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A clinical review of aripiprazole in bipolar depression and maintenance therapy of bipolar disorder
Journal of Affective Disorders 128S1 (2011) S21–S28
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
A clinical review of aripiprazole in bipolar depression and maintenance therapy of bipolar disorder Lakshmi N. Yatham* Professor of Psychiatry, Vice Chair for Research and International Affairs, UBC Department of Psychiatry, The University of British Columbia, UBC Hospital, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada
article info
abstract
Keywords: Aripiprazole Bipolar depression Bipolar disorder Maintenance therapy
Background: Bipolar disorder is a chronic, recurrent disorder with a significant negative impact on quality of life. Effective treatments are available for acute mania. In contrast, there is a lack of consensus on the treatment of acute bipolar depression and long treatment options for bipolar disorder require more study. Aripiprazole is FDA approved for the treatment of acute mania. This paper reviews current data on the efficacy of aripiprazole in the treatment of acute bipolar depression and in maintenance therapy of bipolar disorder. Methods: PubMed and abstracts of recent conferences were searched for randomized, double-blind studies that investigated the efficacy of aripiprazole in acute bipolar depression or maintenance therapy of bipolar disorder. Results: Two studies assessed the efficacy of aripiprazole monotherapy in the treatment of acute bipolar depression. These showed that although aripiprazole significantly reduced depressive symptoms early in treatment, the results were not significantly different from placebo at the primary end point of week 8. As to long-term treatment, aripiprazole was superior to placebo in delaying time to relapse for manic episodes, but not for depressive episodes after 26 and 100 weeks of maintenance therapy. Aripiprazole was as effective as lithium, and adjunctive aripiprazole with lithium or valproate was more effective than placebo plus lithium or valproate, in preventing a manic relapse. Reductions in manic and mixed relapse rates compared to placebo were achieved in a study combining aripiprazole with lamotrigine; however, the results were not statistically significant. Similar to other maintenance studies, depressive relapse rates were not significantly reduced compared to placebo. Limitations: Negative findings for aripiprazole in the treatment of acute bipolar depression have been attributed to high study doses, rapid titration, and high placebo rates. A recent post-hoc analysis demonstrated that aripiprazole was more effective in patients with severe depressive symptoms, particularly for patients on a lower dose. Further research is needed to confirm this finding. The inability of aripiprazole to reduce the time to depressive relapse during maintenance therapy may be due to the recruitment of patients with an index manic episode and a consequent lower incidence of depressive relapses. Therefore, studies using a depression index episode are needed to appropriately evaluate relapse prevention. Conclusions: Although aripiprazole has proven efficacy for acute mania and the prevention of mania, the evidence available thus far does not support the efficacy of aripiprazole for the treatment of acute bipolar depression and prevention of depressive relapse. Further studies with appropriate doses and a depressive index episode are needed to clarify the role of aripiprazole in bipolar disorder. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Bipolar disorder is a chronic, recurrent lifetime condition with a significant negative impact on functioning and quality * Correspondence: Tel.: +1 604 822 7325; fax: +1 604 822 7922. E-mail address: [email protected] (L.N. Yatham). 0165-0327/$ – see front matter © 2010 Elsevier B.V. All rights reserved..
of life. Indeed, a recent review of studies that assessed functioning and disability in bipolar patients revealed that social, family and occupational functioning remains chronically impaired in almost half of bipolar patients (Sanchez-Moreno et al., 2009). Impairments in social and occupational functioning lead to a lower quality of life for patients with bipolar disorder. The data suggest that fewer
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than 50% of individuals with bipolar disorder report being actively employed. As their illness progresses, many who continue to work do so in roles requiring less responsibility than they were capable of in their premorbid state (SanchezMoreno et al., 2009). Thus, early and optimal treatment of bipolar disorder, both in the short- and long-term, is essential to improve functioning and quality of life for bipolar patients. There is evidence and consensus for the treatment of acute mania with lithium, anticonvulsant (e.g., valproate, carbamazepine), or atypical antipsychotic (e.g., olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone) monotherapy, or a combination of lithium or valproate with an atypical antipsychotic (Keck et al., 2003; Grunze et al., 2009; Sachs et al., 2006; Yatham et al., 2005; Yatham et al., 2006; Yatham et al., 2009). What is not yet sufficiently agreed upon is how to optimally manage acute bipolar depression (Grunze et al., 2010) or bipolar disorder in the longterm (Yatham et al., 2005; Yatham et al., 2006). Judd and colleagues (2002) demonstrated that bipolar I patients are symptomatic 47.3% of the time. Further, several researchers have found that depressive symptoms are experienced approximately three times more frequently than manic episodes (Altshuler et al., 2006; Judd et al., 2002; Kupka et al., 2007; Post et al., 2003) and more negatively affect quality of life compared to manic or hypomanic episodes (Michalak et al., 2008). Thus, effective treatments for acute depression and maintenance therapy in bipolar disorder are essential for optimizing the immediate and long-term functioning and quality of life of bipolar patients. An increasing number of atypical antipsychotics are being investigated for their efficacy in bipolar disorder. Efficacy in the treatment of acute mania has been established for many atypical antipsychotics (Bowden et al., 2010; Suppes et al., 2009; Tohen et al., 2004; Vieta et al., 2008a; Vieta et al., 2008b); however, the number of studies investigating their potential in acute bipolar depression or long-term relapse prevention is limited (Cruz et al., 2010). These agents typically demonstrate a more rapid onset of action when used to treat mania and are less likely to induce a switch to depression (Cruz et al., 2010; Fountoulakis and Vieta, 2008). Unfortunately, many of these agents have a significant side effect burden, including elevated lipid and prolactin levels and significant weight gain (Edwards and Smith, 2009; Fagiolini et al., 2008). Aripiprazole is an atypical antipsychotic with a novel mechanism of action. Its pharmacological profile shows partial agonist activity at dopamine D2 and D3 , and serotonin 5-HT1A receptors, and antagonist activity at serotonin 5-HT2A receptors (Shapiro et al., 2003; Vieta et al., 2010). Aripiprazole is approved by the FDA for the treatment of acute bipolar mania and maintenance treatment of bipolar I disorder. Further, aripiprazole adjunctive therapy has shown some benefits in the treatment of bipolar depression (Dunn et al., 2008; Kemp et al., 2007; Ketter et al., 2006; McElroy et al., 2007; Quante et al., 2010; Sokolski, 2007) and major depressive disorder (Berman et al., 2007; Marcus et al., 2008). The purpose of this paper is to review double-blind placebo-controlled studies that examined the efficacy of aripiprazole in the treatment of acute bipolar depression and maintenance therapy of bipolar disorder.
2. Methods This review was limited to data from randomized, double-blind, placebo-controlled studies. Searches using PubMed/Medline with the terms “bipolar depression,” “aripiprazole,” “maintenance therapy,” “double-blind,” and “randomized” were conducted. Abstracts of completed clinical trials presented at various (e.g., American Psychiatric Association [APA] and New Clinical Drug Evaluation Unit [NCDEU]) meetings since 2004 were also included.
3. Acute bipolar depression Several small open-label and double-blind studies have been conducted to examine the efficacy of aripiprazole in bipolar depression (Dunn et al., 2008; Kemp et al., 2007; Ketter et al., 2006; McElroy et al., 2007; Quante et al., 2010; Sokolski, 2007). However, to date, only two large, randomized, doubleblind, placebo-controlled clinical trials have been performed to examine the efficacy in bipolar depression (Thase et al., 2008). These studies involved two identically designed 8-week trials where adult patients were randomized to either aripiprazole (5–30 mg/day) (n = 186, 187 for studies 1 and 2, respectively), or placebo (n = 188 for each study). Patients were included if they were diagnosed with bipolar I disorder experiencing a major depressive episode without psychotic features. The primary and secondary efficacy end ˚ points were the mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impressions-Bipolar Version (CGI-BP) Severity of Illness Score-Depression from baseline to week 8, respectively. Statistically significant improvements with aripiprazole compared to placebo were seen in each trial in the MADRS change scores (Fig. 1) and CGI-BP scores at various time points until 5 to 6 weeks into treatment. The magnitude of early improvements in MADRS and CGI-BP scores was similar to those seen in previous trials with olanzapine and lamotrigine (Calabrese et al., 1999; Tohen et al., 2003); however, separation from placebo disappeared with aripiprazole by week 8 (Table 1). While these results may suggest a true lack of efficacy, other reasons for the loss of statistical significance by 8 weeks may include a high placebo response and improper dosing. Placebo response rates have been high in bipolar depression studies (Vieta and Carne, ´ 2005) and the reasons for this are not clear. High placebo response rates are puzzling, particularly in light of the fact that patients with bipolar depression are difficult to treat in clinical practice. Several possible explanations have been considered, including the types of bipolar patients recruited, severity of depressive episodes, sensitivity of rating instruments in detecting signal change, variability in rater agreement, and inflation of depressive symptom scores to meet entry threshold for inclusion. Placebo responses tend to be higher in mild compared with severe disease states and are higher in multiple-site studies (Vieta and Carne, ´ 2005). The placebo responses observed in the aripiprazole studies were similar to the placebo responses reported in bipolar depression studies with other atypical antipsychotics
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(A)
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Table 1 Effects of aripiprazole versus placebo in bipolar depression: change in MADRS scores Study
Study group
Baseline
MADRS week 8 Total
MADRS-6
Thase et al. (2008) CN138–096
Aripiprazole
29.07
−12.0
−
Placebo
28.49
−11.4
−
Aripiprazole
29.56
−12.3
−
Placebo
29.35
−11.8
−
Aripiprazole
33.72
−16.18 −11.74
Placebo
33.53
−11.97
−8.06
0.07
<0.05
p-value CN138–146
p-value Nashat et al. (2009)
(B)
Bech-6 ≥15
p-value Bech-6 <15 Aripiprazole
28.69
−11.5
Placebo
28.09
−10.82
−7.44
>0.05
>0.05
p-value
−7.76
˚ MADRS = Montgomery-Asberg Depression Rating Scale.
Fig. 1. Adjusted mean±SE change in MADRS scores from baseline in (A) study 1 and (B) study 2. *p ≤ 0.05 versus placebo; † p < 0.01 versus placebo. Baseline scores in study 1: placebo, 28.49; aripiprazole, 29.07. Baseline scores in study 2: placebo, 29.35; aripiprazole, 29.56. Reprinted with permission from Lippincott, Williams and Wilkins.
and other agents (Calabrese et al., 2005, 2008; Thase et al., 2006; Tohen et al., 2003). Of these studies, only trials with quetiapine demonstrated significant separation from the placebo group at week 8 (Calabrese et al., 2005; Thase et al., 2006). Olanzapine showed separation from placebo on MADRS scores; however, the items that contributed to this separation were not changes in core depressive symptoms (Tohen et al., 2003). Thus, in aggregate, these data suggest that quetiapine is clearly an effective agent for bipolar depression, while the efficacy of other agents needs further investigation given the high placebo response rates in these studies. Another potential explanation for the loss of statistical significance in MADRS and CGI-BP scores by week 8 with aripiprazole may have to do with a high initial dose or titration rate. Aripiprazole was initiated at 10 mg/day using twice-daily 5 mg doses. Patients who could not tolerate 10 mg/day were subsequently reduced to 5 mg. If 5 mg/day was not tolerated, the patient was removed from the study. Other patients were titrated upward by 5 mg each week until an effective dose was found with acceptable tolerability. Discontinuation rates for the aripiprazole groups were statistically greater than placebo (46.8% vs. 35.1% and 41.2% vs. 29.8% for studies 1 and 2, respectively). Also, time to discontinuation was significantly earlier for aripiprazole
compared to placebo. Significantly more patients withdrew due to adverse events compared to placebo (16.7% vs. 7.4%, 10.2% vs. 5.3% for studies 1 and 2, respectively), and side effects were experienced earlier in the aripiprazole groups. Further, the incidence of extrapyramidal-related symptoms was significantly higher in the aripiprazole group compared to placebo (34.3% vs. 9.7%, 29.7% vs. 10.5% for studies 1 and 2, respectively). High discontinuation rates and tolerability issues may point to higher than optimal dosing and titration in these studies. The efficacy of aripiprazole in acute bipolar depression may be better evaluated in a study with lower drug doses, titration rates, or a more severely depressed patient population. Indeed, a recent post-hoc analysis (Nashat et al., 2009) demonstrated that aripiprazole was more effective in patients with severe depressive symptoms, particularly at a lower dose. The Bech-6 Scale (six items from the Hamilton Depression Scale [HAMD17]) was used to separate patients with more severe core depressive symptoms. These items were related to 6 items on the MADRS scale (MADRS-6: apparent sadness, reported sadness, inner tension, lassitude, inability to feel, pessimistic thoughts) and the threshold between more and less severe core depressive symptoms was set at 15. Mean changes in MADRS total score and MADRS-6 score from baseline to week 8 were used as efficacy end points. MADRS Total and MADRS-6 score changes were also separated for each severity group by aripiprazole dose (5–10 mg, 15–20 mg, 25–30 mg). The results demonstrated significantly reduced MADRS-6 scores at week 8 in patients with more severe core depressive symptoms, but not for those with less severe core depressive symptoms (Table 1). When patients were separated further according to aripiprazole dose, only severely depressed patients on lower dose (5–10 mg) of aripiprazole differed significantly from placebo at 8 weeks. Similar results were seen for the MADRS total scores;
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Table 2 Comparison of time to relapse for any mood episode, manic episode, or depressive episode between aripiprazole and placebo maintenance therapy Study
Time to relapse Any mood episode
Manic episode
Depressive episode
0.52 (0.30–0.91)
0.31 (0.12–0.77)
0.83 (0.35–2.01)
Keck et al. (2006) [26 weeks]
HR (95% CI) p-value
0.02
0.01
0.68
Keck et al. (2007) [100 weeks]
HR (95% CI)
0.53 (0.32–0.87)
0.35 (0.16–0.75)
0.81 (0.36–1.81)
Owen et al. (2010)
Carlson et al. (2010)
p-value
0.011
0.005
0.602
HR (95% CI)
0.54 (0.33–0.89)
0.35 (0.15–0.83)
0.73 (0.36–1.48)
p-value
0.014
0.013
0.384
HR (95% CI)
0.67 (0.45–1.01)
0.55 (0.30–1.03)
0.78 (0.45–1.35)
p-value
0.055
0.058
0.381
HR = hazard ratio, CI = confidence interval.
45 40
Placebo Aripiprazole
Distribution of depressive relapses (%)
35 30
28% N=83
25 20
23% N=83
15
15% N=169
10 5 0
8% N=77
Ar vs. Pbo 26 weeks
10% N=173
12% N=77 7% N=168 Ar vs. Pbo 100 weeks
Ar+Li/V vs. Pbo+Li/V
5% N=178 Ar+Lam vs. Pbo+Lam
Fig. 2. Distribution of manic relapses with aripiprazole vs. placebo in the long-term treatment of bipolar disorder. Note: Data for Ar+Li/V vs. Pbo+Li/V includes mixed relapses. Ar = aripiprazole, Li = lithium, Pbo = placebo, V = valproate, Lam = lamotrigine. Data from Keck et al. (2006) [Ar vs. Pbo 26 weeks], Keck et al. (2007) [Ar vs. Pbo 100 weeks], Owen et al. (2010) [Ar+Li/V vs. Pbo+Li/V], and Carlson et al. (2010) [Ar+Lam vs. Pbo+Lam].
however, these differences disappeared after 6 weeks. The results of this post-hoc analysis demonstrate that further research involving dose optimization and separation of symptom severity are needed to fully evaluate aripiprazole efficacy in acute bipolar depression.
4. Maintenance treatment Four randomized, double-blind, placebo-controlled trials assessed the efficacy of aripiprazole for maintenance therapy of bipolar disorder. Aripiprazole monotherapy was studied over 26 weeks (Keck et al., 2006) and 100 weeks (Keck et al., 2007) in patients who had recently experienced a manic or mixed episode. Participants were stabilized on aripiprazole over a period of 6 to 18 weeks (15 or 30 mg/day) and then randomized to either aripiprazole or placebo for the doubleblind phase of the study. The primary efficacy end point was the time to relapse for any mood episode, whether manic, depressive, or mixed, during the double-blind phase.
Secondary end points included time to relapse for mania and time to relapse for depression. Aripiprazole was superior to placebo in delaying time to relapse (Table 2) both after 26 weeks and 100 weeks of maintenance therapy. Further, the proportion of patients that had a manic relapse (Fig. 2), but not depressive relapse (Fig. 3) was significantly lower in the aripiprazole group compared with the placebo group after 26 and 100 weeks of maintenance therapy. The relapse rate after 100 weeks of therapy was 33% and 52% for aripiprazole and placebo, respectively. Similarly, the Young Mania Rating Scale (YMRS) scores were significantly improved from baseline in the aripiprazole groups (Table 3) while no significant improvements were noted in the MADRS scores (Table 4). These data suggest that aripiprazole is effective in preventing manic but not depressive relapses. However, few patients in this study had depressive relapses even in the placebo group. This may be due to the fact that this study
L.N. Yatham / Journal of Affective Disorders 128S1 (2011) S21–S28
Distribution of depressive relapses (%)
35 30
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Placebo Aripiprazole
25 20
17% N=173
16% N=83
13% N=83
15
11% N=169
10
12% N=77
14% N=77
5 0
13% N=178
8% N=168 Ar vs. Pbo 26 weeks
Ar vs. Pbo 100 weeks
Ar+Li/V vs. Pbo+Li/V
Ar+Lam vs. Pbo+Lam
Fig. 3. Distribution of depressive relapses with aripiprazole vs. placebo in the long-term treatment of bipolar disorder. Note: Data for Ar+Li/V vs. Pbo+Li/V includes mixed relapses. Ar = aripiprazole, Li = lithium, Pbo = placebo, V = valproate, Lam = lamotrigine. Data from Keck et al. (2006) [Ar vs. Pbo 26 weeks], Keck et al. (2007) [Ar vs. Pbo 100 weeks], Owen et al. (2010) [Ar+Li/V vs. Pbo+Li/V], and Carlson et al. (2010) [Ar+Lam vs. Pbo+Lam].
Table 3 Effects of aripiprazole and lithium versus placebo in bipolar maintenance therapy: Change in YMRS scores Study
Study group
Keck et al. (2007) [100 weeks]
Aripiprazole Placebo
Keck et al. (2009) [3 weeks]
Keck et al. (2009) [12 weeks] Owen et al. (2010) [52 weeks] Carlson et al. (2010) [52 weeks]
Baseline
YMRS change
p-value
2.5
4.9
0.01
2.1
9.4
Aripiprazole
28.5
−12.6
≤0.001
Lithium
29.2
−12.0
0.005
Placebo
28.9
−9.0
Aripiprazole
28.5
−14.5
-
Lithium
29.2
−12.7
-
Aripiprazole + lithium/valproate
4.1
−0.1
Placebo + Lithium/Valproate
4.0
2.9
Aripiprazole + lamotrigine
4.1
1.5
Placebo + lamotrigine
4.1
3.8
≤0.001 0.006
YMRS = Young Mania Rating Scale.
Table 4 Effects of aripiprazole and lithium versus placebo in bipolar maintenance therapy: Change in MADRS scores Study
Study Group
Keck et al. (2007) [100 weeks]
Aripiprazole
3.9
6.2
Placebo
4.5
7.9
Keck et al. (2009) [3 weeks]
Keck et al. (2009) [12 weeks] Owen et al. (2010) [52 weeks] Carlson et al. (2010) [52 weeks]
a
Baseline
MADRS total change
p-value 0.31
Aripiprazole
11.3
−2.1
−
Lithium
11.4
−1.1
−
−0.7
Placebo
11.4
Aripiprazole
11.3
−0.9
−
Lithium
11.4
−0.2
−
Aripiprazole + lithium/valproate
4.6 a
3.47
Placebo + lithium/valproate
4.4 a
1.46
Aripiprazole + lamotrigine
5.2
4.71
Placebo +lLamotrigine
5.4
4.86
≤0.05 0.89
Baseline at week 4.
recruited patients with an index manic or mixed episode. Indeed, Calabrese et al. (2004) have shown that bipolar patients are more likely to relapse in the direction of the most recent episode at a ratio of 2:1 to 3:1. Therefore, one could argue that the sample size in this study did not
provide adequate power to assess the efficacy of aripiprazole for prevention of depression. Hence, further studies using a depression index episode are needed to appropriately evaluate the efficacy of aripiprazole in relapse prevention of bipolar depression.
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One randomized, double-blind, placebo-controlled trial has compared lithium monotherapy (900 to 1500 mg/day) with aripiprazole monotherapy (15 to 30 mg/day) (Keck et al., 2009) in the continuation treatment of bipolar disorder using a similar design. Bipolar patients suffering from a current manic or mixed episode were randomized to placebo, aripiprazole, or lithium, and were monitored for 3 weeks. Following the 3-week acute phase, patients in the placebo group were switched to the aripiprazole group. Patients in the aripiprazole and lithium groups were then followed for an additional 9 weeks. A statistically significant improvement in the mean YMRS total score from baseline to week 3 was observed for both aripiprazole and lithium groups in comparison to the placebo (Table 3) group. Also, significant improvements over placebo were seen earlier with aripiprazole (day 2) compared to lithium (1 week). Improvements in YMRS scores continued to week 12 for both treatment groups (Table 3). Improvements in MADRS scores were also seen with aripiprazole and lithium at 3 weeks; however, the results were not significantly different from placebo (Table 4). While the study was not designed with enough power to formally compare the efficacy of aripiprazole with lithium, the results demonstrated similar patterns of improvement in YMRS and MADRS scores, as well as other secondary efficacy measures. Together, these monotherapy studies show that aripiprazole is effective for the maintenance treatment of bipolar mania; however, there is insufficient data to support its use for depressive relapse prevention. Two randomized, double-blind, placebo-controlled studies examining the long-term efficacy of adjunctive aripiprazole in bipolar disorder have recently been completed. Owen et al. (2010) compared the effect of aripiprazole plus lithium or valproate to placebo plus lithium or valproate. Patients with an acute manic or mixed episode were treated with either lithium or valproate monotherapy for a period of at least 2 weeks. Those who did not respond adequately (YMRS ≥16) were treated with adjunctive aripiprazole (10 to 30 mg/day) in addition to lithium or valproate. Patients who remained stable (YMRS ≤12 and MADRS ≤12) for 12 consecutive weeks entered the double-blind phase of the study where they were randomized to aripiprazole plus lithium/valproate or placebo plus lithium/valproate. Patients were followed for up to 52 weeks and relapse of mood episode was assessed. Owen et al. (2010) found that the time to relapse of any mood episode and the time to relapse of a manic episode was significantly longer in the adjunctive aripiprazole group compared with the adjunctive placebo group (Table 2). These data are consistent with previous studies indicating that aripiprazole is effective in preventing mania both in monotherapy and in combination therapy with lithium or valproate. A lack of efficacy in preventing depression may suggest a true lack of efficacy or it may be due to a lack of statistical power as only patients with an index manic episode were recruited in this trial study. Carlson et al. (2010) evaluated the efficacy of aripiprazole combined with lamotrigine over 52-weeks. Patients with a manic or mixed episode were treated with aripiprazole (10–30 mg/day) plus open-label lamotrigine (25 mg/day to a target dose of 100–200 mg/day) for 9 to 24 weeks. Those
that met stabilization criteria (YMRS ≤12 and MADRS ≤12 for 8 consecutive weeks) were then randomized in the double blind maintenance phase to aripiprazole plus lamotrigine or placebo plus lamotrigine and followed for up to 52 weeks. The results showed that adjunctive aripiprazole was numerically superior to adjunctive placebo in preventing any mood episode or manic/mixed episode, but the differences failed to reach statistical significance with p-values just over 0.05 (Table 2). Consistent with previous studies, adjunctive aripiprazole failed to separate from placebo in preventing depressive relapses. This may again be due to the fact that only index manic/mixed episode patients were recruited; however, it could also be due to the fact that lamotrigine monotherapy is an effective strategy for preventing depressive relapse. Interestingly, in a post-hoc analysis examining the effect of baseline mood episode on time to depressive relapse, mixed-episode patients in the adjunctive aripiprazole group showed a statistically significant delay in time to relapse to a depressive episode compared with placebo (hazard ratio: 0.397, 95% CI: 0.158– 0.995, p = 0.041). No differences were seen in the time to depressive relapse for the manic-episode patients (hazard ratio = 1.330, 95% CI: 0.614–2.882, p = 0.468). These data clearly suggest that further studies with index depressive episodes are warranted to fully understand the spectrum of efficacy of aripiprazole. The four maintenance studies reviewed here extend the evidence from previously reported data on aripiprazole and acute mania treatment, supporting its use for preventing relapse of a manic episode. Further research investigating whether similar benefits can be extended to the prevention of depressive relapse is needed. Overall, aripiprazole dosing in bipolar depression requires further investigation, and the inclusion of patients with an index depression episode is essential. The issue of index episode is further supported given the post-hoc results of Carlson et al. (2010) on mixedepisode patients. The results on adjunctive therapy are encouraging given the statistically significant changes in MADRS scores when aripiprazole was used in combination with lithium or valproate. 5. Conclusions and future directions Although aripiprazole has proven efficacy for acute mania and the prevention of mania, the evidence available thus far does not support the efficacy of aripiprazole for the treatment of acute bipolar depression and prevention of depressive relapse. Additional studies with appropriate doses and a depressive index episode are needed to further understand the role of aripiprazole in bipolar disorder. Conflict of interests Dr Yatham received an honorarium for writing this manuscript. There was no interference from the sponsor (Bristol–Myers Squibb [BMS]), which was not involved in the collection, analysis and interpretation of data, or in manuscript preparation. Dr. Yatham has participated on advisory boards, and/or consulted, for numerous pharmaceutical companies, including BMS, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen-Ortho. The author has indicated that there are no other conflicts of interest regarding the content of this article.
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Acknowledgements The author would like to thank Jennifer Durkin for her assistance in the preparation of this manuscript. References Altshuler, L.L., Post, R.M., Black, D.O., Keck, P.E., Jr., Nolen, W.A., Frye, M.A., Suppes, T., Grunze, H., Kupka, R.W., Leverich, G.S., McElroy, S.L., Walden, J., Mintz, J., 2006. Subsyndromal depressive symptoms are associated with functional impairment in patients with bipolar disorder: results of a large, multisite study. J. Clin. Psychiatry. 67, 1441–1560. Berman, R.M., Marcus R.N., Swanink R., McQuade, R.D., Carson, W.H., Corey-Lisle, P.K., Khan, A., 2007. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J. Clin. Psychiatry. 68, 843–853. Bowden, C.L., Vieta, E., Ice, K.S., Schwartz, J.H., Wang, P.P., Versavel, M., 2010. Ziprisidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J. Clin. Psychiatry. 71, 130–137. Calabrese, J.R., Bowden C.L., Sachs G.S., Ascher, J.A., Monaghan, E., Rudd, G.D., 1999. A double-blind placebo controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J. Clin. Psychiatry 60,79–88. Calabrese, J.R., Vieta, E., El-Mallakh, R., Findling, R.L., Youngstrom, E.A., Elhaj, O., Gajwani, P., Pies, R., 2004. Mood state at study entry as predictor of the polarity of relapse in bipolar disorder. Biol. Psychiatry 56, 957– 963. Calabrese, J.R., Keck P.E. Jr., Macfadden W., Minkwitz, M., Ketter, T.A., Weisler, R.H., Cutler, A.J., McCoy, R., Wilson, E., Mullen, J., 2005. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am. J. Psychiatry 162, 1351–1360. Calabrese, J.R., Huffman, R.F., White, R.L., Edwards, S., Thompson, T.R., Ascher, J.A., Monaghan, E.T., Leadbetter, R.A., 2008. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 10, 323–333. Carlson, B.X., Sun, W., Timko, K., Vester-Blokland, E., McQuade, R., Sanchez, R., Marcus, R., 2010. Efficacy and safety of aripiprazole in combination with lamotrigine in a long-term maintenance study in manic or mixed subjects with bipolar I disorder (CN138–392). 50th Annual Meeting of the New Clinical Drug Evaluation Unit, June 14–17, Boca Raton, FL. Cruz, N., Sanchez-Moreno, J., Torres, F., Goikolea, J.M., Valenti, M., Vieta, E., 2010. Efficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis. Int. J. Neuropsychopharmacol. 13, 5–14. Dunn, R.T., Stan, V.A., Chriki, L.S., Filkowski, M.M., Ghaemi, S.N., 2008. A prospective, open-label study of aripiprazole mono- and adjunctive treatment in acute bipolar depression. J. Affect. Disord. 110, 70–74. Edwards, S.J., Smith, C.J., 2009. Tolerability of atypical antipsychotics in the treatment of adults with schizophrenia or bipolar disorder: a mixed treatment comparison of randomized controlled trials Clin. Ther. 31 Pt 1, 1345–1359. Fagiolini, A., Chengappa, K.N.R., Soreca, I., Chang, J., 2008. Bipolar disorder and the metabolic syndrome. Causal factors, psychiatric outcomes and economic burden. CNS Drugs 22, 655–669. Fountoulakis, K.N., Vieta, E., 2008. Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int. J. Neuropsychopharmacol. 11, 999–1029. Grunze, H., Vieta, E., Goodwin, G.M., Bowden, C., Licht, R.W., Moller, ¨ H-J., Kasper, S., WFSBP Task Force on Treatment Guidelines for Bipolar Disorders., 2009. The World Federation of Societies of Biological Psychiatry (WFSBP): Update 2009 on the treatment of acute mania. World J. Biol. Psychiatry 10, 85–116. Grunze, H., Vieta, E., Goodwin, G.M., Bowden, C., Licht, R.W., Moller, ¨ H-J., Kasper, S., WFSBP Task Force on Treatment Guidelines for Bipolar Disorders, 2010. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the biological treatment of bipolar disorders: Update 2010 on the treatment of acute bipolar depression. World J. Biol. Psychiatry 11, 81–109. Judd, L.L., Akiskal, H.S., Schettler, P.J., Endicott, J., Maser, J., Solomon, D.A., Leon, A.C., Rice, J.A., Keller, M.B., 2002. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch. Gen. Psychiatry 59, 530–537.
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from a North American study of quetiapine in combination with lithium or divalproex (trial 127). Am. J. Psychiatry 166, 476–488. Thase, M.E., Macfadden, W., Weisler, R.H., Chang, W., Paulsson, B., Khan, A., Calabrese, J.R., BOLDER II Study Group., 2006. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebocontrolled study (the BOLDER II study). J. Clin. Psychopharmacol. 26, 600– 609. Thase, M.E., Jonas, A., Khan, A., Bowden, C.L., Wu, X., McQuade, R.D., Carson, W.H., Marcus, R.N., Owen, R., 2008. Aripiprazole monotherapy in non-psychotic bipolar I depression. Clin. Psycho. Pharmacol. 28, 13–20. Tohen, M., Vieta, E., Calabrese, J., Ketter, T.A., Sachs, G., Bowden, C., Mitchell, P.B., Centorrino, R., Risser, R., Baker, R.W., Evans, A.R., Beymer, K., Dube, S., Tollefson, G.D., Breier, A., 2003. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch. Gen. Psychiatry 60, 1079–1088. Tohen, M., Chengappa, K.N., Suppes, T., Baker, R.W., Zarate, C.A., Bowden, C.L., Sachs, G.S., Kupfer, D.J., Ghaemi, S.N., Feldman, P.D., Risser, R.C., Evans, A.R., Calabrese, J.R., 2004. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabilizer v. mood stabiliser alone. Br. J. Psychiatr. 184, 337–345. Vieta, E., Carne, ´ X., 2005. The use of placebo in clinical trials on bipolar disorder: a new approach for an old debate. Psychother. Psychosom. 74, 10–16. Vieta, E., Suppes, T., Eggens, I., Persson, I., Paulsson, B., Brecher, M., 2008a. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J. Affect. Disord. 109, 251–263. Vieta, E., T-Joen, C., McQuade, RD., Carson, W.H., Jr., Marcus, R.N., Sanchez, R., Owen, R., Nameche, L., 2008b. Efficacy of adjunctive aripiprazole to either
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
A clinical review of aripiprazole in bipolar depression and maintenance therapy of bipolar disorder Lakshmi N. Yatham* Professor of Psychiatry, Vice Chair for Research and International Affairs, UBC Department of Psychiatry, The University of British Columbia, UBC Hospital, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada
article info
abstract
Keywords: Aripiprazole Bipolar depression Bipolar disorder Maintenance therapy
Background: Bipolar disorder is a chronic, recurrent disorder with a significant negative impact on quality of life. Effective treatments are available for acute mania. In contrast, there is a lack of consensus on the treatment of acute bipolar depression and long treatment options for bipolar disorder require more study. Aripiprazole is FDA approved for the treatment of acute mania. This paper reviews current data on the efficacy of aripiprazole in the treatment of acute bipolar depression and in maintenance therapy of bipolar disorder. Methods: PubMed and abstracts of recent conferences were searched for randomized, double-blind studies that investigated the efficacy of aripiprazole in acute bipolar depression or maintenance therapy of bipolar disorder. Results: Two studies assessed the efficacy of aripiprazole monotherapy in the treatment of acute bipolar depression. These showed that although aripiprazole significantly reduced depressive symptoms early in treatment, the results were not significantly different from placebo at the primary end point of week 8. As to long-term treatment, aripiprazole was superior to placebo in delaying time to relapse for manic episodes, but not for depressive episodes after 26 and 100 weeks of maintenance therapy. Aripiprazole was as effective as lithium, and adjunctive aripiprazole with lithium or valproate was more effective than placebo plus lithium or valproate, in preventing a manic relapse. Reductions in manic and mixed relapse rates compared to placebo were achieved in a study combining aripiprazole with lamotrigine; however, the results were not statistically significant. Similar to other maintenance studies, depressive relapse rates were not significantly reduced compared to placebo. Limitations: Negative findings for aripiprazole in the treatment of acute bipolar depression have been attributed to high study doses, rapid titration, and high placebo rates. A recent post-hoc analysis demonstrated that aripiprazole was more effective in patients with severe depressive symptoms, particularly for patients on a lower dose. Further research is needed to confirm this finding. The inability of aripiprazole to reduce the time to depressive relapse during maintenance therapy may be due to the recruitment of patients with an index manic episode and a consequent lower incidence of depressive relapses. Therefore, studies using a depression index episode are needed to appropriately evaluate relapse prevention. Conclusions: Although aripiprazole has proven efficacy for acute mania and the prevention of mania, the evidence available thus far does not support the efficacy of aripiprazole for the treatment of acute bipolar depression and prevention of depressive relapse. Further studies with appropriate doses and a depressive index episode are needed to clarify the role of aripiprazole in bipolar disorder. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Bipolar disorder is a chronic, recurrent lifetime condition with a significant negative impact on functioning and quality * Correspondence: Tel.: +1 604 822 7325; fax: +1 604 822 7922. E-mail address: [email protected] (L.N. Yatham). 0165-0327/$ – see front matter © 2010 Elsevier B.V. All rights reserved..
of life. Indeed, a recent review of studies that assessed functioning and disability in bipolar patients revealed that social, family and occupational functioning remains chronically impaired in almost half of bipolar patients (Sanchez-Moreno et al., 2009). Impairments in social and occupational functioning lead to a lower quality of life for patients with bipolar disorder. The data suggest that fewer
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than 50% of individuals with bipolar disorder report being actively employed. As their illness progresses, many who continue to work do so in roles requiring less responsibility than they were capable of in their premorbid state (SanchezMoreno et al., 2009). Thus, early and optimal treatment of bipolar disorder, both in the short- and long-term, is essential to improve functioning and quality of life for bipolar patients. There is evidence and consensus for the treatment of acute mania with lithium, anticonvulsant (e.g., valproate, carbamazepine), or atypical antipsychotic (e.g., olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone) monotherapy, or a combination of lithium or valproate with an atypical antipsychotic (Keck et al., 2003; Grunze et al., 2009; Sachs et al., 2006; Yatham et al., 2005; Yatham et al., 2006; Yatham et al., 2009). What is not yet sufficiently agreed upon is how to optimally manage acute bipolar depression (Grunze et al., 2010) or bipolar disorder in the longterm (Yatham et al., 2005; Yatham et al., 2006). Judd and colleagues (2002) demonstrated that bipolar I patients are symptomatic 47.3% of the time. Further, several researchers have found that depressive symptoms are experienced approximately three times more frequently than manic episodes (Altshuler et al., 2006; Judd et al., 2002; Kupka et al., 2007; Post et al., 2003) and more negatively affect quality of life compared to manic or hypomanic episodes (Michalak et al., 2008). Thus, effective treatments for acute depression and maintenance therapy in bipolar disorder are essential for optimizing the immediate and long-term functioning and quality of life of bipolar patients. An increasing number of atypical antipsychotics are being investigated for their efficacy in bipolar disorder. Efficacy in the treatment of acute mania has been established for many atypical antipsychotics (Bowden et al., 2010; Suppes et al., 2009; Tohen et al., 2004; Vieta et al., 2008a; Vieta et al., 2008b); however, the number of studies investigating their potential in acute bipolar depression or long-term relapse prevention is limited (Cruz et al., 2010). These agents typically demonstrate a more rapid onset of action when used to treat mania and are less likely to induce a switch to depression (Cruz et al., 2010; Fountoulakis and Vieta, 2008). Unfortunately, many of these agents have a significant side effect burden, including elevated lipid and prolactin levels and significant weight gain (Edwards and Smith, 2009; Fagiolini et al., 2008). Aripiprazole is an atypical antipsychotic with a novel mechanism of action. Its pharmacological profile shows partial agonist activity at dopamine D2 and D3 , and serotonin 5-HT1A receptors, and antagonist activity at serotonin 5-HT2A receptors (Shapiro et al., 2003; Vieta et al., 2010). Aripiprazole is approved by the FDA for the treatment of acute bipolar mania and maintenance treatment of bipolar I disorder. Further, aripiprazole adjunctive therapy has shown some benefits in the treatment of bipolar depression (Dunn et al., 2008; Kemp et al., 2007; Ketter et al., 2006; McElroy et al., 2007; Quante et al., 2010; Sokolski, 2007) and major depressive disorder (Berman et al., 2007; Marcus et al., 2008). The purpose of this paper is to review double-blind placebo-controlled studies that examined the efficacy of aripiprazole in the treatment of acute bipolar depression and maintenance therapy of bipolar disorder.
2. Methods This review was limited to data from randomized, double-blind, placebo-controlled studies. Searches using PubMed/Medline with the terms “bipolar depression,” “aripiprazole,” “maintenance therapy,” “double-blind,” and “randomized” were conducted. Abstracts of completed clinical trials presented at various (e.g., American Psychiatric Association [APA] and New Clinical Drug Evaluation Unit [NCDEU]) meetings since 2004 were also included.
3. Acute bipolar depression Several small open-label and double-blind studies have been conducted to examine the efficacy of aripiprazole in bipolar depression (Dunn et al., 2008; Kemp et al., 2007; Ketter et al., 2006; McElroy et al., 2007; Quante et al., 2010; Sokolski, 2007). However, to date, only two large, randomized, doubleblind, placebo-controlled clinical trials have been performed to examine the efficacy in bipolar depression (Thase et al., 2008). These studies involved two identically designed 8-week trials where adult patients were randomized to either aripiprazole (5–30 mg/day) (n = 186, 187 for studies 1 and 2, respectively), or placebo (n = 188 for each study). Patients were included if they were diagnosed with bipolar I disorder experiencing a major depressive episode without psychotic features. The primary and secondary efficacy end ˚ points were the mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impressions-Bipolar Version (CGI-BP) Severity of Illness Score-Depression from baseline to week 8, respectively. Statistically significant improvements with aripiprazole compared to placebo were seen in each trial in the MADRS change scores (Fig. 1) and CGI-BP scores at various time points until 5 to 6 weeks into treatment. The magnitude of early improvements in MADRS and CGI-BP scores was similar to those seen in previous trials with olanzapine and lamotrigine (Calabrese et al., 1999; Tohen et al., 2003); however, separation from placebo disappeared with aripiprazole by week 8 (Table 1). While these results may suggest a true lack of efficacy, other reasons for the loss of statistical significance by 8 weeks may include a high placebo response and improper dosing. Placebo response rates have been high in bipolar depression studies (Vieta and Carne, ´ 2005) and the reasons for this are not clear. High placebo response rates are puzzling, particularly in light of the fact that patients with bipolar depression are difficult to treat in clinical practice. Several possible explanations have been considered, including the types of bipolar patients recruited, severity of depressive episodes, sensitivity of rating instruments in detecting signal change, variability in rater agreement, and inflation of depressive symptom scores to meet entry threshold for inclusion. Placebo responses tend to be higher in mild compared with severe disease states and are higher in multiple-site studies (Vieta and Carne, ´ 2005). The placebo responses observed in the aripiprazole studies were similar to the placebo responses reported in bipolar depression studies with other atypical antipsychotics
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(A)
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Table 1 Effects of aripiprazole versus placebo in bipolar depression: change in MADRS scores Study
Study group
Baseline
MADRS week 8 Total
MADRS-6
Thase et al. (2008) CN138–096
Aripiprazole
29.07
−12.0
−
Placebo
28.49
−11.4
−
Aripiprazole
29.56
−12.3
−
Placebo
29.35
−11.8
−
Aripiprazole
33.72
−16.18 −11.74
Placebo
33.53
−11.97
−8.06
0.07
<0.05
p-value CN138–146
p-value Nashat et al. (2009)
(B)
Bech-6 ≥15
p-value Bech-6 <15 Aripiprazole
28.69
−11.5
Placebo
28.09
−10.82
−7.44
>0.05
>0.05
p-value
−7.76
˚ MADRS = Montgomery-Asberg Depression Rating Scale.
Fig. 1. Adjusted mean±SE change in MADRS scores from baseline in (A) study 1 and (B) study 2. *p ≤ 0.05 versus placebo; † p < 0.01 versus placebo. Baseline scores in study 1: placebo, 28.49; aripiprazole, 29.07. Baseline scores in study 2: placebo, 29.35; aripiprazole, 29.56. Reprinted with permission from Lippincott, Williams and Wilkins.
and other agents (Calabrese et al., 2005, 2008; Thase et al., 2006; Tohen et al., 2003). Of these studies, only trials with quetiapine demonstrated significant separation from the placebo group at week 8 (Calabrese et al., 2005; Thase et al., 2006). Olanzapine showed separation from placebo on MADRS scores; however, the items that contributed to this separation were not changes in core depressive symptoms (Tohen et al., 2003). Thus, in aggregate, these data suggest that quetiapine is clearly an effective agent for bipolar depression, while the efficacy of other agents needs further investigation given the high placebo response rates in these studies. Another potential explanation for the loss of statistical significance in MADRS and CGI-BP scores by week 8 with aripiprazole may have to do with a high initial dose or titration rate. Aripiprazole was initiated at 10 mg/day using twice-daily 5 mg doses. Patients who could not tolerate 10 mg/day were subsequently reduced to 5 mg. If 5 mg/day was not tolerated, the patient was removed from the study. Other patients were titrated upward by 5 mg each week until an effective dose was found with acceptable tolerability. Discontinuation rates for the aripiprazole groups were statistically greater than placebo (46.8% vs. 35.1% and 41.2% vs. 29.8% for studies 1 and 2, respectively). Also, time to discontinuation was significantly earlier for aripiprazole
compared to placebo. Significantly more patients withdrew due to adverse events compared to placebo (16.7% vs. 7.4%, 10.2% vs. 5.3% for studies 1 and 2, respectively), and side effects were experienced earlier in the aripiprazole groups. Further, the incidence of extrapyramidal-related symptoms was significantly higher in the aripiprazole group compared to placebo (34.3% vs. 9.7%, 29.7% vs. 10.5% for studies 1 and 2, respectively). High discontinuation rates and tolerability issues may point to higher than optimal dosing and titration in these studies. The efficacy of aripiprazole in acute bipolar depression may be better evaluated in a study with lower drug doses, titration rates, or a more severely depressed patient population. Indeed, a recent post-hoc analysis (Nashat et al., 2009) demonstrated that aripiprazole was more effective in patients with severe depressive symptoms, particularly at a lower dose. The Bech-6 Scale (six items from the Hamilton Depression Scale [HAMD17]) was used to separate patients with more severe core depressive symptoms. These items were related to 6 items on the MADRS scale (MADRS-6: apparent sadness, reported sadness, inner tension, lassitude, inability to feel, pessimistic thoughts) and the threshold between more and less severe core depressive symptoms was set at 15. Mean changes in MADRS total score and MADRS-6 score from baseline to week 8 were used as efficacy end points. MADRS Total and MADRS-6 score changes were also separated for each severity group by aripiprazole dose (5–10 mg, 15–20 mg, 25–30 mg). The results demonstrated significantly reduced MADRS-6 scores at week 8 in patients with more severe core depressive symptoms, but not for those with less severe core depressive symptoms (Table 1). When patients were separated further according to aripiprazole dose, only severely depressed patients on lower dose (5–10 mg) of aripiprazole differed significantly from placebo at 8 weeks. Similar results were seen for the MADRS total scores;
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Table 2 Comparison of time to relapse for any mood episode, manic episode, or depressive episode between aripiprazole and placebo maintenance therapy Study
Time to relapse Any mood episode
Manic episode
Depressive episode
0.52 (0.30–0.91)
0.31 (0.12–0.77)
0.83 (0.35–2.01)
Keck et al. (2006) [26 weeks]
HR (95% CI) p-value
0.02
0.01
0.68
Keck et al. (2007) [100 weeks]
HR (95% CI)
0.53 (0.32–0.87)
0.35 (0.16–0.75)
0.81 (0.36–1.81)
Owen et al. (2010)
Carlson et al. (2010)
p-value
0.011
0.005
0.602
HR (95% CI)
0.54 (0.33–0.89)
0.35 (0.15–0.83)
0.73 (0.36–1.48)
p-value
0.014
0.013
0.384
HR (95% CI)
0.67 (0.45–1.01)
0.55 (0.30–1.03)
0.78 (0.45–1.35)
p-value
0.055
0.058
0.381
HR = hazard ratio, CI = confidence interval.
45 40
Placebo Aripiprazole
Distribution of depressive relapses (%)
35 30
28% N=83
25 20
23% N=83
15
15% N=169
10 5 0
8% N=77
Ar vs. Pbo 26 weeks
10% N=173
12% N=77 7% N=168 Ar vs. Pbo 100 weeks
Ar+Li/V vs. Pbo+Li/V
5% N=178 Ar+Lam vs. Pbo+Lam
Fig. 2. Distribution of manic relapses with aripiprazole vs. placebo in the long-term treatment of bipolar disorder. Note: Data for Ar+Li/V vs. Pbo+Li/V includes mixed relapses. Ar = aripiprazole, Li = lithium, Pbo = placebo, V = valproate, Lam = lamotrigine. Data from Keck et al. (2006) [Ar vs. Pbo 26 weeks], Keck et al. (2007) [Ar vs. Pbo 100 weeks], Owen et al. (2010) [Ar+Li/V vs. Pbo+Li/V], and Carlson et al. (2010) [Ar+Lam vs. Pbo+Lam].
however, these differences disappeared after 6 weeks. The results of this post-hoc analysis demonstrate that further research involving dose optimization and separation of symptom severity are needed to fully evaluate aripiprazole efficacy in acute bipolar depression.
4. Maintenance treatment Four randomized, double-blind, placebo-controlled trials assessed the efficacy of aripiprazole for maintenance therapy of bipolar disorder. Aripiprazole monotherapy was studied over 26 weeks (Keck et al., 2006) and 100 weeks (Keck et al., 2007) in patients who had recently experienced a manic or mixed episode. Participants were stabilized on aripiprazole over a period of 6 to 18 weeks (15 or 30 mg/day) and then randomized to either aripiprazole or placebo for the doubleblind phase of the study. The primary efficacy end point was the time to relapse for any mood episode, whether manic, depressive, or mixed, during the double-blind phase.
Secondary end points included time to relapse for mania and time to relapse for depression. Aripiprazole was superior to placebo in delaying time to relapse (Table 2) both after 26 weeks and 100 weeks of maintenance therapy. Further, the proportion of patients that had a manic relapse (Fig. 2), but not depressive relapse (Fig. 3) was significantly lower in the aripiprazole group compared with the placebo group after 26 and 100 weeks of maintenance therapy. The relapse rate after 100 weeks of therapy was 33% and 52% for aripiprazole and placebo, respectively. Similarly, the Young Mania Rating Scale (YMRS) scores were significantly improved from baseline in the aripiprazole groups (Table 3) while no significant improvements were noted in the MADRS scores (Table 4). These data suggest that aripiprazole is effective in preventing manic but not depressive relapses. However, few patients in this study had depressive relapses even in the placebo group. This may be due to the fact that this study
L.N. Yatham / Journal of Affective Disorders 128S1 (2011) S21–S28
Distribution of depressive relapses (%)
35 30
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Placebo Aripiprazole
25 20
17% N=173
16% N=83
13% N=83
15
11% N=169
10
12% N=77
14% N=77
5 0
13% N=178
8% N=168 Ar vs. Pbo 26 weeks
Ar vs. Pbo 100 weeks
Ar+Li/V vs. Pbo+Li/V
Ar+Lam vs. Pbo+Lam
Fig. 3. Distribution of depressive relapses with aripiprazole vs. placebo in the long-term treatment of bipolar disorder. Note: Data for Ar+Li/V vs. Pbo+Li/V includes mixed relapses. Ar = aripiprazole, Li = lithium, Pbo = placebo, V = valproate, Lam = lamotrigine. Data from Keck et al. (2006) [Ar vs. Pbo 26 weeks], Keck et al. (2007) [Ar vs. Pbo 100 weeks], Owen et al. (2010) [Ar+Li/V vs. Pbo+Li/V], and Carlson et al. (2010) [Ar+Lam vs. Pbo+Lam].
Table 3 Effects of aripiprazole and lithium versus placebo in bipolar maintenance therapy: Change in YMRS scores Study
Study group
Keck et al. (2007) [100 weeks]
Aripiprazole Placebo
Keck et al. (2009) [3 weeks]
Keck et al. (2009) [12 weeks] Owen et al. (2010) [52 weeks] Carlson et al. (2010) [52 weeks]
Baseline
YMRS change
p-value
2.5
4.9
0.01
2.1
9.4
Aripiprazole
28.5
−12.6
≤0.001
Lithium
29.2
−12.0
0.005
Placebo
28.9
−9.0
Aripiprazole
28.5
−14.5
-
Lithium
29.2
−12.7
-
Aripiprazole + lithium/valproate
4.1
−0.1
Placebo + Lithium/Valproate
4.0
2.9
Aripiprazole + lamotrigine
4.1
1.5
Placebo + lamotrigine
4.1
3.8
≤0.001 0.006
YMRS = Young Mania Rating Scale.
Table 4 Effects of aripiprazole and lithium versus placebo in bipolar maintenance therapy: Change in MADRS scores Study
Study Group
Keck et al. (2007) [100 weeks]
Aripiprazole
3.9
6.2
Placebo
4.5
7.9
Keck et al. (2009) [3 weeks]
Keck et al. (2009) [12 weeks] Owen et al. (2010) [52 weeks] Carlson et al. (2010) [52 weeks]
a
Baseline
MADRS total change
p-value 0.31
Aripiprazole
11.3
−2.1
−
Lithium
11.4
−1.1
−
−0.7
Placebo
11.4
Aripiprazole
11.3
−0.9
−
Lithium
11.4
−0.2
−
Aripiprazole + lithium/valproate
4.6 a
3.47
Placebo + lithium/valproate
4.4 a
1.46
Aripiprazole + lamotrigine
5.2
4.71
Placebo +lLamotrigine
5.4
4.86
≤0.05 0.89
Baseline at week 4.
recruited patients with an index manic or mixed episode. Indeed, Calabrese et al. (2004) have shown that bipolar patients are more likely to relapse in the direction of the most recent episode at a ratio of 2:1 to 3:1. Therefore, one could argue that the sample size in this study did not
provide adequate power to assess the efficacy of aripiprazole for prevention of depression. Hence, further studies using a depression index episode are needed to appropriately evaluate the efficacy of aripiprazole in relapse prevention of bipolar depression.
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One randomized, double-blind, placebo-controlled trial has compared lithium monotherapy (900 to 1500 mg/day) with aripiprazole monotherapy (15 to 30 mg/day) (Keck et al., 2009) in the continuation treatment of bipolar disorder using a similar design. Bipolar patients suffering from a current manic or mixed episode were randomized to placebo, aripiprazole, or lithium, and were monitored for 3 weeks. Following the 3-week acute phase, patients in the placebo group were switched to the aripiprazole group. Patients in the aripiprazole and lithium groups were then followed for an additional 9 weeks. A statistically significant improvement in the mean YMRS total score from baseline to week 3 was observed for both aripiprazole and lithium groups in comparison to the placebo (Table 3) group. Also, significant improvements over placebo were seen earlier with aripiprazole (day 2) compared to lithium (1 week). Improvements in YMRS scores continued to week 12 for both treatment groups (Table 3). Improvements in MADRS scores were also seen with aripiprazole and lithium at 3 weeks; however, the results were not significantly different from placebo (Table 4). While the study was not designed with enough power to formally compare the efficacy of aripiprazole with lithium, the results demonstrated similar patterns of improvement in YMRS and MADRS scores, as well as other secondary efficacy measures. Together, these monotherapy studies show that aripiprazole is effective for the maintenance treatment of bipolar mania; however, there is insufficient data to support its use for depressive relapse prevention. Two randomized, double-blind, placebo-controlled studies examining the long-term efficacy of adjunctive aripiprazole in bipolar disorder have recently been completed. Owen et al. (2010) compared the effect of aripiprazole plus lithium or valproate to placebo plus lithium or valproate. Patients with an acute manic or mixed episode were treated with either lithium or valproate monotherapy for a period of at least 2 weeks. Those who did not respond adequately (YMRS ≥16) were treated with adjunctive aripiprazole (10 to 30 mg/day) in addition to lithium or valproate. Patients who remained stable (YMRS ≤12 and MADRS ≤12) for 12 consecutive weeks entered the double-blind phase of the study where they were randomized to aripiprazole plus lithium/valproate or placebo plus lithium/valproate. Patients were followed for up to 52 weeks and relapse of mood episode was assessed. Owen et al. (2010) found that the time to relapse of any mood episode and the time to relapse of a manic episode was significantly longer in the adjunctive aripiprazole group compared with the adjunctive placebo group (Table 2). These data are consistent with previous studies indicating that aripiprazole is effective in preventing mania both in monotherapy and in combination therapy with lithium or valproate. A lack of efficacy in preventing depression may suggest a true lack of efficacy or it may be due to a lack of statistical power as only patients with an index manic episode were recruited in this trial study. Carlson et al. (2010) evaluated the efficacy of aripiprazole combined with lamotrigine over 52-weeks. Patients with a manic or mixed episode were treated with aripiprazole (10–30 mg/day) plus open-label lamotrigine (25 mg/day to a target dose of 100–200 mg/day) for 9 to 24 weeks. Those
that met stabilization criteria (YMRS ≤12 and MADRS ≤12 for 8 consecutive weeks) were then randomized in the double blind maintenance phase to aripiprazole plus lamotrigine or placebo plus lamotrigine and followed for up to 52 weeks. The results showed that adjunctive aripiprazole was numerically superior to adjunctive placebo in preventing any mood episode or manic/mixed episode, but the differences failed to reach statistical significance with p-values just over 0.05 (Table 2). Consistent with previous studies, adjunctive aripiprazole failed to separate from placebo in preventing depressive relapses. This may again be due to the fact that only index manic/mixed episode patients were recruited; however, it could also be due to the fact that lamotrigine monotherapy is an effective strategy for preventing depressive relapse. Interestingly, in a post-hoc analysis examining the effect of baseline mood episode on time to depressive relapse, mixed-episode patients in the adjunctive aripiprazole group showed a statistically significant delay in time to relapse to a depressive episode compared with placebo (hazard ratio: 0.397, 95% CI: 0.158– 0.995, p = 0.041). No differences were seen in the time to depressive relapse for the manic-episode patients (hazard ratio = 1.330, 95% CI: 0.614–2.882, p = 0.468). These data clearly suggest that further studies with index depressive episodes are warranted to fully understand the spectrum of efficacy of aripiprazole. The four maintenance studies reviewed here extend the evidence from previously reported data on aripiprazole and acute mania treatment, supporting its use for preventing relapse of a manic episode. Further research investigating whether similar benefits can be extended to the prevention of depressive relapse is needed. Overall, aripiprazole dosing in bipolar depression requires further investigation, and the inclusion of patients with an index depression episode is essential. The issue of index episode is further supported given the post-hoc results of Carlson et al. (2010) on mixedepisode patients. The results on adjunctive therapy are encouraging given the statistically significant changes in MADRS scores when aripiprazole was used in combination with lithium or valproate. 5. Conclusions and future directions Although aripiprazole has proven efficacy for acute mania and the prevention of mania, the evidence available thus far does not support the efficacy of aripiprazole for the treatment of acute bipolar depression and prevention of depressive relapse. Additional studies with appropriate doses and a depressive index episode are needed to further understand the role of aripiprazole in bipolar disorder. Conflict of interests Dr Yatham received an honorarium for writing this manuscript. There was no interference from the sponsor (Bristol–Myers Squibb [BMS]), which was not involved in the collection, analysis and interpretation of data, or in manuscript preparation. Dr. Yatham has participated on advisory boards, and/or consulted, for numerous pharmaceutical companies, including BMS, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen-Ortho. The author has indicated that there are no other conflicts of interest regarding the content of this article.
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