INTRODUCTION — Although numerous treatments are available for unipolar major depression (major depressive disorder), patients may be highly resistant (refractory) to many sequential treatment regimens, including multiple classes of antidepressants and adjunctive drugs, as well as psychotherapy, repetitive transcranial magnetic stimulation, and electroconvulsive therapy.
This topic reviews management and treatment of refractory depression. The epidemiology, assessment, prognosis, and treatment of resistant depression are discussed separately, as are the initial treatment of depression and clinical features and diagnosis of depression.
●(See "Unipolar depression in adults: Choosing treatment for resistant depression".)
●(See "Unipolar major depression in adults: Choosing initial treatment".)
●(See "Unipolar depression in adults: Clinical features".)
●(See "Unipolar depression in adults: Assessment and diagnosis".)
DEFINITIONS
Unipolar major depression — Unipolar major depression (major depressive disorder) is diagnosed in patients who have suffered at least one major depressive episode and have no history of mania (table 1) or hypomania (table 2) [1]. A major depressive episode is a period lasting at least two weeks, with five or more of the following symptoms: depressed mood, anhedonia, insomnia or hypersomnia, change in appetite or weight, psychomotor retardation or agitation, low energy, poor concentration, thoughts of worthlessness or guilt, and recurrent thoughts about death or suicide (table 3). Additional information about the clinical presentation and diagnosis of major depressive disorder is discussed separately. (See "Unipolar depression in adults: Clinical features" and "Unipolar depression in adults: Assessment and diagnosis".)
Treatment-resistant depression — The term “treatment-resistant depression” typically refers to major depressive episodes that do not respond satisfactorily after one or two trials of antidepressant monotherapy; however, the definition has not been standardized [2-4]. The definition of treatment-resistant depression is discussed separately. (See "Unipolar treatment resistant depression in adults: Epidemiology, risk factors, assessment, and prognosis", section on 'Treatment resistant depression'.)
Treatment-refractory depression — The term “treatment-refractory depression” typically refers to unipolar major depressive episodes that are highly resistant to treatment and do not respond satisfactorily to many sequential treatment regimens. However, the definition has not been standardized, and there is no clear demarcation between treatment-resistant depression (an episode that does not respond to at least one or two trials of antidepressant monotherapy) and treatment-refractory depression.
Our definition of treatment-refractory depression is drawn in part from the inclusion criteria for studies of investigational treatments such as deep brain stimulation [5-7] and ablative neurosurgery [8,9]. In addition, the definition is consistent with the criteria developed for an entity termed “multiple-therapy-resistant major depressive disorder,” which refers to patients who have not responded to numerous standard treatments and are perhaps appropriate candidates for nonstandard therapies, instead of further trials with standard treatments that may be futile [10]. We use the term treatment-refractory depression for patients with unipolar major depression who do not respond to or tolerate, or who decline, the following:
●Antidepressants – Several trials (eg, three to six) with different drugs and classes, including older drugs such as tricyclics or monoamine oxidase inhibitors
●Adjunctive drugs – Multiple trials (eg, two to four) that combine antidepressants with different adjunctive drugs, such as second-generation antipsychotics, lithium, or ketamine/esketamine
●Adjunctive psychotherapy – At least one trial administered in conjunction with pharmacotherapy
●Repetitive transcranial magnetic stimulation – At least one course (eg, 20 to 30 treatments)
●Electroconvulsive therapy (ECT) – At least one course (eg, 6 to 12 treatments), which includes bilateral electrode placement if patients do not improve initially with right unilateral ECT
MANAGEMENT
General principles — The standard approach to managing highly resistant (refractory) depression includes evaluating the patient to confirm the diagnosis is unipolar depression, determine whether comorbid disorders are present and require treatment, and to assess adherence to current and past treatment [11,12]. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Differential diagnosis' and "Unipolar depression in adults: Clinical features", section on 'Comorbidity' and "Unipolar depression in adults and initial treatment: General principles and prognosis", section on 'Adherence to antidepressants'.)
Referral — We recommend referral of patients with refractory depression to mental health clinicians at specialty clinics that treat depressive disorders. Although many internists and primary care clinicians can administer initial treatment for unipolar depression, and some can treat resistant depression, most lack the training and experience for managing refractory depression.
Therapeutic approach — For treatment-refractory depression, we suggest a conservative approach that includes ongoing pharmacotherapy and psychotherapy that provides some measure of relief and follows evidence-based practice guidelines, and avoids excessive, futile investigations and treatments (eg, polypharmacy with four or more psychotropic medications). Repeated treatment failures may lead patients to feel helpless, pessimistic, and demoralized; thus, management should include regular visits (eg, every two to eight weeks) to monitor safety and provide support [13].
Clinicians can encourage patients to function as best they can despite their refractory symptoms and to conceptualize their depression as a chronic disease, analogous to rheumatoid arthritis, diabetes mellitus, and chronic pain [13,14]. Management includes interventions to help patients [13-17]:
●Learn about the signs, symptoms, and prognosis of unipolar major depression.
●Understand the limitations of current treatment.
●Learn healthy physical habits related to sleep and exercise. (See "Risk factors, comorbidities, and consequences of insomnia in adults" and "The benefits and risks of aerobic exercise" and "Unipolar major depression in adults: Choosing initial treatment", section on 'Supportive care'.)
●Learn healthy mental health habits related to coping with difficult situations and increasing self-awareness and social skills.
●Focus upon psychosocial functioning and quality of life.
●Find or rediscover meaning and a purpose in life.
Clinicians should maintain hope for improvement but temper unrealistic expectations and try to help patients with treatment-refractory depression accept ongoing symptoms without blaming themselves [13,14].
Evidence supporting a conservative approach includes a prospective, 48-week, observational study of a depression management program in 19 patients and their family members suggested that this approach may possibly improve depressive symptoms, psychosocial functioning, and quality of life [15].
Additional information about managing treatment-refractory depression is discussed separately. (See "Unipolar depression in adults: General principles of treating resistant depression".)
Setting — In managing treatment-refractory depression, the setting depends upon the severity; mild to moderate episodes are typically treated on an outpatient basis, and severe episodes on an inpatient basis. (See "Unipolar depression in adults: Choosing treatment for resistant depression".)
Specialized inpatient settings can be beneficial but their availability is limited, especially for extended hospitalizations. In a prospective observational study, 113 patients (approximately 70 percent with unipolar depression) were treated in a national-referral hospital unit dedicated to refractory, complex mood disorders [18]. Prior to hospitalization for the current mood episode, patients had received on average 10 medications, and most had received electroconvulsive therapy (ECT). Multimodal treatment (including pharmacotherapy and psychotherapy, as well as assessment for neurosurgical interventions) was provided during a mean hospitalization of 23 weeks. At discharge, response (reduction of baseline symptoms ≥50 percent) had occurred in 50 percent, with an average time to response of approximately 18 weeks; functional improvement occurred in 69 percent.
Duration of an adequate trial — We generally treat unipolar major depression for 6 to 12 weeks before deciding whether a regimen has sufficiently relieved symptoms [19-21]. However, for patients who show little improvement (eg, reduction of baseline symptoms ≤25 percent) after four to six weeks, we administer next-step treatment [22]. Additional information about the duration of an adequate treatment trial is discussed separately. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Duration of an adequate trial'.)
Measurement-based care — Measurement-based care is the systematic, quantitative assessment of symptoms that is typically performed at each visit [22]. Clinicians can also measure psychosocial functioning, quality of life, medication adherence, and tolerability of treatment.
The nine-item Patient Health Questionnaire is a self-report, standardized, rating scale that measures the severity of symptoms in patients with major depression and is widely used to ascertain response to pharmacotherapy or psychotherapy (table 4) [23,24]. Scores >20 indicate severe depression, whereas scores <5 indicate remission. A decrease ≥50 percent indicates a clinically significant response. (See "Using scales to monitor symptoms and treat depression (measurement based care)", section on 'Patient Health Questionnaire - Nine Item'.)
CHOOSING TREATMENT
Combination therapy — For patients with treatment-refractory depression, we suggest pharmacotherapy combined with psychotherapy (eg, cognitive-behavioral therapy [CBT]), based upon randomized trials in patients with treatment-resistant depression, as well as patients who present for initial treatment of unipolar major depression. However, pharmacotherapy alone is a reasonable alternative if adjunctive psychotherapy is declined or not available. Evidence supporting the use of combination therapy is discussed separately. (See "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Psychotherapy' and "Unipolar major depression in adults: Choosing initial treatment", section on 'Efficacy of antidepressants plus psychotherapy'.)
Pharmacotherapy — Patients with treatment-refractory unipolar major depression frequently receive an antidepressant augmented with another drug, based upon the efficacy of augmentation in randomized trials of patients with treatment-resistant depression. However, antidepressant monotherapy is a reasonable alternative, especially if tolerability is problematic. Many antidepressants and adjunctive drugs are available, and the choice begins with drugs that have not been previously used for the current depressive episode at a sufficient dose and for a sufficient length of time. Multiple reviews have concluded that the efficacy of different antidepressants is generally comparable across and within classes, and that there are no robust or replicated results that have established clinically meaningful differences. Given the lack of clear superiority in efficacy among antidepressants, selecting a drug is based upon other factors, such as safety and adverse effects. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Selecting a specific antidepressant'.)
Our general order of preference in choosing an antidepressant is as follows:
●Selective serotonin reuptake inhibitor (SSRI) (see "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects")
●Serotonin-norepinephrine reuptake inhibitor (SNRI) (see "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects")
●Atypical antidepressant (see "Atypical antidepressants: Pharmacology, administration, and side effects")
●Serotonin modulator (see "Serotonin modulators: Pharmacology, administration, and side effects")
●Tricyclic antidepressant (see "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects")
●Monoamine oxidase inhibitor (MAOI) (see "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects")
While there is no evidence-based sequence for selecting augmentation agents, our general order of preference in choosing an adjunctive medication is as follows:
●Second-generation antipsychotic
●Second antidepressant from a different class
●Thyroid hormone
Second-generation antipsychotics have the best balance of efficacy and tolerability among these options, particularly in combination with more modern, first-line antidepressants such as SSRIs and SNRIs. However, it is reasonable to use these augmentation drugs in a different order.
Other augmentation agents that can be useful for treatment-refractory depression are intravenous ketamine and intranasal esketamine. The role of ketamine and esketamine in treating major depression, as well as their administration, efficacy, and adverse effects, are discussed separately. (See "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Ketamine or esketamine' and "Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects".)
One rarely used pharmacotherapy regimen that may be indicated for patients with treatment-refractory depression is the combination of a tricyclic antidepressant and an MAOI. This combination is a treatment of last resort due to potential life-threatening drug-drug interactions, including the serotonin syndrome and hypertensive crisis [25-27]. Combining these two drug classes requires a thorough discussion of the risks and benefits, as well as careful monitoring. Generally, the MAOI is added after a failed trial of tricyclic monotherapy, rather than vice versa or simultaneous initiation of both drugs [28]. In addition, the dose for each drug is comparable to the dose used for monotherapy (table 5). Drug-drug interactions (including the serotonin syndrome) between MAOIs and tricyclics may be determined using the Lexicomp drug interactions tool (Lexi-Interact Online) included in UpToDate. Detailed information about the administration and safety of tricyclics and MAOIs is discussed separately. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects" and "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects".)
Low-quality evidence supporting the use of a tricyclic plus an MAOI includes a retrospective study of 62 cases [28]. The tricyclics included desipramine, doxepin, and nortriptyline, and the MAOIs included isocarboxazid, phenelzine, and tranylcypromine. The combination appeared to be effective and safe; serotonin syndrome occurred in one case and hypertension was not observed. Other adverse effects were consistent with those that may occur with monotherapy (table 6).
Lack of response to numerous standard treatments may impel clinicians to prescribe many concomitant medications (≥4 psychotropic drugs). However, we generally avoid complex medication regimens because there are no data supporting their utility, and patients may feel worse due to the cumulative side effects.
Additional information about choosing adjunctive pharmacotherapy, including the efficacy and tolerability of different options, is discussed separately in the context of treatment-resistant depression. (See "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Pharmacotherapy'.)
Adjunctive psychotherapy — There are multiple psychotherapies available for patients with treatment-refractory depression, and the choice begins with available therapies that have not yet been administered. In addition, there is no compelling evidence that one is superior to the rest, based upon randomized trials in patients who present for initial treatment of unipolar major depression. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Selecting a specific psychotherapy'.)
Among the major psychotherapies, CBT has been studied most often in treatment-resistant depression, and interpersonal psychotherapy has been widely studied for the initial treatment of depression. Other alternatives include psychodynamic psychotherapy, mindfulness-based cognitive therapy, behavioral activation, problem solving therapy, supportive psychotherapy, and family therapy. The efficacy and administration of these psychotherapies is discussed separately in the context of treatment-resistant depression and the initial treatment of depression. (See "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Psychotherapy' and "Interpersonal Psychotherapy (IPT) for depressed adults: Indications, theoretical foundation, general concepts, and efficacy" and "Unipolar depression in adults: Psychodynamic psychotherapy" and "Unipolar major depression: Treatment with mindfulness-based cognitive therapy" and "Unipolar depression in adults: Supportive psychotherapy" and "Unipolar depression in adults: Family and couples therapy" and "Overview of psychotherapies".)
Treatments with potential benefit — Patients with treatment-refractory depression may not respond to multiple sequential trials of different antidepressants and augmentation with other medications (eg, second-generation antipsychotics, lithium, thyroid hormone, or a second antidepressant) and/or psychotherapy, as well as a trial of ECT and a trial of repetitive transcranial magnetic stimulation. These patients are candidates for augmentation with less established treatments, including anti-inflammatory drugs, such as celecoxib, cytokine inhibitors, glucocorticoids, and minocycline [29]. Other potentially beneficial treatments, listed below alphabetically, are botulinum toxin, D-cycloserine, exercise, lithium monotherapy, methylfolate, omega-3 fatty acids, pimavanserin, quetiapine monotherapy, S-adenosyl methionine, statins, and stimulants or stimulant-like drugs such as modafinil or pramipexole.
●Botulinum toxin – Randomized trials suggest that adjunctive botulinum toxin may benefit patients with unipolar major depression, but loss of blinding due to the drug’s effect upon facial muscles is common [30,31]. A pooled analysis of individual patient data from three randomized trials (total n = 134 patients), each lasting six weeks, compared onabotulinumtoxinA (29 units for females or 40 units for males) with placebo [32]. At baseline, antidepressants were prescribed to 64 percent of the patients; onabotulinumtoxinA and placebo were injected in a single session into the glabellar frown muscles of the forehead. Remission occurred in more patients who received active treatment than placebo (31 versus 7 percent), and adverse events for the two groups were comparable. However, the investigators acknowledged the difficulty of blinding patients and outcome raters.
●Celecoxib – Multiple meta-analyses of randomized trials consistently indicate that celecoxib can ameliorate depressive syndromes [33,34]. As an example, three meta-analyses from the same group of investigators showed that celecoxib was superior to placebo:
•A meta-analysis of four trials lasting six or eight weeks compared celecoxib (200 to 400 mg per day) plus an antidepressant (generally an SSRI) with placebo plus an antidepressant in 132 depressed patients with no somatic comorbidity [35]. Remission was much more likely to occur in patients who received add-on celecoxib (odds ratio 8, 95% CI 3-21).
•Another meta-analysis (10 trials, 2750 patients with either major depression or depressive symptoms) compared celecoxib with placebo, used as monotherapy or add-on therapy for six weeks to one year [35]. The analyses showed a significant, clinically small to moderate effect favoring celecoxib. However, heterogeneity across studies was high, as was risk of bias.
Although adverse gastrointestinal or cardiovascular effects were comparable for celecoxib and placebo, the duration of treatment may have been too short for these adverse effects to manifest; several observational studies have found that treatment with SSRIs plus nonsteroidal anti-inflammatory drugs is associated with bleeding [36]. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Bleeding'.)
•A third meta-analysis included 13 randomized trials (n = 4214) that compared nonsteroidal anti-inflammatory drugs (primarily celecoxib) with placebo as monotherapy or add-on treatment [37]. Improvement was superior with active drug and the clinical benefit was small to moderate.
Some clinicians have emphasized that anti-inflammatory drugs such as celecoxib should be reserved for patients with signs of increased inflammation, as indicated by elevated inflammatory biomarkers such as C-reactive protein [38]. (See "Unipolar depression: Neurobiology", section on 'Inflammation'.)
●Cytokine inhibitors – Cytokine inhibitors may be useful for depressive syndromes. A meta-analysis of eight randomized trials compared cytokine inhibitors with placebo for 12 or 52 weeks in patients with depressive symptoms (n = 3345) [37]. Active treatments included adalimumab, ixekizumab, or methotrexate; nearly all patients had somatic comorbidity, such as psoriasis or rheumatoid arthritis, and received study treatments as monotherapy. Improvement of depression was superior with cytokine inhibitors and the clinical effect was moderate; however, heterogeneity across studies was large. In studies of patients with rheumatologic illnesses, serious but infrequent adverse effects of cytokine inhibitors include elevated liver enzymes and infection.
●D-cycloserine – A small, six-week randomized trial in 26 patients with unipolar major depression resistant to antidepressants found that improvement was greater with add-on D-cycloserine (1000 mg/day) than placebo [39]. However, in a previous trial in 22 treatment-resistant patients, the same investigators found that a smaller dose of adjunctive D-cycloserine (250 mg/day) was not beneficial [40].
●Exercise – Exercise as an add-on treatment may help patients who do not respond to pharmacotherapy. A 10-week randomized trial enrolled 42 patients with major depression who did not respond to at least six weeks of antidepressant treatment and compared adjunctive aerobic exercise (two sessions per week, each lasting one hour, in a physical therapy setting) with a single consultation focused upon advice for physical activity [41]. Improvement of both depression and cardiovascular fitness was greater with exercise. Another study found that even low dose exercise (eg, 20 minutes, three times/week of moderate intensity exercise) may perhaps be beneficial [42].
The administration of exercise is discussed separately, as is additional information about the efficacy of exercise. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Supportive care'.)
●Glucocorticoids – Randomized trials suggest that a short course of glucocorticoids may help treatment-refractory depression. A meta-analysis of two trials compared corticosteroids (corticotropin-releasing hormone, dexamethasone, or hydrocortisone) as add-on treatment for two or four days in 59 patients with unipolar major depression [37]. Improvement was superior with glucocorticoids and the clinical effect was large.
●Lithium monotherapy – Older studies suggest that lithium monotherapy may effectively treat unipolar depression, but lithium is generally used as augmentation for treatment-resistant patients (see 'Pharmacotherapy' above). There is far less evidence for lithium monotherapy than for antidepressants [43-45], and lithium can be difficult to use because of the risk of toxicity and need to monitor serum concentrations [46]. (See "Unipolar depression in adults: Treatment with lithium" and "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Minimal response to initial treatment'.)
●Methylfolate – Methylfolate is the form of folate that crosses the blood brain barrier, and limited evidence suggests that adjunctive methylfolate may be effective for treatment-refractory depression. A meta-analysis of two randomized trials compared methylfolate (15 mg/day) with placebo as add-on treatment in 99 patients with unipolar major depression that had not responded to an antidepressant [47]. Improvement was greater with active drug and the clinical effect was moderate to large. The larger of the two trials compared methylfolate plus an SSRI with placebo plus an SSRI for eight weeks in 75 patients, and found that response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received adjunctive methylfolate than placebo (32 versus 15 percent); tolerability was comparable for the two groups [48]. Use of methylfolate is consistent with multiple practice guidelines [25,49,50].
●Minocycline – For patients with treatment-refractory depression, multiple randomized trials indicate that the antibiotic minocycline may be beneficial [51]. A meta-analysis of three trials compared minocycline (200 mg/day) with placebo, either as add-on therapy or monotherapy, in 151 patients with depressive syndromes [37]. Improvement was greater with active drug and the clinical effect was large; however, heterogeneity across studies was moderate to large. Another meta-analysis of the same three trials also found a clinically large, beneficial effect favoring minocycline over placebo, and that adverse effects were comparable for the two groups [52].
In one of the more recent and longer trials, which compared add-on minocycline with placebo in 41 patients for 12 weeks, nearly all of the patients had been depressed for at least one year [53]. All patients were currently treated with antidepressants (primarily SSRIs) and most patients were also receiving adjunctive medications such as second-generation antipsychotics. Response (reduction of baseline symptoms ≥50 percent) occurred more frequently with adjunctive minocycline than placebo (63 versus 22 percent of patients).
Some clinicians have emphasized that anti-inflammatory drugs such as minocycline should be reserved for patients with signs of increased inflammation, as indicated by elevated inflammatory biomarkers such as C-reactive protein [38]. Evidence supporting this approach includes a four-week randomized trial that compared add-on minocycline (200 mg/day) with placebo in 39 patients with treatment-resistant depression plus low-grade inflammation, defined as C-reactive protein serum concentration ≥1 mg/L. Although the benefit of minocycline and placebo was comparable, among patients with C-reactive protein ≥3 mg/L, improvement was greater with minocycline.
Additional information about inflammation in unipolar depression is discussed elsewhere. (See "Unipolar depression: Neurobiology", section on 'Inflammation'.)
●Omega-3 fatty acids – Omega-3 fatty acids, which are found in oily fish, may be helpful as add-on therapy for treatment-refractory depression. For patients treated with omega-3 fatty acids, we suggest prescribing the most widely studied formulations, either [50,54]:
•Pure eicosapentaenoic acid 1 to 2 g/day, or
•Eicosapentaenoic acid 1 to 2 g/day plus docosahexaenoic acid 1 to 2 g/day, in a ratio greater than 2:1
The starting dose of eicosapentaenoic acid is 1 g/day [54]. For patients who tolerate the medication but do not respond satisfactorily for after two to four weeks, the dose is increased to 2 g/day.
Based upon expert consensus, an adequate acute treatment trial lasts at least eight weeks; randomized trials have lasted up to 16 weeks [54].
Omega-3 fatty acids are generally well tolerated with little risk of serious adverse effects [50,54]. The most common mild side effects include belching, fishy aftertaste, nausea, pruritus, and skin eruptions. However, patients receiving omega-3 fatty acid-containing products (or changing their diets to substantially increase the content of omega-3 fatty acids) in conjunction with an anticoagulant should be monitored for signs and symptoms of bleeding or excessive bruising [50]. Specific interactions of omega-3 fatty acids with other medications may be determined using the Lexicomp drug interactions tool (Lexi-Interact Online) included in UpToDate.
Evidence supporting augmentation of antidepressants with omega-3 fatty acids, especially eicosapentaenoic acid, for treatment-refractory depression includes multiple meta-analyses of randomized trials [50,54-56]:
•One meta-analysis of 11 trials compared omega-3 fatty acids with placebo in patients diagnosed with unipolar major depression (n = 475) [57]. Improvement was superior with active treatment and the clinical effect was moderate. However, heterogeneity across studies was moderate to large, and additional analyses found that:
-Formulations of pure or mainly eicosapentaenoic acid were efficacious, whereas formulations of pure or mainly docosahexaenoic acid were not. In addition, there was a dose-response relationship with eicosapentaenoic acid.
-Omega-3 fatty acids were efficacious when combined with antidepressants, but not as monotherapy.
-Baseline severity of depression was not associated with efficacy.
•A second meta-analysis (13 trials) compared omega-3 fatty acids with placebo in 1233 patients diagnosed with unipolar major depression through standardized clinical interviews; approximately half of the patients were taking antidepressants [58]. Improvement was greater with omega-3 fatty acids than placebo, and the clinical effect was small to moderate. However, heterogeneity across studies was large; analyses of the heterogeneity found that higher doses of eicosapentaenoic acid (eg, 2 grams/day) and concurrent treatment with antidepressants were each associated with better outcomes for omega-3 fatty acids.
•A meta-analysis with 535 patients who were clinically diagnosed with depressive syndromes showed that augmentation of antidepressants with eicosapentaenoic acid-predominant formulations of omega-3 fatty acids was superior to placebo, and the clinical effect was moderate to large; however, heterogeneity across studies was also moderate to large [59]. Further analysis found a trend towards greater efficacy for augmentation with eicosapentaenoic acid-predominant formulations of omega-3 fatty acids, compared with monotherapy.
In addition, use of omega-3 fatty acids for depressive syndromes is consistent with multiple practice guidelines [50,54,60].
Information about the use of omega-3 fatty acids for the initial treatment of unipolar depression, as well as the benefits, adverse effects, and safety of omega-3 fatty acids for cardiovascular health, is discussed separately. (See "Unipolar depression in adults and initial treatment: Investigational and nonstandard approaches", section on 'Omega-3 fatty acids' and "Fish oil: Physiologic effects and administration".)
●Pimavanserin – Pimavanserin is a second-generation antipsychotic approved for treating psychosis in Parkinson disease, and may be efficacious for treatment-refractory depression. A 10-week randomized trial compared add-on pimavanserin (34 mg/day) with placebo in 207 patients with unipolar major depression that did not respond to a current SSRI or SNRI [61]. Improvement of depression, including anxiety, insomnia, and sexual functioning, was greater with pimavanserin than placebo [61-64]. In addition, functioning (work, social, and family) improved more with active treatment. Discontinuation of treatment due to adverse effects was comparable in both groups. The most common adverse effects with adjunctive pimavanserin included dry mouth, nausea, and sinusitis.
Information about using other second-generation antipsychotics for treatment-resistant depression is discussed elsewhere. (See "Unipolar depression in adults: Treatment with second-generation antipsychotics".)
●Quetiapine monotherapy – Quetiapine monotherapy may benefit patients with treatment-refractory depression, but the drug is typically used as an adjuvant with an antidepressant (see 'Pharmacotherapy' above). Randomized trials that compared quetiapine monotherapy with placebo for episodes of nonpsychotic unipolar major depression enrolled patients who either had not been treated or had not responded satisfactorily to a single antidepressant trial; the trials excluded patients who did not respond to two or more antidepressants. Some advantages for quetiapine were observed in the trials. Additional information about the efficacy of quetiapine monotherapy is discussed separately, as are its adverse effects (table 7). (See "Unipolar depression in adults: Treatment with second-generation antipsychotics", section on 'Monotherapy for nonpsychotic depression' and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)
●S-adenosyl methionine – S-adenosyl methionine (SAMe) is a metabolite of folate that facilitates the synthesis of neurotransmitters (including dopamine, norepinephrine, and serotonin) and is available over-the-counter as a dietary supplement in the United States [65]. Several reviews suggest that SAMe may be effective and well tolerated as an adjunct for treatment-refractory depression [55,65-67]. Evidence supporting the use of SAMe includes a six-week randomized trial that compared add-on SAMe (800 mg twice per day) with placebo in 73 patients with unipolar major depression who failed treatment with an SSRI or SNRI; remission occurred in more patients who received SAMe (36 versus 12 percent) [68]. In addition, the rate of discontinuation of treatment due to adverse effects was numerically lower with SAMe than placebo (5 versus 9 percent). Use of SAMe for treatment-refractory depression is consistent with multiple practice guidelines [25,49,50]. Additional information about SAMe is available from the United States National Institutes of Health: Office of Dietary Supplements and the National Center for Complementary and Integrative Health.
●Statins – Meta-analyses of randomized trials suggest that statins may possibly be beneficial for treatment-refractory depression [69]. As an example, a meta-analysis of seven trials lasting six weeks to two years compared statins with placebo as monotherapy or add-on therapy with an SSRI in 1576 patients with depressive syndromes [37]. Statins included atorvastatin, lovastatin, pravastatin, and simvastatin. Improvement was greater with statins than placebo, but the clinical effect was small; in addition, heterogeneity across studies was moderate to large.
●Stimulants and stimulant-like drugs – Augmenting antidepressants with stimulants (eg, lisdexamfetamine or methylphenidate) or stimulant-like drugs (eg, modafinil or pramipexole) may be helpful for some specific symptoms and patients. The use and efficacy of these options are discussed separately. (See "Unipolar major depression in adults: Augmentation of antidepressants with stimulants and stimulant-like drugs".)
Treatments with little to no benefit — Randomized trials in patients with treatment-resistant depression indicate that there is little to no benefit from buspirone, cannabis, folate, inositol, lamotrigine, magnesium, memantine, metyrapone, pindolol, pioglitazone, riluzole, testosterone for females, or vagus nerve stimulation.
●Buspirone – Two trials (n = 119 and 102) compared buspirone with placebo as augmentation in patients who did not respond to initial treatment of major depression with an SSRI; responses with adjunctive buspirone and placebo were comparable [70,71]. In addition, a STAR*D trial found that improvement of depression and tolerability were inferior with adjunctive buspirone compared with adjunctive bupropion [46]. (See "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Partial response to initial treatment'.)
●Cannabis – For treatment-refractory depression, we suggest that patients avoid using plant-based and pharmaceutical cannabinoids due to the lack of any apparent benefit and the potential for adverse effects and harms.
Evidence indicating that cannabis is not helpful for depression includes a meta-analysis of 12 randomized trials, which compared adjuvant cannabinoids with placebo in 1656 patients with depressive syndromes [72]. The primary indication in each trial was a general medical disorder, such as chronic noncancer pain or multiple sclerosis, with depression as a secondary indication. Active treatment in nearly all trials consisted of pharmaceutical grade delta-9-tetrahydrocannabinol (THC) in the form of dronabinol, nabilone, or nabiximols; one trial used an extract of THC plus cannabidiol. During treatment that generally lasted from 4 to 12 weeks, improvement of depression was comparable with cannabinoids and placebo.
The same study also examined the adverse effects of adjunctive cannabinoids in patients with symptoms of depression, anxiety, attention deficit hyperactivity disorder, or posttraumatic stress disorder [72]. A meta-analysis of 10 trials (n = 1495 patients) found that adverse events occurred more often with cannabinoids than placebo (odds ratio 2.0, 95% CI 1.2-3.3). In addition, a meta-analysis of 11 trials (n = 1621 patients) showed that discontinuation of treatment due to adverse events was more likely with add-on cannabinoids (odds ratio 2.8, 95% CI 1.6-4.9).
The risk of harm from using cannabis in patients with depression led The National Academies of Sciences, Engineering, and Medicine to issue a report in 2017, which concluded that cannabis use is associated with an increased incidence of suicide attempts and deaths [73]. The following year, the American Psychiatric Association published a resource document opposing the use of cannabis as medicine [74]. The document states that the risks of cannabis in patients with unipolar major depression include increased rates of suicidal ideation and attempts.
Adverse consequences of cannabis use are discussed in detail separately. (See "Cannabis use: Epidemiology, pharmacology, comorbidities, and adverse effects".)
●Folate – Meta-analyses of randomized trials indicate that folate (folic acid) is not useful for treatment-refractory depression. In one meta-analysis of four randomized trials that compared add-on folic acid (0.5 to 10 mg per day) with placebo in patients currently unresponsive to antidepressants (n = 671), the benefit of adjunctive folic acid and placebo was comparable [55]. A second meta-analysis of four trials, including three of the same trials from the first meta-analysis, compared adjunctive folic acid (0.5 to 10 mg per day) with placebo in 657 patients receiving an antidepressant, and also found no advantage with folate [47]. In addition, other studies of folate have raised safety concerns, including masked B12 deficiency [67].
Additional information about folate is available from the United States National Institutes of Health: Office of Dietary Supplements and the National Library of Medicine Monographs.
●Inositol – A meta-analysis of two small randomized trials in patients receiving SSRIs (n = 78) for unipolar major depression compared add-on inositol (12 mg/day) with placebo four weeks, and found that the benefit was comparable [75].
●Lamotrigine – Based upon two randomized, placebo-controlled trials (n = 96 and 34), augmentation of antidepressants with lamotrigine for treatment-resistant, unipolar major depression is not beneficial [76,77].
●Magnesium – In a meta-analysis of eight randomized trials in 538 patients with depressive syndromes who were treated for 1 to 12 weeks with magnesium (225 to 4000 mg/day) or placebo, improvement was comparable [78].
●Memantine – Three small trials compared eight weeks of memantine (generally 20 mg/day) with placebo as monotherapy or augmentation in patients with unipolar or bipolar depression (total n = 92); a meta-analysis showed that the likelihood of response was comparable in the two groups (odds ratio 1.6, 95% CI 0.6-4.6) [79].
●Metyrapone – The antiglucocorticoid metyrapone does not appear to help patients with treatment-refractory depression. A five-week randomized trial in patients with treatment-resistant depression (n = 143) found that improvement of depressive symptoms was comparable with add-on metyrapone (500 mg twice daily) and placebo [80].
●Pindolol – We do not augment antidepressants with pindolol for treatment-resistant depression, based upon negative results in multiple randomized trials (n = 80, 38, 16, and 10) [81-84], as well as a network meta-analysis [85].
●Pioglitazone – A meta-analysis of two small randomized trials compared pioglitazone with placebo as add-on treatment with antidepressants in patients with unipolar major depression (total n = 77), and found that the benefit was comparable [37].
●Riluzole – Although low-quality evidence suggests that riluzole may be useful for unipolar major depression, higher quality studies indicate otherwise [86]. In one randomized trial, which was comprised of two consecutive phases that each lasted four weeks, patients (n = 104) treated with antidepressants were randomly assigned to add-on treatment with riluzole/riluzole, placebo/placebo, or placebo/riluzole; the dose of riluzole was 50 mg twice daily [87]. Improvement with riluzole and placebo was comparable.
●Testosterone for females – Testosterone does not appear to be beneficial for females with treatment-resistant depression. An eight-week randomized trial compared add-on, low-dose testosterone cream (12 mg/day) with placebo in female patients with unipolar major depression (n = 101) who had not responded to at least one course of antidepressants; free testosterone levels were no higher than the third quartile of the normal range. The proportion of patients who responded (reduction of baseline symptoms ≥50 percent) was nearly the same in both groups (approximately 48 percent) [88].
●Vagus nerve stimulation – We generally do not prescribe vagus nerve stimulation, which is a clinically available intervention that involves surgery to attach an electrode around one vagus nerve; the electrode is connected by a wire to a pulse generator implanted subcutaneously in the chest wall. There are no compelling data that indicate vagus nerve stimulation is efficacious for treatment-refractory unipolar major depression. A 10-week trial enrolled 222 patients who did not respond to pharmacotherapy (two to six regimens) and randomly assigned them to vagus nerve stimulation or sham treatment; response (reduction of baseline symptoms ≥50 percent) in the two groups was comparable (15 and 10 percent of patients) [89]. Avoiding vagus nerve stimulation is consistent with practice guidelines from the American Psychiatric Association, the United Kingdom National Institute for Health and Care Excellence, and other groups [90-95].
Nevertheless, other clinicians do refer patients for vagus nerve stimulation, based upon prospective observational studies that suggest it may possibly help treatment-refractory depression [96,97]. One proposed explanation for the negative randomized trial described above is that several months may be required for the benefits of vagus nerve stimulation to manifest. The treatment is approved by the US Food and Drug Administration and the European Medicines Agency [98,99]; in addition, prescribing the intervention is consistent with multiple treatment guidelines, including those issued by the Canadian Network for Mood and Anxiety Treatments and British Association for Psychopharmacology [25,49,100,101].
Additional information about vagus nerve stimulation, including its efficacy, safety, and side effect profile, is discussed separately. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Vagus nerve stimulation'.)
INVESTIGATIONAL APPROACHES — Investigational therapies for refractory major depression include:
●Drug therapies
●Noninvasive neuromodulation
●Nonpharmacologic treatments
●Invasive/surgical neuromodulation
Patients with treatment-refractory depression may be candidates for drug therapies, noninvasive neuromodulation interventions, and nonpharmacologic treatments, whereas surgical interventions are reserved for patients with severe, intractable, and incapacitating major depression.
Drug therapies — Investigational drug treatments that potentially may help patients with refractory unipolar major depression include the following. Unless indicated otherwise, each of these medications is available to patients with unipolar major depression in the United States only through a research protocol:
●Basimglurant – Basimglurant is a glutamatergic antagonist akin to ketamine and may perhaps be useful for treatment-refractory depression [102]. One trial enrolled patients (n = 332) with treatment-resistant depression and ongoing antidepressant treatment and randomly assigned them to six weeks of adjunctive basimglurant 0.5 mg/day, basimglurant 1.5 mg/day, or placebo [103]. Assessments by clinicians found that improvement with each dose of add-on basimglurant and placebo was comparable. However, patient self-report assessments indicated that remission occurred in more patients who received basimglurant 1.5 mg/day than placebo (36 versus 22 percent). Discontinuation of treatment due to adverse events was comparable across the three groups (approximately 5 to 7 percent of patients).
●Buprenorphine plus samidorphan – Buprenorphine and samidorphan each act upon opioid receptors. Based upon multiple randomized trials, the combination of these medications is not useful as adjunctive therapy for treatment-refractory depression. A meta-analysis of five trials typically lasting four to six weeks compared add-on buprenorphine plus samidorphan with placebo in patients who did not respond to an antidepressant (n >1200); the combination provided no advantage over placebo [104].
●Lanicemine – Lanicemine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is administered intravenously. The efficacy of lanicemine for refractory depression is not clear due to mixed results across randomized trials and clinical development of the drug has ceased [105,106].
Evidence of efficacy for depression includes multiple randomized trials [107]. As an example, a three-week trial enrolled patients (n = 152) receiving pharmacotherapy and randomly assigned them to add-on lanicemine 100 mg, lanicemine 150 mg, or placebo; infusions were administered three times per week [108]. Response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received lanicemine 100 mg or 150 mg than placebo (37 and 29 versus 16 percent).
However, other trials indicate that lanicemine is not beneficial for unipolar major depression. The largest and most recent trial enrolled 302 patients currently receiving pharmacotherapy and randomly assigned them to 15 infusions of lanicemine 50 mg, lanicemine 100 mg, or placebo, given as add-on therapy over 12 weeks [109]. The number of patients who responded to lanicemine 50 mg, 100 mg, or placebo was comparable (36, 44, and 39 percent). The lack of a statistical difference among the groups can be attributed to the relatively large placebo response rate of 39 percent, compared with 16 percent in the trial described above. This discrepancy may be due to the use of a placebo run-in phase in the preceding trial but not the second trial.
●N-acetylcysteine – N-acetylcysteine is derived from the amino acid cysteine, is available over-the-counter, and may possibly be useful for highly resistant depression [56]. A 12-week randomized trial compared N-acetylcysteine (1000 mg twice daily) with placebo as add-on treatment in 252 patients with unipolar major depression [110]. Exclusion criteria included failure of three or more antidepressants or electroconvulsive therapy (ECT) during the current depressive episode. Although improvement at week 12 was comparable for the two groups, follow-up assessments at week 16 found that improvement was greater with active drug; as an example, response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received add-on N-acetylcysteine than placebo (37 versus 25 percent). However, adverse gastrointestinal and musculoskeletal complaints were greater with N-acetylcysteine.
●Nitrous oxide – Nitrous oxide is a clinically available NMDA receptor antagonist akin to ketamine and a standard anesthetic drug that may perhaps help patients with treatment-refractory depression. A randomized trial compared adjunctive inspiratory nitrous oxide (50 percent nitrous oxide plus 50 percent oxygen) with placebo (50 percent nitrogen plus 50 percent oxygen) in patients who met criteria for treatment-resistant depression at baseline and were receiving a stable treatment regimen (n = 20) [111]. Study drugs were administered in a single session lasting one hour. Improvement of depression was greater with add-on nitrous oxide than placebo at 2 hours, 24 hours, and one-week posttreatment. However, nitrous oxide may be abused because of its intoxicating properties.
●Psilocybin – Psilocybin is a serotonergic, psychedelic (hallucinogenic) drug that is derived from a particular genus of mushrooms. In multiple randomized trials, psilocybin plus psychotherapy was efficacious for treatment-resistant unipolar major depression:
•A six-week trial compared psilocybin with escitalopram in 59 patients; the mean number of previously used psychiatric medications was two, and more than 90 percent had previously received psychotherapy [112]. The psilocybin group received a single dose (25 mg) at the beginning of the study and a second dose three weeks later, as well as placebo pills daily for six weeks. Patients treated with escitalopram received 10 mg/day for three weeks and 20 mg/day for the next three weeks; in addition, they received two separate doses of psilocybin (1 mg) three weeks apart. Throughout the study, all patients received psychological support, which included preparation for ingesting psilocybin, support during the visits in which psilocybin was administered, and discussions of the psilocybin experience in subsequent sessions. Multiple outcomes suggested that improvement was either comparable for the two groups or superior with psilocybin. As an example, remission of depression occurred in twice as many patients in the psilocybin group (57 and 28 percent). However, escitalopram may have performed better in a longer trial, and the absence of a placebo group limits interpretation of the results. No serious adverse effects occurred in either group, and the most common adverse effects in both groups was headache and nausea.
•An eight-week, open-label trial randomly assigned 24 patients to psilocybin or a waiting list; the mean lifetime duration of depression exceeded 20 years and the mean duration of the current episode exceeded two years [113]. The psilocybin group received a single dose (20 mg/70 kg) at week 3 and a second dose (30 mg/70 kg) at week 4, plus psychological support, which included preparation for ingesting psilocybin, support during the visits in which psilocybin was administered, and discussions of the psilocybin experience in subsequent sessions. Improvement at week 8 was greater in patients who received psilocybin than controls, and the clinical effect was large. In addition, the benefit of psilocybin was rapid and related to mystical and personally meaningful experiences induced by the drug. No serious adverse effects occurred in either group; common adverse effects of psilocybin included fear, sadness, and headache.
In both trials, exclusion criteria included history of psychosis, serious suicide attempt, substance use disorder, and comorbid psychopathology that could interfere with the therapeutic alliance between the patient and study clinicians (eg, borderline personality disorder) [112,113]. In addition, psilocybin was administered in the absence of additional pharmacotherapy throughout the studies. Sessions in which psilocybin was administered lasted four to six hours in one trial [112] and eight hours in the other one [113].
Other randomized trials have shown that psilocybin can be efficacious for depressive syndromes in patients with life-threatening cancer [114,115]. Treatment models across different trials include assessment to determine patient suitability, education to prepare patients for the psychedelic experience, administering the medication in a controlled setting and providing support during the experience, and integration sessions afterwards [116]. The use of psilocybin once or twice over a period of a few weeks is often conceptualized as drug-assisted psychotherapy [116,117].
Among depressed patients who improve with psilocybin, functional magnetic resonance imaging suggests that response is associated with decreased cerebral blood flow in the amygdala, as well as increased and decreased resting-state functional connectivity, depending upon the specific brain circuit [118]. One hypothesis is that the medication disrupts circuits that underlie maladaptive thoughts of guilt and ruminations about one’s inadequacies [116].
●Rapastinel – One randomized trial in 116 patients with treatment-resistant depression found that improvement with a single intravenous dose of the investigational drug rapastinel was superior to placebo at one and seven days after infusion [119]. However, three larger, subsequent trials (total n>1500) compared rapastinel with placebo; each trial found that active drug provided no advantage over placebo [120].
●Additional therapies – Additional drug therapies that potentially may help patients with refractory unipolar major depression include treatments that have been studied as investigational treatments in patients who present for initial treatment of major depression. These treatments include sarcosine, statins, and zuranolone. (See "Unipolar depression in adults and initial treatment: Investigational and nonstandard approaches".)
Noninvasive neuromodulation — Noninvasive neuromodulation procedures use an electric current or magnetic field to stimulate the central nervous system [121]. Clinically available procedures for patients with treatment-resistant depression include ECT and repetitive transcranial magnetic stimulation (TMS). ECT and TMS are discussed separately, including their efficacy and tolerability. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Unipolar depression in adults: Indications, efficacy, and safety of transcranial magnetic stimulation (TMS)" and "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Compared with transcranial magnetic stimulation'.)
For patients with unipolar major depression who are refractory to numerous sequential regimens of standard treatments, including pharmacotherapy, psychotherapy, ECT, and repetitive TMS, several noninvasive neuromodulation procedures are under investigation in research settings at tertiary referral centers; these include magnetic seizure therapy, focal electrically administered seizure therapy, transcranial direct current stimulation, transcranial low voltage pulsed electromagnetic fields stimulation, transcutaneous vagus nerve stimulation, trigeminal nerve stimulation, and low field magnetic stimulation. The efficacy, safety, and side effects of experimental noninvasive neuromodulation procedures are discussed separately. (See "Unipolar depression in adults: Overview of neuromodulation procedures", section on 'Noninvasive neuromodulation therapies'.)
Nonpharmacologic interventions — Investigational nonpharmacologic treatments that are clinically available for treatment-refractory depression include bright light therapy and meditation.
Bright light therapy, also called phototherapy, is a standard initial treatment for mild to moderate unipolar major depression with a seasonal pattern, and may possibly be useful for nonseasonal, treatment-refractory depression. A meta-analysis of five small trials compared add-on bright light therapy with a control condition in patients with nonseasonal depression that did not respond to pharmacotherapy (total n = 135) [122]. The trials lasted one to four weeks; the dose of bright light therapy ranged from 2500 to 10,000 lux, and the duration of exposure was generally two hours/day. Although improvement was comparable in the two groups, the dose of bright light therapy appeared to be suboptimal in all but one study, which found a large clinical benefit by administering 10,000 lux. In addition, other randomized trials indicate that bright light therapy may be helpful as initial treatment of nonseasonal depression, and multiple practice guidelines include bright light therapy as an option for depressive syndromes [25,50,60]. Additional information about bright light therapy, including its administration and benefits, is discussed separately. (See "Seasonal affective disorder: Treatment", section on 'Bright light therapy' and "Unipolar depression in adults and initial treatment: Investigational and nonstandard approaches", section on 'Bright light therapy'.)
Meditation may perhaps be beneficial for treatment-refractory depression as add-on treatment [123]. An eight-week, open-label randomized trial compared adjunctive meditation with a wait list control condition in patients (n = 25) with unipolar major depression that did not respond to at least eight weeks of antidepressant treatment [124]. The meditation intervention was a group program that included breathing exercises, yoga postures, and sitting meditation; the program required 3.5 hours/day for the first week and 2 hours/day for the remaining seven weeks. Improvement of depression was greater with adjunctive meditation, compared with the control condition, and the active treatment was well tolerated.
Invasive/surgical neuromodulation — Patients with severe, intractable, and disabling unipolar major depression, which does not respond to numerous (eg, 7 to 10) trials of standard therapies and has persisted for years (eg, ≥2 to 5), may be candidates for investigational neurosurgical interventions that lack high-quality efficacy data [5,125]. The most widely studied surgical intervention is deep brain stimulation; however, in the one randomized trial that has been conducted, deep brain stimulation was not beneficial for refractory depression [126]. Less common invasive approaches include direct cortical stimulation and ablative neurosurgery. Invasive treatments should be pursued only at tertiary referral centers that are conducting research and providing rigorous oversight to ensure that the procedure is indicated. The efficacy, safety, and side effects of experimental invasive/surgical neuromodulation procedures are discussed separately. (See "Unipolar depression in adults: Treatment with surgical approaches".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Depression (The Basics)" and "Patient education: When you have depression and another health problem (The Basics)")
●Beyond the Basics topics (see "Patient education: Depression in adults (Beyond the Basics)" and "Patient education: Depression treatment options for adults (Beyond the Basics)" and "Patient education: Electroconvulsive therapy (ECT) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definitions
•Unipolar major depression – Unipolar major depression (major depressive disorder) is diagnosed in patients who have suffered at least one major depressive episode (table 3) and have no history of mania (table 1) or hypomania (table 2). (See "Unipolar depression in adults: Assessment and diagnosis".)
•Treatment-resistant depression – Treatment-resistant depression typically refers to a major depressive episode that does not respond satisfactorily after two trials of antidepressant monotherapy; however, the definition has not been standardized. (See "Unipolar treatment resistant depression in adults: Epidemiology, risk factors, assessment, and prognosis", section on 'Treatment resistant depression' and "Unipolar depression in adults: Choosing treatment for resistant depression".)
•Treatment-refractory depression – Treatment-refractory depression typically refers to unipolar major depressive episodes that do not respond satisfactorily to many sequential standard regimens, including multiple antidepressants and adjunctive drugs, as well as at least one trial each of adjunctive psychotherapy, repetitive transcranial magnetic stimulation, and electroconvulsive therapy. However, the definition has not been standardized, and there is no clear demarcation between treatment-resistant and treatment-refractory depression. (See 'Treatment-refractory depression' above.)
●General principles – Patients with refractory depression should be evaluated to confirm the diagnosis is unipolar depression, assess adherence to treatment, and determine whether comorbid disorders are present and require treatment. In addition, referral to specialty clinics that treat depressive disorders is advisable. (See 'General principles' above and 'Referral' above.)
●Therapeutic approach – For treatment-refractory depression, we typically adopt a conservative approach that avoids excessive investigations and treatments, rather than administering aggressive, complicated regimens (eg, polypharmacy with four or more psychotropic drugs). (See 'Therapeutic approach' above.)
●Choosing treatment – Treatment-refractory depression is generally managed with pharmacotherapy plus psychotherapy; however, pharmacotherapy alone is a reasonable alternative. (See 'Combination therapy' above and "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Psychotherapy'.)
•Pharmacotherapy – Pharmacotherapy for treatment-refractory depression frequently involves an antidepressant augmented with another drug; however, antidepressant monotherapy is a reasonable alternative, especially in patients sensitive to adverse effects. The choice begins with drugs that have not yet been administered. Our general order of preference in choosing an antidepressant is as follows: selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, atypical antidepressant, serotonin modulator, tricyclic, and monoamine oxidase inhibitor. Our general order of preference in choosing an adjunctive medication is: second-generation antipsychotic, lithium, a second antidepressant from a different class, and thyroid hormone. Augmentation with ketamine and esketamine can also be useful. (See 'Pharmacotherapy' above.)
•Psychotherapy – In selecting psychotherapy for treatment-refractory depression, the choice begins with available therapies that have not yet been administered. We prefer either cognitive-behavioral therapy or interpersonal psychotherapy. Other reasonable alternatives include psychodynamic psychotherapy, mindfulness-based cognitive therapy, behavioral activation, problem solving therapy, supportive psychotherapy, and family therapy. (See 'Adjunctive psychotherapy' above.)
●Treatments with potential benefit – Less established treatments that are potentially beneficial for treatment-refractory depression include exercise, lithium monotherapy, methylfolate, omega-3 fatty acids, pimavanserin, quetiapine monotherapy, S-adenosyl methionine, and stimulants. (See 'Treatments with potential benefit' above.)
●Treatments with little to no benefit – For patients with treatment-refractory depression, we suggest not prescribing cannabis due to the lack of benefit and the potential for adverse effects and harms (Grade 2C). In addition, we generally do not refer patients with treatment-refractory depression for vagus nerve stimulation; however, other clinicians do prescribe the procedure. (See 'Treatments with little to no benefit' above.)
●Investigational approaches – Some patients with treatment-refractory depression may decline a conservative approach that relies upon established pharmacotherapies plus psychotherapies. For these patients, a reasonable alternative is an investigational treatment such as psilocybin, bright light therapy, and meditation. (See 'Investigational approaches' above.)
Patients with severe, intractable, and disabling unipolar major depression may be candidates for clinical trials investigating neurosurgical interventions, including deep brain stimulation and direct cortical stimulation. (See 'Invasive/surgical neuromodulation' above and "Unipolar depression in adults: Treatment with surgical approaches".)
