Treatment resistance affects 20-60% of patients with psychiatric disorders; and is associated with increased healthcare burden and costs up to ten-fold higher relative to patients in general. Whilst ...there has been a recent increase in the proportion of psychiatric research focussing on treatment resistance (R
= 0.71, p < 0.0001), in absolute terms this is less than 1% of the total output and grossly out of proportion to its prevalence and impact. Here, we provide an overview of treatment resistance, considering its conceptualisation, assessment, epidemiology, impact, and common neurobiological models. We also review new treatments in development and future directions. We identify 23 consensus guidelines on its definition, covering schizophrenia, major depressive disorder, bipolar affective disorder, and obsessive compulsive disorder (OCD). This shows three core components to its definition, but also identifies heterogeneity and lack of criteria for a number of disorders, including panic disorder, post-traumatic stress disorder, and substance dependence. We provide a reporting check-list to aid comparisons across studies. We consider the concept of pseudo-resistance, linked to poor adherence or other factors, and provide an algorithm for the clinical assessment of treatment resistance. We identify nine drugs and a number of non-pharmacological approaches being developed for treatment resistance across schizophrenia, major depressive disorder, bipolar affective disorder, and OCD. Key outstanding issues for treatment resistance include heterogeneity and absence of consensus criteria, poor understanding of neurobiology, under-investment, and lack of treatments. We make recommendations to address these issues, including harmonisation of definitions, and research into the mechanisms and novel interventions to enable targeted and personalised therapeutic approaches.
Thase presents the study by Sachs et al which describes the main findings of a randomized controlled trial of the second-generation antipsychotic (SGA) cariprazine as an adjunctive treatment for ...patients with major depressive disorder (MDD). Because not all of the participants had received two or more adequate trials of therapy with standard antidepressants in the current episode, the sample does not technically meet regulatory criteria for treatment-resistant depression but does represent the pool of depressed patients who are considered for second- or third-line treatment options. This paper is important for a number of reasons. First, MDD is a common and potentially disabling condition that is recognized as one of the world's greatest public health problems. Second, although prompt recognition and vigorous treatment is inarguably the best strategy to reduce the profound suffering and illness burden attributable to MDD, many depressed people--perhaps up to 40%--do not respond to sequential trials of standard antidepressant medications.
Thase focuses on the paper by Rhee et al. which presents data collected as part of the National Ambulatory Medical Care Surveys (NAMCS) to provide an up-to-date and nationally representative ...description of recent trends in the pharmacotherapy of bipolar disorder. The new data on temporal trends in the therapeutics of bipolar disorder provides an objective way of taking stock of how our treatment choices have evolved since the late 1990s. Some changes in prescription patterns, such as the brief uptick in off-label prescription of gabapentin that occurred between 2001 and 2004, were short-lived. Other changes have occurred more gradually, as illustrated by the slow decline in use of first-generation antipsychotics. Yet others reflect valuable additions to the options available for psychiatrists to treat their patients. Hopefully, learning from the past will help psychiatrists be more mindful about the possibility that what appears to be an exciting new development is actually a fad and, on occasion, about recognizing that there may still be a role for strategies that appear to have fallen out of favor.
Specific challenges that profoundly affect the outcome of treatment for depression include 1) patient engagement and retention in care and optimization of treatment adherence, 2) optimization of ...symptom and side effect control by medication adjustments using measurement-based care procedures, 3) restoration of daily functioning and quality of life, and 4) prevention or at least mitigation of symptomatic relapse or recurrence. According to data from the Sequenced Treatment Alternatives to Relieve Depression study, some 10%–15% of patients will not return for treatment after an initial thorough evaluation visit; an additional 20%–35% will not complete the first acute-phase treatment step, and another 20%–50% will not complete 6 months of continuation treatment. Among patients who stay in treatment, over 50% exhibit poor adherence. Thus, most patients do not overcome the first two challenges. There are no systematic, widely agreed-upon psychosocial approaches to any of these four major challenges. The authors propose “patient-centered medical management” to address each of the four challenges, using psychoeducational, behavioral, cognitive, interpersonal, and dynamic models and methods. A renewed emphasis on the development and testing of systematic approaches to overcoming these common clinical challenges could enhance the chances of patient recovery and care system cost efficiencies.AJP AT 175: Remembering Our Past As We Envision Our FutureJuly 1933: Psychotherapeutics at StockbridgeHorace K. Richardson: “Frequently, in the simpler situations, very few interviews are required in order that he the patient discover for himself what part of the adaptive machinery is at fault, and for him to develop a technique of handling the maladjustment on a more satisfactory level in the future.” (Am J Psychiatry 1933; 90:45–56)
Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate ...medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial – a rater- and patient-blind randomized controlled trial. Patients were randomized to treatment as usual (TAU) or a pharmacogenomics-guided intervention arm in which clinicians had access to a pharmacogenomic test report to inform medication selections (guided-care). Medications were considered congruent (‘use as directed’ or ‘use with caution’ test categories) or incongruent (‘use with increased caution and with more frequent monitoring’ test category) with test results. Unblinding occurred after week 8. Primary outcome was symptom improvement change in 17-item Hamilton Depression Rating Scale (HAM-D17) at week 8; secondary outcomes were response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. At week 8, symptom improvement for guided-care was not significantly different than TAU (27.2% versus 24.4%, p = 0.107); however, improvements in response (26.0% versus 19.9%, p = 0.013) and remission (15.3% versus 10.1%, p = 0.007) were statistically significant. Patients taking incongruent medications prior to baseline who switched to congruent medications by week 8 experienced greater symptom improvement (33.5% versus 21.1%, p = 0.002), response (28.5% versus 16.7%, p = 0.036), and remission (21.5% versus 8.5%, p = 0.007) compared to those remaining incongruent. Pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for difficult-to-treat depression patients over standard of care (ClinicalTrials.gov NCT02109939).
About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with ...treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.
This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures.
Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.
Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.
PDF
