Neurotransmitter Imaging of the Serotoninergic System

The serotoninergic system is thought to be critically involved in a large number, if not the majority, of psychiatric illnesses. The most important and well studied of these is major depressive disorder (MDD). However, the serotonin system is also considered important in schizophrenia, anxiety and phobias, obsessive-compulsive disorder, eating disorders, sleep, and numerous other psychiatric conditions.

Serotonin and Depression. Several studies have found evidence for an increased availability of serotonin 5-HT2A receptors in the brains of unmedicated depressed patients and suicide victims (Cheetham et al., 1988; D'Haenen et al., 1992; Stanley and Mann, 1983). The extent to which these findings exist in depressed persons without recent suicide attempts remains controversial. A [18F]setoperone PET study assessed the 5-HT2 receptor binding potential in 14 depressed and 19 healthy subjects (Meyer et al., 1999b). Interestingly, the 5-HT2 binding potential was not increased in untreated depressed subjects who have not made recent suicide attempts (Meyer et al., 1999b). However, the authors conclude that this negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.

In another study, the uptake of [11C]-5-hydroxytryptophan was found to be decreased in the frontal cortex of unmedicated depressed patients, indicating an abnormality in the transport of the serotonin precursor substance 5-hydroxytryptophan across the blood-brain barrier (Agren et al., 1991; Hartvig et al., 1991). Finally, neuroimaging studies have also provided evidence for a blunted regional metabolism in response to oral d,l-fenfluramine induced serotonin release in 6 patients diagnosed with MDD (Mann et al., 1996). However, this could not be replicated in a larger sample of 13 depressed patients using [15O]H2O PET after intravenous d-fenfluramine administration, which revealed similar neuronal responsivity to d-fenfluramine in depressed and healthy subjects (Meyer et al., 1998).

In addition to the noted 5-HT2 results, two PET studies recently reported a lower number of 5-HT1A receptors in untreated depression (Drevets et al., 1999; Sargent et al., 2000) and depression treated with SSRIs (Sargent et al., 2000). There is also evidence for altered serotonin transporter (5-HTT) density in depression. A SPECT study using 3 -CIT as a ligand for 5-HTT and DAT found significantly reduced 5-HTT availability in depression (Malison et al., 1998). This result was subsequently replicated in patients suffering from seasonal affective disorder (Willeit et al., 2000).

Taken together, these findings provide ample proof of the involvement of the serotonergic system in the pathophysiology of depression. This is further substantiated by a number of studies that have shown antidepressant drugs to bind to 5-HTT in vivo. For the majority of the substances, and similar to those described for antipsychotics above, curves representing the relationship of dosage to the percentage of inhibited 5-HTT may be calculated from the appropriate PET data. It is interesting to note, however, that while the clinically used dose of paroxetine is 20 to 60 mg a day, data from neuroimaging studies has shown 20 mg of paroxetine to effectively occupy around 80 percent of available 5-HTT in most patients (Meyer et al., 2001). Because of the exponential nature of the dose/occupancy relationships and the resulting hyperbolic shape of these curves, small increases in daily dosage may lead to significantly greater increases of 5-HTT occupancy within the low dose range, while at high doses great increases in daily dosage are necessary in order to effect even minor increases in 5-HTT occupancy. In this sense, the above-mentioned finding suggests that an escalation of the dose of paroxetine beyond the range of 20 mg per day would lead to only nonsignificant increases in 5-HTT occupancy (Meyer et al., 2001). Clinically, although many patients respond well to 20 mg of paroxetine, some only show a reasonable response once the dose is raised to 40 or even 60 mg a day. The clue to solving this apparent discrepancy may lie in the possibility that some antidepressants cause their clinical effects at least partially through mechanisms other than 5-HTT blockade.

Serotonin and Schizophrenia. Postmortem studies showed an elevation in cortical serotonin 5-HTiA receptor density in schizophrenia using [3H]-8-OH-DPAT as a ligand (Hashimoto et al., 1993). The ligand WAY-100635 has been labeled at the [carbonyl-11C] position (Farde et al., 1997) and can be used for the quantitative analysis of binding to 5-HT1A receptors in humans (Farde et al., 1998). Using PET and [11C]WAY-100635, our group demonstrated an age-dependent decline of cortical 5-HT1A receptor BP (binding potential) in healthy volunteers (Tauscher et al., 2001b), consistent with postmortem studies that showed a decline in 5-HT1A receptor numbers with age (Dillon et al., 1991; Lowther et al., 1997; Matsubara et al., 1991).

Our group recently completed a PET study in 14 neuroleptic-naive patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia suffering from a first psychotic episode. On the basis of human postmortem studies, we hypothesized that the in vivo 5-HT1A receptor BP as measured with [carbonyl-11C]WAY-100635 and PET will be higher in frontal and temporal cortex of schizophrenic patients, as compared to an age-matched control group of healthy volunteers. In a PET study comparing the 5-HT1A BP of 14 antipsychotic naive patients to 14 age-matched healthy controls, we found a medio-temporal increase of cortical 5-HT1A receptor BP in patients suffering from a first episode of schizophrenia (Tauscher et al., 2002b) (Fig. 6.3).

Publisher's Note:

Permission to reproduce this image online was not granted by the copyright holder. Readers are kindly requested to refer to the printed version of this article.

Figure 6.3. Composite mean 5-HTia receptor binding potential images of 14 healthy controls and 14 age-matched patients with schizophrenia indicating higher 5-HT-|A binding potential values in patients in the left and right mediotemporal regions of interest. (With permission from the Archives of General Psychiatry, this figure was first published in Arch Gen Psychiatry 59:514-520.) See ftp site for color image.

The published studies of 5-HT2A receptors in schizophrenic patients to date have mainly involved postmortem brain samples and produced conflicting results. While six studies found a reduction in 5-HT2A receptor density in the frontal cortex of schizophrenic patients, four others did not find significant differences compared to controls. Among numerous PET tracers developed for 5-HT2A receptors, only [18F]altan-serin, [18F]setoperone, and [11C]MDL 100,907 have demonstrated appropriate in vivo properties for a successful imaging agent in humans. In two recent [18F]setoperone PET studies using ROI analysis, no decreases in 5-HT2A receptors were observed in neuroleptic-free or neuroleptic-naive schizophrenic patients (Lewis et al., 1999; Trichard et al., 1998). However, localized differences may have been diluted in these ROIs, if either some areas were considerably smaller than the ROIs or if some areas were omitted or only partially included in the ROIs. Therefore, additional 5-HT2A PET studies have been performed using voxel-by-voxel analysis by the application of SPM. One study reanalyzed data from 13 schizophrenic patients obtained in a previous study (Lewis et al., 1999) but compared them with a larger group of 35 age-matched controls (Verhoeff et al., 2000). No substantial 5-HT2A receptor changes were observed in the schizophrenic patients. Another [18F]setoperone PET study indicated significant 5-HT2A receptor decreases in the left and right prefrontal cortex in 6 schizophrenic patients versus 7 age-matched controls (Ngan et al., 2000). It is conceivable that the 5-HT2A receptor decreases observed in earlier postmortem studies in schizophrenic patients either on antipsychotic medication or withdrawn from antipsychotics before death was confounded by medication effects. The discrepant findings between the in vivo studies could, similar to the discrepancies between the postmortem studies, be due to heterogeneity in the populations of schizophrenic patients studied. An in vivo SPECT study investigating potential alterations of stri-atal DAT and brainstem 5-HTT density in schizophrenia did not find alterations of DAT in the striatum or 5-HTT in the brainstem (Laruelle et al., 2000), despite one postmortem study in schizophrenic patients that showed decreased 5-HTT in the pre-frontal cortex.

Serotonin and Anxiety. Serotonin 5-HT1A receptors are thought to play a role in modulating anxiety. Lately, there has been a report of an inverse correlation between 5-HT1A receptor BP and anxiety in healthy subjects (Tauscher et al., 2001a), but thus far there are no published reports on in vivo 5-HT1A binding in anxiety disorders.

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