Schizophrenia
Conditions
Keywords
schizophrenia, dronabinol, P50, cannabis, memory, symptoms
Brief summary
Approximately 25% of people with schizophrenia abuse marijuana. These people may be using marijuana to self-medicate symptoms such as hallucinations (hearing or seeing things that are not heard or seen by others) or delusions (false beliefs i.e. people are harassing or persecuting them) or the depressed and anxious feelings brought on by these symptoms. Currently, it is unknown whether marijuana makes schizophrenia better or worse. Marijuana intoxication in people without schizophrenia generally causes decreased recall of words, may decrease reaction time and decrease inhibition. Additionally, marijuana may cause distractibility as demonstrated by difficulty keeping their eyes on a moving target and difficulty inhibiting their response to repetitive tones. However, marijuana may have different effects in schizophrenia. Receptors for cannabis (marijuana) are concentrated in the brain and maladjustment of the cannabinoid system may be associated with the difficulty in thinking found in schizophrenia. The proposed research project examines if clinical symptoms, learning, memory, inhibition and distractibility are improved or made worse by the acute ingestion of tetrahydrocannabinol (THC).
Detailed description
The trial will be a double two period (visit) blind cross-over trial with one arm dronabinol 10 mg one arm a placebo control. The order of doses and placebo will be randomized with the restriction that half of the subjects will receive each order. This counterbalances possible visit effects or learning effects associated with the visits. The use of an oral cannabis analog is not equivalent to smoking as the onset of action is slower. This is why people who use dronabinol for chronic pain prefer to smoke cannabis. There is no high associated with dronabinol. However, the active ingredients are the same, THC, which will have similar effects on the cannabinoid 1 receptor. Ethically, we did not feel we could ask people to smoke cannabis on one day of study. Subjects will present to the GCRC at 5:00 p.m. They will abstain from use of cannabis overnight. The following morning, at 8:00 a.m., the subject will provide a urine sample for a toxicology screen and a blood sample for quantitative THC levels. They will then be administered either 10 mg of dronabinol or an identical placebo on an alternate day. The subject will then have a baseline assessment of clinical positive and negative symptoms measured by the Brief Psychiatric Rating Scale (BPRS). The majority (70-90%) of people with schizophrenia smoke cigarettes. Thus, it is likely that in this population that smokes cannabis, 100% will also be cigarette smokers. The effects of nicotine via cigarette smoking on the endophenotypes studied is an acute effect, with a peak at about 5 minutes. To preclude nicotine effects on endophenotypes, we have the patient not smoke for 20 minutes prior to and during testing. Nicotine is quickly removed from the body when inhaled and its effects wear off within 20 minutes. Two hours after administration, the subject will perform the following tests: P50 auditory evoked potential- the recording will consist of the presentation of 5 sets of 16 click pairs with an intrapair interval of 500 ms heard through headphones with a 3-minute rest between sets. Brain wave responses will be recorded; neurocognitive assessment-the California Verbal Learning Test will measure verbal memory and the Stroop will measure inhibition; clinical symptom assessment- The BPRS will again be administered measure positive and negative symptoms; and a blood sample will be collected for quantitative THC levels. They will then be escorted by a Clinical Research Center nurse over to a laboratory at Colorado Psychiatric Hospital to perform smooth pursuit eye movements In performing smooth pursuit eye movements, they will watch a dot moving across a computer screen while infrared sensors that are placed just in front of their eyes record their eye movements. Each subject performs 3 trials of one minute each, with 2 minutes rest between each recording. Subjects will be reassessed by the BPRS for drug exacerbation of symptoms, will have vitals, will be checked for adverse effects, will perform a sobriety test (the standard test used in roadside testing i.e. walking a straight line and finger to nose testing) which will be assessed by Dr. Olincy, who is experienced in assessing sobriety, to assure that the patient is not acutely intoxicated and able to perform normal functions that require coordination. If they fail the sobriety test, they will be asked to remain in the (General Clinical Research Center (GCRC) until they can pass the sobriety test. Otherwise, they will then will be discharged at 5:00 p.m. Transportation to and from the GCRC will be by a provided cab service. Subjects will be randomized in blocks of 4 or 6 to the order in which they receive placebo or dronabinol. The interval between the two days of testing will be 1 week.
Interventions
DRUGDronabinol
dronabinol 10 mg one capsule by mouth at 8:00 a.m.
OTHERPlacebo Comparator
one capsule given by mouth at 8:00 a.m.
Sponsors
National Alliance for Research on Schizophrenia and Depression
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Male and females * 18 and 50 years of age * Diagnosis of schizophrenia * Chronic cannabis users who have used for at least 1 year * Using cannabis at least once weekly * Currently being treated with antipsychotic medication * Must be on a the same dose of antipsychotic medication for at least 3 months. * Females of childbearing potential must use an adequate form of birth control while participating. * Participants will be required to have blood pressures greater than 90/60 and less than 140/90.
Exclusion criteria
* Use of illicit drugs other than cannabis * Any psychiatric hospitalizations within 3 months * pregnancy in females * taking clozapine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| P50 Auditory Evoked Potential | 2 hours after drug administration | electrophysiological measure of ability to filter extraneous stimuli measured as the amplitude of the evoked response to the second auditory stimulus divided by the amplitude of the evoked response to the first auditory stimulus in mV. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| California Verbal Learning Test Change at 2 Hours From Baseline | 2 hours after drug administration | ability to remember a list of words given 5 trials. Number of words remembered is normalized to a schizophrenia population and average scores are calculated with age correction. The normal T-score is 50 and scores greater than 50 correspond with greater ability to remember words as compared to a schizophrenia population norm. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Brief Psychiatric Rating Scale Change From Baseline at 1 Hour | at 1 hour after drug administration | Measures psychiatric symptoms. Each item is scored from 1-7. Positive symptoms are calculated from sum of scores on hallucinatory behavior, unusual thought content and conceptual disorganization. Thus, the range of Total Positive Symptoms can be from a score of 3-21 .The higher the score, the more severe the symptom. Negative symptoms have been calculated from sum of blunted affect, emotional withdrawal and motor retardation. The range of Total Negative Symptoms can be from a score of 3-21. The higher the score, the more severe the symptoms. As this is a difference from baseline, there can be either negative or positive results as the subjects can either be better than baseline (positive score) or worse than baseline (negative score). |
Countries
United States
Participant flow
Recruitment details
Age-eligible participants were recruited from May 2005 to May 2010 and were recruited from local mental health centers.
Pre-assignment details
14 recruited; 14 screened: 1 excluded (did not meet inclusion criteria)
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population includes groups randomized to receive placebo first or dronabinol 10 mg first | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age, Continuous | 32 years STANDARD_DEVIATION 11.04 |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
P50 Auditory Evoked Potential
electrophysiological measure of ability to filter extraneous stimuli measured as the amplitude of the evoked response to the second auditory stimulus divided by the amplitude of the evoked response to the first auditory stimulus in mV.
Time frame: 2 hours after drug administration
Population: One participant did not complete the treatment or the placebo arm (crossover study design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dronabinol | P50 Auditory Evoked Potential | .62 test to conditioning ratio | Standard Deviation 0.69 |
| Placebo | P50 Auditory Evoked Potential | .52 test to conditioning ratio | Standard Deviation 0.43 |
Secondary
California Verbal Learning Test Change at 2 Hours From Baseline
ability to remember a list of words given 5 trials. Number of words remembered is normalized to a schizophrenia population and average scores are calculated with age correction. The normal T-score is 50 and scores greater than 50 correspond with greater ability to remember words as compared to a schizophrenia population norm.
Time frame: 2 hours after drug administration
Population: One participant did not complete the treatment or the placebo arm (crossover study design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dronabinol | California Verbal Learning Test Change at 2 Hours From Baseline | -.5 T scores | Standard Deviation 1.92 |
| Placebo | California Verbal Learning Test Change at 2 Hours From Baseline | -.77 T scores | Standard Deviation 1.19 |
Other Pre-specified
Brief Psychiatric Rating Scale Change From Baseline at 1 Hour
Measures psychiatric symptoms. Each item is scored from 1-7. Positive symptoms are calculated from sum of scores on hallucinatory behavior, unusual thought content and conceptual disorganization. Thus, the range of Total Positive Symptoms can be from a score of 3-21 .The higher the score, the more severe the symptom. Negative symptoms have been calculated from sum of blunted affect, emotional withdrawal and motor retardation. The range of Total Negative Symptoms can be from a score of 3-21. The higher the score, the more severe the symptoms. As this is a difference from baseline, there can be either negative or positive results as the subjects can either be better than baseline (positive score) or worse than baseline (negative score).
Time frame: at 1 hour after drug administration
Population: One participant did not complete the treatment or the placebo arm (crossover study design).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dronabinol | Brief Psychiatric Rating Scale Change From Baseline at 1 Hour | 3.73 units on a scale | Standard Deviation 1.1 |
| Placebo | Brief Psychiatric Rating Scale Change From Baseline at 1 Hour | 3.18 units on a scale | Standard Deviation 0.6 |