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

Summary & key facts

Treatment-resistant depression means depression that does not get better after usual treatments. Scientists do not all agree on one clear definition, which makes it hard to know exactly how common it is or which treatments work best. Using the definition that regulators often use, about 30% of people with depression fit this label. Several treatments can help some people, including intravenous ketamine, a nasal form of ketamine given with an antidepressant, magnetic brain stimulation, and electroconvulsive therapy, while talking therapies help more when added to medicines. The lack of a single definition also means some people are labeled treatment-resistant when the real problem was that a medication trial was too short or the person stopped taking it.

Key facts:

• There is no single agreed definition of treatment-resistant depression, and many different definitions are used in research and care.
• Regulators in the US and Europe most often call treatment-resistant depression failure to improve after at least two adequate antidepressant treatments.
• Using that common definition, about 30% of people with depression meet the criteria for treatment-resistant depression.
• Some people counted as treatment-resistant are actually "pseudo-resistant" because their medication trials were not adequate or they did not stick with the treatment.
• Intravenous ketamine and a nasal form of ketamine called esketamine, when given along with an antidepressant, have been shown to help people with treatment-resistant depression.
• Repetitive transcranial magnetic stimulation, which uses magnetic pulses to the brain, is approved and effective for treatment-resistant depression; a faster version called accelerated theta-burst TMS has also shown benefit.
• Electroconvulsive therapy is effective for short-term relief and maintenance in treatment-resistant depression, and early studies suggest it may work about as well as a single ketamine infusion for immediate relief.
• Some newer antipsychotic drugs can help when added to antidepressants for people who only partly improve, but only the olanzapine-plus-fluoxetine combination has been tested specifically in people who meet the regulators' definition of treatment-resistant depression.
• Evidence is mixed about whether trying antidepressants for longer, switching medicines, or combining antidepressants reliably helps more people.
• Talk therapies by themselves are not proven to fix treatment-resistant depression, but adding psychotherapy to medication often gives additional symptom relief.

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

Electroconvulsive Therapy Studies Transcranial Magnetic Stimulation Studies Treatment of Major Depression

Categories

Health Sciences Medicine Pharmacology

Tags

Antidepressant Anxiety Aripiprazole Clinical trial Depression (economics) Economics Intensive care medicine Internal medicine Macroeconomics Medicine Olanzapine Psychiatry Psychological intervention Quetiapine Schizophrenia (object-oriented programming) Treatment-resistant depression

Substances

Ketamine

Conditions & symptoms

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