Original articleFunctional effects of antipsychotic drugs: comparing clozapine with haloperidol
Introduction
Half a century ago, Delay and Deniker (1952) observed that the sedative drug chlorpromazine has selective antipsychotic activity. The hypothesis that antipsychotic drugs work through dopamine receptor blockade Anden et al 1970, Carlsson and Lindquist 1963 allowed the subsequent development of many effective antidopaminergic compounds. That their antipsychotic potency correlates roughly with dopamine blockade strengthened this hypothesis (Creese et al 1976). Haloperidol is the prototypical first-generation antipsychotic drug. A second generation of antipsychotic drugs was launched with the demonstration that clozapine has superior antipsychotic actions and reduced motor side effects compared with chlorpromazine (Kane et al 1988). This second generation now includes four additional compounds. Clozapine is the prototypical drug of this second generation, by having low motor side effects and a mixed receptor profile. In addition, clozapine has superior antipsychotic action compared with first- and second-generation drugs Breier et al 1999, Conley et al 1998, Wirshing et al 1999.
Functional imaging techniques assess regional neuronal activity in living human brain in response to stimuli, including drug administration. Regional cerebral blood flow (rCBF) patterns can demonstrate relevant central nervous system regions involved in drug action by indicating where specific drugs produce a physiologic brain change. These data are distinct from, but complementary to, neurochemical imaging techniques, which measure the drug occupancy at cerebral receptors Farde 1992, Farde et al 1995, Kapur et al 1998, Okubo et al 1997. The functional techniques sample not only primary neuronal targets but also “downstream” areas affected indirectly by the drug. Improved technologies deliver functional data with greater sensitivity and precision to define these brain regions involved in antipsychotic response.
Numerous publications have reported the effect of chronic antipsychotic drug treatment on regional brain metabolism or blood flow. Early studies reported an increase in basal ganglia metabolism Bartlett et al 1991, Buchsbaum et al 1987, Miller et al 1997, Wolkin et al 1985, Wolkin et al 1996 and reductions in frontal lobe activity Bartlett et al 1991, Wolkin et al 1996; however, these early studies were often complicated by the inclusion of multiple antipsychotics at different dose levels and were performed on lower-resolution machines. More recent studies have focused on the selective study of individual drugs (Holcomb et al 1996) or on contrasting a first- with a second-generation drug Cohen et al 1997, Miller et al 2001. In this project, we studied schizophrenia volunteers scanned with positron emission tomography (PET) and 15O water, both while medication-free and while treated with either haloperidol or clozapine. Our goal was to identify brain regions where these two drugs would show similar and dissimilar patterns of rCBF changes. We hypothesized that regions showing similar rCBF pattern change would identify areas involved in antipsychotic action, whereas distinct rCBF pattern changes between the two drugs would identify areas mediating the motor side effect profile of haloperidol or the superior therapeutic action of clozapine. Based on its preclinical characteristics Chiodo and Bunney 1983, Robertson and Fibiger 1992, White and Wang 1983, we hypothesized that clozapine would show lower dorsal striatal activation, consistent with its lack of motor side effect.
Section snippets
Volunteers
Six medically healthy schizophrenic persons were recruited from the Residential Research Unit of the Maryland Psychiatric Research Center (MPRC) in Baltimore, MD. Each underwent a Structured Clinical Interview for DSM-III-R at hospital admission. Two research psychiatrists reached a consensus diagnosis of schizophrenia based on the clinical interview plus all other sources of data utilizing DSM-III-R criteria.
The schizophrenia volunteer group, all right handed, included five men and one woman
Areas of rCBF increase
Haloperidol increases rCBF in the right ventral striatum and in the left caudate and putamen (Table 2). The increase is also present in the left ventral striatum and right caudate and putamen, respectively, but fails to reach significance (Figure 1, left upper panel). In cortex, haloperidol increases rCBF in a part of the right dorsolateral frontal cortex (Brodmann area [BA] 8/9) (Figure 1, Table 2).
Areas of rCBF decrease
Haloperidol decreases rCBF in the right hippocampus. The decrease is also apparent on the left
Discussion
In this study we describe and contrast rCBF changes induced, from an unmedicated baseline, by a first- and a second-generation antipsychotic, haloperidol and clozapine. Both haloperidol and clozapine increase rCBF in the ventral striatum and caudate nucleus, and both decrease rCBF in the hippocampus and ventrolateral frontal cortex. The rCBF increase associated with haloperidol was greater than that with clozapine in the dorsal and ventral striatum; the rCBF increase with clozapine was greater
Acknowledgements
The William K. Warren Medical Research Institute and the National Institute of Mental Health grants ROIMH57971 (ACL) and P30-MH40279 Intervention Research Center Grant supported this work.
The authors thank all the volunteers with schizophrenia who took part in this project; Dale Warfel, Tamara Michaelidis, Michael Hardin, and the nursing staff of the Residential Research Unit of the Maryland Psychiatric Research Center for clinical care; Kristen Frey for statistical expertise; and Tonia Austin
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