Treatment-resistant depression

Treatment-resistant depression
Classification and external resources
MeSH D061218

Treatment-resistant depression (TRD) or treatment-refractory depression is a term used in clinical psychiatry to describe cases of major depressive disorder (MDD) that do not respond adequately to appropriate courses of at least two antidepressants.[1] The term was first coined with the development of the concept in 1974. Inadequate response has traditionally been defined as no response whatsoever. However, many clinicians consider a response inadequate if the patient does not achieve full remission of symptoms.[2] Cases of treatment-resistant depression in which the course of treatment was not adequate are sometimes referred to as pseudoresistant.[3] Some factors that contribute to inadequate treatment are: early discontinuation of treatment, insufficient dosage of medication, patient noncompliance, misdiagnosis, and concurrent psychiatric disorders.[3] Cases of treatment-resistant depression may also be referred to by which medications they are resistant to (e.g.: SSRI-resistant).[4]


Treatment-resistance is relatively common in cases of MDD. Rates of total remission following antidepressant treatment are only 50.4%. In cases of depression treated by a primary-care physician, 32% of patients partially responded to treatment and 45% did not respond at all.[2]


Comorbid psychiatric disorders

Comorbid psychiatric disorders commonly go undetected in the treatment of depression. If left untreated, the symptoms of these disorders can interfere with both evaluation and treatment. Anxiety disorders are one of the most common disorder types associated with treatment-resistant depression. The two disorders commonly co-exist, and have some similar symptoms. Some studies have shown that patients with both MDD and panic disorder are the most likely to be nonresponsive to treatment. Substance abuse may also be a predictor of treatment-resistant depression. It may cause depressed patients to be noncompliant in their treatment, and the effects of certain substances can worsen the effects of depression. Other psychiatric disorders that may predict treatment-resistant depression include personality disorders, obsessive compulsive disorder, and eating disorders.[5]

Comorbid medical disorders

Some patients who are diagnosed with treatment-resistant depression may have an underlying undiagnosed health condition that is causing or contributing to their depression. Endocrine disorders like hypothyroidism, Cushing's disease, and Addison's disease are among the most commonly identified as contributing to depression. Others include diabetes, coronary artery disease, cancer, HIV, and Parkinson's disease. Another factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of antidepressants or cause depression symptoms.[5]

Features of depression

Cases of depression in which the patient also displays psychotic symptoms such as delusions or hallucinations are more likely to be treatment resistant. Another depressive feature that has been associated with poor response to treatment is longer duration of depressive episodes.[4] Finally, patients with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.[6]

Drug treatment

There are three basic categories of drug treatment that can be used when a medication course is found to be ineffective. One option is to switch the patient to a different medication. Another option is to add a medication to the patient’s current treatment. This can include combination therapy: the combination of two different types of antidepressants, or augmentation therapy: the addition of a non-antidepressant medication that may increase the effectiveness of the antidepressant.[7]

Dose increase

Increasing the dosage of an antidepressant is a common strategy to treat depression that does not respond after adequate treatment duration. Practitioners who use this strategy will usually increase the dose until the patient reports intolerable side effects, symptoms are eliminated, or the dose is increased to the limit of what is considered safe.[8]

Switching antidepressants

Studies have shown a wide variability in the effectiveness of switching antidepressants, with anywhere from 25-70% of patients responding to a different antidepressant.[9] There is support for the effectiveness of switching patients to a different SSRI; 50% of patients that were nonresponsive after taking one SSRI were responsive after taking a second type. Switching patients to a different class of antidepressants may also be effective. Patients who are nonresponsive after taking an SSRI may respond to bupropion or a MAOI.[8]

Adding medication

Medications that have been shown to be effective in cases of treatment-resistant depression include lithium, triiodothyronine, benzodiazepines, atypical antipsychotics, and stimulants. Adding lithium may be effective for patients taking some types of antidepressants, I it does not appear to be effective in patients taking SSRI’s. Triiodothyroxine (T3) is a type of thyroid hormone and has been associated with improvement in mood and depression symptoms. Benzodiazepines may improve treatment-resistant depression by decreasing the adverse side effects caused by some antidepressants and therefore increasing patient compliance.[10] Since the entry of olanzapine into psychopharmacology, many psychiatrists have been adding low dose olanzapine to antidepressants and other atypical antipsychotics such as aripiprazole and quetiapine. Eli Lilly, the company that sells both olanzapine and fluoxetine individually, has also released a combo formulation which contains olanzapine and fluoxetine in a single capsule.

These have shown promise in treating refractory depression but come with serious side effects.[11] Stimulants such as amphetamines and methylphenidate have also been tested with positive results but have potential for abuse. However, stimulants have been shown to be effective for the unyielding depressed combined lacking addictive personality traits or heart problems.[12][13][14]

Ketamine has been tested as a rapid-acting antidepressant[15] for treatment-resistant depression in bipolar disorder, and major depressive disorder.[16]

Other treatment options

Electroconvulsive therapy

Electroconvulsive therapy is generally only considered as a treatment option in severe cases of treatment-resistant depression. It is used when medication has repeatedly failed to improve symptoms, and usually when the patient’s symptoms are so severe that they have been hospitalized. Electroconvulsive therapy has been found to reduce thoughts of suicide and relieve depressive symptoms.[17] It is associated with an increase in glial cell line derived neurotrophic factor.[18]

Vagus nerve stimulation

Vagus nerve stimulation is a more invasive procedure than electroconvulsive therapy, but it has been shown to be well tolerated. During the procedure a stimulating electrode is surgically attached to the vagus nerve; this allows for continuous stimulation after implantation. Like electroconvulsive therapy, it is usually only used in severe cases of treatment-resistant depression that have been non-responsive to medication.[19]


There is sparse evidence on the effectiveness of psychotherapy in cases of treatment-resistant depression.[20] However, a review of the literature suggests that it may be an effective treatment option.[21] Psychotherapy may be effective in these cases because it can help relieve stress that may contribute to depressive symptoms.[22]


rTMS (Repetitive Transcranial Magnetic Stimulation) is gradually becoming recognised as a valuable therapeutic option in treatment-resistant depression. A number of randomised placebo-controlled trials have compared real versus sham rTMS. These trials have consistently demonstrated the efficacy of this treatment against major depression. There have also been a number of meta-analyses of RCTs [23] confirming the efficacy of rTMS in treatment-resistant major depression, as well as naturalistic studies showing its effectiveness in "real world" clinical settings [24][25]


dTMS (Deep Transcranial Magnetic Stimulation) is a continuation of the same idea as rTMS, but with the hope that deeper stimulation of subcortical areas of the brain leads to increased effect.[26] A 2015 systematic review and health technology assessment found lacking evidence in order to recommend the method over either ECT or rTMS because so few studies had been published.[26]


Treatment-resistant depression is associated with more instances of relapse than depression that is responsive to treatment. One study showed that as many as 80% of patients who needed more than one course of treatment relapsed within a year. Treatment-resistant depression has also been associated with lower long term quality of life.[27]


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