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August 1993

Monoamine Neurotransmitter Interactions in Drug-Free and Neuroleptic-Treated Schizophrenics

Author Affiliations

From the ExperimentalTherapeutics Branch (Drs Hsiao,Doran, Konicki, and Pickar andMs Colison), Section on ClinicalPharmacology, ExperimentalTherapeutics Branch (Dr Potter),and Division of Applied andServices Research (Dr Bartko),National Institute of MentalHealth, Bethesda, Md; CanyonSprings Hospital, Palm Springs,Calif (Dr Doran); and theDepartment of Psychiatry, CaseWestern Reserve University,Cleveland, Ohio (Dr Konicki).

Arch Gen Psychiatry. 1993;50(8):606-614. doi:10.1001/archpsyc.1993.01820200016002

Objective:  To study recent suggestions by a number ofinvestigators that interactions between monoamine neu-rotransmitter systems play an important role in schizo-phrenia. It has not been clear how hypotheses about in-teractions might be tested in clinical data. One meansfor indexing interactions between monoamine neu-rotransmitter systems may be to compare correlationsbetween cerebrospinal fluid (CSF) monoamine metab-olite (homovanillic acid [HVA], 5-hydroxyindoleaceticacid [5-HIAA], and 3-methoxy-4-hydroxyphenylglycol[MHPG]) or ratios of these metabolites (HVA/5-HIAAand HVA/MHPG).

Design:  We compared these putative measures of monoam-ine neurotransmitter interaction in 50 drug-free patientswith schizophrenia (hospitalized on an inpatient ward ofa tertiary care hospital) and 33 normal controls and ex-amined the effects of neuroleptic antipsychotic treatmenton these measures in 41 patients (22 of whom had an-tecedent drug-free CSF data).

Results:  Drug-free patients with schizophrenia had sig-nificantly smaller correlations between CSF monoaminemetabolites than normal controls. Longer drug-free timewas associated with even smaller correlations between me-tabolites, suggesting that the difference between controlsand patients was not due to acute drug withdrawal. Aftertreatment with neuroleptic antipsychotics there were sig-nificant increases in the HVA/5-HIAA and HVA/MHPGratios, as well as increases in correlations between monoam-ine metabolites. After treatment, there were no significantdifferences in metabolite correlations between patients andcontrols. Metabolite ratios and correlations did not pre-dict subsequent treatment response, but preliminary anal-yses demonstrated negative relationships between HVA/5-HIAA and HVA/MHPG ratios and Brief Psychiatric RatingScale rating at that time.

Results:  Neuroleptic treatment significantly raised HVA concentrations and significantly increased the ratio between HVA and 5-HIAA. The increase in HVA was not related to symptomatic improvement, whereas the increase in the HVA/5-HIAA ratio was significantly correlated with reduction in overall symptomatology.

Conclusions:  The present findings are consistent withand support hypotheses suggesting that interactions be-tween monoamine systems are altered in schizophreniaand that antipsychotic treatment may affect the func-tional balance between different monoamine neurotrans-mitters (although one should keep in mind factors otherthan interactions between monoamine systems that affectmetabolite correlations and ratios).