Using D-cycloserine to Enhance the Benefits of Cognitive Behavioral Therapy for Schizophrenia

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