Cerebrospinal Fluid and Plasma Monoamine Metabolites and Their Relation to Psychosis Implications for Regional Brain Dysfunction in Schizophrenia David Pickar, MD; Alan Breier, MD; John K. Hsiao, MD; Allen R. Doran, MD; Owen M. Wolkowitz, MD; Carlos N. Pato, MD; P. Eric Konicki, MD; William Z. Potter, MD, PhD \s=b\ The relationship between central (cerebrospinal fluid [CSF]) and peripheral (plasma) monoaminergic metabolites and psy- chotic symptoms was examined in 22 drug-free schizophrenic inpatients. The CSF homovanillic acid levels did not differ signifi- cantly between patients and normal controls (n = 33). The CSF homovanillic acid levels, however, were negatively correlated with ratings of psychosis and positive symptoms, and the CSF homovanillic acid and 5-hydroxyindoleacetic acid levels corre- lated negatively with individual deficit symptoms. Stepwise and hierarchical multiple-regression analysis revealed that among monoaminergic measures, only the CSF and plasma homovanil- lic acid levels contributed significantly to the total Brief Psychiat- ric Rating Scale and positive symptom variance with negative and positive partial correlations, respectively. Levels of CSF 3\x=req-\ methoxy-4-hydroxyphenylglycol, but not of CSF norepinephrine, were significantly elevated in the schizophrenic patients com- pared with controls, and plasma 3-methoxy-4-hydroxyphenyl- glycol levels were positively correlated with negative symptoms. We discuss the potential implications of these findings for a model of dopaminergic dysfunction in schizophrenia involving distinct cortical and subcortical contributions. (Arch Gen Psychiatry. 1990;47:641-648) The sensitive determination of amine metabolites in cere- brospinal fluid (CSF) as a means for assessing brain neurotransmitter activity represented a significant méthodo¬ logie advance for schizophrenia research. The expectation, however, that these methods would support the hypothesized overactivity of dopamine systems was never borne out. In fact, although a clearly defined dopamine abnormality has yet to be identified, there may be better support for diminished CSF dopamine metabolite levels than for their increase in schizophrenic patients (C. A. Kaufman, MD, unpublished data, 1990). "4 Nevertheless, consistent evidence linking the antipsychotic effects of neuroleptic drugs with effects on central nervous system (CNS) dopamine systems continues to implicate dopaminergic dysfunction in schizophrenia.15,16 The delineation of the structure and function of CNS dopa¬ minergic systems, in conjunction with recent clinical data, has helped to renew speculation regarding the nature of dopa¬ mine dysfunction in schizophrenia. Functional brain-imaging studies, for example, have, with remarkable consistency, demonstrated diminished activity of the prefrontal cortex in patients with schizophrenia.17"20 Because of the possible role of dopamine innervation for prefrontal cortex-mediated beha¬ viors,21 deficient mesocortical dopamine activity in schizo¬ phrenia has been suggested.22"25 Relevant to this hypothesis are the unique properties of mesocortical neurons,26 including evidence from animal experiments that lesioning of the meso¬ cortical dopamine system increases functional output of the subcortical nigrostriatal and mesolimbic systems.27 Thus, as discussed by Weinberger,22 diminished mesocortical activity could be coupled with increased subcortical dopaminergic activity, resulting in a "bidirectional" dopamine model of psychosis. The effects of a negative feedback relationship between cortical and subcortical dopamine systems on CSF dopamine metabolite levels are likely to be complex. For instance, while Accepted for publication December 7,1989. From the Section on Clinical Studies, Clinical Neuroscience Branch, Nation- al Institute of Mental Health, Bethesda, Md. Dr Breier is now with the Maryland Psychiatric Research Center, Baltimore. Dr Hsiao is now with the Section on Analytic Biochemistry, Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Md. Dr Doran is now with the Depart- ment of Psychiatry, University of California-Davis, Sacramento. Dr Wolkowitz is now with the Langley-Porter Psychiatric Institute and Universi- ty of California, San Francisco. Dr Pato is now with the Schizophrenia Research Branch, Division of Clinical Research, National Institute of Mental Health, Rockville, Md. Reprint requests to Section on Clinical Studies, Clinical Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bldg 10, Room 4N212, 9000 Rockville Pike, Bethesda, MD 20892 (Dr Pickar). Downloaded From: http://archpsyc.jamanetwork.com/ by a Department of Veterans Affairs User on 08/11/2016