D-Cycloserine Augmentation of Cognitive Behavioral Therapy for Delusions

Study Overview
=================
Brief Summary
-----------------
This study is 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.

Detailed Description
-----------------
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 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 (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.

Official Title
-----------------
D-Cycloserine Augmentation of Cognitive Behavioral Therapy for Delusions

Conditions
-----------------
Schizophrenia, Schizoaffective Disorder, Delusional Disorder

Intervention / Treatment
-----------------
* Drug: D-Cycloserine
* Other: Placebo
* Behavioral: Cognitive Behavioral Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 68 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants receive a weekly dose of placebo by mouth one hour before Cognitive Behavioral Therapy (CBT) sessions from week 1-12 (12 visits). | Other: Placebo<br>* Participants will receive 12 weekly administrations of placebo by mouth 1 hour before CBT sessions, from weeks 1-12.<br>* Other names: Sugar pill;Behavioral: Cognitive Behavioral Therapy<br>* Participants will engage in a Cognitive Behavioral Therapy treatment plan designed for psychotic delusions. The program will consist of 12 one hour sessions, once weekly from study week 1-week 12.<br>* Other names: CBT;|
| Experimental: D-Cycloserine<br>Participants will receive a weekly dose of placebo by mouth one hour before Cognitive Behavioral Therapy (CBT) sessions from weeks 1-2 (2 visits), then a weekly 50 mg dose of D-Cycloserine by mouth one hour before CBT sessions from weeks 3-12 (10 visits). | Drug: D-Cycloserine<br>* Participants will receive 10 administrations of 50 mg of D-Cycloserine by mouth one hour before CBT sessions, weekly, in weeks 3-12.<br>* Other names: Seromycin;Behavioral: Cognitive Behavioral Therapy<br>* Participants will engage in a Cognitive Behavioral Therapy treatment plan designed for psychotic delusions. The program will consist of 12 one hour sessions, once weekly from study week 1-week 12.<br>* Other names: CBT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Psychotic Symptoms Rating Scale-Delusions (PSYRATS-D) | The change in the Delusions subscale total of the Psychotic Symptoms Rating Scale (PSYRATS) from Baseline to Week 12. The Delusions subscale is a composite score of 6 items each rated from 0-4 with 4 indicating more severe symptomology. The Delusions subscale has a possible range of 0-24. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Logical Memory Test-WMS-III | The Logical Memory Test of the Wechsler Memory Scale is a measure of verbal declarative memory. We are using it to evaluate memory consolidation by analyzing the number of thematic elements recalled after a delay of 7 days. Participants are read two different stories-one at Screening visit #2 and one at Baseline. They are asked to recall specific items and narrative themes after 7 days. Scores range from 0-7, 7 indicating perfect thematic recall, and 0 indicating no thematic elements were remembered and worse thematic recall. We hypothesize that improved memory consolidation (assessed with the Logical Memory Test) tested 7 days after the first dose of D-cycloserine will predict improvement of delusional scores measured by the PSYRATS-D. The reported outcome (change in Logical Memory Test score) was calculated by subtracting the screening visit 2 score from the baseline score for each participant. | 7 days after Baseline, and 7 days after Screening visit 2 | 
| Change in Alternate Beliefs Exercise (ABE) | The Alternate Belief Exercise is a measurement of cognitive flexibility. The scores range from 0-21, and a higher score indicates an increased number of alternative beliefs reported. This outcome measurement reports the change in number of alternate beliefs generated from weeks 3 to 4 as a predictor of improvement of the PSYRATS Delusions Subscale total score at 12 weeks. Thus a higher score in this outcome measurement indicates a greater number of alternative beliefs reported at week 4 as compared to week 3. This implies greater cognitive flexibility at week 4 as compared to week 3 directly after drug administration. | Week 3 to Week 4 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CBT, Schizophrenia, Delusions, D-Cycloserine