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No Evidence of Altered in Vivobenzodiazepine Receptor Binding in Schizophrenia

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No Evidence of Altered in Vivobenzodiazepine Receptor Binding in Schizophrenia No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia Anissa Abi-Dargham, M.D., Marc Laruelle, M.D., John Krystal, M.D., Cyril D’Souza, M.D., Sami Zoghbi, Ph.D., Ronald M. Baldwin, Ph.D., John Seibyl, M.D., Osama Mawlawi, Ph.D., Gabriel de Erasquin, M.D., Ph.D., Dennis Charney, M.D., and Robert B. Innis, M.D., Ph.D. Deficits in gamma-amino-butyric acid (GABA) of this measurement was established in four healthy neurotransmitter systems have been implicated in the volunteers. No differences in regional BDZ VT were pathophysiology of schizophrenia for more than two observed between 16 male schizophrenic patients and 16 decades. Previous postmortem and in vivo studies of matched controls. No relationships were observed between benzodiazepine (BDZ) receptor density have reported BDZ VT and severity of psychotic symptoms in any of the alterations in several brain regions of schizophrenic regions examined. In conclusion, this study failed to patients. The goal of this study was to better characterize identify alterations of BDZ receptors density in possible alterations of the in vivo regional distribution schizophrenia. If this illness is associated with deficits in volume (VT) of BDZ receptors in schizophrenia, using the GABA transmission, these deficits do not substantially selective BDZ antagonist [123I]iomazenil and single photon involve BDZ receptor expression or regulation. emission computerized tomography (SPECT). Regional [Neuropsychopharmacology 20:650-661, 1999] BDZ VT was measured under sustained radiotracer © 1999 American College of Neuropsychopharmacology. equilibrium conditions. The reproducibility and reliability Published by Elsevier Science Inc. KEY WORDS: Schizophrenia; Benzodiazepine receptors; that disinhibition of dopamine function in schizophre- [123I]iomazenil; SPECT nia may stem from a deficit in inhibitory, GABA medi- ated systems (Roberts 1972; Stevens 1975; van Kammen Alterations of gamma-amino-butyric acid (GABA) sys- 1977). In addition, postmortem studies have reported tem have been implicated in the pathophysiology of alterations in regional concentrations of several mark- schizophrenia for more than two decades. The recogni- ers of the GABAergic system in schizophrenia. tion that GABA has an inhibitory effect on dopamine In accordance with the hypothesis of a GABA de- transmission prompted several authors to postulate ficit in schizophrenia, GABAergic cells and markers of GABAergic cells have usually been reported to be de- creased in postmortem studies in patients with schizo- From the Departments of Psychiatry and Diagnostic Radiology (AA-D, ML, JK, CD’S, SZ, RMB, JS, GDE, DC, RBI), Yale University phrenia (Bird et al. 1977; Perry et al. 1979; Simpson et al. School of Medicine, New Haven, and VA Connecticut Healthcare 1989; Reynolds et al. 1990; Benes et al. 1991; Sherman et System, West Haven, Connecticut; and Department of Psychiatry al. 1991; Akbarian et al. 1995b; Beasley and Reynolds and Radiology (AA-D, ML, OM), College of Physicians and Sur- geons, Columbia University, New York, and New York State Psy- 1997). However, few of these observations have been chiatry Institute, New York, New York. replicated (Bennett et al. 1979; Cross et al. 1979; Akbar- Address correspondence to: Anissa Abi-Dargham, New York ian et al. 1995b; Woo et al. 1997). State Psychiatric Institute, Unit 42, 1051 Riverside Dr, New York, NY, 10032 As far as postsynaptic markers are concerned, in- 3 Received May 19, 1998; accepted October 1, 1998. creased binding of the GABAA receptor agonist [ H]mus- NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 6 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00107-9 NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 6 Benzodiazepine Receptors in Schizophrenia 651 cimol has been consistently reported in prefrontal cor- is insensitive to possible group differences in blood tex, caudate nucleus, hippocampus and cingulate flow and peripheral clearance which affect semi-quanti- cortex in schizophrenia (Hanada et al. 1987; Benes et al. tative methods following single bolus injection (Carson 1992; Benes et al. 1996). However, GABAA receptor sub- et al. 1992). In addition, regions of interest (ROI) were units mRNA was unchanged in prefrontal cortex (Ak- identified following coregistration with MRI. This method barian et al. 1995a). Benzodiazepine receptors have yields several potential outcome measures, depending been reported to be unchanged in the hippocampus on the nature of the concentration parameter used in and prefrontal cortex (Reynolds and Stroud 1993; Benes the denominator of the distribution volume ratio. The et al. 1997; Pandey et al. 1997), decreased in hippocam- first goal of this investigation was to assess the repro- pus, anterior cingulate cortex, somatomotor cortex, cer- ducibility and reliability of each candidate outcome ebellum, globus pallidus (Squires et al. 1993), and in- measure in a test/retest study in four healthy subjects. creased in frontal, temporal and putamen (Kiuchi et al. The second goal was to compare BDZ receptor density 1989). The increase in [3H]muscimol binding to the between patients with schizophrenia and healthy con- / GABA binding site of the GABAA BDZ receptor com- trols using the most reliable outcome measure. plex, in the face of unchanged BDZ receptor binding in some regions of schizophrenic brains, has been inter- preted as indicating an uncoupling of GABAA and BDZ MATERIALS AND METHODS receptors in schizophrenia (Benes et al. 1997). Thus, the Subjects overall picture is suggestive of a functional and/or structural decrease in GABAergic activity, possibly as- The study was performed according to protocols ap- sociated with a compensatory regulation of postsynap- proved by the Yale School of Medicine and VA Con- tic receptors. Still, many contradictory reports have necticut at West Haven Institutional Review Boards. been published, and most of these findings await inde- Patients were recruited from the VA Connecticut at pendent replication. West Haven. Study criteria for patients with schizo- In contrast to the abundant postmortem literature, phrenia were as follows: 1) diagnosis of schizophrenia very few in vivo studies of GABA transmission in according to Diagnostic and Statistical Manual (DSM- schizophrenia have been reported. Busato et al. (1997) IV); 2) no other DSM-IV axis I diagnosis; 3) no history of using SPECT and the BDZ receptor radiotracer [123I]iom- alcohol or substance abuse or dependence; 4) absence of azenil, reported no regional differences in the uptake of benzodiazepine administration for at least 21 days; 5) [123I]iomazenil between 15 patients with schizophrenia no concomitant or past severe medical conditions; 6) no and 12 healthy controls. In the schizophrenic group, se- pregnancy; 7) no metallic objects in the body; and 8) verity of positive symptoms was associated with de- ability to provide informed consent. Patient clinical creased [123I]iomazenil uptake in the left medial tempo- evaluation at intake included the Positive and Negative ral region, and severity of negative symptoms was Symptoms Scales (PANS) (Kay et al. 1987), a scale that correlated with decreased medial frontal [123I]iomazenil includes the Brief Psychiatric Rating Scale (BPRS) uptake. However, these correlations were not signifi- (Overall and Gorham 1962), and the AIMS (Munetz and cant after Bonferroni correction. Schröder et al. (1997) Benjamin 1988). Since BDZ receptor density is not con- investigated [123I]iomazenil binding in 20 patients with sistently affected by chronic antipsychotic administra- schizophrenia, but no control group was studied. They tion (Gavish et al. 1988; Giardino et al. 1991), neurolep- reported that BPRS scores were correlated with in- tic withdrawal was not required for this study. creased [123I]iomazenil binding in the medial prefrontal Study criteria for healthy controls were: 1) absence of cortex. Both studies were semi-quantitative and, as past or present neurological or psychiatric illnesses; 2) such, are subject to numerous potential artifacts. Yet, absence of concomitant or past severe medical condi- these reports suggested that BDZ receptors density tions; 3) no pregnancy; 4) no metallic objects in the might be associated with symptomatic features of body; and 5) informed consent. Healthy controls were schizophrenia. group matched to patients for age (65 years), gender, In the present study, we used the constant infu- and race. Four healthy controls were scanned twice, at 1 sion/sustained equilibrium paradigm with SPECT and to 2 week intervals, to evaluate the reproducibility and [123I]iomazenil (Laruelle et al. 1993, 1994; Abi-Dargham reliability of the measurements. et al. 1994b; Lassen 1996) to examine possible alter- ations of BDZ receptor binding potential (BP) in 16 pa- Radiolableing tients with schizophrenia and 16 matched controls, and to study possible relationships of regional BDZ receptor Sodium [123I]iodide (no-carrier-added in 0.1 M NaOH) density with symptomatology. In contrast to the semi- was purchased from Nordion International, Vancouver, quantitative methods used in the above-described stud- B.C. [123I]Iomazenil is a high affinity antagonist of the / 5 8 ies, the constant infusion sustained equilibrium method BDZ receptor (KD 0.35 nM at 22 C) (Beer et al. 1990; 652 A. Abi-Dargham et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 6 Laruelle et al. 1994).
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