Optimizing Response in Psychosis Study

The goal of the proposed pilot study is to investigate the feasibility and efficacy of the
long-acting injectable form of the second generation antipsychotic, risperidone, for the
treatment of first episode patients who fail to respond to 12 weeks of treatment with an oral
antipsychotic. The rationale for using this long-acting medication is that it eliminates
covert non-adherence, which may be a factor in poor response. In addition, pharmacokinetic
and pharmacodynamic differences between injectable and oral formulations may result in
differences in treatment response favoring the injectable form. Subjects who have not
responded sufficiently to treatment with an antipsychotic will be approached for the proposed
long-acting risperidone trial. Risperidone treatment will be open label with titration based
upon individual response (within FDA approved dose ranges). Treatment will begin with a phase
of supplementation with oral risperidone. Subjects will stop their previous antipsychotic,
start 2 mg of oral risperidone per day for one day and then increase the dose to 4 mg per
day. Subjects who tolerate one week of oral risperidone will then begin injections of 25 mg
long-acting risperidone every 2 weeks for a total of 12 weeks. If clinically indicated, the
dose may be increased up to a maximum of 50 mg as per FDA guidelines.

Inclusion Criteria:

- Current DSM-IV-defined diagnosis of schizophrenia, schizophreniform disorder,
schizoaffective disorder, or psychotic disorder NOS as assessed using the Structured
Clinical Interview for Axis I DSM-IV Disorders (SCID-I/P) (First et al, 1998)

- Is in the first episode of illness. First episode is defined as having had 6 months or
less of lifetime treatment with an antipsychotic.

- Has not responded sufficiently to treatment with an antipsychotic. Lack of response is
defined as a rating at study entry of 4 (moderate) or more on at least one of the
following BPRS-A items: conceptual disorganization, grandiosity, hallucinatory
behavior, unusual thought content.

- Continuous antipsychotic treatment at the time of study entry of a minimum of 12 weeks
with the same antipsychotic agent.

- Antipsychotic dosing at some point during the 12 weeks must have reached a sufficient
dose for antipsychotic response (e.g. patients who received only low dose quetiapine
for insomnia or anxiety would not qualify). Sufficient dose for second generation
antipsychotics is defined as a minimum dose of risperidone 3 mg/day, olanzapine 10
mg/day, quetiapine 500 mg/day, ziprasidone 100 mg/day or aripiprazole 15 mg/day.
Sufficient dose for first generation antipsychotics is defined as 3 mg/day of
haloperidol or its equivalent for other first generation agents.

- Aged 15 to 40.

- If age 18 or older, competent and willing to sign informed consent.

- If under age 18, parent or guardian consent and subject assent.

- For women, a negative urine pregnancy test and agreement to use a medically accepted
method of birth control.

Exclusion criteria:

- Meets DSM-IV criteria for a current substance-induced psychotic disorder, a psychotic
disorder due to a general medical condition, delusional disorder, brief psychotic
disorder, shared psychotic disorder, or a mood disorder (major depression or bipolar)
with psychotic features.

- Persistence of psychotic symptoms due to nonadherence to antipsychotic medication.

- Medical contraindications to treatment with long-acting injectable risperidone.

- Serious neurological or endocrine disorder or medical condition /treatment known to
affect the brain.

- A medical condition requiring medication with psychotropic effects.

- Clinical assessment that trial participation is contraindicated due to risk for
homicidal or suicidal behavior.

- A diagnosis of diabetes (fasting glucose > 126 mg/dl).

- Requires with antidepressant or mood stabilizing medication.

- Previous treatment with a long acting formulation of an antipsychotic