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

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In today’s psychiatric practice, 20% to 60% of all cases are eventually labeled “treatment resistant,” though second opinions identify remaining treatment options for more than two-thirds of these patients. Obviously, application of this pessimistic assessment too often precedes adequate consideration or awareness of these remaining solutions, reflective review of treatment failure, or creative reconceptualization of the problem to be solved.

This poorly defined category likely reflects errors in cognition, incomplete assessments, inadequate treatment planning, poor compliance, and faulty therapeutic alliances.

Rather than identify treatment resistance as an endpoint diagnosis, or as an entity at all, clinicians would better serve their patients by considering this situation a phase of treatment, still expecting eventual remission as they take steps to move past a clinical impasse.

Patients not responding to trusted treatments have been reported since the initiation of psychotherapeutic, symptomatic, occupational, somatic, and pharmacological interventions for mental illness. Initially these reports described therapies that failed to help all patients, and the focus was on the quality of the treatment, not the diagnosis. Therapy-resistant or treatment-refractory schizophrenia (TRS) has been discussed in the literature for over 50 years. Similarly, treatment-resistant (or refractory) depression (TRD) as a specific term first appeared in the 1970s, mostly referring to resistance to a particular treatment, such as tricyclic antidepressants. Starting around 1990, TRD became both an entity and a consistent term in the literature, despite inconsistent criteria. Oliver Howes, M.B.B.S., Ph.D., Michael Thase, M.D., and Toby Pillinger, B.M.B.Ch., have determined that the percentage of articles addressing treatment resistance, compared with total articles published in psychiatry, has increased by about 75% during the past two decades.

Because early references focused more on the inadequacy of a treatment’s efficacy, there was essentially no effort to define a new diagnosis. Much work originally centered on finding the right treatments for the right patient. This activity should continue, as clinicians are responsible for applying the best available evidence to treatment planning. The focus has since shifted, though, from evaluation of a treatment to description of a patient’s condition.

Consensus on TRD Definition Is Lacking

Although the term treatment resistance is now all too common, from the beginning there has been insufficient consensus on definition and criteria. Efforts to confirm or reject the hypothesis of treatment resistance as a valid concept are stymied by this lack of agreement.

Number, type, length, quality, and assessment methods of treatment attempts are not standardized for consistent attribution of the concept within most diagnoses, most notably depression, schizophrenia, obsessive compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). The calculations of incidence and prevalence of treatment resistance, as well as meta-analysis of interventional strategies, are also stymied by these inconsistencies. However, although 100% of practitioners queried in a 2021 expert consensus survey published in Depression and Anxiety still sought an operational definition, 92% of psychiatrists considered TRD a useful concept, and 85% reported using the concept in clinical practice.

Inherent in any discussion of the concept of treatment resistance is the necessity of restricting its application, withholding its use in conditions we do not currently expect to treat successfully. People with schizophrenia or OCD are particularly difficult to label as treatment resistant because we do not presently expect any treatment to result in a full remission. Positive symptoms of schizophrenia have responded well to many pharmacological treatments, whereas negative symptoms, although more amenable to treatment with atypical second-generation antipsychotic medications, still prevail for most patients.

Outcome expectations for OCD therapies were similarly low until clomipramine was confirmed effective almost four decades ago. Currently, 40% to 60% of patients with OCD are likely to respond to treatment, although still without resolution, and perhaps with episodic remission. It appears useful to restrict cases of distinct treatment failure (and any consideration of treatment resistance) to psychiatric conditions that we can usually treat to sustained remission.

Some authors have considered the use of the term pseudo resistance, indicating that treatments attempted were flawed and inadequate in their execution, rather than that competent application of state-of-the-art, previously proven procedures had failed. It has also been proposed that the term treatment resistance be restricted to when the most promising treatments have been applied. For some, this includes the competent application of cognitive-behavioral therapy before affixing a label of treatment resistance or drug resistance.

There are also important differences in the assessment of and reaction to (1) no response, (2) partial response, and (3) insufficient response (that is, response compared with remission). Since the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, it is more common to see TRD “diagnosed” following the failure of two attempts at pharmacological treatment. Occasionally, only one trial is still used, such as the pivotal study and indication for transcranial magnetic stimulation. Response is usually defined as a 50% decline in symptomatology measured by a peer-reviewed, published scale. Although remission is difficult to define for schizophrenia and OCD, many authors accept a HAM-D score ≤7 for major depression. The STAR*D one-year naturalistic follow-up study showed better longer-term outcomes for patients reaching this level of response to one or more treatment attempts. The term recovery is reserved for a symptom-free status. Some authors urge changing the informal definition of treatment resistance from nonresponse to non-remission, as used in the STAR*D study, seeking functional rather than syndromal change.

Many efforts have been made to stage degrees of treatment effort and response. The methods most commonly applied to TRD are the Thase and Rush model, the Massachusetts General Hospital staging method, Maudsley criteria, and the Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD). Unfortunately, these staging criteria differ as widely as the original disparate definitions of TRD and the value of staging has not been adequately assessed for its predictive value, largely because of heterogeneity.

Few methods include even limited options for psychotherapy, as do DM-TRD and a strategy proposed by Charles Conway, M.D., Mark George, M.D., and Harold Sackeim, Ph.D. John Markowitz, M.D., and colleagues have described the complexity of considering attempts at psychotherapy alongside previous pharmacological or somatic treatments when assessing for or attempting to stage treatment resistance. Although following a consistent staging strategy may help a single clinician methodically work through various treatment options, it is not yet clear which method will lead to the best results.

Broad literature review shows more success in identifying individual explanations for treatment failure than actually identifying a “diagnosis” of treatment resistance. Some authors have explored the possibility that iatrogenic alterations from therapies may contribute to treatment failure, and the question of in vivo tachyphylaxis remains unclear. Declining response rates with subsequent pharmaceutical trials may be more a factor of lower placebo response rates and less spontaneous improvement than treatment resistance to a specific therapy. There is no association with TRD and specific drugs or molecules, nor with augmentation or switching strategies.

The number of previous treatment trials is predictive in some reviews but not prognostic in others. Data supporting associations with personality disorders are weak or nonconfirmatory. There is some evidence that genetic and epigenetic factors play a role in TRD and psychosis (including TRS). Some genetic polymorphisms are linked to a wide definition of treatment resistance, and evidence exists of rare metabolic disorders that infrequently preclude response to standard treatments.

The lack of consensus on definition or research results, due to myriad subdivisions of possible outcomes, argues against any useful conception of treatment resistance. Henry Nasrallah, M.D., reminds us that heterogeneous biotypes respond to different mechanisms of action or other necessary interventions. The preponderance of evidence tells us that treatment resistance is not a discrete entity, but instead is the result of many different origins—an individual situation that must be determined for each treatment failure, with specific causes that are unlikely to be identical to many other cases. Adopting treatment resistance as an explanation, rather than treatment failure as a stage, misdirects the clinician from discovering critical solutions to improve the sometimes desperate, and always initially undesirable, conditions of the patient. It also threatens to worsen prognosis by unnecessarily extending the length of an index or recurrent episode and increases the risk of death and burden of disease by prolonging categorical and functional impairments. Koen Demyttenaere, M.D., Ph.D., has wisely suggested that the term difficult to treat may be more useful for cases continuing to seek remission.

Clinical Persistence Is a Responsibility

To move past treatment failures, practitioners must remain persistent in the face of a few initially negative findings and still complete full assessments of systems. An evaluation of soft neurological signs is not complete, for example, until negative results from both structural (imaging) and functional (electroencephalography) studies accompany physical examination. To stop after obtaining negative results from one or the other runs the risk of missing seizures, tumors, and degenerative diseases with or complicating psychiatric presentations. A patient may also have or develop more than one diagnosis in a system, such as multiple endocrine or neurological disorders. Clinicians must approach every case of treatment failure individually, applying labels carefully and continuing to search for one or more unique causes.

Treatment failure resulting in the relabeling of a diagnosis as treatment resistance represents a failure of clinical problem-solving. Rather than conceptualizing a global origin for treatment failure that evades reproducibility, explanation, and validity, psychiatrists need to consider factors in addition to comorbidity that may coexist with our current categorical diagnoses and that fight against successful remission in a particular case. The weight of evidence shows that, in addition to a positive association with psychiatric and medical comorbidities, treatment failure is linked most specifically to the severity and length of symptoms, but also it is sometimes connected to illness behavior; 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.

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 Recovery

The 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. ■

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.