Bipolar Disorder, Generalized Anxiety Disorder, Panic Disorder
Conditions
Keywords
Bipolar disorder, Anxiety, Panic, GAD, Generalized Anxiety Disorder
Brief summary
The specific aim of this study is to evaluate the efficacy, tolerability, and safety of ziprasidone monotherapy in comparison to placebo in the treatment of ambulatory bipolar disorder with co-morbid lifetime panic disorder or generalized anxiety disorder and current at least moderately severe anxiety.
Detailed description
This is a randomized, double-blind, placebo controlled, parallel-group, 8-week trial of ziprasidone compared to placebo in outpatient subjects with a lifetime bipolar I, II, or NOS disorder, a lifetime panic or generalized anxiety disorder, and current diagnosis at least moderately severe anxiety symptoms. Approximately 50 subjects will be randomized. Subjects will be randomized to ziprasidone or placebo in a 1:1 ratio. No concomitant psychotropic medication will be allowed throughout the study except for prn lorazepam during the first two weeks for the management of affective and anxiety symptoms, prn zolpidem and zaleplon for the management of insomnia and benztropine for the management of EPS. Throughout the study, psychiatric scales will be used to assess psychiatric symptoms and the presence of treatment-emergent adverse events will be monitored and recorded.
Interventions
DRUGZiprasidone
The minimum dose during study participation will be 40 mg/day, and the maximum dose allowed will be 160 mg/day.
DRUGPlacebo
Inactive control
Sponsors
Pfizer
University of South Florida
Lindner Center of HOPE
VA Palo Alto Health Care System
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects must be at least 18 and not older than 65. * Subjects must have lifetime bipolar I, II, or NOS disorder as defined by DSM-IV TR criteria (26). * Subjects must have lifetime panic disorder or generalized anxiety disorder (GAD) as defined by DSM-IV criteria (except clause does not occur exclusively during a mood disorder of Criterion F for GAD). * Subjects' bipolar symptoms must be no more than moderate in severity, defined as a CGI-BP\< 4 (27). * Subjects' anxiety symptoms must be at least moderate in severity, defined as a CGI-S \> 4 (28). * Subjects must not be receiving regular mood stabilizing, antidepressant, antipsychotic, or anxiolytic medication for at least one week prior to baseline. Patients receiving fluoxetine or depot antipsychotics should be off these medications for at least four weeks prior to baseline. * Subjects or their legally authorized representative must sign the Informed Consent Document after the nature of the trial has been fully explained. * If female, subjects must be: postmenopausal, surgically incapable of childbearing, or practicing medically acceptable effective method(s) of contraception (e.g., hormonal methods, barrier methods, intrauterine device) for at least one month prior to study entry and throughout the study.
Exclusion criteria
* Subjects who do not have lifetime bipolar disorder by DSM-IV-TR criteria (26). * Subjects who do not have lifetime panic disorder or GAD by DSM-IV-TR criteria (26). * Subjects who are receiving treatment with an anti-manic or mood stabilizing medication (lithium, valproate, carbamazepine, or an antipsychotic), and in the investigators' judgment, require ongoing treatment with that medication. * Subjects whose bipolar symptoms are presently more than moderately severe (CGI-BP \> 5) (27). * Subjects whose anxiety symptoms are presently less than moderately severe (CGI-S \< 3) (28). * Subjects with clinically significant suicidal or homicidal ideation. * Subjects with a current DSM-IV TR Axis I diagnosis of delirium, dementia, amnesia, or other cognitive disorders; a DSM-IV TR diagnosis of a substance dependence disorder within the past six months; a lifetime DSM-IV TR psychotic disorder (e.g., schizophrenia or schizoaffective disorder). * Subjects with serious general medical illnesses as determined by the clinical judgment of the clinical investigator. Subjects with hypo- or hyperthyroidism unless stabilized on thyroid replacement \> 3 months. * Subjects with a clinically significant abnormality in their pre-study physical exam, vital signs, EKG, or laboratory tests. * Subjects who are allergic to or who have demonstrated hypersensitivity or intolerance to ziprasidone. * Women who are pregnant or nursing. * Subjects who have received an experimental drug or used an experimental device within 30 days. * Subjects who have a history of neuroleptic malignant syndrome. * A patient with diabetes mellitus (DM) fulfilling one of the following criteria: * Unstable DM defined as enrollment glycosylated hemoglobin (HbAlc) \>8.5% * Admitted to hospital for treatment of DM or DM related illness within the past 12 weeks * Not under physician care for DM * Physician responsible for patient's DM care has not indicated that the DM is controlled * Physician responsible for patient's DM care has not approved the patient's participation in the study * Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for the 4 weeks before randomization. For thiazolidinediones(glitazones)this period should not be less than 8 weeks before randomization. * Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks Note: If a patient with DM meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinician Global Improvement Scale (CGI-21) | 8 weeks | CGI-21 Anxiety Scale ranges from -10 (Very Bad. Could not be worse) to +10 (Major Improvement. Back to normal self). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Anxiety Rating Scale (HAM-A) | 8 weeks | Scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. |
| Young Mania Rating Scale | 8 weeks | Four items that are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. These four items are given twice the weight of the others to compensate for poor cooperation from severely ill patients. There are well described anchor points for each grade of severity. The authors encourage the use of whole or half point ratings once experience with the scale is acquired. Typical YMRS baseline scores can vary a lot. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in manic symptoms. Total score ≤12 indicates remission (13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania). |
| Montgomery-Asberg Depression Rating Scale (MADRS) | 8 weeks | Ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Questionnaire includes questions on the following symptoms 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts. Usual cutoff points are: 0 to 6 - normal /symptom absent; 7 to 19 - mild depression; 20 to 34 moderate depression; \>34 - severe depression. |
| CGI-BP | 8 weeks | A guide for rating severity of manic and depressive episodes and the degree of change from the immediately preceding phase and from the worst phase of illness. Provides a set of instructions to facilitate the reliability of these ratings of mania, depression, and overall bipolar illness during treatment of an acute episode or in longer-term illness prophylaxis. Comprises two companion one-item measures evaluating the following:(a) severity of psychopathology from 1 to 7 and (b) change from the initiation of treatment on a similar seven-point scale. The minimum value in each category is a score of 1 (indicating 'normal' or 'not ill') and the maximum value is a score of 7 (indicating 'very severely ill'). Higher scores indicate a worse outcome due to greater severity of bipolar symptoms. 1 = Very much improved 5 = Minimally worse 2 = Much improved 6 = Much worse 3 = Minimally improved 7 = Very much worse 4 = No change 3. Efficacy Index Rate this item on the basis of drug effect only. |
| Sheehan Disability Scale (SDS) | 8 weeks | A composite of three self-rated items designed to measure the extent to which three major sectors in the patient's life are impaired by panic, anxiety, phobic, or depressive symptoms. Patient rates the extent to which his or her 1) work, 2) social life or leisure activities, and 3) home life or family responsibilities are impaired by his or her symptoms on a 10-point visual analog scale. In each sector of the overall scale, the minimum score is a 1 (indicating that symptoms have been 'not at all' disruptive to functioning) and the maximum score is a 10 (indicating that symptoms have been 'extremely' disruptive to functioning). Each area of functioning is rated on a scale of 0 to either 3 or 5 (maximum score = 29-extreme vegetative state, minimum score = 0-person without disability) with the highest scores representing the higher level of disability. Higher scores indicate a worse outcome stemming from greater disability/impairment. |
| Sheehan Irritability Scale (SIS) | 8 Weeks | SIS consists of seven items that assess symptoms of irritability, frustration, edginess/impatience, moodiness, anger with self, anger with others and temper during the previous week. Each item is assessed on an 11-point numeric rating scale ranging from 0 (not at all) to 10 (extremely). The SIS total score is calculated by summing of the scores for each of the seven individual items and ranges from 0 to 70. A higher score indicates a higher rate of irritability symptoms and therefore, a worse outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ziprasidone Ziprasidone in the form of 40 and/or 80 mg capsules. Dose range: 40 to 160 mg/day. | 25 |
| Placebo Administered in capsules identical to the ziprasidone capsules. | 24 |
| Total | 49 |
Baseline characteristics
| Characteristic | Placebo | Ziprasidone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 25 Participants | 49 Participants |
| Age, Continuous | 34.6 years STANDARD_DEVIATION 12.2 | 37.7 years STANDARD_DEVIATION 17.7 | 36.1 years STANDARD_DEVIATION 15.2 |
| Region of Enrollment United States | 24 participants | 25 participants | 49 participants |
| Sex: Female, Male Female | 17 Participants | 19 Participants | 36 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 25 | 0 / 24 |
| serious Total, serious adverse events | 1 / 25 | 1 / 24 |
Outcome results
Primary
Clinician Global Improvement Scale (CGI-21)
CGI-21 Anxiety Scale ranges from -10 (Very Bad. Could not be worse) to +10 (Major Improvement. Back to normal self).
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | Clinician Global Improvement Scale (CGI-21) | 7.8 units on a scale | Standard Deviation 1.7 |
| Placebo | Clinician Global Improvement Scale (CGI-21) | 3.4 units on a scale | Standard Deviation 4.5 |
Secondary
CGI-BP
A guide for rating severity of manic and depressive episodes and the degree of change from the immediately preceding phase and from the worst phase of illness. Provides a set of instructions to facilitate the reliability of these ratings of mania, depression, and overall bipolar illness during treatment of an acute episode or in longer-term illness prophylaxis. Comprises two companion one-item measures evaluating the following:(a) severity of psychopathology from 1 to 7 and (b) change from the initiation of treatment on a similar seven-point scale. The minimum value in each category is a score of 1 (indicating 'normal' or 'not ill') and the maximum value is a score of 7 (indicating 'very severely ill'). Higher scores indicate a worse outcome due to greater severity of bipolar symptoms. 1 = Very much improved 5 = Minimally worse 2 = Much improved 6 = Much worse 3 = Minimally improved 7 = Very much worse 4 = No change 3. Efficacy Index Rate this item on the basis of drug effect only.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | CGI-BP | 3.0 units on a scale | Standard Deviation 1.5 |
| Placebo | CGI-BP | 3.0 units on a scale | Standard Deviation 1.2 |
Secondary
Hamilton Anxiety Rating Scale (HAM-A)
Scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | Hamilton Anxiety Rating Scale (HAM-A) | 10.2 units on a scale | Standard Deviation 6.6 |
| Placebo | Hamilton Anxiety Rating Scale (HAM-A) | 13.1 units on a scale | Standard Deviation 10.4 |
Secondary
Montgomery-Asberg Depression Rating Scale (MADRS)
Ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Questionnaire includes questions on the following symptoms 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts. Usual cutoff points are: 0 to 6 - normal /symptom absent; 7 to 19 - mild depression; 20 to 34 moderate depression; \>34 - severe depression.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | Montgomery-Asberg Depression Rating Scale (MADRS) | 17.3 units on a scale | Standard Deviation 11.5 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) | 19.1 units on a scale | Standard Deviation 10.1 |
Secondary
Sheehan Disability Scale (SDS)
A composite of three self-rated items designed to measure the extent to which three major sectors in the patient's life are impaired by panic, anxiety, phobic, or depressive symptoms. Patient rates the extent to which his or her 1) work, 2) social life or leisure activities, and 3) home life or family responsibilities are impaired by his or her symptoms on a 10-point visual analog scale. In each sector of the overall scale, the minimum score is a 1 (indicating that symptoms have been 'not at all' disruptive to functioning) and the maximum score is a 10 (indicating that symptoms have been 'extremely' disruptive to functioning). Each area of functioning is rated on a scale of 0 to either 3 or 5 (maximum score = 29-extreme vegetative state, minimum score = 0-person without disability) with the highest scores representing the higher level of disability. Higher scores indicate a worse outcome stemming from greater disability/impairment.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | Sheehan Disability Scale (SDS) | 5 units on a scale | Standard Deviation 4 |
| Placebo | Sheehan Disability Scale (SDS) | 9.9 units on a scale | Standard Deviation 10 |
Secondary
Sheehan Irritability Scale (SIS)
SIS consists of seven items that assess symptoms of irritability, frustration, edginess/impatience, moodiness, anger with self, anger with others and temper during the previous week. Each item is assessed on an 11-point numeric rating scale ranging from 0 (not at all) to 10 (extremely). The SIS total score is calculated by summing of the scores for each of the seven individual items and ranges from 0 to 70. A higher score indicates a higher rate of irritability symptoms and therefore, a worse outcome.
Time frame: 8 Weeks
Population: Outpatients with lifetime bipolar I disorder, bipolar II disorder, or bipolar disorder NOS by DSM-IV-TR criteria (26), who have co-morbid lifetime panic or generalized anxiety disorder, whose bipolar symptoms are no worse than moderately severe, and whose anxiety symptoms are currently at least moderately severe.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ziprasidone | Sheehan Irritability Scale (SIS) | 25 Participants |
| Placebo | Sheehan Irritability Scale (SIS) | 24 Participants |
Secondary
Young Mania Rating Scale
Four items that are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. These four items are given twice the weight of the others to compensate for poor cooperation from severely ill patients. There are well described anchor points for each grade of severity. The authors encourage the use of whole or half point ratings once experience with the scale is acquired. Typical YMRS baseline scores can vary a lot. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in manic symptoms. Total score ≤12 indicates remission (13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania).
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | Young Mania Rating Scale | 4.2 units on a scale | Standard Deviation 5.1 |
| Placebo | Young Mania Rating Scale | 4.4 units on a scale | Standard Deviation 4.8 |