Inpatient Evaluation of Adults With Schizophrenia

Objectives:

Schizophrenia and related psychoses are chronic brain disorders whose prognosis is often poor
and whose pathophysiology remains obscure. Neuroimaging technologies such as PET (positron
emission tomography), fMRI (functional magnetic resonance imaging), DTI (diffusion tensor
imaging) and MRSI (magnetic resonance spectroscopic imaging) offer opportunities to elucidate
the pathophysiology by studying brain function in living research subjects. The use of these
techniques to study psychotic disorders is severely limited, however, by a critical
methodological confound: antipsychotic treatment. The purpose of this protocol is to admit
research subjects with schizophrenia and other related disorders to the Clinical Center,
carefully evaluate their neuropsychiatric status, and discontinue psychotropic medications
for a brief period so research subjects can be studied without the confound of antipsychotic
treatment.

Study Population:

700 participants

The study will include research subjects with schizophrenia.

Study Design:

There are several phases to this protocol. The first phase is the Screening Evaluation and
Stabilization Phase ( Standard part of the protocol) and includes gathering historical data,
structured diagnostic interviews, general physical and laboratory assessments, basic
physiological monitoring, neuropsychological testing, limited collection of blood and urine
samples, and serial behavioral ratings. In the second phase (Coded Medication Phase or Coded
part of the protocol), research subjects will receive blinded compounds that will contain
inactive placebo or active antipsychotic administered in a crossover fashion. Patients and
unit clinical nursing staff evaluating and caring for the patient will be blind to arm
status. Each arm normally lasts 4 to 6 weeks. The total duration of this phase is 8 to 12
weeks. During the Coded Medication Phase, research subjects are enrolled in a series of
neuroimaging and other approved studies designed to elucidate the neurobiology of these
disorders. These include studies using neuropsychological testing, MEG, PET, fMRI, DTI, and
MRSI. The antipsychotic free period is essential to distinguish the effects of illness versus
medication.

Outcome Measures:

Parameters under investigation include traits that are candidate phenotypes for genetic
studies and state-dependent aspects of brain function. The combined use of many neuroimaging
modalities will allow us to look at the functional relationship between a variety of brain
abnormalities hypothesized to play a role in schizophrenia. These include hippocampal
neurochemical abnormalities, deficits in prefrontal cortical activation, and dysregulation of
subcortical dopamine in a single research subject.

- INCLUSION CRITERIA:

- Age 18 or older

- Male or female

- Diagnosis of Schizophrenia, Schizoaffective Disorder or Psychosis NOS. Subjects with
other neuropsychiatric disorders may also be admitted and participate in the protocol
if there is sufficient evidence to believe they have an underlying, undiagnosed
schizophrenia, schizoaffective disorder or psychosis NOS.

EXCLUSION CRITERIA:

- Currently treated with depot medications. Because of the long half-life of depot
medications such as paliperidone palmitate (Invega Sustenna), applicants to our
program will be excluded if they are currently receiving depot medications monthly.
However, applicants may decide to switch from depot to oral medications on their own,
in conjunction with their personal physician, before coming to the program. This is
not part of research and we do not participate in this decision. A sufficient washout
period based on the particular long-acting injectable medication s elimination
half-life will be required in order for prospective participants to be eligible. Most
such medications require a 6-month washout period, but some with shorter elimination
half-lives, such as risperidone powder (Risperdal Consta), only require 3 months.
Subjects may complete the last 3 months of washout in the inpatient unit while being
evaluated during the Screening Evaluation and Stabilization Phase.

- Major medical illness. Research subjects identified as having major medical problems
other than their primary neuropsychiatric disorder will be excluded from admission.

- Applicants judged to be unsuitable for medication free studies will also be excluded.
Possible reasons for exclusion include prior history of dangerousness to self or
others, particularly when off medication.

- Applicants who are pregnant are excluded from this study. Volunteers who are found to
be pregnant after testing will be terminated from study and referred to an OB-GYN for
follow up care.

- Infection with syphilis, hepatitis, or HIV.

- History of of any (excepting nicotine-related) DSM5-defined moderate to severe
substance use disorder (or DSM-IV-defined substance dependence).

- Cumulative lifetime history of any (excepting nicotine-related) DSM5-defined mild
substance use disorder (or any DSM-IV-defined substance abuse), either in excess of 5
years total or not in remission for at least 6 months.

- Lack of capacity to provide consent.

Exclusion Criteria for Previously Enrolled Research Subjects

- No longer satisfying the above inclusion criteria or meeting any of the above
exclusion criteria

- Inability to safely participate in planned research (e.g., development of acute
suicidal behavior during prior research participation)

- Unlikely to provide sufficient additional research data