Advertisement
Research Article| Volume 34, ISSUE 3, P178-187, August 01, 1993

Acute effects of neuroleptics on unmedicated schizophrenic patients and controls

  • Alexander L. Miller
    Correspondence
    Address reprint requests to Dr. Alexander L. Miller, Department of Psychiatry, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7792.
    Footnotes
    Affiliations
    Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA

    Audie L. Murphy Memorial Veterans' Hospital, San Antonio, Texas, USA
    Search for articles by this author
  • James W. Maas
    Footnotes
    Affiliations
    Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA
    Search for articles by this author
  • Salvador Contreras
    Footnotes
    Affiliations
    Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA

    Audie L. Murphy Memorial Veterans' Hospital, San Antonio, Texas, USA
    Search for articles by this author
  • Ermias Seleshi
    Footnotes
    Affiliations
    Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA

    Audie L. Murphy Memorial Veterans' Hospital, San Antonio, Texas, USA
    Search for articles by this author
  • Janet E. True
    Footnotes
    Affiliations
    Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA
    Search for articles by this author
  • Charles Bowden
    Footnotes
    Affiliations
    Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA
    Search for articles by this author
  • Joseph Castiglioni
    Footnotes
    Affiliations
    Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA
    Search for articles by this author
  • Author Footnotes
    ∗∗ We thank the following for their active participation and assistance in this research: the staff of Unit 1C at Audie Murphy Memorial Veterans Hospital, Valarie Robbins, RN, Donna Irish, RN, Rochelle Javors, Betsy Cuvelier, and Ray Benavides.
    1 Salvador Contreras' present address is School of Medicine, Department of Psychiatry, Texas Tech, University Health Science Center, Lubbock, TX 79430.
    2 Ermias Selshi's present address is One Bratenahl Place, Suite 1012, Bratenahl, Ohio 44108.
    3 Joseph Castiglioni's present address is 511 University Dr., Suite 204, College Station, TX 77840.
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Acute administration of haloperidol (0.2 mg/kg) produced many more side effects in normal controls than in unmedicated schizophrenic patients. Prior to the neuroleptic challenge, both groups were on the peripheral monoamine oxidase inhibitor, debrisoquin, for at least 1 week, in order to enhance the relative contribution of CNS catecholamine metabolites to those measured in both plasma and urine. The patient group had higher plasma levels of methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) and higher urinary MHPG output than controls, but there were no effects of haloperidol challenge, compared to placebo challenge. In both groups there were significant declines in plasma HVA levels from 8:30 am to 12 noon. These declines were unaffected by the haloperidol challenge. Explanations for the marked differences in behavioral effects of haloperidol on patients and controls include the possibility that dopamine receptor numbers were increased in the brains of the schizophrenic patients.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Amin F.
        • Davidson M.
        • Davis K.L.
        Homovanillic acid measurement in clinical research: A review of methodology.
        Schizophr Bull. 1992; 18: 123-148
        • Anden M.
        • Grabowska-Anden M.
        Formation of deaminated metabolites of dopamine in noradrenaline neurons.
        Naunyn Schmiedeberg's Arch Pharmacol. 1983; 324: 1-6
        • Andreasen N.C.
        • Carson R.
        • Diksic M.
        • Evans A.
        • Farde L.
        • Gjedde A.
        • Hakiim A.
        • Lal S.
        • Nair N.
        • Sedvall G.
        • Tune L.
        • Wong D.
        Workshop on schizophrenia, PET, and dopamine D2 receptors in the human neostriatum.
        Schizophr Bull. 1988; 14: 471-484
        • Anggard E.
        • Lewander T.
        • Sjoquist B.
        Determination of homovanillic acid turnover in man.
        Life Sci. 1974; 15: 111-122
        • Bacopoulos N.
        • Buntos G.
        • Redmond D.E.
        • Baulu J.
        • Roth R.H.
        Chronic haloperidol or fluphenazine: effects on dopamine metabolism in brain, cerebrospinal fluid and plasma of Cercopithecus Aethiops (Vervet monkey).
        J Pharmacol Exp Ther. 1980; 212: 1-5
        • Bacopoulos N.
        • Heninger G.R.
        • Roth R.H.
        Effects of haloperidol and probenecid on plasma and CSF dopamine metabolites in th rhesus monkey (Macacca Mulatta).
        Life Sci. 1978; 23: 1805-1812
        • Bacopoulos N.
        • Spokes E.G.
        • Bird E.D.
        • Roth R.H.
        Antipsychotic drug action in schizophrenic patients: Effect on cortical dopamine metabolism after long-term treatment.
        Science. 1979; 205: 1405-1407
        • Bell C.
        Dopamine release from sympathetic nerve terminals.
        Prog Neurobiol. 1988; 30: 193-208
        • Bowers Jr, M.B.
        • Heninger G.R.
        • Sternberg D.
        • Meltzer H.Y.
        Clinical processes and central dopaminergic activity in psychotic disorders.
        Commun Psychopharmacol. 1980; 4: 177-188
        • Breier A.
        • Wolkowitz O.M.
        • Roy A.
        • Potter W.Z.
        • Pickar D.
        Plasma norepinephrine in chronic schizophrenia.
        Am J Psychiatry. 1990; 147: 1467-1470
        • Bunney B.S.
        • Grace A.A.
        Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity.
        Life Sci. 1978; 23: 1715-1728
        • Burt D.R.
        • Creese I.
        • Snyder S.H.
        Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain.
        Science. 1977; 196: 326-328
        • Chiodo L.A.
        • Freeman A.S.
        • Bunney B.S.
        Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons.
        J Neurosci. 1983; 3: 1607-1619
        • Contreras S.A.
        • Maas J.W.
        • Seleshi E.
        • Bowden C.L.
        Urine and plasma levels of dopamine metabolites in response to apomorphine and neuroleptics in schizophrenics.
        Biol Psychiatry. 1988; 24: 818-822
        • Creese I.
        • Burt D.R.
        • Snyder S.H.
        Dopamine receptor binding predicts clinical and pharmacologic potencies of antipsychotic drugs.
        Science. 1976; 192: 81-84
        • Cutler N.R.
        • Jeste D.V.
        • Karoum F.
        • Wyatt R.J.
        Low-dose apomorphine reduces serum homovanillic acid concentrations in schizophrenic patients.
        Life Sci. 1982; 30: 753-756
        • Davidson M.
        • Giordani A.B.
        • Mohs R.C.
        • Horvath T.B.
        • Davis B.M.
        • Powchik P.
        • Davis K.L.
        Short-term haloperidol administration acutely elevates human plasma homovanillic acid concentration.
        Arch Gen Psychiatry. 1987; 44: 189-190
        • Davidson M.
        • Kendler K.S.
        • Davis B.M.
        • Horvath T.B.
        • Mohs R.C.
        • Davis K.L.
        Apomorphine has no effect on plasma homovanillic acid in schizophrenic patients.
        Psychiatry Res. 1985; 16: 95-99
        • Davidson M.
        • Kendler K.S.
        • Mohs R.C.
        • Hollander E.
        • Ryan T.
        • Davis K.
        Effect of apomorphine infusion on plasma homovanillic acid in normal subjects.
        J Psychiatr Res. 1986; 20: 131-135
        • Davidson M.
        • Losonczy M.F.
        • Mohs R.C.
        • Lesser J.C.
        • Powchik P.
        • Freed L.B.
        • Davis B.M.
        • Mykytyn V.V.
        • Davis K.L.
        Effects of debrisoquin and haloperidol on plasma homovanillic acid concentration in schizophrenic patients.
        Neuropsychopharmacol. 1987; 1: 17-23
        • Davila R.
        • Zumarraga M.
        • Andia I.
        • Friedhoff A.J.
        Persistence of cyclicity of the plasma dopamine metabolite, homovanillic acid, in neuroleptic treated schizophrenic patients.
        Life Sci. 1989; 44: 1117-1121
        • Davila R.
        • Zumarraga M.
        • Perea K.
        • Andia I.
        • Friedhoff A.J.
        Elevation of plasma homovanillic acid level can be detected within four hours after initiation of haloperidol treatment.
        Arch Gen Psychiatry. 1987; 44: 837-838
        • Debonnel G.
        • Gaudreau P.
        • Quirion R.
        • de Montigny C.
        Effects of long-term haloperidol treatment on the responsiveness of accumbens neurons to cholecystokinin and dopamineL electrophysiological and radioligand binding studies in the rat.
        J Neurosci. 1990; 10: 469-478
        • Dinan T.G.
        • Aston-Jones G.
        Acute haloperidol increases impulse activity of brain noradrenergic neurons.
        Brain Res. 1984; 307: 359-362
        • Doran A.R.
        • Labarca R.
        • Wolkowitz O.M.
        • Roy A.
        • Douillet P.
        • Pickar D.
        Circadian variation of plasma homovanillic acid levels is attenuated by fluphenazine in patients with schizophrenia.
        Arch Gen Psychiatry. 1990; 47: 558-563
        • Elchisak M.A.
        • Polinsky R.J.
        • Elbert M.H.
        • Modlin L.T.
        • Kopin I.J.
        Kinetics of homovanillic acid and determination of its production rate in the rhesus monkey.
        Life Sci. 1979; 24: 1493-1502
        • Farde L.
        • Wiesel F.
        • Hall H.
        • Halldin C.
        • Stone-Elander S.
        • Sedvall G.
        No D2 receptor increase in PET study of schizophrenia.
        Arch Gen Psychiatry. 1987; 44: 671-672
        • Farley I.J.
        • Price K.S.
        • McCullough E.
        • Deck J.H.N.
        • Hordynsky W.
        • Hornykiewicz O.
        Norepinephrine in chronic paranoid schizophrenia: Above-normal levels in limbic forebrain.
        Science. 1978; 200: 456-457
        • Farley I.J.
        • Shannak K.S.
        • Hornykiewicz O.
        Brain monoamine changes in chronic paranoid schizophrenia and their possible relation to increased dopamine receptor sensitivity.
        Adv Biochem Psychopharmacol. 1980; 21: 427-433
        • Favre R.
        • de Haut M.
        • Dalmaz Y.
        • Pequignot J.M.
        • Peyrin L.
        Peripheral distribution of free dopamine and its metabolites in the rat.
        J Neural Transmiss. 1986; 66: 135-149
        • Freedman R.
        • Kirch B.
        • Bell J.
        • Adler L.E.
        • Pecevich M.
        • Pachtman E.
        • Denver P.
        Clonidine treatment of schizophrenia: double-blind comparison to placebo and neuroleptic drugs.
        Acta Psychiatr Scand. 1982; 65: 35n45
        • Glantz S.A.
        Primer of Biostatistics.
        2nd ed. McGraw-Hill, New York1987
        • Glazer W.M.
        • Charney D.S.
        • Heninger G.R.
        Noradrenergic function in schizophrenia.
        Arch Gen Psychiatry. 1987; 44: 898-904
        • Goff D.C.
        • Henderson D.C.
        • Amico E.
        Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects.
        Am J Psychiat. 1992; 149: 1189-1194
        • Gomes U.C.R.
        • Shanley B.C.
        • Potgieter L.
        • Roux J.T.
        Noradrenergic overactivity in chronic schizophrenia: evidence based on cerebrospinal fluid noradrenaline and cyclic nucleotide concentrations.
        Br J Psychiatry. 1980; 137: 346-351
        • Grace A.A.
        • Bunney B.S.
        Induction of depolarization block in midbrain dopamine neurons by repeated administration of haloperidol: analysis using in vivo intracellular recordi.
        J Pharmacol. 1986; 238: 1092-1100
        • Grenhoff J.
        • Svensson T.H.
        Clonidine modulates dopamine cell firing in rat ventral tegmental area.
        Eur J Pharmacol. 1988; 165: 11-18
        • Grenhoff J.
        • Svensson T.H.
        Clonidine regularizes substantia nigra dopamine firing.
        Life Sci. 1988; 42: 2003-2009
        • Jerlicz M.
        • Kostowski W.
        • Bidzinski A.
        • Hauptmann M.
        Effects of lesions in the ventral noradrenergic bundle on behavior and response to psychotropic drugs in rats.
        Pharmacol Biochem Behav. 1978; 9: 721-724
        • Karoum F.
        • Wyatt R.
        • Costa E.
        Estimation of the contribution of peripheral and central noradrenergic neurons to urinary 3-methoxy-4-hydroxyphenylglycol in the rat.
        Neuropharmacology. 1974; 13: 165-176
        • Kemali D.
        • Del Vecchio M.
        • Maj M.
        Increased noradrenaline levels in CSF and plasma of schizophrenic patients.
        Biol Psychiatry. 1982; 17: 711-717
        • Kendler K.S.
        • Heninger G.R.
        • Roth R.H.
        Brain contribution to the haloperidol-induced increase in plasma homovanillic acid.
        Eur J Pharmacol. 1981; 71: 321-326
        • Kendler K.S.
        • Heninger Gr.
        • Roth R.H.
        Influence of dopamine agonists on plasma and brain levels of homovanillic acid.
        Life Sci. 1982; 30: 2063-2069
        • King D.J.
        • Turkson S.N.A.
        • Liddle J.
        • Kinney C.D.
        Some clinical and metabolic aspects of propranolol in chronic schizophrenia.
        Br J Psychiatry. 1980; 137: 458-468
        • Ko G.N.
        • Jimerson D.C.
        • Wyatt R.J.
        • Bigelow L.B.
        Plasma 3-methoxy-4-hydroxyphenylglycol changes associated with clinical state and schizophrenic subtype.
        Arch Gen Psychiatry. 1988; 45: 842-846
        • Konicki P.E.
        • Owen R.R.
        • Litman R.E.
        • Pickar D.
        The acute effects of central- and peripheral-acting dopamine antagonists on plasma HVA in schizoprenic patients.
        Life Sci. 1991; 48: 1411-1416
        • Kopin I.J.
        • Bankiewicz K.S.
        • Harvey-White J.
        Assessment of brain dopamine metabolism from plasma HVA and MHPG during debrisoquin treatment: validation in monkeys treated with MPTP.
        Neuropsychopharmacol. 1988; 1: 119-125
        • Kopin I.J.
        • White J.H.
        • Bankiewicz K.
        A new approach to biochemical evaluation of brain dopamine metabolism.
        Cell Molec Neurobiol. 1988; 8: 171-179
        • Kostowski W.
        • Jerlicz M.
        • Bidzinski A.
        • Hauptmann M.
        Behavioral effects of neuroleptics, apomorphine and amphetamine after bilateral lesion of the locus coeruleus in rats.
        Pharmacol Biochem Behav. 1977; 7: 289-293
        • Lackovic Z.
        • Relja M.
        • Neff N.H.
        Catabolism of endogenous dopamine in peripheral tissues: is there an independent role for dopamine in peripheral neurotransmission?.
        J Neurochem. 1982; 38: 1453-1458
        • Lambert G.W.
        • Eisenhofer G.
        • Cox H.S.
        • Horne M.
        • Kalff V.
        • Kelly M.
        • Jennings G.L.
        • Esler M.D.
        Direct determination of homovanillic acid release from the human brain, an indicator of central dopaminergic activity.
        Life Sci. 1991; 49: 1061-1072
        • Lategan A.J.
        • Marien M.R.
        • Colpaert F.C.
        Effects of locus coeruleus lesions on the release of endogenous dopamine in the rat nucleus accumbens and caudate nucleus as determined by intracerebral microdialysis.
        Brain Res. 1990; 523: 134-138
        • Maas J.W.
        • Contreras S.A.
        • Miller A.L.
        • Berman N.
        • Bowden C.L.
        • Javors M.A.
        • Seleshi E.
        • Weintraub S.
        Studies of catecholamine metabolism in schizophrenia/psychosis-I.
        Neuropsychopharmacol. 1993; 8: 97-109
        • Maas J.W.
        • Contreras S.A.
        • Miller A.L.
        • Berman N.
        • Bowden C.L.
        • Javors M.A.
        • Seleshi E.
        • Weintraub S.E.
        Studies of catecholamine metabolism in schizophrenia/psychosis-II.
        Neuropsychopharmacol. 1993; 8: 111-116
        • Maas J.W.
        • Contreras S.A.
        • Seleshi E.
        • Bowden C.L.
        Dopamine metabolism and disposition in schizophrenic patients: studies using debrisoquin sulfate.
        Arch Gen Psychiatry. 1988; 45: 553-559
        • Maas J.W.
        • Hattox S.E.
        • Greene N.M.
        • Landis D.H.
        Estimates of dop;amine and serotonin synthesis by the awake human brain.
        J Neurochem. 1980; 34: 1547-1549
        • Maas J.W.
        • Hattox S.E.
        • Landis D.H.
        Differential effects on brain catecholamines by debrisoquin.
        Biochem Pharmacol. 1979; 28: 3153-3156
        • Maas J.W.
        • Hattox S.E.
        • Martin D.M.
        • Roth R.H.
        A direct method for studying brain amine metabolism in awake animals.
        in: Usdin E. Weiner N. Youdim M.B.H. Structure and Function of Monoamine Enzymes. Marcel Dekker, New York1977
        • Medina M.A.
        • Giachetti A.
        • Shore P.A.
        On the physiological disposition and possible mechanism of the antihypertensive action of debrisoquin.
        Biochem Pharmacol. 1969; 18: 891-901
        • Pickar D.
        • Labarca R.
        • Doran A.
        • Wolkowitz O.M.
        • Roy A.
        • Breier A.
        • Linnoila M.
        • Paul S.M.
        Longitudinal measurement of plasma homovanillic acid levels in schizophrenic patients.
        Arch Gen Psychiatry. 1986; 43: 669-676
        • Pickar D.
        • Labarca R.
        • Linnoila M.
        • Roy A.
        • Hommer D.
        • Everett D.
        • Paul S.M.
        Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients.
        Science. 1984; 225: 954-957
        • Riddle M.A.
        • Leckman J.F.
        • Cohen D.J.
        • Anderson M.
        • Ort S.I.
        • Caruso K.A.
        • Shaywitz B.A.
        Assessment of central dopaminergic function using plasma-free homovanillic acid after debrisoquin administration.
        J Neural Transm. 1986; 67: 31-43
        • Sack D.A.
        • James S.P.
        • Doran A.R.
        • Sherer M.A.
        • Linnoila M.
        • Wehr T.A.
        The diurnal variation in plasma homovanillic acid level persists but the variation in 3-methoxy-4-hydroxyphenylglycol level is abolished under constant conditions.
        Arch Gen Psychiatry. 1988; 45: 162-166
        • Scheinin M.
        Apomorphine does not lower the concentration of homovanillic acid in the plasma of normal humans.
        Psychopharmacol Bull. 1984; 20: 660-666
        • Scheinin H.
        Enhanced noradrenergic neuronal activity increases homovanillic acid levels in cerebrospinal fluid.
        J Neurochem. 1986; 47: 665-667
        • Seeman M.V.
        • Seeman P.
        Psychosis and positron tomography.
        Can J Psychiatry. 1988; 33: 299-306
        • Seeman P.
        • Bzowej N.H.
        • Guan H.C.
        • Bergeron C.
        • Reynolds G.P.
        • Bird E.D.
        • Riederer P.
        • Jellinger K.
        • Tourtellotte W.W.
        Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's and Huntington's diseases.
        Neuropsychopharmacol. 1987; 1: 5-15
        • Seeman P.
        • Lee T.
        • Chau-Wong M.
        • Wong K.
        Antipsychotic drug doses and neuroleptic/dopamine receptors.
        Nature. 1976; 261: 717-719
        • Seeman P.
        • Ulpian C.
        • Bergeron C.
        • Riederer P.
        • Jellinger K.
        • Gabriel E.
        • Reynolds G.P.
        • Tourtellotte W.W.
        Bimodal distribution of dopamine receptor densities in brains of schizophrenics.
        Science. 1984; 225: 728-731
        • Snyder S.H.
        The dopamine hypothesis in schizophrenia: focus on the dopamine receptor.
        Am J Psychiatry. 1976; 133: 197-202
        • Sternberg D.E.
        • Charney D.S.
        • Heninger G.R.
        • Leckman J.F.
        • Hafstad K.M.
        • Landis D.H.
        Impaired presynaptic regulation of norepinephrine in schizophrenia. Effects of clonidine in schizophrenic patients and normal controls.
        Arch Gen Psychiatry. 1982; 39: 285-289
        • Sternberg D.E.
        • Heninger G.R.
        • Roth R.H.
        Plasma homovanillic acid as an index of brain dopamine metabolism: enhancement with debrisoquin.
        Life Sci. 1983; 32: 2447-2452
        • Sternberg D.E.
        • van Kammen D.P.
        • Lake C.P.
        • Ballenger J.C.
        • Marder S.R.
        • Bunney Jr, W.E.
        The effect of pimozide on CSF norepinephrine in schizophrenia.
        Am J Psychiatry. 1981; 138: 1045-1051
        • Suhara T.
        • Inoue O.
        • Kobayasi K.
        Effect of desipramine on dopamine receptor binding in vivo.
        Life Sci. 1990; 47: 2119-2126
        • Swann A.C.
        • Maas J.W.
        • Hattox S.E.
        • Landis D.H.
        Catecholamine metabolites in human plasma as indices of brain function: Effects of debrisoquin.
        Life Sci. 1980; 27: 1857-1862
        • Tassin J.P.
        • Studler J.M.
        • Harvé D.
        • Blanc G.
        • Glowinski J.
        Contribution of noradrenergic neurons to the regulation of dopaminergic (D1) receptor denervation supersensitivity in rat prefrontal cortex.
        J Neurochem. 1986; 46: 243-248
        • van Kammen D.P.
        • Antelman S.
        Impaired noradrenergic transmission in schizophrenia?.
        Life Sci. 1984; 34: 1403-1413
        • van Kammen D.P.
        • Peters J.
        • Yao J.
        • van Kammen W.B.
        • Neylan T.
        • Shaw D.
        • Linnoila M.
        Norepinephrine in acute exacerbations of chronic schizophrenia.
        Arch Gen Psychiatry. 1990; 47: 161-168
        • van Kammen D.P.
        • Peters J.L.
        • van Kammen W.B.
        • Rosen J.
        • Yao J.K.
        • McAdam D.
        • Linnoila M.
        Clonidine treatment of schizophrenia: Can we predict treatment response?.
        Psychiatry Res. 1989; 27: 297-311
        • White F.J.
        • Wang R.Y.
        Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat.
        Life Sci. 1983; 32: 983-993
        • Wong D.F.
        • Wagner Jr, H.N.
        • Tune L.E.
        • Dannals R.F.
        • Pearlson G.D.
        • Links J.M.
        • Tamminga C.A.
        • Broussole E.P.
        • Ravert H.T.
        • Wilson A.A.
        • Toung J.K.T.
        • Malat J.
        • Williams J.A.
        • O'Tuama L.A.
        • Snyder S.H.
        • Kuhar M.H.
        • Gjedde A.
        Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics.
        Science. 1986; 234: 1558-1563