Conditions: Schizophrenia Cannabis Abuse Cannabis Dependence Dual Diagnosis
Keywords: Schizophrenia Cannabis Abuse Cannabis Dependence Dual Diagnosis Clozapine Risperidone
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 49
Healthy volunteers: no

Brief summary:
Many individuals with schizophrenia also suffer from marijuana addiction that worsens their problems related to schizophrenia. Most of the medications prescribed for schizophrenia have no effect on reducing marijuana use. Preliminary data suggests that clozapine, an atypical antipsychotic, may limit marijuana use in people diagnosed with schizophrenia, but it is not commonly used due to its side effects and is reserved for people who do not respond to other antipsychotic medications.

In the proposed study, 132 individuals who are diagnosed with both schizophrenia and a cannabis use disorder will be randomized to a 12-week treatment course with either clozapine or risperidone (another commonly prescribed antipsychotic medication) to test the hypothesis that patient treated with clozapine will have decreased cannabis use as compared to patients treated with risperidone.

Should this study indicate that clozapine will lessen marijuana use in persons diagnosed with schizophrenia more than risperidone, it will provide evidence needed to begin to shift clinical practice toward its use in this population.

Detailed description:
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 Catechol-O-methyltransferase (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.

Arms:
arm 1: The blinded CLOZ will be titrated on a recommended standard schedule, supervised by a study physician (or other prescriber) who can make the necessary adjustments to account for symptom control and tolerability. The titration is recommended to begin at 12.5 mg and then increase while the open-label base antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 25% each week. If clinically tolerated, the target dose of CLOZ is 400 mg/day. arm 2: The blinded RISP will also be titrated in the first weeks, using a titration schedule, with a target dose of 4 mg/day, while the open label base antipsychotic is tapered in a similar fashion.

Interventions: intervention 1: Clozapine intervention 2: Risperidone
Intervention descriptions: intervention 1: Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day intervention 2: Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Clozapine for Cannabis Use Disorder in Schizophrenia 
(CLOCS) 
NCT number: 
NCT01639872 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
1/15/16 
 
 


V 01.15.2016
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Study Title: Clozapine for Cannabis Use Disorder in Schizophrenia (CLOCS) 
 
Funding Source (Sponsor): National Institute on Drug Abuse 
 
Principal Investigator: Alan I. Green, M.D. 
 
 
 
 
 
Attachments:  
 Attachment A:  Nonsignificant Risk Devices 
 Attachment B:  Placebo 
 Attachment C:  Genetic Research 
 Attachment D:  Employees and Students 
 Attachment E:  Illiterate Participants 
 Attachment F:  Research Involving Children 
Attachment G:  Research Involving Individuals With Impaired Decision-Making Capacity 
 (formerly referred to as incompetent) 
 Attachment H:  Request for Waiver of Participant Consent  
 Attachment I:  Request for Waiver of Participant Signed Consent Form 
 Attachment J:  Drugs or Biologics 
 Attachment L:  International Research 
 Attachment M:  Pregnant Women, Fetuses and Neonates 
 
1. Abstract.   
 
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 


V 01.15.2016 
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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). The primary specific aim of this 
proposal is: (1) To test the hypothesis that patients treated with CLOZ will have decreased 
cannabis use as compared to patients treated with RISP. Subsidiary aims will further elucidate 
the effects of CLOZ in this population: (2) a) To determine whether patients treated with CLOZ 
will have improvements in (i) psychiatric symptoms; (ii) quality of life; and (iii) 
neuropsychological functions as compared to those taking RISP; and b) to explore whether 
patients taking CLOZ will show improved reward responsiveness as compared to those taking 
RISP; and (3) To 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. Given the increased morbidity associated 
with CUD in patients with SCZ, doing so could dramatically improve the clinical outcome of 
these individuals. Lastly, CLOZ's use in this study may also reflect its potential to serve as a 
prototype of the next generation of medications for treatment of SCZ and co-occurring CUD. 
 
2. Objectives & Hypotheses:   
 
The primary specific aim of this proposal is: 
 
(1) To test the hypothesis that patients treated with clozapine (CLOZ) will have decreased 
cannabis use (intensity and frequency of use) as compared to patients treated with risperidone 
(RISP). 
 
Subsidiary aims will further elucidate the effects of CLOZ in this population:  
(2) (a) To determine whether patients treated with CLOZ will show improved (i) psychiatric 
symptoms; (ii) quality of life; and (iii) neuropsychological function, as compared to those taking 
RISP; and (b) to explore whether patients taking CLOZ will show improved reward 
responsiveness as compared to those taking RISP. 
 
(3) To 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 genotype.  
 
 


V 01.15.2016 
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3.  Introduction:   
 
Note: This introduction is an abridged version of the grant proposal submitted to NIDA.  
Reviewers desiring a more detailed background for this study are referred to pages 3-7 
of the grant proposal.  The reference list can be found in Appendix I. 
Cannabis use disorder in schizophrenia (SCZ) is an important public health issue:  SCZ is a 
severe psychiatric disorder occurring in 1% of the population worldwide.  Most surveys of 
substance use disorders (SUDs) in patients with SCZ have reported lifetime prevalence of 
drug/alcohol use disorder in this population ranging from 10 to 60%17-21 The most 
comprehensive of these studies, the large-scale NIMH Epidemiologic Catchment Area (ECA) 
community-based co-morbidity survey, provided clear evidence that patients with SCZ are 
much more vulnerable to SUDs than are people in the general population.22  In the ECA study, 
47% of patients with SCZ were noted to have serious problems with substance use during their 
lifetime compared to 16% of the general population.  Cannabis is a very common  co-occurring 
substance use disorder in patients with SCZ21-25 with lifetime rates ranging from 13 to 42%,26-32  
a three to ten-fold increase over the lifetime prevalence of 4% in the general population.22  
Substance abuse or dependence worsens the course of SCZ.  This is true despite the data 
suggesting that substance abuse in patients with SCZ is characterized by regular but modest 
levels of use, and with much greater likelihood of substance abuse than dependence in this 
population.33  Nonetheless, co-occurring SUD in patients with SCZ is associated with 
relapse,34-36 non-compliance with treatment,37 poorer overall response to typical neuroleptic 
medication,38 more rehospitalizations,35, 39 and an increased risk for violence.14, 22, 40 Cannabis 
use disorder (CUD) in particular has been associated with clinical exacerbations, non-
compliance 
with 
treatment, 
poor 
global 
functioning, 
and 
increased 
relapse 
and 
rehospitalization rates.27, 29, 41-45  Clearly, CUD adds greatly to the financial costs and emotional 
toll that SCZ places on patients, families and the entire mental health system. e.g., 53, 54   
Given the clear negative effects of cannabis use in patients with SCZ, the frequent use and 
abuse of cannabis in these patients is puzzling – why would they use a drug that worsens the 
symptoms and course of their underlying disease?  One common explanation for the use of 
cannabis/other substances in patients with SCZ invokes the "self-medication" hypothesis,84, 85 
which suggests that use of drugs, despite their negative effects, "corrects" an underlying 
"deficit", potentially involving negative symptoms,55, 85 or the side effects of antipsychotic 
drugs.55   Despite the observation by some investigators that cannabis use can decrease 
negative symptoms, 27, 42  a few studies do not support the causal proposition that use of 
substances is due to negative symptoms.  Moreover, the rationale of cannabis use as a means 


V 01.15.2016 
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of overcoming antipsychotic-induced side effects is also subject to question since cannabis 
and other substance use is common in first episode patients, even before exposure to 
antipsychotic medications.88  Thus, while it may be reasonable to suggest that cannabis and 
other substances may lessen negative symptoms in some patients and also decrease 
medication-induced side effects, the "reason" for use of substances in these patients may not 
be merely an attempt at "self medication"  of such negative symptoms or medication induced 
side effects.   
We have proposed an alternative formulation of this self-medication hypothesis,5 based on 
neurobiological studies that provide some clues about the reason for the high prevalence of 
CUDs in patients with SCZ.  Studies in animals suggest that many brain areas that are 
dysfunctional in SCZ are part of the DA-mediated "brain reward circuit".e.g., 92  While cannabis's 
neuropharmacological actions are complex, and may involve many other neural systems, 
including  norepinephrine and opioid peptides,e.g., 93, 94 it appears that cannabis, like alcohol, 
cocaine and other drugs of abuse (including nicotine), produces its reinforcing effects on 
animal behavior via midbrain DA neurons projecting into the prefrontal cortex and limbic 
system.94-99  In patients with SCZ, cannabis and other substance use may decrease negative 
symptoms via increase in DA activity in the prefrontal cortex (PFC),e.g., 97, 98, 99, 102 but may also 
enhance functioning of the dysfunctional brain reward system by an increase in the neuronally-
based "signal detection" of these DA-rich systems.103, 104 Thus, while the abuse of cannabis 
and other substances may decrease negative symptoms in patients with SCZ, the "basis" of 
the use of these substances may be related to the difficulty that these patients have in 
experiencing "normal" levels of reward from the environment and to the ability of cannabis and 
other substances of abuse to ameliorate this "reward system" deficit.5, 92, 105, 106  In this sense, 
use of cannabis is based on the need for patients to “self-medicate” this deficit.   
For most of the past six decades, the treatment of psychotic disorders has involved the use of 
the standard or typical antipsychotic (i.e., neuroleptic) drugs.  However, for "dual diagnosis" 
psychotic patients who are comorbid for SUDs, it appears that the typical antipsychotics are 
only partially useful.  Although the drugs are effective for the underlying psychosis, the side 
effects they produce (the feeling of being "snowed", and the extrapyramidal system effects) 
may lead to the further use of cannabis or other substances in an attempt to override (or "self-
medicate") such side effects produced by these agents.42, 55 Thus, while there may be an 
increased rate of CUD/SUD in patients with SCZ whether treated or not, the typical 
antipsychotics appear to be of limited value in controlling cannabis or other substance use. 
By contrast, a number of reports, including several from the PI's group, suggest that the newer 


V 01.15.2016
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atypical antipsychotic CLOZ may be helpful in limiting cannabis and other substance abuse in 
patients with SCZ.  In the early 1990s, we described two patients with SCZ who had used 
alcohol extensively to make them "feel more outgoing", and who dramatically decreased their 
alcohol use after beginning treatment with CLOZ.56  Other groups also reported evidence that 
substance use may decrease during CLOZ treatment.57-61 
Subsequent studies by our group provided further evidence of the potential role of CLOZ in 
"dual diagnosis" patients. The first study,62 a naturalistic, clinical services survey, followed 151 
patients who were comorbid for SUD and SCZ or schizoaffective disorder for 3 years.  In our 
analysis of data from this prospective study, we noted that the patients taking CLOZ had 
higher rates of remission of cannabis abuse (6/9 = 67%) compared to those treated with a 
typical neuroleptic (12/37 = 32%).  Similarly, remission of alcohol abuse was higher in patients 
taking CLOZ (15/19 = 79%) compared to those treated with typical neuroleptics (29/86 = 34%; 
Bonferroni corrected p=.003).  In a continuing assessment of those patients whose abuse 
remitted, only 8% of those treated with CLOZ relapsed to abuse in the following 6 months vs. 
40% of those treated with other antipsychotics (p=.003).63 
These findings were further confirmed by our retrospective studies of dual diagnosis patients 
treated at a separate site, indicating that between 54% and 72% achieved abstinence from 
cannabis and alcohol during treatment with CLOZ. 64, 65  A report presented by Buckley et al.66 
provided further support for our data (an abstinent rate for all substances of 73% in patients 
who took CLOZ for 12 weeks), as did another report by Lee et al.67   
Under support from NIDA, we recently completed a randomized “stay or switch” 12-week trial 
of CLOZ vs. continued atypical antipsychotics in 35 patients with SCZ and co-occurring CUD.  
During the study, the patients were not provided extra "dual diagnosis" psychosocial treatment 
(i.e. 
beyond 
clinical 
care 
for 
this 
population.)  Data regarding intensity of 
cannabis use over the course of the study 
are indicated in Figure 1.  The primary 
finding 
from 
this 
study1 
is: 
 
using 
longitudinal random effects models, we 
determined that the intensity of cannabis 
smoking between the two groups (those 
randomized to CLOZ and those staying on 
their 
original 
antipsychotic) 
was 
systematically different (effect size ~ .6; p<.09), such that, as compared to those staying on 


V 01.15.2016 
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their original antipsychotic, those treated with CLOZ used less cannabis during the 12-week 
study (with CLOZ, heavy users [> 10 joints/week] had a decrease in cannabis use, and most 
other users [< 10 joints/week] approached abstinence).  
    Many investigators are currently assessing whether other atypical antipsychotics share with 
CLOZ an ability to limit co-occurring SUDs in patients with SCZ.  Unfortunately, available data 
are somewhat mixed and not overly promising.65  Although Smelson et al.68, 69 reported that 
risperidone (RISP) reduced craving scores and relapse to cocaine use (as compared to typical 
antipsychotics) in patients with SCZ and co-occurring cocaine abuse, our retrospective survey 
of patients with SCZ and co-occurring alcohol or cannabis abuse did not demonstrate an 
important effect of RISP (on alcohol and/or cannabis use) compared to CLOZ.70  While there 
are a few reports of case series suggesting that olanzapine may have a modest effect in 
limiting substance abuse in these patients,71, 72 including one from the PI’s group,73  there are 
two reports74,75 suggesting that olanzapine may be no more likely to decrease comorbid 
substance use than are typical antipsychotics.  Regarding quetiapine, there are very 
preliminary reports76-78 suggesting that this medication may have some beneficial effects in 
patients with SUD and co-occurring bipolar disorder or SCZ, but further study is needed.  And 
lastly, there have been three open label (small N) reports indicating that aripiprazole, a partial 
dopamine agonist, may also have some ability to decrease substance use in co-occurring 
patients.79-81  Thus, despite the emerging data suggesting that certain of the non-CLOZ 
atypical medications may have some value in patients with SCZ and co-occurring SUD, CLOZ 
remains the only one where there is consistent evidence of a substantive decrease in cannabis 
and other substance use. 
Our neurobiological formulation also suggests that CLOZ’s unique pharmacological profile may 
help explain its unusual clinical profile in patients with SCZ and co-occurring cannabis (and 
other substance) use disorder.  We have proposed, based on animal studies, that CLOZ’s 
unusual clinical effects may relate to its varied pharmacologic actions, including those on 
dopaminergic and, particularly, noradrenergic systems.  Work of a number of groups has 
suggested that some of CLOZ's clinical effects may result from release of DA in the PFC,e.g., 
107-109 which, through regulation of the mesolimbic DA pathway, may contribute to its 
antipsychotic potential.e.g., 89, 90 However, CLOZ's unusual actions on noradrenergic neurons 
may be of paramount importance in understanding its clinical effects.5, 110   Specifically, we 
have proposed that CLOZ’s activation of the norepinephrine (NE) system (including its 
antagonistic effects at the NE α2 receptor and its ability to release NE)e.g., 111-120 may potentiate 
functioning of (and ameliorate dysfunction in) the DA-mediated "reward system" through 


V 01.15.2016 
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increase of signal detection in DA subcortical neurons.5  Within our proposed study (in Aim 
2b), we will begin to explore, through study of reward responsiveness,e.g., 4 whether CLOZ, but 
not RISP, modulates this aspect of reward circuit functioning in patients with SCZ and CUD, 
and thus improves their response to reward cues. 
Following our neurobiologic formulation, the lack of effect on alcohol/substance use of other 
antipsychotics may indicate that these antipsychotics are less likely than CLOZ to ameliorate a 
reward system deficit.  We are assessing, under funding from NIAAA and industry, the action 
of antipsychotic medications in alcohol-preferring rodents with an eye toward creation of a 
CLOZ-like agent that could decrease alcohol and other substance use in patients with SCZ.  
Our animal studies have provided considerable support for our neurobiologic formulation of the 
action of CLOZ. They have suggested that increasing the DA D2 receptor potency of CLOZ (by 
the addition of raclopride to CLOZ) will diminish the ability of CLOZ to suppress alcohol 
drinking; and adding the NE reuptake inhibitor desipramine (DMI) to RISP will allow RISP, 
which does not decrease alcohol drinking when given alone, to suppress alcohol drinking. 
Given our formulation of the mechanism of action of CLOZ in patients with SCZ and CUD or 
other SUD, we are interested in beginning to investigate whether patients with the val/val 
genotype at the COMT (catechol-o-methyl transferase) Val158Met locus are more likely to 
decrease cannabis use with CLOZ than are those with (particularly) the met/met genotype and 
(possibly) the val/met genotype.  We base our hypothesis about this on the action of COMT, 
which breaks down DA (and NE) particularly in the frontal cortex (given the relative lack of DA 
reuptake capacity in this brain region).124, 125  The val/val genotype subjects (25 – 30% of the 
population) would have a “high output” form of COMT, thus increasing the metabolism of DA in 
their PFC (where DA-ergic activity is deficient in patients with SCZ).126 Moreover, the COMT 
val allele has been reported to predict the development of psychosis following adolescent 
cannabis use in a longitudinal study of a birth cohort followed through adulthood.16  Given our 
formulation of the action of CLOZ, we would expect that those individuals whose cannabis use 
occurs in the presence of the COMT val/val genotype would be more likely to respond to CLOZ 
(with a decrease in cannabis use, and potentially a decrease in symptoms) than will individuals 
who have the met/met (and possibly the val/met) COMT genotype.     
The preliminary data from our group and others, including our recent NIDA – funded pilot study 
of CLOZ vs. other atypical antipsychotics in SCZ and CUD, suggest that CLOZ, despite its 
side-effect burden, should be considered as a routine treatment option for patients with SCZ 
and CUD, even for those patients who are not classically “treatment resistant” (i.e., regarding 
their psychosis).  With CLOZ, however, increasing use is an uphill battle – given its potential 


V 01.15.2016 
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side effects (e.g., rare seizures, and very rare agranulocytosis or myocarditis, as well as weight  
gain, and glucose and lipid increases),82, 83 requiring regular blood monitoring, and the 
resulting “medicalization” of treatment, which may be uncomfortable for psychiatrists working in 
mental health centers.  With CLOZ, the evidence in favor of its use needs to be very solid 
before its use will become routine for treatment of co-occurring CUD.  As noted by the 
Schizophrenia PORT Treatment Recommendations group,13 the studies generating the 
existing data regarding the beneficial effects of CLOZ in this population all have limitations.  It 
is the special nature of this drug that indicates to us that the field needs a well-powered trial of 
CLOZ vs. another (preferably atypical) antipsychotic that will provide the base for change in 
practice.  We are proposing such a trial. 
In addition, we will explore whether the val/val COMT genotype may identify those subjects 
with SCZ most likely to respond to CLOZ with a decrease in cannabis use.  Given the side 
effects of CLOZ, it will be important to be able to exclude from CLOZ treatment any patient in 
whom CLOZ is not likely to be effective. 
 
4.  Design, procedures, materials and methods:   
 
This a longitudinal, randomized, double-blind 12-week study of CLOZ and RISP in a group of 
132 participants diagnosed with SCZ and co-occurring CUD, cannabis abuse or dependence.  
To reach 132 randomized participants we believe we will need to consent and screen 
approximately 300 participants due to the high screenfail and drop out rate in this population.      
 
Individuals who appear eligible will meet with the study physician to review and, if appropriate, 
sign the consent document.  
 
Participants will be screened for medications, diagnosis, substance abuse history and health 
status.  If participants appear eligible at the end of the screening, then the next phase of the 
study will begin. 
 
If an individual is on a medication that is exclusionary, but appears otherwise eligible and 
expresses a desire to be in the study, our procedure will be to have the medication regimen 
and proposed change reviewed by the Medication Adjustment Group (MAG), consisting of all 
study physicians that serve in an advisory capacity on the study and patient care, and led by 
Dr. Brunette, to ensure that medication decisions are made in a similar fashion across all sites.    


V 01.15.2016 
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The procedure for considering and making such a medication change as deemed appropriate 
will be as follows: 
        o Assess whether a change in or elimination of the agent is likely to worsen the clinical 
condition of the patient.  If the MAG determines the risk to be too great, then the person may 
not enter the study. 
       o If there is no reason to assume that elimination of the exclusionary medication or use of 
an alternate medication would worsen the patient's condition and the patient wants to be in the 
study, he/she will be consented to the study at that time (if not already consented), and the 
change in medication will be made in consultation with the person's regular physician. 
       o The MAG will determine the length of time the person must be off of the exclusionary 
medication before beginning the study and set an interval at which the study doctor is to meet 
with the person to supervise his or her medication change.   Participants will be paid for their 
time and travel up to $25 per visit for these additional visits. 
 
At the end of the period set by the MAG, if the patient appears to be likely to continue to meet 
study entry criteria, he or she will continue the screening visit.  If not, the person will continue 
to be transitioned back to the regular treating physician. 
 
At baseline, subjects will be randomly assigned to one of 2 groups of approximately 66 
subjects: taking (blinded) RISP or CLOZ.    The blinded CLOZ will be titrated on a 
recommended standard schedule, supervised by a study physician (or other prescriber) who 
can make the necessary adjustments to account for symptom control and tolerability.  The 
titration is recommended to begin at 12.5 mg and then increase while the open-label base 
antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 
25% each week.  If clinically tolerated, the target dose of CLOZ is 400 mg/day.  The blinded 
RISP will also be titrated with a target dose of 4 mg/day, while the open label base 
antipsychotic is tapered in a similar fashion.  Participants, treatment providers and study staff 
will be blinded to study condition by having study medications prepared to look the same.   
 
After the initial 4 week cross-titration period, the prescribing psychiatrist will conduct a formal 
medication review and, after consulting with the MAG, may elect to increase or lower the dose 
of blinded medication to achieve optimal response or to accommodate side effects.  Study 
physicians may change doses to address symptom control or tolerability at any time.  The 
principle to be followed is that CLOZ and RISP should be maintained at an optimal dose for 
psychiatric symptoms.  To keep RISP in the dosage range thought to be "atypical" and to 


V 01.15.2016 
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minimize the seizure potential of CLOZ, we will employ a maximum dose of 6 mg of RISP and 
550 mg of CLOZ per day  – doses likely to be sufficient for most patients.  Compliance with 
study medication will be monitored by packaging the pills into some form of blister-pack or 
planner, conducting pill counts, and paying participants $5 per week for returning their blister-
pack or planner.   
 
The question of concurrent psychotropic medication is a complex issue for this study.  
Although completely restricting non-study medications in the protocol would make for a 
methodologically pure design, we are concerned that such a protocol restriction would limit 
study feasibility and severely curtail the generalizability of our findings.  Nonetheless, providing 
no restrictions on concurrent medications during the trial would confound the experimental 
design.  Therefore, we have decided on the following guidelines:  (1) Where clinically 
appropriate, patients will be taking only RISP or CLOZ  during the course of the study; (2) 
enrolled patients will have concurrent psychotropic medications reduced prior to randomization 
unless (a) the "MAG" indicates the medication is necessary for their treatment and should not 
be removed; and (b) the concurrent medication is neither specifically prohibited in the study 
nor contraindicated in combination with CLOZ or RISP.  Wherever possible, concurrent 
medications will be held stable during the trial. Prospective participants requiring benzotropine 
and propanolol (or other similar side-effect medications) will be allowed into the study following 
approval by the MAG.  Sedative-hypnotics will be severely restricted (allowed only on an 
occasional basis, approved by the MAG prior to study entry or for emergencies).  The principle 
to be followed is that concurrent agents may only be used for non-substance-related 
psychiatric disorders.  We believe that this plan will allow us to achieve our specific aims while 
providing good clinical care. 
 
Participants will be followed for 12 weeks past baseline with weekly study visits.  If participants 
cannot tolerate their assigned study medication after randomization, it will be stopped, though 
the participant may continue to be followed on another treatment (ideally their pre-study 
antipsychotic medication) for the remaining weeks of the study. 
 
At the end of an individual's participation (whether as scheduled or earlier if the person leaves 
the study early), he or she will be asked to have a final study visit.  The research physician will 
work with the participant and his or her treatment team to determine the best course of 
treatment following the study.  If the decision is for the participant to remain on the same 
antipsychotic as during the study, then the patient and his or her treatment team will be 


V 01.15.2016 
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unblinded to study condition but the research team will remain blinded.  If the participant opts 
to stop the study medication and the clinical team will be responsible for the transition to 
another medication, the study team will provide for four additional blood draws after clozapine 
is stopped.  They will unblind the participant's treatment provider to the individual's study 
treatment condition so that the treatment provider can supervise the cross titration of the 
antipsychotic medications.   
 
Occasionally, after a patient completes the study, a piece of data is missing or that we come to 
understand that it would be helpful to ask an additional question of all participants.  For this 
reason, participants will be asked as part of the consent process if they are willing to be 
contacted after their study participation ends. 
 
While our study teams strive to have all participants complete all assessments, this is a 
population that struggles with the impact of two debilitating disorders.  Symptoms of psychosis, 
including avolition, apathy and cognitive disturbances, commonly lead to behavior that can be 
inconsistent and result in poor appointment attendance and variable tolerance of assessment 
batteries.  Substance use disorders can similarly contribute to persons having complex lives 
that can be unpredictable and lead to a variety of difficulties with participation in research 
activities.  Additionally, problems related to symptoms of schizophrenia and substance 
dependence can cause a number of challenges to carrying out the protocol with a given 
participant, including: missed appointments, visits outside of the window, inability to complete 
all study assessments, not taking medication correctly, and not returning medication containers 
and extra pills.  Such events will not be considered protocol deviations unless they impact a 
participant's safety or the scientific validity of the study. 
 
Pharmacy Problem: In February 2014, the pharmacy providing the medications for this study 
ceased doing business.  The study team intends to arrange services with a new pharmacy, but 
this may take weeks or months.  During this time, participants will be randomized to open label 
treatment with either risperidone or clozapine.  The only other change in the protocol during 
this time is that after the baseline visit participants randomized to risperidone, will not need the 
weekly clozapine blood monitoring.  A new consent form is being created for this period of 
time.  Any participants consented using the existing consent form with be reconsented.   Once 
arrangements are made with a new pharmacy, participants who were randomized to open 
label study medication will remain on open label medication.  New individuals entering the 
study after a new pharmacy begins to provide services will be consented using the currently 


V 01.15.2016 
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approved consent describing the use of double-blind study medication and double-blind 
randomization will re-commence.  We will notify the CPHS when this occurs. 
 
Transition Back to Double-Blind: As the various study sites receive all necessary approvals to 
transition back into the double-blind design, screening will continue and some patients who 
screen positive may not be randomized immediately so that they can be randomized when the 
double-blind design is operating again. This delay may be as short as a few days or as long as 
a few weeks, and may potentially involve one or more extra study visits and possibly one more 
blood test for blood cell count.   
 
Taping:  We hope to audio or video record research interviews for training and reliability 
purposes. Recording will be done on digital equipment when possible, and on traditional 
analog equipment when necessary. We plan to transfer digital recordings either directly from 
the digital recorder to the supervisor's computer or through email as password-protected 
attachments. When transmitting analog recordings, research interviewers will either hand-carry 
the tapes back to the supervisor or mail the tapes via registered mail 
 
5.  Inclusion/Exclusion Criteria:   
 
Inclusion Criteria: 
1.  Ages 18-55   
2. Meets the DSM-IV TR criteria for diagnoses of schizophrenia or schizoaffective disorder and 
a cannabis use disorder (abuse or dependence) based on the Structured Interview for the 
DSM-IV TR [SCID].  
3. Has used cannabis on 8 or more days over the 28 days prior to randomization (assessed by 
the Timeline Followback [TLFB] interview)  
4. Stable outpatients as determined by the MAG ( e.g. no psychiatric hospitalization for 
increased psychosis within the past 4 weeks) 
5. Stable on antipsychotic medication as determined by the MAG (i.e. no substantial change in 
dose/type of antipsychotic in the past 4 weeks.) 
6. Treated with an antipsychotic drug other than CLOZ  at the time of study entry and willing to 
be treated with either CLOZ or RISP  
7. Is willing and able to provide informed consent 


V 01.15.2016 
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Exclusion Criteria 
1. Current diagnosis of a substance use disorder other than a CUD or an Alcohol Use 
Disorder.  Caffeine and nicotine (tobacco smoking) use will be allowed, but monitored. Note: 
Persons using synthetic cannabinoids will be allowed in the study assuming they also have a 
CUD. 
2. Is currently pregnant, trying to become pregnant or nursing 
3. Has a history of a seizure disorder 
4. Is currently treated with CLOZ or RISP 
5. Contraindication to treatment with RISP or CLOZ  
6. Treatment with two or more antipsychotics, unless the MAG determines that one of the 
antipsychotics is prescribed at a dose that is less than therapeutic for psychosis (e.g. low 
doses of quetiapine for sleep.) 
7. Receives treatment with a psychotropic agents proposed to curtail substance use (e.g., 
disulfiram, naltrexone, acamprosate, topiramate, valproate, levetiracetam, varenicline or 
bupropion) as determined by the MAG. 
8. Is at risk of suicide (as determined by the MAG.) 
9. Has a medical condition that would increase risk of study participation. 
10. Is deemed inappropriate for the study by the study team or MAG (e.g. due to other medical 
conditions, medication, psychiatric concerns or other circumstances that could cause safety 
concerns or impair the person’s ability to participate in or benefit from the study.  
 
6.  Statistical Methods and Review Statement:   
 
The primary outcome measures (Aim 1) will be intensity (number of joints) and frequency 
(days of use) of cannabis use (per week) during follow-up.  We will also assess global 
severity of use monthly.  Secondary auxiliary measures (Aim 2) will include symptoms: the 
BPRS score (total, positive and negative subscales), the SANS (negative symptoms), and the 
CGI total score; quality of life: QLS (composite, interpersonal relations and instrumental role 
subscales), QLI (satisfaction score); neuropsychological functioning:  five subcomponents 
from the MATRICS battery:  attention/vigilance (CPT IP); verbal learning and memory (Letter 


V 01.15.2016 
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Number Span, Hopkins learning and memory trials); nonverbal learning and memory (Spatial 
Span and BVMT learning and memory trials); reasoning and problem solving (NAB Mazes); 
and speed of processing (Trail Making A, Category Fluency, Symbol-Coding); and reward 
responsiveness: delta response bias (delta RB) on the Probabilistic Reward Task.  The 
measures for Aim 3 will include:  val/val, val/met and met/met COMT genotypes. 
 
        Aim 1: For both explanatory and intent-to-treat comparisons, we will first graphically 
describe treatment differences over time and check for unusual data and patterns.  For the 
LRE models, polynomial time trends (e.g., slopes) will be used to fit the population mean 
response curve for the RISP (control) group. Group-by-time interactions will be modeled as a 
function of time to fit between-group effects. Subject-specific parameters will be estimated to 
model individual subject deviations from the group mean.  For efficiency, baseline measures of 
intensity of cannabis use and clinical symptoms will be included in the model as covariates; 
history of treatment resistance and indicators of the COMT genotype subgroup will be included 
to control for possible imbalances between groups.  While not a specific aim, secondary 
analyses of SUD will assess the effects of CLOZ vs. RISP on nicotine and other substance 
use, using baseline measures as controls.   
       Aim 2:  The analyses for this aim will be carried out as for Aim 1, but using the auxiliary 
measures described above. Nicotine dependence at baseline will serve as a control for RR 
comparisons. 
       Aim 3:  The analyses for this aim will be explanatory, using LRE models that include 
measures of cannabis use and clinical symptoms as baseline covariates.  Subjects in the 
CLOZ group will be stratified into three subgroups according to their COMT genotype (val/val, 
val/met, met/met).  Separate models for each subgroup will also be used to explore 
differences, as there is likely to be insufficient power for (subgroup x time) interactions.  
Differences in use over time will be qualitatively assessed using categorical response (50% 
decrease, based on predicted values from LRE models).   
 
Sample Size: The sample size for this study was chosen to provide statistical power for an 
effect size (ES) for Aim 1 as small as 0.45, based on results from our preliminary “stay or 
switch” study for assessing the effects of CLOZ vs. other antipsychotics on cannabis use.  That 
study provided an ES of 0.6, but to be conservative (given uncertainty in estimated effect sizes 
from small pilot data), we power this study for a smaller ES.  For our primary explanatory 
analyses, assuming 30% of the 132 subjects fail to complete the study on assigned 
medication, the detectable ES (two-sided tests, alpha = .05, power = .80) for primary analyses 


V 01.15.2016 
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is .30 for small within-subject correlation (r = .2) and .44 for moderate within-subject correlation 
(r =.5). 
 
7.  Data and Safety Monitoring:  
 
The Dartmouth Department of Psychiatry has created a Data Safety Monitoring Board (DSMB) 
to independently oversee clinical trials and other studies. The DSMB for this study will be 
composed of at least three people and will include (at minimum) a clinician knowledgeable 
about SCZ and co-occurring substance use disorders, and a biostatistician who will be 
independent of the study group. The group will follow the NIH policy for data and safety 
monitoring and guidelines as published on http://www.nimh.nih.gov/research-
funding/grants/nimh-policy-on-data-and-safety-monitoring-in-extramural-investigator-initiated-
clinical-trials.shtml.  Study data regarding subject enrollment, characteristics, symptoms, 
substance use, adverse events and serious adverse events will be submitted to the DSMB for 
review and analysis quarterly. The DSMB will review study data quarterly to oversee the safety 
of study participants and conduct of the study. It will advise the PI (and the Departmental 
Research Committee) on continuation of the study and provide reports to the IRB regarding 
recruitment of appropriate subjects and presence of adverse effects.   
 
8. Instruments:  
 
Please refer to Appendix II: Schedule of Events for the specific timing of assessments.  
Diagnosis:  Patients will be assessed at recruitment with the Structured Clinical Interview for 
DSM-IV (SCID).176 Information gathered from all sources (e.g., charts, clinicians, patients).   
Cannabis and other substance use: Cannabis/other substance use (including nicotine) will 
be assessed primarily by weekly self-report using the Timeline Followback (TLFB) method,139, 
181 enhanced by procedures to strengthen the reliability and validity of this measure, as well as 
data from collateral informants, urinary and breath measures.   
 
 Participants’ urine will be tested weekly for the presence of cannabis and other 
substances. We will also test for alcohol (using a breathalyzer).  At three points in the study, 
we will obtain a urinary cotinine level.  Urine screen tests that are positive for cannabis use will 
be quantified using liq. chromatography/mass spectrometry (LC/MS/MS).  In addition, a urine 
specimen sample each month will be sent for testing of synthetic cannabinoids. The 
Fagerström Test for Nicotine Dependence will be used to assess smoking status. 


V 01.15.2016 
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    Psychiatric symptoms:  Level of psychiatric symptoms will be assessed with the modified 
Brief Psychiatric Rating Scale (BPRS),190 the Clinical Global Inventory (CGI),191 and the 
Schedule for the Assessment of Negative Symptoms (SANS). 192  Suicidality will be assessed 
with the Columbia Suicide Severity Rating Scale (C-SSRS).9 Extrapyramidal system effects 
will be assessed with the Simpson-Angus Scale (S-A),194 the Abnormal Involuntary Movements 
Scale (AIMS),195 and the Barnes Akathisia Scale (BAS).196   
 
Quality of life (QOL):  Quality of life measures can provide a broad assessment of the 
status of patients, including those with substance use disorders.174, 197 We will use items from 
the Quality of Life scale (QLS) scale199 and the "subjective section" from the Quality of Life 
interview (QLI)200 for the proposed study.   
 
Neuropsychological (NP) functions:  In this study, to complement the quality of life 
functional measures, and because cannabis use produces cognitive effects201 we will utilize a 
small battery of NP tests to assess the effects of the two treatments on aspects of NP function 
that have been shown to be impaired in patients with both schizophrenia and CUD (i.e., 
attention/vigilance, verbal and visual short- and long-term memory, and executive functions).  
This will include components from the  Wechsler Abbreviated Scale of Intelligence,204 and an 
abbreviated online cognitive assessment ("Integneuro"), a 20 minute assessment that, 
includes brief visual memory span, attention switching, processing speed.  There is also an 
additional brief functional capacity assessment using virtual reality (another 10 -20 minutes).  
 Reward responsiveness (RR):  In an exploratory aim, in order to obtain empirical data 
regarding functioning of brain reward circuitry during treatment with CLOZ and RISP, we will 
assess reward responsiveness using the computerized Probabilistic Reward Task4. This task 
measures the extent to which a participant biases their responding toward a more rewarded 
versus less rewarded stimulus, consistent with the view that frequency of responding is 
increased toward reinforcers.208 Relevant for the proposed research, impaired RR in this task 
has been associated with increased levels of nicotine dependence209 and affective flattening in 
patients with schizophrenia.210   
   CLOZ/RISP blood levels:  We will draw blood samples to measure CLOZ/RISP levels, and 
to explore for possible effects of the CLOZ/RISP level on cannabis use.    
    DNA collection and COMT Val158Met genotyping:  A venous blood sample (5 ml) will be 
drawn and sent to Dartmouth for DNA extraction and genotyping.  (Note: An extra tube of 
blood will be drawn [with permission] and frozen for possible subsequent genetic testing.)   
 
Treatment and service utilization:  We will monitor treatment for drug/alcohol abuse and 
psychosis with a modified version of the Treatment Services Review (TSR).221   


V 01.15.2016 
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Other assessments: Other assessments that will be done and are mentioned elsewhere 
in this Study Plan include: a medical history and physical at screening; an EKG at screening 
and as clinically appropriate; laboratory testing, including CBC with diff (to obtain blood cell 
counts) and glucose, cholesterol and triglyceride levels, renal and hepatic function tests; 
monitoring of vital signs (including weight); monitoring medication compliance via pill counts; 
reviewing current medications and adverse events; pregnancy tests;  monitoring for signs of 
withdrawal from alcohol and cannabis; and assessing for possible cardiac side effects.  EKGs 
and blood cardiac enzymes will be taken as appropriate clinically.   
Note: In order to assure a high degree of reliability in the rating for this study, some of the 
assessments may be conducted via secure video conference using centralized raters. 
 
9.  Risks and Benefits:   
 
Potential risks and benefits for participants:   
(1) Medications:  
 (a) Safety of CLOZ: Risks of CLOZ include agranulocytosis – occurs in approximately 0.37% 
of patients, if a weekly blood count monitoring system is in place (as will be done in this study 
– see below).  All subjects in this study will participate in this weekly blood count monitoring 
system. The study will follow the FDA package insert for monitoring for neutropenia and 
treatment recommendations.  If the package insert recommends interrupting or discontinuing 
treatment with clozapine, this will be done in consultation with the patient and his/her clinical 
psychiatrist, another antipsychotic will be started and the patient’s care will be transition from 
the study to the clinical team.  Patients and staff will be specifically instructed to recognize and 
report any evidence of leukopenia or granulocytopenia such as fever, malaise, sore throat, etc.  
We limit our population under study to patients between ages 18 and 55 primarily because of 
the slightly increased risk of agranulocytosis in children and the elderly, and to avoid the 
confounding effects of age for our neuropsychological measures.  (Most patients meeting our 
inclusion criteria, however, will be within this age range).   
The second major risk is the development of seizures. In patients who had no seizure history 
seizures occurred in 0.9% of people at doses less than 600 mg/day, and 1.5% at doses 
greater than 600 mg/day.  Higher rates have been reported in patients with medical 
comorbidities and history of head injuries.  For this reason we will carefully exclude patients 
with unstable medical conditions and history of previous seizures and we will utilize a target 
dose of CLOZ of 400 mg/day.  We will exclude patients with a history of a seizure disorder, 
and carefully assess for prodromal signs of seizures, including myoclonus, in patients within 


V 01.15.2016 
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the study.  Should a seizure occur, the medication trial will be terminated and the patient will 
be treated as appropriate clinically.  The doses of CLOZ chosen (target of 400 mg/day, with an 
upper limit of 550 mg/day) will lower the rate of seizures.  
CLOZ is associated with a minimally increased risk of myocarditis early in treatment (between 
0.015% and 0.188%). Although this is a very rare effect of CLOZ, patients will be carefully 
assessed at each visit for signs indicative of myocarditis (e.g., chest congestion, syncope, 
heart failure, etc.).  EKGs will be taken as appropriate clinically.   
 CLOZ can also cause cardiometabolic side effects such as weight gain, increased glucose 
levels (with increased rate of diabetes), as well as increased levels of triglycerides and 
cholesterol. Potential cardiometabolic side effects will be carefully monitored.  Patients will be 
weighed at each visit, vital signs will be taken and patients will be provided brief advice for 
exercise and nutrition.  Patients will be tested for glucose, triglycerides and cholesterol at 
screening, 6 and 12 weeks.  Patients who have elevations in triglycerides or cholesterol will be 
managed clinically.  Patients with clinically significant elevations in glucose will be switched 
back to pre-study medication or another medication mutually agreed upon by the study 
physician, the patient, and the patient’s clinical physician. 
Lastly, CLOZ can also cause hypotension, tachycardia, fever, sedation and sialorrhea. Study 
physicians will ask participants about side effects each week and will instruct them to call the 
study team at any time between study visits should adverse events occur.  Management of 
side effects will be discussed with participants.  Any moderate to severe side effect will trigger 
the study physician to consider taking measures to minimize the side effect burden.  Lowering 
the dose of study medication or discontinuing the study medication will be considered and 
discussed with the MAG and with the participant.   
 (b) Safety of RISP: Neurologic side effects associated with the short term use of RISP include, 
in order of frequency:  rigidity and stiffness (30%), restlessness (20%), tardive dyskinesia 
(<3%), and, rarely, neuroleptic malignant syndrome (<1%) -- although the rates of these 
neurologic side effects are lower than with standard (typical) antipsychotic drugs. We will 
monitor patients for these effects weekly.  In our previous studies of these patients, the rates of 
neurologic effects have been quite low.  If a participant experiences significant side effects, 
dose adjustment will be attempted or an anticholinergic medication (or propranolol) will be 
added.   


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RISP is often associated with elevations in serum prolactin, which is usually asymptomatic but 
can lead to breast discharge and menstrual difficulties.    Participants will be monitored for 
these potential side effects weekly. 
RISP may also cause cardiometabolic side effects (although at rates significantly lower than 
CLOZ), including weight gain, increased glucose and diabetes, and increased triglycerides and 
cholesterol. All participants will also be monitored for cardiometabolic side effects as described 
above. 
Other side effects of RISP may include anxiety, stomach upset, and rhinitis. Study physicians 
will ask patients about side effects weekly and address them by adjusting the dose of the 
medication or using other strategies.  If medication side effects are problematic, the medication 
may be discontinued. 
(2) Relapse of psychosis:  Although patients will be under treatment for their psychosis during 
the study, and both RISP and CLOZ are very effective antipsychotics, patients who switch 
antipsychotic medication may not do as well on either RISP or CLOZ as on their previous 
antipsychotic medication.  Patients who experience an exacerbation are vulnerable to a 
number of dangerous behaviors, including self-harm or harm toward others. Symptoms will be 
assessed weekly.  Interviewers will consult with the study psychiatrist if there is any evidence 
of exacerbation of psychosis or dangerous behavior.  Research staff will be on call at all times 
and available for after hours consultation if needed.  If, in the opinion of the study staff, further 
intervention is needed, the team will coordinate with the participant’s clinical treatment team to 
ensure that the participant gets appropriate care, including emergency care and/or 
hospitalization.  In addition, if necessary, study medication will be terminated and the patient 
placed on the most appropriate medication for clinical management. 
(3) Confidentiality: This research involves monitoring and treatment of patients who may use a 
variety of illegal substances in addition to cannabis.  Participants may engage in other illegal 
activities. Maintaining confidentiality is an area of utmost importance for this population. See 
Section 27 for details on how the study team will maintain participant’s confidentiality. 
(4) Research assessments (cannabis/substance use measures, symptom and side effect 
measures, breath and urine testing):  Answering the questions asked by the interviewers may 
cause some discomfort, boredom, embarrassment, anxiety or fatigue.  It is also possible, but 
not likely, that the patients may experience an increase in their underlying symptoms due to 
the process of research assessments. Participants will be advised that they can take a break, 
refuse to answer question(s), or end the interview if they become uncomfortable in any way.  


V 01.15.2016 
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Research staff will involve the study psychiatrist (on-call) to provide consultation if a patient 
becomes more symptomatic during a study procedure.  In addition, each study site provides 
emergency services that can be accessed at any time if the study psychiatrist is unavailable.  
Additionally, either our co-investigator, Dr. Brunette, or her coverage, Dr. Noordsy, both of 
whom are experienced psychiatrists, will be available via pager for emergency consultation. 
(5) Cannabis (or alcohol) withdrawal:  Although participants will be using cannabis (and 
possibly some alcohol as well) mostly in a moderate fashion, heavy cannabis users who 
drastically reduce or discontinue use during the study may experience withdrawal symptoms.  
Such symptoms, although not medically dangerous, may consist of mood disturbance such as 
anxiety or irritability, sleep disturbance, loss of appetite, diarrhea, tremors, and night sweats.  
While alcohol withdrawal can be more of a serious issue, given the exclusion of patients with 
alcohol dependence, we do not expect to see alcohol withdrawal symptoms.  (In our previous 
studies of patients with SCZ and CUD [as well as alcohol use disorder], we have not seen 
withdrawal symptoms in our patients.) Patients will be educated about cannabis (and alcohol) 
withdrawal with a fact sheet that includes a brief list of coping strategies.  Participants will be 
monitored with weekly vital signs and questions to assess withdrawal symptoms (following 
symptoms with the Cannabis Withdrawal Scale172 [CWS] and the Clinical Institute Withdrawal 
Assessment for Alcohol Scale [CIWA]171).  If patients experience severe cannabis or alcohol 
withdrawal symptoms, research staff will link the patient with clinical support from their 
treatment team or other resources as necessary for appropriate medical treatment. 
 (6) Suicidality:  Suicidality is increased in patients with SCZ, especially those with substance 
use disorders. Since CLOZ is known to limit suicidality more than other antipsychotic 
medications, patients on CLOZ may be less likely than those on RISP to have suicidality.  
Nonetheless, all patients will be monitored with the Columbia Suicide Severity Rating Scale (C-
SSRS) weekly.  Interviewers will consult immediately with the study psychiatrist if the C-SSRS 
indicates any evidence of suicidal ideation or suicide attempts.  Should the patient be deemed 
to be at risk, the study team will ensure appropriate emergency care, and if necessary, 
termination from study medication, use of a different medication, and/or hospitalization. 
(7) Genetic testing:  The major risks of genetic testing are related to maintaining confidentiality 
of results. The confidentiality of genetic data will be closely guarded.  The DNA samples will be 
securely stored in a locked freezer, and labeled with study number and date of sample.  
Participants will be assigned a study code number used to cross-link participant data sets.  No 
identifying data will be contained in these data sets.  Study records will be maintained in a 
locked file cabinet with controlled access.  Following the Dartmouth guidelines for protection of 


V 01.15.2016 
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human subjects, we will not inform participants of the results of the genetic testing used here, 
because they do not, at this time, have any clinical relevance and would potentially be 
confusing to participants. 
(8) Venipuncture: There is risk of discomfort and a slight risk of infection due to venipunctures. 
Standard high quality clinical practice will be used to draw blood in order to avoid discomfort 
and infection. 
(9) Risk to pregnant or nursing women: Since the risk of these medications to developing 
fetuses and pregnant women is unknown, we will exclude women who are pregnant, nursing, 
or who wish to become pregnant from study participation.  Female participants will be tested 
for pregnancy at screening, 6 weeks and 12 weeks, and they will be required to use birth 
control. Should pregnancy occur during the study, the patient will be discontinued from the 
study, and will be referred to appropriate aftercare treatment.  It should be noted that there are 
currently no data suggesting that either CLOZ or RISP is teratogenic for animals or humans.  
Managing risks 
We will take a variety of precautions to protect participants from these risks. The first step in 
protecting against risks is informed consent.  As described above, only patients who give 
informed consent will participate in any study procedure.  Moreover, the informed consent 
process will continue throughout the study.   
The PI and the DSMB will monitor safety of participants throughout the study.  Confidentiality 
will be maintained with the standard procedures described below.  A participant’s clinical status 
will be monitored throughout the protocol and care will be coordinated with each person’s 
clinical treatment team.  Patients may discontinue a study procedure at any time if they are 
uncomfortable or the study procedures appear to be causing exacerbation of illness.   
 Potential Benefits:  Participants may not benefit from participation in the study.  Participants 
with SCZ and CUD may benefit from the treatment with CLOZ by experiencing a reduction in 
cannabis use.  All study participants will be monitored closely, which may be beneficial to 
them. 
Risk/Benefit Analysis: Although the study medications have multiple potential risks, they 
are both effective treatments for psychosis.  All study patients will have diagnoses of 
schizophrenia and will already be taking an antipsychotic medication for it.  Thus, they are 
already being exposed to potential medication side effects.  Since there are preliminary 
data suggesting that clozapine may be effective in decreasing cannabis use in this 
population, those who receive CLOZ may benefit from the effect of the drug, although the 


V 01.15.2016 
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risks related to clozapine are somewhat higher than for risperidone.  However, benefits of 
participation in the study may occur whether or not a subject receives clozapine within the 
study.  In addition, significant knowledge will likely accrue from the study, which may be of 
help in the treatment of the patients recruited or other patients with similar problems.  
Though the medications and treatment offered in this study are available for use outside 
the study, involvement in the study offers benefits not otherwise available.  Clients with 
schizophrenia and cannabis use disorder may not have access to the following:  the 
opportunity to have a comprehensive assessment done, to meet with a doctor weekly for 
13-14 weeks (usual community mental health care involves doctor visits once in 3 months), 
and to have an accurate longitudinal assessment of symptoms and substance use with 
standardized measures to understand whether medication and treatment are helping or not 
(standard care doesn’t involve the multiple standardized measures used in this study).   At 
the end of the study, the client will have experienced a comprehensive assessment of 
symptoms and function, and of the response of symptoms, function, and substance use to 
medication.  These assessments are more comprehensive than would have been possible 
without involvement in the study protocol. 
Study participants will be carefully informed of all potential risks and will not participate if they 
have concerns about these risks.  We will monitor study participants carefully and will address 
all side effects immediately as they occur.  The other potential risks of study participation are 
minimal.   We will use our standard procedures to maintain the highest level of confidentiality 
and to minimize all potential risks related to the study.  Overall we believe the potential benefits 
outweigh the risks. 
 
10. Adequacy of Resources to Protect Subjects: 
 
Describe availability of psychological, social, or medical services, which include counseling or 
social support services, that may be required as a consequence of research participation.  
 
All study participants will be engaged in treatment and have access to their usual case 
manager and psychiatrist as well as psychological and medical services available in their 
communities. The medications being prescribed in this study have been FDA-approved and 
typically prescribed for many years. While in the study, participants will be monitored very 
closely.  If need for increased assessment or treatment arises, the study doctor will access any 
and all services needed, including inpatient hospitalization.     
 
Describe psychological, social, or medical monitoring, ancillary care, equipment needed to 


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protect participants (e.g. close proximity to resuscitation equipment or a plan for monitoring of 
emotional state during study procedures).  
 
Investigators and site personnel, trained and experienced at conducting assessments in 
persons with schizophrenia, will assess for deteriorating mental status and/or suicidal ideation.  
Participants will meet with a study physician at each visit and have routine monitoring of 
psychiatric symptoms.  As described above staff have a number of means of addressing 
psychiatric symptoms.  Staff will also monitor participants through schedule weekly 
assessments for changes in vital signs, withdrawal from alcohol, and medication side effects.  
Changes in status will be referred to the treating study physician for follow-up.  Each site will 
have access to medical care in the unlikely event that a participant should develop severe side 
effects. 
 
Describe other resources needed for the protection of subjects in the conduct of this research 
(e.g. language translation services). 
None 
 
11. Pregnant Women:
Are pregnant women eligible for enrollment into this study?  
 Yes   
 No 
 
Although women of childbearing capacity, pregnant women, and nursing women who have 
SCZ and co-occurring CUD can benefit from treatment with RISP and CLOZ, the risks for 
pregnant or nursing mothers, and for fetuses and nursing babies are not clear.  Thus, pregnant 
and nursing mothers will not be included in the study.  Women with childbearing capacity will 
be required to use birth control and pregnancy tests will be conducted at baseline, week 6, and 
week 12 (cost covered by the study).  
 
 
12. Fetuses and Neonates:   
Are fetuses and neonates participants in the research?    
 Yes   
 No  
 
 
13. Women of Child-Bearing Capability  
Are women of child-bearing capability eligible for enrollment into this study?   
 Yes   
 No 
 
Although women of childbearing capacity who have SCZ and co-occurring CUD can benefit 
from treatment with RISP and CLOZ, the risks for pregnant or nursing mothers, and for fetuses 
and nursing babies are not clear.  Women with childbearing capacity will be required to use 


V 01.15.2016
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birth control and pregnancy tests will be conducted at baseline, week 6, and week 12 (cost 
covered by the study).      
 
 
14.  Individuals With Impaired Decision-Making Capacity:   
Will participants potentially lacking capacity to provide informed consent be eligible to enroll in 
this study?  
 Yes   
 No 
 
Is it likely study participants may lose their capacity to provide informed consent during the 
conduct of the study? 
 Yes   
 No 
 
If yes to a or b, respond to Research Involving Individuals with Impaired Decision-Making 
Capacity:  Attachment G    
 
 
15.  Recruitment:   
 
Individuals who are interested in learning about the study will be invited to meet with the study 
coordinator to review the consent and their possible eligibility.  They will be given information 
about the protocol as well as the opportunity to ask questions.  Because these individuals are 
often coming in for a special appointment to meet with study staff, they will be compensated 
with a $25 voucher for attending this session.  
 
16.  Consent Process:   
 
Our group has a procedure for the consent of participants into medication studies. It allows for 
only physicians and ARNPs to consent participants to be in studies.  Other staff may present a 
consent form to participants and review it with them, but a physician or ARNP must meet with 
the person (face-to-face or via telephone) to answer questions, and assess understanding and 
voluntariness prior to the participant signing the consent form. The physician or ARNP will also 
assess the competency to consent of each potential participant.  If an individual's capacity to 
consent is in doubt and the person does not have a guardian, the consent process will stop.  
The physician or ARNP will consult with the individual's primary psychiatrist.  If in the opinion of 
the psychiatrist, the person cannot consent and the person lacks a guardian, the person will 
not be recruited.  If the treating psychiatrist believes that the diminished capacity is more of a 
transitory state, then the consent process will be tried again on another day. Potential 
participants are encouraged to read the consent form and ask questions.  They are further 
encouraged to solicit input from significant others and/or care providers, if appropriate. To 
minimize coercion, the consent form has language that clearly spells out that participation in 


V 01.15.2016
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the study is voluntary and refusal to participate will not affect a person's health/mental health 
care.   
Because we do not have foreign language version of all of the assessments, we do not 
anticipate consenting persons who do not speak English.  We do not intend to recruit persons 
who are illiterate, but if illiteracy is a problem, our group follows the Dartmouth Committee for 
the Protection of Human Subjects procedure for consenting persons who cannot read or 
cannot read well.  Finally, our group makes a concerted effort to make the language in consent 
forms understandable to participants. 
 
17.  Privacy and Confidentiality:   
 
From the moment that a subject is approached to participate in the study, every effort to 
protect his/her confidentiality will be maintained. To minimize risk of divulging confidential 
information regarding substance use or other illegal activities as well as other study 
information, strict attention to confidentiality will be maintained throughout every aspect of this 
research with standard policies and procedures.  Unless contraindicated by recent 
interpretations of the governing law, a Certificate of Confidentiality (provided by NIDA) will be 
obtained.  All members of the research team, including investigators and research staff, will 
follow the procedures to protect confidentiality adhered to by research groups at Dartmouth.   
Each patient will be assigned a unique identification number.  The list of subject names and 
identification numbers will be kept separate from the database.  This list will be maintained in a 
locked file cabinet. All hard copies of research records will be kept in separate locked files.  
Access to the computerized data system is carefully protected by a secured password entry 
system. Ratings done by video conference will be conducted using a secure system (e.g. 
WebEx)  Subjects will be made aware of the various parties who will have access to their data 
in the informed consent document, including research personnel, IRBs and the DSMB. Access 
to participants' data will be restricted to project investigators on a need to know basis. Patient 
information, if reported, will be reported as group data or anonymously in case reports.  No 
patients will be individually identified.  
18.  Responsibility for costs of injury or illness related to research: 
Will the sponsor or other funding agency be responsible for costs of injury or illness related to 
the research?    
 Yes   
 No 
 
NIDA funding is unable to bear the cost of a hospitalization.  If a participant requires 
hospitalization, it will be billed to their insurance.


V 01.15.2016
page 26 of 42
 
19. Participant Remuneration: 
 
Participants will receive a $50 gift card for each of the 14 scheduled research visits listed in 
Appendix II (14 x $50= $700). Participants will also receive $5 cash each week if they return 
their medication packs to monitor medication compliance (12 X $5 = $60).  This is a total of 
$760. 
 
In addition, participants will "win" between $15-$20 for completing the Rewards 
Responsiveness Task.  Because many vendors only provide gift cards in $5 increments, the 
first $15 at each session will be paid in the form of a gift card and the remainder in cash.  Over 
the three sessions, this would not total more than $50.  We do not state the exact amount in 
the consent because it invalidates the testing.   
 
Individuals who attend appointments to learn about the study will be compensated with a $25 
voucher for their time and travel (see p. 33 for details.) 
 
Finally, if additional in-clinic visits are required (e.g. due to switching medications to be eligible 
for the study or post-study blood tests conducted by the research team), then participants will 
receive a $25 gift card for these visits. 
 
20. Use of Drug or Biological Agent:   
List the drugs and biologic agents to be used in this study: 
 
The drugs used in this study are clozapine and risperidone.  The FDA has determined that an 
IND is not required for this study.  Dartmouth will provide a copy of the FDA’s determination to 
any site requiring this.   
 
21. Conflict of Interest:   
  No:  The Principal Investigator or other key personnel do not have any financial interests listed in 
a. - g. above. 
  Yes:  The Principal Investigator or other key personnel do have financial interests listed in items a. - 
g. above. 
Only if you have answered yes to the question above about study-specific financial interests for a 
member of the research team, please provide the following additional information. 
Name of each individual with a listed financial interest:  
 
 
 
 
 


V 01.15.2016
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Attachment C 
Genetic Research  
 
For research studies involving genetic testing the CPHS describes below two categories of studies to 
assist its further review.  The researcher should determine if the research falls into category A or B as 
described below. If the research falls into category A. indicate by checking below and add comments as 
appropriate to this research project. 
If the research falls into category B. please respond to questions that follow.  
 
Respond to A or B: 
 
 A. The study is looking for an association between a genotype or a biomarker and a specific disease 
or condition, but at this point it is not clear if the genetic marker has predictive value. The uncertainty 
regarding the predictive value of the genetic marker is such that studies in this category will not involve 
referral of participants to genetic counseling. 
 
Comment: 
 
()'!,!!!!$,*()$#)$-%!$',)')+!+!#$).%".#).
)$((*)(,)"$()! !.)$'(%$#)$,)'(###(*(

+#)()($),$*!#"%$')#)+#)$!)$-!*
'$")')"#)#.%)#)#,$"(#$)! !.)$)+	$!!$,#)
')"$*)*!#($'%'$))$#$*"#(*)(,,!!#$)#$'"%')%#)($)
'(*!)($)#))()#*('*().$#$)))()"+#.!#!
'!+##,$*!%$)#)!!.$#*(#)$%')%#)(,!!!($( #$'#
-)')*$!$$)$',#,)%'"(($##'$/#$'%$((!(*(&*#)
#))()# 
 
 
 
B. The study is based on the premise that a link between a genotype or a biomarker and a specific 
disease or condition is clinically useful in predicting the development of that specific disease or 
condition.  
 
 
 
 


V 01.15.2016
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Attachment G 
Research Involving Individuals With Impaired Decision-Making Capacity  
 
 
Please indicate the option(s) requested to allow for consent if a subject is incompetent to provide 
consent:    
Durable power of attorney for health care (DPAHC) 
 YES 
NO  
Court appointed legal guardian 
 
 
 
 YES 
NO 
Next-of-kin.   
 
 
 
 
 
 YES 
NO 
Even with the permission of a DPAHC, or court appointed legal guardian, the federal regulations will 
not permit a subject who lacks capacity to give informed consent to participate in a research study that 
offers little chance of DIRECT BENEFIT to the research subject over what they could receive outside 
the research setting and involves a meaningful increase in the risk of harm or discomfort, regardless of 
the potential gain to future subjects or society in general.  
Please complete a) and b): 
a) Does participating in this study offer the subject a chance of direct benefit over what they could 
receive outside the research setting? 
 
 
While both medications are FDA approved for the treatment of schizophrenia and 
available to prospective study participants, the level of care offered in this study (e.g. 
weekly physician visits, level of symptom and medical assessment) is not possible in 
standard care. 
 
b) Is there an increase in the risk of harm or discomfort for the subject over what they would 
experience outside the research setting?
 
 
$$)$)(")$#(''($#!)')"#)($')(%$%*!)$#$%)#)(
#.)#)'('$+!((#()"!'( ()$%')%#)(
*().$($#$)(")$#(#%*'!.)')"#)())#).$*!
#$)))(!+!$"$#)$'#$#!.#'(#'( ()*$'()'((*)$)
!+!$(((("#)(#')')#,)($'#()#'' 
 
 
 
 
 
 
  
 
 
 
 
 
 
Clozaril for Cannabis Use Disorder in Schizophrenia 


V 01.15.2016 
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GLOSSARY OF ACRONYMS 
 
AIMS = Abnormal Involuntary Movements Scale 
AUS = alcohol use disorder 
BAS = Barnes Akathisia Scale  
BPRS = Brief Psychiatric Rating Scale  
BVMT = Brief Visuospatial Memory Test 
CBC = complete blood count 
CGI = Clinical Global Inventory 
CIWA = Clinical Institute Withdrawal Assessment for Alcohol Scale  
CLOZ = clozapine 
COMT = catechol-o-methyl transferase 
CPT IP = Continuous Performance Test – Identical Pairs 
C-SSRS = Columbia Suicide Severity Rating Scale  
CUD = cannabis use disorder 
CWS = Cannabis Withdrawal Scale 
DA = dopamine 
DMI = desipramine 
DSM-IV TR  
ECA = Epidemiologic Catchment Area 
EKG = electrocardiogram 
ES = effect size 
LC/MS/MS = liquid chromatography/mass spectrometry 
LRE = longitudinal random effects 
MAG = medication adjustment group 
NE = norepinephrine 
NIAAA = National Institute on Alcohol Abuse and Alcoholism 
NIDA = National Institute on Drug Abuse 
NP = neuropsychological 
PORT = Patient Outcomes Research Team 
QLI = Quality of Life interview 
QLS = Quality of Life scale 
RISP = risperidone 
RR = reward responsiveness 
S-A = Simpson-Angus Scale 
SANS = Schedule for the Assessment of Negative Symptoms 
SCID = Structured Clinical Interview for DSM-IV 
SCZ = schizophrenia 
SUD = substance use disorder 
TLFB = Timeline Followback 
TSR = Treatment Services Review  
WRAT-4 = Wide Range Achievement Test Revision 4, Word Reading Subtest 
 
 


V 01.15.2016 
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