This study will examine whether pretreatment with D-cycloserine before cognitive behavioral therapy can reduce impairments still present in people with stable cases of schizophrenia as well as determine which traits make schizophrenics most likely to respond to D-cycloserine treatment.

Schizophrenia is a debilitating chronic condition that affects approximately 1 % of Americans, who experience symptoms such as hallucinations, delusions, and disorders of thought and movement. These symptoms are described as positive symptoms, because they are experienced in addition to what healthy individuals experience. Negative symptoms, which are reductions in normal functioning, and cognitive deficits, which are problems in thinking, also plague people with schizophrenia. The negative symptoms and cognitive deficits associated with schizophrenia are produced in otherwise healthy people by neurotransmitters inhibiting the glutamatergic N-methyl-d-aspartate NMDA receptors in the brain. This inhibition of NMDA receptors also causes intensification of psychotic symptoms in otherwise stabilized schizophrenic patients. The drug D-cycloserine partially excites NMDA receptors, and it has been used to help patients with anxiety disorders to overcome phobias while they are receiving cognitive behavioral therapy. This study will examine whether D-cycloserine can increase the cognitive flexibility of someone undergoing CBT and thereby enhance the therapy's ability to reduce a patient's belief in paranoid delusions, preoccupation with delusions, and related distress.

All participants will be screened to ensure proper diagnosis of schizophrenia without other conditions. Those who pass will be randomly assigned to receive either D-cycloserine first or a placebo pill first. One week after the screening, participants in the D-cycloserine group will be given the drug before a 1-hour session of simulated CBT treatment. Those in the placebo condition will receive a placebo pill before an identical session. Two weeks after the screening, both groups will be called back for another session of CBT, but the pills they receive will be switched. Those who received D-cycloserine the first week will receive placebo, and those who received placebo will receive D-cycloserine. The CBT sessions will attempt to increase cognitive flexibility in patients by asking them to provide alternate explanations for common situations. At screening, at the start of visits on the first and second weeks, and at a follow-up visit on the third week, participants will undergo a series of assessments, including interviews, computerized tests, and self-report measures. Belief in, preoccupation with, and distress caused by delusions, as well as degree of cognitive flexibility, will be assessed.

Inclusion Criteria:

• Meets DSM-IV criteria for schizophrenia, schizoaffective disorder, or schizophrenia, paranoid subtype, based on chart review, Structured Clinical Interview for DSM-IV, and consultation with the patient's clinicians
• Medicated with an antipsychotic agent other than clozapine at a stable dose for at least 6 weeks
• Scores at least 3, or "moderate," on the Scale for the Assessment of Positive Symptoms global delusion rating
• Paranoid or referential delusional content
• Never engaged in formal CBT psychotherapy in the past

Exclusion Criteria:

• Diagnosis of a comorbid Axis I disorder other than schizophrenia
• Active substance abuse or dependence within 6 months
• Significant suicidal ideation within 6 weeks
• Pregnant or nursing
• Unstable medical disorder
• impaired renal clearance (creatinine <60mg/dL/min)
• Suffering from dementia
• Suffering from seizure disorder

Three week period from baseline until week 2 of treatment.

No adverse events were reported following ingestion of study drug.

The cross-over design of this study produced results that are difficult to interpret due to a significant order effect. Larger and longer trials are needed to assess whether this treatment may benefit patients with medication resistant delusions.