Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats

Hodges, Matthew R.; Echert, Ashley E.; Puissant, Madeleine M.; Mouradian, Gary

doi:10.1016/j.resp.2013.02.020

Cited by 21 publications

(21 citation statements)

References 31 publications

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“…10,35 Pharmacologic manipulation to enhance central chemoreceptor sensitivity has been demonstrated successfully in animal studies using SSRIs, 36,37 and SSRIs protect against postictal respiratory arrest in DBA/2 mice. 10,35 Pharmacologic manipulation to enhance central chemoreceptor sensitivity has been demonstrated successfully in animal studies using SSRIs, 36,37 and SSRIs protect against postictal respiratory arrest in DBA/2 mice.…”

Section: Discussionmentioning

confidence: 99%

Ventilatory response to CO₂ in patients with epilepsy

et al. 2019

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Summary Objective Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs). Methods Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (VE), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope (ΔVE/ΔETCO2) for each subject was determined by linear regression. During the video–electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO2, and capillary oxygen saturation (SPO2). Results Sixty‐eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from −0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO2. Both the duration and magnitude of postictal tcCO2 rise following GCSs were inversely correlated with HCVR slope. Significance Measurement of the HCVR is well tolerated and can be performed rapidly and safely at the bedside in the EMU. A subset of individuals has a very low sensitivity to CO2, and this group is more likely to have a prolonged increase in postictal CO2 after GCS. Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study.

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Section: Discussionmentioning

confidence: 99%

Ventilatory response to CO₂ in patients with epilepsy

et al. 2019

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“…There is also a reduced hypercapnic ventilatory response in these mice [30], and in Brown Norway rats [31], whose levels of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) were low in the brain [32]. Administration of fluoxetine can reverse the arousal deficit in Brown Norway rats [33]. If this defect in arousal contributes to S-IRA in DBA/1 mice, fluoxetine may prevent S-IRA by enhancing arousal mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies on the effect of fluoxetine on breathing have yielded conflicting results [33–35]. For example, centrally administered fluoxetine increased basal breathing and the ventilatory response to CO 2 in one study [35].…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice

Zeng¹,

Long²,

Cotten³

et al. 2015

Epilepsy & Behavior

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Sudden unexpected death in epilepsy (SUDEP) is a fatal epileptic event. The DBA/1 mouse is a relevant animal model for study of SUDEP, as these mice exhibit seizure-induced respiratory arrest (S-IRA) leading to death, which has been observed in witnessed SUDEP patients. Fluoxetine, a selective serotonin (5-hydroxytryptamine or 5-HT) reuptake inhibitor (SSRI), reduces S-IRA in DBA/1 mice. Given that DBA/1 mice with S-IRA can be resuscitated using a ventilator, we hypothesized that breathing stimulants can prevent S-IRA and that fluoxetine prevents S-IRA by enhancing ventilation in these mice. Spontaneous respiratory function in anesthetized or awake DBA/1 mice was examined using non-invasive plethysmography before and after administering fluoxetine or breathing stimulants, doxapram and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP). The effects of these drugs on S-IRA in DBA/1 mice were tested. As reported previously, systemic administration of fluoxetine reduced S-IRA in awake DBA/1 mice, but fluoxetine in anesthetized and awake DBA/1 mice did not increase basal ventilation or the ventilatory response to 7% CO2. Both doxapram and PK-THPP increased ventilation in room air and in air + 7% CO2 in anesthetized DBA/1 mice. However, neither of the breathing stimulants reduced the incidence of S-IRA. Our studies confirm that fluoxetine reduces S-IRA in DBA/1 mice, but without enhancing basal ventilation in the absence of seizures. Although breathing stimulants increased ventilation in the absence of seizures, they were ineffective in reducing S-IRA, indicating that drug-induced increases in ventilation are insufficient to compensate for S-IRA in DBA/1 mice.

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“…The discoveries linking respiratory failure and SUDEP led to preliminary pharmacological explorations of the widely available serotonin reuptake inhibitors (SSRIs) with respect to the SUDEP risk [25,26]. The exogenous administration of fluoxetine ameliorated seizure severity and ictally induced respiratory arrest and death in the DBA model in a dose-dependent fashion [26], whereas it improved the inherent serotonin deficiency and low ventilatory sensitivity to hypercapnia in the Brown Norway rats [27]. The animal research was subsequently validated in a cohort of patients with epilepsy chronically exposed to the commonly used SSRIs [28] that exhibited a reduced severity of ictal desaturation less than 85% during a partial seizure, albeit the effect was not seen during the secondarily generalized seizures [28].…”

Section: Sudden Unexpected Death In Epilepsy Risk Factors and Candidamentioning

confidence: 99%

Mechanisms of sudden unexplained death in epilepsy

Goldman

2015

Current Opinion in Neurology

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Purpose of review Human and experimental research has identified cardioautonomic and respiratory dysfunction as a frequent accompaniment in human and animal model events of sudden unexpected death in epilepsy (SUDEP). This review aims to provide an overview of the scientific evidence behind the currently accepted risk factors and working hypotheses regarding SUDEP pathophysiology. Recent findings Epidemiological analysis of public health burden of SUDEP has shown that it rates second only to stroke in the years of potential life lost. Clinical and experimental studies uncovered the dynamic cardiorespiratory dysfunction interictally and imminently to SUDEP, and model systems have facilitated discoveries in SUDEP mechanistic understanding and application of pilot therapeutic interventions. Pilot molecular profiling of human SUDEP has uncovered complex genomic structure in the candidate gene network. Summary Extensive clinical and experimental work has established a rationale for the conceptual thinking about SUDEP mechanisms. The application of the global molecular profiling will be invaluable in unraveling the individually unique genomic complexities and interactions that underlie the physiological signature of each patient. At the same time, sophisticated model systems will be critical in the iterative translation of human genetics, physiology, pharmacological interventions, and in testing preventive interventions.

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Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats

Cited by 21 publications

References 31 publications

Ventilatory response to CO₂ in patients with epilepsy

Ventilatory response to CO₂ in patients with epilepsy

Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice

Mechanisms of sudden unexplained death in epilepsy

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Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats

Cited by 21 publications

References 31 publications

Ventilatory response to CO2 in patients with epilepsy

Ventilatory response to CO2 in patients with epilepsy

Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice

Mechanisms of sudden unexplained death in epilepsy

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Ventilatory response to CO₂ in patients with epilepsy

Ventilatory response to CO₂ in patients with epilepsy