Marked Hypofrontality in Clozapine-responsive Patients

Abstract

Previous data show that the effects of clozapine on regional brain activity are different from those of other antipsychotic agents. It seemed of interest to study the brain activity patterns after treatment with clozapine, since this drug might correct basal deficits directly related to schizophrenia or instead induce changes that would in some way compensate distant abnormalities. In order to study the activity pattern resulting from clozapine treatment we have used FDG-PET and statistical parametric mapping (SPM) to explore the functional status of patients after chronic treatment with this drug, We compared their metabolic activity with normal controls and neuroleptic-naive (NN) patients, with the aim to identify if a reversion of pre-existing deficits or a induction of different changes was the result of clozapine administration. We compared metabolic patterns in 23 treatment-resistant (TR) patients after 6 months of treatment with clozapine, eighteen healthy subjects, and 17 NN schizophrenia patients. After treatment with clozapine, TR patients showed a clear hypofrontality and caudate hypometabolism in comparison with both the controls and NN patients, and also a lower thalamic activity than the healthy controls. In conclusion, our results support a preferential role for prefrontal regions and their subcortical connections in the mechanism of action of clozapine, resulting in a clearly hypofrontal state as compared to both controls and schizophrenia patients without previous treatment.

References

• 1 Andreasen NC. PET and the [¹⁵O]H₂O technique, Part 2: Choosing a significance threshold.  Am J Psychiatry. 1996;  153 6
• 2 Andreasen NC, Rezai K, Alliger R, Swayze VWd, Flaum M, Kirchner P, Cohen G, O’Leary DS. 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
• 3 Barbas H. Architecture and cortical connections of the prefrontal cortex in the rhesus monkey.  Adv Neurol. 1992;  57 91-115
• 4 Bartlett EJ, Brodie JD, Simkowitz P, Dewey SL, Rusinek H, Wolf AP, Fowler JS, Volkow ND, Smith G, Wolkin A. et al . Effects of haloperidol challenge on regional cerebral glucose utilization in normal human subjects.  Am J Psychiatry. 1994;  151 681-686
• 5 Buchsbaum MS, Haier RJ, Potkin SG, Nuechterlein K, Bracha HS, Katz M, Lohr J, Wu J, Lottenberg S, Jerabek PA. et al . Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics.  Arch Gen Psychiatry. 1992;  49 935-942
• 6 Cohen RM, Nordahl TE, Semple WE, Andreason P, Litman RE, Pickar D. The brain metabolic patterns of clozapine- and fluphenazine- treated patients with schizophrenia during a continuous performance task.  Arch Gen Psychiatry. 1997;  54 481-486
• 7 Desco M, Gispert J, Reig S, Sanz J, Pascau J, Sarramea F, Benito C, Santos A, Palomo T, Molina V. Cerebral metabolic patterns in chronic and recent-onset schizophrenia.  Psychiatry Res: Neuroimaging. 2003;  122 125-135
• 8 Efron B, Tibshirani R. Bootstrap methods for standard errors, confidence intervals, and other measures of statistical accuracy.  Statistical Science. 1986;  1 54-77
• 9 Frackowiak RSJ, Friston KJ, Frith CD, Dolan RJ, Mazziotta JC. Human Brain function. Academic Press: New York 1997
• 10 Fuster J. (editor) .The prefrontal lobe. Philadelphia: Lippincott-Raven 1997
• 11 Fuster J. Chemical Neurotransmission. In: Fuster J (editor) The prefrontal lobe. Philadelphia: Lippincott-Raven 1997: 61
• 12 Fuster JM. Synopsis of function and dysfunction of the frontal lobe.  Acta Psychiatr Scand Suppl. 1999;  395 51-57
• 13 Gispert JD, Pascau J, Reig S, Martinez-Lazaro R, Molina V, Garcia-Barreno P, Desco M. Influence of the normalization template on the outcome of statistical parametric mapping of PET scans.  Neuroimage. 2003;  19 601-612
• 14 Grobin AC, Deutch AY. Dopaminergic regulation of extracellular gamma-aminobutyric acid levels in the prefrontal cortex of the rat.  J Pharmacol Exp Ther. 1998;  285 350-357
• 15 Gross A, Joutsiniemi SL, Rimon R, Appelberg B. Clozapine-induced QEEG changes correlate with clinical response in schizophrenic patients: a prospective, longitudinal study.  Pharmacopsychiatry. 2004;  37 119-122
• 16 Heckers S, Rauch SL, Goff D, Savage CR, Schacter DL, Fischman AJ, Alpert NM. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia.  Nat Neurosci. 1998;  1 318-323
• 17 Holcomb HH, Cascella NG, Thaker GK, Medoff DR, Dannals RF, Tamminga CA. Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol.  Am J Psychiatry. 1996;  153 41-49
• 18 Huntley GW, Vickers JC, Morrison JH. Cellular and synaptic localization of NMDA and non-NMDA receptor subunits in neocortex: organizational features related to cortical circuitry, function and disease.  Trends Neurosci. 1994;  17 536-543
• 19 Lahti AC, Holcomb HH, Weiler MA, Medoff DR, Tamminga CA. Functional effects of antipsychotic drugs: comparing clozapine with haloperidol.  Biol Psychiatry. 2003;  53 601-608
• 20 Laruelle M. Imaging dopamine transmission in schizophrenia. A review and meta-analysis.  Q J Nucl Med. 1998;  42 211-221
• 21 Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RS. Patterns of cerebral blood flow in schizophrenia.  Br J Psychiatry. 1992;  160 179-186
• 22 Meltzer HY, Bastani B, Ramirez L, Matsubara S. Clozapine: new research on efficacy and mechanism of action.  Eur Arch Psychiatry Neurol Sci. 1989;  238 332-339
• 23 Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia.  Nat Neurosci. 2002;  5 267-271
• 24 Miller DD, Andreasen NC, O'Leary DS, Watkins GL, Boles Ponto LL, Hichwa RD. Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia.  Biol Psychiatry. 2001;  49 704-715
• 25 Moghaddam B, Bunney BS. Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study.  J Neurochem. 1990;  54 1755-1760
• 26 Molina Rodriguez V, Montz Andree R, Perez Castejon MJ, Capdevila Garcia E, Carreras Delgado JL, Rubia Vila FJ. SPECT study of regional cerebral perfusion in neuroleptic-resistant schizophrenic patients who responded or did not respond to clozapine.  Am J Psychiatry. 1996;  153 1343-1346
• 27 Molina V, Gispert JD, Reig S, Pascau J, Palomo T, Martínez R, Desco M. Olanzapine-induced cerebral metabolic changes. Relation to symptom changes in schizophrenia.  Int Clin Psychopharmacol. 2005a;  20 13-18
• 28 Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, Desco M, Palomo T. Cerebral metabolic changes induced by clozapine in schizophrenia.  Psychopharmacology. 2005;  178 17-26
• 29 Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, Palomo T, Desco M. Cerebral metabolism and risperidone treatment in schizophrenia.  Schizophrenia Res. 2003;  60 1-7
• 30 Molina V, Sanz J, Reig S, Martínez R, Sarramea F, Luque R, Benito C, Gispert JD, Pascau J, Desco M. Hypofrontality in males with first-episode psychosis.  Br J Psychiatry. 2005;  186 203-208
• 31 Molina V, Reig S, Sarramea F, Sanz J, Artaloytia FJ, Luque R, Aragüés M, Pascau J, Benito C, Palomo T, Desco M. Anatomical and functional brain variables associated to clozapine response in treatment-resistant schizophrenia.  Psychiatry Res:Neuroimaging. 2003;  124 153-161
• 32 Molina V, Sarramea F, Sanz J, Benito C, Palomo T. Prefrontal atrophy in first episodes of schzophrenia associated with limbic hyperactivity.  J Psychiatric Res. 2005;  39 117-127
• 33 Poline JB, Worsley KJ, Evans AC, Friston KJ. Combining spatial extent and peak intensity to test for activations in functional imaging.  Neuroimage. 1997;  5 83-96
• 34 Potkin SG, Basile VS, Jin Y, Masellis M, Badri F, Keator D, Wu JC, Alva G, Carreon DT, Bunney Jr WE, Fallon JH, Kennedy JL. D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine.  Mol Psychiatry. 2003;  8 109-113
• 35 Rodríguez VM, Andrée RM, Castejón MJ, Zamora ML, Alvaro PC, Delgado JL, Vila FJ. Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A ^99mTc-HMPAO study.  Psychiatry Res. 1997;  76 51-61
• 36 Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain. Thieme Medical Stuttgart, New York 1988
• 37 Tauscher J, Hussain T, Agid O, Verhoeff NP, Wilson AA, Houle S, Remington G, Zipursky RB, Kapur S. Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics.  Am J Psychiatry. 2004;  161 1620-1625
• 38 Volk DW, Lewis DA. Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction.  Physiol Behav. 2002;  77 501-505
• 39 Volk DW, Pierri JN, Fritschy JM, Auh S, Sampson AR, Lewis DA. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia.  Cereb Cortex. 2002;  12 1063-1070
• 40 Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex.  Nature. 1995;  376 572-575
• 41 Winterer G, Weinberger DR. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia.  Trends Neurosci. 2004;  27 683-690
• 42 Yamamoto BK, Pehek EA, Meltzer HY. Brain region effects of clozapine on amino acid and monoamine transmission.  J Clin Psychiatry. 1994;  55 ((Suppl B)) 8-14
• 43 Zink M, Schmitt A, May B, Muller B, Braus DF, Henn FA. Differential effects of long-term treatment with clozapine or haloperidol on GABA transporter expression.  Pharmacopsychiatry. 2004;  37 171-174

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