Current Approaches to the Treatment of Bipolar Disorder
With Atypical Antipsychotics
Needs Assessment: This article deals with the availability of novel therapies for the long-term treatment of bipolar disorder, and whether atypical antipsychotics have mood-stabilizing properties. Recent data suggest that atypical antipsychotics may play a role in the long-term management of bipolar illness, particularly when used in combination with other medications and psychoeducation.
• Recognize unmet needs in the treatment of bipoar disorder.
• Discuss limitations of the currently available maintenance treatments for bipolar disorder.
• Assess the use of atypical antipsychotics in the long-term treatment of bipolar disorder.
Target Audience: Primary care physicians and psychiatrists.
CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
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This activity has been peer-reviewed and approved by Eric Hollander, MD, chair at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: February 13, 2007.
Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.
To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged to measure outcomes for this CME activity. Please submit this posttest by March 1, 2009 to be eligible for credit. Release date: March 2007. Termination date: March 1, 2009. The estimated time to complete all three articles and the quiz is 3 hours.
Primary Psychiatry. 2007:14(3):70-76
Dr. Vieta is director of the Bipolar Disorders Program at the Hospital Clinic of the University of Barcelona and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) in Barcelona, Spain.
Disclosure: Dr. Vieta is a consultant to AstraZeneca, Bial, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, sanofi-aventis, Servier, and UCB Pharma; on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Otsuka, Pfizer, sanofi-aventis, and Servier; and receives grant support from AstraZeneca, Bial, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Otsuka, Pfizer, sanofi-aventis, Servier, the Spanish Ministry of Health, REM-TAP Network, and the Stanley Foundation.
Please direct all correspondence to: Eduard Vieta, MD, PhD, Director, Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain; Tel: 34-932-275-401;
Fax: 34-932-275-477; E-mail: email@example.com.
Bipolar disorder has an episodic and chronic nature that requires long-term treatment in all patients. There is an unmet need for well-tolerated and clinically effective maintenance therapy with enhanced patient adherence. Few well-tolerated treatment options are available that are effective in all phases of bipolar disorder and prevent episode recurrence. Lithium has established efficacy in the prevention of further manic episodes and may also be effective in the prevention of depression and suicide. Safety is a concern due to a narrow therapeutic window. For valproate and carbamazepine, data appear much less compelling. Lamotrigine has been shown to be effective for long-term prevention of depressive episodes, but is not effective in acute episodes. Controlled studies suggest that some atypical antipsychotics may also have mood-stabilizing properties and may become standard for long-term therapy. The role of psychoeducation in improving adherence to medication in long-term treatment and patient outcomes is also emphasized.
Bipolar disorder is an episodic, chronic, and progressive illness that usually requires long-term treatment in most, if not all, patients.1-3 Although treatment may resolve symptoms during episodes, impaired functioning may persist for many patients.4,5 Maintenance therapy is necessary in order to maintain and develop initial success of treatment. Maintenance therapy aims to prevent relapses as well as reduce subthreshold symptoms, risk of suicide, cycle frequency, and mood instability.6 Long-term or even life-long therapy is usually required to improve functioning and maintain quality of life.
Identifying clinically effective maintenance therapy treatments for bipolar disorder has been a significant challenge. An ideal long-term treatment or mood stabilizer would effectively treat episodes of mania and depression as well as prevent relapses. In addition, such treatment should be well tolerated and have few side effects. In the absence of an ideal mood stabilizer, lithium has been the recommended treatment for maintenance therapy.7,8 Some randomized, controlled studies suggest that lithium, carbamazepine, divalproex, and lamotrigine may be clinically useful as maintenance treatment for bipolar disorder.2,9-11
Nevertheless, a substantial number of patients with bipolar disorder do not respond, suffer recurrence, or cannot tolerate side effects of these agents. Intolerance to side effects and inadequate long-term adherence to treatment potentially translates into poor treatment outcomes. Although few adequately designed long-term maintenance studies have been conducted, emerging data suggest that certain atypical antipsychotics may be effective in maintenance therapy for patients with bipolar disorder. Recent evidence for long-term therapies in bipolar disorder is reviewed in this article with particular emphasis on the long-term use of atypical antipsychotics.
Early research has shown that lithium is a standard choice for the long-term treatment of bipolar disorder. However, this research has been criticized due to methodological limitations. Moreover, naturalistic studies, which more closely approximate clinical practice, have shown less activity with lithium maintenance therapy.12 In addition, many bipolar disorder patients have some residual illness with lithium maintenance treatment as well as with other treatment modalities.13 Due to this effect, most patients are treated with combinations of several drugs. Clinicians also accept that abrupt withdrawal from lithium can induce a manic episode.
In addition to these limitations, some patient subsets are intolerant to lithium or are unable to achieve adequate efficacy and/or adherence at serum levels necessary for symptom remission.14 Results from a double-blind, prospective maintenance trial in which bipolar disorder patients were randomly assigned to therapy targeting either standard (0.8–1.0 mmol/L) or low (0.4–0.6 mmol/L) serum lithium levels, showed that higher serum lithium levels were associated with a higher rate of side effects and lower rate of adherence.14 A post-hoc re-analysis of the data—which accounted for baseline lithium levels—showed that patients with standard serum lithium levels at baseline who were randomized to the low range had the highest risk of recurrence.15
However, recent trials have provided further support to the long-term efficacy of lithium, including lamotrigine long-term studies. Furthermore, studies find that lithium may have specific anti-suicidal effects,16 which has only also been shown for clozapine in schizophrenia.17
Lamotrigine is an anticonvulsant with limited efficacy during acute episodes, no efficacy for mania, and some efficacy for depression. However, it has proven effectiveness in the long-term treatment of bipolar disorder.11 A main concern during lamotrigine treatment is emergence of skin rash. Two 18-month, randomized, double-blind trials compared lamotrigine, lithium, and placebo as maintenance treatment in a total of 1,315 recently manic or depressed patients with bipolar I disorder.11,18 Individual and combined study analyses showed that both lamotrigine and lithium significantly prolonged the time to intervention for any mood episode compared with placebo (Figure 1). Despite the enriched design for lamotrigine responders, lithium prevented manic episodes more effectively than lamotrigine and placebo.19 Lamotrigine was particularly efficacious in the prevention of depressive episodes, which is the primary use of the drug in bipolar disorder.
Only one randomized, placebo-controlled study has assessed divalproex in comparison with placebo for maintenance therapy in bipolar disorder patients.9 Divalproex, lithium, or placebo were given to 372 patients and time to relapse of any mood episode during the 1-year treatment period was determined. There was no significant difference between treatments (Figure 2), although a post-hoc analysis showed that patients who had already began divalproex prior to randomization and were receiving divalproex in the study had significantly fewer relapses than those receiving placebo.20
Prior studies of carbamazepine for the long-term treatment of bipolar disorder have shown the drug is not efficacious.21 Lithium (n=74) and carbamazepine (n=70) were compared in a randomized study of 144 bipolar disorder patients followed for 2.5 years.21 Patients treated with carbamazepine had significantly more recurrences and use of concomitant medication (P=.041) and/or adverse events (P=.007) compared with lithium.
In a smaller double-blind study, 52 bipolar disorder patients were randomly assigned to 1 year of treatment with lithium or carbamazepine, then treated with the opposite drug for 1 year, and additionally treated with a combination of the two drugs for 1 year.22 More patients treated with carbamazepine (37.1%) failed to complete the first full year of treatment due to lack of efficacy compared with those treated with lithium (31%). With the combination treatment, 24.1% of patients withdrew from the study due to lack of efficacy.
Another study randomized 94 patients in remission to double-blind treatment with lithium (n=44) or carbamazepine (n=50) for 2 years.23 The frequency of mood episodes and the proportion of patients exiting the study were higher with carbamazepine treatment than with lithium, with a completion rate of 32% and 36% respectively.
Nevertheless, data suggest that some efficacy in prevention of relapse and recurrence of manic or mixed episodes can be demonstrated for an extended-release formulation of carbamazepine.24 Patients (N=92) in a 3-week double-blind study of carbamazepine or placebo were assigned to 6 months of further open-label treatment with carbamazepine. The estimated mean time to relapse was 141.8 days, standard deviation (SD)=5.6 days, and 14.3% patients relapsed during the study. Patients who had previously received carbamazepine in the 3-week treatment period maintained their improvement and those who had received placebo demonstrated significant improvements in manic symptoms. The most common adverse events with carbamazepine were headache, dizziness, and rash. These results indicate that further studies to determine the role of carbamazepine in the long-term treatment of patients with bipolar disorder are warranted.
Atypical Antipsychotics as Maintenance Therapy
Due to their superior tolerability profile regarding extrapyramidal symptoms and tardive dyskinesia liability compared with conventional antipsychotics, atypical antipsychotics are increasingly being used for bipolar disorder treatment. Olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole have demonstrated efficacy in the treatment of bipolar mania in 3-week studies as monotherapy.25 When used in combination with lithium, divalproex, and other traditional mood stabilizers, olanzapine, risperidone, and quetiapine also proved to be more efficacious than lithium or valproate monotherapy.25 Evidence also suggests that some atypical antipsychotics are effective in the treatment of bipolar depression.26,27 Data indicating the efficacy in long-term treatment of bipolar disorder for each of these agents are reviewed in this article.
Several studies have addressed the efficacy of olanzapine as long-term therapy in bipolar disorder.28-30 Data from a study in which a 6–12-week phase of open-label olanzapine and lithium combination therapy was followed by 52 weeks of double-blind olanzapine or lithium monotherapy found that the prevention of depressive relapse—which was indicated by maintaining a 21-item Hamilton Rating Scale for Depression (HAM-D)21 score of £15—was quite similar with both agents. However, in the study, olanzapine was superior to lithium (P<.001) in reducing the incidence of manic relapse, which was indicated by an increase in Young Mania Rating Scale (YMRS) scores to ≥15.30
The efficacy of olanzapine in manic and depressive episodes and maintenance of remission has also been corroborated in a comparative study against divalproex.28 In this investigation, 251 adult patients with a bipolar I disorder, manic or mixed, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria were randomly assigned to olanzapine (5–20 mg/day) or divalproex (500–2,500 mg/day) during a 3-week, randomized, double-blind phase followed by a double-blind continuation phase of 44 weeks.28
Olanzapine was significantly superior to divalproex in mean improvement in YMRS total scores from baseline to endpoint (last observation carried forward to week 47; P=.03). A numerical but not significant difference was also observed in mean improvement of HAM-D21 scores in all patients and in those with moderate-to-severe depressive symptoms (HAM-D21 ≥20 at baseline).28 The median time to symptomatic remission of mania (YMRS £12) was significantly shorter for olanzapine (14 days) than for divalproex (62 days) (P=.05),28 although there was no significant difference between groups in mania remission rates and subsequent relapse into mania or depression. Treatment with olanzapine was associated with somnolence, increased appetite, and weight gain more frequently (P<.05) than divalproex.28
In another study, bipolar disorder patients who had previously received open-label treatment with olanzapine, were randomized to double-blind treatment for up to 52 weeks. Olanzapine was shown to be associated with lower rates of relapse and a longer time to relapse compared with placebo (P<.001).31
Olanzapine added to lithium or valproate has been evaluated in an 18-month study for prevention of relapse.29 Patients achieving syndromic remission after 6 weeks of treatment with olanzapine and lithium or valproate were randomized to further treatment with olanzapine (n=51) or placebo (n=48) in addition to lithium or valproate. At the end of the treatment period, symptomatic (using the total score on the YMRS and HAM-D21) but not syndromic relapse (meeting DSM-IV criteria for a manic, mixed, or depressive episode), was significantly different in patients treated with olanzapine and lithium or valproate compared with the group treated with placebo and lithium or valproate (P=.023).
Concerns raised by olanzapine as a long-term therapy for bipolar patients are related to weight gain and metabolic syndrome.
Quetiapine monotherapy has been shown to be superior to placebo in the improvement of mania and associated symptoms as well as the maintenance of response and remission rates in two double-blind, 3-month studies of bipolar disorder patients.32,33 In one study, patients were randomized to quetiapine (n=107), lithium (n=98), or placebo (n=95). Both quetiapine and lithium decreased YMRS scores significantly more than placebo at 3 weeks (P<.001) and this difference was maintained to week 12 (P<.001).32 Another study found a similar improvement in YMRS scores in patients treated with quetiapine or haloperidol versus placebo. The response (≥50% reduction in YMRS scores) and remission (YMRS £12) rates in the quetiapine-treated group were significantly greater than placebo at week 3 and week 12. Haloperidol was more efficacious than quetiapine at week 3, but not at week 12.33 A combined analysis of these two studies indicated that the majority of patients who responded by week 3 maintained their response through the end of the 3-month study period. Of the proportion of patients who did not respond by week 3 and who had a further assessment, 72% of quetiapine-treated versus 41% of placebo-treated patients responded by the end of the study. Similarly, remission rates in the quetiapine group were maintained to the end of treatment. Compared with placebo, a significantly greater proportion of patients in the quetiapine group met all clinical remission/euthymia criteria (YMRS £12 or YMRS £2 + MADRS £10 or YMRS £12 + Montgomery-Asberg Depression Rating Scale [MADRS] £8) by the primary endpoint (day 21; P<.01) and rates of remission/euthymia continued to improve to the end of the 3-month treatment period (P<.001).34 The results from these controlled studies show that the early treatment effect of quetiapine was maintained over a period of 3 months in patients with bipolar mania, but no controlled trials are available for quetiapine beyond 3-month follow-up.
Quetiapine has also been shown to have benefits as long-term therapy in two prospective, open-label studies of patients with rapid cycling.35,36 One study assessed 14 patients with rapid cycling, according to DSM-IV criteria (manic, hypomanic, mixed, depressive, or euthymic), treated with quetiapine, which was initiated at 50 mg/day and dosed according to tolerability and clinical response in combination with ongoing psychotropic medication for 112 days (SD=33 days).35 The Clinical Global Impressions for Bipolar Disorder (CGI-BP), YMRS, and HAM-D17 rating scales were included in efficacy assessments (Figure 3).
No controlled trials are available with risperidone beyond 12 weeks. A 6-month, open-label study suggests that monotherapy or combination therapy with risperidone may maintain the improvement of manic and depressive symptoms in patients with bipolar disorder over time.37 Forty-four patients who met DSM-IV criteria for bipolar II with a current hypomanic episode and a YMRS score >7 showed a significant reduction from baseline in YMRS score (P<.001) by the first week of risperidone treatment (Figure 4).37 This improvement in manic symptoms was maintained throughout the 6-month study period. There was no significant difference in the rate of improvement between patients receiving combination therapy or monotherapy with risperidone.37 Seventy-three percent of patients found a ≥50% reduction in YMRS scores from baseline and were considered responders. Risperidone treatment also significantly reduced HAM-D17 scores by week 1 (P<.001) and until the end of the 6-month treatment period (P<.001).37
Study data were included in an analysis involving patients with different index episodes, including manic, hypomanic, mixed, or depressive episodes, as well as those with schizoaffective disorder, bipolar type.38 In this heterogeneous sample (n=541), significant reductions in mean YMRS score occurred by week 1 and continued for 6 months (P£.001 versus baseline) for all groups except patients with depression (P<.05 versus baseline).38 Risperidone, either in combination with mood stabilizers or as monotherapy, was well tolerated in bipolar II patients with little evidence of tardive dyskinesia or extrapyramidal symptoms related adverse events emerging over a 6-month period.37 Double-blind controlled studies in patients with bipolar disorder are needed to confirm the findings from these open-label studies. Safety and tolerability concerns about risperidone in bipolar disorder included EPS liability, hyperprolactinemia, and weight gain.
There is evidence that suggests clozapine is effective against mood and psychotic symptoms in patients with schizoaffective disorder, bipolar type, and bipolar I disorder. In addition, results from an open study in patients (n=38) who met DSM-IV criteria for treatment-resistant schizoaffective or bipolar disorder suggest that clozapine may have utility as maintenance treatment.39 Patients in this study were randomly assigned to clozapine add-on treatment or treatment without clozapine and evaluated for 1 year. The CGI, HAM-D24, Brief Psychiatric Rating Scale (BPRS), and Bech-Rafaelsen Mania scales were included in the monthly assessments.39
Significant advantages across all measures, except the HAM-D24, were observed with clozapine versus treatment as usual.39 In particular, clozapine was a strong anti-manic and anti-mood lability agent. The decrease in the mean rate of change in BPRS score over 1 year or until last visit in the clozapine group revealed significant improvement, whereas there was worsening in the treatment-as-usual group (-3.68% versus 2.51% respectively; P=.001). Sixty-five percent of patients taking clozapine met the criteria for response—30% improvement in BPRS from baseline—by 3 months and 82% by 6 months.
Patients who were switched from treatment-as-usual to clozapine also benefitted. The nine patients (seven with bipolar I disorder) who had clozapine substituted for treatment-as-usual showed significant improvement in BPRS score (P<.05) over 1 year compared with scores at the termination of usual treatment.39 Overall, findings suggest that clozapine may have a role for bipolar disorder patients who do not respond to standard treatments but this should be confirmed in larger controlled studies. The safety profile of clozapine appeared to be worse than other atypical antipsychotics with side effects noted throughout the study.39 Somatic complaints increased relative to baseline in clozapine-treated patients and were more severe than in the treatment-as-usual group. No patient developed agranulocytosis but this side effect is a known concern in the use of clozapine,40 besides weight gain and metabolic effects.
One randomized, double-blind study has compared aripiprazole versus placebo in the maintenance treatment of bipolar disorder patients.41 Patients (n=161) who had recently experienced a manic episode or who had just completed an aripiprazole acute mania study were assigned to aripiprazole or placebo for 26 weeks. Time to relapse of symptoms and total number of relapses (P=.013) significantly decreased in patients treated with aripiprazole versus those treated with placebo. No effect was seen in prevention of depression or mixed episodes. Adverse events >10% in the aripiprazole group included anxiety, insomnia, depression, and nervousness.
There is little evidence on the use of amisulpride in bipolar disorder,42 and even less on its long-term use. Carta and colleagues43 reported an open-label study suggesting effective long-term prevention of mania with amisulpride.
Role of Psychoeducation in Long-Term Treatment
Concomitant psychosocial intervention during bipolar maintenance treatment is increasingly recognized as an important tool to enhance treatment adherence and other aspects of illness management.6 Supporting benefits of psychoeducation in the maintenance setting are findings from a study of bipolar I and II outpatients who were all receiving a standard pharmacologic treatment that showed concomitant group psychoeducation produces significantly more stable lithium levels over time (P£.05 at 6, 16, and 24 months) than nonstructured group meetings.44 Stable lithium levels most likely reflect enhanced long-term adherence to treatment.
Furthermore, intervention with psychoeducation translated into improved outcomes in a study that consisted of a 21-week, single-blind, randomized treatment phase and 2-year follow-up (Figure 5).45 At the follow-up period end, group psychoeducation significantly reduced the number of relapsed patients (P<.001 psychoeducation versus control) and increased the time to any recurrence (P<.001) including depressive (HAM-D17 ≥17), mixed (YMRS ≥20; HAM-D17 ≥12), and manic (YMRS ≥20) or hypomanic (YMRS ≥12) episodes.45 The number and length of hospitalizations per patient were also lower in those who received psychoeducation (P<.05). Despite the benefits of psychoeducation, however, >50% of patients receiving group psychoeducation and standard pharmacologic treatment had relapsed by the end of the 2-year follow-up period.
The treatment of patients with bipolar disorder remains a challenge for clinicians. Effective therapeutic approaches are required for the management of acute and chronic symptoms as well as prophylaxis against future episodes. In addition to lithium and certain anticonvulsants, atypical antipsychotics have shown promising results in bipolar disorder maintenance therapy but concerns about weight gain and metabolic syndrome are increasing. Strategies, such as psychoeducation in combination with effective drug therapy, may also improve bipolar disorder maintenance therapy. In the future, supplementary interventions, such as cognitive rehabilitation, may help reduce the gap between symptomatic recovery and functional recovery. PP
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41. Keck PE Jr, Calabrese JR, McQuade RD, et al, and the Aripiprazole Study Group. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67(4):626-637.
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