Treatment-resistant depression

Treatment-resistant depression is a type of depression that does not respond to traditional treatments such as medication and psychotherapy. 

Factors associated with poor response and treatment in resistant depression include: chronic comorbid medical conditions, the presence of cerebral vascular disease, coexisting anxiety, substance abuse, and bereavement.

TRD is commonly defined as a lack of response to 2 or more pharmacological treatments given for an adequate duration and adequate dose during the same major depressive episode.

A sufficient trial of a therapeutic agent is generally considered to be eight weeks.

TRD affects 10 to 30% of patients with major depressive disorder, is associated with increased hospitalizations and coexisting conditions, higher mortality and suicide rates.

Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time.

Treatment-resistant depression may require alternative treatments such as transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), or ketamine infusions.

Depression often persists, despite appropriate treatment with first line anti-depressants. 

Treatment resistant depression is typically defined as depression that does not remit despite to adequate trial use of anti-depressant medications. 

In older individuals, treatment resistant depression is associated with decreased psychological well-being, disability, and cognitive decline.

Psychotherapy is the first line treatment for major depression, without psychotic or suicidal features, and includes individual and group, cognitive behavior, therapy, individual, problem-solving, therapy, and interpersonal therapy.

Pharmacologic strategies for treatment of resistant depression include augmentation, in which additional medications are added to existing antidepressants, and the replacement of an anti-depressant with one from a different class.

Inadequate response is defined as less than 50% reduction in depressive symptoms following treatment with at least one antidepressant medication.

Factors that contribute to inadequate treatment are: a history of repeated or severe adverse childhood experiences, early discontinuation of treatment, insufficient dosage of medication, patient noncompliance, misdiagnosis, cognitive impairment, low income and other socio-economic variables, and concurrent medical conditions, including comorbid psychiatric disorders.

Older patients are more susceptible to adverse effects associated with anti-depressants, especially falls.

In treatment-resistant depression adding further treatments such as psychotherapy, lithium, or aripiprazole is weakly supported.

Comorbid psychiatric disorders commonly go undetected in the treatment of depression. 

Anxiety disorders are one of the most common disorder types associated with treatment-resistant depression. 

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, as it may cause depressed patients to be noncompliant in their treatment, and 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.

Some patients diagnosed with treatment-resistant depression 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, but  other processes: diabetes, coronary artery disease, cancer, HIV, and Parkinson’s disease may be present.

Medications used to treat comorbid medical disorders may lessen the effectiveness of antidepressants or cause depression symptoms.

People with depression who also display psychotic symptoms such as delusions or hallucinations are more likely to be treatment resistant. 

Poor response to treatment occurs with longer duration of depressive episodes.

Patients with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.

When a medication course is found to be ineffective options include: switching to a different medication, adding a medication to the patient’s current treatment: includes 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.

Increasing the dosage of an antidepressant is a common strategy to treat depression that does not respond after adequate treatment duration. 

Usually increasing  dose until intolerable side effects, symptoms are eliminated, or the dose is increased to the limit of what is considered safe.

There is a a wide variability in the effectiveness of switching antidepressants, with anywhere from 25–70% of people responding to a different antidepressant.

50% of people that are  non-responsive after taking one SSRI are 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.

However, the more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial.

Some other antidepressants are low dose ketamine and highly serotonergic catecholamines.

Medications that have been shown to be effective in people with treatment-resistant depression include lithium, triiodothyronine, benzodiazepines, atypical antipsychotics, and stimulants. 

Olanzapine antidepressants and other atypical antipsychotics such as aripiprazole and quetiapine are helpful in treating refractory depression but come with serious side effects.

Quetiapine extended release formulation is commonly used for treatment, resistant depression.

Stimulants such as amphetamines and methylphenidate have also been tested with positive results but have potential for abuse. 

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

Ketamine is non-inferior to ECT as therapy for treatment resistant major depression without psychosis.

Spravato, a nasal spray form of esketamine is approved by the FDA for use in treatment-resistant depression when combined with an oral antidepressant.

Esketamine nasal spray plus a selective serotonin reuptake inhibitor or a serotonin norepinephrine reuptake inhibitor are superior to extended release quetiapine plus an SSRI or SNRI with respect to remission at eight weeks (Reif A).

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.

Electroconvulsive therapy is associated with an increase in glial cell line derived neurotrophic factor.

rTMS (repetitive transcranial magnetic stimulation) is a valuable therapeutic option in treatment-resistant depression. 

There is sparse evidence on the effectiveness of psychotherapy in cases of treatment-resistant depression.

Psychotherapy may be effective in people with treatment-resistant depression because it can help relieve stress that may contribute to depressive symptoms.

A Cochrane systematic review has shown that psychological therapies:  cognitive behavioural therapy, dialectal behavioural therapy, interpersonal therapy and intensive short-term dynamic psychotherapy, when added to usual care with antidepressants can be beneficial for depressive symptoms and for response and remission rates over the short term for patients with treatment-resistant depression. 

Psychological therapies added to usual care (antidepressants) seem as acceptable as usual care alone.

Treatment-resistant depression is associated with more instances of relapse than depression that is responsive to treatment. 

As many as 80% of people with treatment-resistant depression that require  more than one course of treatment relapsed within a year. 

Treatment-resistant depression has also been associated with lower long-term quality of life.

Another study saw just 8 of 124 patients in remission after two years of standard depression treatment.

In older adults with treatment resistant depression, augmentation of the existing anti-depressants with aripiprazole improved well-being significantly more over 10 weeks, than switch to bupropion, and was associated with a higher incidence of remission.

Lithium as an augmenting agent has some evidence for benefit.

Augmentation with T3 also has modest evidence among older adults.

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