TRD is best supported by evidence for electroconvulsive therapy, ketamine (including esketamine), and certain neuromodulation approaches (e.g., rTMS/TBS), with some adjunctive agents showing benefit.
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. 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. Spravato is still quite limited in its availability. Patients must be over 18 and be a part of the
Risk Evaluation and Mitigation Strategies program. Additionally, esketamine can not be administered for at-home use and the treatment is very costly, though insurance could cover the costs. 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 (TGA) for treatment of treatment-resistant depression in
Australia as of 2023. 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 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. 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 in treatment-resistant depression reduces the odds of remaining ill by 56-95%. Augmenting an antidepressant with lithium is proven to improve major depressive disorder in multiple
randomized controlled trials. Lithium augmentation therapy was associated with a 41.2% remission rate of unipolar depression compared to 14.4% with placebo. In addition to reducing suicide, lithium also decreases all-cause mortality in people with mood disorders. A disadvantage of lithium is the need for occasional blood tests to check lithium levels. 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. Among studies studies meeting the Cochrane 2019 inclusion criteria, two report that quetiapine augmentation does not improve overall
quality of life. It has also been used to treat patients suffering from
mania,
psychosis,
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,
norepinephrine, and
dopamine. 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 including difficulty with
short-term and
autobiographical memory as well as
attention and learning.
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 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 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. A large retrospective chart review of 495 patients conducted in a naturalistic clinic setting found that rTMS was effective across all age groups (15–78), with no significant differences in treatment response or remission rates by age. This suggests that advanced age should not be considered a barrier to rTMS efficacy in treatment-resistant depression.
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.
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 delivered via electrodes on the head.
Psychotherapy 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 treatment-resistant depression 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,
dialectical behavior 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 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. ==Outcomes==