Schizophrenia Research 153 (2014) 160–168

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A trial evaluating gradual- or immediate-switch strategies from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia Peter J. Weiden a,⁎, Leslie Citrome b, Gus Alva c, Matthew Brams d, Ira D. Glick e, Richard Jackson f, Greg Mattingly g, Farid Kianifard h, Xiangyi Meng h, Linda Pestreich h,1, Marla Hochfeld h,2, Adam Winseck h a

University of Illinois at Chicago, UIC Medical Center, 912 South Wood Street, MC 913, Chicago, IL 60612, USA New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY 10595, USA c ATP Clinical Research, 3151 Airway Avenue, Building T, Suite 3, Costa Mesa, CA 92626, USA d Memorial Park Psychiatry, 550 Westcott, Suite 520, Houston, TX 77007, USA e University School of Medicine Stanford, 251 Campus Drive, Stanford, CA 94305, USA f Wayne State University, Scott Hall, 540 East Canfield, Detroit, MI 48201, USA g Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA h Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA b

a r t i c l e

i n f o

Article history: Received 8 May 2013 Received in revised form 20 November 2013 Accepted 26 November 2013 Available online 12 February 2014 Keywords: Iloperidone Switch strategy Schizophrenia Clinical improvement Safety Tolerability

a b s t r a c t In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2 weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6 mg BID by Day 4, then flexibly dosing between 6 and 12 mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradualand immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: −0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: −0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: −0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (≥10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/ tolerability outcomes, based on the I-CGI-C at 12 weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched. © 2013 Elsevier B.V. All rights reserved.

1. Introduction One of the most common therapeutic options for persistent symptoms or tolerability problems during maintenance treatment of

⁎ Corresponding author at: UIC Medical Center, 912 South Wood Street MC 913, Chicago, IL 60612, USA. Tel.: +1 312 996 9986; fax: +1 312 996 9517. E-mail addresses: [email protected] (P.J. Weiden), [email protected] (L. Citrome), [email protected] (G. Alva), bramsmaooffi[email protected] (M. Brams), [email protected] (I.D. Glick), [email protected] (R. Jackson), [email protected] (G. Mattingly), [email protected] (F. Kianifard), [email protected] (X. Meng), [email protected] (A. Winseck). 1 LP is no longer an employee of Novartis; now employed by Otsuka America Pharmaceuticals Inc., One University Square Drive, Princeton, NJ 08540, USA . 2 MH is no longer an employee of Novartis; now employed by Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA. 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.11.042

schizophrenia is to change antipsychotic medication. Although evidence of the effectiveness of a switching between 2 non-clozapine antipsychotics has mixed reports (Essock et al., 2006; Agid et al., 2011), it remains relevant to examine the methodology and outcomes of switching between individual antipsychotics. Registration trials of an antipsychotic generally center on establishing efficacy and safety and are less concerned about medication switching. Therefore, after approval, the focus moves towards better understanding the specifics of the switching process. Questions regarding switching include the rapidity of switching and pharmacokinetic and pharmacodynamic interactions, including antipsychotic withdrawal problems due to switching off of the previous antipsychotic, as well as additional tolerability problems from temporarily overlapping 2 antipsychotics. Finally, clinicians want to understand the likelihood of achieving a successful switch, which might include consideration of differences in side-effect profiles both

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before and after the switch is completed, and the overall likelihood of success in completing the switch. Iloperidone was approved by the Food and Drug Administration in 2009. Iloperidone is an atypical antipsychotic in that it has a higher affinity for the serotonin 2a receptor than the D2 receptor, but has a distinct receptor binding profile that has a different absolute and relative affinities for the multiple DA, 5HT, and alpha adrenergic receptors such that it is not a derivative or metabolite of any other available antipsychotic, as well as an overall tolerability profile that differs from other available agents. Specifically, iloperidone has a higher affinity for the noradrenergic alpha1 receptor than for the dopamine type 2, and similar affinity to serotonin 2A, receptors (Richelson and Souder, 2000). One issue that has been a concern is that initiation of therapy should take into account this strong affinity as an antagonist at the alpha1 receptor, which may be associated with transient orthostatic hypotension or dizziness (Weiden, 2012). One of the initial concerns was that the delay in reaching therapeutic dose may delay onset of efficacy compared with other antipsychotics that do not require titration (Fanapt PI, 2013). The pivotal trials of iloperidone were conducted in the acute phase of illness (Cutler et al., 2008; Potkin et al., 2008; Weiden et al., 2008), whereas in clinical practice, antipsychotic medications are often changed during maintenance-phase therapy. Therefore, important yet unanswered clinical questions regarding switching to iloperidone include: (1) What is the overall safety of switching stable but symptomatic outpatients from other antipsychotic medications to iloperidone, and is there subsequent occurrence of any significant psychiatric or medical problem? (2) Is there any difference in outcome, both efficacy and safety, whether the antipsychotic switch is done slowly (gradual switch) or rapidly (immediate switch) with the prior antipsychotic and iloperidone being prescribed simultaneously? (3) Is there any difference in outcome, both efficacy and safety, depending on the primary reason for changing antipsychotic? (4) Is there any difference in outcome, both efficacy and safety, based on the specific antipsychotic that is being discontinued? This study (the iloperidone Flexible-dose Study Assessing Efficacy and Safety and Tolerability of Two Switch Approaches iN Schizophrenia Patients Currently Receiving Risperidone, Olanzapine or Aripiprazole [i-FANS]) was designed similarly to previous “switch” studies (Casey et al., 2003; Weiden et al., 2003a, 2003b). The basic design was to enroll subjects with a known diagnosis of schizophrenia who had been stabilized on another antipsychotic but who continued to have persistent symptoms or tolerability problems. All subjects therefore had a clinical reason to change therapies, and clinicians considered iloperidone to be a reasonable next therapeutic option. Subjects were then randomized in an open-label fashion to a particular switch method (gradual or immediate).

2. Methods The primary objective of this 12-week study (clinicaltrials.gov registry: NCT01207414) was to evaluate the impact on clinical outcomes of 2 switching strategies to iloperidone 12–24 mg/d by patients with schizophrenia experiencing residual symptoms and/or undesired side effects on their current therapy of risperidone, olanzapine, or aripiprazole. The primary outcome variable was the Integrated Clinical Global Impression of Change (I-CGI-C). The primary analysis time point was 12 weeks after switching so that all completing subjects were on iloperidone monotherapy for at least 10 weeks. This study was conducted at 59 study centers in the United States (US). The study was reviewed and approved by an Institutional Review Board at each study center and the trial was conducted in accordance with Good Clinical Practice as required by the International Conference on Harmonization guidelines. Compliance with these requirements also constitutes conformity with the ethical principles of the Declaration of Helsinki.

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2.1. Study population Patients (18–64 years of age) with a DSM-IV-TR diagnosis of schizophrenia who were outpatients experiencing suboptimal efficacy and/or safety/tolerability symptoms from their current treatment with risperidone, olanzapine, or aripiprazole were eligible for the study. Patients must have been on an optimal dose (as per clinical judgment, but not higher than the labeled maximum dose) of 1 of these 3 antipsychotic treatments for ≥30 days prior to consenting. Suboptimal efficacy was defined as a score of 4 or 5 (moderately or markedly ill) on the Efficacy Clinical Global Impression of Severity (E-CGI-S) scale. Prespecified safety/tolerability symptoms were: (1) extrapyramidal symptoms (EPS), (2) akathisia, (3) elevated prolactin levels (either associated with clinically relevant sequelae or more than 2 times the upper limit of normal [ULN]), (4) weight gain (≥ 7%; maintained for ≥ 6 months based on history or weight measures) attributable to the prior antipsychotic, (5) somnolence/sedation, (6) agitation, or (7) anxiety. Any patient being considered for enrollment based on any one of these prespecified safety/tolerability symptoms required a baseline level of severity of 3 or more (mild impairment) per the Safety and Tolerability CGI-S [ST-CGI-S] rating scale. Patients were excluded if they: had any other current Axis I disorder except the schizophrenia that was the focus of treatment; were currently taking N 1 antipsychotic; had treatment with a long-acting injectable antipsychotic within 6 months; had recent dosage changes with the preswitch antipsychotic or any coprescribed antidepressant; had a history of failure after treatment with clozapine or response only to clozapine or on a therapeutic dose of the current antipsychotic that exceeded the maximum dose recommended in the US product labeling (ie, risperidone, 16 mg/d; olanzapine, 20 mg/d; aripiprazole, 30 mg/d); had a presence of a concomitant CYP3A4 or CYP2D6 inducer or inhibitor that would require adjustment of the target dose of iloperidone; had ≥3 failed antipsychotic treatment trials within the last 2 years; were assessed as acutely psychotic and/or exhibited symptoms requiring hospitalization; were at risk of suicide; had clinical or laboratory evidence of active drug or alcohol abuse or dependence; had significant cardiovascular illness (eg, myocardial infarction, cardiac arrhythmia, or a baseline QTcF N450 ms for men or N470 ms for women); were taking any drug known to prolong the QTc interval; or were pregnant. Subjects were dichotomized into primary reason for switching antipsychotic, with investigators specifying efficacy or tolerability. For subjects who had both efficacy and tolerability reasons for switching, the investigator selected the category that was most clinically important for that individual subject. All subjects provided written informed consent before study participation. 2.2. Study design A total of 500 patients from 3 approximately equally sized cohorts that were defined by patients' current antipsychotic treatment (risperidone, n = 175; olanzapine, n = 155; aripiprazole, n = 170) were randomized 1:1 to either gradually taper their prior antipsychotic dose over the first 2 weeks of iloperidone use (to 50% on Day 1, 25% at Week 1, 0% at Week 2) or immediately switch to iloperidone (Fig. 1). All patients initiated iloperidone on Day 1 and received a titration pack to start at 1 mg twice daily and reach 6 mg twice daily (12 mg total daily dose) on Day 4. After reaching the 12 mg daily dose, at any time during the remainder of the study, investigators were allowed to make necessary dose increases or decreases, within the 12–24 mg daily range, with dose increments not to exceed 2 mg twice daily. 2.3. Evaluation of Clinical Global Impression The Clinical Global Impression (CGI) scale is a well-established assessment of disease severity, with the Severity subscale (CGI-S) covering a 7-point range from 1 (not at all ill) to 7 (extremely ill)

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Fig. 1. Study design. D = day.

(Guy, 1976). It has been found to correlate with both the Positive and Negative Syndrome Scale and the Brief Psychiatric Rating Scale (Leucht and Engel, 2006; Levine et al., 2008). Because the global CGI-S may be less sensitive to different aspects of pharmacologic response in clinical trials (Leucht et al., 2009), we modified and adapted it for schizophrenia by separating out the efficacy and safety domains and included an integrated domain (Targum et al., 2012). The E-CGI-S and STCGI-S were developed to assess clinical outcomes following a switch between antipsychotic medications. These versions of the CGI incorporated the same 1–7 scaling and anchoring but differed in outcome domain. The E-CGI-S score is based on the rater identifying positive and negative symptoms observed over the past week and the impact of these symptoms on the patient's behavior and functioning. The ST-CGI-S score is based on the rater identifying safety/tolerability symptoms observed over the past week and the impact of these symptoms on the patient's behavior and functioning. The integrated CGI-S (I-CGI-S) combines the individual E-CGI-S and ST-CGI-S scores into a single, unified measure of severity. The I-CGI measure of clinical change (I-CGI-C) was used to evaluate clinical changes that occurred from baseline over 12 weeks of treatment. The rater assessed the clinical relevance (ie, impact on behavior and function) of the observed symptomatic changes of clinical efficacy, safety, or medication tolerability (adverse events [AEs]) that had occurred since switching to another antipsychotic medication. All raters had a minimum of 2 years' experience conducting CGI ratings. Inter-rater reliability was assessed by comparing scores on a standardized interview observed on a video recording. 2.4. Safety and tolerability evaluations Safety and tolerability assessments included number and type of AEs, physical examinations, vital sign recordings, clinical laboratory evaluations, and 12-lead electrocardiograms (ECG). Scheduled visits occurred at screening, baseline, and Weeks 1, 2, 3, 4, 6, 8, 10, and 12. Orthostatic vital signs, weight, and AEs were collected at every visit. Routine laboratory assessments (ie, hematology, chemistry, and urinalysis) occurred at screening and Week 12; with glucose, lipids, and prolactin

also assessed at Week 6. Every effort was made to draw blood for laboratory analyses under fasting conditions. A standard 12-lead ECG was performed at screening and Week 1. 2.5. Additional evaluations Other assessments included a patient characteristics questionnaire and the Treatment Satisfaction Questionnaire for Medication (Atkinson et al., 2004). These will be reported in a separate publication. 3. Statistical analysis The full analysis set included all patients to whom study medication was assigned. The safety set included all patients who received at least 1 dose of study medication. Analysis of (co)variance (AN[C]OVA) was used to analyze the I-CGI-C (primary variable) and changes from baseline in the E-CGI-S, ST-CGI-S, and I-CGI-S (secondary variables) with baseline (if applicable), treatment, cohort, and treatment-by-cohort interaction as explanatory variables for the 3 cohorts combined, and with baseline (if applicable) and treatment as the explanatory variables for each cohort, at each time point (week). Least-squares mean (LSM), LSM difference of the treatment groups, and 95% confidence interval (CI) for the difference based on the fitted linear model are reported. Missing data were imputed using the last-observation-carried-forward method. The primary analysis time point was Week 12. It was assumed that each of the 2 treatment groups within each of the 3 cohorts would have a common standard deviation of 1.5 for the I-CGI-C, based on data from a prior iloperidone trial (Kane et al., 2008). With approximately 70 patients in each treatment group within each cohort (total of 140 patients per cohort), one could estimate the difference between mean I-CGI-C of the 2 treatment groups within each cohort at Week 12 with a “margin of error” (half-width of CI) of 0.5 for a 2-sided 95% CI. Allowing for a loss to follow-up rate of 15%, a sample size of approximately 168 patients in each of the 3 cohorts (total of approximately 500 patients) were planned to be randomized.

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All statistical analyses were performed using SAS® Version 9.2 (SAS Institute Inc., Cary, NC, USA). Additional analyses of the CGI will be reported in a separate publication. 4. Results 4.1. Patients A total of 659 patients provided informed consent and were screened to participate in the study, of which 501 (76.0%) were randomized (including 1 patient in the olanzapine cohort who was randomized in error and to whom no medication was dispensed). Of the 500 patients correctly randomized, 175 switched from risperidone, 155 switched from olanzapine, and 170 switched from aripiprazole. A total of 72 patients (30%) discontinued from the gradual-switch group and 82 patients (32%) discontinued from the immediate-switch group, with 39 (8%) and 54 (11%) of patients, respectively, doing so within the first 6 weeks. Reasons for discontinuation throughout the study in the gradual- and immediate-switch groups, respectively, were AEs (10.4% and 15.0%), unsatisfactory therapeutic effect (2.1% and 1.5%), withdrawal of consent (5.8% and 4.2%), lost to follow-up (6.3% and 6.5%), and other (5.4% and 4.2%). The first subject was enrolled on August 31, 2010 and the last subject completed the study on January 4, 2012. The full analysis and safety sets included the 500 patients correctly randomized. In the 3 cohorts combined, 12 mg/d was the most common of the prescribed iloperidone doses administered at the end of the study (46.6% of patients), with 22.0% at 16 mg/d, 15.6% at 20 mg/d, and 15.8% at 24 mg/d. Mean (standard deviation [SD]) and median dose of iloperidone at study end was 16.7 (4.5) mg/d and 16.0 mg/d, respectively. 4.2. Demographics Patients were (mean ± SD) 43.3 ± 11.0 years of age; 56.6% were Black/African American, and 67.0% were male. There were no clinically meaningful differences between the gradual-switch group and the

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immediate-switch group in mean age or in distribution of gender, race, or ethnicity for the individual cohorts or the 3 cohorts combined (Table 1). For each of the prespecified symptoms for entering this study (ie, suboptimal efficacy and/or safety/tolerability symptoms), the number of patients for each symptom, given as the primary reason for switching from risperidone, olanzapine or aripiprazole, are presented in Table 2. The primary reason for switching from risperidone was efficacy issues for 56.0% of patients and safety/tolerability symptoms for 44.0%. For olanzapine, 49.0% and 51.0%, respectively, switched primarily due to efficacy and safety/tolerability. For both of these 2 cohorts, weight gain (12.6% and 25.2%) and somnolence/sedation (13.7% and 14.8%) were the most common safety reasons for switching. With aripiprazole, the primary reason for switching was efficacy for 72.4% and safety/tolerability for 27.6%, with weight gain (9.4%) and akathisia (7.6%) the most common safety reasons.

4.3. Clinical Global Impression Measures Improvement from baseline to Week 12 in I-CGI-C scores (primary variable) in the 3 cohorts combined and the individual cohorts was similar between the gradual- and immediate-switch approaches. For the 3 cohorts combined, LSM scores at Week 12 were 2.83 for the gradualand 2.84 for the immediate-switch groups (LSM difference: − 0.012; 95% CI: −0.232, 0.208), indicating clinical improvement. Results for the individual cohorts were similar to the 3 cohorts combined, with LSM differences between gradual- and immediate-switch groups of 0.141 for risperidone, −0.157 for olanzapine, and −0.019 for aripiprazole. Changes from baseline to Week 12 in E-CGI-S, ST-CGI-S, and I-CGI-S were similar between gradual- and immediate-switch groups for the 3 cohorts combined (Table 3). Results for the individual cohorts were similar to the 3 cohorts combined, with no clinically meaningful differences between the gradual- and immediate-switch groups (Table 3). Over the duration of the study, no differences in I-CGI-C, E-CGI-S, ST-CGI-S, and/or I-CGI-S scores between treatment groups were clinically meaningful for the 3 cohorts combined or any of the individual cohorts at any time point from Week 1 to Week 12.

Table 1 Demographic and baseline characteristics (safety set). Category

Cohorts Combined (N = 500)

Cohorts Combined (N = 500)

Risperidone (n = 175)

Olanzapine (n = 155)

Aripiprazole (n = 170)

Gradual + Immediate

Gradual (n = 240)

Immediate (n = 260)

Gradual (n = 81)

Immediate (n = 94)

Gradual (n = 79)

Immediate (n = 76)

Gradual (n = 80)

42.3 (10.98)

44.2 (10.92)

42.9 (9.22)

46.5 (9.96)

41.2 (12.06)

43.3 (10.54)

42.8 (11.55)

42.6 (11.87)

70.8 (170) 29.2 (70)

63.5 (165) 36.5 (95)

70.4 (57) 29.6 (24)

62.8 (59) 37.2 (35)

74.7 (59) 25.3 (20)

73.7 (56) 26.3 (20)

67.5 (54) 32.5 (26)

55.6 (50) 44.4 (40)

35.0 (84) 57.9 (139) 0.4 (1) 0.8 (2) 0.8 (2) 5.0 (12) 95.2 (22.5) 32.0 (7.48) 16.0 (10.80)

40.8 (106) 55.4 (144) 1.5 (4) 0 0 2.3 (6) 93.8 (22.9) 31.6 (8.59) 15.7 (10.64)

28.4 (23) 65.4 (53) 1.2 (1) 0 0 4.9 (4) 93.3 (20.45) 31.8 (7.01) 14.6 (9.36)

34.0 (32) 60.6 (57) 1.1 (1) 0 0 4.3 (4) 96.0 (23.47) 32.6 (8.14) 17.6 (10.81)

38.0 (30) 51.9 (41) 0 0 2.5 (2) 7.6 (6) 90.2 (19.51) 30.2 (6.85) 16.7 (11.77)

50.0 (38) 50.0 (38) 0 0 0 0 90.4 (19.55) 29.5 (6.02) 15.6 (10.13)

90.8 (218) 9.2 (22)

90.4 (235) 9.2 (24)

91.4 (74) 8.6 (7)

91.5 (86) 8.5 (8)

91.1 (72) 8.9 (7)

90.8 (69) 9.2 (7)

90.0 (72) 10.0 (8)

88.9 (80) 10.0 (9)

19.6 (47) 79.6 (191) 0.8 (2)

20.8 (54) 78.8 (205) 0

8.6 (7) 90.1 (73) 1.2 (1)

23.4 (22) 75.5 (71) 0

27.8 (22) 72.2 (57) 0

17.1 (13) 82.9 (63) 0

22.5 (18) 76.3 (61) 1.3 (1)

21.1 (19) 78.9 (71) 0

Mean (SD) age, y 43.3 (10.98) Sex, % (n) Male 67.0 (335) Female 33.0 (165) Predominant race, % (n) Caucasian 38.0 (190) African American 56.6 (283) Asian 1.0 (5) Native American 0.4 (2) Pacific Islander 0.4 (2) Other 3.6 (18) Mean (SD) weight, kg 94.4 (22.7) 2 Mean (SD) BMI, kg/m 31.8 (8.07) Time since schizophrenia diagnosis, 15.8 (10.71) y (SD) Adherent to antipsychotic at screening, % (n) Yes 90.6 (453) No 9.2 (46) Hospitalized in previous 12 months, % (n) Yes 20.2 (101) No 79.2 (396) Unknown 0.4 (2) BMI, body mass index; and SD, standard deviation.

38.8 (31) 56.3 (45) 0 2.5 (2) 0 2.5 (2) 102.0 (25.64) 34.1 (8.07) 16.6 (11.15)

Immediate (n = 90)

40.0 (36) 54.4 (49) 3.3 (3) 0 0 2.2 (2) 94.3 (24.87) 32.5 (10.47) 13.7 (10.63)

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Table 2 Primary reason for switching from risperidone, olanzapine, or aripiprazole (safety set). Primary Reason, n (%)

Cohorts Combined (N = 500)

Risperidone (n = 175)

Olanzapine (n = 155)

Aripiprazole (n = 170)

Primary efficacy Primary safety/tolerability Weight gain Somnolence/sedation Akathisia Extrapyramidal symptoms⁎ Anxiety† Agitation† Increased prolactin

297 (59.4) 203 (40.6) 77 (15.4) 53 (10.6) 27 (5.4) 19 (3.8) 14 (2.8) 11 (2.2) 2 (0.4)

98 (56.0) 77 (44.0) 22 (12.6) 24 (13.7) 9 (5.1) 11 (6.3) 4 (2.3) 5 (2.9) 2 (1.1)

76 (49.0) 79 (51.0) 39 (25.2) 23 (14.8) 5 (3.2) 2 (1.3) 7 (4.5) 3 (1.9) 0

123 (72.4) 47 (27.6) 16 (9.4) 6 (3.5) 13 (7.6) 6 (3.5) 3 (1.8) 3 (1.8) 0

⁎ Includes Parkinsonism and tremor, excludes akathisia. † Included as a potential proxy for akathisia.

4.4. Safety 4.4.1. Adverse events The overall incidence of AEs was similar for the gradual- and immediate-switch groups for the 3 cohorts combined (81.7% and 79.6%, respectively; Table 4), with dizziness (17.5% and 22.3%) and dry mouth (17.9% and 20.8%) the most common treatment-emergent AEs (TEAEs) for both switch groups. Dizziness was reported in this study at similar, dose-proportional rates as that observed within the previous studies with iloperidone (10%–20%) of shorter duration (4–6 weeks) within the 12–24 mg/d dose range (Cutler et al., 2008; Weiden et al., 2008). Rates of dry mouth in this study were higher than those observed in these previous studies (8%–10%). In the risperidone cohort, overall incidence of AEs was slightly lower in the gradual-switch than in the immediate-switch group, similar between switch groups for olanzapine, and higher in the gradual-switch group for the aripiprazole cohort. For the individual cohorts, the most common TEAEs (≥15%) in the gradual- and the immediate-switch groups were: for risperidone: somnolence (gradual: 16.0%; immediate: 8.5%), dizziness (gradual:

14.8%; immediate: 19.1%), and dry mouth (gradual: 9.9%; immediate: 19.1%); for olanzapine: dizziness (gradual: 20.3%; immediate: 25.0%), dry mouth (gradual: 24.1%, immediate: 18.4%), and insomnia (gradual: 8.9%; immediate: 17.1%); and for aripiprazole: dry mouth (gradual: 20.0%; immediate: 24.4%), dizziness (gradual: 17.5%; immediate: 23.3%), and weight increase (gradual: 21.3%: immediate: 11.1%) (Table 4). Most AEs were mild or moderate in severity. There were no deaths in the study. TEAEs led to study discontinuation in 25 (10.4%) patients in the gradual-switch group and 39 (15.0%) in the immediate-switch group for the 3 cohorts combined, and 6 (7.4%) and 12 (12.8%) patients, respectively, with risperidone, 9 (11.4%) and 11 (14.5%) with olanzapine, and 10 (12.5%) and 16 (17.8%) with aripiprazole. Dizziness accounted for the most discontinuations due to AEs for both the gradual- and immediate-switch groups in the 3 cohorts combined (1.7% and 4.2%, respectively), the risperidone group (1.2% [the same rate as all other AEs reported] and 4.3%), and the olanzapine group (3.8% and 2.6% [the same rate as 1 other AE reported]). In the aripiprazole group, discontinuations due to AEs were most frequently due to dizziness in

Table 3 LSM difference (gradual–immediate) in CGI scores at Week 12 (full analysis set). CGI Assessment (gradual-switch n, immediate-switch n) I-CGI-C Cohorts combined (n = 235, 256) Risperidone (n = 81, 92) Olanzapine (n = 77, 74) Aripiprazole (n = 77, 90)

LSM Gradual Switch 2.83 2.82 2.87 2.79

LSM Immediate Switch 2.84 2.67 3.03 2.81

LSM Difference (Gradual–Immediate)

95% CI for Difference

−0.012 0.141 −0.157 −0.019

−0.23, 0.21 −0.23, 0.51 −0.55, 0.24 −0.41, 0.37

Change from baseline in E-CGI-S* Cohorts combined (n = 235, 256) −0.83 −0.83 −0.006 −0.16, 0.15 Risperidone (n = 81, 92) −0.91 −0.91 0 −0.24, 0.24 Olanzapine (n = 77, 74) −0.77 −0.62 −0.155 −0.44, 0.13 Aripiprazole (n = 77, 90) −0.81 −0.94 0.138 −0.13, 0.40 *Mean baseline scores for E-CGI-S were 4.1 [gradual] and 4.1 [immediate] (3 cohorts combined), and 4.1 and 4.1 (risperidone), 4.1 and 3.9 (olanzapine), and 4.1 and 4.1 (aripiprazole), respectively. Change from baseline in ST-CGI-S* Cohorts combined (n = 235, 256) −0.89 −0.80 −0.085 −0.29, 0.12 Risperidone (n = 81, 92) −1.10 −0.94 −0.157 −0.51, 0.20 Olanzapine (n = 77, 74) −0.94 −0.94 0.006 −0.35, 0.36 Aripiprazole (n = 77, 90) −0.64 −0.53 −0.105 −0.47, 0.26 *Mean baseline scores for ST-CGI-S were 3.4 [gradual] and 3.3 [immediate] (3 cohorts combined), and 3.4 and 3.4 (risperidone), 3.5 and 3.5 (olanzapine), and 3.3 and 2.9 (aripiprazole), respectively. Change from baseline in I-CGI-S* Cohorts combined (n = 235, 256) −0.89 −0.88 −0.008 −0.18, 0.16 Risperidone (n = 81, 92) −0.93 −0.94 0.011 −0.25, 0.27 Olanzapine (n = 77, 74) −0.78 −0.76 −0.018 −0.32, 0.29 Aripiprazole (n = 77, 90) −0.94 −0.96 0.019 −0.29, 0.33 *Mean baseline scores for I-CGI-S were 4.2 [gradual] and 4.2 [immediate] (3 cohorts combined), and 4.1 and 4.2 (risperidone), 4.2 and 4.1 (olanzapine), and 4.3 and 4.2 (aripiprazole), respectively. CI, confidence interval; E-CGI-S, Efficacy Clinical Global Impression of Severity; I-CGI-C, Integrated Clinical Global Impression of Change; I-CGI-S, Integrated Clinical Global Impression of Severity; LSM, least-squares mean; and ST-CGI-S, Safety and Tolerability Clinical Global Impression of Severity.

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the immediate-switch group (5.6%) and to depression and insomnia (each 2.5%) in the gradual-switch group. Serious AEs (SAEs) occurred in a total of 15 (3.0%) patients in the 3 cohorts combined (gradual-switch group, 8 [3.3%]; immediate-switch group, 7 [2.7%]). In the risperidone cohort (4 patients with an SAE), lower gastrointestinal hemorrhage and concomitant disease progression (n = 1) were reported in the gradual-switch group, and esophageal perforation (n = 1), chronic obstructive pulmonary disease and dyspnea (n = 1), and syncope (n = 1) occurred in the immediateswitch group, with only syncope suspected to be related to study drug. In the olanzapine cohort (4 patients with an SAE), all events occurred in the immediate-switch group and were pneumonia (n = 1), pulmonary embolism (n = 1), and schizophrenia (n = 2), none of which were suspected to be study drug related. In the aripiprazole cohort (7 patients with an SAE), all events occurred in the gradual-switch group and included appendicitis (n = 1), arthralgia and syncope (n = 1), depression (n = 1), overdose (n = 1), respiratory failure (n = 1), schizophrenia (n = 1), and social stay hospitalization (n = 1), with only mild syncope suspected to be related to study drug. 4.4.2. Laboratory and vital signs In the combined cohort, there were few clinically meaningful abnormalities: hematology (n = 1 [immediate-switch group]; a low hematocrit value ≤ 37%) or clinical chemistry (n = 1 [immediate-switch group]; an increased level of alanine aminotransferase, ≥ 3 × ULN). There were 29 clinically meaningful urinalysis abnormalities, none of which were reported as an AE. The numbers of patients with elevated urinary glucose and casts were similar between treatment groups. Only 1 patient (in the gradual-switch group) had elevated urinary protein. There were 5 (2.1%) patients in the gradual-switch group and 3 (1.2%) in the immediate-switch group with QTcF interval N450 msec. Three of the abnormalities (1 in the gradual- and 2 in the immediateswitch groups) were reported as AEs but none were classed as serious. No action was taken with study medication for any of these patients and all 3 completed the study. No subjects experienced a QTcF interval N500 msec. 4.4.3. Weight and metabolic measures During the 12-week treatment period, there was a mean change in weight of approximately 0.8 kg in the 3 cohorts combined (Table 5). Over the entire study, an increase in weight ≥ 7% occurred in 8.7% (43/492) of patients, with similar percentages for the gradual- and immediate-switch groups (9.6% and 7.7%, respectively). Approximately 33% (14/43) of these increases in weight were reported as AEs. Within the first 6 weeks, 4.7% (11/236, gradual) and 3.9% (10/256, immediate)

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experienced an increase in weight ≥ 7%. The percentage of patients exhibiting both weight gain and weight loss from baseline to Week 12, for the 3 cohorts combined and within each cohort, is presented in Table 5. Over the entire study, there were minimal changes versus baseline in mean fasting cholesterol in both the gradual- and immediateswitch groups (− 0.4 mg/dL and − 4.3 mg/dL, respectively), mild changes in mean fasting triglycerides (14.8 mg/dL and − 6.3 mg/dL), negligible changes in mean fasting prolactin (− 0.6 ng/mL and − 0.8 ng/mL), and mild changes in mean fasting glucose (7.7 mg/dL and 7.5 mg/dL) (Table 6).

5. Discussion 5.1. Safety of switching to iloperidone The main finding of this study is that switching to iloperidone from risperidone, olanzapine, or aripiprazole, either immediately or gradually, was safe and well tolerated. The study retention rate of 70% over 12 weeks is comparable to that of other switch studies with similar designs involving other first-line atypical antipsychotics. Safety assessments confirm the favorable safety profile for iloperidone, with the incidence of AEs comparable between patients who were switched gradually or switched immediately, although a slightly higher percentage of patients in the latter group discontinued due to an AE (cohorts combined: gradual, 10.4%; immediate, 15.0%), and dizziness in particular (1.7% and 4.2%, respectively). This finding is very relevant for iloperidone because of the gradual up-titration schedule that is required due to its strong alpha1 receptor antagonist properties. The results show that most outpatients are able to follow the recommended uptitration schedule and that side effects associated with peripheral alpha1 antagonism (eg, dizziness) are fairly common but transient, and are unlikely to lead to discontinuation. Using the AE “dizziness” as a proxy for transient peripheral alpha1 effects, we found that the incidence of dizziness was always lower with the gradual-switch approach (17.5% for cohorts combined) compared with the immediate-switch approach (22.3%), regardless of prior antipsychotic. This suggests that a more gradual down-titration of the prior antipsychotic regimen may attenuate, but not prevent, peripheral alpha1 side effects. Another finding is that patients who had switched from risperidone gradually were less likely to experience dizziness than those switched from olanzapine or aripiprazole. Because risperidone already has relatively strong alpha1 receptor antagonism, this finding suggests that there may be some cross-drug accommodation to peripheral alpha effects.

Table 4 Most common⁎ TEAEs (safety set). TEAEs, % (n)

Total adverse events Anxiety Dizziness Dry mouth Headache Insomnia Nasal congestion Sedation Somnolence Weight increased

Cohorts Combined (N = 500)

Risperidone (n = 175)

Olanzapine (n = 155)

Aripiprazole (n = 170)

Gradual (n = 240)

Immediate (n = 260)

Gradual (n = 81)

Immediate (n = 94)

Gradual (n = 79)

Immediate (n = 76)

Gradual (n = 80)

Immediate (n = 90)

81.7 (196) 4.6 (11) 17.5 (42) 17.9 (43) 7.1 (17) 8.3 (20) 5.8 (14) 9.2 (22) 14.2 (34) 12.1 (29)

79.6 (207) 6.9 (18) 22.3 (58) 20.8 (54) 7.3 (19) 9.6 (25) 4.2 (11) 8.5 (22) 9.6 (25) 7.7 (20)

70.4 (57) 2.5 (2) 14.8 (12) 9.9 (8) 8.6 (7) 8.6 (7) 2.5 (2) 8.6 (7) 16.0 (13) 8.6 (7)

75.5 (71) 5.3 (5) 19.1 (18) 19.1 (18) 5.3 (5) 8.5 (8) 2.1 (2) 7.4 (7) 8.5 (8) 7.4 (7)

82.3 (65) 6.3 (5) 20.3 (16) 24.1 (19) 6.3 (5) 8.9 (7) 2.5 (2) 12.7 (10) 7.6 (6) 6.3 (5)

84.2 (64) 3.9 (3) 25.0 (19) 18.4 (14) 6.6 (5) 17.1 (13) 5.3 (4) 5.3 (4) 9.2 (7) 3.9 (3)

92.5 (74) 5.0 (4) 17.5 (14) 20.0 (16) 6.3 (5) 7.5 (6) 12.5 (10) 6.3 (5) 18.8 (15) 21.3 (17)

80.0 (72) 11.1 (10) 23.3 (21) 24.4 (22) 10.0 (9) 4.4 (4) 5.6 (5) 12.2 (11) 11.1 (10) 11.1 (10)

TEAE, treatment-emergent adverse event. ⁎ ≥10% In either switch group in the risperidone, olanzapine, or aripiprazole cohort.

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Table 5 Changes from baseline (BL) to Week 12 in weight for the entire cohort and by preswitch antipsychotic (safety set). Cohorts combined Gradual switch (n = 216) Mean change from BL, kg (SD) Weight gain, % (n) 0 to ≤2 kg N2 to ≤5 kg N5 to ≤10 kg N10 kg Weight loss 0 to b5 kg ≥5 to b 10 kg

0.9 (3.94)

Immediate switch (n = 239) 0.8 (3.59)

25.0 (54) 22.2 (48) 8.3 (18) 4.2 (9)

24.3 (58) 19.7 (47) 6.7 (16) 2.5 (6)

32.4 (70) 7.9 (17)

41.8 (100) 5.0 (12)

Gradual Switch (n = 74)

Immediate Switch (n = 87)

5.3. Side-effect changes associated with switching to iloperidone

Risperidone

Mean change from BL, kg (SD) Weight gain, n (%) 0 to ≤2 kg N2 to ≤5 kg N5 to ≤10 kg N10 kg Weight loss, n (%) 0 to b5 kg ≥5 to b 10 kg

0.7 (4.04)

0.5 (3.36)

27.0 (20) 20.3 (15) 5.4 (4) 5.4 (4)

27.6 (24) 16.1 (14) 6.9 (6) 1.2 (1)

33.8 (25) 8.1 (6)

43.7 (38) 4.6 (4)

Gradual Switch (n = 71)

Immediate Switch (n = 69)

Olanzapine

Mean change from BL, kg (SD) Weight gain, n (%) 0 to ≤2 kg N2 to ≤5 kg N5 to ≤10 kg N10 kg Weight loss, n (%) 0 to b5 kg ≥5 to b 10 kg

0.2 (3.13)

0.3 (3.67)

28.2 (20) 19.7 (14) 5.6 (4) 0.0 (0)

26.1 (18) 11.6 (8) 4.4 (3) 2.9 (2)

39.4 (28) 7.0 (5)

47.8 (33) 7.3 (5)

Gradual Switch (n = 71)

Immediate Switch (n = 83)

Aripiprazole

Mean change from BL, kg (SD) Weight gain, n (%) 0 to ≤2 kg N2 to ≤5 kg N5 to ≤10 kg N10 kg Weight loss, n (%) 0 to b5 kg ≥5 to b 10 kg

olanzapine may have relatively better efficacy than other first-line agents (Lieberman et al., 2005), and it may be harder to switch from olanzapine to other first-line antipsychotics. One caveat is that these safety findings pertain to iloperidone switching in patients selected for good adherence and at least reasonable efficacy on their prior antipsychotic. There is no evidence from this study that it is safe to switch treatment-resistant patients on clozapine to iloperidone, or patients who require long-acting injectable therapy for adherence reasons (as these were not evaluated in this trial). The current results indicate that patients who switched to iloperidone from risperidone, olanzapine, or aripiprazole showed improvement in clinical outcomes (I-CGI-C) over 12 weeks regardless of the switch approach or current medication.

2.0 (4.36)

1.4 (3.70)

19.7 (14) 26.8 (19) 14.1 (10) 7.0 (5)

19.3 (16) 30.1 (25) 8.4 (7) 3.6 (3)

23.9 (17) 8.5 (6)

34.9 (29) 3.6 (3)

Observed cases at Week 12. SD, standard deviation.

5.2. Clinical improvements after switching to iloperidone Like most switch studies, i-FANS used an open-label design that did not have a “non-switch” comparison group. Therefore, any improvements in efficacy during the 12 weeks cannot be attributed to relative differences in efficacy from switching agents. Regardless, the efficacy changes were all positive using both efficacy versions of the CGI (where the I-CGI-C assessed global improvement including tolerability changes, and the E-CGI-S excluding tolerability changes). A conservative interpretation might be that if iloperidone is selected as a switch agent primarily for tolerability, it is likely that relative efficacy will be sustained. The efficacy ratings were also noted in the olanzapine switch subgroup, which is noteworthy given the common clinical belief that

Weight gain, metabolic abnormalities, and hyperprolactinemia are common in patients receiving antipsychotic treatment (Cha and McIntyre, 2012). In the current study, the metabolic profile of iloperidone was favorable, with minimal or no effect on fasting mean glucose, lipids, and prolactin measures in either switch group, and with a mean change in weight of less than 2 pounds (b1 kg) over the 3-month treatment period. These results are consistent with those of a previous clinical trial, which demonstrated that iloperidone 24 mg/d is associated with minimal changes in fasting mean cholesterol or triglyceride levels over 4 weeks (Cutler et al., 2008). Negligible mean changes (−0.6 to −0.8 ng/mL) in plasma prolactin levels were seen in the current trial. Slightly higher mean increases from baseline (2.6 ng/ mL) were observed in a previous 4-week trial (Cutler et al., 2008). In the current study, there were minimal changes in weight (0.9 kg [gradual switch] and 0.8 kg [immediate switch]) and mild changes in mean fasting glucose (7.7 mg/dL [gradual switch] and 7.5 mg/dL [immediate switch]). Rates of EPS and akathisia were low with iloperidone treatment (0.8% and 1.8% of patients, respectively). This relatively low burden of EPS and akathisia associated with switching to iloperidone is consistent with data from other iloperidone trials (Potkin et al., 2008; Weiden, 2012), which is in contrast to many other currently available D2/5-HT2A antagonist antipsychotics in which EPS are a safety/tolerability issue (Peluso et al., 2012). Events of clinically meaningful prolonged QTcF (N 450 ms male; N 470 ms female) were infrequent, occurring in 8 (1.6%) patients (gradual: 5; immediate: 3), with no intervals ≥500 ms. This study has some limitations. The flexible-dose design does not permit assessment of dose–response. The open-label design and absence of a placebo control does not allow for an adequate assessment of treatment effect—improvement may be a function of time and/or the result of receiving care within the context of a structured clinical trial. However, this design can be better generalized to the ‘real world’ in which patients are aware of their treatment type and physicians adjust dosage based upon clinical response and side effects. Although the variant of the CGI used in this study (Targum et al., 2012) has not yet been validated, the classic CGI itself correlates well with other measures of psychopathology, such as the Positive and Negative Syndrome Scale (Levine et al., 2008) and the Brief Psychiatric Rating Scale (Leucht and Engel, 2006). The relatively short duration of this trial (12 weeks) is another potential limitation. 6. Conclusions The improvement in overall clinical outcomes (I-CGI-C) after switching to iloperidone from risperidone, olanzapine, or aripiprazole observed in this study suggests that iloperidone is an appropriate antipsychotic choice for patients who have experienced suboptimal therapy (including weight increase, dyslipidemia, EPS, and complications related to prolactin elevations) with other agents. Our results support the clinical decision that a patient can be switched to iloperidone either by a gradual or immediate method, as similar overall clinical outcomes

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Table 6 Change from baseline to Week 12 in fasting metabolic measures (safety set). Metabolic Measure

Cohorts combined Cholesterol, mg/dL Triglycerides, mg/dL HDL, mg/dL LDL, mg/dL Glucose, mg/dL Risperidone Cholesterol, mg/dL HDL, mg/dL LDL, mg/dL Triglycerides, mg/dL Glucose, mg/dL Olanzapine Cholesterol, mg/dL HDL, mg/dL LDL, mg/dL Triglycerides, mg/dL Glucose, mg/dL Aripiprazole Cholesterol, mg/dL HDL, mg/dL LDL, mg/dL Triglycerides, mg/dL Glucose, mg/dL

Gradual-switch Group

Immediate-switch Group

n

Mean (SD)

Median (interquartile range)

n

Mean (SD)

Median (interquartile range)

178 178 178 171 179

−0.4 (29.58) 14.8 (70.32) −0.8 (9.73) −3.2 (25.37) 7.7 (26.69)

−1.0 (34.0) 6.0 (75.0) 0 (10.0) −3.0 (32.0) 5.0 (22.0)

180 180 180 174 180

−4.3 (33.67) −6.3 (97.49) −0.6 (8.79) −1.0 (24.47) 7.5 (32.79)

−3.0 (29.5) −3.0 (45.5) 0 (9.0) −1.0 (26.0) 4.0 (18.0)

60 60 55 60 61

5.3 (33.31) 0 (11.66) 1.0 (26.60) 13.0 (82.78) 10.4 (33.29)

1.0 (38.0) 0.5 (9.0) −1.0 (41.0) 0 (72.5) 7.0 (23.0)

65 65 64 65 65

−3.6 (29.80) −0.5 (7.63) −2.6 (24.72) −0.9 (71.52) 9.9 (22.49)

−1.0 (22.0) 0 (9.0) −3.5 (19.5) 4.0 (46.0) 5.0 (19.0)

55 55 54 55 55

−6.3 (27.10) 0.6 (9.97) −8.8 (25.46) 6.1 (60.74) 2.6 (17.73)

−5.0 (34.0) 0 (10.0) −7.0 (24.0) 6.0 (77.0) −1.0 (21.0)

53 53 51 53 53

−10.3 (43.26) 0.2 (9.48) −2.3 (23.93) −31.9 (108.84) 3.0 (24.22)

−10.0 (33.0) 0 (9.0) −4.0 (32.0) −12.0 (44.0) 2.0 (19.0)

63 63 62 63 63

−0.5 (27.18) −2.9 (6.91) −2.1 (23.66) 24.2 (65.00) 9.5 (25.78)

2.0 (36.0) −2.0 (11.0) −2.5 (29.0) 14.0 (81.0) 6.0 (21.0)

62 62 59 62 62

0.2 (27.36) −1.4 (9.36) 1.8 (24.83) 9.9 (107.51) 8.9 (45.80)

0 (35.0) −0.5 (10.0) 4.0 (34.0) −3.0 (42.0) 7.0 (16.0)

HDL, high-density lipoprotein; LDL, low-density lipoprotein; and SD, standard deviation.

were observed. Having this supportive data from a large patient population serves to offer clinicians flexibility in choosing the method of switching a patient over to therapy with iloperidone, based on the patient's individual treatment needs. Role of funding source Funding for this study was provided by Novartis Pharmaceuticals Corporation, which contributed to the design of the study, collection and analysis of the data, and authorship of the manuscript. Oxford PharmaGenesis Inc. provided editorial assistance and styling of the manuscript for submission, which was funded by Novartis Pharmaceuticals Corporation. Contributors All authors (Peter J. Weiden, Gus Alva, Matthew Brams, Leslie Citrome, Ira D. Glick, Richard Jackson, Greg Mattingly, Farid Kianifard, Xiangyi Meng, Linda Pestreich, Marla Hochfeld, Adam Winseck) were involved in the design of the study and interpretation of the data. Peter J. Weiden wrote the first draft of the manuscript and all authors were involved in the revisions. Farid Kianifard and Xiangyi Meng undertook the statistical analysis. All authors approved the final manuscript. Conflicts of Interest P Weiden: Research/grant support: Ortho-McNeil Janssen, Novartis, Roche/Genentech, and Sunovion Pharmaceuticals Inc. Consultant to: Delpor, Genentech, Ortho-McNeil Janssen, Novartis, Sunovion, and Vanda. Speaker: Merck, Novartis, Ortho-McNeil Janssen, and Sunovion. G Alva: Honoraria, speakers' bureaus, consultancy, and clinical research grants: Novartis, Pfizer, Otsuka/BMS, and Forest. Honoraria and speakers' bureaus compensation: Merck and Sunovion. Clinical research grants: Sanofi-Aventis and Precision Med. M Brams: Speaker: AstraZeneca, Noven, Novartis, Shinogi, and Sunovion. Consultant: Eli Lilly, Novartis, and Noven. L Citrome: Consultant: Alexza, Alkermes, Avanir, Bristol-Myers Squibb, Eli Lilly, Envivo, Forest, Genentech, Janssen, Lundbeck, Novartis, Noven, Otsuka, Pfizer, Shire, Sunovion, and Valeant. Speaker: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Otsuka, Pfizer, and Sunovion. Stock holdings: Bristol-Myers Squibb, Eli Lilly, J&J, Merck, and Pfizer. ID Glick: Over the past 3 years, compensation received for Advisory boards: Merck, Novartis, Roche, and Synovian. Research support: Abbott, Amgen, AstraZeneca, Envivo, Lilly, Merck, Novartis, Otsuka, Pfizer, Roche, Shire, Takeda, Targacept, and Vanda. Small amounts of equity in Johnson & Johnson. R Jackson: Current or prior relationships in the past 3 years with AstraZeneca, BMS, Eli Lilly, Forest, Janssen, Novartis, Noven, Otsuka, Shionogi, Shire, and Sunovion related to speaker bureau, consultation, or research. G Mattingly: Research support: AstraZeneca, Ayerst, Dainippon-Sumitomo, Eli Lilly and Co, Forest, GlaxoSmithKline, Janssen, Lundbeck, McNeil, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Organon, Otsuka, Pfizer Inc, Sanofi- Synthelabo, Schwabe/

Ingenix, Sepracor, Shinogi, Shire, Solvay, Sunovion, Takeda, and Vanda Pharmaceuticals. Speakers' bureaus: Eli Lilly and Co, Forest, Novartis, Noven, Shire, and Sunovion. Consultant: Eli Lilly and Co, Forest, Novartis, Noven, Shire, Shinogi, and Sunovion. F Kianifard, X Meng, L Pestreich, M Hochfeld, A Winseck: At the time of the study and manuscript preparation, all these authors were employees of Novartis Pharmaceuticals Corporation.

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