Treatment-resistant depression
Treatment-resistant depression is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Electroconvulsive therapy, ketamine, esketamine, and psilocybin are the most effective and safe first-line treatments for treatment-resistant depression.
Inadequate response has most commonly been defined as less than 25% reduction in depressive symptoms following treatment with an antidepressant. Many clinicians and researchers question the construct validity and clinical utility of treatment-resistant depression as currently conceptualized. There is ongoing debate as to whether inadequate response to other treatment modalities, such as psychotherapy, should be included in defining TRD.
Treatment resistance is becoming more prominent with nearly 30% of individuals with major depressive disorder being termed treatment-resistant as defined above. There are many factors that may contribute to inadequate treatment, such as: a history of repeated or severe adverse childhood experiences, early discontinuation of treatment, failure to consider psychotherapy and other psychosocial interventions, patient noncompliance, misdiagnosis, cognitive impairment, low income and other social determinants, and concurrent medical conditions, including comorbid psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications people are resistant to. They may also be staged based on how many treatments they have tried. Despite being called treatment-resistant, there are many treatment options available which are described in the treatment section below.
Risk factors
Comorbid psychiatric disorders
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 major depressive disorder 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 attention deficit hyperactivity disorder, personality disorders, obsessive compulsive disorder, and eating disorders.
Comorbid medical disorders
Some people 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.
Features of depression
People with depression who also display 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. Individuals with depression who struggle with insomnia or develop depression at a younger age are also more likely to be resistant to treatment. Finally, people with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.Demographic
Multiple populations have been identified as being more at risk for treatment resistance. Individuals who are not married or identify as single are one of these groups that may be more at risk. Another population who seems to have poor response to treatment are individuals who are unemployed. Finally, while both male and female gender have been identified as risk factors, it appears that females are more prone to struggle with resistance to treatment.Treatment
Electroconvulsive therapy, ketamine, esketamine, and psilocybin are the most effective and safe first-line treatments for treatment-resistant depression, with esketamine and psilocybin showing slightly lower tolerability.Medication
Antidepressants
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 person reports intolerable side effects, symptoms are eliminated, or the dose is increased to the limit of what is considered safe.Switching or combining antidepressants
Studies have shown a wide variability in the effectiveness of switching antidepressants, with anywhere from 25 to 70% of people responding to a different antidepressant. There is support for the effectiveness of switching people to a different SSRI; 50% of people that were non-responsive after taking one SSRI were responsive after taking a second type. Switching people with treatment-resistant depression to a different class of antidepressants may also be effective. People who are non-responsive after taking an SSRI may respond to moclobemide or tricyclic antidepressants, bupropion or an MAOI.Ketamine has been tested as a rapid-acting antidepressant for treatment-resistant depression in bipolar disorder, and major depressive disorder. Spravato, a nasal spray form of esketamine, was approved by the FDA in 2019 for use in treatment-resistant depression when combined with an oral antidepressant. One promising finding regarding ketamine has been a reduced suicide rate in patients struggling with treatment resistance. While ketamine does appear to have some effectiveness in treating treatment-resistant depression, there seems to be significant variability in its effect.
Psilocybin is approved by the Therapeutic Goods Administration for treatment of treatment-resistant depression in Australia as of 2023.
Some low to moderate quality evidence points to success in the short term using mianserin to augment antidepressant medications. Simply switching to mianserin might also produce an improvement, but the effect size is smaller. No data on quality of life is reported. Data derived from a single study meeting Cochrane 2019 inclusion criteria. The antidepressant mirtazapine has also been used for augmentation. One study on this practice was included in the Cochrane 2019 meta-analysis. The study found that mirtazapine augmentation is not superior to placebo augmentation.
Stimulants, or dopaminergic and/or norepinephrinergic agents
s are a class of medications that are most commonly used to treat inattention disorders such as ADHD, but they have also been used to treat patients with depression struggling with treatment resistance. Some of the stimulants that have been studied in treatment-resistant depression include methylphenidate, lisdexamfetamine, modafanil, and atomoxetine. When used, these medications are commonly used to augment traditional antidepressants and while there seems to be a wide range of effects, they do appear to have some benefit, especially in patients struggling with low energy, poor motivation and inattention as a result of their depression.While these medications can be useful, there are some general contraindications to be mindful of. First, these medications are usually avoided in patients with a history of substance abuse due to their abuse potential. However, both modafinil and atomoxetine can be considered in this population due to their lower abuse potential. In addition, stimulants are generally avoided in patients with heart problems and severe hypertension. Other important considerations include history of psychosis as well as anxiety, as both of these may be worsened while taking stimulants.
Other medications
Medications that have been shown to be effective in people with treatment-resistant depression include lithium, liothyronine, benzodiazepines, atypical antipsychotics, and stimulants. Adding lithium may be effective for people taking some types of antidepressants including SSRIs or SNRIs. Lithium augmentation therapy was associated with a 41.2% remission rate of unipolar depression compared to 14.4% with placebo. Liothyronine 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.Atypical antipsychotics such as aripiprazole, quetiapine or olanzapine can be added to anti-depressants as part of augmentation of treatment. Eli Lilly, the company that sells both olanzapine and fluoxetine individually, has also released a combination formulation which contains olanzapine and fluoxetine in a single capsule. Some low to moderate quality evidence point to success in the short term using antipsychotics cariprazine, olanzapine, quetiapine or ziprasidone to augment antidepressant medications. These have shown promise in treating refractory depression but come with more serious side effects. Among studies studies meeting the Cochrane 2019 inclusion criteria, two report that quetiapine augmentation does not improve overall quality of life.
One study on the 5-HT1A receptor partial agonist buspirone met the Cochrane 2019 inclusion criteria. It reported that buspirone augmentation did not provide an improvement over placebo augmentation. Ultimately, there are many medications that have been tried in treatment-resistant depression with varying effects.