Effect of different antipsychotic medications on craving and craving related brain activity in patients with schizophrenia and cannabis abuse or dependence:
a randomized controlled study comparing clozapine and risperidone

Cannabis abuse and dependence in patients with schizophrenia occurs frequently
and is associated with adverse outcomes. Craving is regarded as a central
phenomenon that contributes to the continuation of cannabis use and to relapse
in cannabis use after a period of abstinence. Three partly overlapping
functional craving pathways, associated with dopaminergic neurotransmission,
are: (1) *chronic craving or anhedonia*, referring to the relative
insensitivity to non-drug rewards; (2) *attentional bias*, referring to the
underlying attentional focusing on drug cues as a prerequisite for motivational
behaviour; and (3) *cue elicited physiological reactivity and craving*,
referring to the high motivation to use cannabis elicited by drug-related
stimuli. Antipsychotic medications with high affinity for the dopamine D2
receptor have been found to increase craving. Clozapine, with its low affinity
for the dopamine D2 receptor, is associated with reduced substance use.
However, firm evidence for clozapine*s superiority is lacking (Lange et al.,
2005). Randomized controlled trials to study efficacy of clozapine on reducing
cannabis abuse are difficult to conduct and pharmaceutical companies do not
support these studies since clozapine is off patent. We hypothesize that
abovementioned pathways will be differentially modified by different
antipsychotic medications dependent on their differences in affinity for the
dopamine D1 and D2 receptor.

Objective: To test the hypothesis that clozapine treatment compared to
risperidone treatment is associated with a significant reduction in subjective
craving and in a lower activity of the different functional craving pathways
and their associated brain activity patterns.

A randomized controlled trial comparing the effect of clozapine and risperidone
on cannabis craving in cannabis abusing or dependent patients with
schizophrenia. Specific cognitive tasks will be used to test craving pathways
and associated brain activities are assessed with functional MRI.

Patients will be randomly allocated to receive clozapine or risperidone. Dose
titration scheme of clozapine depends on smoking status of patients: - smokers:
12,5 mg day 1, 25mg day 2, 50 mg day 3, 100 mg day 4, 150 mg day 5, 200 mg day
6, 250 mg day 7, 300 mg day 8, and thereafter adjustment of dose to obtain a
blood level of clozapine of about 350 ng/ml. This dose will be continued till
day 28; - non smokers: 12,5 mg day 1, 25 mg day 2, 50 mg day 3, 75 mg day 4,
100 mg day 5, 125 mg day 6, 150 mg day 7, 200 mg day 8, and thereafter
thereafter adjustment of dose to obtain a blood level of clozapine of about 350
ng/ml. This dose will be continued till day 28.
Dose titration scheme risperidone: during 6 days with daily steps of 0.5 mg to
a dose of 3,5 mg per day, and thereafter continuation of this dose till day 28.
Concomitant psychotropic medications are restricted to oxazepam up to 50 mg if
sedation is necessary and biperiden 2 mg if extrapyramidal symptoms occur.
Biperiden and oxazepam co-medication will be discontinued as soon as possible
and biperiden as a prophylaxis is prohibited. In case of lack of antipsychotic
efficacy resulting in dangerous or disturbing behaviour, dosage of clozapine or
risperidone can be increased if clinically applicable. In case of dose related
side effects dosage of clozapine or risperidone can be decreased or dose
titration scheme can be slowed down if clinically applicable. Clinician or
patient decision can be a reason for discontinuation of the study medication.

Burden: Patients will be randomly allocated to receive clozapine or
risperidone. One extra session is needed to inform patients on the study design
and procedure. Two extra sessions are needed to assess baseline and outcome
data. Two fMRI scanning sessions are needed during which specific tests will be
administered. Duration of first fMRI scanning session is 38 minutes. Duration
of second fMRI session is 32 minutes. Task difficulty of these tests will be
set such that each participant will succeed on approximately 66% of his or her
target responses. Scanning procedures may induce some burden because
participants need to refrain from movements. To diminish the burden from the
noise from the scanner, earplugs are used. Use of cannabis is prohibited in the
three days before scanning. Three hours before scanning participants are not
allowed to smoke cigarettes. One cup of coffee is allowed in the morning before
scanning. Urine drug screen will be taken. Before the second fMRI scan blood
level of risperidone or clozapine will be taken.
The healthy controls will follow the same protocol but they will only have one
baseline fMRI scan.
Risk: There is a risk on adverse effects related to the treatment with
clozapine or risperidone. Careful clinical procedures will be performed to
detect adverse effects and respond to them as needed. There are no known risks
related to fMRI scanning.
Benefit: no direct benefits for participants are predicted, although study
medication may be associated with favourable effects.