Bipolar disorder in adults - Pharmacotherapy for acute mania, mixed episodes, and hypomania.pdf

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Official reprint from UpToDatewww.uptodate.com 2013 UpToDate

Author Jeffrey Stovall, MD

Section Editor Paul Keck, MD

Deputy Editor David Solomon, MD

Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania

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 asmixed episodes of concurrent major depression ( table 3 ) and mania or hypomania [ 1]. Despite clinical differencesamong manic, hypomanic, and mixed episodes, for the purpose of treatment they are considered to be similar andthus 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 ). Theclinical 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 thustreated with the same medications [ 2-4 ]. The clinical features and diagnosis of bipolar disorder are discussedseparately. (See "Bipolar disorder in adults: Clinical features" and "Bipolar disorder in adults: Assessment anddiagnosis" .)

Pharmacotherapy for mania or mixed episodes depends upon their severity. Although there are no establishedcriteria that demarcate severe episodes from mild to moderate illness, we classify episodes as severe if theyinclude 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 lesssevere than mania), for the purpose of treatment they are considered to be similar and thus treated with the samemedications [ 2-6 ].

Goal The goal of treating acute manic, hypomanic, and mixed episodes is remission, which is defined asresolution of the mood symptoms or improvement to the point that only one or two symptoms of mild intensitypersist. If psychotic features (delusions or hallucinations) are also present, resolution of the psychosis is requiredfor remission. For patients who do not achieve remission, a reasonable goal is response, which is defined asstabilization 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 toquantify response [ 7], although this is not standard clinical practice.

General principles Treatment of mood elevated syndromes (ie, manic, hypomanic, and mixed episodes) beginswith an initial psychiatric history and mental status examination that emphasizes symptoms of the mood episode,

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particularly risk of suicide, aggressiveness, and violence to others [ 2,3,8 ]. The assessment should also pursuecomorbid disorders (eg, substance use disorders) that require treatment. The evaluation includes a generalmedical history, physical examination, and focused laboratory studies to establish whether the mood syndrome isdue to the direct physiologic effects of a general medical condition, and to rule out any contraindications totreatment (eg, renal impairment and use of lithium , or hepatic disease and use of valproate ). Additional informationabout the assessment for bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Assessmentand diagnosis", section on 'Assessment' .)

Patients who suffer mania, hypomania, or a mixed episode during maintenance pharmacotherapy should beassessed for adherence to treatment and are initially treated by optimizing medication doses [ 2,9,10 ]. This includesensuring serum concentrations are in the therapeutic range for medications such as lithium or valproate , as well asincreasing the dose to achieve a higher serum level within the therapeutic range, provided that side effects do notintervene. For medications that do not have an established therapeutic serum concentration, such asantipsychotics, the dose can be increased within the target dose range.

Substances may cause or exacerbate a mood elevated syndrome. Thus, antidepressants should be abruptlydiscontinued, 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 withbipolar I manic patients, although the majority of trials included some patients with mixed episodes [ 11,12 ]. Eventhough bipolar II disorder is more prevalent than bipolar I disorder, relatively little research has focused specificallyon treating hypomania [ 13,14 ]. Many randomized trials either exclude patients with bipolar II disorder or lump themtogether with bipolar I patients in the analyses.

Setting and monitoring The treatment setting for manic, hypomanic, or mixed episode patients dependsupon the severity of symptoms, comorbid psychopathology (eg, substance use disorder), level of psychosocialfunctioning, and available support:

Inpatient Hospitalization may be required for managing the patients safety and symptoms such assuicidal ideation with a specific plan and intent, delusions or hallucinations, and poor judgment that poses animminent risk to the patient and others

Partial hospital Moderately ill patients can often be treated in a partial hospital (day) program, includingpatients 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 memberswould 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 grouppsychoeducation) with standard care (pharmacotherapy provided at a local community health center or at apsychiatrists office) in 158 bipolar patients who were discharged from their first, second, or third inpatientadmission [ 15 ]. Readmission to the hospital occurred in more patients who received standard care than specializedcare (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 persistentsymptoms. Hospitalized patients are monitored daily, and patients with active suicidal ideation, a specific plan, andintent to kill themselves may require constant observation. Outpatients who have responded less than 50 percentare 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, mixedepisodes, or hypomania include:


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Lithium Anticonvulsants AntipsychoticsBenzodiazepines

The mainstays of t reatment are lithium , anticonvulsants, and antipsychotics used in combination pharmacotherapy(eg, lithium plus an antipsychotic) or as monotherapy, depending upon the severity of symptoms. Benzodiazepinesare 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 acutelyagitated 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 medicationregimen, it is reasonable to allow up to two weeks for a treatment trial [ 4]. Most randomized trials last threeweeks, and the superior efficacy of active drugs compared with placebo generally begins to manifest within oneweek.

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 (improvementfrom 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 40patients with


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Two other meta-analyses of 6 randomized trials (1396 manic or mixed episode patients) compared secondgeneration antipsychotics (including olanzapine , quetiapine , or risperidone ) with placebo as adjunctivetreatment for patients who did not respond to lithium , valproate , or carbamazepine monotherapy [ 12,25 ]. Inboth studies, improvement was significantly greater with the antipsychotic than placebo. In addition, dropoutdue to adverse events was comparable for the two groups [ 12 ]. However, adjunctive antipsychotics causedsignificantly 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 aripiprazolecompared 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 toeither lithium or divalproex to receive adjunctive treatment twice per day with ziprasidone 20 to 40 mg, ziprasidone60 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 thatfound this combination is no more efficacious than carbamazepine alone [ 27,28 ]. Carbamazepine induces hepaticenzymes 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 andside effects of lithium , valproate , and antipsychotics are discussed elsewhere in this topic. (See 'Medication dosesand side effects' below.)

Specific medication interactions that can occur may be determined using the drug interactions tool (Lexi-InteractOnline) included in UpToDate. This tool can be accessed from the UpToDate online search page or through theindividual drug information topics in the section on Drug interactions.

Patients who cannot tolerate combination pharmacotherapy are treated with monotherapy. (See 'First linemonotherapy' below.)

Resistant patients A severe manic or mixed episode that does not respond to one medication combinationshould 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 targetdoses, 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 valproateare discussed separately. (See 'Lithium' below and 'Anticonvulsants' below.)

Conversely, for patients who do not respond to valproate plus haloperidol within two weeks of reaching targetdoses, 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 2000mg 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, wesuggest starting a third medication combination involving lithium or valproate plus an antipsychotic. The choicebetween lithium and valproate is based upon efficacy and tolerability in the two prior trials. In addition, theantipsychotic 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 . Nohead-to-head trials have compared antipsychotics in combination with lithium or valproate; thus, the choice of anantipsychotic is based upon other factors, including past response to medications, side effect profiles, comorbidgeneral 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 whosemanic 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 chlorpromazinecompared 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 iscompromised [ 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 beenstandardized. Thus, ECT is typically administered with the same technique used for other indications and isgenerally 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 electroconvulsivetherapy (ECT) in adults" .)

Other medications For patients with refractory manic or mixed episodes who decline ECT, do not remitwith it, or have no access to it, and who do not respond to medication combinations involving lithium or valproateplus 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 possiblybenefit from allopurinol plus lithium, tamoxifen monotherapy, and tamoxifen plus lithium [ 39-43 ]. No head-to-headtrials 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-druginteractions, patient preference, and cost.

In randomized trials with 977 manic or mixed episode patients, asenapine 5 to 10 mg two times per day was moreefficacious than placebo, but much less efficacious than olanzapine 5 to 20 mg once per day [ 34,35 ]. Common sideeffects of asenapine include sedation, fatigue, dizziness, extrapyramidal symptoms, vomiting, dry mouth, andweight gain [ 34,35 ]. Additional information about asenapine is discussed separately. (See "Second-generationantipsychotic medications: Pharmacology, administration, and comparative side effects" .)

Limited evidence suggests that clozapine may ameliorate refractory manic or mixed episodes [ 33,36,37 ]. Clozapineis 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 t imes per day. However, clozapine can cause agranulocytosisand other blood dyscrasias, and clinicians must monitor complete blood counts every one or two weeks. Clozapineis 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 clozapineis discussed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, andcomparative side effects", section on 'Clozapine' .)

Paliperidone has demonstrated inconsistent benefits in patients with acute manic and mixed episodes. Arandomized trial compared paliperidone (flexibly dosed 3 to 12 mg per day) with placebo in 268 patients with amanic or mixed episode, and found that remission occurred in significantly more patients who received paliperidonethan 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 groupthat received placebo (37 or 42 or 45 versus 37 percent) [ 44 ]. A third randomized trial found that among patientswith an inadequate response to lithium or valproate monotherapy, there was no significant difference betweenadjunctive paliperidone and adjunctive placebo [ 45 ]. The most common adverse events with paliperidone areheadache, somnolence, dizziness, akathisia, hypertonia, and dyspepsia. Additional information about paliperidone


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is discussed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, andcomparative side effects", section on 'Paliperidone' .)

Allopurinol , which is typically used to prevent attacks of gouty arthritis and nephropathy, has been studied as anoption for treating mania [ 46 ], based upon observations that adenosine, a purine compound and neuromodulator, ismetabolized to uric acid, and that increased uric acid turnover is related to remission of mania [ 39,47 ]. Ameta-analysis of three randomized trials compared allopurinol with placebo as adjunctive treatment in 186 manicpatients, 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 andmixed episodes in several small randomized trials [ 40-43 ]. The largest compared tamoxifen (20 to 40 mg two timesper day) with placebo in 66 patients [ 40 ]. Response (improvement from baseline on the mania rating scale 50percent) occurred in significantly more patients who received tamoxifen than placebo (48 versus 5 percent), as didremission (28 versus 0 percent). Tamoxifen is widely used to prevent breast cancer because it is a selectiveestrogen receptor antagonist, and these antiestrogen effects preclude its use beyond patients unresponsive tomost or all other t reatments.

There is little or no evidence to support treating acute mania or mixed episodes with anticonvulsants other thanvalproate 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 anticonvulsanttiagabine , 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 thatoxcarbazepine has any benefit in adults [ 56 ]. In addition, a randomized trial found that oxcarbazepine wascomparable 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 thepatient 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, wesuggest 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 mixedepisode, 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 betweendrugs. Beginning with the most efficacious drug, the rank order for efficacy was:

HaloperidolRisperidoneOlanzapine

AripiprazoleCarbamazepineLithiumQuetiapine

Valproate (or divalproex)Ziprasidone

Further, the meta-analysis ranked the drugs by frequency of treatment discontinuation for any reason, includingadverse effects and lack of efficacy. Beginning with the drug with the lowest rate of dropout, the rank order was:


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OlanzapineRisperidoneQuetiapineValproateCarbamazepine

AripiprazoleHaloperidolZiprasidoneLithium

The indirect comparisons distinguish this multiple-treatments meta-analysis from smaller, conventionalmeta-analyses, which concluded that efficacy was comparable for aripiprazole , carbamazepine , haloperidol ,lithium , olanzapine , quetiapine , risperidone , valproate , and ziprasidone [11,12,25,58 ]. Although substantialuncertainties are introduced when these sorts of rank orders are created through a multiple-treatmentsmeta-analysis, this is probably the best evidence for comparing drugs for acute hypomania and mild to moderatemanic and mixed episodes. While it is not clear that there are meaningful differences between adjacently rankedmedications, 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 whenchoosing a drug, including the patients past response to medications, the past response of family members withbipolar disorder to medications, specific symptoms, adverse drug effects, comorbid medical illnesses, concurrentmedications, 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 bedifficult to use because of its tendency to increase metabolism of concomitant medications. Medication side effectsare discussed separately. (See 'Medication doses and side effects' below and "Bipolar disorder in adults andlithium: Pharmacology, administration, and side effects", section on 'Lithium side effects' and "Pharmacology of antiepileptic drugs" and "First-generation antipsychotic medications: Pharmacology, administration, andcomparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, andcomparative side effects" .)

The long-term implications of choosing a drug also need to be considered; all patients with bipolar disorder shouldreceive 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-termtreatment with lithium may reduce the risk of suicide attempts and deaths [ 61-64 ]. By contrast, haloperidol isgenerally not used in maintenance treatment because it can cause movement disorders and may increase the riskof bipolar major depression [ 65,66 ]. Maintenance treatment is discussed separately. (See "Bipolar disorder inadults: 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 failedmedication over one week at the same time that another monotherapy is started and titrated up. The failedmedication is generally tapered by the same amount for each dose decrease. As an example, quetiapine 600 mgper 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 respondto three to five monotherapy trials involving aripiprazole , carbamazepine , haloperidol , lithium , olanzapine ,quetiapine , risperidone , valproate , and ziprasidone , we suggest combining lithium or valproate with anantipsychotic. However, lithium plus valproate is a reasonable alternative [ 67,68 ]. Medication combinations involvinglithium or valproate plus an antipsychotic are discussed elsewhere in the topic. (See 'First line medicationcombinations' above.)

Benzodiazepines We suggest clonazepam for patients who have hypomanic or mild to moderate manicor mixed episodes and cannot tolerate lithium , anticonvulsants, or antipsychotics. However, lorazepam is areasonable alternative. Monotherapy with a benzodiazepine is unusual due to the large number of availablemedication 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 highrate of substance use disorders among bipolar patients and the potential for abusing benzodiazepines, these drugsare 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 generallytitrated up to a target dose ranging from 2 to 6 mg per day, depending upon efficacy and tolerability, althoughdoses as high as 24 mg per day have been used [ 70 ]. Side effects include disinhibition, sedation, and respiratorydepression.

Lorazepam is usually started at a dose of 2 to 4 mg per day, taken in three to four divided doses. The drug isgenerally 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, andrespiratory depression.

Evidence of efficacy includes a meta-analysis of five heterogeneous randomized trials (122 manic patients), whichfound 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 itwas not effective. However, one randomized trial directly compared lorazepam (mean daily dose 13 mg) withclonazepam (mean daily dose 14 mg) in 24 manic patients, and found that moderate to marked improvementoccurred in significantly more patients who received lorazepam than clonazepam (63 versus 18 percent), as didremission (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 mgtwice daily) are used in the elderly [ 69,72-74 ]. The dose should be increased by 300 to 600 mg every one to fivedays based upon response, tolerability, and body mass index. The goal is to reach a therapeutic serum level, whichgenerally occurs with a dose of 900 mg to 1800 mg per day. Dose increases generally occur more frequently atthe 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: Acutetreatment", 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 toreduce the risk of toxicity [ 73 ]. Patients who cannot tolerate a level of 0.8 meq/L may respond to a level of 0.6meq/L. Lithium levels should be measured five to seven days after each dose increase. Levels are drawn 12 hoursafter the last dose (12-hour serum trough level) and generally collected in the morning, before the first dose of theday. Additional information about lithium serum levels is discussed elsewhere. (See "Bipolar disorder in adults andlithium: 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 suddenworsening of acute side effects may be a sign of lithium toxicity. Over the long term, lithium can adversely affectthe kidneys and thyroid gland. In addition, cardiac rhythm disturbances have been described; these almost alwaysoccur in patients with preexisting cardiac disease. Additional information about side effects and how to managethem 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 hypomaniainclude valproate and carbamazepine .

Suicidality Bipolar disorder is associated with an increased risk of suicide deaths [ 77 ], and all patientsshould be monitored for emergence or worsening of suicidal thoughts and behavior. Although some observationalstudies suggest that anticonvulsants may increase the risk of suicidal ideation or behavior, these drugs aregenerally safe to use when patients are regularly monitored.

The US Food and Drug Administration warned clinicians that anticonvulsants are associated with an increased riskof suicidal thoughts and behavior, based upon a pooled analysis of 199 controlled trials that included 43,892patients with a variety of illnesses [ 78 ]. In addition, a separate exploratory analysis of a medical and pharmacyclaims database that included 297,620 new episodes of treatment with an anticonvulsant suggested thatgabapentin , 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 specificallywith bipolar disorder found [ 80 ]:

The frequency of suicide attempts in patients treated with antiepileptic drugs and patients not receivingantiepileptic drugs was comparable

For patients treated with antiepileptic drugs, the rate of suicide attempts was greater before treatment thanafter treatment

Patients receiving antiepileptic drug monotherapy (and no concomitant antidepressant or antipsychotic) hadfewer suicide attempts compared to patients receiving no pharmacotherapy

Other observational studies have found that antiepileptics were not associated with an increased risk of suicidalbehavior in bipolar patients [ 81 ]. As an example, analyses using a national database with over 5,000,000 patientsfound that among patients with bipolar disorder, treatment with antiepileptic drugs was not associated with anincreased 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 serumlevel, which generally occurs with 1500 mg to 2500 mg per day [ 74,83 ]. Valproate is usually administered twicedaily (although a once-a-day formulation is available in the United States). Oral loading and rapid titration to a fulldose within one to two days by prescr ibing 20 mg/kg/day may result in earlier improvement in symptoms and areduced 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 toachieve a target serum level between 50 and 125 mcg/mL. Levels should be drawn 12 hours after the last doseand generally collected in the morning, before the first dose of the day. A post hoc analysis of pooled data fromthree 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 largestclinical effect for valproate occurred in patients with a mean serum level of 88 mcg/mL. Levels should be checkedat 6 to 12 month intervals, and are particularly useful in patients receiving medications that affect valproateconcentrations 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 doseadjustments [ 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 associatedwith hepatic failure and thrombocytopenia; liver function tests and platelets should thus be monitored at 6 to 12month intervals in all patients taking the drug [ 33,69,87 ]. (The US Food and Drug Administration recommendschecking liver function tests prior to initiating treatment and at frequent intervals thereafter, especially during thefirst six months.) In addition, valproate rarely causes pancreatitis; symptoms of abdominal pain and vomiting shouldprompt 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 arediscussed 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 800to 1000 mg per day, although the effective dose may range between 200 and 1800 mg per day. Carbamazepine istypically 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-Johnsonsyndrome and toxic epidermal necrolysis), particularly during the first eight weeks of therapy [ 90 ]. This reaction issignificantly more common in patients with the HLA-B*1502 allele (estimated incidence of 5 percent), which occursalmost 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 startingcarbamazepine [ 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 serumconcentrations 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 serumcarbamazepine 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 andnonpsychotic 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 andmixed episodes because it has been widely studied and generally causes less orthostatic hypotension and sedationthan 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 dayor in two divided doses, depending upon tolerability and the patients ability to adhere to treatment with divideddoses. 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 tocarbamazepine , 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 ananticholinergic 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 isnot clear. A meta-analysis of six randomized trials (1774 manic patients; heterogeneity across studies wasmoderate) compared haloperidol with second-generation antipsychotics ( aripiprazole , olanzapine , quetiapine ,risperidone , or ziprasidone ), and found that treatment emergent depression was comparable for patients whoreceived haloperidol or second-generation antipsychotics (10 and 7 percent) [ 99 ]. However, a second analysis thatexcluded one outlier trial (and eliminated the heterogeneity) found that depressive switches occurred in morepatients 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 eachefficacious for treating manic, hypomanic, and mixed episodes [ 54 ], and the choice often depends upon differencesin adverse side effects. Metabolic problems such as weight gain, glucose intolerance, diabetes mellitus, andhyperlipidemia are most likely to occur with olanzapine, followed by quetiapine and risperidone. Thus, patientstaking olanzapine, quetiapine, and risperidone should be regularly monitored for weight, waist circumference, bloodpressure, 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 arediscussed 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 inrandomized monotherapy trials are described below [ 74,100 ]. Target doses can generally be achieved within oneweek of starting the medication. Some drugs are available as oral dissolvable formulations for patients whopretend 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 45mg 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 usualtarget dose is 10 to 30 mg per day, taken at bedtime or in two divided doses. Some patients may requireand tolerate 40 or 50 mg per day. Common side effects include sedation, constipation, dry mouth, increasedappetite, 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 usualtarget dose is 400 to 800 mg taken at bedtime or in two divided doses. Some patients may require andtolerate 1000 or 1200 mg per day. Common side effects include headache, dry mouth, constipation, weightgain, 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 usualtarget dose is 4 to 8 mg per day. It is usually taken in two divided doses per day, but some patients may dowell 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 to80 mg two times per day. Some patients may require and tolerate 200 mg per day or more. Common sideeffects include headache, sedation, extrapyramidal symptoms, akathisia, and dizziness.

Additional information about second-generation antipsychotics is discussed separately. (See "Second-generationantipsychotic medications: Pharmacology, administration, and comparative side effects" .)

SPECIAL CIRCUMSTANCES

Elderly Treatment of geriatric manic, hypomanic, and mixed episodes is discussed separately. (See "Geriatricbipolar disorder: Acute treatment", section on 'Manic, hypomanic, and mixed episodes' .)

Pregnancy Treatment of mania, hypomania, and mixed episodes during pregnancy; the teratogenic andpostnatal risks of pharmacotherapy for bipolar disorder; the principles of teratology; preconception and prenatalmaintenance 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 inwomen: Contraception and preconception assessment and counseling" .)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics andBeyond the Basics. The Basics patient education pieces are written in plain language, at the 5 to 6 gradereading level, and they answer the four or five key questions a patient might have about a given condition. These

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articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyondthe Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are writtenat the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortablewith some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail thesetopics to your patients. (You can also locate patient education articles on a variety of subjects by searching onpatient info and the keyword(s) of interest.)

Basics topics (see "Patient information: Bipolar disorder (The Basics)" and "Patient information: Reducingthe costs of medicines (The Basics)" )

Beyond the Basics topics (see "Patient information: Bipolar disorder (manic depression) (Beyond theBasics)" 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 website 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 TheBipolar 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 KayJamison PhD (published by Random House, 1995).

The Depression and Bipolar Support Alliance ( http://www.dbsalliance.org or 800-826-3632) is a nationalorganization whose mission is to educate patients and family members about bipolar disorder and how to copewith it. Other functions include increasing public awareness of the illness and advocating for more research andservices. 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 organizationdevoted to providing education, support, and advocacy for patients with any mental illness. Bipolar disorder is oneof their priorities.

SUMMARY AND RECOMMENDATIONS

Bipolar disorder is characterized by pathologic mood elevation. Patients with bipolar I disorder experiencemanic episodes ( table 1 ) or mixed episodes (major depression concurrent with mania or hypomania), andnearly always experience major depressive episodes ( table 3 ). Bipolar II disorder is characterized by atleast 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 suicideand homicide, aggressiveness, psychotic features, and poor judgement. Antidepressants should bediscontinued, 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 plusan 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 medicationcombination ( lithium or valproate plus an antipsychotic), we suggest additional medication combination trialsrather 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 sixmedication 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 initialtreatment 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 eff icacy and tolerability, the choice depends upon past response to medications,comorbid medical illness, concurrent medications, specific symptoms, and cost. (See 'First linemonotherapy' above.)

For patients with hypomania or mild to moderate manic or mixed episodes that do not respond to three tofive monotherapy trials involving aripiprazole , carbamazepine , haloperidol , lithium , olanzapine , quetiapine ,risperidone , valproate , and ziprasidone , we suggest combining either lithium or valproate with anantipsychotic (other than ziprasidone) rather than additional monotherapy trials ( Grade 2C ). Another optionis using lithium plus valproate. (See 'First line medication combinations' above.)

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

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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, lastingat 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 psychomotoragitation

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 occupationalfunctioning, usual social activities, or relationships with others, 2) necessitates hospitalization toprevent 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 irr itable 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 havepersisted (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 psychomotoragitation

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 occupationalfunctioning, 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-weekperiod, and represent a change from previous functioning. At least one of the symptoms is eitherdepressed mood or loss of interest or pleasure.

(Note: Do not include symptoms that are clearly due to a general medical condition, ormood-incongruent delusions or hallucinations.)

Depressed mood most of the day, nearly every day (or alternatively can be irritable mood in childrenand 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 agitat ion 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 specificplan, 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 otherimportant areas of functioning.

D. The symptoms are not due to the direct physiological effects of substance or a general medicalcondition.

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, orpsychomotor retardation.

Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4thed, Text Revision. American Psychiatric Association, Washington, DC 2000.


Documents

Bipolar disorder in adults - Pharmacotherapy for acute mania, mixed episodes, and hypomania.pdf