Effects of Risperdal Consta on Ability to Benefit From Social Skills Training in Schizophrenia

The study will be conducted at the University of Illinois at Chicago and New York
Presbyterian Hospital-Westchester Division. Patients with schizophrenia or schizoaffective
disorder who are considered by their clinicians to not be clinically stable, or to be stable
but still symptomatic, will be referred to the study. After obtaining informed consent,
patients will be randomized either to the Risperdal Consta or control conditions. Patients
in the control condition will remain on their oral antipsychotic medication for the duration
of the study (note - patients currently taking oral risperidone will not be eligible for the
study). Patients randomized to the Consta condition will take oral risperidone for 3 days,
and if there are no adverse effects, they will begin receiving injections of Consta every 2
weeks over the next 6 months. During the first month, they will remain on oral risperidone,
which will be tapered by the end of the month along with other antipsychotic medications
other than Consta. At baseline, and every 4 weeks for 6 months, all patients will complete a
computerized cognitive testing battery (CogTest), and be interviewed about social
functioning and symptomatology. During months 4-6 of study participation, all patients will
participate in a social skills group, the UCLA Basic Conversation Skills Module. Before and
after this group, patients will be interviewed and participate in role-play based
assessments regarding skills to be taught in the group. Patients will also receive physical
exams, including and ECG, at baseline, and be monitored for side effects and adverse events
every 2 weeks. The hypothesis driving this study is that patients in the Consta group will
demonstrate greater improvement in verbal learning, skill acquisition in the training group,
and improved social functioning, over the course of the 6 months. This hypothesis is based
on prior data demonstrating that oral risperidone improves verbal memory, which is a
mediator of skill acquisition in structured skills training groups. If this hypothesis is
supported, it would be an important demonstration that a novel medication preparation
(injectable Risperdal Consta) can, when combined with psychiatric rehabilitation, improve
functional outcomes for patients participating in rehabilitation.

Efficacy Measures:

1. The primary efficacy measure for this study will be the Micro-Module Learning Tests
(MMLT) (Silverstein et al., in press). This is a set of 7 psychometrically equivalent
tests that assess responsiveness to the key components of skills training. Each test
has 3 parts: 1) a verbal learning component wherein the patient is read material from
an actual skills training group and then asked questions about the material; 2) a
modeling component in which the patient views a model performing a specific behavior on
a videotape, and is then asked questions about what was viewed; and 3) a role-play
component in which the patient is asked to demonstrate, via a role-play, the behavior
that the model demonstrated in the prior section. The MMLT is a dynamic assessment
measure in that, in addition to measuring what people can recall/perform after an
initial presentation of information, it allows for a determination of learning
potential after repeated exposure to the information. With the MMLT, each time a
question is initially answered incorrectly, a briefer version of the material, that
highlights the most relevant information is presented. If an incorrect answer is given
at this point, an even more focused version of the item is presented. With this scoring
system, responsiveness to skills training as it occurs in the real world (where
repetition of material is built into the teaching method) can be assessed more
accurately than when using a static assessment (where information is only presented
once).

2. A second primary efficacy measure will be the Comprehensive Module Test for the Basic
Conversation Skills Module. This measure is administered before and after the group.

3. A secondary efficacy measure is the CogTest computerized cognitive battery. This
battery was developed by Tonmoy Sharma, M.D. and colleagues, and has been used with
over 2000 schizophrenia patients in studies of risperidone or Consta to date.

4. Another secondary efficacy measure is the Social Functioning Scale (SFS) (Birchwood et
al., 1990). This is a 74 item scale that is rated by the patient. The SFS has seven
subscales: 1) social engagement/withdrawal; 2) interpersonal communication; 3)
independence-performance of activities of daily living; 4) independence-competence to
perform activities of daily living; 5) frequency of engagement in recreational
activities; 6) frequency of participation in social activities; and 7) employment.

5. A third secondary efficacy measure will be the observational measure of attentiveness
in groups that was developed as part of the PI’s current NIMH grant on cognitive
rehabilitation in schizophrenia. This measure will allow us to determine: 1) if
Risperdal Consta is improving a real-world measure of attention; and 2) whether there
are any relationships between skill acquisition, medication, and attention.

6. The final efficacy measure will be the Positive and Negative Syndrome Scale, which will
be used to measure symptoms.

Adverse Events: Side effects and adverse events will be assessed using a semi-structured
interview given by a research nurse or psychiatrist. There are 40 specific side effects in 6
categories (general, neurological, cardiovascular, autonomic, urologic, muscular skeletal).
Adverse events will be rated on an intensity scale of 0 to 4 and a relationship to
medication of 0 to 5. Side effects will be counted as adverse events for scores of 3 or 4 on
intensity (moderate or severe) and scores of 3-5 for relationship (possible to definite).
These adverse events will then be aggregated into one of the 6 groups for analysis across
groups.

Serious adverse events will include those that require medical intervention such as
additional monitoring by the subject’s primary physician or medical hospitalization. All
significant adverse events (such as those listed above or any side effect with an intensity
level of 4) will be reviewed with the treating psychiatrist and the independent medical
reviewers. Each site will have two independent medical reviewers (one internist, one
psychiatrist) to examine any serious or significant adverse events and determine if the
subject should be withdrawn from the study. The two reviewers will not be directly connected
to the research group and will not be investigators in the protocol.

In addition to the assessment of side effects, other scales will be used to measure side
effects commonly associated with antipsychotic medications. Each month, a blinded research
assistant will perform an Abnormal Involuntary Movement Scale (AIMS, to assess for tardive
dyskinesia), Barnes Akathisia Scale, and Simpson-Angus Scale (to assess for dystonia and
parkinsonian side effects). Movement disorders can affect the ability of patients to perform
on cognitive tests and in skills training groups. Patients with akathisia often have reduced
attention and reduced ability to concentrate in groups. Patients with parkinsonian symptoms
can be slower on manual tasks and may have slower mental abilities.

Laboratory Assessment (to be done at baseline and last month of participation):

1. Complete Blood Count (CBC) to determine major hematological indices as some
antipsychotic medications affect the white count.

2. Complete Chemistries including electrolytes, BUN, creatinine, liver function tests, and
glucose. Some antipsychotic medications may increase the risk of diabetes and some
medications may cause an increase in liver enzymes.

3. Lipid profile including cholesterol, triglycerides, LDL, and HDL. Some antipsychotic
medications cause an increase in lipids particularly triglycerides

4. Prolactin: some antipsychotics may increase prolactin leading to menstrual
irregularities, sexual dysfunction, and possibly osteoporosis. Months 0, 3, 6, only.

5. Thyroid stimulating hormone (TSH): thyroid functioning can affect cognition. Patients
with a history of hypothyroidism will be allowed in the study if they are on stable
dose of replacement and the TSH is in the normal range. Months 0, 3, 6, only.

6. Glycohemoglobin (HgA1c): to measure the overall level of glucose over the prior 2-3
months. Months 0, 3, 6, only.

Laboratory Assessment (monthly)

1. For women of childbearing potential, urine screen for pregnancy.

Inclusion Criteria:

1. Schizophrenia or schizoaffective disorder

2. Ages 18-55

3. Ability to give informed consent

4. Good general physical health or stable chronic medical conditions

5. Ability to be on a single antipsychotic medication

6. History of inattentiveness in psychosocial treatment settings

7. Poor social skills

8. Must be receiving a single antipsychotic medication

9. Must be clinically stable – defined by the absence of prominent delusions,
hallucinations, disorganized speech, or grossly disorganized or catatonic behavior.
However, there must also be continuing evidence of impairment, as indicated by the
presence of negative symptoms or two or more symptoms of schizophrenia listed in
Criterion A of the DSM-IV, in attenuated form (e.g., odd beliefs, unusual perceptual
experiences).

Exclusion Criteria:

1. Inability to give informed consent

2. Substance dependency in the past 6 months

3. Diagnosis of dementia

4. Significant head injury or other brain injury leading to cognitive impairment

5. Mental retardation (premorbid IQ < 65)

6. Pregnant or nursing

7. Allergy or other significant adverse reaction to risperidone

8. Contraindication to Risperdal Consta as only antipsychotic

9. Currently taking risperidone