Mood stabilizer treatment increases serotonin type 1A receptor binding in bipolar depression

Abstract

Abnormal serotonin type 1A (5-HT1A) receptor function and binding have been implicated in the pathophysiology of mood disorders. Preclinical studies have consistently shown that stress decreases the gene expression of 5-HT1A receptors in experimental animals, and that the associated increase in hormone secretion plays a crucial role in mediating this effect. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus. Lithium has further been shown to enhance 5-HT1A receptor function. To assess whether these effects translate to human subject with bipolar disorder (BD), positron emission tomography (PET) and [18F]trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N-(2-pyridyl) cyclohexanecarboxamide ([18F]FCWAY) were used to acquire PET images of 5-HT1A receptor binding in 10 subjects with BD, before and after treatment with lithium or divalproex. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala). When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action.

The Role of the Magnesium Valproate in Therapy for Patients with Treatment-Resistant Depression (TRD): Meat-Analysis Results of Chinese Data

“…When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action in TRD [29].…”

“…The some study suggests that the acute effect of mood stabilizer lamotrigine augmentation therapy for a major depressive episode is not related to either BDNF or IL-6, at least in patients with treatment-resistant depressive disorder [28]. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus, which may be one of their mechanisms [29]. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala).…”

Clinical neuroimaging markers of response to treatment in mood disorders

“…A few studies performed with nuclear medicine investigations investigated on the imaging of patients in treatment with these drugs. Nugent AC et al [57] receptor expression [58]. Other researches focalised their attention on the effect of these medications on the dopaminergic circuits: one PET study performed using 18 F-6-fluoro-L-Dopa ( 18 F-DOPA)…”

Developing Biomarkers in Mood Disorders Research Through the Use of Rapid-Acting Antidepressants

“…Moreover, biomarkers identified as presenting early in a pathophysiological process are regarded as proximal/target engagement biomarkers, e.g. increased serotonin 1A receptor occupancy[6], while more distal biomarkers often reflect common disease pathway components, e.g. improved anhedonia.…”

“…for these clinical endpoints to predict clinical benefit or harm. Moreover, biomarkers identified as presenting early in a pathophysiological process are regarded as proximal/target engagement biomarkers, for example, increased serotonin 1A receptor occupancy, [6] while more distal biomarkers often reflect common disease pathway components, for example, improved anhedonia. To be clinically useful, a biomarker must have high sensitivity/specificity (construct validity), be reproducible and acceptable to the patient (face validity).…”