Priority CommunicationsPet imaging of serotonin 1A receptor binding in depression
Introduction
The serotonin-1A (5HT1A) receptor system has been implicated in depression by evidence that depressed subjects have blunted physiological responses to 5HT1A receptor agonists in vivo and decreased 5HT1A receptor binding postmortem Bowen et al 1989, Laporte et al 1994, Lopez et al 1998. During 5HT1A receptor agonist challenge, the incremental increases in plasma corticotropin and cortisol concentrations and the decrease in body temperature seen in healthy controls are attenuated in unmedicated subjects with major depressive disorder (MDD) Lesch 1992, Lesch et al 1990a, Maes and Meltzer 1995. The significance of these data remained unclear, however, because the ceiling cortisol concentration achieved in response to 5HT1A agonist challenge in these studies was similar in depressives and controls, and the smaller change seen in MDD may have been accounted for by the elevated baseline cortisol levels in the depressives (Lesch 1992). Postmortem studies of cerebral 5HT1A receptor binding and mRNA expression in MDD and bipolar disorder (BD) subjects provided more direct evidence of 5HT1A receptor dysfunction in mood disorders, but these data remained preliminary, being limited to two studies involving small samples: Lopez et al (1998) showed that 5HT1A receptor mRNA levels were abnormally reduced in the hippocampus in six MDD subjects who died by suicide, and Bowen et al (1989) found reduced 5HT1A receptor binding to [3H]8-OH-DPAT in the temporal polar and frontal opercular cortices in seven medicated depressives with MDD or BD dying of natural causes.
Other postmortem studies investigated 5HT1A receptor binding in samples of unselected suicide victims, that presumably contained subjects suffering from primary mood disorders as well as subjects suffering from depression arising secondary to other psychiatric and medical condi tions. Results differed widely across these studies, as in the hippocampus the 5HT1A receptor binding in unmedicated suicide victims was reported to be decreased (Cheetham et al 1990), trending toward decreased (Lowther et al 1997), not different (Stockmeier et al 1997), and increased (Joyce et al 1993) relative to controls (the latter result, however, might be accounted for by the 30-year difference in mean age between suicides and controls studied by Joyce et al, because 5HT1A receptor Bmax correlated inversely with age in other studies [Dillon et al 1991, Lowther et al 1997, Matsubara et al 1991]). In the raphe, 5HT1A receptor binding was abnormally reduced in one study (Kassir et al 1998) but increased in another (Stockmeier et al 1998) in suicide victims relative to controls. Finally, in the prefrontal cortex (PFC) 5HT1A receptor binding did not differ between suicide and control samples in dorsal or anterior prefrontal cortical areas Arranz et al 1994, Cheetham et al 1990, Dillon et al 1991, Matsubara et al 1991, Stockmeier et al 1997, but was abnormally increased in the ventrolateral PFC (Arango et al 1995). The dissimilar results across studies suggest that abnormalities of 5HT1A receptor binding may be specific to clinical subsets of subjects prone to suicide, rather than being nonspecifically associated with behaviors such as suicide or depressed mood.
Neuroimaging studies using the 5HT1A receptor radioligand, [carbonyl-11C]WAY-100635, to investigate regional 5HT1A receptor binding potential (BP) in clinically well-characterized depressed subjects hold the potential to determine whether abnormalities of 5HT1A binding are specific to mood disordered subgroups. A preliminary PET study comparing PET measures of [11C]WAY-100635 between depressives (n = 8; selected by MDD criteria) and controls (n = 7) reported nonsignificant trends toward reduced 5HT1A receptor BP in the MTC and raphe (Sargent et al 1997). Because these subjects were taking selective serotonin reuptake inhibitor (SSRI) at scanning these trends may have been accounted for by drug effects.
Nevertheless, the trend toward reduced mesiotemporal 5HT1A receptor BP in this study was consistent with the finding of Lopez et al (1998) that suicide victims diagnosed as having MDD by psychological autopsy had reduced 5HT1A receptor mRNA in the hippocampus postmortem. Lopez et al (1998) hypothesized that the cortisol hypersecretion associated with MDD reduced 5HT1A gene expression in the hippocampus, because in rats hippocampal 5HT1A receptor mRNA expression is under tonic inhibition by corticosteroid receptor stimulation. In rats 5HT1A receptor density and mRNA levels in the hippocampus decrease in response to corticosterone administration and chronic stress, and increase after adrenalectomy Bagdv et al 1989, Chalmers et al 1993, Meijer and de Kloet 1994, Mendelson and McEwen 1991, Mendelson and McEwen 1992, Zhono and Ciaranello 1994. The stress-induced down-regulation of 5HT1A receptor expression is prevented by adrenalectomy, showing the importance of circulating adrenal steroids in mediating this effect (Lopez et al 1998).
In contrast, 5HT1A receptors in the raphe seem insensitive to circulating corticosteroids (Chalmers et al 1993). Abnormal 5HT1A receptor binding in this structure in mood disordered samples may instead reflect neuromorphological abnormalities that affect 5HT1A receptor number. Baumann and Bogerts (1998) observed reduced neuronal counts in the dorsal raphe nucleus (DRN) in MDD and BD subjects studied postmortem, and Kassir et al (1998) found the cumulative area of the DRN abnormally reduced in depressed, nonalcoholic, suicide victims.
These data suggest the sensitivity for detecting 5HT1A receptor abnormalities in depressed samples may be enhanced by selecting subjects with a higher likelihood of having glucocorticoid hypersecretion or serotonergic dysfunction. Selection of major depressives with primary BD or familial MDD may prove useful in this regard. Both bipolar depressives and unipolar depressives with familial pure depressive disease (FPDD: primary MDD subjects who have first degree relatives with MDD, but not BD, alcoholism or antisocial personality disorder [ASPD]) have been more likely to show evidence of LHPA-axis hyperactivity than subjects with depression spectrum disease (DSD: primary MDD subjects who have first degree relatives with alcoholism or ASPD but not BD), sporadic depressive disease (SDD: primary MDD subjects with no first degree relatives with MDD, BD, alcoholism, or ASPD) or depression secondary to other psychiatric conditions Arana et al 1985, Lewis et al 1984, Winokur 1982. Moreover, Lewis and McChesney (1985) showed that the mean platelet [3H]imipramine uptake was abnormal in BD and FPDD but not in DSD or SDD, suggesting the former subtypes may more likely manifest serotonergic dysfunction.
In the current study the likelihood of detecting an abnormality of 5HT1A receptor binding was enhanced by selecting subjects with primary mood disorders who had first degree relatives with primary MDD or BD. Because of the small number of subjects imaged, statistical sensitivity was enhanced by reducing comparisons to the two regions where multiple studies demonstrated abnormal 5HT1A receptor BP in depression or suicide, namely the raphe and the hippocampus, and by combining subjects with MDD and BD into a single sample. Differences between depressive subgroups were examined post hoc.
Section snippets
Methods and materials
Entrance criteria for the depressed sample (n = 12) were meeting DSM-IV criteria (American Psychiatric Association 1994) for a current major depressive episode, having a past history of recurrent mood episodes that preceded other medical or psychiatric disorders, and having a first degree relative with primary MDD or BD. Of the 12 subjects entered, 4 had BD, most recent episode depressed (BD-D) and 8 had recurrent MDD (American Psychiatric Association 1994). Of the MDD subjects, 4 had both BD
Results
Demographic characteristics, clinical ratings and laboratory data for the depressed and control samples appear in Table 1. The groups were similar with respect to age and gender composition, but significantly differed for HRSD scores and “stressed” plasma cortisol concentrations (t = 2.4; p < .05; Table 1). The mean volumes of the ROI defined in the MTC did not significantly differ between groups, being 9.73 ± 1.22 mL and 9.01 ± 0.785 mL for the depressives and controls, respectively (t =
Discussion
The mean 5HT1A receptor BP was decreased 42% in the midbrain raphe and 25% to 33% in limbic (MTC) and neocortical areas in depressives relative to controls. The magnitude of these differences seemed most prominent in bipolar depressives and unipolar depressives who had bipolar relatives Table 2, Figure 3. The abnormality in the MTC was consistent with the postmortem data of Lopez et al (1998) showing that the mean 5HT1A receptor mRNA was decreased 31% to 49% across hippocampal subfields in
Acknowledgements
Supported by NIH grants MH59769, MH30915, MH51137, MH54715, and MH52247.
The authors thank Dr. Bruce McEwen for discussions related to the design and interpretation of the image data, Dr. Roger Gunn for providing software and advice on implementing the reference tissue model used in the image analysis, Dr. David Townsend and Dr. Carolyn Meltzer for guidance related to image acquisition and analysis, Shawnette Proper and Rob Sembrat for assistance with image analysis, Sue Morris, RN and Michele
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