Effect of Serotonin 1A Agonists and Selective Serotonin Reuptake Inhibitors on Behavioral and Nighttime Respiratory Symptoms in Rett Syndrome

Ohno, Kiyotaka; Saito, Yoshiaki; Ueda, Riyo; Togawa, Masami; Ohmae, Takanori; Matsuda, Eriko; Fujiyama, Misato; Maegaki, Yoshihiro

doi:10.1016/j.pediatrneurol.2016.03.016

Cited by 17 publications

(10 citation statements)

References 16 publications

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“…Since dendrites receive electrical signals and neurotransmitters from pre-synaptic neurons, a neurotransmitter signaling defect was proposed in RTT. In support of this idea, dysfunction in dopamine (Wenk 1995), serotonin (Paterson et al 2005; Ohno et al 2016), norepinephrine (Viemari 2005; Santos et al 2010), glutamate (Chao et al 2010; Abdala et al 2016), and NMDA signaling (Katz et al 2016; Patrizi et al 2016) has been observed in Mecp2 -mutant mice. Treatments that target these pathways have shown varied effects in mice, and a few have been tested in clinical trials.…”

Section: Using Mouse Models To Develop Therapeutics For Rtt Targetingmentioning

confidence: 94%

Treating Rett syndrome: from mouse models to human therapies

Vashi

Justice

2019

Mamm Genome

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Rare diseases are very difficult to study mechanistically and to develop therapies for because of the scarcity of patients. Here, the rare neuro-metabolic disorder Rett syndrome (RTT) is discussed as a prototype for precision medicine, demonstrating how mouse models have led to an understanding of the development of symptoms. RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 ( MECP2 ). Mecp2- mutant mice are being used in preclinical studies that target the MECP2 gene directly, or its downstream pathways. Importantly, this work may improve the health of RTT patients. Clinical presentation may vary widely among individuals based on their mutation, but also because of the degree of X chromosome inactivation and the presence of modifier genes. Because it is a complex disorder involving many organ systems, it is likely that recovery of RTT patients will involve a combination of treatments. Precision medicine is warranted to provide the best efficacy to individually treat RTT patients.

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Section: Using Mouse Models To Develop Therapeutics For Rtt Targetingmentioning

confidence: 94%

Treating Rett syndrome: from mouse models to human therapies

Vashi

Justice

2019

Mamm Genome

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“…Certain medications, including selective serotonin reuptake inhibitors (SSRIs), are known to cause prolongation of the QT interval . These medications and other agents with effects on serotonin have been shown to have a positive impact on behaviour, sleep, and respiratory patterns in patients with RTT . Our goal was to evaluate patients with RTT with prolonged QTc at baseline and monitor patients with normal QTc to evaluate who would develop QTc prolongation over time.…”

mentioning

confidence: 99%

“…14 These medications and other agents with effects on serotonin have been shown to have a positive impact on behaviour, sleep, and respiratory patterns in patients with RTT. [15][16][17] Our goal was to evaluate patients with RTT with prolonged QTc at baseline and monitor patients with normal QTc to evaluate who would develop QTc prolongation over time. The identification of patients who develop prolonged QTc and determination of potential risk factors may allow for proper surveillance and monitoring of patients with RTT.…”

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confidence: 99%

Serial follow‐up of corrected QT interval in Rett syndrome

Clark

Kopp

Morey

et al. 2019

Develop Med Child Neuro

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Aim To identify factors associated with baseline prolonged corrected QT (QTc) and higher risk of QTc prolongation during follow‐up in patients with Rett syndrome (RTT). Method A retrospective review of patients receiving an electrocardiogram (ECG) between June 2012 and June 2018 was performed. Age, methyl‐CpG binding protein 2 gene (MECP2) mutation, RTT Severity Scale (RSSS) score, breathing abnormalities, seizure frequency, medications, and ECG parameters were collected. Prolonged QTc was defined as greater than or equal to 460ms. Comparisons at baseline and during follow‐up were made. Results In total, 129 unique patients (all female) had 349 ECGs. At baseline, 12 (9.3%) had a prolonged QTc (median 474ms, interquartile range 470–486ms) and were more likely to have moderate/severe breathing abnormalities (66.7% vs 24.8%; p=0.005) and take selective serotonin reuptake inhibitors (SSRIs) (41.7% vs 15.4%; p=0.04). There was no difference in age, RSSS score, seizures, or mutation. Twenty‐six developed prolonged QTc during a median follow‐up of 1 year 7 months (interquartile range 0–3y 6mo). QTc prolongation was associated with p.(Thr158Met) mutation versus the remaining six common mutations (hazard ratio 4.1, 95% confidence interval 1.4–12.0; p=0.01) but not with age, RSSS score, seizures, breathing abnormalities, or SSRIs. Interpretation Breathing abnormalities and SSRIs were associated with baseline QTc prolongation and those with p.(Thr158Met) mutation were more likely to develop prolonged QTc over time. Identification of patients with prolonged QTc warrants increased clinical monitoring. What this paper adds Breathing abnormalities and selective serotonin reuptake inhibitors are associated with prolonged baseline corrected QT (QTc). Development of QTc prolongation is associated with the p.(Thr158Met) mutation.

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“…Although mirtazapine blocks 5-HT 2/3 receptors, the fact that it blocks α 2 -adrenoceptors results in an increased firing rate of 5-HT neurons of the raphe, 5-HT release and tonic activation of hippocampal 5-HT 1A receptors 48 . Currently, information on the effects of FLX and other SSRIs in patients with RTT is limited to a few case reports showing that these drugs may be effective on psychiatric, behavioral and motor symptoms and sleep apneas [49][50][51] . An open study on the effects of FLX in RTT was terminated prematurely (EudraCT Number: 2008-000787-16) and to our knowledge no other clinical assessments of the effects of SSRIs in RTT have been published.…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine increases brain MeCP2 immuno-positive cells in a female Mecp2 heterozygous mouse model of Rett syndrome through endogenous serotonin

Villani

Carli

Castaldo

et al. 2021

Sci Rep

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Motor skill deficit is a common and invalidating symptom of Rett syndrome (RTT), a rare disease almost exclusively affecting girls during the first/second year of life. Loss-of-function mutations of the methyl-CpG-binding protein2 (MECP2; Mecp2 in rodents) gene is the cause in most patients. We recently found that fluoxetine, a selective serotonin (5-HT) reuptake inhibitor and antidepressant drug, fully rescued motor coordination deficits in Mecp2 heterozygous (Mecp2 HET) mice acting through brain 5-HT. Here, we asked whether fluoxetine could increase MeCP2 expression in the brain of Mecp2 HET mice, under the same schedule of treatment improving motor coordination. Fluoxetine increased the number of MeCP2 immuno-positive (MeCP2+) cells in the prefrontal cortex, M1 and M2 motor cortices, and in dorsal, ventral and lateral striatum. Fluoxetine had no effect in the CA3 region of the hippocampus or in any of the brain regions of WT mice. Inhibition of 5-HT synthesis abolished the fluoxetine-induced rise of MeCP2+ cells. These findings suggest that boosting 5-HT transmission is sufficient to enhance the expression of MeCP2 in several brain regions of Mecp2 HET mice. Fluoxetine-induced rise of MeCP2 could potentially rescue motor coordination and other deficits of RTT.

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Effect of Serotonin 1A Agonists and Selective Serotonin Reuptake Inhibitors on Behavioral and Nighttime Respiratory Symptoms in Rett Syndrome

Cited by 17 publications

References 16 publications

Treating Rett syndrome: from mouse models to human therapies

Treating Rett syndrome: from mouse models to human therapies

Serial follow‐up of corrected QT interval in Rett syndrome

Fluoxetine increases brain MeCP2 immuno-positive cells in a female Mecp2 heterozygous mouse model of Rett syndrome through endogenous serotonin

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