Antidepressant treatment reduces serotonin-1A autoreceptor binding in major depressive disorder

Abstract

Background: Chronic selective serotonin reuptake inhibitor (SSRI) administration to rodents desensitizes or downregulates raphe 5-hydroxytryptamine 1A (5-HT1A) autoreceptors. We previously found elevated 5-HT1A binding in antidepressant-naive and not recently medicated major depressive disorder (MDD) and now report the effect of SSRI treatment on 5-HT1A autoreceptors in depressed patients.

Methods: 5-HT1A binding (BPF) was quantified in medication-free subjects using positron emission tomography (PET) with [11C]-WAY-100635 before and after treatment of MDD with an SSRI for 5 to 9 weeks (mean 47 ± 8 days). Nineteen subjects without recent history of antidepressant pharmacotherapy completed both [11C]WAY-100635 PET scans with a metabolite-corrected arterial input function and depression severity was rated before and after the treatment course.

Results: 5-HT1A autoreceptor BPF in the raphe was reduced 18% on SSRI treatment (df = 1,18; F = 5.12; p = .036). However, the degree of reduction in 5-HT1A autoreceptor BPF was unrelated to improvement in depression (df = 1,16; F = 1.27; p = .276).

Conclusions: Downregulation of 5-HT1A autoreceptor binding by SSRI treatment of major depression is consistent with animal studies. This may be a necessary but insufficient requirement for clinical response to SSRIs. A PET agonist ligand that binds selectively to the high-affinity conformation of this receptor can determine whether SSRIs also cause desensitization of the autoreceptor as reported by some rodent studies and whether that effect may be related to clinical response.

Figure 1

Average 5-HT_1A receptor binding of 19 not recently-medicated subjects before and after SSRI treatment. Binding potential maps corrected for free fraction (BP_F) were derived from the PET scans of all subjects. Each subject’s BP_F map was transformed onto their structural MRI via parameters from a PET to MRI co-registration. BP_F maps in MRI space were then transformed into standard MNI space via parameters from an SPM5 MRI to MNI normalization.

Figure 2

5-HT_1A binding in the dorsal raphé nuclei (DRN) is reduced following SSRI treatment in not recently-medicated depressed subjects (df=1,18; F=5.12; p=0.036).