Brain Myelination Effects of Paliperidone Palmitate Versus Oral Risperidone in First Episode Schizophrenia

Schizophrenia is a severely disabling brain disorder. People with schizophrenia often
experience hallucinations, delusions, thought disorders, and movement disorders. Proper
treatment of first-episode schizophrenia may increase the chances of controlling disease
progression on a long-term basis. People experiencing their first episode of schizophrenia
are more responsive to treatment than those with chronic schizophrenia, but are also more
susceptible to adverse treatment side effects. Atypical antipsychotic medications have been
shown to produce fewer extrapyramidal side effects than older "typical" antipsychotics. Oral
risperidone is an atypical antipsychotic medication that is very commonly used to control
the symptoms of schizophrenia. Adherence to prescribed oral medication continues to be a
major clinical issue.

This study will determine the effectiveness of oral risperidone versus a long-acting
injectable alternative, paliperidone palmitate, in improving brain myelination and cognitive
function in people with first-episode schizophrenia. Impact on brain myelination and
clinical symptoms will be examined to test the hypothesis that brain myelination changes
underlie one of the mechanisms of action of antipsychotics. This study will assess
biomarkers at baseline (pre randomization), 6 months, and end of "parent study"
participation.

Participants in the "parent" open label study will be randomly assigned to receive either
orally administered risperidone or long-acting paliperidone palmitate administered via
injection. Participants assigned to oral risperidone will receive medication in doses that
are determined to be optimal by the study psychiatrist. Participants assigned to long-acting
risperidone will receive an injection of paliperidone palmitate once every 4 weeks. Dosages
will be adjusted as necessary to achieve the optimal dosage. Following 2 to 3 months to
achieve outpatient oral risperidone dosage stabilization, the randomized medication
conditions will begin and participants will be monitored for 1 year. Parent study visits
will occur once weekly throughout the study. They will include psychiatrist monitoring of
medication response and side effects; group therapy meetings focused on everyday living
skills; family education about schizophrenia; and individual meetings with a case manager
for counseling and evaluations of schizophrenia symptoms, work recovery, and social
functioning.

Inclusion Criteria (identical to clinical trial "parent study"):

- A first episode of a psychotic illness is occurring or did occur within the last 2
years;

- A diagnosis by DSM-IV of schizophrenia, schizoaffective disorder, depressed type, or
schizophreniform disorder; and

- Between 18 and 45 years of age.

Exclusion Criteria (identical to clinical trial "parent study"):

- Neurological disorder (e.g., epilepsy) or significant head injury;

- Significant alcohol or substance use disorder within the six months prior to the
first episode and evidence that substance abuse triggered the psychotic episode or
makes the schizophrenia diagnosis ambiguous;

- Mental retardation, i.e. premorbid IQ less than 70;

- Insufficient acculturation and fluency in the English language to avoid invalidating
research measures of thought, language, and speech disorder or of verbal abilities;

- Residence likely to be outside of commuting distance of the UCLA Aftercare Research
Program; or

- Patient has shown an inadequate response to an adequate previous trial of oral or
long-acting injectable risperidone, paliperidone, or paliperidone palmitate.