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 ¼ 6) and normal volunteers (NVs) (n ¼ 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 ¼ 5) and/or clozapine (n ¼ 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 haloperidoltreated 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.

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

“…These findings might reflect pathophysiologic processes that may be at least partly ameliorated by antipsychotic medication. Clozapine but not haloperidol treatment re-established normal task-activated regional cerebral blood flow (CBF) patterns in schizophrenia in the ACC [53]. This is consistent with the finding that atypical antipsychotics might have a greater effect on cognitive impairment in schizophrenia than typical [54].…”

Voxel-wise meta-analysis of fMRI studies in patients at clinical high risk for psychosis

“…13 Anterior cingulate function and structure has also been reported to be especially sensitive to remedial antipsychotic treatment in patients with psychosis. 54,55 Because there is evidence indicating that a few weeks of antipsychotic treatment modulates the anterior cingulate response, 50,56 and because the latter has been associated with longitudinal functional outcomes in at-risk patients, 57 the question of the functional significance of dynamic cingulate changes in the prodromal phases of psychosis may have some potential clinical implications for preventive interventions.…”

Treatment-Resistant Schizophrenia Patients Show Elevated Anterior Cingulate Cortex Glutamate Compared to Treatment-Responsive

“…The anterior cingulate appears to be an important region in regards to glutamatergic dysfunction and treatment response 30 while clozapine (as the only effective drug for treatment resistance) modulates its metabolic function differentially to haloperidol. 31,32 Our preliminary study 27 showed that resistant patients had increased anterior cingulate cortex glutamate compared to controls, but lacked enough power to detect differences between the 2 clinical groups. In the present study we used a larger sample that would allow us enough power to detect such differences.…”