Charles T. Nguyen, MD

Bipolar disorder is the sixth leading cause of medical disability worldwide for persons aged 15 to 44 years.

 People with bipolar disorder work 14 years less than the average population,

 and unemployment often exceeds 60%, even among patients with a college education.

 The social consequences are also high. More than 65% of patients have difficulty in maintaining long-term relationships and 60% have troubled relationships with their children.

 Bipolar disorder is further associated with an extreme danger to oneself. Up to 50% of patients with bipolar disorder will attempt suicide and as many as 20% will complete suicide.

 Given these serious consequences, it is important to implement a treatment plan that treats bipolar episodes rapidly and effectively.

After the resolution of an acute episode, maintenance therapy can be used to reduce future relapses. Without treatment, more than 90% of patients will experience subsequent manic or depressive episodes.

 Even with treatment, relapse rates range from 40% to 60%.

 Each additional mood episode worsens a patient’s long-term prognosis and increases the risk of future relapses. Therefore, it is crucial that a prophylactic treatment plan be implemented.

While effective treatments for acute mania and bipolar prophylaxis are available, they are not without risk. Many medication regimens are associated with significant adverse effects. As a result, side effect mitigation has become an important part of the treatment plan.

This article examines the latest research on treating acute manic episodes and reducing the risk of future episodes, including optimal dosing and titration schedules. It also discusses common medication side effects and mitigation strategies.

The treatment of acute mania initially centered on mood stabilizers and typical antipsychotics including lithium, valproate/divalproex, carbamazepine, and chlorpromazine. More recently, second-generation antipsychotics (SGAs) have been found to reduce the duration of manic episodes while minimizing extrapyramidal symptoms (EPS) often associated with typical antipsychotics. Trials studying the efficacy of pharmacologic agents in acute mania have used several approaches. These include the analysis of individual medications versus placebo, active comparator trials, and combination therapy studies. Each type of trial provides clinically relevant information that can be used to improve the treatment of acute mania.

In studies of individual medications versus placebo, 9 agents have shown efficacy and received an FDA indication for the treatment of acute mania. Once efficacy has been established, it is important to evaluate the time to onset of symptom reduction given the high rates of morbidity and mortality associated with mania. Among FDA-approved agents, onset varies from 3 to 21 days.

 Medication dosing and rate of titration can significantly affect clinical response and may increase the risk of side effects.

Early studies demonstrated the benefits of lithium, valproate/divalproex, carbamazepine, and chlorpromazine in the treatment of acute mania. Later trials found that SGAs are also efficacious in reducing the duration of manic episodes. It has been hypothesized that SGAs decrease dopamine transmission through blockade or partial agonism of dopamine D

 receptors. This may explain their antimanic effect, since mania is reportedly associated with dopaminergic hyperactivity.

 
 Treatment of mania with second-generation antipsychotics 

All 5 SGAs (olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole) have been examined in at least 2 placebo-controlled, double-blind trials for the treatment of acute mania. The primary measure of efficacy in the majority of studies was the change from baseline to end point based on the Young Mania Rating Scale (YMRS). Ziprasidone studies evaluated changes based on Mania Rating Scale scores of the Schedule for Affective Disorders and Schizophrenia (MRS-SADS). Most studies lasted 3 weeks, with the exception of olanzapine (4 weeks) and quetiapine (12 weeks). Given the similarity of these trials, it is possible to directly compare important parameters including starting dose relative to onset of action, response rates, completion rates, use of concomitant medications, and statistically significant differences in side effects. The design and results of these studies are summarized in 

 The primary goal in treating bipolar mania is to stabilize the patient as rapidly and safely as possible. Medications with a rapid onset of action may lead to health care savings, shorter hospital stays, and decreased morbidity and mortality. The earliest day at which a medication effect separates from placebo is one indication of how quickly a medication works. However, it is important to note that early placebo-controlled studies used day 7 as the first postrandomization measurement day, while more recent studies used day 2. Tohen and colleagues

 conducted 2 placebo-controlled trials involving olanzapine. The starting dosages were 10 and 15 mg/d, respectively. Although olanzapine separated from placebo at the end of each study, the starting dosage of 15 mg/d had a faster onset of action, separating from placebo at day 7 versus day 21. The mean dose was similar in both studies.

Risperidone trials used day 3 as their first measurement date. Both studies gave an initial dosage of 3 mg/d. One study showed a separation from placebo on day 3,

 while another showed a separation on day 7.

 Quetiapine trials used a titration schedule to minimize adverse effects. The dosage was 100 mg/d on day 1, followed by an increase of 100 mg/d until day 4, and up to a maximum dosage of 600 mg/d on day 5. Separation from placebo occurred on day 4 and day 7.

 Ziprasidone studies used day 2 as the first measurement date. The starting dosage was 80 mg/d on day 1, and 160 mg/d by day 2. Both studies separated from placebo on day 2.

 Aripiprazole studies both started at a dosage of 30 mg/d and could be decreased to 15 mg/d on day 2 to minimize adverse effects. Both studies showed a separation from placebo on day 4.

Concomitant medication and completion rates.

 The examination of concomitant medications is important because they may produce a confounding effect on efficacy measures. For example, hypnotics may help patients sleep better at night, thus reducing the YMRS score for sleep. Likewise, if higher doses of lorazepam are used to treat anxiety, manic symptoms and discontinuations because of side effects may be decreased. In reviewing placebo-controlled trials, there is no consensus on the maximum dose or duration of concomitant medications. Olanzapine studies allowed the use 4 mg/d of lorazepam from days 1 through 7 in one trial, and 2 mg/d from days 1 through 4 in a second trial.

 It is interesting to note that the higher dose of lorazepam was allowed in the trial with a lower starting olanzapine dosage of 10 mg/d.

Both risperidone studies allowed 8 mg/d of lorazepam from days 1 through 3, while a ziprasidone trial allowed 8 mg/d from days 1 through 7.

 Up to 6 mg/d of lorazepam from days 1 through 4 in the aripiprazole studies was allowed. Quetiapine studies also allowed 6 mg/d of lorazepam from days 1 through 4.

 Furthermore, in the quetiapine study by Bowden and colleagues,

 chloral hydrate at dosages of 2000 mg/d was allowed from days 1 through 7 and up to 1000 mg/d from days 8 through 84. In addition, zolpidem was allowed from days 1 through 84.

Although not considered a primary end point in acute mania studies, completion rates may be an important measure of treatment effectiveness. An active medication may separate from placebo in clinical response, but a low completion rate raises questions as to the real-world effectiveness of the medication. Completion rates can be affected by the use of concomitant medications. The quetiapine study by Bowden and colleagues

 that employed concomitant use of lorazepam, chloral hydrate, and zolpidem reported the highest rates of completion. More than 90% of patients in the quetiapine arm and 69% of patients in the placebo arm completed the study. The aripiprazole study by Keck and colleagues

 reported the lowest completion rates with only 42% of patients in the aripiprazole arm and 21% of patients in the placebo arm finishing the study.

 Response to treatment is typically defined as a 50% or greater reduction on the primary efficacy measure (YMRS or MRS) or “much or very much improvement” on the Clinical Global Impression Improvement (CGI-I) scale.

 An estimate of the true response to the medication (placebo-corrected response rate) is the difference in the response rates between the active agent and placebo.

 The average placebo-corrected response rate in all SGA studies ranged from 16% to 23% (olanzapine 23%, risperidone 23%, quetiapine 17%, ziprasidone 16%, and aripiprazole 21%). The placebo-corrected response rates were similar for the olanzapine studies (24.4% and 21.9%), aripiprazole studies (21% in each study), risperidone studies (15% and 19%), and ziprasidone studies (15% and 16.8%). However, the placebo-corrected response rates were quite different in the quetiapine studies (26% and 8%).

 In order to obtain rapid results in the treatment of mania, it is important to quickly reach a therapeutic level of medication. Numerous studies have analyzed this concept with valproate/divalproex. Several studies showed that when oral (“rapid”) loading doses of valproate/divalproex are used, most patients have significant improvement in manic symptoms by day 5, with the greatest percent change on the MRS occurring in the first 3 days of treatment.

 This approach is generally well tolerated. An open-label trial examining valproate oral loading (20 mg/kg/d) showed a therapeutic serum level (of 50 µg/mL or higher) in patients within 24 hours.

In a randomized, double-blind study, Hirschfeld and colleagues

compared oral-loaded valproate (30 mg/kg/d on days 1 and 2, followed by 20 mg/kg/d on days 3 through 10) to standard-titration valproate or lithium and reported that the oral-loaded patients achieved therapeutic serum levels more quickly than the standard-titration group. By day 3, 84% of oral-loaded patients and 30% of standard-titration patients achieved therapeutic serum levels of valproate, while neither group differed statistically in the number and types of adverse events. The oral-loaded group showed a statistically significant improvement relative to the standard-titration group at days 5, 7/8, and 10 in the MRS, Manic Syndrome Scale, and Behavior and Ideation Scale.

Valproate/divalproex: optimal therapeutic serum levels.

 Two randomized controlled trials have shown valproate/divalproex to be effective in the treatment of acute mania, but the relationship between serum levels and efficacy was not fully established.

 The American Psychiatric Association’s practice guidelines describe a broad therapeutic range for trough valproate/divalproex serum concentrations between 50 and 125 µg/mL.

 A number of studies have shown a significant positive relationship between valproate serum levels and clinical response.

 examined 374 patients with mania and found that the efficacy of valproate was significantly higher than that of placebo beginning at 71.4 to 85.0 µg/mL and for all higher valproate levels. In addition, the 94.1 to 107.0 µg/mL and greater than 107.0 µg/mL groups were superior to the lowest valproate serum level group (less than 55.0 µg/mL group). The mean discontinuation rate for adverse events across all groups was 3%, suggesting similar tolerability. Taken together, the data suggest that a valproate/divalproex serum concentration of 94.1 µg/mL or higher provides optimal efficacy without increased side effects.

Active comparator trials are useful in distinguishing the head-to-head efficacy of medications. Studies have compared lithium versus many mood stabilizers and antipsychotics, haloperidol versus all SGAs except for ziprasidone, and olanzapine versus risperidone and valproate/divalproex. In general, all agents have shown similar efficacy relative to each other, although one study found that olanzapine was associated with a greater reduction in YMRS scores than valproate/divalproex.

Two head-to-head studies of olanzapine and divalproex assessed their relative efficacy in the treatment of bipolar disorder. The initial dosing in both studies differed. The study by Zajecka and colleagues

 started olanzapine at 10 mg/d on days 1 through 2 and titrated, at the discretion of the investigator, to a maximum of 20 mg/d. Divalproex was orally loaded at 20 mg/kg/d. The study by Tohen and colleagues

 started olanzapine at 15 mg/d and used a standard-titration divalproex dose of 750 mg/d. The mean YMRS score changes in this study were significantly greater with olanzapine (–13.4) than with divalproex (–10.4, 

 = .028). No significant differences between olanzapine (–17.2) and divalproex (–14.8, 

 = .210) were seen in the study by Zajecka and colleagues.

 The difference may be explained by the smaller group of 120 patients compared with 251 patients in the study by Tohen and colleagues,

Placebo-controlled trials of SGAs showed similar changes in YMRS scores and response rates, but the best way to establish relative efficacy is to conduct a head-to-head comparator trial. To date, only one study compared olanzapine with risperidone in the treatment of acute mania.

 The 3-week trial involved 329 patients with nonpsychotic acute mania and showed no differences in YMRS scores or response rates between the 2 groups. However, the mean improvement in MADRS scores was statistically greater with olanzapine than with risperidone.

Polytherapy is commonly used in the treatment of initial and refractory episodes of mania. This generally involves the combination of a mood stabilizer with an SGA. Such combinations are associated with a 20% higher response rate than individual mood stabilizers.

 However, polytherapy is also associated with significantly higher rates of adverse effects.

Four studies analyzing combination therapy for the treatment of mania in adults have been published.

 In addition, one combined analysis included the published quetiapine study and an unsuccessful quetiapine study that has not been published.

 All studies were double-blind, randomized, and placebo-controlled. Study duration was typically 3 weeks, although the olanzapine trial lasted 6 weeks.

 
 YMRS score reduction with combination therapy 

 Olanzapine, risperidone, and quetiapine, in combination with valproate/divalproex or lithium, resulted in statistically significant reductions in YMRS scores and response rates compared with valproate/divalproex or lithium plus a placebo. In the olanzapine polytherapy group, YMRS scores decreased by 13.1, with a response rate of 68%.

 Risperidone combination therapy resulted in a YMRS score reduction of 14.3 and a response rate of 53%.

 Quetiapine, in the combined analysis of 2 polytherapy trials, was found to reduce YMRS scores by 15.3 and produce a 56% response rate.

Overall, polytherapy was associated with a mean reduction in YMRS scores of 14.2 and a response rate of 59%. In comparison, monotherapy was associated with an average YMRS score reduction of 9.8 and a clinical response of 39% (

One study analyzing combination therapy failed to separate from monotherapy at the primary end point of YMRS score reduction.

 In this trial, risperidone was combined with valproate/divalproex, lithium, or carbamazepine and compared to monotherapy with valproate/divalproex, lithium, or carbamazepine. Although YMRS score changes did not differ from those seen with monotherapy, response rates were significantly higher with combination therapy. In a post hoc analysis, the authors excluded patients in the carbamazepine polytherapy group after discovering that carbamazepine reduced risperidone concentrations by 40%. Excluding carbamazepine, combination therapy separated from monotherapy in YMRS score reduction.

SGA dosing: combination therapy versus monotherapy.

 No clinical trials to date have directly compared SGA combination therapy versus SGA monotherapy. Nevertheless, it is helpful to analyze the efficacy and dosing of SGA polytherapy and SGA monotherapy trials when deciding upon treatment medications. On average, combination trials used lower doses of SGAs compared to monotherapy trials. Doses were 5.3 mg lower with olanzapine, 0.7 mg lower with risperidone, and 115 mg lower with quetiapine.

 Despite the reduced doses, clinical response favored polytherapy versus antipsychotic monotherapy. Response rates were 11% higher with olanzapine polytherapy, 1.3% higher with risperidone polytherapy, and 8% higher with quetiapine polytherapy. The risperidone polytherapy response rate included a CGI-I rating of much or very much improved,

 while response rates in all other studies represent a 50% reduction in YMRS score. This probably accounts for the lower risperidone polytherapy response rate. Although comparisons between SGA combination therapy and SGA monotherapy trials are often unreliable given different study designs, patient populations, and in the case of olanzapine, different study lengths, the response rates suggest that lower antipsychotic doses can be used in polytherapy treatment with good results.

. Side effects in combination therapy were generally greater than those with mood stabilizer monotherapy. Study discontinuations because of adverse events occurred more frequently with olanzapine polytherapy, while no statistical difference was seen in other studies. Combination therapy with olanzapine resulted in a higher frequency of somnolence, dry mouth, tremor, speech disorder, increased appetite, and weight gain (3.1 kg vs 0.23 kg). Risperidone polytherapy was associated with increased EPS in 1 of 2 studies and greater weight gain in both studies (averaging 2.05 kg). Quetiapine polytherapy was associated with more somnolence, dry mouth, asthenia, postural hypotension, and a weight gain of 1.97 kg compared with 0.27 kg in monotherapy.

Overall, polytherapy with an SGA and mood stabilizer produced greater improvements in YMRS scores and clinical response than mood stabilizer monotherapy. Combination therapy also resulted in more weight gain, somnolence and, in the case of risperidone, EPS.

Maintenance therapy is an important component of treatment in bipolar disorder and can effectively reduce the rate of relapse. Practice guidelines for bipolar disorder recommend initiation of maintenance treatment following an initial manic episode to prevent relapse, facilitate functional improvement, reduce the frequency of cycling, and decrease the risk of suicide.

 Four agents have been FDA-approved for maintenance therapy in bipolar disorder: lithium, lamotrigine, olanzapine, and aripiprazole. In addition, valproate/divalproex is commonly used in clinical practice. As with acute mania, studies have analyzed individual medications versus placebo, active comparisons between medications, and combination therapy regimens.

 Much of the early research in bipolar maintenance therapy focused on lithium monotherapy and often showed impressive results. However, early studies were associated with numerous statistical problems, including poor diagnostic criteria, inclusion of unipolar patients, failure to use last observation carried forward methodology, and abrupt discontinuation of lithium at randomization to placebo. It was not until the last decade that comparisons between lithium and placebo occurred using modern methodology, often in studies analyzing newer medications needing an active comparator arm.

Three relatively recent studies have compared lithium with placebo. One included 175 patients with a recent manic or hypomanic episode,

 another included 463 patients with a recent episode of bipolar depression,

 and the third included 372 patients in symptomatic remission from a manic episode.

 Lithium mean serum levels ranged from 0.8 to 1.0 mEq/L. Study discontinuations were notable. Only 2% of subjects treated with lithium in the study by Bowden and colleagues

 and 17% of patients treated with lithium in the study by Calabrese and colleagues

 completed the trials. Lithium significantly delayed time to intervention for a mood episode and time to intervention for a manic episode in the first 2 studies

 but did not separate from placebo on these parameters in the third.

 Lithium failed to delay time to a depressive episode in all 3 studies. Treatment emergent adverse events were more prevalent in the lithium group, including nausea, diarrhea, tremor, and somnolence.

A meta-analysis of randomized controlled trials that compared lithium with placebo, excluding trials that abruptly discontinued lithium, found 5 studies ranging in length from 11 months to 4 years.

 Overall, study withdrawal was lower with lithium relative to placebo. Lithium was more effective in preventing a new affective episode, with an average relapse rate of 40% over 1 to 2 years compared with 60% in the placebo group. In addition, lithium had a lower rate of manic or mixed recurrences. There was no difference in the rate of depressive episodes. The side effects seen more frequently with lithium were somnolence, nausea, and diarrhea.

Studies have also focused on the relationship between lithium treatment and suicidal acts. Findings have consistently demonstrated a reduced rate of suicide attempts and completions during lithium maintenance treatment compared with patients who did not take lithium.

 An analysis of 34 trials that included 17,491 patients with major affective illnesses found that the overall rate of suicidal acts in the group without lithium was 3.1% per year compared with 0.2% per year among patients who received lithium treatment.

 In a subgroup analysis, the rate of suicidal acts in patients with bipolar disorder decreased from 6.1% per year without lithium to 0.295% per year with lithium, a 95% risk reduction.

 Two randomized controlled trials compared lamotrigine with placebo.

 Dosing of lamotrigine ranged from 50 to 400 mg. Patients recovering from manic episodes had a 5% study completion rate, compared with 0% in the placebo group. Patients recovering from a depressive episode had a 17% completion rate versus 10% in the placebo group. Lamotrigine was superior to placebo in delaying time to intervention for any mood episode and time to intervention for a depressive episode. Lamotrigine did not separate from placebo in delaying time to intervention for a manic episode in either study, but a combined analysis of both studies found a significant difference.

 In the combined analysis, lamotrigine did not separate from placebo on any adverse event.

 that compared divalproex, lithium, and placebo is the only double-blind, randomized, placebo-controlled trial to analyze the efficacy of divalproex in delaying the onset of a mood episode in bipolar I disorder. Patients who received divalproex had a mean serum level of 84.8 µg/mL by day 30. The minimum and maximum divalproex concentrations over the 52-week maintenance phase were 0.6 and 156 µg/mL, respectively. Study discontinuations were lower in subjects treated with divalproex than in the placebo group, and divalproex was associated with a significantly lower termination rate for recurrent mania or depression.

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