Schizoaffective Disorder, Schizophrenia, Schizophreniform Disorder
Conditions
Keywords
Schizophrenia, Positive symptoms, Negative symptoms, Cognitive deficits
Brief summary
This is a 6-week, randomized, double blind, parallel groups designed, olanzapine-controlled trial of oral dipyridamole in symptomatic patients with a (DSM IV) diagnosis of schizophrenia, schizoaffective or schizophreniform disorder. This pilot study aims to provide preliminary estimates of whether the effect sizes of dipyridamole on positive symptoms, negative symptoms, and cognitive deficits differ between schizophrenia patients treated with dipyridamole, and schizophrenia patients treated with olanzapine. A total of 30 subjects will be recruited locally.
Detailed description
Since the demonstrated success of chlorpromazine in treating psychosis in the1950's, the pharmacotherapy of schizophrenia has focused mainly on drugs with antidopaminergic actions. These drugs have robust effects on reality distortion and disorganization symptom complexes, but minimal effect on cognitive impairment, negative symptoms, and functional outcome and quality of life measures. Newer generation antipsychotic drugs have a similar profile of effects, with some advantages on the course of depression, hostility, suicide, hospital readmission rates and motor side effect measures. Side effects such as weight gain, increase in cardiovascular stress and diabetes risk are associated with some new generation drugs. A new class of drugs is needed to address the inadequate effectiveness and the side-effect disadvantages of the currently available pharmacological agents for the treatment of schizophrenia. Recently, new treatment strategies using nicotinergic drugs or agonists at the glycine modulatory site of the glutamatergic N-methyl-D-aspartate (NMDA) receptor have been employed in clinical trials with mixed results. Our proposal focuses on a clinically available adenosine agonist, dipyridamole, in a 6-week clinical trial. Published data suggest effectiveness of dipyridamole in treating psychosis when added to haloperidol treatment. The effectiveness of dipyridamole alone in treating schizophrenia symptoms, although indirectly suggested by several lines of evidence, has not been tested.
Interventions
DRUGDipyridamole
Week 1- 50 mg bid Week 2- 50 mg am and 100 mg pm Weeks 3-6 100 mg am and 100 mg pm
OTHEROlanzapine
Week 1- 5 mg BID Week 2- 5 mg am and 10 mg pm Weeks 3-6 10 mg am and 10 mg pm
Sponsors
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subjects between ages 18-65, both males and nonpregnant females (on birth control) Diagnosis of schizophrenia, schizoaffective or schizophreniform disorder Ability to give written informed consent Total BPRS score \> 27 Psychosis subscale scores \> 7
Exclusion criteria
* Patients with coagulative disorders, bleeding diathesis or currently on anticoagulants, and patients with major medical illnesses (including hypertension, angina, and cardiovascular diseases) or an abnormal baseline ECG. Patients with moderate to severe mental retardation. Inability to sign informed consent. Patients with a history of serious violence (e.g., suicide attempts, or assaultive behavior). Patients on clozapine treatment within the 6 weeks leading to the double-blind phase. Patients with a history of olanzapine non-response Positive Urine Toxicology Screen
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Positive Symptoms by Treatment Assignment | Baseline and follow-up | The Brief Psychiatric Rating Scale (BPRS) consists of 20 items, with 6 of these items used to assess positive symptom change. The BPRS positive symptom items are: somatic concern, conceptual disorganization, hostility, suspiciousness, hallucinatory behavior, and unusual thought content. Each scale ranges from 1=Not Present to 7=Very Severe. A higher score indicates a more severe positive symptom rating. |
| Change in Negative Symptoms by Treatment Assignment | Baseline and Follow-Up | The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. Mean SANS total score by treatment and week. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms. |
| The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline and Follow-Up | The RBANS is a brief, individually administered test designed to evaluate neuropsychological status of adults, ages 20-89. The 12 subtests measure attention, language, visuospatial/constructional abilities, and immediate and delayed memory. The raw scores from the subtests are scaled together to create index scores, and these are summed for conversion to a total scale score. Higher score equals a better outcome. The total index score range for the RBANS is 40-160. |
Countries
United States
Participant flow
Pre-assignment details
Four participants were excluded prior to randomization (1:positive urine tox screen; 1:participant uncooperative with clinical interview; 1:withdrew consent; 1:history of cardiovascular disease).
Participants by arm
| Arm | Count |
|---|---|
| Dipyridamole Dipyridamole
Dipyridamole : Week 1- 50 mg bid Week 2- 50 mg am and 100 mg pm Weeks 3-6 100 mg am and 100 mg pm | 12 |
| Olanzapine Olanzapine
Olanzapine : Week 1- 5 mg BID Week 2- 5 mg am and 10 mg pm Weeks 3-6 10 mg am and 10 mg pm | 8 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Dipyridamole | Olanzapine | 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 | 12 Participants | 8 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 8 |
| serious Total, serious adverse events | 0 / 12 | 0 / 8 |
Outcome results
Primary
Change in Negative Symptoms by Treatment Assignment
The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. Mean SANS total score by treatment and week. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms.
Time frame: Baseline and Follow-Up
Population: Participants completing SANS assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dipyridamole | Change in Negative Symptoms by Treatment Assignment | Baseline (Phase 1/Week 1) | 23.3 units on a scale | Standard Deviation 14.7 |
| Dipyridamole | Change in Negative Symptoms by Treatment Assignment | Follow-Up (Phase 4/Week 1) | 25.8 units on a scale | Standard Deviation 10.7 |
| Olanzapine | Change in Negative Symptoms by Treatment Assignment | Baseline (Phase 1/Week 1) | 25.6 units on a scale | Standard Deviation 20.5 |
| Olanzapine | Change in Negative Symptoms by Treatment Assignment | Follow-Up (Phase 4/Week 1) | 27.0 units on a scale | Standard Deviation 29.7 |
Primary
Change in Positive Symptoms by Treatment Assignment
The Brief Psychiatric Rating Scale (BPRS) consists of 20 items, with 6 of these items used to assess positive symptom change. The BPRS positive symptom items are: somatic concern, conceptual disorganization, hostility, suspiciousness, hallucinatory behavior, and unusual thought content. Each scale ranges from 1=Not Present to 7=Very Severe. A higher score indicates a more severe positive symptom rating.
Time frame: Baseline and follow-up
Population: Participants completing the BPRS assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Baseline - Somatic Concern | 2.222 units on a scale | Standard Deviation 1.716 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Somatic Concern | 1.60 units on a scale | Standard Deviation 1.34 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Baseline - Conceptual Disorganization | 2.667 units on a scale | Standard Deviation 1.225 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Conceptual Disorganization | 2.00 units on a scale | Standard Deviation 1.41 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Baseline - Hostility | 1.222 units on a scale | Standard Deviation 0.667 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Hostility | 1.00 units on a scale | Standard Deviation 0 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Baseline - Suspiciousness | 4.11 units on a scale | Standard Deviation 1.54 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Suspiciousness | 3.000 units on a scale | Standard Deviation 1.581 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Baseline - Hallucination | 2.67 units on a scale | Standard Deviation 2.12 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Hallucination | 2.600 units on a scale | Standard Deviation 2.191 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Baseline - Unusual Thought Content | 3.111 units on a scale | Standard Deviation 1.167 |
| Dipyridamole | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Unusual Thought Content | 2.800 units on a scale | Standard Deviation 2.168 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Baseline - Unusual Thought Content | 3.400 units on a scale | Standard Deviation 0.894 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Baseline - Somatic Concern | 1.400 units on a scale | Standard Deviation 0.548 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Baseline - Suspiciousness | 3.40 units on a scale | Standard Deviation 1.82 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Somatic Concern | 1.00 units on a scale | Standard Deviation 0 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Hallucination | 2.500 units on a scale | Standard Deviation 0.707 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Baseline - Conceptual Disorganization | 2.600 units on a scale | Standard Deviation 0.894 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Suspiciousness | 1.500 units on a scale | Standard Deviation 0.707 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Conceptual Disorganization | 2.00 units on a scale | Standard Deviation 1.41 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Unusual Thought Content | 1.500 units on a scale | Standard Deviation 0.707 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Baseline - Hostility | 1.200 units on a scale | Standard Deviation 0.447 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Baseline - Hallucination | 3.80 units on a scale | Standard Deviation 1.3 |
| Olanzapine | Change in Positive Symptoms by Treatment Assignment | Follow-Up - Hostility | 2.00 units on a scale | Standard Deviation 1.41 |
Primary
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
The RBANS is a brief, individually administered test designed to evaluate neuropsychological status of adults, ages 20-89. The 12 subtests measure attention, language, visuospatial/constructional abilities, and immediate and delayed memory. The raw scores from the subtests are scaled together to create index scores, and these are summed for conversion to a total scale score. Higher score equals a better outcome. The total index score range for the RBANS is 40-160.
Time frame: Baseline and Follow-Up
Population: Participants completing cognitive testing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dipyridamole | The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline (Phase 1/Week 1) | 73.00 units on a scale | Standard Deviation 15.41 |
| Dipyridamole | The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Follow-Up (Phase 3/Week 6) | 77.40 units on a scale | Standard Deviation 14.83 |
| Olanzapine | The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline (Phase 1/Week 1) | 59.00 units on a scale | Standard Deviation 1.41 |
| Olanzapine | The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Follow-Up (Phase 3/Week 6) | 65.00 units on a scale | Standard Deviation 2.83 |