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INTRODUCTION — Bipolar disorder is marked by episodes of mania (table 1) and hypomania (table 2), and nearly always includes episodes of major depression (table 3) . Despite clinical differences between manic and hypomanic episodes, for the purpose of treatment they are considered to be similar and thus treated with the same medications [2-5].
This topic reviews pharmacotherapy for acute mania and hypomania in adults. Pharmacotherapy for acute bipolar depression and maintenance treatment are discussed separately. (See "Bipolar disorder in adults: Pharmacotherapy for acute depression" and "Bipolar disorder in adults: Choosing maintenance treatment".)
DEFINITION OF BIPOLAR DISORDER — Bipolar disorder is a mood disorder that is characterized by episodes of mania (table 1), hypomania (table 2), and major depression (table 3) . The subtypes of bipolar disorder include bipolar I and bipolar II. Patients with bipolar I disorder experience manic episodes, and nearly always experience hypomanic and major depressive episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode, and the absence of manic episodes. Additional information about the clinical features and diagnosis of bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical features" and "Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.)
Despite clinical differences among manic and hypomanic 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 [2-5].
Pharmacotherapy for manic 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
●Psychotic features (ie, delusions or hallucinations)
●Poor judgement that places the patient or others at imminent risk of being harmed
TREATMENT — Despite clinical differences between manic and hypomanic 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 [2-5].
Goal — The goal of treating acute mania and hypomania 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. Patients with subsyndromal symptoms of mania are at increased risk of relapse .
For patients who do not achieve remission, a reasonable goal is response, which is defined as stabilization of the patient’s 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 , although this is not standard clinical practice.
General principles — Treatment of mood elevated syndromes (ie, manic and hypomanic episodes) begins with an initial psychiatric history and mental status examination that emphasizes symptoms of the mood episode, particularly risk of suicide, aggressiveness, and violence to others, as well as signs of catatonia [7-9]. 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 or hypomania during maintenance pharmacotherapy should be assessed for adherence to treatment and are initially treated by optimizing medication doses [7,10,11]. 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 second-generation 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; the majority of trials included some patients with mixed features (ie, mania accompanied by symptoms of depression) [12,13]. Even though bipolar II disorder is more prevalent than bipolar I disorder, relatively little research has focused specifically on treating hypomania [14,15]. Many randomized trials either exclude patients with bipolar II disorder or combine them with bipolar I patients in the analyses.
Setting and monitoring — The treatment setting for manic or hypomanic 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 patient’s 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, patients with fleeting thoughts of killing oneself, vague or nonexistent plans, and no intent)
●Outpatient – Outpatient care may be suitable for less acutely ill patients (eg, patients with 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 psychiatrist’s office) in 158 bipolar patients who were discharged from their first, second, or third inpatient admission . Readmission to the hospital occurred in fewer patients who received specialized care than standard care (36 versus 55 percent). In addition, the median duration of the readmission was nearly two times shorter for patients who had received specialized care rather than standard care (12 versus 22 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.
Drug classes — Based upon randomized trials, drug classes commonly used to treat acute mania or hypomania include:
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 in adults" and "Assessment and emergency management of the acutely agitated or violent adult" and "Pharmacotherapy for generalized anxiety disorder in adults".)
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 . However, 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 randomized trial that compared olanzapine with risperidone in patients with pure mania or mania with mixed features, improvement at week one was evaluated as a predictor of either remission or response (reduction of baseline symptoms ≥50 percent) at week three . 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 — Among patients with mania, clinical factors that consistently predict a good response to pharmacotherapy have not been identified. As an example, several studies suggest that mixed features are associated with a poorer response [14,18,19]; one randomized trial found that among 36 manic patients who were assigned to lithium, response was worse in patients (n = 14) with depressive symptoms than patients with pure mania [20,21]. However, other studies found that response to medications was comparable for patients with pure mania and mania with mixed features [22,23].
Patients who discontinue successful maintenance treatment and then suffer a relapse are often restarted on the same medication. Although concerns have been raised that the same medication is less effective after treatment is interrupted, a meta-analysis of three prospective observational studies (n = 212 patients with bipolar disorder) suggested that this was not the case.
Severe manic 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 typically require treatment with a medication combination [2,7,24]. 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 . 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, drug preparation (eg, intramuscular or oral disintegrating), 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 (reduction of baseline symptoms ≥50 percent) with lithium or valproate plus aripiprazole, olanzapine, quetiapine, or risperidone was 20 percent higher compared with lithium or valproate alone . 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 . Improvement was greater in patients who received an adjunctive antipsychotic.
●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 [13,28]. In both studies, improvement was greater with the antipsychotic than placebo. In addition, dropout due to adverse events was comparable for the two groups . However, adjunctive antipsychotics caused 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 . Remission occurred in more patients who received aripiprazole compared with placebo (66 versus 51 percent). However, aripiprazole caused higher rates of akathisia (19 versus 5 percent).
Combination pharmacotherapy for severe manic episodes is endorsed by several treatment guidelines [2,5,7].
However, adding ziprasidone to lithium or divalproex is not efficacious, based upon two randomized trials [13,25]. As an example, a three week trial assigned 656 patients with pure mania or mania with mixed features 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 . 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 [30,31]. Carbamazepine induces hepatic enzymes that metabolize antipsychotics, and in one trial lowered the antipsychotic blood level by 40 percent .
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 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, or risperidone.
The antipsychotic is generally tapered over one week by the same amount for each dose decrease (eg, 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.)
Electroconvulsive therapy — We suggest electroconvulsive therapy (ECT) for refractory patients whose manic episode does not respond to four to six medication combinations [2,32,33]. Several studies suggest that ECT is effective for mania. (See "Bipolar disorder in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Mania'.)
ECT is generally safe and there are no absolute contraindications, even in patients whose general medical status is compromised . 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 mania 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 mania 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 clozapine [35-37]. Patients unresponsive to lithium or valproate plus clozapine may possibly benefit from allopurinol plus lithium, tamoxifen monotherapy, and tamoxifen plus lithium [38-42]. 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.
Limited evidence suggests that clozapine may ameliorate refractory mania [35,36,43]. 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 side effects".)
Allopurinol, which is typically used to prevent attacks of gouty arthritis and nephropathy, has been studied as adjunctive treatment for mania. The results across studies are inconsistent:
●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 . 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 episodes in several small randomized trials [39-42]. The largest trial compared tamoxifen (20 to 40 mg two times per day) with placebo in 66 patients . Response (reduction of baseline symptoms ≥50 percent) occurred in 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 with anticonvulsants other than valproate and carbamazepine. Lamotrigine, gabapentin, and topiramate are not effective for treating mania [46-51]. In addition, a systematic review found that there was insufficient evidence to evaluate the anticonvulsant tiagabine, and results from available case series are conflicting .
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 . In addition, a randomized trial found that oxcarbazepine was comparable with placebo in 116 children and adolescents with pure mania or mania with mixed features .
Acutely agitated patients — Hospitalized patients with mania who are acutely agitated may require oral or intramuscular medications, as well as seclusion and physical restraints. Severely ill patients generally receive antipsychotics (eg, aripiprazole, haloperidol, or olanzapine) as part of their daily medication regimen (see 'First line medication combinations' above), and the same antipsychotic is typically used on an as needed basis for controlling acute behavioral disturbances.
Several first and second-generation antipsychotics are efficacious as a short acting intramuscular injection. As an example, a randomized trial found that among inpatients who received haloperidol for acute agitation (n = 110), the median time to sedation was 20 minutes, and sedation within 120 minutes occurred in 92 percent . Other studies have found that intramuscular aripiprazole, olanzapine, and ziprasidone are also efficacious .
Additional information about managing acute agitation is discussed separately in the context of the emergency department. (See "Assessment and emergency management of the acutely agitated or violent adult", section on 'Management'.)
Hypomania and mild to moderate mania — Hypomania and mild to moderate mania are 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 initially treating hypomania and mild to moderate mania.
First line monotherapy — For patients with either hypomanic or mild to moderate manic episodes, we suggest monotherapy with risperidone or olanzapine, based upon efficacy and tolerability [51,57]. This approach is consistent with treatment guidelines [58,59]. However, reasonable alternatives include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, paliperidone, quetiapine, valproate, or ziprasidone. Doses and side effects are discussed elsewhere in the topic. (See 'Medication doses and side effects' below.)
A network meta-analysis of 57 randomized trials (n >14,000 patients with an acute episode of pure mania or mania with mixed features, treated for three or four weeks) found that 12 standard drugs were each more efficacious than placebo: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone . The nonstandard medication tamoxifen was also more effective than placebo. Five drugs were no more effective than placebo: lamotrigine, licarbazepine, oxcarbazepine, topiramate, and verapamil.
In addition, the network meta-analysis ranked the 12 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:
●Valproate (or divalproex)
Nevertheless, the probability of response (reduction of baseline symptoms ≥50 percent) was comparable across all of the drugs.
The network meta-analysis also ranked the 12 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:
The indirect comparisons distinguish this network meta-analysis from smaller, conventional meta-analyses [12,13,28,60]. Although substantial uncertainties are introduced when these sorts of rank orders are created through the indirect comparisons that are used in a network meta-analysis, this is probably the best evidence for comparing drugs for acute hypomania and mild to moderate mania. Network meta-analysis is discussed separately. (See "Systematic review and meta-analysis", section on 'Network meta-analysis'.)
Clinicians should consider other factors in addition to the rank order of efficacy and treatment discontinuation when choosing a drug, including the patient’s 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 "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects" and "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and 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 [61,62], and long-term treatment with lithium may reduce the risk of suicide attempts and deaths . 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 [64,65]. Although olanzapine is efficacious for mania as well as mania with mixed features , olanzapine is not a first-line drug for maintenance treatment because of concerns about weight gain and diabetes mellitus. Valproate is often not prescribed to women of childbearing potential because many pregnancies are unplanned and the drug is generally regarded as teratogenic . Maintenance treatment is discussed separately. (See "Bipolar disorder in adults: Choosing maintenance treatment".)
For patients with hypomania or mild to moderate mania, 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 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 [68,69]. 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.
Benzodiazepine monotherapy is unusual due to the large number of available medication options for manic and hypomanic episodes; benzodiazepines are generally used as adjunctive 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 . However, maintenance treatment with benzodiazepines is administered to catatonic patients who remit with benzodiazepines. (See "Catatonia: Treatment and prognosis", section on 'Benzodiazepine safety and administration'.)
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 . 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 . Side effects include disinhibition, sedation, and respiratory depression.
Evidence of efficacy includes a meta-analysis of five randomized trials (122 manic patients) that compared clonazepam monotherapy (2 to 24 mg per day) with haloperidol, lithium, lorazepam, or placebo, and found that clonazepam was efficacious; however, heterogeneity across studies appeared to be substantial . A meta-analysis of four randomized trials (108 manic patients) that compared lorazepam monotherapy (4 to 24 mg per day) with clonazepam, haloperidol, lithium, or placebo found that lorazepam 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 more patients who received lorazepam than clonazepam (63 versus 18 percent), as did remission (38 versus 0 percent) . The frequency of side effects did not differ between the clonazepam and lorazepam .
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 [70,73-75]. 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 (0.8 and 1.2 mmol/L); levels should not exceed 1.2 mEq/L (1.2 mmol/L) to reduce the risk of toxicity . Patients who cannot tolerate a level of 0.8 mEq/L (0.8 mmol/L) may respond to a level of 0.6 to 0.7 mEq/L (0.6 to 0.7 mmol/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 [75-77]. 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 lithium side effects and how to manage them, as well as contraindications to lithium, lithium toxicity, drug interactions with lithium, the different available preparations of lithium, and laboratory tests for monitoring patients treated with lithium is discussed separately. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects", section on 'Lithium side effects' and "Lithium poisoning" and "Renal toxicity of lithium" and "Lithium and the thyroid".)
Suicidality — Bipolar disorder is associated with an increased risk of suicide deaths , 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 . 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 . However, an observational study using data from a medical and pharmacy claims database of geriatric patients with a variety of illnesses (n >90,000) suggested that suicidal thoughts and behavior were more likely to occur during the 30 days prior to initial use of an anticonvulsant than any other time period in the year before and after exposure .
In addition, an analysis of a different national claims database that involved 47,918 patients diagnosed with bipolar disorder found :
●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 also found that antiepileptics were not associated with an increased risk of suicidal behavior in bipolar patients . 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 .
Carbamazepine — Carbamazepine is usually started at a dose of 100 mg to 200 mg one or two times per day [75,85]. 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 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 .
The major systemic side effects of carbamazepine are nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, leukopenia, and fluid retention (table 4). 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 (table 5) . 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 [88-90]. The United States Food and Drug Administration recommends screening for this allele in patients of these ethnic groups prior to starting carbamazepine . 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 [43,70,92]. 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 "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.)
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 [75,93]. 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 .
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 concentrations increased . 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 concentration of 88 mcg/mL. After target serum levels have been achieved, 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 .
Common side effects of valproate include weight gain, nausea, vomiting, hair loss, easy bruising, and tremor (table 4). Divalproex is a formulation of valproate that can minimize gastrointestinal distress. In addition, valproate is rarely associated with hepatic failure and thrombocytopenia (table 5); liver function tests and platelets should thus be monitored at 6 to 12 month intervals in all patients taking the drug [43,70,92]. (The United States 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.
Additional information about the pharmacology of valproate and its adverse effects and available preparations are discussed separately, as well as problems using valproate in women of childbearing age. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate' and "Bipolar disorder in women: Contraception and preconception assessment and counseling".)
Antipsychotics — First- and second-generation antipsychotics are efficacious for treating both psychotic and nonpsychotic manic and hypomanic episodes [7,8,12,13,24,27,28,97].
First-generation — Among first-generation antipsychotics, we prefer haloperidol for treating manic episodes because it has been widely studied and generally causes less orthostatic hypotension and sedation than chlorpromazine, which is also efficacious [60,98]. Other first-generation antipsychotics such as fluphenazine, loxapine, perphenazine, thiothixene, and trifluoperazine are effective as well .
We suggest patients initially receive haloperidol at a dose of 5 to 15 mg per day, depending upon the severity of symptoms, the patient’s 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 patient’s ability to adhere to treatment with divided doses. One useful guide is to prescribe 0.2 mg per kg per day . In a meta-analysis of 15 randomized trials (2022 acutely ill patients with pure mania or mania with mixed features), which found that haloperidol was comparable to carbamazepine, olanzapine, risperidone, and valproate, the dose of haloperidol ranged from 2 to 85 mg per day .
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) 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); heterogeneity across studies was moderate . 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 "Tardive dyskinesia: Etiology and epidemiology" and "Neuroleptic malignant syndrome".)
Second-generation — Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone are each efficacious for treating mania and hypomania , and the choice often depends upon differences in adverse side effects (table 6). 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 (table 7). Extrapyramidal side effects (EPS) are more common with aripiprazole, olanzapine, risperidone, or ziprasidone compared with 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", section on 'Extrapyramidal symptoms'.)
The usual starting and target dose for second-generation antipsychotics that were used in randomized monotherapy trials for mania, and side effects that commonly occurred, are described below [75,102-110]. 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 clinicians are 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.
●Asenapine – Asenapine is started at 5 or 10 mg twice daily on day 1, and thereafter dosed at 5 or 10 mg two times per day. Some patients may respond to a total daily dose of 15 mg per day, split between two doses. Common side effects include sedation, fatigue, dizziness, extrapyramidal symptoms, vomiting, dry mouth, and weight gain.
●Cariprazine – The standard dose range for cariprazine is 3 to 12 mg/day once daily. On day 1 the dose is 1.5 mg/day, and on day 2 the dose is 3 mg/day. Depending upon response and tolerability, the dose is subsequently increased by increments of 1.5 or 3 mg/day to a maximum of 12 mg/day. Common side effects include akathisia, extrapyramidal symptoms (parkinsonism), tremor, sedation, blurred vision, dizziness, dyspepsia, diarrhea, and vomiting.
●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.
●Paliperidone – The standard dose range for paliperidone is 3 to 12 mg/day once daily. Paliperidone is started at either 3 or 6 mg/day on day 1; thereafter, the dose is titrated up by increments of 3 mg/day every one to three days to a maximum of 12 mg/day, depending upon response and tolerability. The most common adverse events are headache, somnolence, dizziness, akathisia, hypertonia, and dyspepsia.
●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 side effects".)
Elderly — Treatment of geriatric manic and hypomanic episodes is discussed separately. (See "Geriatric bipolar disorder: Acute treatment", section on 'Mania and hypomania'.)
Pregnancy — Treatment of mania and hypomania 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 "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy" and "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy" and "Bipolar disorder in women: Contraception and preconception assessment and counseling".)
INDICATIONS FOR REFERRAL — Although some primary care clinicians have the requisite training and experience to manage bipolar disorder, many patients are referred to psychiatrists and other mental health clinicians if these specialists are available. Common indications for referral include:
●Suicidal ideation and behavior
●Psychotic features (eg, auditory hallucinations commanding patients to kill themselves)
●Impulsive and dangerous behavior
●Comorbid psychopathology (eg, anxiety disorders and substance use disorders)
●Multiple (eg, two to four) failed medication trials
●Administration of adjunctive psychotherapy
●Recurrence of mood episodes
Primary care clinicians who refer patients to specialists are encouraged to remain involved in management. General internists and other clinicians can help educate patients and families about pharmacotherapy and reinforce the need for adherence, and typically collaborate in evaluating patients prior to treatment and monitoring vital signs, weight, height, and waist size during treatment.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Bipolar disorder (manic depression) (Beyond the Basics)" and "Patient education: 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," which 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), and nearly always experience hypomanic episodes (table 2) and major depressive episodes (table 3). Bipolar II disorder is characterized by at least one episode of hypomania and one or more episodes of major depression. (See 'Definition of bipolar disorder' above and "Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.)
●Patients presenting with acute mania 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.)
●For patients with severe manic 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 mania that does 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, quetiapine, or risperidone. (See 'Resistant patients' above.)
●For treatment refractory patients with severe mania 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 mania, 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 mania that does 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.)
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