Safety Study of Olanzapine and a Comparator in Patients With Schizophrenia and Schizoaffective Disorder

• -Assess if olanzapine and risperidone are associated with a significant within-treatment group change in insulin sensitivity over 12-week period as measured by rinsulinemic euglycemic clamp.
• -For the primary and key secondary analyses, insulin sensitivity will be measured by the insulin sensitivity index ([mean glucose infusion rate/fat free mass]/mean insulin concentration)determined
• at steady state during the low insulin infusion phase of a two-step hyperinsulinemic euglycemic clamp.

• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Weight. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in weight
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Body Mass Index (BMI) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in BMI
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Ratio of Visceral Fat Area to the Subcutaneous Fat Area. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in ratio of visceral far area to subcutaneous fat area
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Brief Psychiatric Rating Scale Scores. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin senstivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in Brief Psychiatric Rating Scale scores
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Clinical Global Impression - Severity of Illness Scale Scores. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in Clinical Global Impression-Severity of Illness scale scores
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Abnormal Involuntary Movement Scale Scores. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in Abnormal Involuntary Movement Scale scores
• Pairwise Correlation Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Barnes Akathisia Scale Scores. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in Barnes Akathisia scores
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in the Simpson Angus Scale Scores. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in the Simpson Angus Scale scores
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Waist Circumference. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in waist circumference
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Visceral Fat Area. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in visceral fat area
• Pairwise Correlations Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Subcutaneous Fat Area. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in subcutaneous fat area
• Pairwise Correlations Between Between Changes in Normalized Insulin Sensitivity Index at Low Insulin Phase and Changes in Eating Behavior Assessment Scale Scores. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Normalized insulin sensitivity index (Mffm/I) at low insulin phase-pairwise correlations between changes in Mffm/I and changes in Eating Behavior Assessment Scale scores
• Change From Baseline to 12 Week Endpoint in Body Mass Index [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Within-and Between-Treatment Group changes in Body Mass Index from baseline to last observation carried forward.
• Change From Baseline to 12 Week Endpoint in Weight [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Weight change from baseline to last visit (last observation carried forward)
• Change From Baseline to 12 Week Endpoint in Waist Circumference [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Waist circumference change from baseline to last observation carried forward.
• Change From Baseline to 12 Week Endpoint in Visceral Fat Area [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Visceral fat area change from baseline to last observation carried forward, all randomized patients, double-blind treatment period
• Change From Baseline to 12 Week Endpoint in Subcutaneous Fat Area [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Subcutaneous fat area change from baseline to last observation carried forward, all randomized patients, double-blind treatment period
• Change From Baseline to 12 Week Endpoint in the Ratio of the Visceral Fat Area to the Subcutaneous Fat Area [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Ratio of the visceral fat area to the subcutaneous fat area change from baseline to last observation carried forward, all randomized patients, double-blind treatment period
• Change From Baseline to 12 Week Endpoint in Brief Psychiatric Rating Scale (BPRS) Scores [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
  Brief Psychiatric Rating Scale (BPRS) is an 18-item clinician-administered scale used to assess the degree of severity of a subject's general psychopathological symptoms. Item scores range from 0 (not present) to 6 (extremely severe). Total Scores range from 0 to 108; Positive Subscale Scores range from 0 to 24. Negative Subscale Scores range from 0 to 18. Anxiety-Depression Subscale Scores range from 0 to 24.
• Change From Baseline to 12 Week Endpoint in Clinical Global Impression - Severity of Illness Scores [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
  Measures severity of illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients.
• Change From Baseline to 12 Week Endpoint in Abnormal Involuntary Movement Scale Scores [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  A 12-item instrument assesses observed abnormal movements in different parts of body. Seven items are scored in a 5-point scale (0 = none/normal, 4 = severe) which evaluates abnormal movements in 3 main anatomic areas (orofacial area, extremities, and trunk). Total scores range from 0 to 28. Five collected elements are not used in this total.
• Change From Baseline to 12 Week Endpoint in Barnes Akathisia Rating Scale (BARS) Scores [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  The BARS is a 4-item instrument that evaluates akathisia associated with use of antipsychotic medications. Item 4 is the Global clinical assessment and is rated 0 to 5 (0 = absent, 5 = severe). The other 3 items (related to objective and subjective assessments) are not used for these analyses.
• Change From Baseline to 12 Week Endpoint in Simpson Angus Scale Scores [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Measures neuroleptic-induced parkinsonism. Total score of Simpson Angus Scale consists of the sum of 10 items rated on a 5-point severity scale where 0=normal and 4=extreme. The total score ranges from 0 to 40.
• Change From Baseline to 12 Week Endpoint in Eating Behavior Assessment Scale Scores [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Eating Behavior Assessment Scale is a 9-item self-rated tool used to evaluate appetite and eating behaviors. Item scores range from 0 (never) to 4 (always).
• Change From Baseline to 12 Week Endpoint in Fasting Lipid Parameters Including Total Cholesterol [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Fasting lipid parameters including total cholesterol, change from baseline to last observation carried forward.
• Change From Baseline to 12 Week Endpoint in Fasting Lipid Parameters Including Direct Low Density Lipoprotein (LDL) [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Fasting lipid parameters including Direct LDL, change from baseline to last observation carried forward.
• Change From Baseline to 12 Week Endpoint in Fasting Lipid Parameters Including High Density Lipoprotein (HDL) [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Fasting lipid parameters including HDL change from baseline to last observation carried forward.
• Change From Baseline to 12 Week Endpoint in Fasting Lipid Parameters Including Triglycerides [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: Yes ]
  Changes in fasting lipid parameters including triglycerides last observation carried forward (LOCF) mean change from baseline
• Change From Baseline to 12 Week Endpoint in Fasting Lipid Parameters Including Lipoprotein Subclasses [ Time Frame: baseline and 12 weeks. ] [ Designated as safety issue: Yes ]
  Changes in lipid parameters and subclass lipoproteins last observation carried forward (LOCF) mean change from baseline. HDL=High Density Lipoprotein, IDL=Intermdiate Density Lipoprotein, LDL=Low Density Lipoprotein, VLDL=Very Low Density Lipoprotein.

• -Comparison of effects of olanzapine vs. risperidone on the change in insulin sensitivity index from baseline to endpoint.
• -Evaluation for each treatment group of the relationships between change in insulin sensitivity index and changes in:
• weight, BMI, waist circumference, visceral fat area, subcutaneous fat area, ratio of visceral fat area to subcutaneous fat area.
• -Evaluation for each treatment group of the relationship between change in insulin sensitivity index and changes in:
• BPRS, CGI-S, AIMS, Barnes Akathisia, Simpson-Angus Scale and Eating Behavior Assessment Scale.
• -Evaluation of within-treatment group and between-treatment groups changes in: BMI, weight, waist circumference, visceral fat area,
• subcutaneous fat area, ratio of visceral fat area to subcutaneous fat area,
• BPRS, CGI-S, AIMS, BAS, Simpson-Angus Scale, Eating Behavior Assessment Scale for olanzapine and risperidone.
• -Evaluate the within-treatment group and between-treatment group changes in fasting lipid parameters for olanzapine and risperidone.

This study will assess whether olanzapine and/or risperidone affect the way the human body uses sugar in the blood.

• Schizophrenia
• Schizoaffective Disorder

• Drug: olanzapine
  5-20 mg, oral, capsules, daily, 12 weeks.
  Other Names:

  • LY170053
  • Zyprexa
• Drug: risperidone
  2-6 mg, oral, capsules, twice daily (BID), 12 weeks.

• Experimental: Olanzapine
  Intervention: Drug: olanzapine
• Active Comparator: Risperidone
  Intervention: Drug: risperidone

Inclusion Criteria:

• 18-65 years old
• Diagnosed with Schizophrenia or Schizoaffective disorder
• Ability to visit the doctor's office for scheduled visits

Exclusion Criteria:

• Women who are pregnant or breastfeeding
• Have a body mass index (BMI) greater than 40
• Have diabetes, heart disease or any other unstable illness
• Have known positive human immunodeficiency virus (HIV)
• Are currently taking olanzapine, risperidone, clozapine, glucocorticoids, injectable antipsychotics