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Cerebral Metabolic Changes Induced by Clozapine in Schizophrenia and Related to Clinical Improvement

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Cerebral Metabolic Changes Induced by Clozapine in Schizophrenia and Related to Clinical Improvement Psychopharmacology (2005) 178: 17–26 DOI 10.1007/s00213-004-1981-9 ORIGINAL INVESTIGATION Vicente Molina . Juan D. Gispert . Santiago Reig . Javier Sanz . Javier Pascau . Andrés Santos . Manuel Desco . Tomás Palomo Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement Received: 14 October 2003 / Accepted: 26 January 2004 / Published online: 10 September 2004 # Springer-Verlag 2004 Abstract Rationale: The study of the different effects on primary and association visual areas. The change in brain metabolism between typical and atypical antipsy- negative symptoms was related with the decrease of basal chotics would aid in understanding their mechanisms of ganglia activity; the improvement in disorganization action. Clozapine is of special interest, since it is one of related to the metabolic decrease in the motor area, and the most effective antipsychotic drugs and demonstrates a the change in positive symptoms was associated to the distinctive mechanism of action in pre-clinical studies with increase of activity in the visual area. Conclusions: These respect to typical neuroleptics. Objective: To study the results show that haloperidol and clozapine produce differences in cerebral activity induced by clozapine as different patterns of metabolic changes in schizophrenia. compared to those produced by haloperidol. Methods: Compared to the haloperidol baseline, clozapine inhibited [18F]Fluoro-deoxy-glucose (FDG)-positron emission the metabolic activity of the prefrontal and motor cortical tomography (PET) scans were obtained in the resting regions and basal ganglia and induced a higher activation condition before and after 6 months of treatment with of the visual cortex. The improvement in disorganization, clozapine in 22 treatment-resistant patients with schizo- negative and positive syndromes with clozapìne may be phrenia. Before inclusion, patients had been chronically respectively associated with metabolic changes in the treated with classical drugs, and all of them received motor area, basal ganglia, and visual cortex. haloperidol during the last month. Data were analyzed with statistical parametric mapping (SPM′99) methods, Keywords Brain metabolism . (FDG)-PET . comparing pre-treatment and post-treatment conditions. Hypofrontality . Haloperidol . Clozapine . SPM The association between the changes in symptom scores and metabolism was also assessed to corroborate the functional relevance of possible metabolic changes. Introduction Results: Clozapine decreased prefrontal and basal ganglia activity, and increased occipital metabolism, including The study of the changes in brain metabolism induced by neuroleptics provides useful information for understanding the action of these drugs, especially if those changes relate V. Molina . J. Sanz . T. Palomo Department of Psychiatry, Hospital Doce de Octubre, to clinical improvement. Clozapine is one of the most Madrid, Spain effective antipsychotic drugs and probably its mechanism of action differs from that of typical neuroleptics. In V. Molina (*) particular, clozapine appears to act more selectively than Department of Psychiatry, Hospital Clínico Universitario, Servicio de Psiquiatría, typical neuroleptics on the prefrontal (PF) region (Rob- Paseo de San Vicente, 58-182, ertson and Fibiger 1992), an area of special relevance in Salamanca, 37007, Spain higher cognitive functions and schizophrenia. e-mail: [email protected] Few studies have investigated the effect of clozapine on Fax: +34-92-3291383 brain metabolism in schizophrenia. A cross-sectional J. D. Gispert . S. Reig . J. Pascau . M. Desco study reported a global decrease of gray matter activity Department of Experimental Medicine, Hospital General similar for both clozapine and fluphenazine accompanied Universitario Gregorio Marañón, by a higher decrease of the activity of the inferior PF Madrid, Spain cortex with clozapine (Cohen et al. 1997). A similar A. Santos decrease of PF activity with clozapine was reported by Department of Electrical Engineering, Universidad Politécnica, Potkin et al. (1994). The same group later found that only Madrid, Spain patients with a particular allele for the D1 dopamine 18 receptor showed both clinical improvement and a cortical Table 1 Patient demographic data. Values expressed as mean (SD) metabolic decrease with clozapine (Potkin et al. 2003). Mean (SD) N=22 Longitudinal data in five patients showed an inhibition in the resting state with clozapine of some PF areas and Duration (years) 7.40 (8.50) hippocampus as compared to an haloperidol baseline, Age at onset (years) 24.03 (6.39) while other PF areas were instead activated (Lahti et al. Age (years) 31.31 (10.22) 2003b). Education (years) 12.90 (5.51) Pre-clinical data also show that clozapine inhibits the Parental socioeconomic status 2.1 (0.9) metabolic activity in PF and limbic regions in the rat and increases immediate-early gene expression in the same region (Cochran et al. 2002). Along the same lines, Tsai et nicotine or caffeine, drug abuse during the past 3 months al. (2001) have reported a decrease of glucose metabolism (current consumption being ruled out by urinalysis), and in thalamic, limbic, and cortical (including PF) regions in any current treatment with known CNS action. No patient rats following acute and chronic clozapine treatment. had received mood-stabilizers, antidepressants, or depot These results suggest that the superior therapeutic neuroleptics during the 6 months preceding the study. All effects of clozapine in treatment-resistant cases might be patients and controls underwent a cautionary MRI scan to related to its inhibitory effects in the PF region and/or its exclude any abnormality of neurological relevance as limbic connections. That possibility can be addressed by judged by an expert radiologist. After full description of means of a longitudinal study of the activity changes the study to the subjects, written informed consent was resulting from switching from typical neuroleptics to obtained from each patient and from a first-degree relative. clozapine, also considering the extent to which these The research and ethics boards of the participating changes relate to clinical improvement. institutions endorsed the study. Therefore, the objective of this paper is to analyze the effect clozapine has on brain metabolic patterns. 18F- deoxy-glucose positron emission tomography (FDG-PET) Medication status images are analyzed using statistical parametric mapping (SPM) methods to carry out pair-wise comparisons Patients evinced a poor response to at least two different between pre-treatment and post-treatment conditions classical treatments during the previous year, each one using a paired, longitudinal design (i.e. switching from lasting for more than 1 month, at doses above 800 mg/day haloperidol to clozapine) in the same subjects. Further- in CPZ equivalents (Table 2). At the time of the basal scan, more, we assessed the relationship between metabolic and symptom changes to test the functional relevance of Table 2 Treatment status of patients. The two last drugs to which metabolic changes with clozapine. each case was resistant are shown. Doses are expressed in mg/day, in chlorpromazine equivalents. Every case was only treated with haloperidol during the month preceding the first PET scan Materials and methods Patient Gender (M/F) Treatments Dose mg/day Subjects 1 F Haloperidol; thioridazine 850 2 M Haloperidol; thioridazine 900 Our sample included 22 cases (16 males; 19 paranoid and 3 M Pimozide; thioridazine 800 3 undifferentiated patients, according to DSM-IV schizo- 4 M Trifluoperazine; haloperidol 840 phrenia criteria). Diagnosis was confirmed using the SCID 5 F Haloperidol; chlorpromazine 900 (patients version) and data obtained from clinical inter- 6 M Triflouperazine; thioridazine 950 views and information from families and clinical staff. The 7 M Sulpiride; haloperidol 1000 SANS (Andreasen 1983a), SAPS (Andreasen 1983b), and 8 F Haloperidol; thioridazine 900 UKU scale were used to evaluate symptoms and parkin- 9 F Pimozide; trifluoperazine 1200 sonian side effects, respectively, immediately prior to 10 M Haloperidol; thioridazine 920 initiating treatment with clozapine and 6 months later. 11 M Haloperidol; chlorpromazine 800 Symptoms were grouped into the following syndromes 12 M Haloperidol; thioridazine 870 according to the usual convention: positive (delusions and 13 M Sulpiride; chlorpromazine 970 hallucinations), disorganization (formal thought disorder, 14 F Pimozide; thioridazine 1000 bizarre behavior, and attention disorder), and negative 16 M Haloperidol; thioridazine 1200 (alogia, affective blunting, apathy, and anhedonia). The 17 M Pimozide; thioridazine 1100 corresponding scores were calculated as the sum of the 18 F Haloperidol; thioridazine 900 symptoms included in each syndrome, according to SAPS 19 M Haloperidol; chlorpromazine 870 and SANS, not including the global scores (Table 1). Exclusion criteria were: any other axis I diagnosis, any 20 M Haloperidol; thioridazine 860 neurological illness, history of cranial trauma with loss of 21 M Sulpiride; trifluoperazine 1100 consciousness, past substance dependence, excluding 22 M Haloperidol; thioridazine 900 19 all patients were receiving haloperidol at least for the 4 standard PET template included in SPM99 (Gispert et al. weeks preceding the scan. Eleven subjects had abandoned 2003). Images were reformatted to a final voxel size of their medication during the months prior to the
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