The Failed Concept of Treatment Resistance

In current psychiatric practice, 20%–60% of all clinical problems eventually become labeled “treatment resistant (TR)” (1), although second opinions identify remaining and effective treatment options for more than two thirds of the patients who have these illnesses (2, 3, 4). Lack of response to standard treatments has been reported since the initiation of psychotherapeutic, symptomatic, occupational, somatic, and pharmacological interventions for mental disorders. Initially, concern focused on the quality of a treatment, not the diagnosis. Therapy resistant or treatment refractory schizophrenia (TRS) has been discussed in the literature for over 50 years; treatment‐resistant (or refractory) depression (TRD) as a specific term first appeared in the 1970’s, and in the early 1990’s became an entity, a consistent term in the literature despite inconsistent criteria. The percentage of articles addressing TR, compared with total articles published in psychiatry, has increased by 75% during the past two decades (1).

Insufficient consensus on definition and criteria stymies efforts to confirm or reject TR as a valid concept. It also interferes with the calculation of incidence and prevalence, the evaluation of proposed staging methods, and meta‐analysis of interventional strategies. Number, type, length, quality, and assessment methods of treatment attempts are not standardized for consistent attribution of the concept within most diagnoses, including depression, schizophrenia, obsessive compulsive disorder (OCD), and post‐traumatic stress disorder. However, although 100% of practitioners queried in one recent expert consensus survey still sought an operational definition, 92% of psychiatrists considered TRD a useful concept, and 85% reported they used the concept in clinical practice (5).

Some authors apply the term “pseudo resistance” to indicate that treatment attempts were flawed, rather than that competent application of state‐of‐the‐art, previously proven procedures failed (1). Others propose that the term TR be restricted unless failure follows the application of the most promising treatments, including competent application of cognitive‐behavioral therapy. Others urge changing the informal definition of TR from nonresponse to nonremission, as used in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, seeking functional rather than syndromal change.

Individual diagnoses of schizophrenia and OCD are particularly difficult to label as TR because we do not presently expect any treatment to result in a full remission. Currently, 40%–60% of OCD cases are likely to respond to treatment, perhaps with episodic remission (6). It appears reasonable to restrict cases of distinct treatment failure (TF) (and any consideration of TR) to psychiatric conditions that we can usually treat to sustained remission.

There are important differences in the assessment of and reaction to (1) no response, (2) partial response, and (3) insufficient response (i.e., response compared with remission). Since the 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. Attempts at psychotherapy are seldom considered alongside previous pharmacological or somatic treatments, a complex task when assessing for or attempting to stage TR (7).

A literature review shows more success in identifying individual explanations for TF than actually identifying a “diagnosis” of TR. Some authors explore the possibility that iatrogenic alterations from therapies may contribute to TF, 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 TR to a specific therapy (8). 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 no association with TRD and specific drugs or molecules, nor with augmentation or switching strategies.

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 TR, and evidence exists of rare metabolic disorders that infrequently preclude response to standard treatments (9). Ethnic and socioeconomic factors also play a role in TF.

The lack of consensus on definition or research results, due to myriad subdivisions of possible outcomes, argues against any useful conception of TR. Heterogeneous biotypes respond to different mechanisms of action or other necessary interventions (10). The preponderance of evidence tells us that TR is not a discrete entity, but instead is the result of many different origins—an individual situation that must be determined for each TF, with specific causes that are unlikely to be identical to many other cases.

Adopting TR as an explanation, rather than TF as a stage, closes our minds to further inquiry and misdirects us from discovering critical solutions to improve a patient's condition. 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. The term “difficult (or challenging) to treat” may be more useful for cases continuing to seek remission (11), but remembering that these situations result from TFs, and not a diagnosis of “resistance,” is essential.

Our responsibility to our therapeutic alliances demands that we avoid applying the term TR in practice and never quit searching for the true and possibly multiple causes of TF. We must always recall that the clinical tasks we face are inherently complex; routine solutions are unlikely to fit and often lead to TF. The treatment attempts themselves, but neither the patient nor the diagnosis, may be labeled TFs. A treatment attempt may be described as pending remission, rather than TR, because it is likely treatment options remain and that new factors can still be uncovered. When we label an individual's diagnosis as TR, 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. 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 TR, even when technically employed and well meaning, surely, they hear it as hopelessness. 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.

We can begin to address so‐called TR, or, rather, TF 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.