D-Cycloserine Augmentation of Cognitive Behavioral Therapy for Delusions

This study consists of a placebo-controlled 12 week trial of DCS augmentation of once-weekly
CBT sessions in 60 schizophrenia subjects with antipsychotic-resistant delusions. In addition
to testing efficacy, this trial will characterize DCS effects in terms of time course and
persistence of response and will examine DCS effects on memory consolidation and cognitive
flexibility as possible mediators of DCS enhancement of CBT for delusions. This study will be
conducted by the Schizophrenia Research Group of the NYU Langone Medical Center at One Park
Avenue 8th Floor and the Psychiatry Outpatient Clinic of Bellevue Hospital located in New
York, NY.

Upon signing consent, patients will undergo screening procedures to assess eligibility. A
diagnosis of schizophrenia, schizoaffective disorder, or delusional disorder will be
determined by the Structured Clinical Interview for DSM IV (SCID) completed by a research
clinician using all available clinical data and will be confirmed by consensus diagnosis. A
comprehensive medical history and physical exam, including measurement of vital signs, will
be performed. A psychiatric history, including diagnosis, treatment history, current
medications, and substance use will also be performed. A research assistant will complete the
demographics and administer the Scale for Assessment of Positive Symptoms-Delusions (SAPS-D).

At screening only, a fasting blood sample will be obtained to perform routine laboratory
tests including electrolytes, BUN, creatinine, liver function tests, fasting glucose,
calcium, phosphate, magnesium, albumin and CBC with differential. Urinalysis will be
performed to identify unstable medical illness. A urine toxicology screen will be performed
and a urine pregnancy test will be done for women of child bearing potential.

Subjects who meet study eligibility criteria will complete the Logical Memory Test portion of
the Weschler Memory Scale-III (WMS-III) one week before the baseline visit.

The baseline visit will include the following assessments: SAPS-D, Psychotic Symptom Rating
Scales (PSYRATS), Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative
Symptoms (SANS), Calgary Depression Rating Scale (CDRS), Clinical Global Impression (CGI),
Heinrich's Quality of Life Scale (Heinrich's QOL), Peter's Delusion Inventory (PDI),
Birchwood Insight Scale (BIS), Drug and Alcohol Questionnaire (DAUQ), and the Pittsburg Sleep
Quality Index (PSQI) . At the baseline visit the following cognitive assessments will be
administered: the Logical Memory Test of the WMS-III, The Wisconsin Card Sort Test (WCST),
Verbal Fluency Test (VFT), and the MATRICS Consensus Cognitive Battery (MCCB).

The clinical battery of assessments including the PSYRATS, BPRS, SANS, CDRS, CGI, and
Heinrich's QOL will be performed on weeks 4, 8, 12, 24, and 36. The delusions section only of
the PSYRATS will be performed on weeks 2, 3, 6, and 10. The Logical Memory Test will be
administered on screening visit 2, baseline, week 3, and week 4. The Alternative Beliefs
Exercise will occur on weeks 3, 4, and 12. The WCST and VFT will be given to participants at
the baseline visit and week 12. Side effects will be assessed using the Systematic Assessment
for Treatment Emergent Events (SAFTEE)on weeks 3, 4, 8, and 12.

Beginning at week 1, participants will engage in hour long sessions of Cognitive Behavioral
Therapy for delusions. This treatment course will continue weekly from week 1 until week 12
(12 sessions).

For the first two sessions of CBT during weeks 1 and 2, both the experimental and the placebo
group will receive a 50 mg placebo pill by mouth one hour before CBT sessions. Starting week
2, the placebo and experimental groups will receive their respective drugs one hour before
CBT sessions from weeks 3-12 (50 mg placebo by mouth to placebo group, 50 mg D-cycloserine by
mouth to experimental group).

The primary outcome of interest in the study is the change in PSYRATS Delusions Subscale
total score compared to placebo from baseline to week 12. Secondary outcome measures include
changes as defined by a 20% reduction in PSYRATS Delusions Subscale total score from baseline
after 2 weeks of DCS treatment versus placebo as well changes as defined by maintenance of a
20% or greater reduction in the PSYRATS Delusions Subscale total score from baseline at a 3
and 6 month follow up as compared to placebo.

Inclusion Criteria:

- Age 18-68

- Diagnosis of schizophrenia, schizoaffective disorder, or delusional disorder

- Treated with any antipsychotic except clozapine for at least 8 weeks or antipsychotic
naive for lifetime

- Willing to participate in CBT

- Sufficient proficiency in English to complete assessments

- Score of at least 3 on the SAPS at two assessments, four weeks apart

Exclusion Criteria:

- Current treatment with clozapine

- SSRI treatment

- Active alcohol or other substance abuse within six weeks

- Unstable medical illness

- Pregnant or nursing

- Anemia

- Renal insufficiency