Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions

Abstract

Treatment‐resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision‐making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision‐making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo‐resistant (e.g., due to inadequacy of treatment trials or non‐adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non‐response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co‐administered with an antidepressant) are established as efficacious in the management of TRD. Some second‐generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine‐fluoxetine combination has been studied in FDA‐defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA‐approved for individuals with TRD, with accelerated theta‐burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non‐inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual‐based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

The definition of treatment resistance in anxiety disorders: a Delphi method‐based consensus guideline

“…The panel additionally proposed a non‐dichotomous, escalating staging model of TR‐AD, in analogy to those suggested for obsessive‐compulsive disorder 78 and major depressive disorder 79‐81 (see Table 1, statement 7). This model – or alternatively a pseudo‐linear scale of degree of resistance – would allow clinical trials for regulatory purposes or other studies to describe a particular population on a dimensional spectrum of treatment resistance, ranging from isolated resistance to pharmacological or psychotherapeutic treatment to composite resistance to several trials of multiple modalities delivered in different episodes of the anxiety disorder.…”

“…It is desirable to identify factors predicting and mechanistically underlying treatment resistance in anxiety disorders. Some studies of limited quality and highly heterogeneous in design suggest a number of potential risk factors -such as high expressed emo tions within the family, higher severity and longer duration of the disorder, earlier age of onset, or presence of comorbid conditions -which however have not been consistently replicated 13,19,81,82 . In a similar vein, the identification of reliable and valid biomark ers indicating an increased risk of treatment resistance would be helpful to inform algorithms for individually tailoring an intensi fied treatment for those patients 22,23,25,93,94,115 .…”

Longitudinal Clusters of Long-Term Trajectories in Patients with Early-Onset Chronic Depression: 2 Years of Naturalistic Follow-Up after Extensive Psychological Treatment

“…In clinical practice, it provides the necessary information for clinicians to consider individual courses in order to decide which treatment should be offered to a specific patient at a certain point of time [40]. This might be particularly useful to manage long-term consequences of prolonged pharmacological treatment [35,36,41] and to advance the ongoing debate about treatment-resistance and difficult-to-treat depression [42][43][44][45].…”

Recent developments pertaining to treatment‐resistant depression: a 40‐year perspective

“…Episodes that follow this course are commonly called treatment resistant de pression (TRD), and account for a dispro portionately large proportion of the illness burden associated with MDD 1 . This is the subject of the excellent pa per by McIntyre et al 4 , which provides a con cise, yet com prehensive review of the topic, in cluding up to date summaries of the best studied and most promising treatment strat egies.…”