Adjunctive Ziprasidone in the Treatment of Bipolar I Depression

A Six-Week, Double-Blind, Multicenter, Placebo Controlled Study Evaluating The Efficacy And Safety Of Flexible Doses Of Oral Ziprasidone As Add-On, Adjunctive Therapy With Lithium, Valproate Or Lamotrigine In Bipolar I Depression

The purpose of this study is to determine if a treatment regimen of ziprasidone plus a mood stabilizer is safe and effective in the short term treatment of Bipolar I Depression. Ziprasidone will be added to lithium, valproate or lamotrigine after the patient has been on a therapeutic dose of one of these mood stabilizers for at least 4 weeks.

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder; Depression, Bipolar
• Intervention / Treatment: Drug: Ziprasidone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 298
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Pfizer Investigational Site
  • Queensland
    • Everton Park, Queensland, Australia, 4053
      • Pfizer Investigational Site
    • Spring Hill, Queensland, Australia, 4000
      • Pfizer Investigational Site
  • Victoria
    • Richmond, Victoria, Australia, 3121
      • Pfizer Investigational Site
• India
  • Ahmedabad
    • Ellisbridge, Ahmedabad, India, 380 006
      • Pfizer Investigational Site
  • Gujarat
    • Ahmedabad, Gujarat, India, 380 006
      • Pfizer Investigational Site
  • Maharashtra
    • Aurangabad, Maharashtra, India, 431005
      • Pfizer Investigational Site
    • Pune, Maharashtra, India, 411 001
      • Pfizer Investigational Site
    • Pune, Maharashtra, India, 411 004
      • Pfizer Investigational Site
  • New Delhi
    • Delhi, New Delhi, India, 110027
      • Pfizer Investigational Site
• United States
  • Arizona
    • Chandler, Arizona, United States, 85226
      • Pfizer Investigational Site
    • Litchfield Park, Arizona, United States, 85340
      • Pfizer Investigational Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Pfizer Investigational Site
    • Little Rock, Arkansas, United States, 72223
      • Pfizer Investigational Site
    • Springdale, Arkansas, United States, 72762
      • Pfizer Investigational Site
  • California
    • Costa Mesa, California, United States, 92627
      • Pfizer Investigational Site
    • Oceanside, California, United States, 92056
      • Pfizer Investigational Site
    • San Diego, California, United States, 92108
      • Pfizer Investigational Site
    • Torrance, California, United States, 90502
      • Pfizer Investigational Site
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Pfizer Investigational Site
    • Boca Raton, Florida, United States, 33486-1340
      • Pfizer Investigational Site
    • Jacksonville, Florida, United States, 32256-2006
      • Pfizer Investigational Site
    • Orlando, Florida, United States, 32806
      • Pfizer Investigational Site
    • Saint Petersburg, Florida, United States, 33702
      • Pfizer Investigational Site
    • Sanford, Florida, United States, 32771
      • Pfizer Investigational Site
    • West Palm Beach, Florida, United States, 33407
      • Pfizer Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60640
      • Pfizer Investigational Site
    • Skokie, Illinois, United States, 60077
      • Pfizer Investigational Site
  • Indiana
    • Greenwood, Indiana, United States, 46143
      • Pfizer Investigational Site
    • Indianapolis, Indiana, United States, 46260
      • Pfizer Investigational Site
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Pfizer Investigational Site
    • Wichita, Kansas, United States, 67207
      • Pfizer Investigational Site
  • Louisiana
    • Lake Charles, Louisiana, United States, 70601
      • Pfizer Investigational Site
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Pfizer Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02135
      • Pfizer Investigational Site
    • Watertown, Massachusetts, United States, 02472
      • Pfizer Investigational Site
  • Michigan
    • Clinton Township, Michigan, United States, 48038
      • Pfizer Investigational Site
  • Missouri
    • Saint Charles, Missouri, United States, 63301
      • Pfizer Investigational Site
    • Saint Louis, Missouri, United States, 63044-2588
      • Pfizer Investigational Site
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Pfizer Investigational Site
  • New Hampshire
    • Nashua, New Hampshire, United States, 03060
      • Pfizer Investigational Site
  • New Jersey
    • Cherry Hill, New Jersey, United States, 08002
      • Pfizer Investigational Site
    • Clementon, New Jersey, United States, 08021
      • Pfizer Investigational Site
  • New York
    • Brooklyn, New York, United States, 11201
      • Pfizer Investigational Site
    • Glen Oaks, New York, United States, 11004
      • Pfizer Investigational Site
    • New York, New York, United States, 10023
      • Pfizer Investigational Site
    • Olean, New York, United States, 14760
      • Pfizer Investigational Site
    • Rochester, New York, United States, 14618
      • Pfizer Investigational Site
    • Staten Island, New York, United States, 10312
      • Pfizer Investigational Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Pfizer Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Pfizer Investigational Site
    • Cincinnati, Ohio, United States, 45267-0516
      • Pfizer Investigational Site
    • Columbus, Ohio, United States, 43210
      • Pfizer Investigational Site
    • Dayton, Ohio, United States, 45408
      • Pfizer Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73116
      • Pfizer Investigational Site
    • Oklahoma City, Oklahoma, United States, 73119
      • Pfizer Investigational Site
  • Oregon
    • Portland, Oregon, United States, 97210
      • Pfizer Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Pfizer Investigational Site
    • Philadelphia, Pennsylvania, United States, 19139
      • Pfizer Investigational Site
  • Tennessee
    • Memphis, Tennessee, United States, 38117
      • Pfizer Investigational Site
  • Texas
    • Austin, Texas, United States, 78756
      • Pfizer Investigational Site
    • Austin, Texas, United States, 78754
      • Pfizer Investigational Site
    • Houston, Texas, United States, 77074
      • Pfizer Investigational Site
    • Houston, Texas, United States, 77040
      • Pfizer Investigational Site
    • Lake Jackson, Texas, United States, 77566
      • Pfizer Investigational Site
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Pfizer Investigational Site
  • Washington
    • Kirkland, Washington, United States, 98033
      • Pfizer Investigational Site
    • Richland, Washington, United States, 99352
      • Pfizer Investigational Site
    • Seattle, Washington, United States, 98104
      • Pfizer Investigational Site
  • Wisconsin
    • Brown Deer, Wisconsin, United States, 53223
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for Bipolar I disorder, most recent episode depressed, with or without rapid cycling and without psychotic features. Subjects receive therapeutic dose of lithium, valproate or lamotrigine for at least 4 weeks prior to randomization.

Exclusion Criteria:

• Patients with ultra-fast rapid cycling (8 or more mood episodes per year)
• Significant heart disease including abnormalities in the heart's rhythm (QT prolongation)
• Psychotic symptoms (hallucinations and/or delusions).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ziprasidone; Active treatment, double-blind, randomized treatment arm	Drug: Ziprasidone; Oral capsule formulation to be administered every day for duration of patient's participation in the trial - 40 mg on Day 1; 40 mg twice a day (BID) on Day 2; Flexible BID dosing of 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg or 160 mg total daily dose from Day 3 through Week 6. Dose increases of up to 40 mg/day can occur after subject has received previous lower dose for at least 1 day.; Other Names: Geodon, Zeldox
PLACEBO_COMPARATOR: Placebo; Inactive, placebo treatment, double-blind, randomized arm	Drug: Placebo; Matching placebo oral capsules to be administered as per the instructions for the ziprasidone arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score	MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Change calculated as a difference between post-baseline observation and baseline MADRS score values.	Baseline, Week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 6 in Clinical Global Impression - Severity Scale (CGI-Severity or CGI-S)	CGI-S is a single-item clinician rated scale used to assess global severity of bipolar illness based on an overall evaluation of symptoms of bipolar mania, associated behavioral symptoms, and condition of the subject. Scored from 1 (normal, not at all ill) to 7 (among the most severely ill subjects). Higher score = more affected. Change calculated as a difference between post-baseline observation and baseline CGI-S score values.	Baseline, Week 6
MADRS Remission: Number of Subjects With Total MADRS Score ≤ 12 at Week 6	Number of subjects with MADRS total score ≤ 12 (indicates remission). MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms).	Week 6
MADRS Response: Number of Subjects With Total MADRS Score Reduction ≥ 50 Percent From Baseline at Week 6	Number of subjects with reduction of ≥50 percent (%) in MADRS total score (indicates response). MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Reduction calculated as ([A-B]/B*100): A=value at observation; B=baseline value.	Week 6
Clinical Global Impression - Improvement Scale (CGI-Improvement or CGI-I): Number of Subjects With Response (Much Improved or Very Much Improved) at Week 6	Number of subjects with improvement defined as CGI-I response of 1 (very much improved) or 2 (much improved). CGI-I is a single-item clinician rated scale used to assess global improvement in the subject's clinical state (bipolar mania) in response to study treatment and as compared to their status at pre-treatment baseline. Scores range from 1 (very much improved) to 4 (no change) to 7 (very much worse). Higher score = more affected.	Baseline, Week 6
Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6)	MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Change calculated as a difference between post-baseline observation and baseline MADRS score values.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5
Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6)	CGI-S is a single-item clinician rated scale used to assess global severity of bipolar illness based on an overall evaluation of symptoms of bipolar mania, associated behavioral symptoms, and condition of the subject. Scores range from 1 (normal, not at all ill) to 7 (among the most severely ill subjects). Higher score = more affected. Change calculated as a difference between post-baseline observation and baseline CGI-S score values.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5
CGI-Improvement Score	CGI-I is a single-item clinician rated scale used to assess global improvement in the subject's clinical state (bipolar mania) in response to study treatment and as compared to their status at pre-treatment baseline. Scores range from 1 (very much improved) to 4 (no change) to 7 (very much worse). Higher score = more affected. Week 6 is the primary timepoint.	Week 1, Week 2, Week 3, Week 4, Week 5, Week 6
Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score	HAM-A is a clinician rated 14-item scale that rates the intensity of psychic anxiety (items 1 to 6 and item 14) and somatic anxiety (items 7 to 13) on a 5-point severity scale; scores range from 0 (not present) to 4 (very severe); lower score indicates less affected. Change calculated as a difference between post-baseline observation and baseline HAM-A score values. Week 6 is the primary timepoint.	Baseline, Week 2, Week 4, Week 6
Change From Baseline in Young Mania Rating Scale (YMRS) Total Score	YMRS is clinician rated 11-item scale (elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech [rate and amount], language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight) used to assess the severity of manic symptoms and effect of treatment on mania severity. Seven items ranked on scale from 0 to 4; 4 items ranked 0 to 8. Higher scores indicate greater severity. Change calculated as a difference between post-baseline observation and baseline YMRS score values. Week 6 is the primary timepoint.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6
Change From Baseline in Global Assessment of Functioning (GAF) Scale at Week 6	GAF is a clinician rated scale to measure the severity of illness-related impairment in psychological, social, and occupational functioning using a 100-point scale (single score of 1 to 100) with 100 indicating a superior level of function. Change calculated as a difference between post-baseline observation and baseline GAF score values.	Baseline, Week 6
Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3)	SDS is a 5-item subject rated scale to measure the extent to which work and or school, social life and or leisure activities, and home life and or family responsibilities were impaired by psychiatric illness. Items 1 to 3 rated on 11-point scale ranging 0 (not at all) to 10 (extremely affected). Total score 0 to 30; higher score indicates greater impairment; items 4 and 5 report number of days in the last month (0 to 31) subject missed work or school or was unproductive and are rated separately. Change calculated as a difference between post-baseline observation and baseline SDS score values.	Baseline, Week 6
Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5)	SDS is a 5-item subject rated scale to measure the extent to which work and or school, social life and or leisure activities, and home life and or family responsibilities were impaired by psychiatric illness. Items 1 to 3 rated on 11-point scale ranging 0 (not at all) to 10 (extremely affected). Total score 0 to 30; higher score indicates greater impairment; items 4 and 5 report number of days in the last month (0 to 31) subject missed work or school or was unproductive and are rated separately. Change calculated as a difference between post-baseline observation and baseline SDS score values.	Baseline, Week 6
Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6	Q-LES-Q is a 16-item subject rated scale to measure satisfaction with areas of daily functioning (physical health, social relationships, medication, and overall life satisfaction); rated on a 5-point Likert scale: higher scores indicate greater enjoyment and satisfaction with general life activities. Scores for items 1 to 14 are summed for a total score and converted to 0 to 100 range. Items 15 and 16 measure satisfaction with medication and overall satisfaction and are analyzed separately. Change calculated as a difference between post-baseline observation and baseline Q-LES-Q score values.	Baseline, Week 6

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Simpson Angus Scale (SAS) Score	SAS is a clinician rated 10-item scale to measure extrapyramidal side effects (Parkinsonism or Parkinsonian side effects induced with antipsychotics); rated on a 5-point scale with range 0 (absence of condition) to 4 (presence of condition in extreme form). Global score is sum of all scores divided by the total number of items. Change calculated as a difference between post-baseline observation and baseline SAS score values.	Baseline, Week 2, Week 4, Week 6
Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS)	BARS is a clinician rated scale to evaluate akathisia associated with use of antipsychotic medications: objective motor restlessness, range 0 to 3; subjective complaints of restlessness and associated distress, range 0 to 3; global clinical assessment of akathisia, range 0 to 5. Higher scores indicate more affected. Change calculated as a difference between post-baseline observation and baseline BARS score values.	Baseline, Week 2, Week 4, Week 6
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores	AIMS is a clinician rated 12-item scale to rate 7 body areas and global judgments on the severity of abnormal movements, incapacitation and subject's awareness of abnormal movements. Items 1 to 10 scored 0 (none) to 4 (severe); items 11 to 14 are No or Yes response to dental status and sleep movements and are assessed separately. AIMS total score is sum of first 7 items. Change calculated as a difference between post-baseline observation and baseline AIMS score values.	Baseline, Week 2, Week 4, Week 6

Collaborators and Investigators

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Publications and helpful links

General Publications

• Sachs GS, Ice KS, Chappell PB, Schwartz JH, Gurtovaya O, Vanderburg DG, Kasuba B. Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011 Oct;72(10):1413-22. doi: 10.4088/JCP.09m05934.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (ACTUAL): December 1, 2008
• Study Completion (ACTUAL): December 1, 2008

Study Registration Dates

• First Submitted: June 5, 2007
• First Submitted That Met QC Criteria: June 5, 2007
• First Posted (ESTIMATE): June 7, 2007

Study Record Updates

• Last Update Posted (ACTUAL): March 10, 2021
• Last Update Submitted That Met QC Criteria: February 18, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Depression; Depressive Disorder; Bipolar Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; Ziprasidone
• Other Study ID Numbers: A1281158