Special Report: Rethinking Treatment Resistance as Impasse, Rather Than Endpoint

Back to table of contents Next article Clinical cognitive impairment (especially rumination); and genetic, epigenetic, and rare metabolic factors.Understanding how a patient perceives illness and treatment recommendations can help mitigate treatment failure. Illness behavior may be ameliorated or exacerbated by the doctor-patient relationship; at the very least, we must be aware that treatment outcomes are contingent on our therapeutic alliances. Lifestyle decisions and behaviors also commonly contribute to treatment success or failure and may masquerade as treatment resistance.Missing underlying or comorbid psychiatric and nonpsychiatric medical conditions often leads to treatment failure. Comorbidity, in general, does indicate that each diagnosis may be more difficult to treat, with response rates being 25% to 30% lower. Three-quarters of psychiatric patients have at least one chronic nonpsychiatric medical problem, and 50% have two or more. These comorbidities are frequently not diagnosed because of atypical presentations and often cause or worsen psychiatric symptoms. Accepting this as treatment resistance is abdicating our full role as physicians and providers and abandons our responsibility to the therapeutic alliance. The earlier these illnesses are diagnosed and treated, the greater the chance for full recovery.Approaching practice as a generalist and searching for and addressing all of a patient's medical problems, often in consultation with primary care providers or specialists, not only helps avoid psychiatric treatment failure but also may lead to quicker and more complete responses to treatment for all conditions present. For example, more than 20% of adults have experienced head trauma with loss of consciousness, which may predispose them to psychiatric symptoms and disorders for many years. Posttraumatic seizures are often subclinical, and patients with these may present with many different psychiatric symptoms. Many primary endocrine disorders, including all types of diabetes mellitus, adrenal insufficiency, and hypercortisolism, may manifest primarily or exclusively with psychiatric symptoms, and the effects are often bidirectional. Psychiatric patients, as a group, have a higher incidence and prevalence of infectious diseases that contribute to mood, thought, and cognitive disorders. Respiratory disorders are the most common medical comorbidity for our patients and the gastrointestinal system has a potent bidirectional association with the central nervous system.Important Steps to Follow1. Conduct semi-structured interviews.2. Record and review all data.3. Search for comorbidities, including those outside psychiatry.4. Examine your clinical reasoning.5. Think and plan for the long term.6. Seek and heed feedback.7. Self-assess and self-correct.8. Prescribe evidence-based treatments.9. Monitor your therapeutic alliances.The use of over-the-counter dietary stimulants often contributes to sleep, anxiety, and mood symptoms, as does the use of alcohol and recreational and illegal drugs, including edibles. Smoke from nicotine use lowers serum levels of antipsychotic medications, and reduction of nicotine use may destabilize patients with bipolar disorder. The effects of drug-drug interactions on safety and treatment outcome must be carefully considered during any use of polypharmacy. Bioavailability, and resultant treatment effectiveness, may be altered by changes in delivery system or brand, particularly of generic preparations.The conceptual error we make is confusing treatment resistance with treatment failure. In considering treatment resistance, we may be indicating our inability to predict response for a single patient more than we are saying that treatment never works for this patient. Some patients require treatment plans that differ from others' with the same diagnosis. The application of the term treatment resistance is unnecessary, tautological, and misconceptualized from misdiagnosis and treatment error, a reification that too many people have come to believe exists apart from the conditions that lead to this mirage. At the very least, this awareness should constantly redirect us to consider and explore the individual characteristics of cases and the circumstances around each treatment failure, rather than adopting an assault on a poorly characterized and operationally nonexistent entity. Constant vigilance for and incorporation of new, broad data are key to avoiding and reversing treatment failure.Many treatment failures result from inadequate gathering of information from the literature and from the patient during initial and ongoing assessment. Misconceptualization, errors in problem-solving, insufficient adherence to evidence-based medicine, and inadequate initial and ongoing assessment may all lead to unsuccessful treatment efforts. Clinical success, measured by a patient's interest in improving functionality or a clinician's goal of reducing symptoms, can be found by conscious efforts to avoid or uncover each of these potential missteps, often by the same practitioner who made the initial error(s). All factors that contribute to symptoms or reduce a patient's functionality must be addressed.Detailed and accurate record keeping is essential for finding clinical solutions during treatment impasses and may be threatened by technological progress (such as incautious use of electronic medical record EMR features). Copying data from a previous visit, rather than recording reassessments in detail, can obscure new data that may harbor subtle but key differences and could lead to important treatment plan changes upon chart review. Data from previous sessions should be substantially reexamined at each session and confirmed, corrected, or reappreciated as necessary. A clinician facing treatment failure will benefit from taking time to review the complete treatment record, often together with the patient. Clinical reasoning is best based on abductive logic with iterative and creative reassessment and requires full consideration of complete data.Much of the care provided in modern psychiatry is long term for chronic conditions. As such, practitioners should expect that, over time, there will be multiple opportunities to encounter interferences with otherwise successful treatment plans. These may include changes in serum levels by alterations in absorption, compliance, or bioavailability; contributions from the many additional medical problems patients may develop during treatment; and the constant risk of new medical treatments added by a psychiatrist, other providers, or the patients themselves. Patients may describe symptoms in ways that do not fit our cognitive mindsets, resulting in misdiagnosis. Rather than quickly labeling a case as treatment failure or treatment resistance, these threats must be anticipated, investigated, and addressed, sometimes repeatedly, allowing sustained successful outcomes. Never-ending persistence with the effort to find solutions, rather than the quick application of meaningless labels, often leads to response and remission for our patients, as well as to enhanced professional satisfaction.Conceptualizing treatment failure as treatment resistance involves circular reasoning: The commonly asked question "What do you use to treat treatment-resistant psychiatric disorder?" is an oxymoron: If there is an effective treatment, the disorder is not resistant. If we are using the term treatment resistance to ask what the next treatment should be after one or more failed attempts, we are asking not about treatment failure but about a second or third treatment option. This is, again, an unhelpful question because there is no standard order of treatments, and the correct answer always depends on the individual case. Although treatment algorithms provide basic guidance, they become quickly outdated (50% within five years) and cannot possibly encompass enough of the complexity in our clinical situations to provide solutions more accurate than those determined through thorough and ongoing individual assessment.Hope Is Essential to RecoveryThe concept of treatment resistance adds no value to treatment planning and abdicates our responsibility to solve clinical dilemmas with our patients. There is no utility in defining one treatment attempt as targeting treatment resistance and another as targeting nontreatment resistance. Again, this is the circular logic of the failed treatment resistance concept—projecting treatment failure into a diagnosis rather than focusing on the practitioner's control over finding solutions. Passively accepting the concept and term treatment resistance abrogates our responsibility as clinicians to work tirelessly to find the right answers with our patients and so often prevents us from finding effective solutions.Overconfidence from years of unexamined practice breeds mediocrity and defeats clinical success. The longer we are experts, the narrower our focus and the more rigid our mindsets. We have a duty to use tools to evaluate and improve our practice skills. Seeking regular feedback through consultation, supervision, standardized assessment instruments, second opinions, review of our own records, and monitoring our therapeutic alliances enhances outcomes for patients. Many paramedical professions have already embraced these steps. Instead of expecting ideal outcomes from initial efforts, we provide more value by anticipating roadblocks and persistently altering treatments as needed.Because we know that hope is essential for recovery, a rush to therapeutic nihilism can lead to malignant psychodynamics that limit clinical success as additional treatment attempts proceed. We must create and sustain a holding environment that communicates caring, while sharing a sense of optimism that the patient may not be capable of sustaining. Most importantly, we must never lose the expectation of eventual improvement or stop trying to obtain it. Otherwise, our patients will detect this sense of pessimism. When we codify this by applying the label treatment resistant, even when technically employed and well meaning, surely patients hear it as hopelessness. Moreover, we are essentially objectifying our patient, distancing ourselves from our failure, and effectively abandoning the patient, along with the sense of hope we should be sharing. The actual value we offer to our patients is our problem-solving skill and our willingness to be with them through the difficulties of reaching their goals. As Joel Yager, M.D., writes in a November 2021 paper in the Journal of Psychiatric Practice, we should help with patient concerns that stretch beyond categorical symptoms and functionality and increase our appreciation for the value of personal growth and quality of life, particularly for the seriously mentally ill. We must never forget that it is the perspective of our patients, within their environment, that has the stronger influence on treatment planning, compliance, and outcome, and we must ultimately define success through their eyes.Our responsibility to our therapeutic alliances demands that we avoid applying the term treatment resistance in practice and never quit searching for the true and possibly multiple causes of treatment failure. We must always recall that the clinical tasks we face are inherently complex; routine solutions are unlikely to fit and often lead to treatment failure. The treatment attempts themselves, but neither the patient nor the diagnosis, may be labeled treatment failures. A case may be described as pending remission, rather than treatment resistant, because it is likely that treatment options remain and that new factors can still be uncovered.We can begin to address so-called treatment-resistant, or rather difficult-to-treat, cases by confirming our diagnostic validity and accuracy, the thoroughness of our evaluations and monitoring efforts, the clarity of our therapeutic guidance, and the quality of our therapeutic alliances. There is still abundant reason for hope when early treatment attempts are disappointing. Our attitude must embody this optimism, and we must share it generously with our patients as we continue to work with them and our colleagues until answers are found. Not only is this sharing the truth; it is an essential factor in their recovery. ■ReferencesHowes OD, Thase ME, Pillinger T: Treatment Resistance in Psychiatry: State of the Art and New Directions. Mol. Psychiatry 27(1): 58–72, 2022.Rybak YE, et al: Treatment‐Resistant Major Depressive Disorder: Canadian Expert Consensus on Definition and Assessment. Depress. Anxiety. 2021; 38(4): 456-467.Thase ME, Rush AJ. When at First You Don't Succeed: Sequential Strategies for Antidepressant Nonresponders. J. Clin. Psychiatry. 1997; 58 Suppl 13: 23-29.Petersen T, et al.: Empirical Testing of Two Models for Staging Antidepressant Treatment Resistance. J. Clin. Psychopharmacol. 2005; 25(4): 336-341.Fekadu A, et al.: A Multidimensional Tool to Quantify Treatment Resistance in Depression: The Maudsley Staging Method. J. Clin. Psychiatry. 2009: 70(2):177-184.Peeters F, et al.: The Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD): An Extension of the Maudsley Staging Method. Journal of Affective Disorders. 2016: 205: 365-371.Conway CR, et al. Toward an Evidence-Based, Operational Definition of Treatment-Resistant Depression. JAMA Psychiatry. 2017; 74(1): 9-10.Demyttenaere K: What Is Treatment Resistance in Psychiatry? A "Difficult to Treat" Concept. World Psychiatry. 2019; 18(3): 354-355.Yager J: Targeting 3 Tiers of Psychiatric Problems in Patient-focused Psychiatric Practice: Diagnostic Signs, Symptoms, and Impairments; Specific Complex Subjective Complaints; and Contributing Meta-problems. Journal of Psychiatric Practice. 2021; 27(6):472-477.Nasrallah H: From the Editor: Treatment Resistance Is a Myth! Current Psychiatry. 2021; 20(3): 14-16.H. Paul Putman III, M.D., is a practicing psychiatrist and mentor for over 30 years and has performed phase 1 to 4 studies in psychopharmacology, published in peer-reviewed journals, and served as a supervisor and lecturer in academic psychiatry. He is the author of Encountering Treatment Resistance: Solutions Through Reconceptualization and Rational Psychopharmacology: A Book of Clinical Skills from APA Publishing. APA members may purchase the books at a discount here. ISSUES NewArchived