[3][4] Other factors that may contribute to inadequate treatment are: 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.
[10] Increasing the dosage of an antidepressant is a common strategy to treat depression that does not respond after adequate treatment duration.
[14] 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.
[15][16] Some low to moderate quality evidence points to success in the short term (8–12 weeks) using mianserin to augment antidepressant medications.
[17] Primarily dopaminergic and/or norepinephrinergic stimulants, in low doses, have been used especially in the past, or in conjunction with a multidisciplinary therapy approach, although more targeted and "mild" agents, including modafinil and atomoxetine are considered first line[by whom?]
for both childhood and adult lethargy and inattention disorders, due to their virtually nonexistent abuse potential (limited to one or two cases per 10 000), and higher selectivity, safety, and thus slightly broader therapeutic index.
When depression is related or co-morbid to an inattention disorder, often ADHD, then both can be carefully managed with the same first line stimulant medication, typically both methylphenidate and lisdexamfetamine.
However, stimulants have been shown to be effective for the unyielding depressed combined lacking addictive personality traits or heart problems.
[19][20][21] Medications that have been shown to be effective in people with treatment-resistant depression include lithium, liothyronine, benzodiazepines, atypical antipsychotics, and stimulants.
Benzodiazepines may improve treatment-resistant depression by decreasing the adverse side effects caused by some antidepressants and therefore increasing patient compliance.
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.
[17] A 2016 placebo randomized controlled trial evaluated the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression with positive outcome.
[32] rTMS (repetitive transcranial magnetic stimulation) is gradually becoming recognised as a valuable therapeutic option in treatment-resistant depression.
There have also been a number of meta-analyses of RCTs[33] confirming the efficacy of rTMS in treatment-resistant major depression, as well as naturalistic studies showing its effectiveness in "real world" clinical settings.
[36] 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.
[37] Deep brain stimulation has been used in a small number of clinical trials to treat people with severe treatment-resistant depression.
Transcranial direct-current stimulation is a form of neuromodulation that uses constant, low direct current delivered via electrodes on the head.