Treatment-resistant depression (TRD) is often defined as

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

in which an affected person does not respond adequately to at least two different

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

medications at an adequate dose and for an adequate duration. 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 disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s. Cases of treatment-resistant depression may also be referred to by which medications people are resistant to (e.g.,

SSRI Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by ...

-resistant). 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

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 disorder Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal functions are significantly impaired. Anxiety may cause phys ...

s 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 Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definition ...

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 Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

personality disorder Personality disorders (PD) are a class of mental health conditions characterized by enduring maladaptive patterns of behavior, cognition, and inner experience, exhibited across many contexts and deviating from those accepted by the culture. ...

s, obsessive compulsive disorder, and

eating disorder An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's health, physical or mental health, mental health. These behaviors may include eating too much food or too little food. Types of eatin ...

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 Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (spec ...

, and Addison's disease are among the most commonly identified as contributing to depression. Others include

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

, HIV, and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. Another factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of

s or cause depression symptoms.

Features of depression

People with depression who also display psychotic symptoms such as

delusion A delusion is a fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some other m ...

s or

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s 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 Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

or develop depression at a younger age are also more likely to resistant to treatment. Finally, people with more severe depression and those who are suicidal are more likely to be nonresponsive to

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

There are multiple strategies that can be used when a medication course is found to be ineffective. The first would be to increase the dosage of medication. Another option is to switch the patient to a different

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

. The last two strategies,

combination therapy In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...

and augmentation therapy, include adding a medication to the patient's current treatment. Combination therapy involves the addition of a different type of

while augmentation therapy requires adding a non-antidepressant medication such as a mood stabilizer. These treatment options are discussed in more detail below.

Medication

Antidepressants

=Dose increase

= Increasing the dosage of an

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 effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s, 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

s, 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

; 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 Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat Clinical depression, depression and social anxiety. It is not ...

or tricyclic antidepressants, bupropion or an MAOI.

Ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

has been tested as a rapid-acting antidepressant for treatment-resistant depression in

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

, and

. Spravato, a nasal spray form of

esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...

, 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. Some low to moderate quality evidence points to success in the short term (8–12 weeks) 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 Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...

is reported. Data derived from a single study meeting Cochrane 2019 inclusion criteria. The antidepressant

mirtazapine Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, atypical tetracyclic antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks but ca ...

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

Stimulants Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognitio ...

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 Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

lisdexamfetamine Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used as a treatment for attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge ...

, modafanil, and

atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...

. 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 In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

as well as

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, 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 Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...

, liothyronine,

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s, atypical antipsychotics, and

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

s. 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 (synthetic 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. 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 (7 studies meeting Cochrane 2019 inclusion criteria) point to success in the short term (8–12 weeks) 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

. One study on the 5-HT_1A receptor partial agonist

buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

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.

=Research

= A 2016

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

evaluated the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression with positive outcome. In 2018, the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) granted breakthrough therapy designation for psilocybin-assisted therapy for treatment-resistant depression. A systematic review published in 2021 found that the use of psilocybin as a pharmaceutical substance was associated with reduced intensity of depression symptoms.

Physical psychiatric treatments

Electroconvulsive therapy

Electroconvulsive therapy Electroconvulsive therapy (ECT) is a psychiatry, psychiatric treatment that causes a generalized seizure by passing electrical current through the brain. ECT is often used as an intervention for mental disorders when other treatments are inadequ ...

(ECT) 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. It involves inducing a controlled

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

in a patient for a short time (30-90 seconds). Often patients receive a total of 6-12 sessions over the course of multiple weeks (receiving 2-3 sessions per week). Electroconvulsive therapy has been found to reduce thoughts of

suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...

and relieve depressive symptoms. It has also been used to treat patients suffering from

mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...

, catatonia, and more. While the exact mechanism by which ECT treats depression is unknown, we know that many aspects of the brains chemical structure and function are altered during seizure activity. This includes alterations of important neurotransmitters such as

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

, and

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. It is also associated with an increase in glial cell line derived neurotrophic factor. When considering ECT, it is important to take into account the potential side effects. Most commonly, patients report

cognitive impairments Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, i ...

including difficulty with short-term and

autobiographical An autobiography, sometimes informally called an autobio, is a self-written account of one's own life, providing a personal narrative that reflects on the author's experiences, memories, and insights. This genre allows individuals to share thei ...

memory as well as

attention Attention or focus, is the concentration of awareness on some phenomenon to the exclusion of other stimuli. It is the selective concentration on discrete information, either subjectively or objectively. William James (1890) wrote that "Atte ...

and learning. While these side effects can be distressing, they are often short-term and resolve within a few days with many patients seeing an overall improvement in cognitive function, including memory, following completion of treatment.

rTMS

rTMS ( repetitive transcranial magnetic stimulation) is gradually becoming recognised as a valuable therapeutic option in treatment-resistant depression. It involves placing an

electromagnetic coil An electromagnetic coil is an electrical Electrical conductivity, conductor such as a wire in the shape of a wiktionary:coil, coil (spiral or helix). Electromagnetic coils are used in electrical engineering, in applications where electric curre ...

near the head and stimulating the nerves in the areas of the brain that play a role in mood regulation and 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 Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

of RCTs confirming the efficacy of rTMS in treatment-resistant major depression, as well as naturalistic studies showing its effectiveness in "real world" clinical settings. While effective, it is also generally tolerated well with very few side effects.

dTMS

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. A 2015

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

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.

Vagus nerve stimulation

Vagus nerve stimulation has also been used for treatment-resistant depression. While more studies are needed to better understand its effect, a meta analysis found evidence that it may provide some benefit to individuals struggling with treatment-resistance.

Deep brain stimulation

Deep brain stimulation has been used in a small number of clinical trials to treat people with severe treatment-resistant depression.

Magnetic seizure therapy

Magnetic seizure therapy is currently being investigated for treating refractory depression.

Transcranial direct-current stimulation

Transcranial direct-current stimulation is a form of neuromodulation that uses constant, low

direct current Direct current (DC) is one-directional electric current, flow of electric charge. An electrochemical cell is a prime example of DC power. Direct current may flow through a conductor (material), conductor such as a wire, but can also flow throug ...

delivered via electrodes on the head.

Psychotherapy

There is sparse evidence on the effectiveness of

psychotherapy Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of Psychology, psychological methods, particularly when based on regular Conversation, personal interaction, to help a person change behavior, increase hap ...

in cases of treatment-resistant depression. However, a review of the literature suggests that it may be an effective treatment option. Psychotherapy may be effective in people with treatment-resistant depression because it can help relieve stress that may contribute to depressive symptoms. A Cochrane

has shown that psychological therapies (including cognitive behavioural therapy,

dialectical behavior therapy Dialectical behavior therapy (DBT) is an evidence-based psychotherapy that began with efforts to treat personality disorders and interpersonal conflicts. Evidence suggests that DBT can be useful in treating mood disorders and suicidal ideati ...

, interpersonal therapy and intensive short-term dynamic psychotherapy) added to usual care (with antidepressants) can be beneficial for depressive symptoms and for response and remission rates over the short term (up to six months) for patients with treatment-resistant depression. Medium- (7–12 months) and long‐term (longer than 12 months) effects seem similarly beneficial. Psychological therapies, including cognitive behavioral therapy, added to usual care (antidepressants) seem as acceptable as usual care alone and may be used as a first line treatment for mild to moderate treatment resistant depression. These findings were echoed by another systematic review finding improved response and remission rates for CBT over the short, medium, and long-term.

Outcomes

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 people with treatment-resistant depression 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. Individuals struggling with treatment-resistant depression report lower work productivity, higher rates of unemployment, and difficulty completing daily tasks when compared to the general population. While we defined treatment resistance as failing to respond to at least two antidepressants, we know that as you try the third and fourth medication, there is even a higher likelihood of resistance and therefore, depression recurrence. This is evidenced by a study that saw just 8 of 124 patients in remission after two years of standard depression treatment. This can lead to significant hardships for the individuals struggling with treatment resistance as outlined in the paragraph above.

References

External links

{{Medical resources , DiseasesDB = , ICD10 = , ICD9 = , ICDO = , OMIM = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = D061218 Major depressive disorder Drug resistance