Investigation into the long-term metabolic effects of aripiprazole adjunctive to lithium, valproate, or lamotrigine

Journal of Affective Disorders 148 (2013) 84–91

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Investigation into the long-term metabolic effects of aripiprazole adjunctive to lithium, valproate, or lamotrigine David E. Kemp a,n, Marc De Hert b, Zia Rahman c, Paula Fyans d, James M. Eudicone c, Sabrina V. Marler e, Ross A. Baker f, Berit X. Carlson c a

University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA University Psychiatric Center campus Kortenberg, KU Leuven, Kortenberg, Belgium c Bristol-Myers Squibb, Plainsboro, NJ, USA d Bristol-Myers Squibb, Uxbridge, Middlesex, UK e Bristol-Myers Squibb, Wallingford, CT, USA f Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 24 August 2012 Accepted 20 November 2012 Available online 20 December 2012

Background: Bipolar I disorder (BPD) patients are often overweight or obese, and likely to have metabolic syndrome. Several medications used to treat BPD are associated with increased body weight and/or worsening metabolic parameters. Methods: Metabolic data were analyzed from two efficacy studies of aripiprazole plus the mood stabilizers, lithium/valproate (Study CN138–189), or lamotrigine (Study CN138–392), in the long-term treatment (52 weeks) of BPD. Changes in body weight, individual metabolic parameters, and incidence of metabolic syndrome were assessed. Results: In the lithium/valproate study, modest increases in body weight were observed at Week 52 in both groups: 1.7 70.8 kg in the lithium/valproate group, and 1.6 70.7 kg in the adjunctive aripiprazole group; this difference was nonsignificant. In the lamotrigine study, decreases in body weight were observed at Week 52 with lamotrigine alone (  2.2 7 1.0 kg), whereas a modest increase was observed when combined with aripiprazole (0.4 7 1.0 kg). In both studies, rates of metabolic syndrome at 52 weeks did not increase from baseline with aripiprazole, and median changes from baseline in individual metabolic syndrome parameters were similar with both mood stabilizer monotherapy and the addition of aripiprazole as an adjunctive therapy. Limitations: This was a post-hoc analysis, and a low percentage of patients completed the lamotrigine study. Conclusions: Aripiprazole plus a mood stabilizer has minimal impact on metabolic changes in predominantly overweight/obese BPD patients over a 52-week period. In both studies, modest mean increases in weight with the addition of aripiprazole were not accompanied by increased rates of metabolic syndrome or changes in metabolic parameters. & 2012 Elsevier B.V. All rights reserved.

Keywords: Aripiprazole Lithium Valproate Lamotrigine Bipolar disorder Metabolic syndrome

1. Introduction Metabolic syndrome is a collection of clinical and biochemical risk factors that predispose affected individuals to diabetes mellitus, cardiovascular disease, stroke, and premature mortality (McIntyre et al., 2010; Alberti et al., 2009; Lorenzo et al., 2007). Abdominal obesity and insulin resistance are the central underlying risk factors for the development of metabolic syndrome, with habitual inactivity, aging, and hormonal imbalances also playing a role (McIntyre et al., 2010).

n

Corresponding author. Tel.: þ1 216 844 2865; fax: þ 1 216 844 2875. E-mail address: [email protected] (D.E. Kemp).

0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.11.054

Patients with bipolar I disorder have been shown to be at greater risk of metabolic syndrome than the general population (Fagiolini et al., 2008; van Winkel et al., 2008). Moreover, excess deaths from medical causes account for more lost years of life in bipolar patients than do suicide and deaths by accidents (Colton and Manderscheid, 2006). The common co-occurrence of bipolar disorder and metabolic disease is in part related to physiological risk factors that are shared between both bipolar disorder and the metabolic syndrome, including endocrine disturbances and sympathetic nervous system dysregulation, as well as similar lifestyle and behavior patterns, such as physical inactivity and overeating (Fagiolini et al., 2008; De Hert et al., 2011). In addition, many of the medications used to treat bipolar I disorder have been shown to contribute to this increased risk by increasing body weight

D.E. Kemp et al. / Journal of Affective Disorders 148 (2013) 84–91

and/or worsening metabolic parameters (Fagiolini et al., 2008). For example, tricyclic antidepressants have been shown to promote hyperglycemia and type 2 diabetes, while the moodstabilizing agents, lithium and valproate, are associated with significant weight gain (McIntyre et al., 2006; Bowden et al., 2000; Pan et al., 2012). In particular, the second-generation (atypical) antipsychotics have been associated with a variety of metabolic effects, including significant weight gain, insulin resistance, hyperglycemia, type 2 diabetes, and dyslipidemia (Simon et al., 2009). However, not all atypical antipsychotics produce the same effects or the same magnitude of effects. Aripiprazole is a pharmacologically distinct atypical antipsychotic (Burris et al., 2002; Jordan et al., 2002; Stark et al., 2007; Shapiro et al., 2003; Kikuchi et al., 1995), with significant activity as add-on therapy in the treatment of bipolar disorder in both short-term and long-term trials (Vieta et al., 2008b; Marcus et al., 2011). Previous studies of aripiprazole as monotherapy or in combination with lithium or valproate showed only small increases in weight and no clinically meaningful changes in modifiable cardiovascular disease risk factors (total cholesterol, high- and low-density lipoprotein cholesterol, glucose, and triglycerides) (Vieta et al., 2008b, 2010; Keck et al., 2003). The present post-hoc analysis examined metabolic data from two separate efficacy trials of aripiprazole in combination with mood stabilizers for the long-term management of patients with mixed/manic bipolar I disorder. Study CN138–189 was of aripiprazole adjunctive to lithium or valproate as compared with either of the mood stabilizers alone, and CN138–392 investigated aripiprazole plus lamotrigine versus lamotrigine alone.

2. Methods 2.1. Populations and study designs This was a post-hoc analysis of two similar, multicenter, randomized, double-blind, placebo-controlled studies of aripiprazole in combination with mood stabilizers for the long-term management of bipolar I disorder. Complete accounts of the methods for these studies have been previously described (Marcus et al., 2011; Carlson et al., 2012). Both studies enrolled patients with bipolar I disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition—Text Revision (DSM-IV-TR) and confirmed by the Structured Clinical Interview for DSM-IV-TR. Patients were included if they experienced an acute manic or mixed episode, with a minimum severity defined by a Young Mania Rating Scale (YMRS) score Z16. Both studies were conducted in accordance with the Declaration of Helsinki, and the ethics committee at each site approved the protocols. All patients provided written informed consent prior to inclusion in the studies. Both studies comprised three phases: (1) a screening phase and washout phase, (2) a single-blind stabilization phase, and (3) a randomized double-blind relapse assessment phase. During the screening phase (14–56 days for the lithium/valproate study and 4–42 days for the lamotrigine study), all prohibited psychiatric medications were washed out, including all antipsychotics, antidepressants, and all other mood stabilizers. In the lithium/ valproate study, confirmation of inadequate response to therapeutic levels of lithium or valproate was established. An inadequate response was defined by YMRS total score Z16 and r35% decrease from baseline; an increased or unchanged YMRS score was also allowed. Confirmation of inadequate response to mood stabilizer was not part of the study design for the lamotrigine study. The stability phase was 13–24 weeks in the lithium/ valproate study and 9–24 weeks in the lamotrigine study. In the

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former, patients with an inadequate response to mood stabilizer monotherapy received single-blind aripiprazole (target dose of 10–30 mg/day; starting dose of 10–15 mg/day) in combination with lithium (0.6–1.0 mmol/L) or valproate (50–125 mg/mL), while in the latter, patients were initiated simultaneously on lamotrigine (target dose of 100–200 mg/day; starting dose of 25 mg/day) and aripiprazole. Stability was defined as YMRS and ˚ Montgomery–Asberg Depression Rating Scale [MADRS] scores r12 and maintained for 12 consecutive weeks in the lithium/ valproate study and 8 consecutive weeks in the lamotrigine study, with one excursion (YMRS or MADRS 412) allowed except at the second-to-last (lamotrigine study only) and last visit. In the randomized phase, patients who maintained mood stability for 8 or 12 consecutive weeks were randomly assigned (1:1) to double-blind aripiprazole (10–30 mg/day) or placebo in combination with lithium, valproate, or lamotrigine and followed up to 52 weeks, or until recurrence.

2.2. Assessments The current analysis compared weight gain and the prevalence of metabolic syndrome and its components in patients treated with mood stabilizers plus either aripiprazole or placebo during the stabilization and randomization phases. Metabolic syndrome components included BMI, triglycerides, high-density lipoprotein cholesterol (HDL-C), blood pressure, and blood glucose. The analysis of metabolic syndrome included only those patients with no missing values for all five metabolic syndrome criteria at baseline and endpoint. Metabolic Syndrome was defined as meeting three or more of the following measures based on modified ATP-III-A criteria: BMI 430 kg/m2, triglycerides (fasting) Z150 mg/dL, HDL-C (fasting) for males o40 mg/dL and females o50 mg/dL, systolic blood pressure Z130 mmHg and/or diastolic blood pressure Z85 mmHg, and blood glucose (fasting) Z100 mg/dL (Health, 2004). These criteria differ from the ATP-III-A criteria in that BMI replaced waist circumference because waist circumference was not available for the majority of patients. BMI has been shown to be a viable substitute for waist circumference in diagnosing metabolic syndrome and predicting risk of cardiovascular disease (Ryan et al., 2008). Receiving treatment for hyperlipidemia was additionally counted as a criterion for metabolic syndrome. The proportion of patients who shifted from one BMI category to another (e.g., from overweight to obese) during the stabilization and randomized phases of both studies was calculated and stratified by treatment. BMI was considered normal at Z18.5 and o25, overweight at Z25 and o30, and obese at Z30.

2.3. Statistical analysis Weight change was assessed using analysis of covariance (ANCOVA) on the last observation carried forward (LOCF) and observed cases (OC) datasets, with treatment and mood stabilizer (lithium/valproate study only) as main effects and baseline values as covariates. Clinically relevant weight change was assessed using the Cochran–Mantel–Haenszel General Association test, controlling for mood stabilizer (lithium/valproate study). Comparison of metabolic syndrome rates at baseline and endpoint was analyzed using McNemar’s test for paired data and stratified by treatment. Comparison of metabolic syndrome rates at endpoint between aripiprazole and placebo was analyzed using Fisher’s Exact Test, and stratified by mood stabilizer (lithium/ valproate study). Metabolic syndrome components were analyzed by Wilcoxon-Rank Sum Test, stratified by mood stabilizer (lithium/valproate study).

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were 80.6 (18.9) kg in the aripiprazoleþlithium/valproate group (n ¼168) and 81.3 (25.1) kg in the placeboþlithium/valproate group (n ¼169). In the lamotrigine study, 27% (n ¼96) were overweight (BMI 25–29.9) and 44% (n ¼156) were obese (BMI Z30) at randomized phase baseline, with mean baseline weights of 85.0 (21.8) kg for the combination arm (n¼178) and 86.6 (24.9) kg for the lamotrigine-alone arm (n ¼173).

3. Results 3.1. Patient population A total of 1270 patients were enrolled in the lithium/valproate study, with 337 (168 aripiprazole þlithium or valproate; 169 placeboþlithium or valproate) randomized (Table 1). In the lamotrigine study, 1169 patients were enrolled and 351 (178 aripiprazole þlamotrigine; 173 placeboþ lamotrigine) were randomized (Table 1). The demographics of the randomized populations were similar between the two groups (Table 2) (Marcus et al., 2011; Carlson et al., 2012). At baseline 34% (n ¼113) of randomized patients in the lithium/valproate study were overweight (BMI 25–29.9) and 33% (n¼112) were obese (BMI Z30). Mean baseline weights (SD) at the start of the randomized phase

3.2. Stabilization phase During the open-label stabilization phase of the lithium/ valproate study, the overall median change from baseline in weight (LOCF) was 1.1 kg (baseline 76.2 kg). In the lamotrigine study, the overall mean (SD) change in weight during the openlabel, stabilization phase (LOCF) was 0.3 kg (4.6).

Table 1 Patient disposition, randomized samples. n (%)

Lithium/valproate study

Completed the study Discontinued Adverse event Withdrew consent Lost to follow up No longer meets study criteria Lack of efficacy Poor/noncompliance Other Total discontinued

Lamotrigine study

Aripiprazole þlithium/ valproate (n¼168)

Placebo þ lithium/ valproate (n¼ 169)

103 (61.3)

89 (52.7)

65 (36.5)

53 (30.6)

16 16 18 6

(9.0) (9.0) (10.1) (3.4)

10 17 18 4

(5.8) (9.8) (10.4) (2.3)

39 8 10 113

(21.9) (4.5) (5.6) (63.5)

54 7 10 120

(31.2) (4.0) (5.8) (69.4)

19 15 6 1

(11.3) (8.9) (3.6) (0.6)

15 14 7 2

(8.9) (8.3) (4.1) (1.2)

14 3 7 65

(8.3) (1.8) (4.2) (38.7)

31 5 6 80

(18.3) (3.0) (3.6) (47.3)

Aripiprazole þ lamotrigine (n¼ 178)

Placebo þlamotrigine (n ¼173)

Table 2 Patient Demographic Characteristics, Randomized Samples. Lithium/valproate study

Mean age, years (SD) Female gender, n (%) Race, n (%) White Black/African American Asian Other Mean weight, kg (SD) Mean BMI, kg/m2 (SD) BMI category, n (%) Normal (o25 kg/m2) Overweight (25–29.9 kg/m2) Obese (Z30 kg/m2) Episode type, n (%) Manic Mixed Rapid cycler in past 12 months Yes No CGI-BP Severity of Illness score (Depression), mean (SD)a YMRS total score, mean (SD)a MADRS total score, mean (SD)a

Lamotrigine study

Aripiprazole þ lithium/ valproate (n¼168)

Placebo þ lithium/ valproate (n¼ 169)

Aripiprazole þ lamotrigine (n ¼178)

Placebo þ lamotrigine (n¼173)

39.2 (12.4) 87 (51.8)

38.8 (12.3) 98 (58.0)

39.6 (11.9) 120 (67.4)

38.6 (12.3) 108 (62.4)

118 12 34 4 80.6 28.5

112 19 33 5 81.3 28.7

159 13 3 3 85.0 30.2

(89.3) (7.3) (1.7) (1.7) (21.8) (7.4)

156 (90.2) 14 (8.1) 3 (1.7) 0 86.6 (24.9) 30.3 (8.3)

(70.2) (7.1) (20.2) (2.4) (18.9) (6.0)

(66.3) (11.2) (19.5) (3.0) (25.1) (7.7)

49 (29.2) 63 (37.5) 56 (33.3)

63 (37.3) 50 (29.6) 56 (33.1)

49 (27.6) 48 (27.0) 80 (44.9)

49 (28.4) 48 (27.7) 76 (43.9)

111 (66.1) 57 (33.9)

119 (70.4) 50 (29.6)

100 (56.2) 78 (43.8)

78 (45.1) 95 (54.9)

3 (1.8) 165 (98.2)

10 (5.9) 159 (94.1)

41 (23.0) 137 (77.0)

54 (31.2) 119 (68.8)

1.3 (0.6) 4.1 (3.6) 4.1 (3.8)

1.4 (0.7) 4.1 (3.3) 3.7 (3.5)

1.6 (0.1) 4.0 (0.2) 5.1 (0.3)

1.7 (0.1) 4.1 (0.2) 5.3 (0.3)

SD, standard deviation; BMI, body mass index; CGI-BP, clinical global impression for bipolar disorder; YMRS, Young Mania Rating Scale; ˚ MADRS, Montgomery–Asberg Depression Rating Scale. a

Standard error was used in place of SD for the lamotrigine study.

D.E. Kemp et al. / Journal of Affective Disorders 148 (2013) 84–91

31.6% (65/206) of patients had metabolic syndrome at baseline. Fig. 2 shows the incidence of metabolic syndrome at Week 52 or earlier by metabolic status at baseline. In both studies, rates of metabolic syndrome for both aripiprazole and placebo were unchanged at Week 52 from baseline for all groups (p¼NS). Also, in both studies, rates of metabolic syndrome between aripiprazole and placebo groups were not significantly different at Week 52 for both those with metabolic syndrome at baseline and those without; however, of those lithium patients who had metabolic syndrome present at baseline, there was a statistically significant difference between treatment and metabolic syndrome status at endpoint. (p ¼0.04). Randomized phase baseline values in individual metabolic syndrome parameters are shown in Table 3 and were generally similar among groups. No clinically significant changes in any of these parameters were observed during the stabilization phases of either study. During the randomization phases of both studies, median changes from baseline in metabolic syndrome parameters were similar in the adjunctive placebo and adjunctive aripiprazole groups (Fig. 3).

There was little shift in BMI categories from baseline to last visit in the stabilization phases of either study. In the lithium/valproate study, 84% and 80% of those treated with aripiprazole plus lithium or valproate, respectively, who were Normal at baseline were Normal at the last visit. In the Overweight category, while the majority of patients stayed Overweight (76% lithium group, 88% valproate group), 15% in the lithium group shifted to Normal while only 9% shifted to Obese; in the valproate group, only 1% shifted to Normal and 11% shifted to Obese. Of those patients who were Normal at baseline and treated with aripiprazole plus lamotrigine, 86% were Normal at last visit. In the Overweight category, 78% remained Overweight, while 8% shifted to Normal and 14% shifted to Obese. 3.3. Randomized phase Mean changes in weight (OC) from baseline during the doubleblind randomized phase were 1.670.7 kg for those who received aripiprazole plus lithium/valproate (n¼95), 1.770.8 kg in the placeboþlithium/valproate group (n¼85), 0.471.0 kg for those who received aripiprazole plus lamotrigine (n¼56), and  2.27 1.0 kg in the placebo plus lamotrigine group (n¼49). In the lithium/ valproate study, the difference in mean change in body weight between treatment arms at 52 weeks (LOCF) was 0.5 kg (95% CI 0.9, 1.8), and for the OC dataset it was  0.05 (95% CI  2.1, 2.0). In the lamotrigine study, LOCF and OC differences in body weight between treatment arms at 52 weeks were 2.2 (LOCF, 95% CI 0.9, 3.6) and 2.6 (OC, 95% CI  0.2, 5.4), respectively. The proportions of patients in the lithium/valproate study who showed clinically relevant ( Z7%) weight gain (LOCF) were 13.8% (22/160) in the aripiprazole plus lithium/valproate group, and 11.8% (19/161) in the placebo plus lithium/valproate group (p¼ 0.58); for the OC analysis, it was 18.9% (18/95) and 18.8% (16/85), respectively. The proportions of patients in the lamotrigine study showing clinically relevant weight gain (LOCF) were 11.9% (18/151) in the aripiprazole plus lamotrigine group, and 3.5% (5/143) in the placebo plus lamotrigine group (p¼0.01); for the OC analysis it was 12.5% (7/56) and 4.1% (2/49), respectively. As seen in Fig. 1, in both the lithium/valproate study and the lamotrigine study, patients did not generally shift from one BMI category to another during the randomized treatment phase in either the aripiprazole or placebo groups. In the lithium/valproate study, 30.5% (93/305) of patients had metabolic syndrome at baseline, and in the lamotrigine study, 100%

4.8

7.7

15.4 16.0

Percentage of patients

90%

7.1

10.0 19.2

23.1

87

4. Discussion These results show that aripiprazole added to either lithium or valproate does not, on average, incur incremental weight gain over the mood stabilizer alone in predominantly overweight or obese bipolar I disorder patients over a 52-week period. Consistent results were observed with lamotrigine, in that the addition of aripiprazole had minimal weight change over 52 weeks, whereas lamotrigine alone showed a decrease in body weight from baseline. However, even with this limited weight gain with aripiprazole, there were no increases in incidence of metabolic syndrome or individual metabolic parameters. This analysis included a substantial proportion (approximately one-third) of patients with metabolic syndrome at baseline, which is consistent with reports on the prevalence of metabolic syndrome in patients with psychiatric disease (Fagiolini et al., 2008, van Winkel et al., 2008). By the end of the trials, overall rates of metabolic syndrome did not increase with aripiprazole added to any of the mood stabilizers investigated, and in fact, of those lithium-treated patients who had metabolic syndrome present at baseline, there was a statistically significant difference between treatment and metabolic syndrome status at endpoint in favor of aripiprazole.

8.8

9.5

4.3

18.2

80% 70% 60% 50% 40%

72.3 95.2 92.3

90.0

78.6 84.6 84.0

90.0 76.9

76.9

84.8 94.3

95.0

89.7 89.1

92.9 91.2 69.7

Obese Overweight Normal

30% 20% 23.4

10%

12.1 11.9 3.8

0% Ari+ Plb+ Ari+ Plb+ Ari+ Plb+ Li Li Val Val Lam Lam

Normal

Ari+ Plb+ Ari+ Plb+ Ari+ Plb+ Li Li Val Val Lam Lam

Overweight

5.0 5.0

12.1 5.0

3.0

5.7

10.3 10.9

Ari+ Plb+ Ari+ Plb+ Ari+ Plb+ Li Li Val Val Lam Lam

Obese

Baseline BMI Category Fig. 1. BMI shift data from baseline to endpoint during the randomized phase, safety sample. (Patient visit data from one site was excluded from the time period between June 20, 2007 and November 7, 2007 in the lamotrigine study.) BMI, body mass index; Ari, aripiprazole; Li, lithium; Plb, placebo; Val, valproate; Lam, lamotrigine.

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D.E. Kemp et al. / Journal of Affective Disorders 148 (2013) 84–91

Lithium +

Valproate +

Lamotrigine + Plb (n=33)

Ari (n=32)

Plb (n=71)

Ari (n=70)

100% 90%

27.3

Metabolic syndrome absent at endpoint Metabolic syndrome present at endpoint

25.0

Percentage of patients

80% 70% 60%

84.5

88.6

15.5

11.4

50% 40%

72.7

75.0

30% 20% 10% 0% MetSyn present at MetSyn absent at baseline baseline

Fig. 2. Incidence of metabolic syndrome (Week 52 or earlier) by metabolic status (Includes only those patients with nonmissing values for all five metabolic syndrome criteria at baseline and endpoint. The five parameters used for evaluation may not have been measured at similar time points. Metabolic syndrome is defined as meeting three or more of the following measures modified from the NCEP ATP III-A criteria: BMI 430 kg/m2, triglycerides (fasting) Z150 mg/dL; HDL-C (fasting) males o40 mg/ dL and females o50 mg/dL, systolic blood pressure Z130 mmHg and/or diastolic blood pressure Z 85 mmHg, and blood glucose (fasting) Z 100 mg/dL.) at baseline for aripiprazole or placebo adjunctive to lithium (A), valproate (B), or lamotrigine (Patient visit data from one site was excluded from the time period between June 20, 2007 and November 7, 2007 in the lamotrigine study.) (C). Plb, placebo; Ari, aripiprazole; MetSyn, metabolic syndrome.

Table 3 Randomized phase baseline median values (fasting) of individual metabolic parameters. mg/dL (mmol/L)

Glucose HDL cholesterol LDL cholesterol Total cholesterol Triglycerides

Lithium/valproate study

Lamotrigine study

Aripiprazole

Placebo

Aripiprazole

Placebo

90.0 45.0 100.0 181.0 134.5

90.0 46.0 104.5 180.0 130.0

94.0 49.0 112.0 190.0 115.0

94.0 49.0 98.5 180.0 113.0

(5.0) (1.2) (2.6) (4.7) (1.5)

(5.0) (1.2) (2.7) (4.7) (1.5)

(5.2) (1.3) (2.9) (4.9) (1.3)

(5.2) (1.3) (2.5) (4.7) (1.3)

Moreover, median changes from baseline in metabolic syndrome parameters were equivalent in the placebo and aripiprazole groups. Because weight gain is a concern of clinicians who prescribe atypical antipsychotics, the risk of weight gain has been extensively studied in both monotherapy and combination trials. Olanzapine monotherapy has been shown to increase weight over valproate monotherapy, with clinically significant ( Z7%)

weight gain seen in a significantly greater proportion of those receiving olanzapine than those receiving valproate (Tohen et al., 2008). Ziprasidone plus either lithium or valproate has demonstrated nonsignificant weight loss versus lithium/valproate monotherapy, while quetiapine plus lithium or valproate has demonstrated weight gain (Kemp et al., 2012; Suppes et al., 2009; Vieta et al., 2008a). It should be noted that the proportion of patients who experienced clinically relevant ( Z7%) weight gain during continued treatment with quetiapine plus lithium/ valproate has also been shown to be greater than those who switched to placebo plus lithium/valproate (Suppes et al., 2009; Vieta et al., 2008a). By comparison, in the current study there was no difference between aripiprazole plus lithium/valproate versus placebo plus lithium/valproate in terms of the proportion of patients with clinically relevant weight gain. Atypical antipsychotics more recently approved by the US FDA for the treatment of bipolar disorder, such as asenapine, also appear to have an increased risk for weight gain (Szegedi et al., 2012). Nevertheless, there was little shifting between BMI categories in either of the present studies with either aripiprazole or placebo plus mood stabilizer. Given the efficacy outcomes were similar for aripiprazole when used in combination with lithium or valproate, the higher potential to shift from normal to overweight with

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Fig. 3. Median change from baseline in metabolic parameters (fasting, LOCF) during the randomized treatment phases of the lithium/valproate study (A) and the lamotrigine study (B), phase 3 safety sample. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides. a n¼ 157 for placebo þlithium/valproate; n¼155 for aripiprazole þlithium/valproate. b n¼ 113 for placebo þ lithium/valproate; n¼ 110 for aripiprazole þ litium/valproate.

valproate may indicate a safety advantage of using the combination of aripiprazole plus lithium, and is worth exploring in future studies. During the stabilization phases of the present analysis, greater weight gain was seen in the lithium/valproate study than in the lamotrigine study, suggesting that the differences in weight observed between the two studies is due to the respective mood stabilizers and less so to a potential weight gain contribution of aripiprazole. Monotherapy with either lithium or valproate is known to be associated with weight gain. Approximately 25% of patients on lithium report weight gain, and the prevalence of weight gain with valproate is between 3% and 20% of patients (Torrent et al., 2008). Lamotrigine, on the other hand, is generally considered weight neutral, and consistent with the results seen in the present study, patients have even demonstrated weight loss when used as monotherapy for the management of bipolar I disorder (Calabrese et al., 2003). Interestingly, in a study that assessed weight changes with either lamotrigine or lithium in both obese and nonobese patients with bipolar I disorder, those who were obese lost weight (  4.2 kg) while taking lamotrigine and gained weight (6.1 kg) while taking lithium, but only minimal differences between the two drugs were observed among nonobese patients (  0.5 kg with lamotrigine versus 1.1 kg with lithium) (Bowden et al., 2006). Although the reasons for these results are unclear, it may be secondary to obese versus nonobese patients being predisposed to gaining more weight while on lithium (Bowden et al., 2006). Because weight gain, per se, is only one sign of metabolic dysfunction, it is important to investigate the effects of any drug on the risk of developing metabolic syndrome, as well as the individual metabolic parameters that comprise metabolic syndrome. A recent meta-analysis determined that the overall rate of metabolic syndrome in patients with bipolar patients was 37.3%, and that patients prescribed antipsychotic medications were at greater risk than antipsychotic-free patients (45.3% versus 32.4%) (Vancampfort et al., in press). In a 26-week maintenance study of aripiprazole or placebo, the proportion of patients with metabolic syndrome did not differ between groups at baseline or Week 26, and there were no significant changes in individual components of metabolic syndrome between aripiprazole and placebo (Kemp et al., 2010a). In a 52-week study of aripiprazole or

lithium monotherapy, small and equal changes were observed in both groups in total cholesterol, HDL-cholesterol, LDL-cholesterol, glucose, triglycerides, and insulin (McIntyre et al., 2011). Similar to the present study, in a ziprasidone study in which close to a quarter of patients had metabolic syndrome at baseline, although changes in the prevalence of metabolic syndrome, as a whole, were not analyzed during the randomized phase, there were no detrimental effects on individual metabolic parameters (Kemp et al., 2012). Quetiapine in combination with lithium or valproate, however, was shown to raise mean blood glucose, HbA1c, and insulin levels as compared with lithium or valproate alone (Suppes et al., 2009). In addition, median triglyceride levels increased with the quetiapine combination compared with a decrease for the placebo combination (Suppes et al., 2009). The results from a retrospective chart review of 24 psychiatric outpatients who switched to aripiprazole monotherapy from another atypical antipsychotic (olanzapine, risperidone or quetiapine) found decreases in weight, total cholesterol, and LDL-cholesterol in those patients who switched to aripiprazole, and changes were most robust in those originally prescribed olanzapine (Spurling et al., 2007). The observation that aripiprazole results in modest weight gain but does not affect risk of metabolic syndrome or individual metabolic parameters has meaningful clinical implications. Metabolic syndrome is associated with a 6-fold increase in the risk of developing type 2 diabetes and a 3- to 6-fold increase in the risk of mortality from coronary heart disease (Fagiolini et al., 2008). In addition, metabolic syndrome is associated with such other conditions as fatty liver, polycystic ovary syndrome, cholesterol gallstones, sleep apnea, and lipodystrophies (Grundy et al., 2005). Thus, agents that do not increase these risks are important for consideration when choosing clinical treatment for bipolar disorder, especially because these patients can be considered an at-risk population for metabolic dysfunction. Furthermore, recent evidence suggests that metabolic syndrome and mental health disorders may share a common pathophysiology based on inflammation, which may be in part why patients with bipolar disorder have an increased risk for metabolic dysfunction (Zeugmann et al., 2010; Capuron et al., 2008; Kemp et al., 2010a, 2010b; Calkin et al., 2012). Components of inflammation, such as Creactive protein and proinflammatory cytokines, have been shown to

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be elevated in patients with metabolic syndrome and are considered risk factors for this condition (Capuron et al., 2008). Metabolic syndrome is also associated with a high rate of mood symptoms, and insulin resistance is considered a risk factor for the development of depression (Raikkonen et al., 2002; McIntyre et al., 2009; Koponen et al., 2008; Almeida et al., 2009). A link between proinflammatory cytokines and depression has been shown, and when innate immune cytokines (interferon-alpha) were administered to infectious disease and cancer patients, the rate of developing major depression was 30% to 50% (Musselman et al., 2001; Capuron and Miller, 2004). Given that inflammation and insulin-signaling pathways have been shown to play a role in the development and severity of mood disorders, treatments that target improvement of physical health may synergistically lead to stabilization of mood and improve overall functioning (Kemp, 2012). In light of the recognition that serious mental health disorders are associated with cardiovascular disease (CVD) risk factors, the European Psychiatric Association (EPA), the European Association for the Study of Diabetes (EASD), and the European Society of Cardiology (ESC) recently developed a position statement regarding this issue (De Hert et al., 2009). They recommend that not only a detailed medical history be taken initially, but that risk factors, such as fasting blood glucose, lipids, and cholesterol, be measured at the initial presentation or first prescription of an antipsychotic medication. Even for patients with normal baseline values, additional measurements should be made at 6- and 12 weeks after initiation of therapy and then at least annually moving forward (De Hert et al., 2009). In addition, patients naı¨ve to antipsychotic therapy are at greater risk of these metabolic changes and should be monitored closely (De Hert et al., 2012). Because switching medication in stable patients is associated with the potential for treatment discontinuation (Weiden, 2011), it is important to choose an initial treatment that is not only efficacious, but takes into consideration any potential comorbidities, such as CVD, to avoid the need for medication changes later in treatment in patients who are otherwise responding well to a given medication. The Canadian Network for Mood and Anxiety Treatments (CANMAT) has also published recommendations regarding the management of mood disorders in patients with comorbid metabolic disorders (McIntyre et al., 2012). They recommend addressing any underlying metabolic conditions and carefully choosing treatments for the mood disorder that do not exacerbate the metabolic dysfunction (McIntyre et al., 2012). A significant limitation of this study was that it is a post-hoc analysis. Previous analyses have shown that subgroup analyses, even of large trials, have reduced statistical power and increases variance and the role of chance in outcome results (Sleight, 2000). In addition, a lower percentage of patients completed the lamotrigine study as compared to the lithium/valproate study, but were consistent with other long-term trials of antipsychotics (Suppes et al., 2009; Bowden et al., 2010). Nevertheless, in two 52-week studies of aripiprazole adjunctive to mood stabilizers, metabolic outcomes were similar, thus strengthening the validity of our interpretations. Because chronic somatic diseases account for half of the excess mortality observed in bipolar disorder (Laursen et al., 2011), the effects of medications on other bodily systems cannot be ignored when selecting maintenance treatment. These results show that aripiprazole added to a mood stabilizer has little effect on metabolic syndrome and metabolic parameters, and is a viable choice to minimize the risk of cardiovascular disease and/or diabetes relative to other adjunctive therapy options in patients with bipolar disorder.

Role of funding source This study was supported by Bristol-Myers Squibb (Princeton, NJ, USA) and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan).

Conflict of interest David E. Kemp has been a consultant for Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Teva, and Corcept Therapeutics. He is on the Speakers Bureau for AstraZeneca and Pfizer, Inc., and his spouse is a minor shareholder of Abbott Laboratories and Sanofi. Marc De Hert has been a consultant for, received grant/research support and honoraria from, and has been on the speakers/advisory boards of AstraZeneca, Lundbeck JA, Janssen-Cilag, Eli Lilly, Pfizer, Inc., Sanofi-Aventis, and Bristol-Myers Squibb. Zia Rahman, James M. Eudicone, Sabrina V. Marler, and Berit X. Carlson are employees of Bristol-Myers Squibb. Paula Fyans was an employee of Bristol Myers Squibb at the time the research was conducted and the manuscript was prepared. Ross A. Baker is an employee of Otsuka Pharmaceutical Development & Commercialization, Inc.

Acknowledgement The authors would like to thank Meredith Rogers, MS, of Bristol-Myers Squibb, for providing writing and editorial assistance, and Robert A. Forbes, formally of Otsuka Pharmaceutical Development & Commercialization, Inc., for his assistance in analyzing the data and preparing the first draft of this report.

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