibility for clinical trials, and support US Food and Drug Administration (FDA) approval for medication indications.

Schizophrenia

The currently accepted definition for treatment-resistant schizophrenia is at least 2 failed trials of antipsychotic medications of adequate dose and duration.¹ As of today, there is only 1 FDA-approved medication for treatment- resistant schizophrenia: clozapine. Luykx et al report that even though clozapine can be effective in reducing positive symptoms, future hospitalizations, and all-cause mortality in patients with treatment-resistant schizophrenia, eventually up to 60% of patients taking clozapine will meet criteria for clozapine-resistant schizophrenia. The Treatment Response and Resistance in Psychosis Working Group defines clozapine-resistant schizophrenia as “the persistence of positive, negative, or cognitive symptoms with at least moderate severity, and less than 20% symptom reduction in patients with schizophrenia after an adequate clozapine trial. An adequate trial of clozapine is in turn defined by plasma concentrations of more than 350 ng/mL, a minimum treatment duration of 8-12 weeks, and the presence of at least moderate functional impairment before treatment.”²

Each psychiatric disorder has both common and unique factors that contribute to the likelihood of treatment resistance. One common factor predictive of a poorer treatment outcome in many psychiatric disorders is the delayed onset of treatment after symptoms emerge. In schizophrenia, this was demonstrated in the National Institute of Mental Health–funded study Recovery After Initial Schizophrenia Episode Early Treatment Program.³ In a cohort of 404 participants, the median duration of untreated psychosis was 74 weeks. Participants receiving the aggressive and comprehensive treatment intervention for first-episode psychosis for 2 years demonstrated a greater improvement in psychopathology and quality of life if their duration of untreated psychosis was less than 74 weeks compared with greater than 74 weeks.

Major Depressive Disorder

Classifying patients with major depressive disorder (MDD) as treatment resistant is more opaque. For reasons primarily related to the need for a definition of treatment resistance for clinical trials of antidepressants in MDD and the labeling of antidepressant indication approvals by the FDA, the commonly used definition is an inadequate response to at least 2 trials of oral antidepressants of adequate dose and duration. For perspective, a patient with MDD could have an inadequate response to 2 different selective serotonin reuptake inhibitors that were deemed to be of adequate dose and duration based on the patient’s self-report, and that would qualify them as being treatment resistant.

I avoid the term treatment resistant for any patient with depression and, in fact, for any psychiatric disorder. This resulted from my experiences with patients years ago who technically met criteria for treatment resistance, and when informed of that responded with hopelessness and helplessness which clearly impacted their self-esteem, increased self-judgment, and often felt that their treatment resistance was their fault. Rather, I explain to them the numerous factors that may be impeding improvement in their symptoms, and inform them that we will proceed step by step toward our shared goal of symptom improvement. I also provide psychoeducation about our limited understanding of the brain and the etiology of psychiatric disorders, and our young field of psychopharmacology with many novel treatment options that will likely emerge over time.

Reframing the Language

As a psychiatrist of 35 years specializing in psychopharmacology, I believe it is erroneous to label a patient as treatment resistant based on 2 failed trials of a medication for a specific diagnosis. The reasons for this are manifold. Let us use the treatment of MDD as an example. A primary mythology at play is that the depressive symptoms are not improving with an administered medication because the depression is resistant to the medication, rather than that the medication is not the correct treatment for that depression. After the second medication “failure,” resulting in the characterization of the depression as treatment resistant, the next step is to be more aggressive pharmacologically or proceed to transcranial magnetic stimulation, electroconvulsive therapy, or vagus nerve stimulation—treatments that are FDA approved for MDD. This common psychiatric treatment scenario for MDD exists in a silo that operates under the assumption that the patient has been correctly diagnosed and appropriately treated with what should be an optimal intervention. The Table lists many factors that may contribute to a patient’s medication nonresponse for any psychiatric disorder, most of which have nothing to do with the medications that failed to improve the symptoms.

TABLE. Factors to Consider When a Patient Is Not Responding to a Medication

How Did We Get Here?

Many roads lead to Rome. In my opinion, many factors have converged to establish a commonly used definition of treatment resistance, which usually means a failure of 2 medication trials of adequate dose and duration to improve the patient’s symptoms. As the Table conveys, numerous reasons could be the primary cause of a patient’s nonresponse to a medication that have nothing to do with the medication.

Many psychiatric providers, trained in the medical model, utilize medications as the primary treatment for many psychiatric disorders. The field of psychiatry is young, and we have a very limited portfolio of mechanisms of action of FDA-approved medications to treat specific disorders. The schizophrenia section provides a good example of this, with only 40% of patients with treatment-resistant schizophrenia ultimately responding to clozapine—the only medication FDA approved for this disorder.

Nonmedication treatments are underutilized, and engaging a patient in these treatments is often challenging. This is especially true for psychotherapy, which, for many diagnoses, especially posttraumatic stress disorder, obsessive-compulsive disorder, mild depression, adjustment disorders, and the various personality disorders, should be the initial primary treatment. Our culture has a high expectation that medications are the solution to what ails you. The medical workup of a patient presenting for their first psychiatric evaluation is commonly underwhelming. Arguably, any new patient should have a battery of laboratory tests, including the standard tests ordered during an initial primary care evaluation and other more specific tests depending on the presenting symptoms. The initial workup could include a urine drug screen—presented as a routine component of every initial evaluation—and, if positive for a psychoactive substance reviewed with the patient in a matter-of-fact, nonjudgmental manner.

The initial evaluation should include psychoeducation about the many lifestyle variables that could benefit or worsen the presenting symptoms including sleep hygiene, current psychosocial stressors, nutrition, exercise, substance use, and relaxation strategies. A comprehensive exploration of current and past psychosocial stressors should be reviewed and documented. Revisiting the status of these stressors and the approaches or resources to improve them should be a part of every follow-up visit. Identifying the patient’s primary support system and inviting them to participate in the treatment process can help enlist a strong ally.

Finally, there needs to be an aggressive evaluation of the current psychiatric training models educating our future psychiatric providers. Trainees are being indoctrinated into a treatment model they assume is adequate and optimal. I strongly support the 90-minute initial psychiatric evaluation that continues to be the standard in the community mental health center where I have worked at for the past 18 years. This provides adequate time for a thorough evaluation to amass a database that includes the many factors listed in the Table that can inform a more comprehensive and targeted treatment plan. The pervasive “15-minute med check,” although adequate for many patients, especially once they are effectively treated and on a stable maintenance regimen, does not provide sufficient time for many psychiatric follow-up appointments.

Concluding Thoughts

Psychiatry is a young, exciting, rapidly evolving, and honorable profession. As is the case with any field of medicine, the structure of our treatment is constantly in flux as we look, listen, and learn from ourselves and our patients how to improve the delivery of quality treatment. Every profession can drift into a siloed treatment model, which can result in missed opportunities for additional interventions that can synergistically improve patient outcomes or possibly modify the treatment plan significantly as information accumulates and the patient’s story unfolds. It is time to reframe one of our core diagnostic descriptors from “treatment resistance” to a medication to “treatment nonresponse to 2 courses of medication class X.” I believe this is a more accurate description of what is occurring clinically. Let us know what you think.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. de Bartolomeis A, Ciccarelli M, Vellucci L, et al. Update on novel antipsychotics and pharmacological strategies for treatment-resistant schizophrenia. Expert Opin Pharmacother. 2022;23(18):2035-2052.

2. Luykx JJ, Gonzalez-Diaz JM, Guu TW, et al. An international research agenda for clozapine-resistant schizophrenia. Lancet Psychiatry. 2023;10(8):644-652.

3. Kane JM, Robinson DG, Schooler NR, et al. Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE early treatment program. Am J Psychiatry. 2016;173(4):362-372.