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 RESEARCH ARTICLE

Metabolic and body mass parameters after treatment with JNJ-37822681, a novel fast-dissociating D2 receptor antagonist, vs olanzapine in patients with schizophrenia

Ella J. Daly, MB, MRCPsych

Janssen Research & Development, LLC, Raritan, NJ, USA

Justine M. Kent, MD

Janssen Research & Development, LLC, Raritan, NJ, USA

Luc Janssens, MSc

Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

John W. Newcomer, MD

Department of Psychiatry and Behavioral Sciences, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA

Gitta Hüsken, PhD

Janssen-Cilag BV, Tilburg, Netherlands

Peter De Boer, PhD

Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

Luc Tritsmans, MD

Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

Mark E. Schmidt, MD

Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

BACKGROUND: The highly selective and fast dissociating D2 receptor antagonist JNJ-37822681 may be associated with lower risk for weight gain and undesirable metabolic effects compared with available antipsychotics.

METHODS: In this double-blind, randomized study, patients were randomly assigned (1:1:1:1:1) to 12 weeks of JNJ-37822681 (10 mg, 20 mg, or 30 mg, twice daily) or olanzapine (10 mg/d during week 1; 15 mg/d after week 1), or 6 weeks of placebo (followed by 6 weeks of olanzapine, 15 mg/d). Metabolic and body mass parameters were assessed at weeks 6 and 12.

RESULTS: For metabolic parameters, at week 6 none of the JNJ-37822681 groups demonstrated significant change vs placebo; however, significant changes (P < .05) were observed in the olanzapine vs placebo group in triglycerides, low-density lipoprotein (LDL) and very-LDL cholesterol, and free fatty acids. For all JNJ-37822681 groups, mean weight changes at week 12 (-0.3 [10 mg], + 0.3 [20 mg], + 0.8 kg [30 mg]) were significantly less (P < .001) than for the olanzapine group (+ 2.7 kg). A higher percentage of overweight or obese patients (baseline body mass index: ≥25 kg/m2) receiving olanzapine had ≥7% increase in weight than those receiving JNJ-37822681 (9.8% vs 2.3%, respectively).

CONCLUSIONS: JNJ-37822681 treatment was associated with a more favorable outcome on weight and metabolic adverse effects vs olanzapine for treating schizophrenia; the 10 mg twice-daily dose demonstrated minimal to no weight gain.

KEYWORDS: antipsychotic, body mass index, dopamine receptor antagonist, JNJ-37822681, metabolic parameters, schizophrenia

ANNALS OF CLINICAL PSYCHIATRY 2013;25(3):173-183

  INTRODUCTION

Coronary heart disease (CHD) is the primary cause of excess premature mortality in patients with schizophrenia, with more than two-thirds of patients dying from CHD compared with approximately one-half of the general population.1 Metabolic syndrome, a constellation of interrelated risk factors—insulin resistance, obesity, dyslipidemia, impaired glucose tolerance, hypertension—is more prevalent among patients with schizophrenia2,3 and contributes to development of type 2 diabetes mellitus (T2DM) and CHD. Ameliorating these risk factors is a key public health consideration for patients with schizophrenia.4,5

A substantial portion of the increased risk of adverse metabolic effects observed in patients with schizophrenia receiving antipsychotics is treatment-related. Evidence from controlled studies indicates that many, but not all, antipsychotics can adversely affect weight and other metabolic endpoints.6-9 For example, weight gain risk is highest among patients taking clozapine, olanzapine, or low-potency phenothiazines such as chlorpromazine; risk is moderate among patients taking quetiapine, risperidone, or other typical antipsychotics and minimal or more limited among patients taking aripiprazole, ziprasidone, or certain typical antipsychotics such as molindone.10-12 Several newer atypical antipsychotics also are reported to have a lower-to-moderate propensity for weight gain, including lurasidone,13 iloperidone,14 and asenapine.15 In general, clinically significant weight gain occurs in up to 50% of patients, with rapid increases seen within a few months of initiating antipsychotic treatment. Some agents are associated with higher rates of weight gain than others, as well as lipid and glucose dysregulation.4,6 Weight gain and adiposity can contribute to key modifiable risk factors for CHD such as obesity, hyperglycemia, dyslipidemia, and hypertension.4 Given these concerns, the consensus statement from the American Diabetes Association, together with the American Psychiatric Association and others,6 has attempted to highlight the relationship between atypical antipsychotics and the risk of weight gain, dyslipidemia, and diabetes, and to foster clinicians’ awareness of these risks. Despite these guidelines, there’s considerable evidence that patients with schizophrenia do not receive adequate monitoring when exposed to antipsychotics, and managing their comorbid medical illnesses is insufficient.4 Given the increased prevalence of metabolic syndrome and CHD in these individuals, the risk vs benefit profile of an antipsychotic must be assessed carefully before initiating treatment and then monitored on an ongoing basis.

JNJ-37822681 is a novel, highly selective, fast dissociating D2 dopamine receptor antagonist that was developed as a potential schizophrenia treatment. Many compounds with affinity for multiple non-D2 receptors have been developed previously, assuming that “atypicality” depends on a balance of pharmacological actions. However, certain pharmacological actions (eg, H1, M3, 5-HT2A, and 5-HT2C receptors) likely are responsible for undesirable effects on weight and metabolism.16 Drug affinity for certain non-D2 receptors is associated with weight gain or increased risk of diabetes.17 Because JNJ-37822681 has no appreciable off-target receptor binding, it may allow a lower incidence of such undesirable side effects.

We conducted a 12-week treatment study to evaluate antipsychotic efficacy and safety of JNJ-37822681 in patients with schizophrenia experiencing an acute episode, with the change in Positive and Negative Symptom Scale (PANSS) total score from baseline to 6 weeks as the primary efficacy endpoint. In this study, all evaluated doses of JNJ-37822681 (10 mg, 20 mg, and 30 mg, twice daily) demonstrated significant efficacy vs placebo on the PANSS; these and other secondary endpoint results are described elsewhere.18

We report on the associated metabolic profile of 3 JNJ-37822681 doses (10 mg, 20 mg, and 30 mg, twice daily) and the impact on body mass and other metabolic parameters at 6 and 12 weeks vs placebo (after 6 weeks) and olanzapine, 15 mg/d (6 to 12 weeks).

  METHODS

Study design

This double-blind, randomized, placebo- and active-controlled, parallel-group, dose-response, study in patients with schizophrenia was conducted at 59 sites in 10 countries from September 2008 to February 2010. The study design has been described previously.18 Briefly, following a screening period (day -21 to -1), 498 patients were randomly assigned to 1 of 5 treatment groups to receive oral doses of: JNJ-37822681 (10 mg [n = 100], 20 mg [n = 104], or 30 mg [n = 100], twice daily) for 12 weeks; olanzapine (n = 93), 10 mg/d for 1 week, then increased to 15 mg/d for 11 weeks; or placebo (n = 101) for 6 weeks followed by olanzapine, 10 mg/d for 1 week, then increased to 15 mg/d for the remaining 5 weeks. Randomization was based on a computer-generated randomization schedule balanced by using permuted blocks of treatments and was implemented using an interactive voice response system. The switch from placebo to olanzapine at week 6 was done for ethical reasons, so that no patient would be without active treatment for >6 weeks. Olanzapine, selected as an active control for assay sensitivity, was dosed in the evening. All patients were hospitalized during the first 2 weeks of treatment.

An independent ethics committee or institutional review board at each study site approved the protocol. The study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki and in accordance with International Conference on Harmonization Good Clinical Practice guidelines, applicable regulatory requirements, and in compliance with the protocol. All patients provided written informed consent.

Study population

Patients age 18 to 65 were enrolled in the study if they had a DSM-IV-TR diagnosis of schizophrenia for >1 year before screening and a body mass index (BMI) ≤40 kg/m2. Patients were included only if they were experiencing an acute exacerbation of schizophrenia symptoms of <6 months duration, with a PANSS total score at screening between 70 and 120 (inclusive), and at baseline of between 60 and 120 (inclusive).

Patients were excluded if they had used clozapine previously for treatment resistance or suicidal risk reduction. All antiparkinsonian medications and most psychotropics were discontinued ≥3 days before randomization. Several psychotropics—antipsychotics, monoamine oxidase inhibitors, other antidepressants, or mood stabilizers—were discontinued at prespecified, earlier time points to allow adequate washout. Medical exclusions included a history of significant or unstable cardiovascular disease or diabetes. Patients were prohibited from using moderate or strong cytochrome P450 (CYP) 3A4 or CYP1A2 inhibitors or inducers such as ketoconazole and carbamazepine. Other exclusions and prohibited medications or restrictions have been described previously.18

Outcome measures

Body mass parameters included body weight, BMI (kg/m2), and waist circumference (cm). Body weight was assessed at baseline, weekly from weeks 2 to 8 and at weeks 10 and 12. Waist circumference was assessed at baseline and at weeks 6 and 12. Waist circumference and BMI have been shown to be powerful independent predictors of T2DM,19 obesity prevalence,20 risk of CHD,21 and all-cause mortality.22 Metabolic parameters included fasting total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, free fatty acids, glycosylated hemoglobin (HbA1c), glucose, and insulin. Blood samples for all metabolic markers were obtained in a fasting condition at baseline and at weeks 2, 6, and 12 (except for HbA1c which was not obtained at week 2).

Statistical analysis

The intention-to-treat analysis set included all randomized patients who received ≥1 dose of the study drug and had ≥1 postbaseline PANSS total score during the double-blind treatment phase. Safety analysis set included all randomized patients who received ≥1 dose of the double-blind study drug.

The least squares (LS) adjusted means for change in body mass and metabolic parameters were estimated and compared between each treatment group and placebo using a mixed model repeated measures (MMRM) analysis on the observed change from baseline to week 12. The MMRM model included baseline value and baseline weight as covariates, with country, treatment, visit, and treatment-by-visit as fixed effects. A similar MMRM model was used to estimate and compare LS adjusted means for change at week 12 between the JNJ-37822681 groups and the olanzapine group; no direct comparison was made between JNJ-37822681 and placebo groups at week 12.

  RESULTS

Participant disposition and demographic and baseline characteristics

Of the 498 randomized patients, 298 (60%) completed the study. The most common reasons for withdrawal from the study were lack of efficacy (19%), withdrawal of consent (10%), and adverse event (7%). Demographic and baseline characteristics were comparable across the groups (TABLE 1). Three months before study screening, the most commonly used antipsychotics were haloperidol (41%), risperidone (25%), chlorpromazine (18%), and trifluoperazine (11%); only a small number of patients were taking olanzapine (10%) or clozapine (2%).


TABLE 1

Demographic and baseline characteristics (ITT analysis set)

  Placebo and
olanzapinea
15 mg/d
JNJ-37822681
10 mg,
twice daily
JNJ-37822681
20 mg,
twice daily
JNJ-37822681
30 mg,
twice daily
Olanzapine
15 mg,
twice daily
N 99 99 103 98 93
Age (years), mean (SD) 38.0 (10.50) 40.2 (11.71) 40.9 (10.84) 39.4 (10.61) 38.6 (10.80)
Men, n (%)b 59 (60) 52 (53) 65 (63) 56 (57) 49 (53)
Race, n (%)b
   White 82 (83) 84 (85) 83 (81) 80 (82) 76 (82)
   Asian 12 (12) 11 (11) 15 (15) 13 (13) 11 (12)
   African American 2 (2) 1 (1) 1 (1) 2 (2) 2 (2)
   Other 3 (3) 3 (3) 4 (4) 3 (3) 4 (4)
Weight (kg), mean (SD) 73.3 (14.24) 72.5 (15.98) 72.3 (15.04) 70.0 (14.00) 71.3 (15.07)
Height (cm), mean (SD) 170.3 (9.23) 168.8 (8.86) 169.7 (8.89) 169.7 (9.25) 169.7 (8.38)
BMIc (kg/m2), mean (SD) 25.3 (4.55) 25.5 (5.30) 25.1 (4.71) 24.2 (4.30) 24.7 (4.71)
Waist circumference (cm), mean (SD) 85.6 (12.58) 85.9 (13.28) 86.3 (12.82) 84.5 (12.19) 84.8 (13.32)
Schizophrenia type, n (%)b
   Paranoid 84 (85) 88 (89) 86 (83) 89 (91) 83 (89)
   Disorganized 5 (5) 2 (2) 5 (5) 4 (4) 4 (4)
   Catatonic 1(1) 0 0 0 0
   Residual 2 (2) 3 (3) 1 (1) 1 (1) 1 (1)
   Undifferentiated 7 (7) 6 (6) 11 (11) 4 (4) 5 (5)
aFor ethical reasons, the placebo and olanzapine group received placebo for 6 weeks followed by olanzapine, 15 mg/d, for 6 weeks.
bPercentages calculated with the number of patients in each treatment group as denominator.
cBMI was calculated from height and weight as BMI=(weight in kg)/(height in meters)2.

BMI: body mass index; ITT: intention-to-treat; SD: standard deviation.

Participants were age 18 to 65 (mean [standard deviation (SD)], 39.4 [10.9]), mostly male (57%) and white (82%); the mean PANSS total score was 90.5 points (range: 61 to 120 points). Baseline BMI was 16 to 38 kg/m2, with a mean of 25.0 kg/m2 (SD = 4.7) (TABLE 1).

Body weight, BMI, and waist circumference

For all JNJ-37822681 groups, the changes from baseline to week 6 in body weight (FIGURE 1), BMI (FIGURE 2), and waist circumference (FIGURE 3) vs placebo consistently were numerically less than the corresponding changes from baseline in the olanzapine-treated group vs placebo. Compared with olanzapine, all JNJ-37822681 groups showed significantly less change from baseline in BMI and body weight (FIGURE 4) at each time point throughout the study and at endpoint (P < .01) and in waist circumference at weeks 6 and 12 (all P < .05). Compared with placebo, the 20 mg and 30 mg JNJ-37822681 groups showed significant increases in body weight and BMI (P < .02) at week 6 and olanzapine treatment resulted in statistically significant increases (P < .001) in BMI and weight between weeks 2 and 6 and in waist circumference at week 6.

FIGURE 1: Least squares mean change (±SE) in body mass parameters from baseline to week 6 by MMRM (ITT analysis set): body weight (kg)a
aOlanzapine was initiated at 10 mg/d; after 1 week: 15 mg/d.
ITT: intention-to-treat; JnJ 10 mg: JNJ-37822681, 10 mg twice daily; JnJ 20 mg: JNJ-37822681, 20 mg twice daily; JnJ 30 mg: JNJ-37822681, 30 mg twice daily; MMRM: mixed model repeated measures; Olz: olanzapine, 15 mg/d; SE: standard error.

FIGURE 2: Least squares mean change (±SE) in body mass parameters from baseline to week 6 by MMRM (ITT analysis set): BMIa
aOlanzapine was initiated at 10 mg/d; after 1 week: 15 mg/d.
BMI: body mass index; ITT: intention-to-treat; JnJ 10 mg: JNJ-37822681, 10 mg twice daily; JnJ 20 mg: JNJ-37822681, 20 mg twice daily; JnJ 30 mg: JNJ-37822681, 30 mg twice daily; MMRM: mixed model repeated measures; Olz: olanzapine, 15 mg/d; SE: standard error.

FIGURE 3: Least squares mean change (±SE) in body mass parameters from baseline to week 6 by MMRM (ITT analysis set): waist circumference (cm)a
aOlanzapine was initiated at 10 mg/d; after 1 week: 15 mg/d.
ITT: intention-to-treat; JnJ 10 mg: JNJ-37822681, 10 mg twice daily; JnJ 20 mg: JNJ-37822681, 20 mg twice daily; JnJ 30 mg: JNJ-37822681, 30 mg twice daily; MMRM: mixed model repeated measures; Olz: olanzapine, 15 mg/d; SE: standard error.

FIGURE 4: Least squares mean change (±SE) in body weight from baseline to week 12 by MMRM (ITT analysis set)a
aOlanzapine was initiated at 10 mg/d; after 1 week: 15 mg/d.
ITT: intention-to-treat; JnJ 10 mg: JNJ-37822681, 10 mg twice daily; JnJ 20 mg: JNJ-37822681, 20 mg twice daily; JnJ 30 mg: JNJ-37822681, 30 mg twice daily; MMRM: mixed model repeated measures; Olz: olanzapine, 15 mg/d; SE: standard error.

In the safety analysis set, more overweight or obese patients (BMI ≥25 kg/m2) at baseline in the olanzapine group (9.8%) had a ≥7% weight increase at week 12 than in the pooled JNJ-37822681 group (2.3%). In contrast, approximately 10% of such patients in the pooled JNJ-37822681 group had a ≥5% weight decrease at week 12 compared with 0% in the olanzapine group. More patients with normal weight at baseline (BMI ≥18.5 and <25 kg/m2) in the olanzapine group showed a ≥7% weight increase at week 12 than in the pooled JNJ-37822681 group (TABLE 2). A mean total increase occurred in those who were underweight (BMI <18.5 kg/m2) or were normal weight at baseline in the JNJ-37822681 10-mg and 20-mg groups, but not in those who were overweight (BMI <30 kg/m2) or obese (BMI ≥30 kg/m2) at baseline. In contrast, the mean changes in weight from baseline to week 12 after olanzapine treatment were comparable across the groups based on baseline BMI.


TABLE 2

Percentage of patients with ≥7% change in body weight and mean change in body weight from baseline to week 12 by baseline BMI and treatment group (safety analysis set)a

Baseline BMIb group Placebo and
olanzapined
15 mg/d
JNJ-37822681
10 mg, twice daily
JNJ-37822681
20 mg, twice daily
JNJ-37822681
30 mg, twice daily
Olanzapine
15 mg, twice daily
Underweight (BMI <18.5)
  n/N (%)c 0/1 (0) 1/3 (33) 5/10 (50) 3/6 (50) 3/6 (50)
  Mean change (kg) +1.2 +3.1 +3.2 +2.6 +4.3
Normal (BMI ≥18.5 and <25)
  n/N (%)c 1/50 (2) 5/47 (11) 3/44 (7) 5/55 (9) 17/46 (37)
  Mean change (kg) +0.4 +0.3 +0.2 +0.8 +3.1
Overweight (BMI ≥25 and <30)
  n/N (%)c 2/35 (6) 1/28 (4) 0/31 (0) 2/29 (7) 2/29 (7)
  Mean change (kg) +0.2 -0.3 -0.2 +0.2 +1.4
Obese (BMI ≥30)
  n/N (%)c 0/13 (0) 0/20 (0) 0/16 (0) 0/9 (0) 2/12 (17)
  Mean change (kg) 0.0 -1.1 -0.2 -0.1 +2.7
aAn LOCF approach was used.
bBMI was calculated from height and weight as BMI=(weight in kg)/(height in meters)2.
cPercentages calculated with the number of patients in each treatment group as denominator.
dFor ethical reasons, the placebo and olanzapine group received placebo for 6 weeks followed by olanzapine, 15 mg/d, for 6 weeks.

BMI: body mass index; LOCF: last observation carried forward; n: number of patients in a group with ≥7% changes from baseline to week 12 in body weight; N: total number of patients in a group.
Lipid and glucose parameter

Postbaseline changes. There was no significant change from baseline to week 6 in mean fasting triglycerides, HDL cholesterol, LDL cholesterol, VLDL cholesterol, free fatty acids, glucose, HbA1c, or insulin for any of the JNJ-37822681 groups vs placebo. In contrast, significant changes in triglycerides, LDL cholesterol, VLDL cholesterol, and free fatty acids at week 6 (all P ≤ .5) occurred for the olanzapine group vs placebo. At week 12, both glucose (P ≤ .01) and insulin levels (P < .05) decreased significantly from baseline in the JNJ-37822681 20-mg and 30-mg groups vs olanzapine. However, free-fatty acids levels increased significantly for the 10-mg JNJ-37822681 group compared with the olanzapine group (P < .05) from baseline to week 12.

Postbaseline categorical shifts. In the safety analysis set, more patients in the JNJ-37822681 groups had favorable shifts in fasting triglycerides2 than in the olanzapine group (TABLE 3); more patients in the olanzapine group had unfavorable shifts in LDL cholesterol than patients in the JNJ-37822681 groups. Specifically, more patients in the olanzapine group (37%) had a postbaseline shift from the National Cholesterol Education Program category of borderline (LDL levels between 100 mg/dL and 160 mg/dL) to high (LDL levels ≥160 mg/dL) for LDL cholesterol compared with the placebo group (13%) and all JNJ-37822681 dose groups (10 mg: 13%; 20 mg: 9%; 30 mg: 18%).


TABLE 3

Post-baseline shift in NCEP category for fasting triglyceridesa

Post-baseline worst observation categorical shift Placebo/
olanzapine
JNJ-37822681
10 mg, twice daily
JNJ-37822681
20 mg, twice daily
JNJ-37822681
30 mg, twice daily
JNJ-37822681
pooled
Olanzapine
15 mg,
twice daily
Favorable shifts n/N (%)b
Very high/high to
normal/borderline
6/14 (43) 8/18 (44) 6/18 (33) 5/16 (31) 19/52 (37) 2/13 (15)
High to normal 2/14 (14) 2/16 (13) 3/18 (17) 3/16 (19) 8/50 (16) 0/12 (0)
Borderline to normal 8/17 (47) 6/17 (35) 3/15 (20) 2/9 (22) 11/41 (27) 2/15 (13)
Unfavorable shifts n/N (%)b
Increase ≥50 mg/dL 19/91 (21) 25/94 (27) 26/95 (27) 28/89 (31) 79/278 (28) 35/91 (38)
Normal/borderline to
high/very high
9/77 (12) 11/76 (14) 12/77 (16) 14/73 (19) 37/226 (16) 15/78 (19)
Normal to borderline/
high/very high
13/60 (22) 9/59 (15) 14/62 (23) 19/64 (30) 42/185 (23) 20/63 (32)
Very high ≥500 mg/dL 1/91 (1) 2/94 (2) 2/95 (2) 0/89 (0) 4/278 (1) 1/91 (1)
aCategories: normal: <150 mg/dL; borderline: ≥100 and <200 mg/dL; high: ≥200 and <500 mg/dL; very high: ≥500 mg/dL; very high/high: ≥200 mg/dL.
bn/N (%) stands for fraction and percentage of patients in a particular treatment group showing corresponding categorical shift as worst observation.

NCEP: National Cholesterol Education Program.

  DISCUSSION

The metabolic profile of JNJ-37822681 suggests the compound is associated with minimal or no weight gain in patients after 12 weeks of treatment. Of the patients at heightened metabolic risk at baseline because of being overweight or obese (BMI ≥25 kg/m2), those treated with JNJ-37822681 (pooled group) were less likely to gain ≥7% of their baseline body weight by week 12 compared with those treated with olanzapine. In fact, overweight or obese patients in the JNJ-37822681 pooled group were more likely than those in the olanzapine group to have a clinically significant decrease in weight (≥5% decrease from baseline) at week 12. The mean change in weight for those who were overweight or obese at baseline was found to be most favorable in the JNJ-37822681 10-mg group.

There’s considerable evidence suggesting that increased metabolic and cardiovascular risk associated with long-term use of atypical antipsychotics primarily is mediated by weight gain6 and adiposity.4 However, there’s evidence that certain atypical antipsychotics may have an adverse impact on metabolism and cardiovascular risk via mechanisms unrelated to weight gain—eg, an independent effect on insulin sensitivity or pancreatic β-cell function.23 Reports indicating that hyperglycemia can improve quickly after discontinuing antipsychotics,24 and the fact that diabetes can develop in some patients without associated weight gain25 further support this. Recent experiments with cultured cell models indicate that atypical antipsychotics differentially affect insulin action and metabolism through direct effects on adipocytes.26 Interestingly, existing literature suggests that lower prolactin levels may contribute to a lower incidence of weight gain.27 We previously reported a low risk of prolactin elevation, and decreases in prolactin levels during treatment with JNJ-37822681 groups in both men and women.18

Data from phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness study show random assignment to olanzapine was associated with increased metabolic risk, including increases in triglycerides, HbA1c, and total cholesterol.8 Moreover, significant increases in insulin levels have been reported with olanzapine.28 These data are consistent with other evidence suggesting risk for metabolic-related adverse events occurring in patients varies across compounds.9

The results from this study suggest that JNJ-37822681 has less potential to negatively impact metabolic parameters compared with olanzapine. Placebo comparisons, which were conducted at week 6, showed no significant change in the mean values of the metabolic parameters assessed in the 3 JNJ-37822681 dose groups. In contrast, those treated with olanzapine had significant (P ≤ .5 vs placebo) mean increases in triglycerides, LDL cholesterol, VLDL cholesterol, and free fatty acids.

The use of mean changes in metabolic parameters has been criticized for not fully accounting for those with and without clinically significant shifts in such parameters, which may be important in guiding treatment. We examined favorable and unfavorable shifts observed from baseline to week 12 in LDL cholesterol and triglycerides. Although elevated LDL-cholesterol levels are known to be a strong risk factor for CHD, elevated triglycerides levels are an independent risk factor for CHD. Results of this study suggest that JNJ-37822681 has less potential to negatively impact both of these metabolic parameters compared with olanzapine.

In this study, patients were excluded if they had a history of diabetes, were receiving a glucose lowering agent, or undergoing treatment for diabetes. Given the prevalence of medical comorbidities in this patient population, exclusion of such patients could limit generalizability of the findings to the broader population. We also recognize that weight loss observed in the JNJ-37822681 group could, in part, be attributable to patients switching from other antipsychotic medications associated with greater propensity for weight gain. However, it’s unlikely that the minimal to no weight gain observed over the 12-week JNJ-37822681 exposure period was accounted for by the discontinuation of higher weight gain liability agents such as olanzapine and clozapine because few patients were taking these medications before screening. Although data at week 6 showed the 20-mg and 30-mg JNJ-37822681 groups had significant increases in body weight and BMI (P < .02) compared with placebo, closer examination of the data showed the following: overweight and obese patients in the JNJ-37822681 groups showed an average decrease in weight (-0.1 kg) compared with an increase of +1.4 kg in the olanzapine group at week 6. In normal-weight patients, the increase in weight was <0.5 kg for the JNJ-37822681 groups and <2.1 kg for the olanzapine group, whereas underweight patients in all actively treated groups (JNJ-37822681 and olanzapine) showed an average increase of >2 kg from baseline after 6 weeks (last observation carried forward), suggesting that the average increase in weight at week 6 is driven by the increase in weight in underweight patients. The increased weight gain observed in underweight patients (at baseline) in olanzapine and JNJ-37822681 groups may be explained by a combination of regression to the mean weight, dietary support in the hospital, and perhaps improvement in psychotic symptoms (eg, paranoia, suspiciousness, social isolation) leading to better eating habits.

  CONCLUSIONS

Although the lowest effective dose for JNJ-37822681 has not yet been established, 10 mg twice daily has the most favorable metabolic profile, with evidence of minimal to no weight gain and less propensity for adverse effects on LDL-cholesterol and fasting triglycerides, both of which are recognized as important modifiable risk factors for CHD. In conjunction with regular monitoring of metabolic indices and a focus on lifestyle intervention in this at-risk population, JNJ-37822681 may offer advantages over existing treatments, particularly in patients at increased baseline risk for CHD.

DISCLOSURES: Drs. Daly and Kent are employees of Janssen Research and Development, LLC, USA and hold equity stocks >$5,000 in Johnson and Johnson. Drs. De Boer, Tritsman, and Schmidt and Mr. Janssens are employees of Janssen Research and Development a division of Janssen Pharmaceutica NV, Beerse, Belgium and hold stocks of >$5,000. Dr. Newcomer receives grant or research support from the National Institute of Mental Health; is a consultant to Boehringer Ingelheim, Bristol-Myers Squibb, Merck, and Vivus; receives royalties, patents, or other income from Jones & Bartlett Publishing; and receives honoraria from the American Physician Institute, the American Psychiatric Association, CMEology, and CME Outfitters. Dr. Hüsken is an employee of Janssen-Cilag BV, and holds equity stocks of >$5,000 in Johnson & Johnson.

ACKNOWLEDGEMENTS: Funding for this study was provided by Janssen Research & Development, LLC (formerly Johnson & Johnson Pharmaceutical Research & Development). Janssen Research & Development, LLC also was involved in the collection, analysis, and interpretation of data, the writing and reviewing of this manuscript, and in the decision to submit the paper for publication.

The authors wish to thank Dr. Nancy Van Osselaer and Dr. Luc Van Nueten who contributed to study design of the primary study and data analysis, and to Dr. Madhoolika Nema (SIRO ClinPharm Pvt Ltd) and Dr. Wendy P. Battisti (Janssen Research & Development, LLC.), who provided writing and editorial support for this manuscript.

The authors also wish to thank the study patients, without whom this study would not have been accomplished, as well as the following investigators for their participation: Bulgaria: Dora Atanasova, MD; Lubomir Jivkov, MD; Temenuzhka Mateva, MD; Loris Sayan, MD; and Todor Tolev, MD Estonia: Kaire Aadamsoo, MD; Ants Puusild, MD; and Kart Uppin, MD Korea: Chul Eung Kim, PhD; Sung-Gon Kim, PhD; Yong Sik Kim; Jong-Il Lee, PhD; In-Ho Paik, PhD; Ji Young Song, MD; and Jin-Sang Yoon, MD Lithuania: Algirdas Dembinskas, MD, PhD; Valentinas Maciulis, MD, PhD; and Regina Satkeviciute, MD, PhD Malaysia: Abdul Kadir Abu Bakar, MD; Rosdinom Razali, MD; Ahmad Hatim Sulaiman, MD; and Rosliwati Yusoff, MD Romania: Irina Dan, MD; Iosif Gabos Grecu, PhD; Cristina Anastasia Iordache, MD; Mirela Manea, PhD; Gheorghe Oros, MD; Bogdan Pacala, MD, PhD; Delia Podea, MD, PhD; Ioana Popescu, MD; and Maria Sandulescu, MD, PhD Russia: Alexey Agarkov, MD; Mikhail Burdukovsky, MD; Natalya Dobrovolskaya, MD; Elena Grigoryeva, MD; Mikhail Ivanov, MD, PhD; Margarita Morozova, MD, PhD; Nikolay Neznanov, MD; Mikhail Popov, MD, PhD; Olga Reshetko, MD, PhD; Oleg Serdyuk, MD; Mikhail Sheyfer, MD, PhD; Anatoly Smulevich, MD, PhD; and Yuri Suchkov, MD South Africa: Lynette Nel, MBCHB, MMed; Daniel Niehaus, MBCHB, MMed (Psych); Paresh Ramjee, MBBS, MMed (Psych); and Juan Paul Schronen, MBCHB, DMH, MMed (Psych) Taiwan: Tzu Ting Chen, MD; Huang-Chih Chou, MD; and Shih-Ku Lin, MD Ukraine: Volodymyr Abramov, MD, PhD; Valery Bitenskyy, MD, PhD; Yuliya Blazhevych, MD; Vladislav Demchenko, MD; Natalia Maruta, MD, PhD; Svitlana Moroz, MD, PhD; Pavlo Palamarchuk, MD; and Viktoriya Verbenko, MD, PhD.

The primary results from this study are published elsewhere. The data presented in the manuscript were previously presented at the Society of Biological Psychiatry Annual Meeting, San Francisco, CA, USA, May 12 to 14, 2011; the 164th Annual Scientific Meeting of the American Psychiatric Association, Honolulu, HI, USA, May 14 to 18, 2011; and the 51st New Clinical Drug Evaluation Unit Annual Scientific Meeting, Boca Raton, FL, USA, June 13 to 16, 2011.

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CORRESPONDENCE: Ella J. Daly, MB, MRCPsych 1125 Trenton-Harbourton Road PO Box 200 Titusville, NJ 08560 USA E-MAIL: edaly2@its.jnj.com