Imaging of the serotonergic system: interactions of neuroanatomical and functional abnormalities of depression

Imaging of the Serotonergic System: Interactions of Neuroanatomical and Functional Abnormalities of Depression Julie K. Staley, Robert T. Malison, and Robert B. Innis For nearly three decades, evidence supporting a role for aberrant serotonergic function in the pathogenesis of depression has accumulated; however, only recently have methodologies and radiotracers suitable for in vivo clinical assessment of depression become available. To date, only a few neurochemical imaging studies have been performed in actively depressed subjects. A preliminary study using single photon emission computed tomography (SPECT) has demonstrated decreased levels of serotonin (5-HT) transporters in the midbrain regions of subjects with major depression. Analysis of the 5-HT2 receptor using positron emission tomography (PET) has suggested that this receptor may not be altered significantly in the depressed brain but may increase in response to antidepressant treatment. These findings are supported by studies in secondary “poststroke” depression that have shown that elevations in 5-HT2 receptor density correlated with the alleviation of symptoms of depressed mood. With the rapid development of novel PET and SPECT radiotracers, future studies of the serotonergic system that evaluate presynaptic (5-HT transporter) and postsynaptic (5-HT1A and 5-HT2A receptors) markers and the interaction of synaptic levels of 5-HT with these sites will make profound contributions to the understanding of the role of the serotonergic synapse in the pathophysiology of depression. Biol Psychiatry 1998;44:534 –549 © 1998 Society of Biological Psychiatry Key Words: Depression, positron emission tomography, single photon emission computed tomography, serotonin transporter, serotonin receptors, tryptophan hydroxylase

Introduction

D

epression is characterized by impairments in core physiological behaviors including mood, sleep, appetite, and cognition. Depressed mood, the cardinal feature

From the Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (JKS, RBI); Veteran Affairs Medical Center, West Haven, Connecticut (JKS, RBI), and Connecticut Mental Health Center, New Haven, Connecticut (RTM). Address reprint requests to Julie K. Staley, PhD, Department of Psychiatry, Yale University School of Medicine and VA Medical Center/116A2, 950 Campbell Avenue, West Haven, CT 06516. Received December 17, 1997; revised April 2, 1998; accepted April 9, 1998.

© 1998 Society of Biological Psychiatry

of depression, has been suggested to be regulated in part by abnormal serotonin (5-HT) function (Maes and Meltzer 1995; Meltzer 1990). Pharmacologic retardation of 5-HT neurotransmission by depletion of 5-HT stores with reserpine, depletion of 5-HT precursor (tryptophan), or inhibition of 5-HT synthesis, precipitates symptoms of depression in healthy and in remitted depressed subjects (Delgado et al 1990; Maes and Meltzer 1995; Meltzer 1990; Young et al 1985). On the contrary, pharmacologic agents that facilitate 5-HT neurotransmission including precursor (L-tryptophan and/or 5-hydroxytryptophan) loading, nonselective serotonin agonists, monoamine oxidase inhibitors, and 5-HT reuptake inhibitors, elevate mood in healthy and depressed subjects (Maes and Meltzer 1995; Meltzer 1990). Sleep disturbances exhibited by depressed subjects also may be induced in part by dysregulation of 5-HT systems. Pharmacologic modulation of 5-HT function has demonstrated that 5-HT modulates the onset and length of REM latency (Fornal and Radulavacki 1983; Sharpley and Cowen 1995). Likewise, extensive literature (Bever and Perry 1976) supporting a role for 5-HT in appetite control suggests that alterations in 5-HT neurotransmission also may contribute to this symptom of depression. While disturbances in 5-HT circuits are believed to play a critical role in depressive symptomatology, it is likely that disturbances in other neurotransmitter systems and the cross talk between them also contribute to the pathophysiology of depression. Since 5-HT plays a key role in the fundamental expression of many of the core behaviors associated with depression, aberrant 5-HT neurotransmission was hypothesized to play an integral (but not exclusive) role in the pathogenesis of depression (Maes and Meltzer 1995; Meltzer 1990). This hypothesis is supported by a multitude of studies that have demonstrated that measures of 5-HT function, including basal cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels, plasma tryptophan levels, blood platelet 5-HT function, and hormonal response to 5-HT specific neuroendocrine challenge agents, are blunted in depressed subjects (Asberg et al 1976; Elliott 1991; Maes and Meltzer 1995; Meltzer 1990; 0006-3223/98/$19.00 PII S0006-3223(98)00185-1

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Owens and Nemeroff 1994). Furthermore, most antidepressants target markers within the 5-HT neural network, suggesting that pharmacologic manipulation of 5-HT neurotransmission alleviates symptoms of depression (Owens et al 1997). At present, little is known about the status of various 5-HT synaptic markers in the depressed brain. The majority of brain neuropharmacology studies have been carried out in postmortem tissue specimens from suicide victims. Although these studies have identified putative neural substrates that may be relevant to the pathogenesis of depression, they are limited by 1) inaccurate retrospective case histories, 2) lack of diagnosis of comorbid neuropsychiatric disorders, 3) insufficient knowledge of antidepressant or drug treatment histories, 4) inability to control interindividual clinical parameters that might alter brain neurochemical measurements, and 5) a single measurement at the end stage of the disease. Furthermore, even though many suicide victims are depressed, the neurochemical etiologies of depression and suicide may be distinct and thus exhibit different alterations in receptor and transporter regulation. The advent of in vivo brain imaging modalities such as positron emission tomography (PET) and single photon emission tomography (SPECT) now affords the opportunity to investigate the state of the 5-HT synapse in living depressed subjects. When combined with enzyme-, receptor-, and transporter-specific radiotracers, these imaging techniques can provide in vivo measures of multiple neurochemical functions, including the synthesis and release of transmitters, the regulatory status of receptors and transporters, and the kinetics of metabolic enzymes and second messenger systems. In vivo imaging techniques are advantageous in that they allow the study of a multitude of synaptic markers at several different time points during the course of an illness (Frost 1990). By imaging wellcharacterized depressed subjects prior to antidepressant exposure, during the course of treatment, and after a remitted, drug-free interval, these tools may serve to delineate “state” and “trait” markers of depression. Furthermore, PET and SPECT imaging can be used to assess the occupancy of a receptor site by a medication that would aid in the individualization of drug therapy and may serve to decrease side effects and risks sometimes associated with the administration of neuropsychiatric medications (Frost 1990). In addition, an understanding of the critical neurochemical adaptations responsible for antidepressant efficacy may lead to the development of more rapid-acting and effective treatments. This article reviews the current state of development of radiotracer probes for PET and SPECT imaging of serotonergic function and describes the findings from in vivo neuroimaging studies of serotonergic synaptic function in depression. These studies illustrate the power and the limitations of modern

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brain imaging techniques, the contributions they have already made, and the potential they hold for elucidating the role of 5-HT neural circuits in the pathophysiology of depression.

The Serotonergic System The brain serotonin system is the single largest brain system known and can be characterized as a “giant” neuronal system. (Azmitia and Whitaker-Azmitia 1991)

Serotonergic neurons originate in the dorsal and median raphe nuclei of the brain stem and project nerve terminals to virtually every region of the brain with primary targets including the substantia nigra, hypothalamus, thalamus, amygdaloid– hippocampal area, caudate, putamen and nucleus accumbens, and cerebral cortical areas including the frontal, occipital, insular, parietal, temporal, and cerebellar cortices (Azmitia and Whitaker-Azmitia 1991). Serotonergic neurotransmission is mediated by interactions of 5-HT with a heterogeneity of receptor subtypes that are distinguished by differences in molecular structure, anatomical localization, signal transduction mechanisms, and pharmacologic responses to 5-HT receptor agonists and antagonists. To date, at least 16 molecularly distinct receptor subtypes have been identified (Bonvento and MacKenzie 1997). Using pharmacologic methodologies, the ability to quantitate individual 5-HT receptor subtypes is limited and often only permits quantitation and neuropharmacologic localization of “families” of receptor subtypes. The 5-HT receptor subtypes have been subdivided into families, including the 5-HT1 receptor family, 5-HT2 receptor family, 5-HT3 receptor (an ion channel), 5-HT4 receptor family, and others, 5-HT5A, 5-HT5B, 5-HT6, and 5-HT7 (Bonvento and MacKenzie 1997). In addition to the multitude of receptors, the 5-HT transporter is a reliable presynaptic marker (Bonvento and MacKenzie 1997). Dysregulation of 5-HT neurotransmission in depression may occur as a consequence of abnormalities in any one or more of these 5-HT neural targets. Furthermore, alterations in synthesis, storage, release, reuptake, or metabolism may disturb 5-HT neurotransmission. Radiotracer development for PET and SPECT imaging studies is still in its youth. At present, radiotracers have been developed only for the 5-HT1A receptor and 5-HT2A receptor subtypes, and the 5-HT transporter, thus in vivo imaging studies of the serotonergic synapse in depression are limited.

The Presynaptic 5-HT Transporter Serotonergic neurotransmission may be altered in depression due to regulatory changes in the 5-HT transporter (Owens and Nemeroff 1994). The 5-HT transporter is located on the presynaptic membrane 5-HT cell bodies in

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the raphe nuclei, and in the vicinity of 5-HT terminal projections throughout the basal ganglia, and cerebral cortex where it functions to regulate 5-HT signaling by modulating 5-HT levels in the synapse (Cooper et al 1996). The 5-HT transporter is the principal target of many efficacious antidepressants, suggesting that alterations in this protein may play a role in the pathogenesis of depression (Owens et al 1997; Owens and Nemeroff 1994). Recent research efforts have focused on the development of radiotracers for imaging the 5-HT transporter in vivo using PET and/or SPECT methodologies. Several selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, dapoxetine (an analog of fluoxetine), paroxetine, and citalopram have been radiolabeled for potential use as radiotracers for PET and SPECT (Hume et al 1991; Livini et al 1994; Scheffel et al 1990; Shiue et al 1995; Villemangne et al 1989); however, due to high nonspecific binding and/or difficulties in radiolabeling, many of these tracers have proven to be unsuitable for in vivo imaging studies. For SPECT, [123I]b-CIT (1R)-2 b-Carbomethoxy3b-(4-iodophenyl)tropane (Laruelle et al 1993b) and [123I]-5-iodo-6-nitroquipazine ([123I]INQUIP) (Jagust et al 1995), and for PET, [11C]McN5652Z (Szabo et al 1995; Suehiro et al 1993), 11C-RTI-55 (Malizia et al 1997), and [11C]nor-b-CIT (Bergstrom et al 1997) have demonstrated some utility. The cocaine congener, [123I]b-CIT (also called RTI-55) has been used with some success to study the 5-HT transporter in vivo in some brain regions. Although b-CIT binds to the 5-HT transporter with high affinity, it suffers from a lack of selectivity, since it binds also to the dopamine (DA) transporter (Boja et al 1992; Little et al 1993; Staley et al 1994). Nevertheless, in vivo displacement studies of [123I]b-CIT labeling in nonhuman primates using selective DA, 5-HT, and norepinephrine transport inhibitors suggest that the vast majority of midbrain uptake reflects labeling of the 5-HT transporter, with no noticeable displacement by DA transporter-selective compounds (Laruelle et al 1993b). Furthermore, human studies have shown displacement of midbrain [123I]b-CIT uptake by the SSRI citalopram (Pirker et al 1995). Nonetheless, some component of [123I]b-CIT midbrain uptake is likely to reflect binding to the DA transporter on dopaminergic cell bodies in the substantia nigra. The des-methyl analogue of b-CIT, nor-b-CIT, has been proposed to be a more suitable ligand for in vivo imaging of the 5-HT transporter (Bergstrom et al 1997). Nor-b-CIT exhibits 10-fold higher affinity for binding to 5-HT transporter as compared to the DA transporter; however, since there is a tenfold higher density of DA as compared to 5-HT transporters in the striatum, the majority of labeling is still primarily to the DA transporter (i.e., density driven) as demonstrated by the inability of citalopram to displace striatal labeling (Bergstrom et al 1997).

J.K. Staley et al

And, although it was postulated that nor-b-CIT may be a sensitive measure of cortical 5-HT transporters, only 20% of [11C]nor-b-CIT labeling was displaced in the thalamus and neocortex, suggesting that cortical labeling was not significantly higher than background (Bergstrom et al 1997). Difficulties detecting cortical 5-HT transporters also have been observed using [123I]INQUIP. While the ratio of specific to nonspecific brain uptake [i.e., V30 5 (region of interest 2 background region)/background region] resulted in values near 3 for brain stem regions, they were only 1–1.5 for frontal and temporal cortex. [123I]INQUIP also suffers from rapid peripheral metabolism and high nonspecific binding (Jagust et al 1995). The PET radiotracer [11C]McN5652 (Suehiro et al 1993; Szabo et al 1995) demonstrated high uptake in the thalamus, midbrain, hypothalamus, and pons, as well as intermediate levels of uptake in the cerebral cortex; however, the midbrain and cortex to cerebellum ratios were 1.8 and 1.0 respectively, indicating low target to background ratios. Furthermore, the specificity of [11C]McN5652 labeling remains to be assessed by displacement studies with other monoamine transport inhibitors. Although some of the aforementioned tracers show promise for in vivo imaging of the 5-HT transporter, many are limited by extensive metabolism, excessive nonspecific binding, poor selectivity, and altered pharmacokinetics. Thus, in vivo imaging of the 5-HT transporter would clearly benefit from the development of a radiotracer with enhanced selectivity for the 5-HT transporter and high levels of specific uptake in cortical brain regions as well as in the midbrain. Recently, the status of the 5-HT transporter in living depressed subjects has been studied using [123I]b-CIT and SPECT (Malison et al in press). Based on previous platelet and postmortem findings (Table 1), it was hypothesized that lower levels of midbrain [123I]b-CIT binding would be observed in depressed subjects. Subjects met DSMIII-R criteria for unipolar major depressive disorder and were antidepressant-free for at least 3 weeks prior to SPECT scanning. Measurements of [123I]b-CIT uptake were taken under equilibrium conditions (i.e., 24 6 2 hours). [123I]b-CIT labeling was markedly decreased in the midbrain, but not the striatum, of depressed subjects. Ratios of specific i.e., {V30 5 (midbrain 2 occipital)/ occipital}[123I]b-CIT labeling in the midbrain were decreased by 20% in depressed subjects as compared to ageand gender-matched control subjects. Furthermore, if 1 healthy or depressed subject outlier was eliminated, then more than half of all depressed subject values were less than those of healthy subjects. In contrast, striatal V30 values for [123I]b-CIT labeling of the DA transporter were similar between groups. These findings extend and support a previous in vivo study, which suggested that [123I]b-CIT uptake was reduced throughout the cortex in a single

Imaging the Serotonin Synapse in Depression

depressed subject who had been drug-free for 72 hours prior to scanning (Kuikka et al 1995). These findings suggest that 5-HT transporter densities are lower in midbrain regions of subjects suffering from depression. Interestingly, it has been suggested that decreased phenotypic expression of the 5-HT transporter may be associated with a short variant of the human 5-HT transporter gene, an allele that may occur at a higher frequency in patients vulnerable to mood disorders (Collier et al 1996; Ogilvie et al 1996). While this hypothesis is provocative, future studies that directly correlate the expression of the short variant of the 5-HT transporter gene with its phenotypic expression as measured using PET and SPECT methodologies will help to determine the pathophysiological relevance of this finding. Prior to the introduction of in vivo neuroimaging methodologies, efforts to understand the state of the 5-HT system in the living depressed brain relied on the evidence indicating similarities in the pharmacologic and biochemical characteristics of the 5-HT transporter between platelets and brain. Researchers hypothesized that the status of the 5-HT transporter in the depressed brain could be assessed indirectly by measurement of its platelet analog. Over 70 studies of platelet 5-HT transporter binding have been conducted since the original report, and a majority (65–75%) of these investigations have demonstrated decreased platelet [3H]imipramine binding in depressed subjects (Briley et al 1980; Elliott 1991; Ellis and Salmond 1994). To determine if the platelet 5-HT transporter is an adequate peripheral marker of brain 5-HT transporters, [3H]paroxetine binding was performed on platelet samples from the same healthy control and depressed subjects who participated in the SPECT imaging study. Interestingly, no appreciable difference in platelet [3H]paroxetine binding affinity (KD), density (Bmax), or binding potential (BP) (i.e., BP 5 Bmax/KD) was observed between groups (Malison et al in press). Furthermore, no significant relationship between platelet [3H]paroxetine Bmax or BP and midbrain [123I]b-CIT uptake was detected. Thus, although in vivo SPECT measures of midbrain 5-HT transporter availability agree with some previous reports of reduced postmortem [3H]imipramine binding in cortical and midbrain regions of depressed suicides (Crow et al 1984; Gross-Isseroff et al 1989; Laruelle et al 1993a; Paul et al 1984; Perry et al 1983; Stanley et al 1982, 1986), they do not provide strong support for the hypothesis that platelet 5-HT transporter function serves as a marker for brain 5-HT transporter function (Malison et al in press). These findings are surprising given the wealth of evidence supporting decreased platelet [3H]imipramine binding in depressed subjects (Briley et al 1980; Elliott 1991; Ellis and Salmond 1994) and the recent studies that demonstrated that human brain and platelet 5-HT transporter are

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encoded by the same single copy gene (Lesch et al 1993). A potential source of variation between the two measures is the radioligand used to measure 5-HT transporter number. Differences in radiotracer sensitivity to residual antidepressant drugs or metabolites sequestered within the membrane (Mellerup and Plenge 1990) or their binding domains on the 5-HT transporter may account for the lack of correlation between the brain and platelet 5-HT transporters; however, the depressed subjects were free of antidepressant drugs for at least 3 weeks prior to imaging. A paucity of studies on long-term residual effects from withdrawal from different classes of antidepressants precludes this explanation. Alternatively, the two distinct classes of 5-HT reuptake inhibitors may exhibit distinct binding interactions with different “states” of the 5-HT transporter. Given the findings of Malison and colleagues, this would suggest that the CIT-sensitive, but not the SSRI-sensitive binding site is decreased in depressed subjects. The hypothesis for unique interactions of distinct 5-HT reuptake inhibitors with the 5-HT transporter is supported by the demonstration of two binding sites for imipramine and only one for citalopram on the cloned 5-HT transporter (Schloss et al 1995). If b-CIT is similar to imipramine and binds to two sites on the 5-HT transporter (Staley et al 1994), and paroxetine is similar to citalopram, the differences observed between brain and platelet 5-HT transporters may be a result of differential regulation of the imipramine/b-CIT and SSRI recognition sites. These hypotheses may explain why some studies have failed to detect decreased 5-HT transporter densities in depressed suicides (Table 1) (Arora and Meltzer 1989a, 1991; Ferrier et al 1990; Lawrence et al 1990a; Little et al 1997; Meyerson et al 1982; Owen et al 1986). Future studies comparing the regulation of the brain and platelet 5-HT transporter using the same radiotracer will determine the validity of this hypothesis.

The 5-HT1 Receptor Family The 5-HT1 receptor family is comprised of at least five subtypes including the 5-HT1A, 5-HT1B/1Da, 5-HT1Db, 5-HT1E, and 5-HT1F receptors. The majority of neuropharmacologic studies have relied on the high affinity of 5-HT for this receptor family. Since [3H]5-HT has often been the radiotracer of choice for in vitro assays, it is likely that the resulting measurements are of multiple receptor subtypes. Therefore, it is difficult to ascertain which receptor subtype has altered regulation. Although it is not possible to selectively measure each of the 5-HT1 receptor subtypes, ligands [(6)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or WAY-100635] that are suitable for selective measures of the 5-HT1A receptor subtype are available.

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The 5-HT1A autoreceptor is located presynaptically on serotonergic somatodendritic cell bodies in the raphe nuclei, where it functions to decrease 5-HT neurotransmission. High densities of postsynaptic 5-HT1A receptors have been localized to limbic areas, including the hippocampus, septum, amygdala, and entorhinal and frontal cortex, where they serve to mediate the effects of released 5-HT (Jacobs and Azmitia 1992; Palacios et al 1991). Dysregulation of the 5-HT1A autoreceptor, the postsynaptic receptor, or both may play a role in the pathogenesis of depression. Postmortem studies in suicide victims with a retrospective diagnosis of depression have demonstrated increased binding of [3H]8-OH-DPAT in frontal cortex. Alternatively, decreased [3H]8-OH-DPAT binding was observed in the pars opercularis and temporal lobe of aged depressed subjects (Bowen et al 1989). In contrast, no significant alterations in 5-HT1 receptor densities were detected when [3H]5-HT was used to measure the density of 5-HT1 receptors (Cheetham et al 1990; Crow et al 1984; Ferrier et al 1990; Mann et al 1986; McKeith et al 1987; Owen et al 1983, 1986). Since [3H]5-HT does not distinguish between 5-HT receptor subtypes, the findings and their relevance to the status of 5-HT1 receptors in depression should be interpreted with caution. These findings demonstrate the need for studies using highly selective radiotracers to clearly delineate the role of the 5-HT1 receptor family in depression. The status of the 5-HT1A receptor in actively depressed subjects has not been studied yet due to the paucity of radiotracers suitable for in vivo imaging. The first highly selective and potent 5-HT1A receptor antagonist, [11C]WAY-100635, is presently under development for in vivo imaging. In the initial study [11C]WAY-100635 demonstrated high uptake in frontal, insular, and entorhinal cortex and hippocampus, and low uptake in the thalamus, hypothalamus, basal ganglia, and cerebellum (Pike et al 1995a, 1995b). Further analysis indicated that a radiolabeled lipophilic metabolite was formed, which entered the brain, causing high nonspecific uptake and decreasing the ratio of specific to nonspecific binding (Osman et al 1995). Moreover, the radiolabeled metabolite bound with high affinity to the a1 adrenergic receptor as well as to the 5-HT1A receptor. In an effort to eliminate the pharmacologically active radiolabeled metabolites, [11C]WAY-100635 was radiolabeled at an internal carbonyl position in contrast to the original externally located carbon atom in the O-methyl position. This clever radiolabeling strategy resulted in a polar radiolabeled metabolite that was unable to cross the blood– brain barrier (Ginovart et al 1996). This radiotracer demonstrated high specificity for in vivo visualization of the 5-HT1A receptor in healthy human subjects with high uptake in the medial temporal lobe relative to the cerebellum (BP 5 7.8 at 60

min postinjection). Moderate levels of uptake were observed also in the somatodendritic 5-HT1A autoreceptorrich midbrain raphe nuclei (Ginovart et al 1996; Pike et al 1995b, 1996). A comparison of the in vitro and in vivo distribution of [3H]WAY-100635 and [11C]WAY-100635 demonstrated similar localization patterns between methodologies, with dense hippocampal labeling, moderate labeling in the cerebral cortex and brain stem, and low labeling in the amygdala, septum, and claustrum (Hall et al 1997). Given these encouraging findings, studies using [11C]WAY-100635 to image the 5-HT1A receptor in depression should be expected in the near future. In addition to [11C]WAY-100635, another selective and high-affinity 5-HT1A receptor antagonist (p-[18F]-MPPF) has been introduced recently (Shiue et al 1997). Although the development of this radiotracer as an imaging agent is still in its infancy, initial studies in rats and baboons have suggested that it may be a useful ligand for imaging the 5-HT1A receptor in vivo. This radiotracer demonstrated high uptake in the 5-HT1A-rich hippocampus as compared to the 5-HT1A-poor cerebellum. Also, labeling was rapidly displaced to background levels when the highly selective 5-HT1A receptor agonist 8-OH-DPAT was administered (Shiue et al 1997). One notable caveat of this radiotracer is that the ratio of uptake in the regions of interest is not as high as that observed for [11C]WAY-100635. Additional characterization studies of this PET radiotracer and its SPECT congener [123I]-MPPI are needed to ascertain their utility as in vivo imaging agents for the study of 5-HT1A receptor regulation in neuropsychiatric disorders.

The 5-HT2 Receptor Family The 5-HT2 receptor family (5-HT2A, 5-HT2B, and 5-HT2C), are postsynaptic receptors associated with fine serotonergic fibers throughout cerebral cortical areas including the cingulate, frontal, temporal, and occipital cortices (Jacobs and Azmitia 1992). In addition moderate densities of 5-HT2 receptors have been localized to the hippocampus, globus pallidus, and thalamus. 5-HT2 receptors modulate motor behavior, sensory functions, cognition, emotion, foot intake, sleep, body temperature, and hormonal release and may play a critical role in depressive symptomatology (Busatto 1996; Cowen 1991). Over the past decade, development of a radiotracer with high affinity and selectivity for the 5-HT2A receptor subtype has been a primary focus. Early studies generated radiolabeled analogs of the prototype in vitro 5-HT2 receptor ligands, ketanserin [[11C]ketanserin and N-v[18F]fluoroethylketanserin ([18F]FEK)] and spiperone [[18F]spiperone (18F-SP) and 3-N-(29-F18)fluoroethylspiperone (FESP)] (Baron et al 1985; Jovkar et al 1991; Moerlein and Perlmutter 1991; Perlmutter et al 1991).

Imaging the Serotonin Synapse in Depression

Despite their reasonable success in vitro, and in early in vivo studies, further development of these ligands was abandoned due to the lack of selectivity [e.g., ketanserin analogs also bind to the monoamine vesicular transporter, histamine H1, a1 adrenergic, and 5-HT2C receptor, and spiperone analogs also bind to D2, D3, and D4 receptors (Darchen et al 1988; Leysen 1989)]. Furthermore, many of these ligands exhibited high nonspecific binding and/or low total to nonspecific binding ratios. N1-([11C]-Methyl)2-Br-LSD ([11C]MBL) demonstrated an anatomical localization pattern consistent with the established regional distribution of the 5-HT2 receptor (i.e., high uptake in frontal, temporal, and parietal cortex, low uptake in caudate and putamen), but exhibited a low cortex to cerebellum ratio (Lever et al 1989; Wong et al 1987). [18F]Setoperone was the first PET radiotracer demonstrating suitable qualities for clinical in vivo imaging studies. Use of this tracer has been limited to studies of cortical 5-HT2 receptors, since [18F]setoperone labels D2 as well as 5-HT2 receptors in the striatum (Blin et al 1988, 1990; Petit-Taboue et al 1996). In contrast, [18F]altanserin does not have appreciable affinity for the D2 receptor, and early studies have suggested that this probe is useful for clinical assessment of 5-HT2 receptor number (Biver et al 1994; Lemaire et al 1991; Sadzot et al 1995). Despite its promise, one potential pitfall is that [18F]altanserin is rapidly metabolized to lipophilic metabolites that, although they are not pharmacologically active, may enhance nonspecific binding (Biver et al 1994; Sadzot et al 1995). More recent studies have suggested that [18F]RP62203 may be a promising in vivo PET radiotracer for the 5-HT2a receptor (Besret et al 1996); however, a recent report indicated that in addition to the 5-HT2a receptor, [18F]RP62203 also demonstrated high affinity for the D4 receptor (Heuillet et al 1996). Preclinical studies that assessed the utility of [3H]SR 46349B as an in vivo imaging agent demonstrated that this highly selective 5-HT2A ligand exhibited high nonspecific binding (Besret et al 1996). At present, the most promising radiotracer for PET imaging of the 5-HT2a receptor is [11C]-MDL100,907. [11C]MDL-100,907 is highly selective for the 5-HT2A receptor, and exhibits a high neocortex to cerebellum ratio (3.5 to 4.5) (Ito et al 1997; Lundkvist et al 1996). For SPECT imaging, 2-123I-iodoketanserin was the first 5-HT2 radiotracer; however, similar to the PET radiotracer analogs of ketanserin, this tracer was not selective and exhibited high nonspecific binding (Mertens et al 1994). [123I]R93274 (also called 123I-5-I-R91150) demonstrates high selectivity for labeling of the 5-HT2 receptor as compared to D2 receptor. Displacement studies using ketanserin decreased cortical labeling to cerebellar levels. Although this tracer has shown some promise, the cortex

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to cerebellum ratio was extremely low in human studies (Busatto et al 1997). Recently, the synthesis of a novel SPECT radiotracer ([123I]-IBSP) with high specificity for the 5-HT2 receptor was reported (Samnick et al 1997). The suitability of this SPECT radiotracer for in vivo imaging remains to be determined. The status of the 5-HT2 receptor has been examined in actively depressed subjects using the radiotracer 2-[123I]ketanserin and SPECT (D’Haenen et al 1992). Overall, no major differences in the 2-[123I]-ketanserin uptake values [(mean counts/voxel of a region)/(mean counts/voxel of whole brain)] were observed in frontal, temporal, and occipital cortex, but higher uptake of 2-[123I]-ketanserin was observed in parietal cortex. Although these findings suggest that there may be higher parietal 5-HT2 receptor densities in depression (D’Haenen et al 1992), the validity of these findings are highly questionable, since this radiotracer has high nonspecific uptake and lacks pharmacologic validation that its uptake reflects the distribution of 5-HT2 receptors. High densities of parietal 5-HT2A receptors may be a neurochemical marker of the depressed state, or alternatively, may be a consequence of antidepressant treatment. Half of the depressed subjects in this study had a drug washout period of only 1 week prior to scanning. Thus, the higher receptor number may be an adaptive response to antidepressant treatment and may reflect recovery from depressive symptoms. In accordance, PET imaging of the 5-HT2 receptor using [11C]-N-methylspiperone demonstrated increased labeling in uninjured regions of the ipsilateral parietal and temporal cortex in patients with right hemisphere strokes as compared with patients with similar lesions in the left hemisphere (Mayberg et al 1988). The ratio of ipsilateral to contralateral binding was correlated significantly with the severity of depressive symptoms in patients with left-hemisphere strokes (Mayberg et al 1988). Furthermore, in a case study of a patient with secondary “poststroke” depression following infarction of the left basal ganglia, a 25% increase in [11C]-N-methylspiperone labeling that correlated with improved mood was observed over a 6-week study (Mayberg et al 1991). These findings suggest that poststroke depression may be a consequence of the failure to upregulate 5-HT2 receptors and that elevated 5-HT2 receptor number may serve to alleviate depressive symptoms (Mayberg et al 1988, 1991). Interestingly, decreased [18F]altanserin labeling in the right posterolateral, orbitofrontal, and anterior insular cortex has been observed in drug-free, unipolar depressed subjects (Biver et al 1997). Fluoxetine- and fluvoxamine-treated depressed subjects demonstrated a moderate, but significant, increase of [18F]setoperone labeling in the frontal cortex as compared to drug-free depressed subjects (Massou et al 1997). The results indicate that chronic treatment with SSRIs caused

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Table 1. Summary of Neuroanatomical and Serotonergic Correlates of Depression 5-HT transporter Volume

Cerebral blood flow

Glucose utilization

Suicide (in vitro)

Striatal areas

Caudate

Putamen

Decrease Decrease Decrease Krishnan et al 1992 Drevets et al Baxter et al 1985 1992a, 1992b Buchsbaum et al Mayberg et al 1994 1986 Decrease Buchsbaum et al 1986

Suicide (in vitro)

Depression (in vivo)

No change Lawrence et al 1990a

Decrease Lowther et al 1994

No change Lawrence et al 1990b Decrease Malison et al in press

Thalamus

Increase Drevets et al 1992a, 1992b Goodwin et al 1993

Hypothalamus

Substantia nigra No change Axelson et al 1993

Amygdala

Cortical areas Frontal

Suicide (in vitro)

No change Malison et al in press

Midbrain areas

Hippocampus

Depression (in vivo)

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Brain region

5-HT1 receptor

Increase Drevets et al 1992a, 1992b Decrease Coffey et al 1993 Drevets et al 1997

Increase Gross-Isseroff et al 1989 No change Lawrence et al 1990a Decrease Paul et al 1984 Gross-Isseroff et al 1989a No change Lawrence et al 1990a No change Owen et al 1986 Gross-Isseroff et al 1989 Decrease Perry et al 1983 Increase Gross-Isseroff et al 1989 No change Lawrence et al 1990a

No change Owen et al 1986 Decrease Cheetham et al 1990

Decrease Owen et al 1986 Cheetham et al 1988 Lowther et al 1994

No change Cheetham et al 1990 Decrease Increase Decrease Decrease a Owen et al 1983 Biver et al Kuikka et al 1995 McKeith et al 1987 Increase 1997 Ferrier et al 1990 Laruelle et al 1993a Meltzer 1990 Ferrier et al 1990 Stanley and Mann 1983 Mann et al 1986 No change Mann et al 1990 Crow et al 1984 Yates et al 1990 Owen et al 1986 Owen et al 1983 No change Bowen et al 1989 Crow et al 1984 Owen et al 1986 Cheetham et al 1988 Yates et al 1990 Lowther et al 1994 ( Table 1 is continued on next page)

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Decrease Decrease Decrease Drevets et al 1997 Drevets et al 1997 Stanley et al 1982 Bench et al 1992 Baxter et al 1989 Crow et al 1984 Dolan et al 1992 Martinot et al 1990 Stanley et al 1989 Bench et al 1993 Increase Laruelle et al 1993a Mayberg et al 1986 Buchsbaum et al Increase 1986 Meyerson et al 1982 Increase No change Drevets et al 1992a: Owen et al 19986 1992b Arora and Meltzer 1989a Gross-Isseroff et al 1989 Lawrence et al 1990b Arora and Meltzer 1991

No change Lowther et al 1994

5-HT transporter Brain region

Volume

Cingulate

Cerebral blood flow

Glucose utilization

Suicide (in vitro)

Posterior Insular

Parietal

No change Bowen et al 1989

Occipital

Temporal

Not significant.

Suicide (in vitro)

Decrease Decrease Mayberg et al 1994 Post et al 1987

Decrease Shahetal1992

Increase Dolan et al 1992

No Change Owen et al 1986 Meyerson et al 1982 Laruelle et al 1993a Decrease Perry et al 1983 No change Lawrence et al 1990a Decrease Gross-Isseroff et al 1989

Decrease No change Kuikka et al 1995 Owen et al 1986

No change Lowther et al 1994 Decrease Bowen et al 1989 No change Owen et al 1986 Cheetham et al 1988 Increase Laruelle et al 1993a

Depression (in vivo)

Decrease Biver et al 1997 Increase D’Haenen et al 1992

No change No change Cheetham et al 1990 Ferrier et al 1990 Decrease Cheetham et al 1988 Bowen et al 1989 Decrease Bowen et al 1989 BIOL PSYCHIATRY 1998;0:534 –549

a

Suicide (in vitro)

5-HT2 receptor

Decrease Drevets et al 1997 Decrease Decrease (responders) No change Bench et al 1992 Mayberg et al 1997 Gross-Isseroff et al 1989 Dolan et al 1992 Increase Bench et al 1993 (nonresponders) Mayberg et al 1994 Mayberg et al 1997 Increase (left) Goodwin et al 1993 Increase (right) Goodwin et al 1993 Decrease Decrease Dolan et al 1992 Gross-Isseroff et al 1989

Anterior

Cerebellar

Depression (in vivo)

5-HT1 receptor

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Table 1. Summary of Neuroanatomical and Serotonergic Correlates of Depression (continued from previous page)

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an up-regulation of 5-HT2 receptors, suggesting that elevated receptor number may contribute, in part, to the therapeutic efficacy of SSRIs. Interestingly, findings from the in vivo imaging studies contrast with results from postmortem analysis of 5-HT2 receptor regulation, which demonstrated unaltered (Cheetham et al 1988; Cooper et al 1986; Crow et al 1984; Lowther et al 1994; Owen et al 1986) or increased (Arora and Meltzer 1989b; Ferrier et al 1990; Laruelle et al 1993a; Mann et al 1986; Stanley and Mann 1983) frontal cortical 5-HT2 receptor densities in drug-free suicide victims. Moreover, receptor numbers were normalized or decreased in suicide victims with a recent history of antidepressant treatment (Owen et al 1983, 1986; Yates et al 1990). The findings from the postmortem studies suggest that 5-HT2 receptor densities may be elevated in the frontal cortex of suicide victims, and that antidepressant treatment may serve to normalize or decrease receptor densities. Although the reason for the contradictory regulation of 5-HT2 receptors between the postmortem and in vivo imaging studies is not understood, it may be hypothesized that 5-HT2 receptor number is differentially regulated in depression and suicide. Retrospective case analyses of the mental state of suicide victims prior to death have revealed that preterminal depression is associated with suicide in approximately 40 – 60% of all cases, suggesting that neurochemical state changes in suicide may reveal some neurochemical substrates related to the depressed state (Horton 1992); however, comparison of the findings from in vivo studies with in vitro postmortem studies should be done with caution, since, although many suicide victims are depressed, the neurochemical etiologies of depression and suicide may be distinct. Thus, differential regulation of the 5-HT2 receptor between in vitro postmortem studies of suicide victims and the in vivo imaging studies in living depressed subjects may support distinct etiological mechanisms for these neuropsychiatric disorders.

Serotonin Synthesis Rate A novel method to measure the rate of serotonin synthesis in brain uses the radiolabeled precursor [11C]-a-methyltryptophan (Diksic et al 1990; Nagahiro et al 1990). The precursor is converted to [11C]-a-methyl-serotonin, which is not a substrate for metabolism by monoamine oxidase. Thus, the time-dependent accumulation of [11C]-amethyl-serotonin in brain provides a measure of 5-HT synthesis rate. This method was based on that previously used for a 2-deoxyglucose paradigm, in which the precursor is converted to a charged compound (2-deoxyglucose6-phosphate) and trapped in brain. PET imaging following injection of [11C]-a-methyl-tryptophan has been per-

formed in both animals and humans (Diksic et al 1991; Nishizawa et al 1997). Preclinical studies provide limited support for the validity of this method, and several technical factors may restrict its application. Nonspecific uptake (i.e., the amount of [11C]-a-methyl-tryptophan compared to [11C]-a-methyl-serotonin) is very high. In addition, the overall formula for 5-HT synthesis rate shows a linear relationship with free plasma tryptophan concentration, which may vary significantly between individuals and groups. For example, the reported difference of 5-HT synthesis rate determined with [11C]-a-methyltryptophan between genders (with male 50% higher than female subjects) may have been primarily derived from the twofold higher plasma tryptophan levels in the male subjects. Finally, the transport of [11C]-a-methyl-tryptophan across the blood– brain barrier is competitive with other large neutral amino acids. Thus, differences in brain uptake and calculated 5-HT synthesis rate could merely reflect altered plasma concentrations of unrelated amino acids. In summary, the [11C]-a-methyl-tryptophan PET method is relatively novel and intriguing but needs additional clinical studies to assess the potentially large and confounding impact of unrelated, peripheral factors.

5-HT Neuronal Activity Serotonin is a powerful vasoconstrictor, thus, alterations in endogenous 5-HT function may alter global or regional neuronal activity (Bonvento and Lacombe 1993; Bonvento and MacKenzie 1997). The rate of cerebral blood flow or glucose utilization has been measured using [15O]H2O or [18F]deoxyglucose ([18F]FDG), respectively, with PET, after pharmacologically induced increases in 5-HT by tryptophan loading, SSRI treatment, or fenfluramine challenge or after depletion of 5-HT by administration of a diet low in tryptophan. The responsivity of the serotonergic system has been tested by examining the effects of fenfluramine challenge or SSRI treatment on glucose utilization (Table 2). Fenfluramine increases 5-HT release from nerve terminals and maintains elevated synaptic 5-HT levels by inhibition of reuptake (Fuller 1986). SSRIs inhibit reuptake and thus maintain increased 5-HT levels in the synapse (Fuller 1986). Higher synaptic concentrations of 5-HT result in increased stimulation of postsynaptic 5-HT receptors, which may have profound effects on neuronal activity. Enhancement of 5-HT neurotransmission by SSRIs has demonstrated differential effects on regional neuronal activity. Fluoxetine decreased neuronal activity throughout limbic areas, including the amygdaloid complex, hippocampal formation, and ventral striatum, and increased neuronal activity in the right superior parietal lobe (Cook et al 1994; Freo et al 1991). In contrast, citalopram

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543

Table 2. Effects of Serotonergic Probes on Neuronal Activity in Healthy Subjects L-Tryptophan

Citalopram

Global

Raphe nuclei Amygdala

Fluoxetine

Fenfluramine

No change Cook et al 1994

No change Cook et al 1992 Decrease w/high baseline Kapur et al 1994 Increase w/ low baseline Kapur et al 1994

Decrease Cook et al 1994 Decrease Cook et al 1994 Decrease Cook et al 1994

Hippocampus Striatum Hypothalamus Thalamus Frontal cortex

Increasea Geaney et al 1991

No change Nagao et al 1995

Temporal cortex

Increasea Geaney et al 1991

No change Nagao et al 1995

Parietal cortex

Increasea Geaney et al 1991 Increasea Geaney et al 1991

No change Nagao et al 1995 No change Nagao et al 1995

Occipital cortex

Increase Cook et al 1994

Decrease Meyer et al 1996 Increase Kapur et al 1994 Meyer et al 1996 Left PFC only Mann et al 1996 Decrease right PFC only Mann et al 1996 Increase left only Mann et al 1996 Decrease Kapur et al 1994 Meyer et al 1996 Increase left only Mann et al 1996 Decrease Kapur et al 1994

PFC, prefrontal cortex. a Not significant.

had no effect on cortical neuronal activity (Nagao et al 1995). Interestingly, fenfluramine also demonstrates differential effects on neuronal activity. Mann and colleagues reported that fenfluramine increased activity in the left prefrontal cortex, and decreased activity in the right prefrontal cortex (Mann et al 1996). Alternatively Kapur, Meyer, and colleagues reported bilateral increases in activity (Kapur et al 1994; Meyer et al 1996). Furthermore, Mann and colleagues reported increased activity in left temporoparietal cortex, whereas Kapur, Meyer, and colleagues reported decreased activity in the temporal and temporal– occipital cortex (Kapur et al 1994; Meyer et al 1996). The difference in fenfluramine effects on neuronal activity between the two research groups is puzzling; however, the difference may be due to subject selection. Cook and colleagues noted differential effects of fenfluramine on global glucose utilization that varied depending upon their placebo levels of glucose utilization. Specifically, subjects with a low global glucose utilization following placebo demonstrated increased activity postfen-

fluramine, whereas subjects who had a high placebo global cerebral metabolic rate of glucose showed a decreased activity postfenfluramine (Cook et al 1992). Although this study focused on global effect of fenfluramine, it is reasonable to hypothesize that interindividual differences in the regional effects of fenfluramine may occur. Serotonergic function may be sensitive to differences in gender, age, as well as the time of day (e.g., circadian effects) and for female subjects, menstrual cycle stage (Golden et al 1996; McBride et al 1990). Differences in these variables may account for the lack of consistency in the tests of serotonergic function and should be controlled in all studies of this nature. There has been one study that tested the effects of fenfluramine on neuronal activity in depression. Overall, as compared to healthy control subjects, the response to fenfluramine was blunted in depressed subjects (Mann et al 1996). Specifically, fenfluramine-induced increase in neuronal activity in the left lateral prefrontal and temporal cortex and bilateral medial prefrontal and parietal cortex

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was blunted. Also, the decrease in the right prefrontal, superior temporal, and parietal cortex was blunted. The decreased response to fenfluramine challenge may be a consequence of lower endogenous levels of releasable 5-HT or decreased postsynaptic 5-HT receptor reactivity. These findings support the hypothesis for hyposerotoninergic function in major depression. In remitted-depressed patients who underwent a tryptophan depletion paradigm, decreased metabolic activity was observed in the dorsolateral prefrontal cortex, orbitofrontal cortex, and thalamus, which correlated with the onset of depressive symptoms (Bremner et al 1997). Even though all participants in this study demonstrated a similar decrease in plasma free and total L-tryptophan levels, only some subjects experienced a relapse, suggesting that depression may not be a function of brain 5-HT levels, but instead may be a consequence of dysfunctional postsynaptic 5-HT neuronal activity (Bremner et al 1997). The regional changes induced by depletion of 5-HT stores overlapped with changes in neuronal activity that have been observed in living depressed subjects (reviewed by Drevets 1998). Interestingly, while tryptophan depletion resulted in decreased neuronal activity in the thalamus, increased cerebral blood flow has been noted in the medial thalamus of actively depressed subjects (Drevets et al 1992a,b; Goodwin et al 1993). These differences may be explained by a compensatory increase in the activity of another neurotransmitter or elevations of thalamic 5-HT neuronal activity in the native depressed state. In agreement with tryptophan depletion studies, decreased cerebral blood and glucose metabolic rate have been observed in prefrontal cortex of actively depressed subjects, which may correlate with the severity of depression (Baxter et al 1985, 1989; Bench et al 1992, 1993; Buchsbaum et al 1986; Dolan et al 1992; Drevets et al 1992a,b; George et al 1993, 1994; Martinot et al 1990; Mayberg 1994). The ability to induce changes in prefrontal cortical neuronal activity by tryptophan depletion, combined with the ability to reverse altered activity after antidepressant treatments, suggests that these changes in the prefrontal cortex are “state” and not “trait” markers of depression.

Future Applications of Neuroimaging in Depression With the ongoing development of novel radiotracers with high specificity not only for pre- and postsynaptic receptor sites and transporters, but also for synthetic enzymes and intracellular messengers, new opportunities to assess the state of the serotonergic synapse in depression and other neuropsychiatric disorders will arise. In addition to baseline measurements of receptor sites, research studies can be designed to assess the

status of a receptor or transporter at different stages of an illness and throughout the course of treatment. With the development of receptor-specific “agonist radiotracers,” and corresponding “antagonist radiotracers,” the ability to examine the percentage of high-affinity Gprotein coupled receptors as compared to total receptor number will be possible (Khawaja 1995). Challenge and depletion studies (Laruelle et al 1997), which utilize pharmacologic agents to alter endogenous neurotransmitter levels (e.g., fenfluramine elevates 5-HT and tryptophan depletion decreases 5-HT), will be used to study the interactions of endogenous neurotransmitter with the receptor of interest. Furthermore, in vivo imaging techniques may be used to study the interactions between multiple neurotransmitter systems (Dewey et al 1995).

Conclusions Although there is a wealth of evidence from postmortem studies of suicide victims that implicates dysfunctional serotonergic neurotransmission in the pathophysiology of depression, only recently have radiotracers suitable for in vivo clinical assessment become available. Thus, there has been little direct evidence in the living human brain supporting the serotonergic hypothesis of depression. To date, only a few neurochemical imaging studies have been performed in depressed patients. A preliminary study using SPECT demonstrated decreased levels of 5-HT transporters in the midbrain regions of subjects with major depression. Analysis of the 5-HT2 receptor using PET suggested that this receptor may not be altered significantly in the depressed brain but may be elevated in response to antidepressant treatment. These findings are supported by studies of 5-HT2 receptor densities in poststroke depression, which clearly demonstrated that elevations in 5-HT2 receptor density correlated with the alleviation of symptoms of depressed mood. With the rapid development of novel PET and SPECT radiotracers, future studies of the serotonergic system that evaluate presynaptic (5-HT transporter) and postsynaptic (5-HT1A and 5-HT2A receptors) markers and the interaction of synaptic levels of 5-HT with these sites will surely make profound contributions to the understanding of the role of the serotonergic synapse in the pathophysiology of depression.

This work was presented at the Neuroscience Discussion Forum “A Decade of Serotonin Research” held at Amelia Island, Florida in November 1997. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.

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