Schizophrenia, Schizoaffective Disorder
Conditions
Keywords
schizophrenia, schizoaffective, cognition, lurasidone, Latuda
Brief summary
24 individuals with schizophrenia or schizoaffective disorders, who are currently considered stable, will be recruited, screened for entry criteria into a blinded study with a 4-week randomization to either lurasidone, haloperidol, or perphenazine to examine glutamate-related outcomes with lurasidone as compared to haloperidol and perphenazine.
Detailed description
At study start all volunteers will be discontinued from their current antipsychotic drug (APD) and switched to haloperidol 4mg for 5 days. At the end of this discontinuation period, all baseline symptom ratings and cognition testing will be done, as well as the baseline imaging procedures. At the end of the baseline procedures, volunteers will be blindly randomized, either to lurasidone at 40mg (N=12), or to haloperidol at 4mg/d or perphenazine at 16mg/d (N=12). Doses will increase to 80mg/d lurasidone, 8 mg/d haloperidol, or 32 mg/d of perphenazine at the beginning of week two. Dose should be stable for the last 3 weeks of treatment unless side effects are prominent, then the dose can be decreased to 40 lurasidone/4 haloperidol/16 perphenazine mg/d for optimal clinical management. The randomization strategy will be designed and implemented by the research pharmacist in four blocks of six volunteers; drug will be dispensed by the research pharmacy according to the randomization schedule. The randomization will be followed by a four week treatment period at optimal dose levels. On the last two days of the 4 week stable dosing period, the specified glutamate outcome measures will be completed (neuroimaging and cognitive testing) along with all the symptom outcome measures, testing for drug plasma levels, and usual blood safety measures. Patients will be seen weekly for clinical evaluation; suicidality will be monitored weekly. All medications other than study drugs will be discontinued, as much as possible, for the 24-48 hr assessment period. After the evaluation phase, patients will be cross-titrated back to their original treatment medication and dosing. This design will generate outcomes from 12 patients on lurasidone vs. 12 patients on haloperidol/ perphenazine.
Interventions
DRUGLurasidone
Compare to haloperidol and perphenazine
DRUGHaloperidol
Compare to lurasidone
DRUGPerphenazine
Compare to lurasidone
Sponsors
Sumitomo Pharma America, Inc.
University of Texas Southwestern Medical Center
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
* Subject at least 18 years old * Subject meets criteria diagnosis of schizophrenia or schizoaffective disorder. * Subject is not pregnant and is not planning pregnancy within the projected duration of the study. * Female subject who is of reproductive potential agrees to remain abstinent or use adequate and reliable contraception throughout the study * Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening. * Eyesight corrected to 20-40 or better * Able to read, speak, and understand English\*
Exclusion criteria
* Any medications being used as mood stabilizers (i.e., anticonvulsants) * Subject currently has a clinically significant medical condition(s) that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study. * Subject demonstrates evidence of acute/chronic hepatitis which is clinically significant * Subject has a history of malignancy \< 5 years prior * Subject has a history of neuroleptic malignant syndrome (NMS). * Subject has a history of alcohol or substance abuse within 3 months prior to screening or alcohol or substance dependence within 12 months prior to screening * Subject tests positive for drugs of abuse at screening. In the event a subject tests positive for cannabis, the investigator will evaluate the subject's ability to abstain from cannabis during the study. * Subjects diagnosed with type 1 diabetes * Subject has a prolactin concentration \> 200 ng/mL at screening * Subject has a history or presence of abnormal ECG which is clinically significant * Subject has a history of hypersensitivity to more than two distinct chemical classes of drug (e.g., sulfas and penicillins). * Subjects have received depot neuroleptics within 12 weeks prior to randomization. * Subject has a history of treatment with clozapine for refractory psychosis and/or subject has been treated with clozapine within 4 months of randomization. * Subject does not have a stable residence for the 3 months prior to randomization. * Subject requires treatment with any potent CYP3A4 inhibitors or inducers during the study. * Subject has received electroconvulsive therapy (ECT) within 90 days prior to * Subject has been randomized in a prior clinical trial of lurasidone. * History of serious head injury with unconsciousness for \>30 minutes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebral Glutamate Levels | Baseline and 4 weeks | Mean values of cerebral glutamate levels was measured by high resolution 3T magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC). Data were acquired from the dorsal anterior cingulate cortex (ACC) using single voxel localized PRESS (TE1, TE2) = (32, 65) ms with an 8-channel head coil in a 3T whole-body scanner (Philips Medical Systems). Voxel size was 30x20x15 mm3 (9 mL) and were placed over the bilateral anterior cingulate cortex (ACC). All values are normalized to water. More negative values represent less cerebral glutamate levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brief Assessments of Cognition in Schizophrenia Scores (BACS) | Baseline and 4 weeks | Mean of cognition was assessed by BACS, which measures neurocognitive function in schizophrenia. BACs is a validated, composite measure of cognition which is used in schizophrenia. It is composed of Verbal memory (range: 0-75), Working memory (range: 0-28), Motor speed (range: 0-100), Verbal Fluency (number of words generated), Information processing (range: 0-110) and Executive functions (range: 0-22). Higher z-scores indicate a better performance and outcome. BACS composite score are represented as z-scores which can be positive or negative. There is no minimum or maximum as this is a continuous measure. |
Countries
United States
Participant flow
Pre-assignment details
35 individuals initially signed the Informed Consent and began the Screening procedures. Only 24 made it to Randomization, with only 22 making it to the end of the study. Generally participants were discontinued because they were lost to follow-up (which requires 3 telephone calls and a letter) and irregular labs that were exclusionary.
Participants by arm
| Arm | Count |
|---|---|
| Lurasidone Lurasidone 40mg po qhs with food x 1 week; Lurasidone 80mg po qhs with food x 3 weeks
Compare to haloperidol and perphenazine groups combined to lurasidone group. | 14 |
| Non-Lurasidone Haloperidol 4mg po qhs with food x 1 week; Haloperidol 8mg po qhs with food x 3 weeks.
OR Perphenazine 16mg po qhs with food x 1 week; Perphenazine 32mg po qhs with food x 3 weeks.
Compare haloperidol and perphenazine groups combined to lurasidone. | 10 |
| Total | 24 |
Baseline characteristics
| Characteristic | Non-Lurasidone | Lurasidone | 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 | 10 Participants | 14 Participants | 24 Participants |
| Age, Continuous | 46 years | 51 years | 49 years |
| Region of Enrollment United States | 8 participants | 14 participants | 22 participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 4 Participants | 9 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 | 3 / 14 | 4 / 8 |
| serious Total, serious adverse events | 1 / 14 | 0 / 8 |
Outcome results
Primary
Cerebral Glutamate Levels
Mean values of cerebral glutamate levels was measured by high resolution 3T magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC). Data were acquired from the dorsal anterior cingulate cortex (ACC) using single voxel localized PRESS (TE1, TE2) = (32, 65) ms with an 8-channel head coil in a 3T whole-body scanner (Philips Medical Systems). Voxel size was 30x20x15 mm3 (9 mL) and were placed over the bilateral anterior cingulate cortex (ACC). All values are normalized to water. More negative values represent less cerebral glutamate levels.
Time frame: Baseline and 4 weeks
Population: Of the original 22 participants, only 15 have both Baseline and Week 4 scans to compare.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lurasidone | Cerebral Glutamate Levels | Baseline (week 0) | -1.434662171 relative unit (RU as compared to water) | Standard Deviation 0.741430931 |
| Lurasidone | Cerebral Glutamate Levels | week 4 | -1.412294235 relative unit (RU as compared to water) | Standard Deviation 0.952600355 |
| Non-Lurasidone | Cerebral Glutamate Levels | Baseline (week 0) | -1.933853656 relative unit (RU as compared to water) | Standard Deviation 1.005387144 |
| Non-Lurasidone | Cerebral Glutamate Levels | week 4 | -1.838991525 relative unit (RU as compared to water) | Standard Deviation 1.20411535 |
Secondary
Brief Assessments of Cognition in Schizophrenia Scores (BACS)
Mean of cognition was assessed by BACS, which measures neurocognitive function in schizophrenia. BACs is a validated, composite measure of cognition which is used in schizophrenia. It is composed of Verbal memory (range: 0-75), Working memory (range: 0-28), Motor speed (range: 0-100), Verbal Fluency (number of words generated), Information processing (range: 0-110) and Executive functions (range: 0-22). Higher z-scores indicate a better performance and outcome. BACS composite score are represented as z-scores which can be positive or negative. There is no minimum or maximum as this is a continuous measure.
Time frame: Baseline and 4 weeks
Population: Of the original 22 participants, only 15 have both Baseline and Week 4 to compare.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lurasidone | Brief Assessments of Cognition in Schizophrenia Scores (BACS) | Baseline (week 0) | -1.596573107 BACS composite score (z score) | Standard Deviation 0.929835487 |
| Lurasidone | Brief Assessments of Cognition in Schizophrenia Scores (BACS) | week 4 | -2.002433521 BACS composite score (z score) | Standard Deviation 1.596431421 |
| Non-Lurasidone | Brief Assessments of Cognition in Schizophrenia Scores (BACS) | Baseline (week 0) | -1.933853656 BACS composite score (z score) | Standard Deviation 1.005387144 |
| Non-Lurasidone | Brief Assessments of Cognition in Schizophrenia Scores (BACS) | week 4 | -1.500292967 BACS composite score (z score) | Standard Deviation 1.477111055 |