Efficacy Study of Quetiapine Plus Topiramate for Reducing Cannabis Consumption and Bipolar Mania

The purpose of this research study is to study the effects (both good and bad) of combining
medicines, called quetiapine and topiramate, for treating your symptoms, and other children
and adolescents' symptoms, of bipolar mania (an illness with periods of elation, excessive
excitement, irritability, high energy, racing thoughts, poor sleep, poor judgment, reckless
behavior). It is estimated that 1% of the population of adolescents in the United States has
bipolar disorder. The purpose of this research study is also to study the effects (both good
and bad) of combining the same two medicines, quetiapine and topiramate, for reducing your
use, and other children and adolescents' use, of cannabis (commonly referred to as "pot"). It
is estimated that 30.5% of adolescents in the United States have used cannabis at least once
in their lifetime. Additionally, the purpose of this research is to look at how bipolar
disorder and cannabis use effects brain chemicals and function.

Quetiapine (marketed under the brand name Seroquel) has been approved by the FDA since 1997
to help adults who suffer from schizophrenia (an illness of feeling, thought, perception and
behavior). On January 12, 2004, the FDA approved quetiapine for the treatment of bipolar
symptoms in adults. As of December 2009, Quetiapine has now been approved by the FDA for use
in adolescents (13-17 years of age) for the treatment of schizophrenia and for the treatment
of manic episodes associated with bipolar I disorder in children and adolescents (10-17 years
of age). Bipolar disorder is an illness characterized by recurrent mood swings including
mania (i.e., periods of elation, excessive excitement, irritability, high energy, racing
thoughts, poor sleep, poor judgment, reckless behavior) and clinical depression (i.e., a
depressed mood, loss of interest in activities and disruption of sleep, appetite and energy).
This study is being carried out to see if quetiapine is effective and safe for treatment of
children and adolescents who have the symptoms of bipolar mania. This study is also being
carried out to see if quetiapine, in combination with topiramate, will further reduce bipolar
mania and reduce cannabis use.

As of December 2, 2009, the US Food and Drug Administration (FDA) approved SEROQUEL
(quetiapine fumarate) tablets for the treatment of schizophrenia in adolescents (13-17 years
of age) as monotherapy, and for the acute treatment of manic episodes associated with bipolar
I disorder in children and adolescents (10-17 years of age), both as monotherapy and as an
adjunct to lithium or divalproex.

Topiramate (marketed under the brand name Topamax) is approved by the U.S. FDA for the
prevention of migraine headaches in adults. The FDA has also approved topiramate for epilepsy
(a seizure disorder) and for use as adjunctive therapy (meaning in combination with other
medicines) for partial onset seizures in adults. Topiramate is not approved by the FDA for
use in adults or for use in children and adolescents who have bipolar disorder. This study is
being done to see if topiramate, in combination with quetiapine, will reduce bipolar mania
and reduce cannabis use.

The FDA has declared research studies with MRI field strengths up to and including 8 Tesla (a
measure of field strength) as non-significant risk. This research study uses an MRI with a
field strength of 4 Tesla.

Inclusion/Exclusion Criteria Inclusion Criteria: To be included, all subjects must…

- have an authorized parent/legal guardian who understands the nature of the study and
who provides written informed consent if the study subject is younger than 18 years of
age. Additionally, each subject must provide assent to the study;

- be fluent in English;

- be 12 to 21 years of age, inclusive;

- be using a medically accepted means of contraception (i.e., oral contraceptives and
barrier methods (diaphragm or condom), medroxyprogesterone acetate injectable
suspension, abstinence) if female and of menarche. Oral contraceptives alone are not
acceptable means of contraception because concomitant use of topiramate and low
estrogen oral contraceptive pills may lead to oral contraceptive failure;

- have a diagnosis of bipolar I disorder in a current manic or mixed episode, in
addition to a cannabis use disorder (which includes abuse or dependence) within 28
days prior to screening, as determined by the WASH-U-KSADS;

- have an initial YMRS total score of >16 at screening and baselines;

- use cannabis a minimum of twice per week on average during the 28 days prior to
screening.

Exclusion Criteria: Subjects will not be eligible for participation if they…

- have a known history of mental retardation;

- are acutely intoxicated, and thus impaired;

- have manic or depressive symptoms resulting entirely from acute medical illness or
acute intoxication or withdrawal from drugs or alcohol, as determined by medical
evaluation and rapid symptom resolution;

- have clinically significant alcohol or other drug withdrawal symptoms, as determined
by vital signs, The Clinical Institute Withdrawal Assessment for Alcohol Scale -
Revised (CIWA-Ar)24, and physician interview;

- have any unstable medical or neurological illness as determined by a study physician;

- have laboratory abnormalities >3 times upper limits of established normal values;

- as females, have a positive serum (screening and week 16) or urine pregnancy test (at
baseline and weeks 1-16), are lactating, or are not practicing a reliable form of
birth control;

- have a history of nephrolithiasis, since topiramate has been associated with an
elevated risk of kidney stones;

- require concurrent treatment with mood stabilizers, anticonvulsants, or
antidepressants

- require concurrent treatment with carbonic anhydrase inhibitors.

- have significant suicidal ideation

- have been treated for a substance use disorder during 28 days prior to screening or
are court-ordered to treatment for substance use to ensure that, if we detect a change
in use with topiramate treatment, it is likely not due to these other confounding
factors that might influence substance use. Peer support groups are not considered
treatment for substance use. **Patients can be enrolled into the study that are
already enrolled in a court ordered substance treatment, for at least 1 month prior to
study enrollment, if they still meet the minimum cannabis use criterion.**

- have been diagnosed or treated for an eating disorder, to make sure any weight loss
does not contribute to an already underlying condition

- have a family history of glaucoma, since topiramate has been associated with an
elevated risk of glaucoma;

- have a history of non-response or hypersensitivity to quetiapine or topiramate;

- if scanning, have claustrophobia and/or contraindicated for magnetic resonance
scanning (i.e. intraocular metallic objects, braces, cochlear implants, pacemakers, or
other electrical, mechanical, or magnetically activated implants); and

- if scanning, have a history of significant head trauma (i.e. injury resulting in loss
of consciousness for greater than five minutes).