Bipolar Disorder in Adults - Treating Major Depression With Antidepressants PDF

Bipolar disorder in adults: Treating major depression with antidepressants
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Official reprint from UpToDate www.uptodate.com 2013 UpToDate
Bipolar disorder in adults: Treating major depression with antidepressants Authors William V Bobo, MD, MPH Richard C. Shelton, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2013. | This topic last updated: Out 22, 2013. INTRODUCTION The use of antidepressants for acute and maintenance treatment of bipolar depression is controversial because of concerns that these drugs are not effective and may harm patients by causing switches from depression to mania as well as rapid cycling [1-3]. Nevertheless, antidepressants (table 1) are the most commonly prescribed drugs for bipolar depression. Studies of bipolar patients in the United States (n = 7760) [4] and Europe (n = 2231) [5] found that an antidepressant had been prescribed for 50 and 81 percent; this may be due in part to the limited efficacy and tolerability of other treatments [6]. This topic reviews the efficacy of antidepressants for patients with bipolar major depression and the risk of these drugs causing a switch in polarity; the risk of rapid cycling is discussed separately. Choosing a medication regimen to treat bipolar major depression, mania, and hypomania is also discussed separately, as is maintenance treatment of bipolar disorder. (See "Rapid cycling bipolar disorder: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Antidepressants'.) (See "Bipolar disorder in adults: Pharmacotherapy for acute depression".) (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania".) (See "Bipolar disorder in adults: Maintenance treatment".) DEFINITION OF BIPOLAR DISORDER Bipolar disorder is a mood disorder that is characterized by episodes of mania, hypomania, and major depression [7]. The subtypes of bipolar disorder include bipolar I and bipolar II. Patients with bipolar I disorder experience manic episodes, and nearly always experience hypomanic and major depressive episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode, and the absence of manic episodes. Additional information about the clinical features and diagnosis of bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical features" and "Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.) ROLE OF ANTIDEPRESSANTS Although the efficacy and safety of antidepressants for bipolar depression remains controversial [8,9], there is a limited role for these drugs as adjuncts to antimanic treatments for treating patients with acute episodes of bipolar major depression. This position is consistent with multiple authorities [3,10-14] and practice guidelines [15-18]. The choice of a specific medication regimen for acute treatment of bipolar major depression is discussed separately, as is maintenance treatment of bipolar disorder. (See "Bipolar disorder in adults: Pharmacotherapy for acute depression" and "Bipolar disorder in adults: Maintenance treatment".) Acute bipolar depression Antidepressants appear to be effective for some patients with acute bipolar depression, and it is thus reasonable to consider adjunctive antidepressants for patients who have responded favorably to these drugs in the past without treatment-emergent affective switching or mood cycle acceleration, as well as patients who have never taken antidepressants [17,19]. By contrast, we suggest that clinicians avoid using antidepressants in patients with bipolar major depression who have previously experienced poor outcomes with antidepressant treatment, including patients with a history of treatment-emergent switching to mania/hypomania, rapid cycling, or suicidal ideation and behavior [17,20-26]. In addition, we generally avoid antidepressants in Section Editor Paul Keck, MD Deputy Editor David Solomon, MD
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patients with concurrent manic symptoms, substance use disorders, early age of onset of bipolar disorder, and a recent history of mania or hypomania (eg, within the last two to three months). The risk of treatment emergent switching, rapid cycling, and suicidality is discussed elsewhere in this topic. (See 'Risk of switching to mania' below and 'Risk of rapid cycling' below and 'Risk of suicidality' below.) Patients with bipolar depression who are treated with adjunctive antidepressants should be educated about the signs of treatment-emergent affective switching and the risk of mood cycle acceleration, and should be monitored for these potential complications. This recommendation is especially important for patients who have never received antidepressants, but also applies to patients who were successfully treated with antidepressants in the past. Using antimanic drugs to prevent switching For patients with bipolar depression who are treated with an antidepressant, we recommend that clinicians concurrently prescribe lithium, valproate, carbamazepine, or a second-generation antipsychotic. A review of randomized trials concluded that switching to mania occurred less often when these antimanic drugs were used with an antidepressant [3]. In addition, avoiding antidepressant monotherapy is consistent with practice guidelines [17,18]. Lithium, valproate, or carbamazepine Lithium, valproate, or carbamazepine can be used in conjunction with antidepressants to prevent switching from depression to mania [17,18]. Evidence for the efficacy of this approach includes the following studies: A pooled analysis of 15 randomized trials (2,691 patients with bipolar or unipolar depression) found that switching polarity during treatment with imipramine monotherapy occurred in 51 percent, with imipramine plus lithium in 28 percent, and with lithium monotherapy in 21 percent [27]. A 26-week randomized trial compared an antidepressant (paroxetine or bupropion) with placebo in 366 patients with bipolar depression; the large majority of patients received lithium, valproate, and/or carbamazepine (the remaining patients received a second-generation antipsychotic). Switching to mania was comparable for antidepressants and placebo (10 and 11 percent) [28]. A retrospective study of 158 patients found that lithium, valproate, and/or carbamazepine prevented switching in bipolar depressed patients treated with tricyclic antidepressants [29]. Second-generation antipsychotics For patients with bipolar major depression who are treated with fluoxetine, concomitant olanzapine can reduce the risk of switching to mania/hypomania: An eight-week randomized trial compared olanzapine plus fluoxetine with placebo in 423 patients with bipolar I depression, and found that treatment emergent mania was comparable for patients who received the combination and patients who received placebo (7 and 6 percent) [30]. A 12-week, open-label, randomized continuation trial compared olanzapine plus fluoxetine with olanzapine monotherapy in 114 patients with bipolar I depression who initially responded to 7 weeks of acute phase therapy with olanzapine plus fluoxetine [31]. Treatment emergent mania was comparable for patients who received the combination or olanzapine monotherapy (2 and 0 percent). However, rates of metabolic side effects and weight gain were higher with the olanzapine-fluoxetine combination. It is not known if olanzapine reduces the risk of switching from other antidepressants, or if other second-generation antipsychotics reduce the risk of antidepressant-induced switching. Avoiding antidepressant monotherapy We suggest that clinicians avoid antidepressant monotherapy in patients with bipolar I or bipolar II major depression [32]. This approach is consistent with multiple practice guidelines [17,18,32]. Although a few randomized trials suggest that antidepressant monotherapy may be effective and safe for some patients with bipolar disorder [33-36], most were small and lacked a placebo control group [33-35]. The largest randomized trial (N = 248 patients with bipolar depression) found that response was comparable for patients who received either paroxetine monotherapy or placebo [37]. In addition, combining an antimanic drug with the antidepressant appears to decrease the rate of switching polarity. (See 'Using antimanic drugs to prevent switching' above.)
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Maintenance treatment For bipolar major depression that remits with an antidepressant plus an antimanic drug, it is unclear how long antidepressants should be continued. Generally, we continue antidepressants for approximately two to four months after remission of the depressive syndrome [15,18]. However, we attempt to avoid continuation and maintenance treatment with antidepressants in patients with a history of antidepressantassociated switch from depression to mania/hypomania or increases in mood cycle frequency; a history of frequent and/or severe manic episodes, including episodes complicated by psychotic features; or a current course of rapid cycling. However, bipolar patients who repeatedly suffer depressive symptoms in the absence of antidepressants may benefit from longer treatment [17]. Monitoring If long-term adjunctive antidepressants are used, mood symptoms should be assessed for increases in mood cycling, including more frequent depressive symptoms or episodes. Self-report mood symptom rating scales may help in monitoring patients: Mood Disorder Questionnaire This 15-item instrument (table 2) is the most widely used measure that screens for episodes of mania and hypomania [38-41]. However, there is little information about using the Mood Disorder Questionnaire to monitor the efficacy of treatment in bipolar patients and provide measurement based care. Patient Health Questionnaire - 9 Item (PHQ-9) This instrument (table 3) has good psychometric properties and is the standard among scales for monitoring symptoms of depression in patients who are receiving treatment for unipolar major depression [42]. The PHQ-9 is discussed separately. (See "Using scales to monitor symptoms and treat depression (measurement based care)", section on 'Patient Health Questionnaire - Nine Item'.) However, it is not known whether using these instruments improves outcomes. Tapering and discontinuing antidepressants Antidepressants should generally be tapered slowly (eg, over two to four weeks) to avoid discontinuation syndrome symptoms and limit the risk of depressive relapses [43]. However, if treatment emergent symptoms of mania/hypomania occur during antidepressant treatment, the antidepressant should be abruptly stopped and antimanic treatments should be optimized [17]. The discontinuation syndrome and antimanic drugs are discussed separately. (See "Antidepressant medication in adults: Switching and discontinuing medication", section on 'Discontinuation of antidepressants' and "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania".) EFFICACY Acute treatment The efficacy of antidepressants collectively (as a drug class) for short term (eg, 4 to 26 weeks) treatment of bipolar I or II major depression is not clear, due to inconsistent results from meta-analyses of randomized trials [44,45]. However, individual trials indicate that fluoxetine combined with olanzapine is effective [30], whereas paroxetine generally is not [28,37,46]. Two meta-analyses of randomized trials that compared antidepressants with placebo for bipolar I or II depression yielded different results: A meta-analysis of five trials compared antidepressants (bupropion, fluoxetine, imipramine, or paroxetine) with placebo in 906 patients with bipolar depression; most patients were treated with an antimanic drug [44]. The analysis found that there was only a trend for a greater rate of response (reduction of baseline symptoms 50 percent) in patients treated with antidepressants (relative risk 1.18, 95% CI 0.99-1.40); heterogeneity across studies was moderate to large. A meta-analysis of seven trials compared antidepressants (bupropion, fluoxetine, imipramine, paroxetine, or phenelzine) with placebo in 1432 patients with bipolar major depression, and found that response was more likely with antidepressants (relative risk 1.4, 95% CI 1.1-1.8) [45]. The trials were described as heterogeneous. The heterogeneity identified in each meta-analysis (perhaps due in part to the different drugs that were studied in the trials) suggests that the results may not be meaningful. (See "Systematic review and meta-analysis", section on 'Heterogeneity'.) Thus, it is informative to examine the largest, most rigorous randomized trials individually:
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An eight-week randomized trial compared fluoxetine (25 or 50 mg per day) plus olanzapine to placebo plus olanzapine in 437 patients with bipolar depression; response occurred in more patients who received fluoxetine than placebo (56 versus 30 percent) [30]. A second randomized trial (n = 410) found that improvement of depressive symptoms was greater with fluoxetine plus olanzapine than lamotrigine monotherapy [47]. A 26-week randomized trial assigned 366 patients with bipolar depression to an antidepressant (either bupropion sustained release 150 to 375 mg per day or paroxetine 10 to 40 mg per day) or placebo; all patients received lithium, valproate, carbamazepine, and/or a second-generation antipsychotic (most patients also received a psychosocial intervention). Response was comparable for patients who received antidepressants and patients who received placebo (32 and 38 percent) [28]. However, there were methodologic problems with this study; most patients were concurrently participating in a psychotherapy trial, and some patients continued to use the antidepressants they were taking at baseline [18]. An eight-week randomized trial compared paroxetine monotherapy (20 mg per day) with placebo in 248 patients with bipolar depression; response was comparable for paroxetine and placebo (55 and 53 percent of patients) [37]. Higher doses of paroxetine may have been more effective [18]. Most antidepressants have not been adequately studied in patients with bipolar depression, and it is not known whether antidepressants vary in their efficacy (only a few head to head comparisons have been conducted). Predictors of response Based upon a randomized trial, depressed bipolar patients with comorbid anxiety are less likely to respond to treatment than patients without anxiety [48]. Prospective observational studies suggest that in patients with bipolar major depression, a positive response to antidepressants plus an antimanic drug (eg, lithium) may be more likely in patients with a prior positive response [49], whereas a poor response may be more likely in patients with concurrent manic symptoms [20] and a prior history of multiple hypomanic episodes (eg, five or more) [49]. Bipolar II depression Based upon randomized trials, the benefits of antidepressants for acute bipolar II depression and bipolar I depression do not differ [37,50]. As an example, a randomized trial found that response to antidepressants plus antimanic drugs (eg, lithium or valproate) was comparable in patients with bipolar II depression (n = 54) and patients with bipolar I depression (n = 118) (20 and 25 percent) [28]. Maintenance treatment For patients with bipolar depression who are treated with an antidepressant and then recover, maintenance treatment with antidepressants generally does not appear to reduce the risk of depressive relapses: A meta-analysis of five randomized trials (246 patients with bipolar I or II disorder) compared antidepressants plus antimanic drugs (eg, lithium) with antimanic drugs alone; treatment lasted for at least six months [51]. Depressive relapses were comparable for the two groups (RR 0.8, 95% CI 0.6-1.3); heterogeneity across studies was not reported. Patients with bipolar major depression (N = 70) who recovered during treatment with antidepressants plus carbamazepine, divalproex, lamotrigine, lithium, or second-generation antipsychotics were randomly assigned to open-label continuation or discontinuation of the antidepressant [50]. At one year follow-up, the mean number of depressive relapses was comparable for antidepressant continuation and discontinuation (0.6 and 0.8). One randomized trial compared fluoxetine monotherapy, lithium monotherapy, and placebo in 81 bipolar II patients who recovered from an episode of major depression with open label fluoxetine [52]. Although the mean time to relapse was longer with fluoxetine than lithium, the time to relapse with fluoxetine and placebo were comparable; thus, it is not clear that fluoxetine was beneficial. In addition, antidepressant monotherapy is nearly always avoided in bipolar disorder [15,18]. RISK OF SWITCHING TO MANIA Treatment of bipolar major depression with antidepressants remains controversial because of concerns that these drugs cause patients to switch polarity directly from depression to mania/hypomania, or within a short time after the depressive episode has remitted (eg, two to three months [53]) [1,2]. However, switching often occurs in bipolar disorder in the absence of antidepressant treatment [2,21], and the evidence indicates that antidepressants may not increase switching during acute or maintenance treatment. As
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an example, a pooled analysis of randomized trials and observational studies (7915 bipolar patients) found that the risk of mania/hypomania was comparable for patients who were exposed to antidepressants and patients who were not (15 and 14 percent); heterogeneity was not reported [54]. Although the evidence suggests that antidepressants collectively (as a drug class) do not induce switching polarity, the risk of treatment emergent mania may nevertheless exist for specific antidepressants; patients who are treated with antidepressant monotherapy; and patient subgroups, including certain genotypes [17,55]. If manic or hypomanic symptoms emerge during antidepressant treatment, antidepressants should be abruptly stopped and antimanic treatments should be optimized [17]. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania".) During acute treatment Acute (eg, 4 to 26 weeks) treatment of bipolar depression with antidepressants does not appear to increase the risk of switching to mania/hypomania [16]: A meta-analysis of six randomized trials compared antidepressants (bupropion, fluoxetine, imipramine, or paroxetine) with placebo in 1026 patients with bipolar major depression; most patients received concomitant treatment with another drug such as lithium, valproate, or a second-generation antipsychotic [44]. Switch rates were comparable (relative risk 1.0, 95% CI 0.6-1.5), and there was little to no heterogeneity across studies. A pooled analysis found that switch rates for antidepressants and for placebo were 8 and 7 percent. A meta-analysis of five randomized trials compared antidepressants (fluoxetine, imipramine, or paroxetine) with placebo in 779 patients with bipolar depression; 76 percent received concomitant olanzapine or lithium [56]. Switch rates were comparable (relative risk 1.0, 95% CI 0.5-2.1), and there was little to no heterogeneity across studies. A pooled analysis found that switch rates for antidepressants and for placebo were 4 and 5 percent. However, randomized trials typically exclude sicker bipolar patients, including those with rapid cycling, psychiatric comorbidity (eg, substance use disorder), comorbid general medical disorders, and suicidality [11]. Thus, these trials may not generalize to many patients; as an example, comorbidity in bipolar disorder appears to be the rule rather than the exception [57,58]. In addition, randomized trials may provide closer monitoring than occurs in routine clinical care, permitting study investigators to discontinue antidepressants prior to onset of full blown manic/hypomanic episodes. During maintenance treatment Long-term treatment (eg, 6 months) with antidepressants plus antimanic drugs in bipolar patients does not appear to cause treatment emergent mania: A meta-analysis of five randomized trials (246 patients with bipolar disorder) compared antidepressants plus antimanic drugs (eg, lithium) with antimanic treatments alone; patients were treated for at least six months [51]. Treatment emergent mania was comparable for the two groups (relative risk 1.4, 95% CI 0.8-2.3); heterogeneity was not reported. Patients with bipolar major depression (n = 70) who recovered during treatment with antidepressants plus carbamazepine, divalproex, lamotrigine, lithium, or second-generation antipsychotics were randomly assigned to open-label continuation or discontinuation of the antidepressant [50]. At one year follow-up, the mean number of manic/hypomanic relapses was comparable for antidepressant continuation and discontinuation (0.3 and 0.1). Pharmacologic risk factors The risk of switching in patients with bipolar depression who are treated with antidepressants may vary according to the antidepressant class or specific drug that is used [17]. In addition, prescribing antidepressants in conjunction with antimanic drugs (eg, lithium, valproate, or second-generation antipsychotics) may mitigate the risk of switching to mania/hypomania. (See 'Using antimanic drugs to prevent switching' above.) Case reports describe mania/hypomania following abrupt withdrawal of antidepressants, tapered discontinuation, or a decrease in dose [59]. Antidepressant class and specific drugs It is not established whether the risk of treatment emergent mania/hypomania varies among specific antidepressants because most drugs have not been compared in head to head trials. However, randomized trials indicate that switching polarity during treatment of bipolar depression
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occurs more often with tricyclics or venlafaxine, compared with bupropion, selective serotonin reuptake inhibitors (SSRIs), and placebo [3,17]: Two trials found that among patients who received venlafaxine plus antimanic drugs (combined n = 95), switching occurred in 15 percent [60,61]. A meta-analysis of six trials (370 patients) found that switching occurred in more patients who received tricyclics (clomipramine, desipramine, or imipramine) than other antidepressants (bupropion, fluoxetine, fluvoxamine, moclobemide, paroxetine, or tranylcypromine) (relative risk 2.9, 95% CI 1.3-6.7); there was little to no heterogeneity across studies [56]. A pooled analysis (415 patients) found that switching occurred in more patients who received tricyclics than SSRIs or placebo (11 versus 4 and 4 percent) [62]. A meta-analysis of two trials (240 patients) found that switching occurred less often with bupropion than other antidepressants (paroxetine, sertraline, or venlafaxine) (relative risk 0.3, 95% CI 0.1-0.9); there was little to no heterogeneity across studies [44]. Clinical risk factors Switching from bipolar major depression to mania/hypomania during treatment with an antidepressant may be more likely to occur in patients with bipolar I disorder than bipolar II disorder [17]. In a meta-analysis of seven randomized trials and six prospective observational studies that compared treatment emergent mood elevation in bipolar I patients (n = 462) with bipolar II patients (n = 315), the risk of switching was greater in patients with bipolar I disorder (relative risk 1.8, 95% CI 1.2-2.6); there was little to no heterogeneity across studies [63]. In addition, switching has been associated with early age of onset of bipolar disorder, female sex, history of suicide attempts, symptoms of mania/hypomania concurrent with depression, and comorbid substance abuse and anxiety disorders [20-25]. However, these factors are generally not consistently associated with switching across multiple studies, and are likely to have little predictive power for any specific patient [26]. RISK OF RAPID CYCLING The possible risks of using antidepressants in bipolar depressed patients include increased mood cycle frequency and/or the development of rapid cycling, which is discussed separately. (See "Rapid cycling bipolar disorder: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Antidepressants'.) RISK OF SUICIDALITY For patients with bipolar depression, it is not clear if antidepressants cause new onset suicidal ideation and behavior. A review of prospective and retrospective observational studies found contradictory results [17]. Suicide deaths in particular are rare and thus difficult to examine in properly designed studies. SUMMARY Antidepressants (table 1) are the most commonly prescribed drugs for bipolar patients. The use of antidepressants for acute and maintenance treatment of bipolar depression is controversial because of concerns that these drugs are not effective, and may harm patients by causing switches from depression to mania as well as rapid cycling. (See 'Introduction' above.) Medication regimens for bipolar patients are selected according to the phase of the illness. (See "Bipolar disorder in adults: Pharmacotherapy for acute depression" and "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania" and "Bipolar disorder in adults: Maintenance treatment".) There is a limited role for antidepressants as adjuncts to antimanic drugs for treating patients with bipolar major depression. (See 'Role of antidepressants' above and "Bipolar disorder in adults: Pharmacotherapy for acute depression".) Antidepressant monotherapy should be avoided. Prescribing an antidepressant in conjunction with an antimanic drug such as lithium, valproate, carbamazepine, or a second-generation antipsychotic appears to decrease the probability of switching from bipolar major depression to mania/hypomania. (See 'Avoiding antidepressant monotherapy' above and 'Using antimanic drugs to prevent switching' above.) If manic or hypomanic symptoms emerge during antidepressant treatment, antidepressants should be abruptly stopped and antimanic treatments should be optimized. (See "Bipolar disorder in adults: 6 de 11 02/12/2013 04:39
Pharmacotherapy for acute mania, mixed episodes, and hypomania".) The efficacy of antidepressants collectively (as a drug class) for short term (eg, 4 to 26 weeks) treatment of bipolar I or II major depression is not clear. However, individual trials indicate that fluoxetine combined with olanzapine is effective, whereas paroxetine generally is not. (See 'Acute treatment' above.) For patients with bipolar depression who are treated with an antidepressant and then recover, maintenance treatment with antidepressants generally does not appear to reduce the risk of depressive relapses. (See 'Maintenance treatment' above.) Switching polarity often occurs in bipolar disorder in the absence of antidepressant treatment, and the evidence indicates that antidepressants collectively may not increase switching from bipolar major depression to mania/hypomania during acute or maintenance treatment. However, the risk of treatment emergent mania may nevertheless exist for patients who are treated with antidepressant monotherapy and patient subgroups (eg, bipolar I disorder). (See 'Risk of switching to mania' above and 'Clinical risk factors' above.) It is not established whether the risk of switching varies according to specific antidepressants. However, across different studies, the switch rate for venlafaxine was 13 to 15 percent, for tricyclics was 10 to 11 percent, and for selective serotonin reuptake inhibitors (SSRIs), bupropion, or placebo was 3 to 5 percent. (See 'Antidepressant class and specific drugs' above.) The possible risks of using antidepressants in bipolar depressed patients include increased mood cycle frequency and/or the development of rapid cycling. (See "Rapid cycling bipolar disorder: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Antidepressants'.) It is not clear whether antidepressants are associated with new onset suicidal ideation and behavior. (See 'Risk of suicidality' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 14655 Version 9.0
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GRAPHICS Unipolar depression in adults: Antidepressant doses*

Usual total starting dose per day (mg) Usual total dose per day (mg) Extreme daily dose range (mg)
Drug
Selective serotonin reuptake inhibitors Citalopram Escitalopram Fluoxetine Fluvoxamine Fluvoxamine CR Paroxetine Paroxetine CR Sertraline 20 10 20 50 100 20 25 50 20 to 40 10 to 20 20 to 60 50 to 200 100 to 200 20 to 40 25 to 50 50 to 200 10 to 40 5 to 30 10 to 80 25 to 300 100 to 300 10 to 50 12.5 to 62.5 25 to 300
Serotonin-norepinephrine reuptake inhibitors Desvenlafaxine Duloxetine Milnacipran Venlafaxine Venlafaxine XR Atypical agents Agomelatine (not available in United States) Bupropion Bupropion SR 12 hour Bupropion XL 24 hour 200 150 300 (maximum single dose 150 mg) 300 (maximum single dose 200 mg) 300 100 to 450 150 to 400 25 25 to 50 25 to 50 50 30 to 60 12.5 37.5 to 75 37.5 50 30 to 120 100 to 200 75 to 375 75 to 225 50 to 400 30 to 120 50 to 300 75 to 450 75 to 375
150
150 to 450 (United States) 150 to 300 (Europe)
Bupropion hydrobromide 24 hour Mirtazapine Serotonin modulators Nefazodone Trazodone Trazodone ER
174
348
174 to 522
15
15 to 45
7.5 to 60
200 100 150
300 to 600 200 to 500 375
50 to 600 100 to 600 150 to 375
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Vilazodone
10
40
10 to 40
Tricyclics and tetracyclics Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Maprotiline Nortriptyline Protriptyline Trimipramine 25 25 25 25 25 25 25 25 10 25 150 to 300 200 to 300 100 to 250 150 to 300 150 to 300 150 to 300 100 to 225 50 to 150 15 to 60 150 to 300 10 to 300 25 to 400 25 to 300 25 to 300 25 to 300 10 to 300 25 to 225 10 to 150 5 to 60 25 to 300
Monamine oxidase inhibitors Isocarboxazid Phenelzine Selegiline transdermal Tranylcypromine 10 15 6 mg/24 hour patch 10 10 to 40 15 to 90 6 to 12 mg/24 hour patch 30 to 60 10 to 60 7.5 to 90 6 to 12 mg/24 hour patch 10 to 60
* Total daily oral doses shown in table may need to be given as two or three equally divided doses per day, depending on specific antidepressant and other factors. For additional detail, refer to individual Lexicomp drug monographs included with UpToDate. Lower end doses may be useful for initiating or maintaining elderly, medically compromised (eg, renal or hepatic illness), or drug sensitive patients, as well as patients with a low body mass index. High doses may be used for medications that are well tolerated but ineffective at lower doses. Maximum recommended dose of citalopram is 20 mg for patients >60 years of age, with significant hepatic insufficiency, or taking interacting medications that can increase citalopram levels. For more information refer to the UpToDate topic on unipolar depression in adults and selective serotonin reuptake inhibitors. Although desvenlafaxine doses up to 400 mg per day have been studied, there is no evidence that doses >50 mg per day provide any additional benefit. Although duloxetine doses up to 120 mg per day have been used, there is no evidence that doses >60 mg per day provide any additional benefit in treatment of depression. Agomelatine may be hepatotoxic and is contraindicated with any degree of liver impairment. Transaminase monitoring is required according to the product information. Caution: can cause liver failure. Not available in Europe, Canada, and several other countries. Conservative starting doses shown in table are lower than starting doses shown in some other references. For additional information, refer to UpToDate topics on unipolar depression in adults and cyclic antidepressants and monoamine oxidase inhibitors for treatment of adults with depression. Data from: 1. The American Psychiatric Publishing Textbook of Psychopharmacology, 4th edition. Schatzberg AF, Nemeroff CB (eds); American Psychiatric Publishing, Inc. Washington, D.C. (2009). 2. Labbate LA, Fava M, Rosenbaum JF, Arana GW. Drugs for the treatment of depression. In: Handbook of Psychiatric Drug Therapy, 6th ed, Lippincott Williams and Wilkins, Philadelphia 2010. p.54. 3. Gartlehner G, Thaler K, Hill S, Hansen RA. How should primary care doctors select which antidepressants to administer? Curr Psychiatry Rep 2012; 14:360. 4. Lexicomp Online. Copyright 1978-2013 Lexicomp, Inc. All Rights Reserved.
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Mood disorder questionnaire

1. Has there ever been a period of time when you were not your usual self and... ...you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble? ...you were so irritable that you shouted at people or started fights or arguments? ...you felt much more self-confident than usual? ...you got much less sleep than usual and found you didn't really miss it? ...you were much more talkative or spoke faster than usual? ...thoughts raced through your head or you couldn't slow your mind down? ...you were so easily distracted by things around you that you had trouble concentrating or staying on track? ...you had much more energy than usual? ...you were much more active or did many more things than usual? ...you were much more social or outgoing than usual, for example, you telephoned friends in the middle of the night? ...you were much more interested in sex than usual? ...you did things that were unusual for you or that other people might have thought were excessive, foolish, or risky? ...spending money got you or your family into trouble? 2. If you checked YES to more than one of the above, have several of these ever happened during the same period of time? Please circle one response only. 3. How much of a problem did any of these cause you - like being unable to work; having family, money, or legal troubles; getting into arguments or fights? Please circle one response only. No problem Minor problem Moderate problem Serious problem Yes No Yes No
Patients screen positively for bipolar disorder if they answer "yes" to seven or more items in section 1, "yes" in section 2, and "moderate problem" or "serious problem" in section 3. The mood disorder questionnaire should not be used to diagnose bipolar disorder. Patients who screen positive should be interviewed to establish the diagnosis; including family members is often helpful.
Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry 2000; 157:1873. Reprinted with permission from the American Journal of Psychiatry (Copyright 2000). American Psychiatric Association.
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PHQ-9 depression questionnaire

Name:
Over the last two weeks, how often have you been bothered by any of the following problems? Little interest or pleasure in doing things Feeling down, depressed, or hopeless Trouble falling or staying asleep, or sleeping too much Feeling tired or having little energy Poor appetite or overeating Feeling bad about yourself, or that you are a failure, or have let yourself or your family down Trouble concentrating on things, such as reading the newspaper or watching television Moving or speaking so slowly that other people could have noticed? Or the opposite, being so 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 Total ___ = ___ + ___ + ___ + ___ 0 1 2 3 0 1 2 3 0 1 2 3 0 0 0 0 0 0 1 1 1 1 1 1
Date:
Not at all Several days More than half the days 2 2 2 2 2 2 3 3 3 3 3 3 Nearly every day
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 do your work, take care of things at home, or get along with other people? Not difficult at all ___ Somewhat difficult ___ Very difficult ___ Extremely difficult ___
PHQ-9 is adapted from PRIME MD TODAY, developed by Drs Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke, and collegues, with an educational grant from Pfizer Inc. For research information, contact Dr Spitzer at rls@columbia.edu. Use of the PHQ-9 may only be made in accordance with the Terms of Use available at www.pfizer.com. Copyright 1999 Pfizer Inc. All rights reserved. PRIME MD TODAY is a trademark of Pfizer Inc.
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