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Unipolar depression in adults: Management of highly resistant (refractory) depression
Authors: Michael Thase, MD, K Ryan Connolly, MD, MS

Section Editor: Peter P Roy-Byrne, MD
Deputy Editor: David Solomon, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2017. | This topic last updated: Nov 21, 2017.
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
electroconvulsive therapy and psychotherapy [1].
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 treatment resistant depression in adults: Epidemiology, risk factors, assessment, and prognosis".)
(See "Unipolar depression in adults: Treatment of resistant 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 (table 1) or hypomania (table 2) [2]. 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: Assessment and diagnosis".)
Treatment resistant depression The term treatment resistant depression typically refers to major depressive episodes that do not respond
satisfactorily after two trials of antidepressant monotherapy; however, the definition has not been standardized [3-5]. 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 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 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 ketamine [6], deep brain stimulation [1,7,8], and ablative neurosurgery [9,10]; the definition stipulates that
patients are refractory to or refuse the following:
Antidepressants several (eg, three to six) trials with different drugs and classes
Adjunctive drugs multiple (eg, two to four) trials with different drugs
Electroconvulsive therapy (ECT) at least one course
Adjunctive psychotherapy at least one trial
MANAGEMENT
General approach For treatment refractory depression, we recommend referral to mental health clinicians, and suggest a conservative approach
that includes ongoing pharmacotherapy and psychotherapy and avoids excessive investigations and treatments (eg, polypharmacy with four or more
psychotropic medications). Repeated treatment failures may lead patients to feel helpless and demoralized; thus, management should include regular
visits (eg, every two to eight weeks) to monitor safety and provide support [11].
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 [11]. Management includes interventions to help patients [11-14]:
Learn about unipolar major depression.
Adhere to ongoing treatment.
Learn healthy physical habits related to sleep and exercise. (See "Overview of insomnia in adults" and "The benefits and risks of exercise".)
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 avoid setting unrealistic expectations, and try to help patients with treatment refractory depression
accept ongoing symptoms without blaming themselves [11]. 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 [12].
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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: Treatment of 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 [15]. 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 [16-18]. However, for patients who show little improvement (eg, reduction of baseline symptoms 25 percent) after 4 to 6 weeks, we
administer next-step treatment [19]. Additional information about the duration of an adequate treatment trial is discussed separately.
Measurement based care Measurement based care is the systematic, quantitative assessment of symptoms that is typically performed at each visit
[19]. Psychosocial functioning, quality of life, medication adherence, and tolerability of treatment can also be measured.
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) [20,21]. Scores >20 indicate severe depression,
whereas scores <5 indicate remission. A decrease 50 percent indicates a significant clinical 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, based upon
randomized trials:
A meta-analysis of 16 trials compared combination treatment with pharmacotherapy alone in 1842 depressed patients (who were not selected for
treatment resistant or treatment refractory depression) [22]. Response occurred in more patients who received combination therapy (odds ratio 1.9,
95% CI 1.4-2.5). However, psychotherapy is often not available or is declined.
A subsequent one year randomized trial compared cognitive-behavioral therapy (CBT; 12 to 18 sessions) plus usual care (eg, pharmacotherapy)
with usual care alone in 419 outpatients with treatment resistant depression [23]. Remission occurred in more patients who received CBT plus
usual care than usual care alone (28 versus 15 percent).
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. Many antidepressants and adjunctive drugs are available, and the choice begins with drugs that have not
been previously used for the current depressive episode. Our general order of preference in choosing an antidepressant is as follows:
Selective serotonin reuptake inhibitor (see "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects")
Serotonin-norepinephrine reuptake inhibitor (see "Serotonin-norepinephrine reuptake inhibitors (SNRIs): 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 (see "Monoamine oxidase inhibitors (MAOIs) for treating depressed adults")
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
Lithium
Thyroid hormone
Second antidepressant from a different class
Second-generation antipsychotics have the best balance of efficacy and tolerability among these options, particularly in combination with modern, first-
line antidepressants such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Additional information about
choosing treatment, the efficacy of different options, and the general principles that are used to administer treatment is discussed separately in the
context of treatment resistant depression. (See "Unipolar depression in adults: Treatment of resistant depression".)
Lack of response to numerous standard treatments may impel clinicians to prescribe many 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.
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. 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, supportive
psychotherapy, and family therapy. The efficacy and administration of these psychotherapies is discussed separately. (See "Overview of
psychotherapies" and "Interpersonal Psychotherapy (IPT) for depressed adults: Indications, theoretical foundation, general concepts, and efficacy" and
"Unipolar depression in adults: Psychodynamic psychotherapy" and "Unipolar depression in adults: Supportive psychotherapy" and "Family and couples
therapy for treating depressed adults".)
Transcranial magnetic stimulation Patients with mild to moderate depression may not respond satisfactorily to several courses of
pharmacotherapy plus psychotherapy [24]. For patients who are refractory to multiple (eg, one to three) next step antidepressant monotherapy trials
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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. 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 [25-35]. In many studies, patients had failed
multiple courses of pharmacotherapy and psychotherapy as well as a trial of electroconvulsive therapy (ECT) [28,31,36,37]. Use of repetitive
transcranial magnetic stimulation for treatment resistant depression is consistent with multiple practice guidelines [38-41]. The efficacy, administration,
safety, and adverse effects of transcranial magnetic stimulation for unipolar depression are discussed separately. (See "Unipolar depression in adults:
Indications, efficacy, and safety of transcranial magnetic stimulation (TMS)".)
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. These patients are candidates for augmentation with less established treatments, including botulinum
toxin, celecoxib, omega-3 fatty acids, S-adenosyl methionine, and pramipexole. In addition, ECT may be beneficial.
Botulinum toxin Randomized trials suggest that adjunctive botulinum toxin may benefit patients with unipolar major depression, but loss of
blinding due to the drugs effect upon facial muscles is common [42,43]. 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 [44]. 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 Add-on treatment with celecoxib may be beneficial for treatment resistant unipolar major depression [45,46]. 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) [47]. 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 selective serotonin reuptake inhibitors (SSRIs) plus nonsteroidal anti-
inflammatory drugs is associated with bleeding [48]. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects",
section on 'Bleeding'.)
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
[49]. 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 [50].
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 [51-53], and lithium can
be difficult to use because of the risk of toxicity and need to monitor serum concentrations [54]. (See "Unipolar depression in adults: Treatment with
lithium" and "Unipolar depression in adults: Treatment of resistant depression", section on 'Lithium'.)
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. In a 60-day randomized 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 add-on
L-methylfolate than placebo (32 versus 15 percent), and tolerability was comparable [55]. However, remission was comparable with active drug and
placebo (13 and 9 percent).
Omega-3 fatty acids Multiple randomized trials suggest that augmentation of antidepressants with omega-3 fatty acids may benefit patients with
treatment refractory depression:
One meta-analysis of eight trials (n = 448 patients) compared adjunctive omega-3 fatty acids with placebo; the trials lasted 4 to 12 weeks and
the dose of eicosapentaenoic acid was typically one gram per day [56]. Improvement was greater with omega-3 fatty acids than placebo, and
the clinical effect was moderate to large. Discontinuation of treatment due to adverse effects was less than 2 percent.
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 [57]. 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 systematic review included a meta-analysis with 535 patients who were clinically diagnosed with depressive syndromes; the meta-analysis
found 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 (heterogeneity across studies was also moderate to large) [58]. In addition, the review
included a second meta-analysis which found a trend towards greater efficacy for augmentation with eicosapentaenoic acid-predominant
formulations of omega-3 fatty acids, compared with monotherapy with eicosapentaenoic acid-predominant formulations of omega-3 fatty acids.
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
approaches", section on 'Omega-3 fatty acids' and "Fish oil and marine omega-3 fatty acids".)
Quetiapine monotherapy Quetiapine monotherapy may benefit patients with treatment refractory 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
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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 5). (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 as an adjunct for treatment refractory depression [56,59,60]. 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) [61]. 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 Supplement 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".)
Treatments 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 [62,63]. In addition, a STAR*D trial found that
symptomatic improvement and tolerability were inferior with adjunctive buspirone compared with adjunctive bupropion [54]. (See "Unipolar
depression in adults: Treatment of resistant depression", section on 'A second antidepressant'.)
Folate Randomized trials indicate that folate (folic acid) is not useful for treatment refractory depression. A meta-analysis of four randomized
trials 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 [56]. In addition, other studies of folate have raised safety concerns, including masked B12
deficiency [60].
Nevertheless, a small, prospective observational study identified 12 patients who had not responded to at least three medication trials and who
manifested cerebral spinal fluid folate deficiency despite normal serum folate levels; treatment with add-on leucovorin (also called folinic acid; 1 to 2
mg/kg for at least six weeks) was associated with improvement in 10 patients [64].
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 [65,66].
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 [67].
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) [68-71], as well as a network meta-analysis [72].
Vagus nerve stimulation We generally do not perform 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 [73,74]. 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) [75]. Avoiding vagus nerve stimulation is consistent with multiple practice guidelines [39,40,76]. 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 (VNS)'.)
INVESTIGATIONAL APPROACHES Investigational therapies for refractory major depression include:
Ketamine
Noninvasive neuromodulation therapies
Invasive/surgical neuromodulation therapies
Other potential therapies
Patients with treatment refractory depression may be candidates for ketamine and noninvasive neuromodulation interventions, whereas surgical
interventions are reserved for patients with severe, intractable, and incapacitating major depression.
Ketamine The delayed therapeutic effect of many antidepressants may be due to their targeted action on the monoaminergic system, which is
thought to be upstream from the central nervous system sites that are more directly involved in response to pharmacotherapy. A potentially more direct
and immediate target is the glutamatergic system, including the N-methyl-D-aspartate (NMDA) receptor [77].
Ketamine is an NMDA receptor antagonist, and is a standard anesthetic drug that can transiently alleviate treatment refractory unipolar major
depression. Most studies have administered the drug intravenously, using subanesthetic doses; other less studied routes of giving the drug include
intramuscular, intranasal, oral, and sublingual administration [78-80].
Although off-label use of ketamine for depression has increased, we suggest that clinicians limit the use of ketamine to research settings [81]. The
demonstrated benefit of ketamine is only short lived, the drug is associated with bladder toxicity and is potentially neurotoxic, and ketamine is liable to
abuse/diversion [82-86]. Nor is it established whether ketamine is a bona fide antidepressant or merely a transient intoxicant/euphoriant [83]. A cautious
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approach to the use of ketamine is consistent with recommendations from the American Psychiatric Association [82].
For patients who receive ketamine outside of a research setting, we suggest that clinicians regularly monitor the patients psychiatric status [84]; as an
example, interviewing acutely ill patients at least once per week and stable patients receiving maintenance treatment with ketamine at least once per
month. At a minimum, clinicians should ask about depression, dissociation/psychosis, and misuse of the drug.
The efficacy of ketamine for treatment refractory depression rests upon randomized trials, which indicate that a single infusion of ketamine produces a
rapid response (eg, within 40 to 120 minutes) in at least 50 percent of patients; however, the effect dissipates by day 10 to 14 [87-89]. As an example:
One systematic review of seven trials compared ketamine with a control condition (placebo or active medication) in 172 patients with unipolar or
bipolar major depression [82]. A single dose of ketamine (0.5 mg/kg) or the control was administered intravenously (six trials) or intranasally (one
trial); most patients received no concomitant therapy. Response (reduction of baseline symptoms 50 percent) at multiple posttreatment time points
occurred in more patients who received ketamine than the control condition:
Two hours 51 versus 2 percent of patients

One day 53 versus 7 percent
Seven days 31 versus 7 percent
By day 14, response was present in only 11 percent of the patients who received ketamine.
A meta-analysis of nine trials compared intravenous ketamine (0.5 mg/kg infused over 40 minutes) with a control condition (typically placebo) in
patients with unipolar depression (n = 208) or bipolar depression (n = 26); study drugs were typically administered as add-on therapy [90].
Response was more likely to occur in patients who received ketamine than controls, starting at 40 minutes and persisting at multiple subsequent
time points; at day 7, response was three times more likely with ketamine (relative risk 3, 95% CI 2-7).
There are no well-established clinical predictors or biomarkers of acute response to ketamine [91].
Sustained improvement of depression may occur with repeated infusions of ketamine [83,92]. One trial randomly assigned patients with treatment
resistant depression (n = 67) to one of four treatments: ketamine two times per week, placebo two times per week, ketamine three times per week, or
placebo three times per week [93]. The dose of ketamine was 0.5 mg/kg, all study drugs were infused intravenously over 40 minutes, and current
antidepressant drugs were continued. Response at day 15 occurred in more patients who received twice weekly ketamine than placebo (69 versus 15
percent), and more often with thrice weekly ketamine than placebo (54 versus 6 percent of patients). The improvement that occurred with ketamine
persisted during subsequent treatment with open-label ketamine for two weeks.
The long-term benefits of ketamine are not known, due to the short duration of treatment and lack of follow-up in most studies [94]. A case series of
three outpatients found variable responses during a 12-month course of treatment that included 16 to 34 total infusions per patient [95]. In addition,
concerns about the long-term adverse effects of ketamine include cognitive impairment [96].
Transient adverse effects of ketamine in randomized trials included significant, clinically large dissociative and psychotomimetic effects at 40 to 60
minutes post infusion, which subsequently resolved within four hours [82,83,87,90]. In addition, hemodynamic effects included time-limited tachycardia
and increases in blood pressure. Two trials observed mean increases in systolic blood pressure of 8 and 19 mm Hg within 40 minutes of infusion, which
normalized 4 hours after infusion [82]. Other common adverse effects included blurred vision, dizziness, and nausea or vomiting [97]. The intensity of
dissociation induced by ketamine appears to diminish with repeated infusions [93].
Augmentation with ketamine may accelerate response to antidepressant treatment, which often takes 6 to 12 weeks [97]. A four-week randomized trial
compared a single infusion of add-on ketamine (0.5 mg/kg) with placebo on day 1 of newly initiated treatment with escitalopram 10 mg/day [98]. The
sample consisted of 27 patients with unipolar major depression, approximately half of whom were classified as treatment resistant. Study drugs were
administered after a two week washout of prior pharmacotherapy. Response occurred in more patients treated with adjunctive ketamine than placebo
(92 versus 57 percent), and the mean time to response was shorter with ketamine plus escitalopram than placebo plus escitalopram (6 versus 27 days).
In addition, more than half of the patients responded within two hours of receiving intravenous ketamine, compared with none of the patients who
received placebo. None of the patients discontinued treatment due to adverse effects.
In addition, one randomized trial (n = 18) suggests that onset of antidepressant effect may be faster with ketamine than electroconvulsive therapy [99],
and a prospective observational study found that ketamine led to a moderately large reduction of depressive symptoms in patients (n = 17) who had
previously not responded to electroconvulsive therapy (ECT) [6]. However, ketamine is not an alternative to ECT [82].
Studies of ketamine for depression have typically occurred in hospital settings in collaboration with anesthesiologists [96,100,101]; however, outpatient
clinics offering treatment are available [83].
Suicidal ideation Randomized trials suggest that ketamine may be useful for short-term treatment of suicidal ideation. A meta-analysis of patient
level data from eight randomized trials compared a single intravenous infusion of ketamine (0.5 mg/kg) with a control condition (either saline or
midazolam) in 167 patients with active or passive suicidal ideation at study entry [102]. Most of the patients were diagnosed with unipolar major
depression (77 percent); other diagnoses included bipolar disorder and posttraumatic stress disorder. Approximately 50 percent of patients were
concurrently treated with psychotropic medications. After adjusting for potential confounds (eg, age, diagnosis, and use of pharmacotherapy) and
concurrent changes in other depressive symptoms, greater improvement with ketamine began within one day of treatment, and resolution of suicidal
ideation by day seven occurred in more patients who received ketamine than controls (60 versus 32 percent).
Additional information about management of suicidal ideation is discussed separately. (See "Suicidal ideation and behavior in adults", section on
'Management'.)
Esketamine Ketamine is a racemic mixture of two stereoisomers that are mirror images of each other and thus not identical in that they cannot be
superimposed upon each other (similar to ones hands). One of the stereoisomers, S-ketamine (esketamine), binds more potently to the NMDA receptor
than the other stereoisomer [103].
The clinical benefit of esketamine appears to be comparable to that of ketamine (see 'Ketamine' above). One trial randomly assigned patients with
treatment resistant depression (n = 30) to receive intravenous infusions of esketamine 0.2 mg/kg, esketamine 0.4 mg/kg, or placebo. Double-blind
treatment occurred during the first week, with infusions on day 1 and day 4, followed by an open-label treatment phase with up to four infusions of
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esketamine over two weeks, and a subsequent follow-up assessment-only phase for another two weeks [103]. Following the first dose of study drug,
response (reduction of baseline symptoms >50 percent) occurred in more patients treated with esketamine 0.2 mg/kg or esketamine 0.4 mg/kg than
placebo (67 and 64 versus 0 percent). The benefit of active treatment persisted for the entire five weeks of the study. The most common adverse effects
of esketamine were dissociation, headache, and nausea; in two cases, esketamine 0.4 mg/kg caused severe dissociation that resolved within four
hours.
Other potential therapies Other investigational treatments that potentially may help patients with refractory unipolar major depression include the
following:
Basimglurant Basimglurant is a glutamatergic antagonist akin to ketamine (see 'Ketamine' above) and may perhaps be useful for treatment
refractory depression [104]. 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 [105]. 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 Adjunctive treatment with the combination of buprenorphine and samidorphan, which both act upon opioid
receptors, may possibly be useful for treatment refractory depression [106]. Patients who did not respond to an antidepressant (n = 135) were
randomly assigned to four weeks of add-on treatment with buprenorphine (2 mg) plus samidorphan (2 mg), buprenorphine (8 mg) plus
samidorphan (8 mg), or placebo [107]. Nonresponders to add-on placebo were then randomly assigned to one of the three adjunctive treatments
for another four weeks. Across the two stages of the entire study, improvement was greater with buprenorphine/samidorphan (2 mg/2 mg) than
placebo, and stopping treatment with buprenorphine/samidorphan did not lead to opioid withdrawal. However, discontinuation of treatment due to
adverse effects was 12 times greater with buprenorphine/samidorphan than placebo (19.3 versus 1.6 percent of patients); relatively common
adverse effects with buprenorphine/samidorphan included dizziness, dysgeusia, headache, nausea, sedation, and vomiting.
Meditation Meditation is an investigational add-on treatment that might benefit patients with treatment refractory depression [108]. 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 [109]. 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.
Nitrous oxide Nitrous oxide is an NMDA receptor antagonist 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) [110]. Study drugs were administered in a single session lasting one hour. Improvement of depression was
greater with add-on nitrous oxide than placebo at two hours, 24 hours, and one week posttreatment. However, nitrous oxide may be abused
because of its intoxicating properties. Antagonism of the NMDA receptor also occurs with ketamine, which is another investigational approach to
managing highly resistant depression. (See 'Ketamine' above.)
Rapastinel The investigational drug rapastinel acts as an NMDA agonist and may have rapid antidepressant effects [106]. A randomized trial
compared a single intravenous dose of rapastinel (5 or 10 mg/kg) with placebo in 70 patients with unipolar major depression who did not respond
to antidepressants [111,112]. Posttreatment assessments on day 1, 3, and 7 found that improvement was greater with each dose of rapastinel than
placebo, and the clinical effect for each dose was approximately moderate. Assessments at day 14 indicated that the benefit of active drug had
dissipated. Dizziness occurred more often with rapastinel than placebo.
Noninvasive neuromodulation Noninvasive neuromodulation procedures use an electric current or magnetic field to stimulate the central nervous
system [38]. 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, trigeminal nerve stimulation, and low field magnetic stimulation. In addition, cranial
electrical stimulation is a clinically available, noninvasive approach. The efficacy, safety, and side effects of experimental noninvasive neuromodulation
procedures are discussed separately. (See "Depression in adults: Overview of neuromodulation procedures", section on 'Noninvasive neuromodulation
therapies'.)
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 [1,113]. The most widely studied surgical intervention is deep brain stimulation; however, one
randomized trial found that deep brain stimulation was not beneficial for refractory depression [114]. 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".)
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.)
6 de 17 05/12/2017 16:55
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
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 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: Treatment of resistant
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 electroconvulsive therapy,
repetitive transcranial magnetic stimulation, and adjunctive psychotherapy. 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.)
For treatment refractory depression, we suggest a conservative approach that avoids excessive investigations and treatments, rather than
administering aggressive, complicated regimens (eg, polypharmacy with four or more psychotropic drugs) (Grade 2C). Regular visits should be
scheduled to monitor safety and provide support. While administering pharmacotherapy and psychotherapy, clinicians can help patients manage
their illness as a chronic disease by learning about unipolar major depression, adhering to ongoing treatment, learning healthy physical habits
related to sleep and exercise, learning healthy mental health habits related to coping with difficult situations and increasing social skills, and
focusing upon psychosocial functioning. (See 'General approach' above.)
For treatment refractory depression, we suggest pharmacotherapy plus psychotherapy, rather than pharmacotherapy alone (Grade 2C). However,
pharmacotherapy alone is a reasonable alternative. (See 'Combination therapy' above.)
Patients with treatment refractory depression frequently receive an antidepressant augmented with another drug; however, antidepressant
monotherapy is a reasonable alternative. 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 as follows: second-generation antipsychotic, lithium, thyroid hormone, and a second antidepressant from a different class. (See
'Pharmacotherapy' above.)
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,
supportive psychotherapy, and family therapy. (See 'Adjunctive psychotherapy' above.)
For patients with treatment refractory depression, we suggest not performing vagus nerve stimulation (Grade 2B). (See 'Treatments with little to no
benefit' above and "Unipolar depression in adults: Treatment with surgical approaches", section on 'Vagus nerve stimulation (VNS)'.)
Patients with treatment refractory depression may be candidates for the anesthetic ketamine, preferably administered in clinical trials investigating
the drug. Treatment with ketamine that occurs outside of a research setting should include regular monitoring of the patients psychiatric status; as
an example, interviewing acutely ill patients at least once per week and stable patients receiving maintenance treatment with ketamine at least
once per month. At a minimum, clinicians should ask about depression, dissociation/psychosis, and misuse of the drug. (See 'Ketamine' above.)
Other investigational approaches include basimglurant, buprenorphine and samidorphan, meditation, nitrous oxide, and rapastinel. In addition,
clinical trials are investigating noninvasive neuromodulation interventions that include magnetic seizure therapy, focal electrically administered
seizure therapy, transcranial direct current stimulation, and transcranial low voltage pulsed electromagnetic fields stimulation, trigeminal nerve
stimulation, and low field magnetic stimulation. Cranial electrical stimulation is a clinically available, noninvasive neuromodulation intervention. (See
'Other potential therapies' above and 'Noninvasive neuromodulation' 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. Although ablative neurosurgery is clinically available, this is a rarely
used, last resort treatment. (See 'Invasive/surgical neuromodulation' above and "Unipolar depression in adults: Treatment with surgical
approaches".)
Use of UpToDate is subject to the Subscription and License Agreement.
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104. Lindemann L, Porter RH, Scharf SH, et al. Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5
negative allosteric modulator in clinical development for depression. J Pharmacol Exp Ther 2015; 353:213.
105. Quiroz JA, Tamburri P, Deptula D, et al. Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical
Trial. JAMA Psychiatry 2016; 73:675.
106. Machado-Vieira R, Henter ID, Zarate CA Jr. New targets for rapid antidepressant action. Prog Neurobiol 2017; 152:21.
107. Fava M, Memisoglu A, Thase ME, et al. Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response
10 de 17 05/12/2017 16:55
to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial. Am J Psychiatry 2016; 173:499.

108. Janakiramaiah N, Gangadhar BN, Naga Venkatesha Murthy PJ, et al. Antidepressant efficacy of Sudarshan Kriya Yoga (SKY) in melancholia: a
randomized comparison with electroconvulsive therapy (ECT) and imipramine. J Affect Disord 2000; 57:255.
109. Sharma A, Barrett MS, Cucchiara AJ, et al. A Breathing-Based Meditation Intervention for Patients With Major Depressive Disorder Following
Inadequate Response to Antidepressants: A Randomized Pilot Study. J Clin Psychiatry 2017; 78:e59.
110. Nagele P, Duma A, Kopec M, et al. Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial. Biol Psychiatry 2015;
78:10.
111. Moskal JR, Burch R, Burgdorf JS, et al. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces
antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin Investig Drugs 2014; 23:243.
112. Preskorn S, Macaluso M, Mehra DO, et al. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial
agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract 2015; 21:140.
113. Shelton RC, Osuntokun O, Heinloth AN, Corya SA. Therapeutic options for treatment-resistant depression. CNS Drugs 2010; 24:131.
114. Dougherty DD, Rezai AR, Carpenter LL, et al. A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral
Striatum for Chronic Treatment-Resistant Depression. Biol Psychiatry 2015; 78:240.
Topic 87500 Version 25.0
11 de 17 05/12/2017 16:55
GRAPHICS
DSM-5 diagnostic criteria for manic episode
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least
one week and present most of the day, nearly every day (or any duration if hospitalization is necessary).
B. During the period of mood disturbance and increased energy or activity, three (or more) of the following symptoms (four if the mood is only irritable) are present
to a significant degree and represent a noticeable change from usual behavior:
1) Inflated self-esteem or grandiosity.
2) Decreased need for sleep (eg, feels rested after only three hours of sleep).
3) More talkative than usual or pressure to keep talking.
4) Flight of ideas or subjective experience that thoughts are racing.
5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed.
6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (ie, purposeless non-goal-directed activity).
7) Excessive involvement in activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or
foolish business investments).
C. The mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to
self or others, or there are psychotic features.
D. The episode is not attributable to the physiological effects of a substance (eg, a drug of abuse, a medication, other treatment) or to another medical condition.
NOTE: A full manic episode that emerges during antidepressant treatment (eg, medication, electroconvulsive therapy) but persists at a fully syndromal level
beyond the physiological effect of that treatment is sufficient evidence for a manic episode and, therefore, a bipolar I diagnosis.
NOTE: Criteria A through D constitute a manic episode. At least one lifetime manic episode is required for the diagnosis of bipolar I disorder.
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association. All Rights
Reserved.
Graphic 91106 Version 5.0
12 de 17 05/12/2017 16:55
DSM-5 diagnostic criteria for hypomanic episode
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least
four consecutive days and present most of the day, nearly every day.
B. During the period of mood disturbance and increased energy and activity, three (or more) of the following symptoms (four if the mood is only irritable) have
persisted, represent a noticeable change from usual behavior, and have been present to a significant degree:
1) Inflated self-esteem or grandiosity.
2) Decreased need for sleep (eg, feels rested after only three hours of sleep).
3) More talkative than usual or pressure to keep talking.
4) Flight of ideas or subjective experience that thoughts are racing.
5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed.
6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation.
7) Excessive involvement in activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or
foolish business investments).
C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the individual when not symptomatic.
D. The disturbance in mood and the change in functioning are observable by others.
E. The episode is not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization. If there are psychotic
features, the episode is, by definition, manic.
F. The episode is not attributable to the physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment).
NOTE: A full hypomanic episode that emerges during antidepressant treatment (eg, medication, electroconvulsive therapy) but persists at a fully syndromal level
beyond the physiological effect of that treatment is sufficient evidence for a hypomanic episode diagnosis. However, caution is indicated so that one or two
symptoms (particularly increased irritability, edginess, or agitation following antidepressant use) are not taken as sufficient for a diagnosis of a hypomanic
episode, nor necessarily indicative of a bipolar diathesis.
NOTE: Criteria A through F constitute a hypomanic episode. Hypomanic episodes are common in bipolar I disorder but are not required for the diagnosis of
bipolar I disorder.
Reserved.
13 de 17 05/12/2017 16:55
DSM-5 diagnostic criteria for a major depressive episode
A. Five (or more) of the following symptoms have been present during the same two-week period and represent a change from previous functioning; at least one of
the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
NOTE: Do not include symptoms that are clearly attributable to another medical condition.
1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad, empty, hopeless) or observations made by others
(eg, appears tearful). (NOTE: In children and adolescents, can be irritable mood.)
2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or
observation)
3) Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly
every day. (NOTE: In children, consider failure to make expected weight gain.)
4) Insomnia or hypersomnia nearly every day
5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)
6) Fatigue or loss of energy nearly every day
7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by their subjective account or as observed by others)
9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing
suicide
B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
C. The episode is not attributable to the direct physiological effects of a substance or to another medical condition.
NOTE: Criteria A through C represent a major depressive episode.
NOTE: Responses to a significant loss (eg, bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include the feelings
of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although
such symptoms may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a
significant loss should also be carefully considered. This decision inevitably requires the exercise of clinical judgement based on the individual's history and the
cultural norms for the expression of distress in the context of loss.
D. The occurence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or
other specified and unspecified schizophrenia spectrum and other psychotic disorders.
E. There has never been a manic or hypomanic episode.
NOTE: This exclusion does not apply if all of the manic-like or hypomanic-like epsidoes are substance-induced or are attributable to the physiological effects of
another medical condition.
Specify:
With anxious distress
With mixed features
With melancholic features
With atypical features
With psychotic features
With catatonia
With peripartum onset
With seasonal pattern
Reserved.
14 de 17 05/12/2017 16:55
PHQ-9 depression questionnaire
Name: Date:
Over the last two weeks, how often have you been bothered by any of the following Not at all Several days More than Nearly every
problems? half the day
days
Little interest or pleasure in doing things 0 1 2 3
Feeling down, depressed, or hopeless 0 1 2 3
Trouble falling or staying asleep, or sleeping too much 0 1 2 3
Feeling tired or having little energy 0 1 2 3
Poor appetite or overeating 0 1 2 3
Feeling bad about yourself, or that you are a failure, or that you have let yourself or your 0 1 2 3
family down
Trouble concentrating on things, such as reading the newspaper or watching television 0 1 2 3
Moving or speaking so slowly that other people could have noticed? Or the opposite, being so 0 1 2 3
fidgety or restless that you have been moving around a lot more than usual.
Thoughts that you would be better off dead, or of hurting yourself in some way 0 1 2 3
Total ___ = ___ + ___ + ___ + ___
PHQ-9 score 10: Likely major depression
Depression score ranges:
5 to 9: mild
10 to 14: moderate
15 to 19: moderately severe
20: severe
If you checked off any problems, how difficult have these problems made it for you to Not difficult at Somewhat Very difficult Extremely
do your work, take care of things at home, or get along with other people? all difficult ___ difficult
___ ___ ___
PHQ: Patient Health Questionnaire.
Developed by Drs. Robert L Spitzer, Janet BW Williams, Kurt Kroenke, and colleagues, with an educational grant from Pfizer, Inc. No permission required to reproduce,
translate, display or distribute.
15 de 17 05/12/2017 16:55
Selected adverse effects of antipsychotic medications for schizophrenia
Weight
Hyper- Prolactin Anticholinergic Orthostatic QTc
gain/diabetes EPS/TD Sedation
cholesterolemia elevation side effects hypotension prolongation
mellitus
First generation agents
Chlorpromazine +++ +++ + ++ +++ +++ +++ +
Fluphenazine + + +++ +++ + /+ ND
Haloperidol + + +++ +++ ++ /+ +
Loxapine ++ ND ++ ++ ++ + + +
Perphenazine ++ ND ++ ++ ++ + ND
Pimozide + ND +++ ++ + + + ++
Thioridazine* ++ ND + +++ +++ ++++ ++++ +++
Thiothixene ++ ND +++ ++ + + + +
Trifluoperazine ++ ND +++ ++ + + + ND
Second generation agents
Aripiprazole + + + /+
Asenapine ++ ++ ++ ++ + +
Brexpiprazole + + + /+ + /+ /+ /+
Cariprazine + /+ ++ /+ + /+ /+ /+
Clozapine ++++ ++++ /+ /+ +++ +++ +++ +
Iloperidone ++ ++ /+ /+ + + +++ ++
Lurasidone /+ /+ ++ /+ ++ + /+
Olanzapine ++++ ++++ + + ++ ++ + +
Paliperidone +++ + +++ +++ + ++ +
Pimavanserin + - -/+ - + + ++ +
Quetiapine +++ +++ /+ /+ ++ ++ ++ +
Risperidone +++ + +++ +++ + + + +
Ziprasidone /+ /+ + + + + ++
Adverse effects may be dose dependent.
EPS: extrapyramidal symptoms; TD: tardive dyskinesia; ND: no data.

* Thioridazine is also associated with dose-dependent retinitis pigmentosa. Refer to text.
Based upon limited experience.
Clozapine also causes granulocytopenia or agranulocytosis in approximately 1 percent of patients requiring regular blood cell count monitoring. Clozapine has been
associated with excess risk of myocarditis and venous thromboembolic events including fatal pulmonary embolism. These issues are addressed in the UpToDate topic
review of guidelines for prescribing clozapine section on adverse effects.
References:
1. Lexicomp Online. Copyright 1978-2017 Lexicomp, Inc. All Rights Reserved.
2. The Medical Letter on Drugs and Therapeutics (April 2016); Some Relative Adverse Effects of Second-Generation Antipsychotics (table 3); Vol. 58 (1493):52.
www.medicalletter.org.
3. Rummel-Kluge C, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic
review and meta-analysis. Schizophr Res 2010; 123:225.
4. Durn CE, Azermai M, Vander Stichele RH. Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol 2013; 69:1485.
16 de 17 05/12/2017 16:55
Contributor Disclosures
Michael Thase, MD Grant/Research Support: Agency for Healthcare Research and Quality [Depression]; Alkermes [Depression]; Forest
Pharmaceuticals [Depression (Vilazodone, Milnacipran)]; National Institute of Mental Health [Depression]; Otsuka Pharmaceuticals [Depression
(Aripiprazole)]; PharmaNeuroboost [Depression]; Roche [Depression]; Johnson & Johnson [Depression (Risperidone, Esketamine)] ; Avenir
[Depression]. Consultant/Advisory Boards: Alkermes [Depression]; Allergan [Depression(Botulinium Toxin A)]; AstraZeneca [Depression (Quetiapine)];
Bristol-Myers Squibb Company [Depression (Aripiprazole)]; Cerecor, Inc. [Depression (Olanzapine, Olanzapine Fluoxetine Combination, Duloxetine)];
Eli Lilly & Co. [Depression]; Forest Laboratories [Depression (Vilazodone Levomilnacipran)]; Gerson Lehrman Group [Depression]; GlaxoSmithKline
[Depression]; Guidepoint Global [Depression]; H. Lundbeck A/S [Depression (Vortioxetine)]; MedAvante, Inc. [Depression]; Merck and Co. Inc.
[Depression (Mirtazapine)]; Moksha8 [Depression]; Neuronetics, Inc. [Depression (Neurostar TMS Device)]; Novartis [Depression]; Johnson & Johnson
[Depression (Risperidone, Esketamine]; Otsuka [Depression (Aripiprazole)]; Pamlab, L.L.C. [Depression (L Methylfolate)]; Pfizer [Depression
(Venlafaxine, Desvenlafaxine, Ziprasidone)]; PGx, Inc. [Depression (Mixed Amphetamine Salts)]; Shire US Inc. [Depression]; Sunovion
Pharmaceuticals, Inc. [Depression (Lurasidone)]; Takeda [Depression (Vortioxetine)]; Genentech [Depression]. Employment (Spouse): Peloton
Advantage. Equity Ownership/ Stock Options: MedAvante, Inc. K Ryan Connolly, MD, MS Consultant/Advisory Boards: Athanaeum Partners
[Antipsychotic adherence]. Peter P Roy-Byrne, MD Employment: Mass Medical Society (journal Watch); Wiley Lliss (Depression and Anxiety) [Editor
in Chief]. Stock Options: Valant Medical Solutions [behavioral health (EMR)]. David Solomon, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
17 de 17 05/12/2017 16:55

Unipolar Depression in Adults - Management of Highly Resistant (Refractory) Depression - UpToDate

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Unipolar depression in adults: Management of highly resistant (refract... https://www.uptodate.com/contents/unipolar-depression-in-adults-man...

Official reprint from UpToDate

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

Authors: Michael Thase, MD, K Ryan Connolly, MD, MS

Learn about unipolar major depression.

Adhere to ongoing treatment.

Focus upon psychosocial functioning and quality of life.

Find or rediscover meaning and a purpose in life.

INVESTIGATIONAL APPROACHES Investigational therapies for refractory major depression include:

Two hours 51 versus 2 percent of patients

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:1155.

to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial. Am J Psychiatry 2016; 173:499.

Topic 87500 Version 25.0

DSM-5 diagnostic criteria for manic episode

1) Inflated self-esteem or grandiosity.

3) More talkative than usual or pressure to keep talking.

4) Flight of ideas or subjective experience that thoughts are racing.

Graphic 91106 Version 5.0

DSM-5 diagnostic criteria for hypomanic episode

1) Inflated self-esteem or grandiosity.

3) More talkative than usual or pressure to keep talking.

4) Flight of ideas or subjective experience that thoughts are racing.

Graphic 91107 Version 4.0

DSM-5 diagnostic criteria for a major depressive episode

4) Insomnia or hypersomnia nearly every day

6) Fatigue or loss of energy nearly every day

NOTE: Criteria A through C represent a major depressive episode.

E. There has never been a manic or hypomanic episode.

With anxious distress

With mixed features

With melancholic features

With atypical features

With psychotic features

With peripartum onset

With seasonal pattern

Graphic 89994 Version 11.0

PHQ-9 depression questionnaire

Little interest or pleasure in doing things 0 1 2 3

Feeling down, depressed, or hopeless 0 1 2 3

Trouble falling or staying asleep, or sleeping too much 0 1 2 3

Feeling tired or having little energy 0 1 2 3

Poor appetite or overeating 0 1 2 3

Trouble concentrating on things, such as reading the newspaper or watching television 0 1 2 3

Total ___ = ___ + ___ + ___ + ___

PHQ-9 score 10: Likely major depression

Depression score ranges:

15 to 19: moderately severe

PHQ: Patient Health Questionnaire.

Graphic 59307 Version 7.0

Selected adverse effects of antipsychotic medications for schizophrenia

First generation agents

Chlorpromazine +++ +++ + ++ +++ +++ +++ +

Fluphenazine + + +++ +++ + /+ ND

Haloperidol + + +++ +++ ++ /+ +

Thioridazine* ++ ND + +++ +++ ++++ ++++ +++

Second generation agents

Clozapine ++++ ++++ /+ /+ +++ +++ +++ +

Olanzapine ++++ ++++ + + ++ ++ + +

Paliperidone +++ + +++ +++ + ++ +

Quetiapine +++ +++ /+ /+ ++ ++ ++ +

Risperidone +++ + +++ +++ + + + +

Total _ = _ + _ + _ + ___