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Low Cerebrospinal Fluid Homovanillic Acid-5-Hydroxyindoleacetic Acid Ratio Predicts Clozapine Efficacy: A Replication

S. Craig Risch, MD; Richard R. J. Lewine, PhD
Arch Gen Psychiatry. 1993;50(8):670. doi:10.1001/archpsyc.1993.01820200088011.
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Pickar et al1 reported the superior efficacy of clozapine over fluphenazine and placebo in eight (38%) of 21 neuroleptic treatment—resistant or —intolerant schizophrenic patients. They noted that this was consistent with the 30% clozapine superiority in the neuroleptic nonresponders reported by Kane et al.2

The superior clozapine response of the patients of Pickar et al was associated with a relatively low ratio of concentrations of cerebrospinal fluid (CSF) homovanillic acid (HVA) to 5-hydroxyindoleacetic acid (5-HIAA) (CSF HVA-5-HIAA ratio) compared with the CSF HVA-5H1AA ratio in patients having an equivalent or superior response to fluphenazine. They found that a low CSF HVA—5-HIAA ratio at any of three time points—(1) placebo washout, (2) during fluphenazine therapy, and/or (3) during clozapine therapy—was associated with superior clozapine efficacy.

We also have been prospectively studying the same problem. Ten patients meeting Research Diagnostic Criteria for schizophrenia received lumbar punctures in a medication-free


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