Background: Pharmacological and postmortem investigations suggest that patients with major depressive disorder have alterations in function or density of brain serotonin 1A (5-HT 1A ) receptors. The aim of the present study was to use positron emission tomography with the selective 5-HT 1A receptor antagonist [11 C]WAY-100635 to measure 5-HT 1A receptor binding in depressed patients before and during treatment with selective serotonin reuptake inhibitors.

Positron emission tomography (PET) studies with the selective 5-HT 1A receptor ligand, [ 11 C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT 1A receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [11 C]WAY-100635 in conjunction with PET imaging to compare 5-HT 1A BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT 1A receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT 1A BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT 1A BP as measured by [ 11 C]WAY-100635 in recovered depressed men. Lowered 5-HT 1A receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.

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The monoamine neurotransmitter serotonin (5-HT) has an important role in both the pathophysiology and treatment of anxiety and panic attacks.1,2 The strongest evidence that a specific abnormality of the serotonin system predisposes or contributes to anxiety comes from studies of the 5-HT 1A receptor. 'Knockout' mice bred without 5-HT 1A receptors in the cerebral cortex and limbic system show increased anxiety behaviours 3 and patients with panic disorder have been shown by challenge testing to have subsensitivity of these receptors. 4 Furthermore, the azapirone 5-HT 1A agonist buspirone is licensed for the treatment of generalised anxiety disorder in the UK. In a systematic review of 36 trials of patients treated for generalised anxiety disorder azapirones, including buspirone, were found to be superior to placebo in short-term studies (4-9 weeks). 5The development of select radiotracers for the 5-HT 1A receptor now allows a direct examination of this receptor system in living patients with panic disorder. Neumeister et al 6 reported the first full positron emission tomography (PET) study of 5-HT 1A binding in 16 unmedicated patients with panic disorder and 15 healthy controls. Regions of interest examined were limited to the anterior cingulate cortex, posterior cingulate cortex, anterior insula, mesiotemporal cortex, anterior temporopolar cortex and midbrain raphe -all areas of high 5-HT 1A binding. Lower 5-HT 1A binding occurred in anterior cingulate, posterior cingulate and raphe only in patients with panic disorder. Seven of the 16 patients with panic disorder had comorbid depression, although there was no difference in 5-HT 1A binding between the patients with panic disorder with comorbid depression and those without. The radiotracer used for Neumeister et al's study [18 F]-FCWAY, gives a reliable signal subcortically, but quantification in cortical areas is limited because of retained fluoride signal in bone. 7A further recent PET study using [11 C]WAY-100635 found reduced 5-HT 1A binding in social anxiety disorder. 8 That study compared 12 unmedicated male patients with social anxiety disorder with 18 healthy controls. Six of these patients had comorbid agoraphobia. Six regions of interest were examined a priorireduction of 5-HT 1A binding was found in the amygdala, anterior cingulate, insula, medial orbitofrontal cortex and raphe. After Bonferroni correction only the differences in the amygdala and anterior cingulate cortex remained significant. There was no significant correlation between state or trait anxiety scores and regional 5-HT 1A binding potential in both groups.In this study, we used the PET tracer [ 11 C]WAY-100635 which allows in vivo quantification of 5-HT 1A receptors with exquisite delineation and precision.9,10 Specifically, we wished to confirm the findings of Neumeister et al, 6 extend the findings to look at more regions of interest and finally examine the effect of SSRI treatment. Our specific hypothesis was that patients with panic disorder would have reductions in 5-HT 1A receptor ...

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We studied the effect of 2 weeks administration of the 5-HT2C receptor agonist, m-chlorophenylpiperazine (mCPP), on appetite and body weight in 18 moderately obese subjects in a double-blind, placebo-controlled trial, mCPP caused a small but significant (0.75 kg) reduction in body weight and in subjective ratings of hunger. Plasma prolactin was significantly elevated by the final dose of mCPP. Our data suggest that during 2 weeks treatment in humans, mCPP may continue to activate brain 5-HT2C receptors, and that this effect is associated with decreases in appetite and body weight.

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