Serotonin 2 Receptors, Agomelatine, and Behavioral and Psychological Symptoms of Dementia in Alzheimer’s Disease

Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI. We performed multimodal analysis of SSRI response in 27 mammalian brain regions using 310 bulk RNA-seq and H3K27ac ChIP-seq datasets, followed by in-depth characterisation of two hippocampal regions using single-cell RNA-seq (20 datasets). Remarkably, fluoxetine induced profound region-specific shifts in gene expression and chromatin state, including in the nucleus accumbens shell, locus coeruleus and septal areas, as well as in more well-studied regions such as the raphe and hippocampal dentate gyrus. Expression changes were strongly enriched at GWAS loci for depression and antidepressant drug response, stressing the relevance to human phenotypes. We observed differential expression at dozens of signalling receptors and pathways, many of which are previously unknown. Single-cell analysis revealed stark differences in fluoxetine response between the dorsal and ventral hippocampal dentate gyri, particularly in oligodendrocytes, mossy cells and inhibitory neurons. Across diverse brain regions, integrative omics analysis consistently suggested increased energy metabolism via oxidative phosphorylation and mitochondrial changes, which we corroborated in vitro; this may thus constitute a shared mechanism of action of fluoxetine. Similarly, we observed pervasive chromatin remodelling signatures across the brain. Our study reveals unexpected regional and cell type-specific heterogeneity in SSRI action, highlights under-studied brain regions that may play a major role in antidepressant response, and provides a rich resource of candidate cell types, genes, gene regulatory elements and pathways for mechanistic analysis and identifying new therapeutic targets for depression and anxiety.

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“…1h ). Similarly, we recapitulated the previously reported SSRI-induced downregulation of Htr2c in NAcC [ 69 – 71 ] (Fig. 1h ).…”

Section: Resultssupporting

confidence: 90%

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

et al. 2022

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“…Therefore, increased availability of melatonin could constitute a new therapeutic target [154]. In addition to this therapy, other alternatives to improve sleep patterns in patients with AD are being explored, such as bright light therapy and melatonin agonists such as ramelteon, agomelatine, and tasimelteon [155][156][157].…”

Section: Sleep Patternmentioning

confidence: 99%

Therapeutic Approach to Alzheimer’s Disease: Current Treatments and New Perspectives

Pardo-Moreno¹,

et al. 2022

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Alzheimer’s disease (AD) is the most common cause of dementia. The pathophysiology of this disease is characterized by the accumulation of amyloid-β, leading to the formation of senile plaques, and by the intracellular presence of neurofibrillary tangles based on hyperphosphorylated tau protein. In the therapeutic approach to AD, we can identify three important fronts: the approved drugs currently available for the treatment of the disease, which include aducanumab, donepezil, galantamine, rivastigmine, memantine, and a combination of memantine and donepezil; therapies under investigation that work mainly on Aβ pathology and tau pathology, and which include γ-secretase inhibitors, β-secretase inhibitors, α-secretase modulators, aggregation inhibitors, metal interfering drugs, drugs that enhance Aβ clearance, inhibitors of tau protein hyperphosphorylation, tau protein aggregation inhibitors, and drugs that promote the clearance of tau, and finally, other alternative therapies designed to improve lifestyle, thus contributing to the prevention of the disease. Therefore, the aim of this review was to analyze and describe current treatments and possible future alternatives in the therapeutic approach to AD.

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“…[3] There are nearly 50 million patients with Alzheimer's disease (AD) worldwide, 90% of whom develop behavioral and psychological symptoms of dementia (BPSD). [4] Disclaimer/Publisher's Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions, or products referred to in the content.…”

Section: Introductionmentioning

confidence: 99%

“…[11] In the genetic interface, there are seven serotonin receptor subtypes, and there are different research results on the association between each subtype and BPSD. [4] The presence of allele 4 of apolipoprotein E was demonstrated to be a probable interface factor between suicide and AD. [12,13] Among other factors, depression stands out as the most likely associated factor, where we can highlight the importance of interpersonal stress in the outbreak of depressive disorders.…”

Section: Introductionmentioning

confidence: 99%

A Pilot Study to Research Associations between Alzheimer’s Disease and Suicide: The Questionnaire Feasibility

Rodrigues,

Atalaia da Silva

et al. 2024

Preprint

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Background: There have been reports of numerous risk factors for Alzheimer's disease. Although widely investigated, some points during the evolution of the disease have been obscure. One of them is a great frustration with therapeutic expectations. Why has there been an increase in suicidal behavior in treatments with anti-beta-amyloid drugs? Interpersonal stress is one of the factors that may be connecting Alzheimer's disease to suicide. Method: To observe possible associations between Alzheimer's disease and suicide, two validated questionnaires were selected. We recruited 20 elderly patients over 65 years old to observe the feasibility of further research using these instruments. The study was considered viable if all participants showed no difficulty in understanding the questions and completed both questionnaires in less than 30 minutes with a tendency to homogeneity. A description of the statistical data obtained was made. Results: All participants adequately understood the questions and completed the questionnaires in less than 30 minutes. In 10% of the sample, suicide attempts occurred throughout their lives. The average age of respondents was 75 years old. The QoSL Pareto diagram demonstrated a large concentration. The data demonstrated homogeneity. Conclusions: The application of the questionnaires in a sample suitable for carrying out analytical statistics was demonstrated. We have two great tools to try to understand the possible association between Alzheimer's disease and suicide.

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Serotonin 2 Receptors, Agomelatine, and Behavioral and Psychological Symptoms of Dementia in Alzheimer’s Disease

Cited by 7 publications

References 45 publications

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

Therapeutic Approach to Alzheimer’s Disease: Current Treatments and New Perspectives

A Pilot Study to Research Associations between Alzheimer’s Disease and Suicide: The Questionnaire Feasibility

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