The cortical serotonin₂ receptors studied with positron-emission tomography and [¹⁸F]-setoperone during depressive illness and antidepressant treatment with clomipramine

Abstract

Background: Changes in serotonin (5-HT)₂ receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT₂ receptors were studied in vivo in depressed patients.

Methods: Cortical 5-HT₂ receptors were investigated prospectively using positron-emission tomography and [¹⁸F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls.

Results: There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [¹⁸F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [¹⁸F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT₂ receptor measurements either in the untreated or in the treated conditions.

Conclusions: These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT₂ serotoninergic receptors in actual therapeutic situations.

Introduction

Abnormalities in brain serotonin function, and specifically of serotonin (5-HT)₂ receptors, were postulated in the pathophysiology of affective disorders on the basis of both changes in 5-HT₂ receptor densities in depression, and of decreased 5-HT₂ receptor number induced by long-term antidepressant treatments; however, using various radioligands, postmortem findings on cortical 5-HT₂ receptor density are discrepant. Significant increases were reported in the brains of depressed patients studied postmortem (Yates et al 1990) and of suicide victims Stanley and Mann 1983, Mann et al 1986, Arora and Meltzer 1989, Arango et al 1990; however, no change was also reported in depressed patients (McKeith et al 1987) and in suicide victims Owen et al 1986, Cheetham et al 1988. Moreover, increased concentration of 5-HT₂ receptor binding sites in blood platelet studies of depressed subjects was observed by some Biegon et al 1990, Pandey et al 1990, but not all investigators (Cowen et al 1987).

Besides, long-term antidepressant treatment with most tricyclics decrease (i.e., down-regulate) 5-HT₂ receptor sites in rodent brains Peroutka and Snyder 1980, Blackshear and Sanders-Bush 1982, particularly clomipramine (CMI) De Ceballos et al 1985, Stolz et al 1983; however, no modification was also reported with tricyclics such as imipramine or amitriptyline Mann and Enna 1982, Schoups et al 1986. Yet other studies reported an increase after chronic treatment with desipramine or fluoxetine (Green 1982 in Bradford et al 1987, Wamsley et al 1987).

Thus, due to the intrinsic limitations of postmortem studies, or of the blood platelet model and of animal models, in vivo data are needed on brain 5-HT₂ receptors in depressed patients before and during antidepressant treatment. The in vivo study of 5-HT₂ receptors by positron-emission tomography (PET) has been limited so far by the lack of an adequate positron emitter-labeled radioligand Wong et al 1984, Baron et al 1985. 2-¹²³I-ketanserin was used with single photon emission computed tomography (SPECT) (D’haenen et al 1992) to study 5-HT₂ receptors in vivo in the brains of depressed patients. The only PET study of 5-HT₂ receptors in depression used ¹¹C-methylspiperone ([¹¹C]NMSP) as a ligand, the K_i value of which for 5-HT₂ is 2.3 nMOL/L (Kennis et al 1986); “depressed” patients with right-hemisphere strokes had significantly higher ipsilateral to controlateral 5-HT₂ binding compared with normal subjects and patients with left-hemisphere strokes (Mayberg et al 1988).

We used setoperone labeled with [¹⁸F]-fluoride at high specific radioactivity as a 5-HT₂ radioligand, for both its better selectivity and sensitivity for 5-HT₂ receptor binding in the cerebral cortex in vivo. [¹⁸F]-setoperone is a high-affinity radioligand [K_i = 0.37 nMOL/L (Middlemiss et al 1986)], with a comparatively much lower affinity for D₂ and alpha₁-adrenergic receptors Kennis et al 1986, Middlemiss et al 1986, Leysen et al 1987b; setoperone has a very low affinity for the 5-HT₁ receptors (5-HT₁/5-HT₂ > 2500) Kennis et al 1986, Middlemiss et al 1986, Leysen et al 1987b. Moreover, ¹⁸F-labeled metabolites of setoperone do not cross the blood–brain barrier in humans (Blin and Crouzel 1992).

In the present study, depressed patients were studied, first untreated in a depressed state, and thereafter treated for at least 3 weeks with 150 mg per day of CMI. The study was designed to 1) search for a difference in the [¹⁸F]-setoperone specific binding between depressed patients (DP) before antidepressant treatment and normal volunteers (NV); and 2) search for a modification of the [¹⁸F]-setoperone specific binding in DP treated with CMI.