Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy

Burstein, Ethan S.

doi:10.1007/s40263-021-00836-7

Cited by 14 publications

(6 citation statements)

References 144 publications

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“…For example, previous evidence have shown that female sex hormones modulate 5-HT1A receptors, which have been suggested as one of the explanations for higher prevalence of major depressive disorder in females [42]. In addition, previous studies have proposed that genetic variation in the serotonin receptor gene 5-HT2A is associated with the occurrence of hallucinations and delusions in patients with AD [43,44]. Also, loss of neuroprotective effects of estrogen, such as modulation of neurotransmitter synthesis, synaptic plasticity and mitochondrial activity, related to menopausal changes in women might play a role in differential manifestations of MBI symptoms [45].…”

Section: Discussionmentioning

confidence: 99%

Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

Wolfová

Creese

Aarsland

et al. 2022

JAD

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Background: While the gender/sex differences in neuropsychiatric symptoms in dementia population are well described, gender/sex differences in mild behavioral impairment (MBI) in dementia-free populations and the relationship to cognitive performance and to subsequent cognitive decline have not been studied. Objective: We aimed to explore gender/sex differences in the association of MBI with the level of cognitive performance and its rate of decline in a dementia-free cohort. Methods: We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, spatial working memory, and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models. Results: Out of 8,181 individuals (median age 63 years, 73% females), 11% of females and 14% of males had MBI syndrome. Females exhibited less often symptoms of decreased motivation (45% versus 36% in males), impulse dyscontrol (40% versus 44% in males; p = 0.001) and social inappropriateness (12% versus 15% ; p < 0.001), while they showed more often symptoms of emotional dysregulation (45% versus 36% ; p < 0.001). The associations of MBI domains with some measures of cognitive performance and decline were stronger in males than females, with the exception of the association of emotional dysregulation with the rate of cognitive decline in verbal reasoning, which was present exclusively in females. Conclusion: MBI may influence cognition to a greater extent in males than in females. We propose that predictors and biomarkers of dementia should consider gender/sex as an effect modifier.

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Section: Discussionmentioning

confidence: 99%

Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

Wolfová

Creese

Aarsland

et al. 2022

JAD

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“…As Hershey et al point out, pimavanserin may fill the gap for patients with DLB psychotic symptoms that do not respond to cholinesterase inhibitors, which are contraindicated in patients with arrhythmias, but caution is needed as pimavanserin may be associated with an increased risk of death for elderly patients [ 14 ]. Burstein has countered that pimavanserin has been well tolerated in multiple studies featuring elderly fragile patients [ 32 ], and that was our experience in this case series, as pimavanserin appeared tolerable for each of our patients and resulted in long-lasting positive effects for 3 of our 4 patients.…”

Section: Discussionmentioning

confidence: 75%

Pimavanserin Treatment for Psychosis in Patients with Dementia with Lewy Bodies: A Case Series

et al. 2023

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Case series Patients: Male, 71-year-old • Male, 56-year-old • Male, 61-year-old • Male, 74-year-old Final Diagnosis: Dementia with Lewy bodies Symptoms: Psychosis Clinical Procedure: — Specialty: Geriatrics Objective: Unusual or unexpected effect of treatment Background: Many patients with dementia with Lewy bodies (DLB) experience cholinesterase inhibitor- and antipsychotic-resistant psychosis. The new second-generation antipsychotic pimavanserin has been used with some success in the treatment of psychosis in other forms of dementia, including Alzheimer disease and Parkinson disease dementia. It is possible that pimavanserin may also be useful in the treatment of psychosis in DLB. We sought to describe the disease course and treatment of psychosis in 4 patients with DLB who were prescribed pimavanserin after other medications failed to reduce the frequency or severity of hallucinations and delusions. Case Report: This is a case series of 4 male patients (ages 56 to 74 at the beginning of the reports) who developed DLB and psychosis (eg, visual illusions, visual and olfactory hallucinations, and paranoid delusions). All 4 patients were prescribed cholinesterase inhibitors (eg, donepezil or rivastigmine) prior to pimavanserin, and only 1 patient experienced improved psychosis while on cholinesterase inhibitors. All 3 patients who were prescribed first-generation antipsychotics (eg, haloperidol) or traditional second-generation antipsychotics (eg, olanzapine, risperidone, or quetiapine) experienced initial or lasting side effects with no improvement of psychosis. Conversely, all 4 patients tolerated pimavanserin well, and 3 of the 4 patients experienced significant improvement of psychosis (eg, fewer hallucinations, fewer delusions, reduced paranoia, and/or reduced distress or agitation related to hallucinations and delusions) when prescribed pimavanserin. Conclusions: This case series suggests that pimavanserin is tolerable in older males with DLB and that it may be useful for the reduction of distressful hallucinations, delusions, and paranoia in patients with DLB.

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“…The results of present study demonstrate that NMDAR hypofunction in cortical PV-positive interneurons confers two contrasting altered 5-HT2AR responses to 5-HT, lack of response in Grin1 -deleted PV interneuron terminals and greater intrinsic excitability in the pyramidal neurons. Since up-regulation of 5-HT2ARs in pyramidal neurons has been proposed as a common neural mechanism that could predispose to psychosis [ 77 , 78 ], the Grin1 mutant mouse can be a suitable model for research into the pathophysiology of psychosis in schizophrenia and other types of psychotic disorders.…”

Section: Discussionmentioning

confidence: 99%

5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction

et al. 2022

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Blockade of N-methyl-D-aspartate receptors (NMDAR) is known to augment cortical serotonin 2A receptors (5-HT2ARs), which is implicated in psychosis. However, the pathways from NMDAR hypofunction to 5-HT2AR up-regulation are unclear. Here we addressed in mice whether genetic deletion of the indispensable NMDAR-subunit Grin1 principally in corticolimbic parvalbumin-positive fast-spiking interneurons, could up-regulate 5-HT2ARs leading to cortical hyper-excitability. First, in vivo local-field potential recording revealed that auditory cortex in Grin1 mutant mice became hyper-excitable upon exposure to acoustic click-train stimuli that release 5-HT in the cortex. This excitability increase was reproduced ex vivo where it consisted of an increased frequency of action potential (AP) firing in layer 2/3 pyramidal neurons of mutant auditory cortex. Application of the 5-HT2AR agonist TCB-2 produced similar results. The effect of click-trains was reversed by the 5-HT2AR antagonist M100907 both in vivo and ex vivo. Increase in AP frequency of pyramidal neurons was also reversed by application of Gαq protein inhibitor BIM-46187 and G protein-gated inwardly-rectifying K+ (GIRK) channel activator ML297. In fast-spiking interneurons, 5-HT2AR activation normally promotes GABA release, contributing to decreased excitability of postsynaptic pyramidal neurons, which was missing in the mutants. Moreover, unlike the controls, the GABAA receptor antagonist (+)-bicuculline had little effect on AP frequency of mutant pyramidal neurons, indicating a disinhibition state. These results suggest that the auditory-induced hyper-excitable state is conferred via GABA release deficits from Grin1-lacking interneurons leading to 5-HT2AR dysregulation and GIRK channel suppression in cortical pyramidal neurons, which could be involved in auditory psychosis.

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Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy

Cited by 14 publications

References 144 publications

Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

Pimavanserin Treatment for Psychosis in Patients with Dementia with Lewy Bodies: A Case Series

5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction

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