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

Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune, Michael Berk, Koen Demyttenaere, Joseph F. Goldberg,

Summary & key facts

Treatment-resistant depression, often called TRD, is when depressive symptoms do not get better after usual treatment. Researchers say there is no single agreed definition for TRD, and that makes it hard to know how common it is or which treatments work best. Using the definition that regulators often use—no adequate response after trying at least two different antidepressants—about 30% of people with depression meet the definition. Several medical treatments are proven to help some people with TRD, while other options show mixed or limited evidence.

Key facts:

There is no single agreed definition of treatment-resistant depression. Different studies and doctors use different rules, and that makes it hard to compare results.
A widely used rule, adopted by major drug regulators, defines TRD as not getting better after at least two adequate antidepressant trials. By that rule, about 30% of people with depression fit the label.
Some people who look like they have TRD actually do not. This can happen when past treatments were not done properly or when people did not take the medicines as prescribed.
Intravenous ketamine and intranasal esketamine, when given together with an antidepressant, have been shown to work for many people with TRD.
Some newer antipsychotic drugs can help when added to an antidepressant for people who only partly improve. But only the combination of olanzapine and fluoxetine has been specifically tested in people who meet the regulator-defined TRD criteria.
Repetitive transcranial magnetic stimulation, a non-invasive brain stimulation treatment, is supported by evidence and is approved for TRD. A faster form called accelerated theta-burst TMS also shows benefit.
Electroconvulsive therapy, which uses controlled brain stimulation under anesthesia, is an effective short-term and maintenance option for TRD. Early evidence suggests it may work about as well as a single course of intravenous ketamine for acute treatment.
Talking therapies that follow a manual are not proven to beat TRD on their own, but they can give meaningful symptom relief when used along with standard antidepressants.
Simple changes like trying a longer antidepressant trial, switching medications, or combining antidepressants have mixed evidence and are not clearly superior in all cases.
Because definitions and study methods vary so much, it is hard to pin down how many people truly have TRD or which factors reliably predict who will or will not respond to different treatments.

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.

Topics

Substances

Ketamine

Conditions & symptoms

Anxiety Depression Lack of energy or motivation Poor sleep Sadness or low mood

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