Pharmacologic and Clinical Testing of a D1 Agonist for Cognitive Enhancement in Neuropsychiatric Disorders

Schizophrenia (SCZ) manifests as positive symptoms, negative symptoms and cognitive
disturbances. To date, all of the available medications to treat schizophrenia bind
primarily to the dopamine-2 (D2) receptor in the brain, and are only effective at treating
the positive symptoms of schizophrenia. This is unfortunate given that negative and
cognitive symptoms account for most of the disability in schizophrenia.

Emerging research over the past several decades has suggested a potential role for the
dopamine-1 (D1) receptor in schizophrenia, as well as a role for D1 receptor stimulation in
improving cognitive deficits. DAR-0100A is a new medication that binds selectively to the D1
receptor. It has been found to be safe when given to individuals with schizophrenia, and
preliminary data suggests that it may be able to help with cognitive deficits.

The investigators propose to recruit individuals with schizophrenia who are symptomatically
stable and already taking medications to participate in this study. The investigators will
recruit 90 individuals with schizophrenia and randomize them to low and high doses of
DAR-0100A, as well as to placebo. Patients will stay in the hospital for several weeks and
receive up to 10 doses of DAR-0100A. The investigators will also test their cognition before
and after receiving DAR-0100A to see if DAR-0100A is helpful and perform MRI scans before
and after taking the medication to see which areas of the brain are activated when DAR-0100A
is administered. These tests will be very important because they will help the investigators
determine whether the D1 receptor is a good treatment target for schizophrenia and whether
more research and resources should be devoted to finding medications that target this
system.

Patients with schizophrenia will be free of other medical, psychiatric and neurological
disorders including alcohol and substance dependence, and will be able to understand the
nature of the study and to provide informed consent.

Inclusion Criteria:

- Males or females between 18 and 55 years old

- Fulfill Diagnostic and Statistical Manual, version 4 (DSM-IV) criteria schizophrenic
illness, schizophreniform or schizoaffective disorder

- A negative urine toxicology

- Capacity to understand the study and to give written informed consent

- Must be on a stable dose of risperidone, aripiprazole, lurasidone, iloperidone,
paliperidone, or haloperidol for at least 4 weeks if oral adn 2 cycles if depot.
Absence of any antipsychotic medications other than risperidone, aripiprazole, or
haloperidol for at least 4 weeks if oral or 2 cycles if depot prior to the study.
Mood stabilizers, benzodiazepines and antidepressants are allowed as long as the
drugs have not been changed for 4 weeks.

- Psychiatrically stable

Exclusion Criteria:

- Pregnancy or lactation, lack of effective birth control during the 15 days before the
initial day of the study and for the duration of the drug trial

- Presence or positive history of severe medical or neurological illness, or any
cardiovascular or liver disease

- Any current use of amphetamines, opiates, cocaine, sedative-hypnotics, cannabis, or
other psychoactive drugs (other than nicotine)

- Metal implants or paramagnetic objects contained within the body which may interfere
with MRI scan

- A history of substance dependence (other than nicotine or cannabis) or substance
abuse within the previous 6 months (other than nicotine)

- Any current use of anticholinergic or anticoagulant medications. Any current use of
any medications that can affect cognition or clotting other than occasional
nonsteroidal antiinflammatory drug (NSAID)

- Impaired intellectual functioning

- Orthostatic hypotension

- BP systolic BP <90 or > 140 or diastolic BP < 60 or > 90

- Antipsychotic polypharmacy within the previous four weeks.