Bipolar Disorder in Adults - Pharmacotherapy For Acute Mania, Mixed Episodes, and Hypomania PDF

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Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania Author Jeffrey Stovall, 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: Ago 5, 2013. INTRODUCTION Bipolar disorder is marked by episodes of mania (table 1) and hypomania (table 2), as well as mixed episodes of concurrent major depression (table 3) and mania or hypomania [1]. Despite clinical differences among manic, hypomanic, and mixed episodes, for the purpose of treatment they are considered to be similar and thus treated with the same medications [2-4]. This topic reviews treatment of acute mania, mixed episodes, and hypomania. Treatment of acute bipolar depression and maintenance treatment are discussed separately. (See "Bipolar disorder in adults: Pharmacotherapy for acute depression" and "Bipolar disorder in adults: Maintenance treatment".) DEFINITIONS Bipolar disorder is a mood disorder that is characterized by periods of pathologic mood elevation (mania or hypomania) [1]. Patients with bipolar I disorder experience manic episodes (table 1) or mixed episodes (major depression concurrent with mania), and nearly always experience major depressive episodes (table 3). The clinical course of bipolar II disorder is characterized by at least one episode of hypomania (table 2), and one or more major depressive episodes. Despite clinical differences among manic, hypomanic, and mixed episodes (eg, hypomania is less severe than mania), for the purpose of treatment they are considered to be similar and thus treated with the same medications [2-4]. The clinical features and diagnosis of bipolar disorder are discussed separately. (See "Bipolar disorder in adults: Clinical features" and "Bipolar disorder in adults: Assessment and diagnosis".) Pharmacotherapy for mania or mixed episodes depends upon their severity. Although there are no established criteria that demarcate severe episodes from mild to moderate illness, we classify episodes as severe if they include any of the following: Suicidal ideation or behavior Homicidal ideation or behavior Aggressive behavior Psychotic features (ie, delusions or hallucinations) Poor judgement that places the patient or others at imminent risk of being harmed TREATMENT Despite clinical differences among manic, hypomanic, and mixed episodes (eg, hypomania is less severe than mania), for the purpose of treatment they are considered to be similar and thus treated with the same medications [2-6]. Goal The goal of treating acute manic, hypomanic, and mixed episodes is remission, which is defined as resolution of the mood symptoms or improvement to the point that only one or two symptoms of mild intensity persist. If psychotic features (delusions or hallucinations) are also present, resolution of the psychosis is required for remission. For patients who do not achieve remission, a reasonable goal is response, which is defined as stabilization of the patients safety and substantial improvement in the number, intensity, and frequency of mood (and psychotic) symptoms. A standardized rating scale, such as the Young Mania Rating Scale, can be used to quantify response [7], although this is not standard clinical practice. General principles Treatment of mood elevated syndromes (ie, manic, hypomanic, and mixed episodes) begins with an initial psychiatric history and mental status examination that emphasizes symptoms of the mood episode, Section Editor Paul Keck, MD Deputy Editor David Solomon, MD
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particularly risk of suicide, aggressiveness, and violence to others [2,3,8]. The assessment should also pursue comorbid disorders (eg, substance use disorders) that require treatment. The evaluation includes a general medical history, physical examination, and focused laboratory studies to establish whether the mood syndrome is due to the direct physiologic effects of a general medical condition, and to rule out any contraindications to treatment (eg, renal impairment and use of lithium, or hepatic disease and use of valproate). Additional information about the assessment for bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Assessment and diagnosis", section on 'Assessment'.) Patients who suffer mania, hypomania, or a mixed episode during maintenance pharmacotherapy should be assessed for adherence to treatment and are initially treated by optimizing medication doses [2,9,10]. This includes ensuring serum concentrations are in the therapeutic range for medications such as lithium or valproate, as well as increasing the dose to achieve a higher serum level within the therapeutic range, provided that side effects do not intervene. For medications that do not have an established therapeutic serum concentration, such as antipsychotics, the dose can be increased within the target dose range. Substances may cause or exacerbate a mood elevated syndrome. Thus, antidepressants should be abruptly discontinued, and patients should discontinue drugs of abuse and reduce or eliminate their use of alcohol, caffeine, and nicotine. Evidence for the efficacy of treating mood elevated syndromes is primarily based upon randomized trials with bipolar I manic patients, although the majority of trials included some patients with mixed episodes [11,12]. Even though bipolar II disorder is more prevalent than bipolar I disorder, relatively little research has focused specifically on treating hypomania [13,14]. Many randomized trials either exclude patients with bipolar II disorder or lump them together with bipolar I patients in the analyses. Setting and monitoring The treatment setting for manic, hypomanic, or mixed episode patients depends upon the severity of symptoms, comorbid psychopathology (eg, substance use disorder), level of psychosocial functioning, and available support: Inpatient Hospitalization may be required for managing the patients safety and symptoms such as suicidal ideation with a specific plan and intent, delusions or hallucinations, and poor judgment that poses an imminent risk to the patient and others Partial hospital Moderately ill patients can often be treated in a partial hospital (day) program, including patients with suicidality that does not pose an imminent risk (eg, fleeting thoughts of killing oneself, vague or nonexistent plans, and no intent) Outpatient Outpatient care may be suitable for less acutely ill patients (eg, thoughts that family members would be better off if the patient was dead, with no plan or intent to commit suicide) For outpatient treatment of bipolar disorder, specialized mood disorder clinics may be preferable to general (standard) psychiatric clinics early in the course of illness. An open label, two year, randomized trial compared a mood disorder clinic (staffed by a cross-disciplinary team who administered pharmacotherapy and group psychoeducation) with standard care (pharmacotherapy provided at a local community health center or at a psychiatrists office) in 158 bipolar patients who were discharged from their first, second, or third inpatient admission [15]. Readmission to the hospital occurred in more patients who received standard care than specialized care (55 versus 36 percent). In addition, the median duration of the readmission was nearly twice as long for patients who had received standard care rather than specialized care (22 versus 12 days). The frequency of assessment generally ranges from daily to monthly, depending upon the severity of persistent symptoms. Hospitalized patients are monitored daily, and patients with active suicidal ideation, a specific plan, and intent to kill themselves may require constant observation. Outpatients who have responded less than 50 percent are generally seen weekly; those who have responded 50 percent or more may be seen every two to four weeks until they remit. Drug classes Based upon randomized trials, drug classes commonly used to treat acute mania, mixed episodes, or hypomania include:
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Lithium Anticonvulsants Antipsychotics Benzodiazepines The mainstays of treatment are lithium, anticonvulsants, and antipsychotics used in combination pharmacotherapy (eg, lithium plus an antipsychotic) or as monotherapy, depending upon the severity of symptoms. Benzodiazepines are primarily used as adjunctive treatment for insomnia, agitation, or anxiety. Treatment of insomnia, agitation, and anxiety are discussed separately. (See "Treatment of insomnia" and "Assessment and management of the acutely agitated or violent adult" and "Pharmacotherapy for generalized anxiety disorder".) Duration Although it is not established how long clinicians should wait to assess the benefit of a medication regimen, it is reasonable to allow up to two weeks for a treatment trial [4]. Most randomized trials last three weeks, and the superior efficacy of active drugs compared with placebo generally begins to manifest within one week. In a post hoc analysis of a randomized trial that treated manic or mixed episode patients with olanzapine or risperidone, improvement at week one was evaluated as a predictor of either remission or response (improvement from baseline on the mania rating scale 50 percent) at week three [16]. Among 234 patients with improvement 25 percent at week one, 52 percent remitted and 71 percent responded at week three. Conversely, of the 40 patients with <25 percent improvement at week one, 5 percent remitted and 25 percent responded at week three. Predictors of response Subgroups of manic or mixed episode patients who respond more favorably to pharmacotherapy have not been identified. One study involving olanzapine found that response (improvement from baseline on the mania rating scale 50 percent) was comparable for manic and mixed episodes, as well as psychotic and nonpsychotic episodes [17]. Response was also independent of rapid cycling (four or more mood episodes in the past 12 months), lifetime number of mood episodes, and history of lifetime comorbid substance use disorder. It is not clear if subgroups of manic or mixed episode patients respond preferentially to a specific drug. Some studies have found that patients with mixed episodes or a greater lifetime number of mood episodes did better with valproate than lithium [13,18-20], and that improvement of rapid cycling was superior with valproate or carbamazepine than lithium [9]. Severe manic and mixed episodes Severe manic or mixed episodes are characterized by suicidal or homicidal ideation or behavior, aggressiveness, psychotic features (ie, delusions or hallucinations), and poor judgement that places the patient or others at imminent risk of being harmed. Severely ill patients generally require hospitalization. First line medication combinations Severely ill patients with acute mania or mixed episodes typically require treatment with a medication combination [2,4,21]. We suggest lithium plus an antipsychotic; however, valproate plus an antipsychotic is a reasonable alternative. We generally combine lithium or valproate with aripiprazole, haloperidol (or another first-generation antipsychotic), olanzapine, quetiapine, or risperidone. In addition, we generally avoid using adjunctive ziprasidone [22]. No head-to-head trials have compared antipsychotics in combination with lithium or valproate. Thus, the choice between lithium and valproate, and the choice of an antipsychotic is based upon other factors, including past response to medications, side effect profiles, comorbid general medical conditions, potential for drug-drug interactions, patient preference, and cost. Evidence for the efficacy of lithium or valproate plus an antipsychotic includes a review of 20 randomized trials, which estimated that the rate of response (improvement from baseline on the mania rating scale 50 percent) with lithium or valproate plus aripiprazole, olanzapine, quetiapine, or risperidone was 20 percent higher compared with lithium or valproate alone [23]. In addition, time to response was significantly shorter. Other evidence supporting lithium or valproate plus an antipsychotic includes the following: A meta-analysis of 8 randomized trials (1124 manic or mixed episode patients) compared haloperidol, olanzapine, quetiapine, or risperidone with placebo as adjunctive treatment for patients who did not respond to lithium, valproate, or carbamazepine monotherapy [24]. Improvement was significantly greater in patients who received an adjunctive antipsychotic.
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Two other meta-analyses of 6 randomized trials (1396 manic or mixed episode patients) compared second generation antipsychotics (including olanzapine, quetiapine, or risperidone) with placebo as adjunctive treatment for patients who did not respond to lithium, valproate, or carbamazepine monotherapy [12,25]. In both studies, improvement was significantly greater with the antipsychotic than placebo. In addition, dropout due to adverse events was comparable for the two groups [12]. However, adjunctive antipsychotics caused significantly greater weight gain, somnolence, and extrapyramidal symptoms. A subsequent randomized trial compared aripiprazole with placebo as add-on treatment to lithium or valproate in 377 patients [26]. Remission occurred in significantly more patients who received aripiprazole compared with placebo (66 versus 51 percent). However, aripiprazole caused significantly higher rates of akathisia (19 versus 5 percent). Combination pharmacotherapy for severe manic or mixed episodes is endorsed by several treatment guidelines [2,4,21]. However, adding ziprasidone to lithium or divalproex is not efficacious, based upon two randomized trials [12,22]. As an example, a three week trial assigned 656 patients with manic or mixed episodes who had not responded to either lithium or divalproex to receive adjunctive treatment twice per day with ziprasidone 20 to 40 mg, ziprasidone 60 to 80 mg, or placebo [22]. Neither high dose nor low dose ziprasidone provided any benefit. In addition, we generally avoid combining carbamazepine with an antipsychotic, based upon randomized trials that found this combination is no more efficacious than carbamazepine alone [27,28]. Carbamazepine induces hepatic enzymes that metabolize antipsychotics, and in one trial lowered the antipsychotic blood level by 40 percent [28]. When prescribing a medication combination, both drugs are started and titrated up simultaneously. The doses and side effects of lithium, valproate, and antipsychotics are discussed elsewhere in this topic. (See 'Medication doses and side effects' below.) Specific medication interactions that can occur may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions. Patients who cannot tolerate combination pharmacotherapy are treated with monotherapy. (See 'First line monotherapy' below.) Resistant patients A severe manic or mixed episode that does not respond to one medication combination should be treated with a second medication combination. Generally, lithium is switched to valproate or vice versa. As an example, for patients who do not respond to lithium plus haloperidol within two weeks of reaching target doses, we suggest tapering and discontinuing lithium at the same time that valproate is started and titrated up. Lithium is generally tapered over one week by the same amount for each dose decrease (eg, lithium 1800 mg per day is decreased by 600 mg per day, every one to two days). The dose and side effects of lithium and valproate are discussed separately. (See 'Lithium' below and 'Anticonvulsants' below.) Conversely, for patients who do not respond to valproate plus haloperidol within two weeks of reaching target doses, we suggest tapering and discontinuing valproate at the same time that lithium is started and titrated up. Valproate is generally tapered over one week by the same amount for each dose decrease (eg, valproate 2000 mg per day is decreased by 500 mg per day, every one to two days). For patients who do not respond to lithium plus an antipsychotic or to valproate plus the same antipsychotic, we suggest starting a third medication combination involving lithium or valproate plus an antipsychotic. The choice between lithium and valproate is based upon efficacy and tolerability in the two prior trials. In addition, the antipsychotic used in the two prior trials is discontinued and a new one chosen from amongst aripiprazole, haloperidol (or another first-generation antipsychotic), olanzapine, quetiapine, risperidone, or ziprasidone. No head-to-head trials have compared antipsychotics in combination with lithium or valproate; thus, the choice of an antipsychotic is based upon other factors, including past response to medications, side effect profiles, comorbid general medical conditions, potential for drug-drug interactions, patient preference, and cost. The antipsychotic is generally tapered over one week by the same amount for each dose decrease (eg,
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haloperidol 10 mg per day is decreased by 5 mg per day, every one to two days), and at the same time, the other antipsychotic is started and titrated up. The dose and side effects of antipsychotics are discussed separately. (See 'Antipsychotics' below.) Refractory patients Electroconvulsive therapy We suggest electroconvulsive therapy (ECT) for refractory patients whose manic or mixed episode does not respond to four to six medication combinations [4,29,30]. In one controlled trial of 30 manic patients, improvement occurred in significantly more patients who received ECT plus chlorpromazine compared with patients who received simulated ECT plus chlorpromazine (80 versus 7 percent) [31]. ECT is generally safe and there are no absolute contraindications, even in patients whose general medical status is compromised [32]. However, safety concerns regarding ECT necessitate preprocedure medical consultation. Adverse effects include cardiopulmonary events, aspiration pneumonia, fractures, dental and tongue injuries, headache, nausea, and cognitive impairment. Medical consultation prior to ECT is discussed separately. (See "Medical consultation for electroconvulsive therapy".) Electrode placement and other aspects of ECT technique for treating geriatric bipolar disorder have not been standardized. Thus, ECT is typically administered with the same technique used for other indications and is generally given three times per week on alternating days. Most patients, regardless of indication, remit with 6 to 12 treatments, but some patients may require 20 or more. Additional information about ECT is discussed separately. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Technique for performing electroconvulsive therapy (ECT) in adults".) Other medications For patients with refractory manic or mixed episodes who decline ECT, do not remit with it, or have no access to it, and who do not respond to medication combinations involving lithium or valproate plus aripiprazole, haloperidol (or another first-generation antipsychotic), olanzapine, quetiapine, risperidone, or ziprasidone, we suggest pharmacotherapy with lithium or valproate plus asenapine, clozapine, or paliperidone [33-38]. Patients unresponsive to lithium or valproate plus asenapine, clozapine, or paliperidone may possibly benefit from allopurinol plus lithium, tamoxifen monotherapy, and tamoxifen plus lithium [39-43]. No head-to-head trials have compared these other medication options. Thus, the choice is based upon other factors, including past response to medications, side effect profiles, comorbid general medical conditions, potential for drug-drug interactions, patient preference, and cost. In randomized trials with 977 manic or mixed episode patients, asenapine 5 to 10 mg two times per day was more efficacious than placebo, but much less efficacious than olanzapine 5 to 20 mg once per day [34,35]. Common side effects of asenapine include sedation, fatigue, dizziness, extrapyramidal symptoms, vomiting, dry mouth, and weight gain [34,35]. Additional information about asenapine is discussed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".) Limited evidence suggests that clozapine may ameliorate refractory manic or mixed episodes [33,36,37]. Clozapine is started at a dose of 12.5 or 25 mg at bedtime, and then increased by 25 mg per day every two days as tolerated, to a target dose of 150 to 450 mg two times per day. However, clozapine can cause agranulocytosis and other blood dyscrasias, and clinicians must monitor complete blood counts every one or two weeks. Clozapine is also associated with the metabolic syndrome. Thus, patients taking clozapine should be regularly monitored for weight, waist circumference, blood pressure, and serum glucose and lipids. Additional information about clozapine is discussed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Clozapine'.) Paliperidone has demonstrated inconsistent benefits in patients with acute manic and mixed episodes. A randomized trial compared paliperidone (flexibly dosed 3 to 12 mg per day) with placebo in 268 patients with a manic or mixed episode, and found that remission occurred in significantly more patients who received paliperidone than placebo (52 versus 29 percent) [38]. However, a second randomized trial found remission did not differ significantly between the groups who received fixed doses of paliperidone 3 mg, 6 mg, or 12 mg, and the group that received placebo (37 or 42 or 45 versus 37 percent) [44]. A third randomized trial found that among patients with an inadequate response to lithium or valproate monotherapy, there was no significant difference between adjunctive paliperidone and adjunctive placebo [45]. The most common adverse events with paliperidone are headache, somnolence, dizziness, akathisia, hypertonia, and dyspepsia. Additional information about paliperidone
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is discussed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Paliperidone'.) Allopurinol, which is typically used to prevent attacks of gouty arthritis and nephropathy, has been studied as an option for treating mania [46], based upon observations that adenosine, a purine compound and neuromodulator, is metabolized to uric acid, and that increased uric acid turnover is related to remission of mania [39,47]. A meta-analysis of three randomized trials compared allopurinol with placebo as adjunctive treatment in 186 manic patients, and found a significant, clinically moderate advantage favoring active drug; there was little to no heterogeneity across studies [48]. In addition, discontinuation due to side effects was comparable. Tamoxifen is a centrally active protein kinase C inhibitor that has demonstrated efficacy for treating manic and mixed episodes in several small randomized trials [40-43]. The largest compared tamoxifen (20 to 40 mg two times per day) with placebo in 66 patients [40]. Response (improvement from baseline on the mania rating scale 50 percent) occurred in significantly more patients who received tamoxifen than placebo (48 versus 5 percent), as did remission (28 versus 0 percent). Tamoxifen is widely used to prevent breast cancer because it is a selective estrogen receptor antagonist, and these antiestrogen effects preclude its use beyond patients unresponsive to most or all other treatments. There is little or no evidence to support treating acute mania or mixed episodes with anticonvulsants other than valproate and carbamazepine. Lamotrigine, gabapentin, and topiramate are not effective for treating mania [49-54]. In addition, a systematic review found that there was insufficient evidence to evaluate the anticonvulsant tiagabine, and results from available case series are conflicting [55]. Nor do we suggest oxcarbazepine, which has been substituted for carbamazepine to treat mania because their molecular structures are similar and oxcarbazepine has fewer side effects. There is no high quality evidence that oxcarbazepine has any benefit in adults [56]. In addition, a randomized trial found that oxcarbazepine was comparable with placebo in 116 manic or mixed episode children and adolescents [57]. Mild to moderate illness Mild to moderate illness is marked by the absence of suicidal or homicidal ideation or behavior, aggressiveness, psychotic features (ie, delusions or hallucinations), and poor judgement that places the patient or others at imminent risk of being harmed. Monotherapy is commonly used for initial treatment of hypomania and mild to moderate manic and mixed episodes. First line monotherapy For patients with hypomania and mild to moderate manic and mixed episodes, we suggest monotherapy with risperidone or olanzapine, based upon efficacy and tolerability [54]. However, reasonable alternatives include aripiprazole, carbamazepine, haloperidol, lithium, quetiapine, valproate, or ziprasidone. Doses and side effects are discussed elsewhere in the topic. (See 'Medication doses and side effects' below.) A multiple-treatments meta-analysis of 68 randomized trials (16,073 patients with an acute manic or mixed episode, treated for three weeks) found that aripiprazole, carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone, valproate, and ziprasidone were each significantly more efficacious than placebo [54]. In addition, the meta-analysis ranked these drugs by efficacy, using indirect comparisons of the drugs (through their relative effect with a common comparator, typically placebo), as well as analyzing direct comparisons between drugs. Beginning with the most efficacious drug, the rank order for efficacy was: Haloperidol Risperidone Olanzapine Aripiprazole Carbamazepine Lithium Quetiapine Valproate (or divalproex) Ziprasidone Further, the meta-analysis ranked the drugs by frequency of treatment discontinuation for any reason, including adverse effects and lack of efficacy. Beginning with the drug with the lowest rate of dropout, the rank order was:
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Olanzapine Risperidone Quetiapine Valproate Carbamazepine Aripiprazole Haloperidol Ziprasidone Lithium The indirect comparisons distinguish this multiple-treatments meta-analysis from smaller, conventional meta-analyses, which concluded that efficacy was comparable for aripiprazole, carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone, valproate, and ziprasidone [11,12,25,58]. Although substantial uncertainties are introduced when these sorts of rank orders are created through a multiple-treatments meta-analysis, this is probably the best evidence for comparing drugs for acute hypomania and mild to moderate manic and mixed episodes. While it is not clear that there are meaningful differences between adjacently ranked medications, drugs near the top of the rank order are probably superior to those near the bottom of the rank order. Multiple-treatments meta-analysis is discussed separately. (See "Systematic review and meta-analysis", section on 'Network meta-analysis'.) Clinicians should consider factors other than the rank order of efficacy and treatment discontinuation when choosing a drug, including the patients past response to medications, the past response of family members with bipolar disorder to medications, specific symptoms, adverse drug effects, comorbid medical illnesses, concurrent medications, and cost. As an example, lithium is generally avoided in patients with significant renal disease, valproate in patients with liver disease, and olanzapine in obese patients. In addition, carbamazepine may be difficult to use because of its tendency to increase metabolism of concomitant medications. Medication side effects are discussed separately. (See 'Medication doses and side effects' below and "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects", section on 'Lithium side effects' and "Pharmacology of antiepileptic drugs" and "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".) The long-term implications of choosing a drug also need to be considered; all patients with bipolar disorder should receive maintenance treatment, which commonly consists of the drug used to induce remission. As an example, maintenance lithium is common because it has been widely studied and is efficacious [59,60], and long-term treatment with lithium may reduce the risk of suicide attempts and deaths [61-64]. By contrast, haloperidol is generally not used in maintenance treatment because it can cause movement disorders and may increase the risk of bipolar major depression [65,66]. Maintenance treatment is discussed separately. (See "Bipolar disorder in adults: Maintenance treatment", section on 'Reduced risk of suicide'.) For mildly to moderately ill patients who do not respond to treatment with one monotherapy trial within two weeks of reaching the target dose, or do not tolerate the drug, we suggest tapering and discontinuing the failed medication over one week at the same time that another monotherapy is started and titrated up. The failed medication is generally tapered by the same amount for each dose decrease. As an example, quetiapine 600 mg per day is decreased by 100 to 200 mg per day, every one to two days. Treatment resistance For hypomanic and mild to moderate manic and mixed episodes that do not respond to three to five monotherapy trials involving aripiprazole, carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone, valproate, and ziprasidone, we suggest combining lithium or valproate with an antipsychotic. However, lithium plus valproate is a reasonable alternative [67,68]. Medication combinations involving lithium or valproate plus an antipsychotic are discussed elsewhere in the topic. (See 'First line medication combinations' above.) Benzodiazepines We suggest clonazepam for patients who have hypomanic or mild to moderate manic or mixed episodes and cannot tolerate lithium, anticonvulsants, or antipsychotics. However, lorazepam is a reasonable alternative. Monotherapy with a benzodiazepine is unusual due to the large number of available medication options for manic, hypomanic, or mixed episodes; benzodiazepines are generally used as adjunctive
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therapy to treat insomnia, agitation, or anxiety in patients with pathologic mood elevated syndromes. Given the high rate of substance use disorders among bipolar patients and the potential for abusing benzodiazepines, these drugs are generally limited to acute treatment [69]. Clonazepam is usually started at a dose of 1 to 3 mg per day, taken in two divided doses. The drug is generally titrated up to a target dose ranging from 2 to 6 mg per day, depending upon efficacy and tolerability, although doses as high as 24 mg per day have been used [70]. Side effects include disinhibition, sedation, and respiratory depression. Lorazepam is usually started at a dose of 2 to 4 mg per day, taken in three to four divided doses. The drug is generally titrated up to a target dose ranging from 3 to 8 mg per day, depending upon efficacy and tolerability, although doses as high as 24 mg per day have been used [70]. Side effects include disinhibition, sedation, and respiratory depression. Evidence of efficacy includes a meta-analysis of five heterogeneous randomized trials (122 manic patients), which found that clonazepam monotherapy (2 to 24 mg per day) was efficacious [70]. The same study analyzed four heterogeneous randomized trials (108 manic patients) involving lorazepam (4 to 24 mg per day) and found that it was not effective. However, one randomized trial directly compared lorazepam (mean daily dose 13 mg) with clonazepam (mean daily dose 14 mg) in 24 manic patients, and found that moderate to marked improvement occurred in significantly more patients who received lorazepam than clonazepam (63 versus 18 percent), as did remission (38 versus 0 percent) [71]. The frequency of side effects does not differ between the two drugs [70]. The pharmacology and abuse of benzodiazepines are discussed elsewhere. Medication doses and side effects Lithium The starting dose of lithium is usually 300 mg two or three times daily; smaller doses (eg, 150 mg twice daily) are used in the elderly [69,72-74]. The dose should be increased by 300 to 600 mg every one to five days based upon response, tolerability, and body mass index. The goal is to reach a therapeutic serum level, which generally occurs with a dose of 900 mg to 1800 mg per day. Dose increases generally occur more frequently at the beginning of treatment, and less often as clinicians approach the target dose. Additional information about the dose of lithium is discussed elsewhere. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects", section on 'Lithium dose and serum concentrations' and "Geriatric bipolar disorder: Acute treatment", section on 'First line medications'.) The target serum level for acute treatment is between 0.8 and 1.2 meq/L; levels should not exceed 1.2 meq/L to reduce the risk of toxicity [73]. Patients who cannot tolerate a level of 0.8 meq/L may respond to a level of 0.6 meq/L. Lithium levels should be measured five to seven days after each dose increase. Levels are drawn 12 hours after the last dose (12-hour serum trough level) and generally collected in the morning, before the first dose of the day. Additional information about lithium serum levels is discussed elsewhere. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects", section on 'Lithium dose and serum concentrations'.) Lithium can cause many acute and long-term adverse effects. The most common acute side effects are nausea, tremor, polyuria and thirst, weight gain, loose stools, and cognitive impairment [74-76]. Severe or sudden worsening of acute side effects may be a sign of lithium toxicity. Over the long term, lithium can adversely affect the kidneys and thyroid gland. In addition, cardiac rhythm disturbances have been described; these almost always occur in patients with preexisting cardiac disease. Additional information about side effects and how to manage them is discussed elsewhere: (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects", section on 'Lithium side effects'.) (See "Lithium poisoning".) (See "Renal toxicity of lithium".) (See "Lithium and the thyroid".) Contraindications to lithium, lithium toxicity, drug interactions with lithium, the different available preparations of lithium, and laboratory tests and monitoring are discussed elsewhere. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects".)
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Anticonvulsants Anticonvulsants that are efficacious for acute mania, mixed episodes, and hypomania include valproate and carbamazepine. Suicidality Bipolar disorder is associated with an increased risk of suicide deaths [77], and all patients should be monitored for emergence or worsening of suicidal thoughts and behavior. Although some observational studies suggest that anticonvulsants may increase the risk of suicidal ideation or behavior, these drugs are generally safe to use when patients are regularly monitored. The US Food and Drug Administration warned clinicians that anticonvulsants are associated with an increased risk of suicidal thoughts and behavior, based upon a pooled analysis of 199 controlled trials that included 43,892 patients with a variety of illnesses [78]. In addition, a separate exploratory analysis of a medical and pharmacy claims database that included 297,620 new episodes of treatment with an anticonvulsant suggested that gabapentin, lamotrigine, oxcarbazepine, and tiagabine may be associated with an increased risk of suicidal acts or violent deaths, compared with topiramate [79]. However, an analysis of a different national claims database that involved 47,918 patients diagnosed specifically with bipolar disorder found [80]: The frequency of suicide attempts in patients treated with antiepileptic drugs and patients not receiving antiepileptic drugs was comparable For patients treated with antiepileptic drugs, the rate of suicide attempts was greater before treatment than after treatment Patients receiving antiepileptic drug monotherapy (and no concomitant antidepressant or antipsychotic) had fewer suicide attempts compared to patients receiving no pharmacotherapy Other observational studies have found that antiepileptics were not associated with an increased risk of suicidal behavior in bipolar patients [81]. As an example, analyses using a national database with over 5,000,000 patients found that among patients with bipolar disorder, treatment with antiepileptic drugs was not associated with an increased risk of suicide attempts [82]. Valproate or divalproex Valproate is usually started at a dose of 250 mg two or three times per day. The dose is increased by 250 mg to 500 mg every one to three days as tolerated to reach a therapeutic serum level, which generally occurs with 1500 mg to 2500 mg per day [74,83]. Valproate is usually administered twice daily (although a once-a-day formulation is available in the United States). Oral loading and rapid titration to a full dose within one to two days by prescribing 20 mg/kg/day may result in earlier improvement in symptoms and a reduced need for adjunctive antipsychotics or benzodiazepines [84]. We suggest drawing valproate serum levels two to five days after each dose increase and prescribing the drug to achieve a target serum level between 50 and 125 mcg/mL. Levels should be drawn 12 hours after the last dose and generally collected in the morning, before the first dose of the day. A post hoc analysis of pooled data from three controlled trials (374 acutely manic inpatients) found that efficacy increased as serum levels increased [85]. In addition, the efficacy of valproate was significantly greater than placebo for levels 71 mcg/mL, and the largest clinical effect for valproate occurred in patients with a mean serum level of 88 mcg/mL. Levels should be checked at 6 to 12 month intervals, and are particularly useful in patients receiving medications that affect valproate concentrations and to confirm problems with adherence. Some patients may not require regular valproate levels, and one review concluded that clinical observation of efficacy and toxicity can be used to guide some dose adjustments [86]. Common side effects of valproate include weight gain, nausea, vomiting, hair loss, easy bruising, and tremor. Divalproex is a formulation of valproate that can minimize gastrointestinal distress. Valproate is rarely associated with hepatic failure and thrombocytopenia; liver function tests and platelets should thus be monitored at 6 to 12 month intervals in all patients taking the drug [33,69,87]. (The US Food and Drug Administration recommends checking liver function tests prior to initiating treatment and at frequent intervals thereafter, especially during the first six months.) In addition, valproate rarely causes pancreatitis; symptoms of abdominal pain and vomiting should prompt an assessment that includes a serum amylase and lipase.
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Additional information about the pharmacology of valproate and its adverse effects and available preparations are discussed separately. (See "Pharmacology of antiepileptic drugs", section on 'Valproate'.) Carbamazepine Carbamazepine is usually started at a dose of 100 mg to 200 mg one or two times per day [74,88]. The dose should be increased by 200 mg per day every one to four days, to a final dose of about 800 to 1000 mg per day, although the effective dose may range between 200 and 1800 mg per day. Carbamazepine is typically administered twice daily. Therapeutic serum levels have not been established for treating acute manic or mixed episodes. However, many clinicians aim for a level of 4 to 12 mcg/mL, which is the target range established for treating epilepsy. Extended release formulations are better tolerated in patients with bipolar disorder [89]. The major systemic side effects of carbamazepine are nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, leukopenia, and fluid retention. In addition, the drug is associated with life-threatening rashes (Stevens-Johnson syndrome and toxic epidermal necrolysis), particularly during the first eight weeks of therapy [90]. This reaction is significantly more common in patients with the HLA-B*1502 allele (estimated incidence of 5 percent), which occurs almost exclusively in patients of Asian ancestry, including South Asian Indians [91-93]. The US Food and Drug Administration recommends screening for this allele in patients of these ethnic groups prior to starting carbamazepine [94]. Neurotoxicity includes drowsiness, dizziness, blurred or double vision, lethargy, and headache. Carbamazepine also induces liver enzymes and frequently causes drug-drug interactions that result in lower serum concentrations of concomitant drugs [33,69,87]. This induction of liver enzymes often decreases serum concentrations of carbamazepine. Liver function tests and a complete blood count, serum sodium, and serum carbamazepine level are recommended every 6 to 12 months. The pharmacology of carbamazepine and its adverse effects and available preparations are discussed in greater detail elsewhere. (See "Pharmacology of antiepileptic drugs", section on 'Carbamazepine'.) Antipsychotics First- and second-generation antipsychotics are efficacious for treating both psychotic and nonpsychotic manic and mixed episodes, as well as hypomania [2,3,11,12,21,24,25,95]. First-generation Among first-generation antipsychotics, we prefer haloperidol for treating manic and mixed episodes because it has been widely studied and generally causes less orthostatic hypotension and sedation than chlorpromazine, which is also efficacious [58,96]. Other first-generation antipsychotics such as fluphenazine, loxapine, perphenazine, thiothixene, and trifluoperazine are effective as well [97]. We suggest patients initially receive haloperidol at a dose of 5 to 15 mg per day, depending upon the severity of symptoms, the patients body mass index, and adverse effects that emerge. The drug is taken either once per day or in two divided doses, depending upon tolerability and the patients ability to adhere to treatment with divided doses. One useful guide is to prescribe 0.2 mg per kg per day [98]. In a meta-analysis of 15 randomized trials (2022 patients with acute manic or mixed episodes), which found that haloperidol was comparable to carbamazepine, olanzapine, risperidone, and valproate, the dose of haloperidol ranged from 2 to 85 mg per day [58]. Conventional antipsychotics are associated with extrapyramidal symptoms, akathisia, and tardive dyskinesia. Extrapyramidal symptoms are usually managed by lowering the dose of the antipsychotic or by adding an anticholinergic drug, either benztropine 1 to 2 mg two to four times daily or trihexyphenidyl 2 to 5 mg two to four times daily. Although switching from mania to depression has been attributed to first-generation antipsychotics, the evidence is not clear. A meta-analysis of six randomized trials (1774 manic patients; heterogeneity across studies was moderate) compared haloperidol with second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone), and found that treatment emergent depression was comparable for patients who received haloperidol or second-generation antipsychotics (10 and 7 percent) [99]. However, a second analysis that excluded one outlier trial (and eliminated the heterogeneity) found that depressive switches occurred in more patients treated with haloperidol (12 versus 7 percent). In assessing patients treated with an antipsychotic, clinicians should distinguish between switching to a depressive syndrome and the side effect of affective blunting or flattening. The pharmacology, administration, and side effects of first-generation antipsychotics are discussed elsewhere. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and
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"Neuroleptic malignant syndrome" and "Tardive dyskinesia: Etiology and epidemiology".) Second-generation Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone are each efficacious for treating manic, hypomanic, and mixed episodes [54], and the choice often depends upon differences in adverse side effects. Metabolic problems such as weight gain, glucose intolerance, diabetes mellitus, and hyperlipidemia are most likely to occur with olanzapine, followed by quetiapine and risperidone. Thus, patients taking olanzapine, quetiapine, and risperidone should be regularly monitored for weight, waist circumference, blood pressure, and serum glucose and lipids. Extrapyramidal side effects (EPS) are more common with aripiprazole, risperidone, or ziprasidone compared with olanzapine or quetiapine. The metabolic syndrome and EPS are discussed separately. (See "The metabolic syndrome (insulin resistance syndrome or syndrome X)" and "Pharmacotherapy for schizophrenia: Side effect management".) The usual starting and target dose for second-generation antipsychotics and common side effects that occurred in randomized monotherapy trials are described below [74,100]. Target doses can generally be achieved within one week of starting the medication. Some drugs are available as oral dissolvable formulations for patients who pretend to swallow their pills (cheek) and spit them out later when the clinician is not looking. Aripiprazole Aripiprazole is started at a dose of 10 to 30 mg once daily. The usual target dose is 15 to 45 mg taken once per day. Common side effects include headache, nausea, vomiting, constipation, insomnia, and akathisia. An oral dissolvable formulation is available. Olanzapine Olanzapine is started at a dose of 10 to 15 mg once daily or in two divided doses. The usual target dose is 10 to 30 mg per day, taken at bedtime or in two divided doses. Some patients may require and tolerate 40 or 50 mg per day. Common side effects include sedation, constipation, dry mouth, increased appetite, weight gain, and orthostatic hypotension. An oral dissolvable formulation is available. Quetiapine Quetiapine is started at a dose of 100 to 200 mg once daily or in two divided doses. The usual target dose is 400 to 800 mg taken at bedtime or in two divided doses. Some patients may require and tolerate 1000 or 1200 mg per day. Common side effects include headache, dry mouth, constipation, weight gain, sedation, dizziness, and orthostatic hypotension. Risperidone Risperidone is started at a dose of 1 to 2 mg once daily or in two divided doses. The usual target dose is 4 to 8 mg per day. It is usually taken in two divided doses per day, but some patients may do well with a single dose at bedtime. Common side effects include prolactin elevation, akathisia, sedation, dyspepsia, nausea, and weight gain. An oral dissolvable formulation is available. Ziprasidone Ziprasidone is started at a dose of 40 mg two times per day. The usual target dose is 40 to 80 mg two times per day. Some patients may require and tolerate 200 mg per day or more. Common side effects include headache, sedation, extrapyramidal symptoms, akathisia, and dizziness. Additional information about second-generation antipsychotics is discussed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".) SPECIAL CIRCUMSTANCES Elderly Treatment of geriatric manic, hypomanic, and mixed episodes is discussed separately. (See "Geriatric bipolar disorder: Acute treatment", section on 'Manic, hypomanic, and mixed episodes'.) Pregnancy Treatment of mania, hypomania, and mixed episodes during pregnancy; the teratogenic and postnatal risks of pharmacotherapy for bipolar disorder; the principles of teratology; preconception and prenatal maintenance pharmacotherapy for bipolar patients; and preconception counseling for patients with bipolar disorder are discussed separately. (See "Bipolar disorder in pregnant women: Treatment of mania and hypomania" and "Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy" and "Principles of teratology" and "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy" and "Bipolar disorder in women: Contraception and preconception assessment and counseling".) 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 11 de 16 02/12/2013 04:38
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Bipolar disorder (The Basics)" and "Patient information: Reducing the costs of medicines (The Basics)") Beyond the Basics topics (see "Patient information: Bipolar disorder (manic depression) (Beyond the Basics)" and "Patient information: Reducing the costs of medicines (Beyond the Basics)") The National Institute of Mental Health also has educational material explaining the symptoms, course of illness, and treatment in a booklet entitled "Bipolar Disorder" that is available online at the website http://www.nimh.nih.gov /health/publications/bipolar-disorder/complete-index.shtml or through a toll-free number, 866-615-6464. The web site also provides references, summaries of study results in language intended for the lay public, and information about clinical trials currently recruiting patients. More comprehensive information is provided in books written for patients and family members, including The Bipolar Disorder Survival Guide: What You and Your Family Need to Know, written by David J. Miklowitz, PhD (published by The Guilford Press, 2002) and An Unquiet Mind: A Memoir of Moods and Madness, written by Kay Jamison PhD (published by Random House, 1995). The Depression and Bipolar Support Alliance (http://www.dbsalliance.org or 800-826-3632) is a national organization whose mission is to educate patients and family members about bipolar disorder and how to cope with it. Other functions include increasing public awareness of the illness and advocating for more research and services. The organization is administered and maintained by members and has local chapters. The National Alliance on Mental Illness (http://www.nami.org or 800-950-6264) is a similarly structured organization devoted to providing education, support, and advocacy for patients with any mental illness. Bipolar disorder is one of their priorities. SUMMARY AND RECOMMENDATIONS Bipolar disorder is characterized by pathologic mood elevation. Patients with bipolar I disorder experience manic episodes (table 1) or mixed episodes (major depression concurrent with mania or hypomania), and nearly always experience major depressive episodes (table 3). Bipolar II disorder is characterized by at least one episode of hypomania (table 2) and one or more episodes of major depression. (See 'Definitions' above and "Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.) Patients presenting with acute mania, mixed episodes, or hypomania should be assessed for risk of suicide and homicide, aggressiveness, psychotic features, and poor judgement. Antidepressants should be discontinued, and substance abuse treated. (See 'General principles' above.) Drug classes commonly used to treat acute mania, mixed episodes, or hypomania include lithium, anticonvulsants, antipsychotics, and benzodiazepines. (See 'Drug classes' above.) For patients with severe manic or mixed episodes, we suggest initial treatment with lithium or valproate plus an antipsychotic, rather than monotherapy (Grade 2B). (See 'First line medication combinations' above and 'Medication doses and side effects' above.) For resistant patients with severe manic or mixed episodes that do not respond to one medication combination (lithium or valproate plus an antipsychotic), we suggest additional medication combination trials rather than electroconvulsive therapy (ECT) (Grade 2B). Lithium is switched to valproate (or vice versa), and the antipsychotic is switched to another antipsychotic from among aripiprazole, haloperidol, olanzapine,
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quetiapine, or risperidone. (See 'Resistant patients' above.) For treatment refractory patients with severe manic or mixed episodes who do not respond to four to six medication combinations, we suggest ECT rather than additional trials of pharmacotherapy combinations (Grade 2C). (See 'Refractory patients' above.) For patients with acute hypomania or mild to moderate manic or mixed episodes, we suggest initial treatment with risperidone or olanzapine monotherapy rather than other drugs (Grade 2B). However, reasonable alternatives include aripiprazole, carbamazepine, haloperidol, lithium, quetiapine, valproate, or ziprasidone. In addition to efficacy and tolerability, the choice depends upon past response to medications, comorbid medical illness, concurrent medications, specific symptoms, and cost. (See 'First line monotherapy' above.) For patients with hypomania or mild to moderate manic or mixed episodes that do not respond to three to five monotherapy trials involving aripiprazole, carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone, valproate, and ziprasidone, we suggest combining either lithium or valproate with an antipsychotic (other than ziprasidone) rather than additional monotherapy trials (Grade 2C). Another option is using lithium plus valproate. (See 'First line medication combinations' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 679 Version 34.0
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GRAPHICS DSM-IV-TR diagnostic criteria for mania

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
1) Inflated self-esteem or grandiosity 2) Decreased need for sleep (eg, feels rested after only 3 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) 6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7) Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
C. The symptoms do not meet criteria for a mixed episode. D. The mood disturbance 1) is sufficiently severe to cause marked impairment in occupational functioning, usual social activities, or relationships with others, 2) necessitates hospitalization to prevent harm to self or others, or 3) has psychotic features. E. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition (Copyright 2000). American Psychiatric Association.
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DSM-IV-TR diagnostic criteria for hypomania

A. A distinct period of persistently elevated, expansive, or irritable mood, lasting at least 4 days, that is clearly different from the usual nondepressed mood. B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
1) Inflated self-esteem or grandiosity 2) Decreased need for sleep (eg, feels rested after only 3 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) 6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7) Excessive involvement in pleasurable 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 person when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. E. The episode 1) is not severe enough to cause marked impairment in social or occupational functioning, 2) does not necessitate hospitalization, and 3) does not have psychotic features. F. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism). Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (eg, medication, ECT, light therapy) should not count toward a diagnosis of bipolar II disorder.
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition (Copyright 2000). American Psychiatric Association.
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DSM-IV-TR diagnostic criteria for major depression

A. Five (or more) of the following symptoms have been present during the same 2-week period, and represent a change from previous functioning. At least one of the symptoms is either depressed mood or loss of interest or pleasure.
(Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations.) Depressed mood most of the day, nearly every day (or alternatively can be irritable mood in children and adolescents) Markedly diminished interest or pleasure in all, or almost all, activities, nearly every day Significant weight loss while not dieting, weight gain, or decrease or increase in appetite Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation nearly every day Fatigue or loss of energy nearly every day Feelings of worthlessness or excessive or inappropriate guilt nearly every day Diminished ability to think or concentrate, or indecisiveness, nearly every day 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 do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of substance or a general medical condition. E. The symptoms are not better accounted for by Bereavement, ie, after the loss of a loved one, the symptoms persist for longer than two months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. American Psychiatric Association, Washington, DC 2000.
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Bipolar Disorder in Adults - Pharmacotherapy For Acute Mania, Mixed Episodes, and Hypomania PDF

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