To characterize further the effects of D-cycloserine augmentation of antipsychotic treatment
on negative symptoms, performance on neurocognitive tasks, and on markers for glutamatergic,
dopaminergic and serotonergic function in serum and cerebrospinal fluid. To determine if
negative symptoms and cognitive function improve over time, if these improvements
meaningfully impact quality of life factors, if they correlate with markers of neuronal
function, and if subpopulations can be identified according to response.
Dysfunction of glutamatergic neuronal systems has recently been implicated in the
pathophysiology of schizophrenia based on the finding that non-competitive inhibitors of the
NMDA receptor can reproduce in normals the positive symptoms, negative symptoms, and
cognitive deficits of schizophrenia. Furthermore, glutamatergic dysfunction may alter
forebrain dopaminergic neuronal activity, a system central to the antipsychotic action of
typical neuroleptics. It is believed that enhancing NMDA receptor function by systemic
treatment with D-cycloserine, a partial agonist at the glycine modulatory site of the NMDA
receptor, will reduce symptoms in schizophrenia.
Sixty schizophrenic outpatients with prominent, primary negative symptoms are treated with
antipsychotic medication and are randomly assigned to D-cycloserine or placebo for a 6-month,
fixed-dose trial. The primary outcome measure is the total score on the Scale for Assessment
of Negative Symptoms (SANS). A neuropsychological battery, which emphasizes tests sensitive
to prefrontal cortical function, is administered. Blood is obtained at several time points
and CSF is obtained at Week 8 for assay of concentrations of D-cycloserine, glutamate, HVA,
and 5HIAA.