Clozapine for Cannabis Use in Schizophrenia

Cannabis use disorder (CUD), which is up to ten times more common in patients with
schizophrenia (SCZ) than in the general population, worsens the course of this severe
psychiatric disorder. Since SCZ occurs in 1% of the population, the co-occurrence of CUD in
13% to 42% of people with this disorder presents society with an important public health
problem. Unfortunately, most antipsychotics available for treatment of patients with SCZ do
not appear to limit their cannabis use. Moreover, the one antipsychotic that preliminary data
suggest may well limit cannabis use in these patients, clozapine (CLOZ), is not used for this
purpose; it is reserved for patients whose psychosis is treatment resistant.

The overarching idea behind this proposal, however, is that CLOZ's use is being unreasonably
restricted and should be made more widely available for patients with SCZ who have a
co-occurring CUD but whose psychosis is not necessarily treatment resistant. This notion is
supported by our preliminary clinical and animal data on the effects of CLOZ, as well as our
neurobiological model of the basis of cannabis use in patients with SCZ that provides a
pharmacologic rationale for this effect of CLOZ.

Even given all the arguments favoring the potential benefits of CLOZ in patients with SCZ and
CUD, however, its side effect profile will likely limit its use until a fully powered study
demonstrates its ability to decrease cannabis use in patients with SCZ. This proposal aims to
launch such a study. If, as we hypothesize, this study confirms and extends our previous
preliminary data of the effects of CLOZ in patients with SCZ and CUD, it will provide a
strong impetus to expand the use of CLOZ in this population.

In the proposed study, 132 patients who are comorbid for both SCZ and CUD will be randomized
to a 12-week treatment course with either CLOZ or risperidone (RISP) to test the hypothesis
that patients treated with CLOZ will have decreased cannabis use as compared to patients
treated with RISP. In addition, the study will determine whether patients treated with CLOZ
will have improvements in psychiatric symptoms, quality of life neuropsychological functions
as compared to those taking RISP. We will also explore whether patients taking CLOZ show
improved reward responsiveness as compared to those taking RISP. Finally, this study will
explore whether those patients with the val/val genotype at the COMT Val158Met locus are more
likely to decrease cannabis use during CLOZ treatment than are those without the val/val COMT
genotype.

Should this study indicate that CLOZ will lessen cannabis use in patients with SCZ more than
RISP, it will provide evidence needed to begin to shift clinical practice toward its use in
these patients.

Inclusion Criteria:

- Clinical diagnosis of schizophrenia

- Clinical diagnosis of a cannabis use disorder (abuse or dependence)

Exclusion Criteria:

- Pregnant,trying to become pregnant or nursing

- History of a seizure disorder

- Current treatment with clozapine or risperidone

- Contraindication to treatment with clozapine or risperidone