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ARTICLE |

Clozapine Treatment of Schizophrenia FREE

David Pickar, MD; John K. Hsiao, MD
[+] Author Affiliations

Reprint requests to Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bldg 10, Room 4N-212, Bethesda, MD 20892 (Dr Pickar).

Grand Rounds at the Clinical Center of the National Institutes of Health section editors: John I. Gallin, MD, the Clinical Center of the National Institutes of Health, Bethesda, Md; David S. Cooper, MD, Contributing Editor, JAMA.


JAMA. 1995;274(12):981-983. doi:10.1001/jama.1995.03530120073044
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SELECTED CASE  A 27-year-old woman was admitted to the National Institutes of Health Clinical Center, Bethesda, Md, for inpatient research protocol for schizophrenia. She first experienced behavioral disturbances at 13 years of age when she became withdrawn and isolated from friends and family. She reported auditory hallucinations for the first time at 16 years and developed delusions of control and persecution over ensuing months. Suicidal ruminations culminated in a serious suicide attempt and her first hospitalization at the age of 17 years. Although standard antipsychotic drugs reduced her delusions, the patient remained socially isolated and had symptom exacerbation when under stress. She discontinued antipsychotic drug treatment because of adverse effects on several occasions; in each case, she became acutely psychotic. Prior to her admission to the National Institute of Mental Health, she was hospitalized 15 times, including several hospitalizations mandated by the court because of risk to herself and to

REFERENCES

Hirsch SR, Weinberger DR, eds. Schizophrenia . London, England: Blackwood Press; 1994;.
Caldwell CB, Gottesman II.  Schizophrenia, a high risk factor for suicide: clues to risk reduction. Suicide Life Threat Behav . 1992;;22:479-493.
Weinberger DR, Aloia MS, Goldberg TE, Berman KF.  The frontal lobes and schizophrenia. J Neuropsychiatry Clin Neurosci . 1994;;6:419-427.
Kane J, Honigfeld G, Singer J, Meltzer H, and the Clozaril Collaborative Study Group.  Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry . 1988;;45:789-796.
Pickar D, Owen RR, Litman RE, Konicki E, Gutierrez R, Rapaport MH.  Clinical and biologic response to clozapine in patients with schizophrenia: crossover comparison with fluphenazine. Arch Gen Psychiatry . 1992;;49:345-353.
Creese I, Burt DR, Snyder SH.  Dopamine receptor binding predicts clinical and pharmacologic potencies of antischizophrenic drugs. Science . 1976;; 192:481-483.
Seeman P, Lee T, Chau-Wong M, Wong K.  Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature . 1976;;261:717-719.
Davis KL, Kahn RS, Ko G, Davidson M.  Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry . 1991;;148:1474-1486.
Pickar D.  Perspective on time-dependent model of neuroleptic action. Schizophr Bull . 1988;;14:255-268.
Pickar D, Labarca R, Linnoila M, et al.  Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science . 1984;;225:954-957.
Pickar D.  Prospects for pharmacotherapy of schizophrenia. Lancet . 1995;;345:557-562.
van Tol HH, Bunzow JR, Guan H-C, et al.  Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature . 1991;;350:610-614.
Seeman P.  Dopamine receptor sequences: therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology . 1992;;7:261-284.
Meltzer HR, Matsubara S, Lee JC.  Classification of typical and atypical antipsychotic drugs on the basis of D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther . 1989;;251:3238-3246.
Pickar D, Litman RE, Hong WE, et al.  Clinical response to clozapine in patients with schizophrenia. Arch Gen Psychiatry . 1994;;51:159-160.
Farde L, Wiesel FA, Halldin C, Sedvall G.  Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry . 1988;;45:71-76.
Weinberger DR, Berman KF, Zec RF.  Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral blood flow evidence. Arch Gen Psychiatry . 1986;;43:114-124.
Andreasen NC, Rezai K, Alliger R, et al.  Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia: assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch Gen Psychiatry . 1992;;49:943-958.
Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RSJ.  Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry . 1992;;160: 179-186.
Tamminga CA, Thaker GK, Buchanan R, et al.  Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch Gen Psychiatry . 1992;;49: 522-530.
Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR.  Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med . 1990;;322:789-794.
Buchsbaum MS, Potkin SG, Siegel BV Jr, et al.  Striatal metabolic rate and clinical response to neuroleptics in schizophrenia. Arch Gen Psychiatry . 1992;;49:966-974.
Wik G, Wiesel FA, Sjogren I, Blomqvist G, Greitz T, Stone-Elander S.  Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission topography. Psychopharmacology . 1989;;97:309-318.
Mega MS, Cummings JL.  Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci . 1994;;6:358-370.
Meltzer HY, Cola P, Way L, et al.  Cost effectiveness of clozapine in neuroleptic-resistant schizophrenia. Am J Psychiatry . 1993;;150:1630-1637.

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Hirsch SR, Weinberger DR, eds. Schizophrenia . London, England: Blackwood Press; 1994;.
Caldwell CB, Gottesman II.  Schizophrenia, a high risk factor for suicide: clues to risk reduction. Suicide Life Threat Behav . 1992;;22:479-493.
Weinberger DR, Aloia MS, Goldberg TE, Berman KF.  The frontal lobes and schizophrenia. J Neuropsychiatry Clin Neurosci . 1994;;6:419-427.
Kane J, Honigfeld G, Singer J, Meltzer H, and the Clozaril Collaborative Study Group.  Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry . 1988;;45:789-796.
Pickar D, Owen RR, Litman RE, Konicki E, Gutierrez R, Rapaport MH.  Clinical and biologic response to clozapine in patients with schizophrenia: crossover comparison with fluphenazine. Arch Gen Psychiatry . 1992;;49:345-353.
Creese I, Burt DR, Snyder SH.  Dopamine receptor binding predicts clinical and pharmacologic potencies of antischizophrenic drugs. Science . 1976;; 192:481-483.
Seeman P, Lee T, Chau-Wong M, Wong K.  Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature . 1976;;261:717-719.
Davis KL, Kahn RS, Ko G, Davidson M.  Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry . 1991;;148:1474-1486.
Pickar D.  Perspective on time-dependent model of neuroleptic action. Schizophr Bull . 1988;;14:255-268.
Pickar D, Labarca R, Linnoila M, et al.  Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science . 1984;;225:954-957.
Pickar D.  Prospects for pharmacotherapy of schizophrenia. Lancet . 1995;;345:557-562.
van Tol HH, Bunzow JR, Guan H-C, et al.  Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature . 1991;;350:610-614.
Seeman P.  Dopamine receptor sequences: therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology . 1992;;7:261-284.
Meltzer HR, Matsubara S, Lee JC.  Classification of typical and atypical antipsychotic drugs on the basis of D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther . 1989;;251:3238-3246.
Pickar D, Litman RE, Hong WE, et al.  Clinical response to clozapine in patients with schizophrenia. Arch Gen Psychiatry . 1994;;51:159-160.
Farde L, Wiesel FA, Halldin C, Sedvall G.  Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry . 1988;;45:71-76.
Weinberger DR, Berman KF, Zec RF.  Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral blood flow evidence. Arch Gen Psychiatry . 1986;;43:114-124.
Andreasen NC, Rezai K, Alliger R, et al.  Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia: assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch Gen Psychiatry . 1992;;49:943-958.
Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RSJ.  Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry . 1992;;160: 179-186.
Tamminga CA, Thaker GK, Buchanan R, et al.  Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch Gen Psychiatry . 1992;;49: 522-530.
Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR.  Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med . 1990;;322:789-794.
Buchsbaum MS, Potkin SG, Siegel BV Jr, et al.  Striatal metabolic rate and clinical response to neuroleptics in schizophrenia. Arch Gen Psychiatry . 1992;;49:966-974.
Wik G, Wiesel FA, Sjogren I, Blomqvist G, Greitz T, Stone-Elander S.  Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission topography. Psychopharmacology . 1989;;97:309-318.
Mega MS, Cummings JL.  Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci . 1994;;6:358-370.
Meltzer HY, Cola P, Way L, et al.  Cost effectiveness of clozapine in neuroleptic-resistant schizophrenia. Am J Psychiatry . 1993;;150:1630-1637.
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