| 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 a condition that affects people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Typical definitions of TRD vary, and they do not include a resistance to psychological therapies. Inadequate response has traditionally been defined as no clinical response whatsoever (e.g. no improvement in depressive symptoms). However, many clinicians consider a response inadequate if the person does not achieve full remission of symptoms. People with treatment-resistant depression who do not adequately respond to antidepressant treatment are sometimes referred to as pseudoresistant. Some factors that contribute to inadequate treatment are: early discontinuation of treatment, insufficient dosage of medication, patient noncompliance, misdiagnosis, and concurrent psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications people with TRD are resistant to (e.g.: SSRI-resistant).
Prevalence
Treatment-resistance
is relatively common in people with MDD. Rates of total remission
following antidepressant treatment are only 50.4%. In cases of
depression treated by a primary care physician, 32% of people partially responded to treatment and 45% did not respond at all.
Predictors
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.
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.
Finally, people with more severe depression and those who are suicidal
are more likely to be nonresponsive to antidepressant treatment.
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.
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 antidepressants
Studies
have shown a wide variability in the effectiveness of switching
antidepressants, with anywhere from 25-70% 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 nonresponsive after taking one
SSRI were responsive after taking a second type. Switching people with
TRD to a different class of antidepressants may also be effective.
People who are nonresponsive after taking an SSRI may respond to a Tricyclic antidepressant, bupropion or a MAOI.
Adding medication
Medications that have been shown to be effective in people with treatment-resistant depression include lithium, triiodothyronine, benzodiazepines, atypical antipsychotics, and stimulants.
Adding lithium may be effective for people taking some types of
antidepressants, 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. 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. 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.
Ketamine has been tested as a rapid-acting antidepressant for treatment-resistant depression in bipolar disorder, and major depressive disorder.
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. It is associated with an increase in glial cell line derived neurotrophic factor.
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.
Psychological therapies
There is sparse evidence on the effectiveness of psychotherapy 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 TRD because it can help
relieve stress that may contribute to depressive symptoms.
A Cochrane systematic review has shown that psychological therapies (including cognitive behavioural therapy, dialectal behavioural therapy, 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 6 months) for patients with TRD. Medium‐ (7-12 months) and
long‐term (longer than 12 months) effects seem similarly beneficial.
Psychological therapies added to usual care (antidepressants) seem as
acceptable as usual care alone.
rTMS
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
confirming the efficacy of rTMS in treatment-resistant major
depression, as well as naturalistic studies showing its effectiveness in
"real world" clinical settings.
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 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.
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 TRD 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.
