Cerebral benzodiazepine receptors in depressed patients measured with [123i]iomazenil SPECT
Introduction
Several reports have suggested abnormalities of γ-aminobutyric acid (GABA) neurotransmission in depression. Others have reported low GABA levels in plasma (Petty et al 1990) and cerebrospinal fluid Gerner et al 1984, Gerner and Hare 1981, Gold et al 1980, Kasa et al 1982, and our group recently reported reduced cortical GABA levels measured in vivo with magnetic resonance spectroscopy (MRS) in patients with major depression (Sanacora et al 1999). GABAA receptors are the major transducer of inhibitory transmission in the central nervous system and are the molecular targets of benzodiazepines (BZs; Barnes 1996); BZ agonists bind allosterically on the GABAA receptor and enhance GABA-mediated chloride conductance (Tallman and Gallager 1985). Changes in GABA affect BZ binding and GABAA-BZ coupling (Tallman et al 1978). In light of the important inhibitory and anxiolytic roles of the GABAA receptor, BZ or GABAA receptor radioligand binding has been extensively investigated in relation to stress and psychiatric disorders. Chronic stress in rodents decreased BZ binding in the frontal cortex, hippocampus, and hypothalamus, with mixed results for cerebellum, midbrain, and striatum Drugan et al 1989, Weizman et al 1990. Learned helplessness, a well-replicated animal model of depression, caused increased GABAA receptor binding in the rat septum, but not in the frontal cortex or hippocampus (Kram et al 2000). In the frontal cortex, BZ binding was increased Cheetham et al 1988, Pandey et al 1997 or unaltered (Crow et al 1984) and unaltered Crow et al 1984, Stocks et al 1990 or decreased in hippocampus Manchon et al 1987, Rochet et al 1992 in suicide victims. Cheetham et al (1988) found an 18% increase in [3H]flunitrazapam binding in Brodmann’s area 10 of suicide victims who had clear evidence of depression. The increase was significant only in the depressed suicide victims taking antidepressants, however, not in patients without medication treatment at the time of death. Pandey et al (1997) measured BZ binding with the antagonist [3H]Ro 15–1788 in these same regions of violent-suicide victims, including some depressed patients. They found twofold elevated BZ binding in suicides by violent compared with nonviolent means. This report did not directly study depressed patients, and the elevation seemed to be attributed to high suicidality or impulsivity rather than to depression. As for hippocampus, one study on suicides with clear evidence of depression failed to find any change in hippocampal BZ binding (Stocks et al 1990), whereas other studies on suicides with unclear diagnosis are controversial Manchon et al 1987, Rochet et al 1992. Thus, these previous studies suggested that unmedicated depressed patients without high suicidality have unaltered BZ binding in the frontal cortex and hippocampus.
In this study, we aimed to investigate in vivo BZ binding in unmedicated depressed patients compared with healthy subjects using single photon emission computed tomography (SPECT). We measured BZ binding with [123I]iomazenil, an antagonist with weak inverse agonist activity (Johnson et al 1990). In previous studies, SPECT imaging with this tracer has provided reliable measurements of patients with alcoholism (Abi-Dargham et al 1998), panic disorder (Bremner et al 2000a), and schizophrenia Abi-Dargham et al 1999, Verhoeff et al 1999b and also receptor occupancy by BZ agonist treatment in human subjects (Fujita et al 1999). Because potential decreased gray matter volumes have been reported in the frontal cortex Coffey et al 1993, Drevets et al 1997, Krishnan et al 1992, Shah et al 1998, hippocampus Bremner et al 2000b, Sheline et al 1996, and amygdala (Sheline et al 1998) of depressed patients, although previous reports are not necessarily consistent as reviewed Sheline 2000, Soares and Mann 1997, we conducted gray matter volume correction before the voxel-by-voxel statistical parametric mapping (SPM) analysis (Friston et al 1995). As a secondary objective, we also measured tissue GABA levels in the occipital cortex with proton MRS to examine the potential relationship between the transmitter (GABA) and its predominant postsynaptic receptor (GABAA).
Section snippets
Subjects
Thirteen depressed patients (Table 1) who met the criteria for major depressive disorder by the Structured Clinical Interview for DSM-IV (First et al 1995) participated in this SPECT study (nine male and four female patients, 39.7 ± 9.8 years, with these and subsequent data expressed as mean ± SD). Each depressed patient had routine tests (complete blood count, electrolytes, thyroid function), electrocardiogram, and physical examination to rule out active medical and neurologic disorders. No
Occipital GABA level
The mean values for GABA level were 1.05 ± 0.46 mmol/kg for six depressed patients and 1.46 ± 0.30 mmol/kg for the 12 control subjects (1.55 ± 0.35 mmol/kg for the newly reported 5 control subjects). The level was significantly lower in depressed patients than in control subjects (F = 5.38, df = 1,16, p = .03) (Figure 1).
Benzodiazepine binding
The depressed and control groups did not differ with regard to several SPECT imaging parameters, including injected dose, bolus-to-infusion ratio, and the time of scan (data
Discussion
To our knowledge, this is the first in vivo investigation of BZ binding in depressed patients. No significant alterations of BZ binding were found in the depressed patients, although a subgroup showed the previously described decrease in tissue GABA levels measured with MRS. The patients were all unmedicated and without a recent history of suicide attempt, which enabled us to evaluate the effect of depression itself on BZ binding.
Because the regions where alterations in BZ binding were
Acknowledgements
This research was supported in part by funds from the Department of Veterans Affairs Research Enhancement Award Program (REAP) Center on “Neural Mechanisms and Treatment Response in Depression” at the VA Connecticut Healthcare System, West Haven Campus. The authors gratefully acknowledge the staff at the Institute for Neurodegenerative Disorders for technical assistance in collecting the data; L. Amici for radiochemical synthesis; and S. Giddings, A. Burke, and L. Dickerson for subject
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