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Unipolar depression in adults: Treatment of resistant depression
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Unipolar depression in adults: Treatment of resistant depression
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jul 20, 2016.

INTRODUCTION — Many patients presenting with unipolar major depression (major depressive disorder) do not recover after their initial treatment. As an example, one prospective observational study found that among 3671 outpatients who were treated with citalopram, remission occurred in 37 percent [1]. In addition, patients who fail their initial treatment often do not respond to subsequent trials, and frequently experience a course of illness marked by chronic depression, impaired psychosocial functioning, and poor overall general health [2].

This topic reviews treatment of resistant depression. The epidemiology, risk factors, assessment, identification, and prognosis of treatment resistant depression are discussed separately, as are the management of highly resistant (refractory) depression, initial treatment of depression, and clinical features and diagnosis of depression.

(See "Unipolar treatment resistant depression in adults: Epidemiology, risk factors, assessment, and prognosis".)

(See "Unipolar depression in adults: Management of highly resistant (refractory) depression".)

(See "Unipolar major depression in adults: Choosing initial treatment".)  

(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 or hypomania [3]. 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. Additional information about the clinical presentation and diagnosis of major depressive disorder is discussed separately. (See "Unipolar depression in adults: Assessment and diagnosis".)

Treatment resistant depression – The term “treatment resistant depression” often refers to major depressive episodes that do not respond satisfactorily to at least two trials of antidepressant monotherapy; however, the definition has not been standardized [4,5]. 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 do not respond satisfactorily to numerous sequential treatment regimens. However, the definition has not been standardized, and there is no clear demarcation between treatment resistant and treatment refractory depression. The definition and management of refractory depression are discussed separately. (See "Unipolar depression in adults: Management of highly resistant (refractory) depression".)

GENERAL PRINCIPLES

Strategies — For patients with unipolar major depression who do not respond to initial treatment with an antidepressant medication, treatment strategies include [6-13]:

Switching treatment

Different antidepressant

Psychotherapy (eg, cognitive-behavioral therapy)

Electroconvulsive therapy (ECT)

Repetitive transcranial magnetic stimulation

Augmentation (adding a treatment)

Medication (eg, second-generation antipsychotic, lithium, or triiodothyronine)

Psychotherapy

Nonspecific care management — Patients with treatment resistant depression who are receiving a specific therapy may also benefit from nonspecific care management, in which clinicians [14,15]:

Educate patients and families about:

Depression, including signs, symptoms (table 1), and prognosis (see "Unipolar depression in adults: Assessment and diagnosis" and "Unipolar depression in adults: Course of illness")

Suicide (see "Suicidal ideation and behavior in adults")

Treatment options (see 'Mild to moderate depression' below and 'Severe depression' below)

Good sleep practices, including sleep hygiene (table 2), stimulus control (table 3), and sleep restriction (table 4) (see "Treatment of insomnia")

Regularly review and quantify depressive symptoms (see 'Measurement based care' below).

Review and manage side effects.

Provide a 24 hour on-call service.

Encourage patients to persist with treatment. We reassure patients that we will not abandon them and will try to help them get better as long as they are willing to work with us.

However, many patients with ongoing symptoms of treatment resistant depression who receive education about their illness nevertheless discontinue pharmacotherapy [16].

The relationship between clinicians and patients may affect treatment outcomes independent of the specific treatment that is administered. A randomized trial that compared imipramine with placebo in 112 patients with unipolar major depression (not selected for treatment resistance) found that about eight percent of the variability in outcome was due to the treating psychiatrist, separate from the study treatment [17].

Measurement based care — Measurement based care is the systematic, quantitative assessment of symptoms that is typically performed at each visit [18]. Psychosocial functioning, quality of life, treatment adherence, and tolerability of treatment can also be measured.

The nine-item Patient Health Questionnaire (PHQ-9) is a self-report, standardized depression rating scale (table 5) that measures the severity of symptoms and is widely used to ascertain response to treatment [19,20]. 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'.)

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 [16,21,22]. However, for patients who show little improvement (eg, reduction of baseline symptoms ≤25 percent) after four to six weeks, we administer next-step treatment [18]. Additional information about the duration of an adequate treatment trial is discussed separately. (See "Unipolar major depression in adults: Choosing initial treatment".)

Referral — Most depressive episodes are initially treated by internists and primary care clinicians [23,24], and treatment-resistant depression is often treated by these clinicians as well, rather than psychiatrists [25]. In one study, patients (n = 727) who did not respond to initial treatment with citalopram were then randomly assigned to next-step treatment; the probability of remission in primary care and psychiatric settings was comparable (odds ratio 1.0) [26].

However, referral to a mental health specialist should be considered for depressive episodes that are unresponsive to multiple (eg, two to four) next-step treatment trials [16,25]. In addition, referral is generally indicated for severe major depression characterized by suicidal or homicidal ideation or behavior, psychosis, or catatonia. (See 'Severe depression' below.)

MILD TO MODERATE DEPRESSION — Mild to moderate major depression is characterized by clinical features such as:

No suicidal or homicidal ideation or behavior, or ideation that does not pose an imminent risk (eg, thoughts that family members would be better off if the patient was dead; or fleeting thoughts of killing oneself, with nonexistent or vague plans to commit suicide and no intent)

No psychotic features (eg, delusions or hallucinations)

Little to no aggressiveness

Intact judgement such that the patient or others are not at imminent risk of being harmed

Mild to moderate depression can generally be treated in an outpatient or partial (day) hospital program setting.

First- and second-line treatment strategies — For mild to moderate depression that is treatment resistant, first- and second-line treatment strategies depend upon the degree to which patients benefit and tolerate the antidepressant that is prescribed at first presentation [27,28]:

For patients who obtain little symptom relief (eg, reduction of baseline symptoms ≤25 to 33 percent), we suggest switching antidepressants (ie, monotherapy with a new antidepressant) as first-line treatment and augmentation as second-line treatment. However, it is reasonable to reverse the order of these treatment strategies.

Treatment resistant patients who cannot tolerate an adequate dose of the initial antidepressant should switch antidepressants as first-line treatment

For patients who obtain definite symptom relief that is not satisfactory and can tolerate the initial antidepressant, we suggest augmentation as first-line treatment and switching antidepressants as second-line treatment. However, it is reasonable to reverse the order of these treatment strategies.

For treatment resistant depression, the evidence suggests that the benefits of switching and augmentation are generally comparable. In addition, patients who experience less symptomatic improvement and more side effects with the antidepressant prescribed at first presentation prefer switching antidepressants [29]. Conversely, patients who partially benefit from the initial antidepressant and experience few adverse effects prefer adjunctive pharmacotherapy rather than switching. The efficacy and implementation of switching and augmentation are discussed elsewhere in this topic. (See 'Efficacy of switching compared with augmentation' below and 'Switching antidepressants' below and 'Augmentation' below.)

Switching antidepressants is often preferable to augmentation for treatment resistant depression because adherence may be better with monotherapy than combination treatment [30]. In addition, monotherapy may cost less and presents fewer risks of drug interactions in patients taking medications for other conditions.

Monotherapy may also cause fewer adverse effects [12], but this is not necessarily the case. The prospective Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study compared side effects in 269 treatment resistant patients who selected switching (from citalopram to bupropion, sertraline, or venlafaxine) as next step treatment, and 269 patients who selected citalopram augmentation (with bupropion or buspirone); the two groups were matched using propensity scores [31]. The overall incidence of distressing side effects for each group was similar.  

For patients with treatment resistant depression who obtain little symptom relief, it is not clear how many trials of antidepressant monotherapy that clinicians should administer before augmenting the antidepressant with a second treatment. We generally provide one to three courses of next step antidepressant monotherapy before using augmentation.  

An alternative to switching antidepressants or augmenting the antidepressant with a second medication is to switch from pharmacotherapy to psychotherapy (eg, CBT), or retain the initial antidepressant and add psychotherapy [7,32,33]. In addition, it is reasonable to augment with both pharmacotherapy and psychotherapy. However, psychotherapy is often not available, and many patients decline it [29]. The efficacy of switching to and augmenting with psychotherapy are each discussed elsewhere in this topic. (See 'Switching to psychotherapy' below and 'Psychotherapy' below.)

For patients with treatment resistant depression, multiple practice guidelines (eg, the American Psychiatric Association and United Kingdom National Institute of Health and Clinical Excellence guidelines) suggest both switching and augmentation as treatment options [6,7,9-13,34].

Efficacy of switching compared with augmentation — For treatment resistant depression, few head to head randomized trials have compared the efficacy of switching antidepressants with augmenting the initial antidepressant. In addition, most studies of treatment resistant depression have not distinguished patients who obtained definite symptom relief that was unsatisfactory from patients who obtained little or no relief.

The existing evidence suggests that the benefits of switching antidepressants and augmenting with pharmacotherapy generally appear to be comparable:

Multiple reviews that examined randomized trials of switching and trials of augmentation concluded that the two strategies achieved comparable results [27,35,36]. As an example, one review found that the mean remission rates for switching and augmentation were 22 and 27 percent [37]; response (reduction of baseline symptoms ≥50 percent) rates for switching and augmentation were 40 and 38 percent.

A prospective observational study compared outcomes in 269 patients who selected switching (from citalopram to bupropion, sertraline, or venlafaxine) as next step treatment, and 269 patients who selected augmentation of citalopram (with bupropion or buspirone); the two groups were matched using propensity scores [38]. The probability of remission for the two groups was comparable.

A randomized trial enrolled 375 patients and randomly assigned them to various therapies that included two switch options and five augmentation options [39,40]. Pooled remission rates for the switch and the augmentation strategies appeared to be comparable (41 and 37 percent; difference was not statistically tested).  

Although we generally prefer to switch antidepressants for patients who minimally respond to the antidepressant prescribed at first presentation, one randomized trial found that augmentation with aripiprazole may be effective for patients with little to no response to antidepressant monotherapy. (See "Unipolar depression in adults: Treatment with second-generation antipsychotics", section on 'Minimal response to antidepressant compared with partial response'.)

Switching antidepressants — For treatment resistant patients who are switching antidepressants, we generally cross-taper, that is, taper and discontinue the failed medication over one to two weeks at the same time that another antidepressant is started and titrated up. The failed medication is generally tapered by the same amount for each dose decrease. As an example, venlafaxine extended release 225 mg per day is decreased by 37.5 to 75 mg per day every one to three days. Implementing switches is discussed separately. (See "Switching antidepressant medications in adults", section on 'Switching antidepressant medication'.)

Although cross-tapering is frequently the best technique for antidepressant switches, clinicians should be aware of overlapping side effect profiles (table 6), as well as potential drug-drug interactions such as the serotonin syndrome (see "Serotonin syndrome (serotonin toxicity)") [27]. Specific interactions between antidepressants may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.

Choosing a drug — For patients with major depression who are resistant to treatment with an SSRI at first presentation and are switching antidepressants, many options are available (table 7). The most commonly studied antidepressants are as follows, and are presented in our general order of preference based upon the number and quality of randomized trials that studied each option, as well as safety issues, side effect profiles (table 6), potential for drug-drug interactions, and ease of use [1,21,41]:

Serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine)

Atypical antidepressants (eg, bupropion or mirtazapine)

Tricyclic antidepressants (eg, imipramine or nortriptyline)

Monoamine oxidase inhibitors (MAOIs; eg, tranylcypromine or phenelzine)

However, it is reasonable to use these drugs in a different sequence, or to switch to a different SSRI at any point in the sequence [42], because in the few head to head studies that have compared different options for treatment resistant depression, efficacy is often comparable [1]. As an example, an eight-week, randomized trial (n = 105 patients) compared switching to either venlafaxine extended release (225 mg per day) or mirtazapine (45 mg per day), and found that remission was comparable (42 and 36 percent) [40]. Other factors to consider in changing antidepressants include treatment history, comorbid general medical conditions, patient preference, and cost. As an example, patients with seizure disorders should avoid bupropion, obese patients should avoid mirtazapine, and patients with cardiovascular disease should avoid tricyclics and MAOIs.

We typically use a drug from a different class when switching antidepressants for treatment resistant depression, rather than switching to an antidepressant within the same class. Evidence supporting this approach includes a meta-analysis of four randomized trials involving 1496 patients with unipolar major depression who were resistant to initial treatment with an SSRI, and were switched either to a non-SSRI antidepressant (bupropion, mirtazapine, or venlafaxine) or to a different SSRI [41]. Remission occurred in more patients who switched to a different drug class (28 versus 24 percent); in addition, discontinuation due to side effects was comparable for the two groups. However, given the modest difference in remission (4 percent), switching from one SSRI to another is reasonable. Patients unresponsive to a second SSRI should be switched to an antidepressant from a different class.

Venlafaxine — For patients with mild to moderate unipolar major depression who do not respond to initial treatment with an SSRI and are switching antidepressants, we generally choose venlafaxine extended release, because it has been most widely studied [41,43]. However, other serotonin-norepinephrine reuptake inhibitors are reasonable alternatives.

Evidence for switching to venlafaxine in treatment resistant patients includes multiple meta-analyses [41,42]. As an example, a meta-analysis of three randomized trials (3375 patients with major depression who did not respond sufficiently to initial treatment with an SSRI) compared switching to venlafaxine to switching to a different SSRI [42]. Remission occurred in more patients who received venlafaxine (54 versus 45 percent). There was little heterogeneity across studies, and the number of dropouts because of side effects was comparable for the two groups.

The pharmacology, administration, and side effects of venlafaxine and other serotonin-norepinephrine reuptake inhibitors are discussed separately. (See "Serotonin-norepinephrine reuptake inhibitors (SNRIs): Pharmacology, administration, and side effects".).

Atypical antidepressant — For depressed patients who are resistant to initial treatment with an SSRI, randomized trials indicate that remission is comparable for patients who switch to either an atypical antidepressant (bupropion or mirtazapine) or a different SSRI:

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study included a 14 week trial that compared bupropion sustained release (mean dose 283 mg per day) with sertraline (mean dose 136 mg per day) in 477 treatment resistant patients; medications were administered on an open label basis and assessment of outcome was blinded [44]. Remission was comparable for bupropion and sertraline (21 and 18 percent), as was tolerability.

An eight-week trial compared mirtazapine (45 mg per day) with paroxetine (20 mg per day) in 100 treatment resistant patients and found that remission was comparable (36 and 47 percent), as was tolerability [40]

An eight week trial compared mirtazapine (mean dose 30 mg per day) with sertraline (mean dose 120 mg per day) in 250 treatment resistant patients; remission was comparable (38 and 28 percent) [45-47]. Adverse events that occurred more often with mirtazapine included sedation, fatigue, weight gain, and dry mouth.

The pharmacology, administration, and side effects of atypical antidepressants are discussed separately. (See "Atypical antidepressants: Pharmacology, administration, and side effects".)

Tricyclic antidepressant — Tricyclic antidepressants are fourth- or fifth-line drugs for treatment of depression due to their greater safety hazards (eg, cardiotoxicity and potential lethality with overdose) and less favorable side effect profiles. However, for patients with treatment resistant depression, the efficacy and tolerability of tricyclics may be comparable to atypical antidepressants and SSRIs:

In the STAR*D study, an open label, 14-week randomized trial (n = 235) compared nortriptyline (mean dose 97 mg per day) with mirtazapine (mean dose 42 mg per day) and found that remission was comparable (20 and 12 percent), as was tolerability [48]

A 12-week study enrolled 168 patients who did not respond to randomly assigned treatment with either imipramine or sertraline, and crossed the patients over (under double blind conditions) to the alternate drug [49]. Remission in patients who switched from sertraline to imipramine, or from imipramine to sertraline, was comparable (23 and 32 percent). However, discontinuation of treatment due to side effects was greater among patients who switched to imipramine (9 versus 0 percent).

The pharmacology, administration, and side effects of tricyclics are discussed separately. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects".)

Monoamine oxidase inhibitor (MAOI) — Monoamine oxidase inhibitors (MAOIs) are seldom prescribed because of potentially lethal drug-drug and drug-food interactions, the danger that MAOIs pose in overdoses, and adverse effects [50]. Nevertheless, switching to an MAOI may be beneficial for patients with major depression that is resistant to other drug classes (table 7) [42,51]. Evidence that supports switching to MAOIs includes a randomized trial in which 46 depressed patients who did not respond to imipramine were crossed over to phenelzine (45 to 90 mg per day) for six weeks under double blind conditions, and 22 patients who did not respond to phenelzine were crossed over to imipramine (150 to 300 mg per day) [52]. Response occurred in more patients who switched to phenelzine than imipramine (67 versus 41 percent).

Although some evidence suggests that major depression with atypical features (hypersomnia, hyperphagia, rejection sensitivity, heavy or leaden feelings in limbs, and/or mood brightens in response to positive events) may respond preferentially to MAOIs [53], other studies call into question the clinical utility of diagnosing major depression with atypical features. (See "Unipolar depression in adults: Clinical features", section on 'Atypical'.)

The pharmacology, administration, dietary restrictions (table 8), and side effects of MAOIs are discussed separately. (See "Monoamine oxidase inhibitors (MAOIs) for treating depressed adults".)

Switching to psychotherapy — Although switching from an antidepressant to psychotherapy may be declined by patients with treatment resistant major depression [29], psychotherapy is a reasonable option for patients who prefer it [54]:

A 12-week trial enrolled 122 patients who did not respond to or tolerate citalopram and randomly assigned them to switch to cognitive-behavioral therapy (CBT) or to a different antidepressant (bupropion, sertraline, or venlafaxine) [55]. Remission was comparable for CBT and pharmacotherapy (25 and 28 percent of patients), as was discontinuation of treatment due to side effects (17 and 27 percent). Acceptability of cognitive therapy was greater among patients with more education (eg, college graduates) and a family history of mood disorders [29].

A 12 week study enrolled 140 patients who did not respond to randomly-assigned treatment with either nefazodone or CBT, and crossed the patients over to the other treatment [56]. Remission in patients who switched from nefazodone to CBT, or from CBT to nefazodone, was comparable (36 and 27 percent). However, discontinuation of treatment occurred in fewer patients who received CBT than nefazodone (13 versus 28).

However, psychotherapy is often not available.

Augmentation — For patients with treatment resistant depression who receive augmentation, drug-drug interactions between antidepressants and adjunctive medications (eg, second-generation antipsychotics, lithium, or triiodothyronine) are generally not a problem. However, combining an MAOI with another antidepressant (eg, SSRI) can cause the serotonin syndrome or a hypertensive crisis [57]. Specific interactions between an antidepressant and another medication may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.

Treatment resistant patients who are treated with an add-on drug and do not respond within 6 to 12 weeks of reaching the target dose, or do not tolerate the combination, should be treated with a second medication combination. We suggest tapering and discontinuing the failed adjunctive medication over one to two weeks at the same time that another adjunctive medication is started and titrated up. The failed medication is generally tapered by the same amount for each dose decrease. As an example, aripiprazole 15 mg per day is decreased by 5 mg per day every one to three days. At the same time, the antidepressant is continued at the same dose. However, it is reasonable to switch the antidepressant after the adjunctive drug has been switched. Switching antidepressants is discussed elsewhere in this topic. (See 'Switching antidepressants' above.)

Choosing a drug — For patients with mild to moderate depression who are treatment resistant and receiving augmentation, many options are available. The most widely studied drugs are as follows, and are presented in our general order of preference, based primarily upon the evidence (especially the number of patients studied in randomized trials) for each option [21,35,47,58-60]:

Second-generation antipsychotics (aripiprazole, quetiapine, risperidone, or olanzapine)

Lithium

Thyroid hormone (typically triiodothyronine)

A second antidepressant from a different class

However, it is reasonable to use these drugs in a different sequence, because in the few head to head studies that compared different options, efficacy was generally comparable [1]. As an example:

An eight-week randomized trial compared paroxetine plus risperidone, paroxetine plus thyroid hormone, and paroxetine plus trazodone in 140 treatment resistant patients, and found that remission was comparable (27, 38, and 43 percent) [39].

A six-week, open label randomized trial compared adjunctive quetiapine (target dose 300 mg per day) with adjunctive lithium (target serum concentration 0.6 to 1.2 mEq/L [0.6 to 1.2 mmol/L]) in 450 treatment resistant patients; remission was comparable (32 and 27 percent of patients) [61].

In addition, a network meta-analysis of 48 randomized trials (n >6000 depressed patients) evaluated the efficacy of 11 augmentation agents by using results from direct comparisons between the drugs (in head to head trials), as well as indirectly comparing drugs through their relative effect with a common comparator (typically placebo) [62]. Response (reduction of baseline symptoms ≥50 percent) or remission occurred more often with add-on aripiprazole, buspirone, lithium, olanzapine, quetiapine, risperidone, or thyroid hormone (T3 or T4), compared with placebo; the benefits of each active treatment were comparable. However, discontinuation of treatment due to side effects was greater with aripiprazole, lithium, olanzapine, and quetiapine, compared with placebo.  

Other factors to consider in choosing add-on pharmacotherapy include past response, safety, comorbid general medical conditions, ease of use, patient preference, and cost. As an example, patients with a history of extrapyramidal side effects should avoid aripiprazole; overweight patients should avoid quetiapine, risperidone, and olanzapine; patients with renal or thyroid disease should avoid lithium; and patients with compromised cardiovascular function should avoid thyroid hormone. In addition, adding a second antidepressant may involve fewer baseline laboratory tests and monitoring than adding lithium or triiodothyronine.

Second-generation antipsychotic — Adjunctive treatment with second-generation antipsychotics is efficacious for unipolar, nonpsychotic major depression that has not responded to antidepressant monotherapy. As an example, a systematic review of 16 randomized trials compared adjunctive aripiprazole, olanzapine, quetiapine, or risperidone with placebo in 3480 patients with nonpsychotic, unipolar major depression who failed at least one course of antidepressant monotherapy [58]. Remission occurred in more patients who received an adjunctive antipsychotic compared with placebo (31 versus 17 percent). However, discontinuation because of adverse effects was greater in patients who received an antipsychotic (9 versus 2 percent). A subsequent trial found that both response and discontinuation of treatment due to side effects were greater with add-on ziprasidone than placebo [63].  

In order of preference, we typically use aripiprazole, quetiapine, risperidone, or ziprasidone as augmentation for treatment resistant depression, based upon the number and quality of randomized trials that have evaluated each drug [58,62]. However, no head to head trials have compared the second-generation antipsychotics and it is reasonable to use these drugs in a different sequence. A systematic review found that the pooled rate of discontinuation of treatment due to adverse events for aripiprazole, quetiapine, and risperidone was 4, 12, and 7 percent [58]; in addition, aripiprazole causes fewer adverse metabolic effects than quetiapine and risperidone (table 9). One continuation trial found that longer treatment with risperidone was not beneficial [64]. Although pooled analyses have found that adjunctive olanzapine is efficacious [62,65,66], we often avoid the drug, especially for long-term treatment (eg, ≥12 weeks) because it is associated with the highest risk of weight gain and metabolic disturbances such as diabetes [67-69].  

For patients with treatment resistant depression who do not respond to one second-generation antipsychotic within 6 to 12 weeks of reaching the target dose, or do not tolerate the drug, we suggest tapering and discontinuing the failed medication over one to two weeks at the same time that a different adjunctive drug (either a second-generation antipsychotic or another drug such as lithium) is started and titrated up. We generally attempt treatment with no more than two second-generation antipsychotics before choosing a different type of drug (eg, lithium, thyroid hormone, or a second antidepressant).

The efficacy, safety issues (eg, metabolic syndrome and tardive dyskinesia), administration, and side effects of second-generation antipsychotics for treatment resistant depression are discussed separately. (See "Unipolar depression in adults: Treatment with second-generation antipsychotics" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

First-generation antipsychotics are typically not used for nonpsychotic, treatment resistant major depression due to concerns about tardive dyskinesia, and because there are less efficacy data for these drugs than second-generation antipsychotics [70].

Lithium — Lithium has been used as augmentation for treatment resistant depression since the 1960s [71], and several studies have subsequently demonstrated its efficacy. As an example, a meta-analysis of nine randomized trials (237 patients) compared adjunctive lithium with placebo and found that response was superior with lithium [72]. In addition, subgroup analyses found that lithium was efficacious for augmenting first-generation antidepressants (eg, tricyclics) and for augmenting second-generation antidepressants (eg, SSRIs). However, other augmentation strategies (eg, thyroid hormone) may be preferred over lithium because lithium can be more difficult to use due to the risk of toxicity, the need to monitor serum concentrations, and adverse effects. The efficacy, dose, safety issues, and side effects of lithium in treatment resistant depression are discussed separately (including the efficacy of adjunctive lithium compared with adjunctive triiodothyronine). (See "Unipolar depression in adults: Treatment with lithium".)

Another possible benefit of lithium is reduced risk of suicide. (See "Suicidal ideation and behavior in adults", section on 'Pharmacotherapy'.)  

Thyroid hormone — Thyroid hormone has been used as augmentation for treatment resistant depression since the 1960s [73], and subsequent studies have provided low quality evidence supporting its efficacy. As an example, a meta-analysis of four randomized trials (95 depressed patients unresponsive to a tricyclic) compared adjunctive triiodothyronine (T3) to either adjunctive placebo or thyroxine (T4) [60]. Although the clinical benefit of T3 was moderately large, and response (reduction of baseline depressive symptoms ≥ 50 percent) occurred in 53 percent more patients who received T3, the difference in the frequency of response between T3 and the control condition was not statistically significant (relative response 1.53, 95% CI 0.70-3.35), and heterogeneity across studies was significant. In addition, it is not clear whether T3 augmentation is efficacious with antidepressants other than tricyclics [74,75]. The efficacy, dose, safety issues, and side effects of thyroid hormone in treatment resistant depression are discussed separately. (See "Unipolar depression in adults: Augmentation of antidepressants with thyroid hormone" and "Unipolar depression in adults: Treatment with lithium", section on 'Triiodothyronine (T3)'.)

A second antidepressant — For treatment resistant depression that responds incompletely to antidepressant monotherapy, it is becoming increasingly common to add a second antidepressant from a different class (often referred to as combination therapy); however, there is inconsistent evidence from randomized trials to support this practice [76]. Trials that included a placebo arm have yielded inconsistent results, and other studies did not include a placebo control. The efficacy of antidepressant combinations for treatment resistant depression is discussed separately. (See "Unipolar depression in adults: Treatment with antidepressant combinations", section on 'Treatment resistant depression'.)

Certain antidepressant combinations should be avoided; as an example, an MAOI plus an SSRI, a serotonin-norepinephrine reuptake inhibitor, or a tricyclic can cause the serotonin syndrome or a hypertensive crisis [57]. (See "Serotonin syndrome (serotonin toxicity)" and "Monoamine oxidase inhibitors (MAOIs) for treating depressed adults".)

Specific interactions between antidepressants may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.

Psychotherapy — For patients with unipolar major depression who are resistant to treatment with an antidepressant, augmentation with psychotherapy is often beneficial [54,77,78]. Cognitive-behavioral therapy (CBT) in particular is supported by multiple randomized trials [79]:

A one year randomized trial compared CBT (12 to 18 sessions) plus usual care (pharmacotherapy and other interventions deemed appropriate, including CBT) with usual care alone in 419 outpatients with treatment resistant depression [80]. Remission occurred in more patients who received CBT plus usual care than usual care alone (28 versus 15 percent). Discontinuation of treatment due to adverse effects was not reported; however, attrition from the group that received CBT was 40 percent (attrition from control group not reported).

A 12 week randomized trial compared citalopram plus CBT (16 sessions) with citalopram plus adjunctive pharmacotherapy (either bupropion or buspirone) in 182 outpatients who did not respond to citalopram monotherapy [55]. Although the mean time to remission was slower for augmentation with CBT than pharmacotherapy (55 versus 40 days), the number of patients who achieved remission was comparable (23 and 33 percent). In addition, discontinuation of treatment due to adverse effects occurred in about half as many patients who received adjunctive CBT, compared with adjunctive pharmacotherapy (9 versus 19 percent).

A 12 week randomized trial compared nefazodone plus CBT (16 to 20 sessions) with nefazodone alone in 446 outpatients with chronic major depression (mean duration 8 years); approximately 80 percent had not responded to prior treatment with antidepressants and/or psychotherapy [81]. Remission occurred in more patients who received combination treatment than nefazodone alone (48 and 29 percent). In addition, discontinuation of treatment due to adverse effects occurred in half as many patients who received combination treatment (7 versus 14 percent). Nefazodone has been withdrawn from many countries because of potential adverse effects on the liver.

Despite the demonstrated benefits of psychotherapy, treatment resistant patients may decline it [29]. In addition, psychotherapy is often not available.

Third-line treatment — Patients with mild to moderate depression may not respond satisfactorily to several courses of first- and second-line treatments [1]. For patients who are resistant to multiple (eg, one to three) next step antidepressant monotherapy trials and multiple (eg, two to four) adjunctive medication trials, as well as treatment with psychotherapy either alone or as augmentation, we suggest repetitive transcranial magnetic stimulation (TMS). Meta-analyses of randomized trials have found that for patients who have not responded to at least one antidepressant medication, repetitive transcranial magnetic stimulation is superior to sham treatment [82-91]. In many studies, patients had failed multiple courses of pharmacotherapy and psychotherapy as well as a trial of ECT [85,88,92,93]. Use of repetitive transcranial magnetic stimulation for treatment resistant depression is consistent with multiple practice guidelines [8-10,13]. The efficacy, administration, safety, and adverse effects of transcranial magnetic stimulation for unipolar depression are discussed separately. (See "Unipolar depression in adults: Treatment with transcranial magnetic stimulation (TMS)".)

Treatments with potential benefit — Patients with treatment resistant depression may not respond to multiple sequential trials of different antidepressants and augmentation with second-generation antipsychotics, lithium, thyroid hormone, or a second antidepressant. These patients are candidates for augmentation with less established treatments, including bright light therapy, celecoxib, omega-3 fatty acids, folate, S-adenosyl methionine, and pramipexole. In addition, electroconvulsive therapy (ECT) may be beneficial.

Bright light therapy – Randomized trials in patients with nonseasonal major depression suggest that antidepressants plus bright light therapy are superior to monotherapy with an antidepressant [94-100]. Among patients who were treated with combination therapy, remission was observed in approximately 40 to 60 percent:

An eight-week trial randomly assigned patients with nonseasonal, unipolar major depression (n = 122) to one of four treatments: fluoxetine (20 mg/day) plus bright light therapy (10,000 lux, 30 minutes/day), fluoxetine plus inactive negative ion generator (fluoxetine alone), placebo pill plus bright light (bright light therapy alone), or placebo pill plus inactive negative ion generator (placebo) [101]. Improvement was greater with fluoxetine plus light therapy and with light therapy alone, compared with placebo; however, fluoxetine monotherapy was not superior to placebo.

An eight-week, open-label, randomized trial compared venlafaxine (150 mg/day) plus bright light therapy with venlafaxine alone in 50 patients hospitalized for nonseasonal major depression [102]. Light therapy (7000 lux each day at 7:00 AM for 60 minutes) was administered for one week at the beginning of clinical management. Improvement was faster and greater in patients who received combination therapy.

A five-week trial compared sertraline (50 mg/day) plus bright white light (10,000 lux, one hour daily) with sertraline plus dim red light (50 lux, 30 min daily) in 102 patients with nonseasonal major depression [103]. Remission occurred in more patients who received combination therapy than sertraline monotherapy (42 versus 19 percent).

The administration, safety, and side effects of bright light therapy are discussed separately. (See "Seasonal affective disorder: Treatment", section on 'Bright light therapy'.)

Celecoxib – Add-on treatment with celecoxib may be beneficial for treatment resistant unipolar major depression [104,105]. A meta-analysis of four randomized trials lasting six or eight weeks compared celecoxib (200 to 400 mg per day) plus an antidepressant (generally a selective serotonin reuptake inhibitor) with placebo plus an antidepressant in 132 patients; remission occurred in more patients who received adjunctive celecoxib (odds ratio 8, 95% CI 3-21) [106]. In the same study, another meta-analysis (10 randomized trials, 2750 patients with either major depression or depressive symptoms) compared celecoxib (used as monotherapy or as add-on treatment) with placebo, and found 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 [107]. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Bleeding'.)  

Electroconvulsive therapy (ECT) – For patients with moderate depression who do not respond to multiple (eg, four to eight) courses of treatment with pharmacotherapy, as well as treatment with psychotherapy (eg, CBT) and repetitive TMS, we suggest that clinicians consider ECT [108,109]. Although ECT is usually reserved for severely ill patients, meta-analyses of randomized trials indicate that ECT is superior to pharmacotherapy for unipolar major depression [110-113], and ECT is generally regarded as the most efficacious treatment for depression [9-11,114]. Use of ECT for moderately ill patients who have repeatedly not responded to pharmacotherapy and psychotherapy is consistent with recommendations in practice guidelines [12,34]. However, ECT is associated with safety risks, adverse effects, logistical constraints, and patient refusal; in addition, relapse rates following remission are high, especially in patients with treatment resistant depression [115,116]. An overview of ECT is discussed separately, as are indications for and efficacy of ECT in unipolar major depression, medical consultation for ECT, and the technique for performing ECT. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)" and "Medical consultation for electroconvulsive therapy" and "Technique for performing electroconvulsive therapy (ECT) in adults".)

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 [117]. Improvement of both depression and cardiovascular fitness was greater with exercise.

Lithium monotherapy – Older studies suggest that lithium monotherapy may effectively treat unipolar depression, but lithium is generally used as augmentation for treatment resistant patients. There is far less evidence for lithium monotherapy than for antidepressants [118-120], and lithium can be difficult to use because of the risk of toxicity and need to monitor serum concentrations [121]. (See "Unipolar depression in adults: Treatment with lithium" and 'Lithium' above.)

Omega-3 fatty acids – Augmentation with omega-3 fatty acids for treatment resistant depression was effective in three small randomized trials [122-124], but the optimal dose has yet to be established [21]. In the largest trial, patients who did not respond to an antidepressant were assigned add-on treatment with eicosapentaenoic acid (1 gram per day) or placebo for 12 weeks [124]. Response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received active treatment (9 of 17; 53 percent) than placebo (5 of 17; 29 percent), and tolerability was comparable for the two groups. (See "Lipid lowering with diet or dietary supplements", section on 'Fish oil and omega-3 fatty acids'.)

Quetiapine monotherapy – Quetiapine monotherapy may benefit patients with treatment resistant depression, but is typically used as an adjuvant with an antidepressant. Randomized trials compared quetiapine with placebo for episodes of nonpsychotic unipolar major depression that 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. (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 may be effective and well-tolerated for treatment resistant depression [125,126]. A six-week randomized trial compared adjunctive SAMe (800 mg twice per day) with placebo in 73 patients with unipolar major depression who failed treatment with an SSRI, and found that remission occurred in more patients who received SAMe (36 versus 12 percent) [127]. In addition, discontinuation of treatment because of adverse effects occurred in fewer patients who received augmentation with SAMe than placebo (5 versus 9 percent). Additional information about SAMe is available from the United States National Library of Medicine Dietary Supplements Database and the National Library of Medicine monographs.

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".)

Drugs with little to no benefit — Multiple randomized trials in patients with treatment resistant depression indicate that there is little to no benefit in augmenting an antidepressant with buspirone, folate, lamotrigine, or pindolol.

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 [128,129]. In addition, a STAR*D trial found that symptomatic improvement and tolerability were inferior with adjunctive buspirone compared to adjunctive bupropion [121]. (See 'A second antidepressant' above.)

Folate – The benefit of folate appears to be modest at best, based upon two randomized trials that used different doses:

A 12 week trial compared folic acid (5 mg per day) with placebo in 440 patients treated with an antidepressant, and found no benefit with active treatment [130].

In a 60 day trial that compared L-methylfolate (15 mg per day) plus an SSRI with placebo plus an SSRI in 75 patients, response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received adjunctive L-methylfolate than placebo (32 versus 15 percent), and tolerability was comparable [131]. However, remission was comparable with active drug and placebo (13 and 9 percent).

Other studies of folate have raised safety concerns, including masked B12 deficiency [126]. Additional information about folate is available from the United States National Library of Medicine Dietary Supplements Database and the National Library of Medicine Monographs.

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 [132,133].

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) [134-137], as well as a network meta-analysis [62].

SEVERE DEPRESSION — Severe major depression is characterized by clinical features such as:

Suicidal or homicidal behavior or ideation with a specific plan and intent (see "Suicidal ideation and behavior in adults")

Psychotic features (eg, delusions or hallucinations) (see "Clinical manifestations, differential diagnosis, and initial management of psychosis in adults")

Catatonia (see "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis")

Poor judgement that places the patient or others at imminent risk of being harmed

Impaired functioning (eg, food and fluid refusal leading to malnutrition and dehydration)

Severely ill patients generally require hospitalization [9,10].

Choosing treatment — For treatment resistant patients with severe unipolar major depression, electroconvulsive therapy (ECT) is often the treatment of choice [6,8-11]. Indications for ECT as first-line treatment include [8,109,138-140]:

Persistent suicidal ideation with intent (see "Suicidal ideation and behavior in adults")

Severe weight loss, malnutrition, or dehydration secondary to refusal of food and fluids

Malignant catatonia (see "Catatonia: Treatment and prognosis", section on 'Treatment algorithm')

ECT may also be indicated on the basis of psychotic features (eg, delusions or hallucinations), as well as prior favorable response and patient preference. (See "Unipolar major depression with psychotic features: Acute treatment", section on 'Electroconvulsive therapy'.)

Prior to using ECT, many patients receive a few (eg, one to four) courses of next step pharmacotherapy using the same regimens that are employed for treatment resistant patients with mild to moderate depression; these options include antidepressant monotherapy (see 'Pharmacotherapy' below) as well as combination treatment with an antidepressant plus a second drug and/or psychotherapy (see 'Mild to moderate depression' above). Although response to ECT may be decreased in patients who have not responded to multiple medication trials, the data are inconsistent. (See "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Predictors of response'.)

For severely depressed patients who do not respond to ECT or who decline ECT, we suggest pharmacotherapy, as well as adjunctive psychotherapy if it is feasible. (See 'Pharmacotherapy' below and 'Adjunctive psychotherapy' below.)

Electroconvulsive therapy (ECT) — ECT is superior to pharmacotherapy for unipolar major depression, based upon meta-analyses of randomized trials [111-113]. As an example, a meta-analysis of 18 trials (1144 patients) compared ECT with pharmacotherapy and found that ECT was more efficacious [110]. In one open label randomized trial that compared ECT with paroxetine in 39 patients with treatment resistant depression (mean number of failed antidepressant trials was 5), response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received ECT than paroxetine (71 versus 28 percent) [141].

ECT is generally regarded as the most efficacious treatment for major depression [9-11,108,109,114], and use of ECT for severe, treatment resistant depression is consistent with recommendations in multiple practice guidelines [8-13]. However, ECT is associated with safety risks, adverse effects, logistical constraints, and patient refusal, and relapse rates following remission are high, especially in patients with treatment resistant depression [115,116]. An overview of ECT is discussed separately, as are indications for and efficacy of ECT in unipolar major depression, medical consultation for ECT, and the technique for performing ECT. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)" and "Medical consultation for electroconvulsive therapy" and "Technique for performing electroconvulsive therapy (ECT) in adults".)

Pharmacotherapy — For severely depressed patients who are treatment resistant, there are no compelling data that indicate one class of antidepressants (table 7) is superior to others. However, limited evidence suggests that tricyclics may be preferred [11]. A meta-analysis of 25 randomized trials compared tricyclics with selective serotonin reuptake inhibitors (SSRIs) in 1377 hospitalized patients who were not selected for treatment resistance [142]. Although tricyclics were more efficacious than SSRIs, the difference was small, and heterogeneity across studies was significant. In addition, discontinuation of treatment was greater with tricyclics than SSRIs (14 versus 9 percent). Additional information about choosing an antidepressant is discussed elsewhere in this topic in the context of mild to moderate depression. (See 'Choosing a drug' above.)

Augmentation of the antidepressant with a second drug is often indicated for severe, treatment resistant major depression. Examples include patients with:

Unrelenting suicidal thoughts and intent – Lithium may reduce the risk of suicide (see "Unipolar depression in adults: Treatment with lithium", section on 'Preventing suicide')

Psychotic features – Meta-analyses of randomized trials have found that an antidepressant plus an antipsychotic is more efficacious than antidepressant monotherapy (or antipsychotic monotherapy) (see "Unipolar major depression with psychotic features: Acute treatment", section on 'Evidence of efficacy')

Catatonia – Depressed patients with catatonia who do not require ECT are treated with antidepressants plus lorazepam (see "Catatonia: Treatment and prognosis", section on 'Treatment')

Other severely ill, treatment resistant patients may benefit from adjunctive medications, based upon randomized trials in mild to moderately ill patients. (See 'Augmentation' above.)

Adjunctive psychotherapy — We typically include adjunctive psychotherapy for severe episodes of major depression that are treatment resistant, based upon indirect evidence from randomized trials in patients with mild to moderate major depression (see 'Psychotherapy' above). Most hospitalized patients receive psychotherapy, provided that they are well enough to participate in therapy. However, small studies of adjunctive psychotherapy in severely ill patients have yielded conflicting results:

A 12 week randomized trial compared cognitive-behavioral therapy (CBT) plus pharmacotherapy with pharmacotherapy alone in 20 patients hospitalized for chronic (duration ≥2 years) depression; improvement was comparable for the two groups [143]  

A 12 week observational study evaluated CBT plus pharmacotherapy in 24 patients hospitalized for chronic depression [144]. Functioning was impaired to the point that many patients had difficulty with basic self-care tasks, and most patients also received family therapy. Mean symptom scores on the depression rating scale improved and 11 (46 percent) patients reported that they were much improved.

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)")

In addition, a brochure entitled, “Therapies for Treatment-Resistant Depression” is available from the United States Agency for Healthcare Research and Quality. The brochure can also be found on PubMed through the PubMed identification number 22624179 or by calling the AHRQ Publications Clearinghouse at 800-358-9295.  

SUMMARY AND RECOMMENDATIONS

Unipolar major depression (major depressive disorder) is diagnosed in patients who have suffered at least one major depressive episode (table 1) and have no history of mania or hypomania. (See "Unipolar depression in adults: Assessment and diagnosis".)

Treatment resistant depression typically refers to major depressive episodes that do not respond satisfactorily to at least 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'.)

Treatment refractory depression generally refers to unipolar major depressive episodes that do not respond satisfactorily to many sequential standard regimens, including pharmacotherapy, psychotherapy, and electroconvulsive therapy. However, the definition has not been standardized, and there is no clear demarcation between treatment resistant and treatment refractory depression. (See "Unipolar depression in adults: Management of highly resistant (refractory) depression", section on 'Treatment refractory depression'.)

Mild to moderate depression

For patients with mild to moderate major depression who obtain little symptom relief from an antidepressant, we suggest switching antidepressants as first-line treatment, rather than augmenting the initial antidepressant with a second drug and/or psychotherapy, or switching from pharmacotherapy to psychotherapy (Grade 2C). However, reasonable alternatives include augmentation with a second drug and/or psychotherapy, as well as switching from pharmacotherapy to psychotherapy. Patients who cannot tolerate an adequate dose of the initial antidepressant should switch to another antidepressant. (See 'First- and second-line treatment strategies' above.)

For patients who switch antidepressants, we suggest selecting a drug from a different class (table 7) rather than the same class (Grade 2A). In choosing a new antidepressant for patients who fail a selective serotonin reuptake inhibitor, our general order of preference is serotonin-norepinephrine reuptake inhibitors, atypical antidepressants, tricyclics, and monoamine oxidase inhibitors. However, it is reasonable to use these drugs in a different sequence or to switch to a different SSRI at any point in the sequence. (See 'Choosing a drug' above.)

For patients with mild to moderate major depression who obtain little symptom relief despite repeated (eg, one to three) antidepressant switches, we suggest augmentation with a second medication and/or psychotherapy as second-line treatment, rather than additional trials of antidepressant monotherapy (Grade 2B). (See 'First- and second-line treatment strategies' above and 'Augmentation' above.)

For patients with mild to moderate major depression who obtain definite symptom relief that is not satisfactory and can tolerate the antidepressant, we suggest augmentation with a second medication and/or psychotherapy as first-line treatment, rather than continuing the initial antidepressant alone (Grade 2B). However, reasonable alternatives include switching antidepressants, as well as switching from pharmacotherapy to psychotherapy. (See 'First- and second-line treatment strategies' above.)

In choosing an adjunctive drug, our general order of preference is second-generation antipsychotics, lithium, triiodothyronine, and a second antidepressant from a different class. However, it is reasonable to use these drugs in a different sequence. Among second-generation antipsychotics, our general order of preference is aripiprazole, quetiapine, risperidone, and olanzapine. (See 'Choosing a drug' above.)

Patients with mild to moderate major depression who obtain definite symptom relief that is not satisfactory despite augmentation with different drugs (eg, two to four) should switch antidepressants as second-line treatment. Patients who do not respond satisfactorily to several (eg, three to nine) courses of first- and second-line treatments should receive repetitive transcranial magnetic stimulation as third-line treatment. (See 'First- and second-line treatment strategies' above and 'Switching antidepressants' above and 'Third-line treatment' above.)

For patients with treatment resistant depression that is mild to moderate and is not responsive to first-, second-, and third-line treatments, other augmentation options include omega-3 fatty acids, folate, S-adenosyl methionine, or pramipexole. (See 'Treatments with potential benefit' above.)

Although electroconvulsive therapy (ECT) is usually reserved for severely depressed patients, it is a reasonable option for patients with moderate depression who are resistant to first-, second-, and third-line treatments. (See 'Treatments with potential benefit' above.)

Severe depression

For treatment resistant unipolar major depression with persistent suicidal ideation/behavior and intent, malnutrition/dehydration secondary to food/fluid refusal, or malignant catatonia, we suggest ECT as first-line treatment rather than pharmacotherapy or psychotherapy (Grade 2B). ECT may also be indicated on the basis of psychotic features, prior favorable response, and patient preference. (See 'Choosing treatment' above and "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Indications'.)

For severely depressed patients who fail two or three next-step antidepressant trials, we suggest ECT rather than additional drug trials (Grade 2B). (See "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Indications'.)

Treatment for severely depressed patients who do not respond to or accept ECT consists of pharmacotherapy, as well as adjunctive psychotherapy if it is feasible. We often use tricyclics, but other antidepressant classes (table 7) are reasonable alternatives. (See 'Pharmacotherapy' above and 'Adjunctive psychotherapy' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate, Inc. would like to acknowledge Drs. Wayne Katon and Paul Ciechanowski, who contributed to earlier versions of this topic review.

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