Schizophrenia, Psychotic Disorders
Conditions
Keywords
Schizophrenia, Clozapine, Treatment, Combination, Unresponsive, Schizoaffective Disorders
Brief summary
This study will assess the effectiveness of pimozide in enhancing the effects of clozapine in the treatment of schizophrenia.
Detailed description
A significant number of schizophrenics exhibit partial or no response to typical antipsychotic medications. Clozapine has been shown to be more effective in treating schizophrenia than typical antipsychotic drugs. However, only an estimated 30% to 60% of people who are unresponsive to treatment with typical antipsychotics will respond to treatment with clozapine. Taking clozapine with pimozide, an antipsychotic drug, can increase clozapine's effects. However, sufficient research on this approach has not yet been performed. This study will assess the effectiveness of pimozide in enhancing the effects of clozapine in the treatment of schizophrenia. Participants in this double-blind study will receive a stable dose of clozapine for eight weeks prior to enrollment. For the first 4 weeks following enrollment, baseline measurements will be taken. Once a week, participants will report to the study site, where symptom severity, cognitive ability, and functional status, including reading level, will be assessed. In addition, participants will receive a standard medical examination, which will include blood tests and an EKG. Upon completion of this initial phase, participants will be randomly assigned to one of two treatment groups: clozapine combined with pimozide; or clozapine combined with placebo. This phase will last for 12 weeks. Study visits will continue to occur weekly, and will be used to re-assess the measurements obtained during baseline. In addition, participants will have an EKG at each study visit for the first 4 weeks of treatment. All baseline measurements will be repeated in Week 12.
Interventions
DRUGPimozide
Each capsule of active treatment will contain 2 mg of pimozide. Dosing will be flexible and will range from a minimum of 2 mg per day to 8 mg per day. Dosing will begin at Week 1 with 1 capsule per day. This will be slowly titrated at a rate of 1 capsule per week to a maximum of 4 capsules depending upon clinical response and side effects.
DRUGPlacebo
Active drug and placebo will be encapsulated in an identical fashion. The placebo capsule will be made to match in appearance and weight. There will be flexible dosing, allowing a minimum of 1 capsule per day to 4 capsules per day, in order to match the dosing range of the active treatment.
Sponsors
National Institute of Mental Health (NIMH)
Icahn School of Medicine at Mount Sinai
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
No
Inclusion criteria
* Diagnosis of schizophrenia according to DSM-IV criteria * Any schizoaffective disorder or subtype * Score greater than 60 on the Positive and Negative Syndrome Scale (PANSS) * Currently taking clozapine * Score of four or higher on two or more items from the positive symptom subscale of the PANSS * Score of 4 or greater on the Clinical Global Impression (CGI) scale * Clozapine plasma level greater than 378 µg/ml * Stable dose of clozapine demonstrated to have been associated with a clozapine plasma level greater than 378 µg/ml for at least eight weeks * Able to read at an 8th grade level or above
Exclusion criteria
* History of unstable coronary artery disease * Congestive heart failure * History of long Q-T syndrome * History of cardiac arrhythmia * History of cardiac conduction delay * Baseline QT correction score greater than 0.425 seconds * Liver disease * History of stroke * History of Neuroleptic Malignant Syndrome * Hypokalemia * Hypocalcemia * Current blindness, deafness, language difficulties, or any other disability which may prevent participation or cooperation in the study * Current suicidal or homicidal thoughts * Currently abusing psychoactive substances * Currently receiving antidepressants, thymoleptics, L-DOPA, buspirone, or antipsychotics other than clozapine (Valproic acid and Divalproex sodium are not criteria for exclusion)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Positive Syndrome Scale (PANSS) Total Score | Variable change from baseline to week 12 | Severity of positive schizophrenic symptoms The Positive Syndrome Scale of the PANSS is comprised of seven items measuring positive such symptoms such as hallucinations, delusions, grandiosity, etc. Each item is scored on a 7 point scale of that particular symptom's severity, ranging from 1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate severe, 6 = severe, and 7 = extreme. The PANSS Positive Subscale seven items has a range of a summed score from 7 (absent) to 49 (extreme psychopathology). Therefore, the higher the score, the more severe the symtpoms. |
| Negative Syndrome Scale (PANSS) Total Score | Variable change from baseline to week 12 | Severity of negative schizophrenic symptoms, The Negative Syndrome scale is compromised of seven items, each scored on severity with numeric assignments ranging from 1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate severe, 6 = severe, and 7 = extreme. The items which comprise the Negative Syndrome Scale of the PANSS measure things such as emotional withdrawal, apathy, difficulty in abstract thinking, etc. The seven items which comprise the PANSS Negative Subscale has an aggregate range of 7 (absent) to 49 (extreme psychopathology), a higher score indicating more severe symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression of Change (CGIC) | variable change from baseline to week 12 | The Clinical Global Impression-improvement (CGI-improvement) scale is a research rating tool, developed for use in NIMH-sponsored clinical trials provides a brief assessment of the clinician's view of the patient's overall clinical improvement prior to and after initiating a study medication. The CGI-change is rated on a seven point scale ranging from 1= very much improved since the initiation of treatment to 7=very much worse since the initiation of treatment. Therefore, a lower score indicates more improvement in symptoms over time. |
Countries
United States
Participant flow
Recruitment details
Subjects recruited from inpatient and outpatient treatment settings at Mount Sinai Hospital, Pilgrim Psychiatric Center and Manhattan Psychiatric Center in New York.
Pre-assignment details
16 subjects were excluded during the 4-week symptom stability-screening period before randomization because of withdrawal of consent or a failure to meet inclusion and exclusion criteria. Seven additional subjects were randomized to a haloperidol adjunctive pilot study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received encapsulated placebo made to match active drug | 28 |
| Pimozide Participants received pimozide flexible dosing | 25 |
| Total | 53 |
Baseline characteristics
| Characteristic | Placebo | Pimozide | Total |
|---|---|---|---|
| Age, Continuous | 44.4 years STANDARD_DEVIATION 8.7 | 45.5 years STANDARD_DEVIATION 10.2 | 44.9 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 20 Participants | 21 Participants | 41 Participants |
| Treatment Setting Inpatient | 19 participants | 15 participants | 34 participants |
| Treatment Setting Outpatient | 9 participants | 10 participants | 19 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 28 | 3 / 25 |
| serious Total, serious adverse events | 0 / 28 | 0 / 25 |
Outcome results
Primary
Negative Syndrome Scale (PANSS) Total Score
Severity of negative schizophrenic symptoms, The Negative Syndrome scale is compromised of seven items, each scored on severity with numeric assignments ranging from 1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate severe, 6 = severe, and 7 = extreme. The items which comprise the Negative Syndrome Scale of the PANSS measure things such as emotional withdrawal, apathy, difficulty in abstract thinking, etc. The seven items which comprise the PANSS Negative Subscale has an aggregate range of 7 (absent) to 49 (extreme psychopathology), a higher score indicating more severe symptoms.
Time frame: Variable change from baseline to week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Negative Syndrome Scale (PANSS) Total Score | -1.59 units on a scale | Standard Deviation 4.46 |
| Pimozide | Negative Syndrome Scale (PANSS) Total Score | 0.65 units on a scale | Standard Deviation 4.65 |
Primary
Positive Syndrome Scale (PANSS) Total Score
Severity of positive schizophrenic symptoms The Positive Syndrome Scale of the PANSS is comprised of seven items measuring positive such symptoms such as hallucinations, delusions, grandiosity, etc. Each item is scored on a 7 point scale of that particular symptom's severity, ranging from 1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate severe, 6 = severe, and 7 = extreme. The PANSS Positive Subscale seven items has a range of a summed score from 7 (absent) to 49 (extreme psychopathology). Therefore, the higher the score, the more severe the symtpoms.
Time frame: Variable change from baseline to week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Positive Syndrome Scale (PANSS) Total Score | -1.05 units on a scale | Standard Deviation 2.98 |
| Pimozide | Positive Syndrome Scale (PANSS) Total Score | -1.30 units on a scale | Standard Deviation 2.56 |
Secondary
Clinical Global Impression of Change (CGIC)
The Clinical Global Impression-improvement (CGI-improvement) scale is a research rating tool, developed for use in NIMH-sponsored clinical trials provides a brief assessment of the clinician's view of the patient's overall clinical improvement prior to and after initiating a study medication. The CGI-change is rated on a seven point scale ranging from 1= very much improved since the initiation of treatment to 7=very much worse since the initiation of treatment. Therefore, a lower score indicates more improvement in symptoms over time.
Time frame: variable change from baseline to week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impression of Change (CGIC) | -0.35 units on a scale | Standard Deviation 0.57 |
| Pimozide | Clinical Global Impression of Change (CGIC) | -0.15 units on a scale | Standard Deviation 4.97 |