Is there a time when prescribing pharmacotherapy in psychiatry is futile?

KEYWORDS:

• Medical futility
• palliative approach
• pharmacotherapy
• treatment response
• treatment resistance

1. Introduction

Medical futility refers to those circumstances in which a treatment or clinical action, either diagnostic, preventive, therapeutic or rehabilitative, is considered unwarranted and/or of minimal benefit to the intended patient [1]. Medical treatments or clinical actions can be considered futile when the chance of success is unlikely, and when they serve no useful purpose in achieving a definite goal for a given patient taking into account that, by definition, the goals of treatment must be explicitly defined in medicine [2]. Qualitative futility focuses on the value of treatments in terms of quality of life, rather than on the success rate, whereas determining quantitative futility implies a physician’s evaluation of the uselessness of a treatment that is based on clinical experience (both personal and shared) and reported empiric data in a sizable number of cases [3]. In its broad sense, medical futility is often discussed, raising many ethical and case-law concerns, in policy and practice of end-of-life decisions, end-stage illnesses, and prolonging life actions in intensive care units and in operating rooms [4].

The topic of futility has been rarely addressed in psychiatry; although psychiatry language does not usually contain concepts as ‘futile treatment,’ psychiatrists have to confront with circumstances in which the question of futility may arise. Not differently from other medical branches, this concept may apply to several conditions frequently occurring in psychiatric clinical practice, such as the wide variability of response to psychopharmacological treatments. The implicit guiding model in the treatment of psychiatric disorders, especially in the acute phase, points to full remission or recovery [5], with the aim of preventing chronicization, relapses, and poor outcomes, including the well-documented burden of premature mortality for preventable physical diseases found in severe and persistent mental disorders [6]. Nevertheless, despite the availability of drugs with good evidence of efficacy, treatment outcomes in real-world psychiatric practice are highly heterogeneous, ranging from partial response to treatment failure and/or treatment resistance. The most common definition for treatment resistance in psychotic and mood disorders requires a minimum of at least two-prior treatment failures and confirmation of prior adequate dose and duration. However, it should be acknowledged that a not insignificant number of patients only marginally improve after various appropriate pharmacological therapies, thus showing multidrug resistance. It has been estimated that up to 60% of patients with schizophrenia poorly respond to antipsychotics at adequate dose and duration [7], as many as 50% of depressed patients do not achieve remission with antidepressants [8], about 40% of patients with anxiety disorders do not significantly respond to treatment [9], whereas low remission rates of 29.6% after 10 years, and 39.3% after 20 years have been found in anorexic patients [10]. This marked heterogeneity in treatment response challenges the implicit assumption of a broad equivalence within groups of patients sharing similar clinical symptoms. Possible sources of variance are the presence of comorbidity with other psychiatric disorders, including personality disorders, and biological and genetic factors, that have been reported to explain up to 42% of the variance in antidepressant response [11], whereas glutamate and brain-derived neurotrophic factor (BDNF) system genes have been associated with response to antipsychotics [12]. Among the clinical factors related to treatment response, clinical staging, a well-established medical construct, has been increasingly integrated within the field of psychiatry. This concept implies that stages reflect increasing levels of disease progression. Moreover, staging models of treatment resistance in depression suggest that the probability of response diminishes sequentially with every failed adequate pharmacotherapy trial, such that the likelihood of remission after 5 failed adequate treatment trials is negligible [13]. Treatment-resistance inevitably prompts clinicians to provide polypharmacological, off-label, and supertherapeutically dosed treatments that are meaningful and rational under certain conditions, although potentially resulting in pharmacokinetic interactions and increased number of side effects [14]. For highly refractory patients, evidence-based illness-modifying strategies remain unsuccessful, leading to reduced quality of life and recurrent and disproportionate use of health-care services.

Once treatment-resistance algorithms have been established, the goals of clinical management progressively move toward harm minimization and disability reduction. Such a shift requires a change from a heroic therapeutic system focused on cure, which exposes patients to higher-risk polypharmacy and prolonged admissions to acute care settings, to a treatment orientation that recognizes and admits chronicity, refocusing on diminishing suffering and enhancing quality of life. Although not explicitly acknowledged or provided in psychiatry, the palliative care approach for severe, chronic, relapsing, and treatment-resistant psychiatric disorders aims at managing symptoms and disability and promoting quality of life rather than achieving remission or modifying disease progression. When the probability of a favorable treatment outcome is low, many established and conventional treatments in psychiatry can be considered palliative [15]. The question may be even more complex and often goes far beyond chronic and treatment-resistant conditions, since many psychiatric disorders, even at the first stage, have a low probability of achieving a complete remission [7–9]. It should also be borne in mind that most psychiatric treatments are symptomatic, not etiological, and often the response criteria imply 50% or less % of symptoms reduction; thus, despite treatment, residual psychiatric symptoms can significantly persist in affected patients. The care approach intended to manage distressing and persistent symptoms that respond poorly to numerous adequate interventions does not exclude the suitability of other treatment strategies, as it can be applied in association with therapies oriented toward relapse prevention, skill acquisition, and rehabilitation, along with supportive care for patients and their families for managing the emotional and psychosocial burden of unremitting or progressively declining mental illness. Within this context, the concept of personal recovery, although distinct from clinical recovery, should be seen as complementary, and not as an alternative to the medical model in serious mental illness. Personal recovery, defined as the process of living with the mental illness, means recovery of personal and social functioning and points toward empowerment, hope, resilience, social connectedness, personal meaning, and quality of life [16].

2. Expert opinion

The clinical management of patients with severe and persistent mental disorders, often treatment-resistant or refractory, unveils the possibility that further psychopharmacological interventions may become futile. The reorientation from a recovery/remission-based approach to a disease-management approach could be a necessary transition, when considering the risks to which such patients are exposed. Beyond the potentially harmful side-effects and drug interactions deriving from combined psychotropic medications from all classes that are usually continued for years with irrelevant benefits, clinicians should also consider the highly distressing emotional and physical burden experienced by patients undergoing multiple ineffective treatments. Repeated unsuccessful treatments can engender and maintain a cycle of learned helplessness, intensifying demoralization and despair in both patients and caregivers. When the likelihood of response to treatment is minimal, and curative approaches would most likely be futile, a palliative approach, starting from the acceptance of chronicity and the admission of the limits of psychopharmacological therapy, may offer a more realistic analysis of attainable goals. The term palliative, unfortunately, maintains its almost negative connotations, given the well-known associations with terminal illness and end-of-life care. Nevertheless, the intrinsic notion of a disease-management model of care borrowed from chronic disease approach and related disciplines does not correspond to the absence of treatment and does not forage hopelessness. It rather implies a necessary redirection of treatment goals from disease modification toward reasonable individualized outcomes that should take into account the presence of persistent symptoms and the patients’ capacity for coping with a chronic disorder. Facing and managing chronicity and poor treatment response in severe and persistent mental disorders implicate a close working alliance of patients and family members who are involved in the process of care, ranging from generic forms of information giving, psychoeducation, self-help, and social support to more complex and multidisciplinary actions, such as partial symptom control, skill acquisition, and cognitive remediation trainings, and rehabilitation. In recent years, there has been a considerable shift in the physician–patient relationship, moving from a paternalistic, asymmetrical, and imbalanced model, toward a participatory, patient-centered approach to medical care, in which both patients and relatives actively participate in the care process, realizing shared decision-making [17]. This significant change in doctor–patient relationship has also led to substantial changes in outcome evaluations. Many clinical trials actually incorporate patients related outcomes (PROs), subjective indicators of the impact of disease, treatment efficacy, patient satisfaction with treatment, functional status, and psychological well-being, among the traditional measures of symptoms severity for evaluating wider aspects of outcome which encompass also disability and functional issues. Within this context, a persistent therapeutic alliance remains a core component of every clinical action, and treatment goals need to be rethought and redefined in a meaningful and feasible way, for providing an integrated, multidisciplinary, and supportive model of care for severe and persistent psychiatric disorders.

Achieving remission in mental disorders remains a desirable outcome, but, regrettably, as it happens in other chronic medical diseases, in some cases it can foster unrealistic expectations. Recognizing that pharmacotherapy can be futile for a subgroup of psychiatric patients entails the awareness that not all mental disorders are successfully treatable. Given the inherent limits of pharmacotherapy, other treatments, such as noninvasive brain stimulation and brain modulation techniques, represent important additional strategies, and they can be proposed as combined interventions to address the burden of psychiatric disorders. Relieving morbidity and mortality from severe and chronic psychiatric conditions still remains a challenge. Future perspectives should entail a better integration among real-world data, clinical research, and basic neuroscience, including human genomic and biomarkers research; such synergic efforts should offer a clearer picture of the complex, underlying phenomena associated with psychiatric disorders, providing the area of multimodal interventions with new treatment targets and biomarkers of illness and drug response.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript was not funded.