title: Clozapine but not haloperidol Re-establishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex.
abstract: Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with (15)O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n=6) and normal volunteers (NVs) (n=12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1). Rest, (2). sensory motor control (SMC) task, and (3). decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n=5) and/or clozapine (n=5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol- and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidol-treated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA. alahti@mprc.umaryland.edu
authors.forename: Adrienne C
authors.initials: AC
authors.lastname: Lahti
authors.forename: Henry H
authors.initials: HH
authors.lastname: Holcomb
authors.forename: Martin A
authors.initials: MA
authors.lastname: Weiler
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Medoff
authors.forename: Kristin N
authors.initials: KN
authors.lastname: Frey
authors.forename: Michael
authors.initials: M
authors.lastname: Hardin
authors.forename: Carol A
authors.initials: CA
authors.lastname: Tamminga
mesh_terms: D000161:Acoustic Stimulation; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001307:Auditory Perception / Q000187:drug effects; D001931:Brain Mapping; D003024:Clozapine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005625:Frontal Lobe / Q000098:blood supply / Q000000981:diagnostic imaging / Q000187:drug effects; D006179:Gyrus Cinguli / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000187:drug effects*; D006220:Haloperidol / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D010104:Oxygen Radioisotopes / Q000493:pharmacokinetics; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time; D012039:Regional Blood Flow / Q000187:drug effects; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D014055:Tomography, Emission-Computed
chemical_list: D014150:Antipsychotic Agents; D010104:Oxygen Radioisotopes; D003024:Clozapine; D006220:Haloperidol