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Table of Contents    
Year : 2022  |  Volume : 70  |  Issue : 5  |  Page : 2125-2129

Use of Fluoxetine to Augment the Inter-Ictal Hypercapnic Ventilatory Response in Patients with Epilepsy: A Pilot Study

1 Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
2 Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA, USA
3 Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
4 Department of Neurology; Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa; Department of Neurology, Veterans Affairs Medical Center, Iowa City, IA, USA

Date of Submission30-Jul-2020
Date of Decision04-Oct-2021
Date of Acceptance12-Oct-2021
Date of Web Publication21-Oct-2022

Correspondence Address:
Rup K Sainju
Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, 8820 JPP, Neurology, Iowa City - 52242, Iowa
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.359160

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 » Abstract 

Background: Severe peri-ictal respiratory dysfunction is a potential biomarker for high SUDEP risk and correlates with an attenuated hypercapnic ventilatory response (HCVR). Prior studies suggest a potential role for selective serotonergic reuptake inhibitors in modifying the HCVR, but this approach has not been studied in the epilepsy population.
Objectives: To assess the feasibility of using fluoxetine to augment HCVR in epilepsy patients.
Methods and Material: An inter-ictal HCVR was measured using a CO2 rebreathing technique in patients with epilepsy aged 18–75 years. Eligible participants were randomized to fluoxetine or placebo, and the HCVR was repeated at the end of week 4. Primary outcomes were recruitment and retention rate.
Results: Of the 30 subjects enrolled, 22 were randomized (mean: 3.8 subjects/3 months), with a retention rate of 100% in fluoxetine and 95% in placebo.
Conclusions: Our results demonstrate feasibility for a larger definitive future study to assess the efficacy of fluoxetine in augmenting HCVR.

Keywords: Epilepsy, fluoxetine, HCVR, SSRI, SUDEP
Key Message: An attenuated hypercapnic ventilatory response (HCVR) is a potential surrogate for high SUDEP risk. Serotonergic drugs have been studied to modify the HCVR but not in an epilepsy population. We assessed and demonstrated the feasibility of a randomized trial of fluoxetine in this population.

How to cite this article:
Sainju RK, Dragon DN, Winnike HB, Eyck PT, Granner MA, Gehlbach BK, Richerson GB. Use of Fluoxetine to Augment the Inter-Ictal Hypercapnic Ventilatory Response in Patients with Epilepsy: A Pilot Study. Neurol India 2022;70:2125-9

How to cite this URL:
Sainju RK, Dragon DN, Winnike HB, Eyck PT, Granner MA, Gehlbach BK, Richerson GB. Use of Fluoxetine to Augment the Inter-Ictal Hypercapnic Ventilatory Response in Patients with Epilepsy: A Pilot Study. Neurol India [serial online] 2022 [cited 2023 Jun 4];70:2125-9. Available from:

SUDEP is a major cause of premature death in patients with epilepsy.[1] Severe respiratory dysfunction following generalized convulsive seizures (GCSs) often precedes death in SUDEP.[2],[3] Thus, severe peri-ictal respiratory dysfunction has been proposed as a biomarker of SUDEP risk.[4] Other competing proposed mechanisms of SUDEP include cardiac abnormalities and autonomic failure, which are mainly based on the reported association of cardiac and autonomic changes in longstanding drug-resistant epilepsy patients as well as peri-ictal changes that occur with GCS.[3],[5],[16] several neurocardiac channelopathies have been identified in some patients with epilepsy which could also support a cardiac hypothesis.[3],[5],[17]

Serotonin (5-HT) neurons in the brainstem mediate central chemoreception (CCR) by sensing a rise in PaCO2 via low tissue pH and stimulate respiration and induce arousal to restore homeostasis.[6],[7] This CCR can be quantified by measuring the change in minute ventilation (VE) in response to increasing end-tidal (ET) CO2, also known as the hypercapnic ventilatory response (HCVR), by using a modified hyperoxic CO2 rebreathing technique.[8] An attenuated inter-ictal HCVR correlates with severe respiratory dysfunction related to GCS, identifying low HCVR as a surrogate of SUDEP risk.[8]

Retrospective studies suggest that selective serotonin reuptake inhibitors (SSRI) use is associated with less severe peri-ictal hypoxemia.[9],[10] The mechanisms for this are unclear but may involve augmentation of the HCVR. SSRIs, including fluoxetine, have been studied in animals and humans to modify the HCVR.[11],[12] Fluoxetine was associated with reduction of the HCVR in patients with panic disorder (PD),[11] but there are reasons to believe this response may be different in patients with epilepsy without PD, a group that has not been studied.[18],[19] Therefore, we conducted a randomized clinical trial to assess the feasibility of such a study in patients with epilepsy.

 » Subjects and Methods Top

Study design

This was a randomized controlled trial to assess the feasibility of studying the effect of fluoxetine on HCVR in patients with epilepsy. The study was approved on 10/14/2016 by the University of Iowa Institutional Review Board ( registration number NCT029296670).


We recruited consecutive patients with epilepsy, aged 18–75 years, at the University of Iowa Hospitals and Clinics from February 2017 to February 2019. Written informed consent was obtained for all subjects. Eligible subjects underwent inter-ictal HCVR measurement; HCVR slope was calculated for each subject using a previously described method.[8] [Table 1] describes inclusion and exclusion criteria for randomization.
Table 1: Patient selection

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Procedures and interventions

We used a screening questionnaire and electronic medical records to identify covariates such as demographics, medical history, and active medications, including anti-epileptic drugs.

After initial enrollment, Patient Health Questionnaire (PH-Q)-9 was assessed as well as the measurement of HCVR to determine further eligibility for randomization to study the drug. Eligible subjects were randomized equally between fluoxetine and placebo [Figure 1] to a 6-week titration plan: week 1-10 mg/day, week 2-20 mg/day, weeks 3 and 4-40 mg/day, week 5-20 mg/day, week 6-10 mg/day, and then stop from week 7 onward. The HCVR and PHQ-9 were repeated at the end of week 4. Follow-up telephone calls were made during weeks 1, 3, and 7 for assessment of compliance and adverse effects. Two subjects proceeded with previously arranged admissions to the epilepsy monitoring unit (EMU) for video EEG with comprehensive cardiorespiratory monitoring as previously described.[13]
Figure 1: (a) Study design, procedure, and visits. (b) CONSORT flow diagram

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Primary outcomes were recruitment and retention rates. Secondary outcomes included a) change in PHQ-9 score, b) change in baseline and maximum VE, c) change in HCVR slope, d) difference in duration of abnormal breathing (bradypnea and/or apnea) in the peri-ictal period, e) difference in oxygen saturation during the peri-ictal period, and f) difference in transcutaneous CO2 level in the peri-ictal period.

Sample size

No sample size calculation was performed.

Randomization and Blinding.

Using block randomization with a block size of 4, the randomization sequence was generated using a tool available at The subjects, investigators, care team, and statistician were all blinded to treatment allocation.

Statistical methods

All analyses utilized the generalized linear mixed modeling framework, specifying an identity link or a log link for normally distributed or right-skewed outcomes, respectively. A random effect was included for study ID. For normally distributed outcomes, the mean difference, standard deviation, 95% confidence interval, and P between groups were calculated (right-skewed outcomes used mean ratio). We set the significance cutoff at α = 0.05.

 » Results Top

Participant flow, recruitment, follow-up, losses, and exclusions

[Figure 1] depicts the participant flow in the study. Of the 126 potentially eligible subjects approached, 30 were enrolled and underwent further screening procedures before randomization to an intervention. Twenty-two eligible subjects were randomized equally (1:1) to one of the treatment arms. Demographics and characteristics of the randomized participants are presented in [Table 2].
Table 2: Demographics and characteristics

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One subject in the placebo group lost for the final telephone follow-up. All remaining participants completed the protocol. Secondary outcomes for the subject lost for the final telephone call follow-up were available; therefore, these were included for analyses.

Compliance and adverse effects of the intervention

Compliance was excellent in both groups. No serious adverse events were recorded except for one subject who reported excessive sleepiness, feeling tired and lethargic, and a feeling of a swollen tongue not visible on physical examination. This subject inadvertently deviated from the scheduled titration protocol, which was deemed to be the likely cause. Once back on schedule, symptoms resolved.

Primary outcome

Thirty subjects were enrolled, with 22 randomized to an intervention, one of whom was lost for the final telephone follow-up. Therefore, the mean recruitment rate of the study was 3.8 subjects every 3 months with a retention rate of 100% in fluoxetine and 95% in placebo groups, respectively.

Secondary outcomes

There was no significant difference between the two groups for PHQ-9 scores (mean ratio: 1.52, 95% CI: 0.36–6.08, P = 0.55), HCVR slope (mean difference: 0.12, 95% CI: 0.87–0.62 L/min/mm Hg, P = 0.75), baseline VE (mean ratio: 0.95, 95% CI: 0.75–1.20, P = 0.65), or maximum VE during HCVR measurement (mean ratio: 0.96, 95% CI: 0.76–1.2, P = 0.71). The two subjects who underwent video EEG study with comprehensive respiratory monitoring did not have any recorded seizures. Therefore, the effect of the intervention on peri-ictal respiratory abnormalities could not be evaluated.

 » Discussion Top

There is an urgent need to develop a therapy to significantly reduce SUDEP risk.[20] Our previous study demonstrated that a low inter-ictal HCVR slope correlates with greater severity of peri-ictal respiratory dysfunction after GCS, suggesting that it is a potential biomarker for SUDEP risk.[8],[21] Given the important role of 5-HT in CCR,[6] we conducted a randomized clinical trial to assess the feasibility of a study using fluoxetine in patients with epilepsy to modify their HCVR. Our successful conclusion of the trial demonstrates such feasibility despite stringent subject selection.

SSRI agents usually take several weeks to exert a positive effect on mood.[14],[22] We assumed that a similar dose and duration of therapy may be sufficient to modify the HCVR. Therefore, we planned a 6-week titration schedule which was well tolerated.

We did not find any statistically significant differences in secondary outcomes between the two groups: HCVR slope, baseline VE, or maximum VE. These findings are not totally unexpected given the study was not powered to measure small differences between the two groups. Biological variables, particularly age, gender, and body size are known to influence HCVR,[15] but it remains unclear if these variables also influence fluoxetine's ability to alter HCVR in any way. If they do, they could have affected the results as we were not able to control them in this study. This would be particularly true for age as this variable was significantly different between the two groups. Alternatively, the dose and duration of fluoxetine to alter the HCVR may be different than that was used in the study. Thus, the results of our study do not answer the question of whether fluoxetine increases the HCVR slope in patients with epilepsy and, if so, what the optimal dose and duration would be.

Interestingly, previous observational studies in patients with epilepsy have suggested that use of SSRI agents was associated with less severe peri-ictal hypoxemia.[9],[10] We were not able to evaluate the effect of fluoxetine on peri-ictal O2 saturation or CO2 changes as the two subjects who underwent VEEG with comprehensive cardiorespiratory monitoring did not have any seizures during the study. Our results suggest that with stringent inclusion/exclusion criteria, it may be difficult to enroll adequate numbers of patients prior to EMU admission to study the effect of SSRIs on HCVR and peri-ictal respiratory changes.

 » Conclusions Top

This phase II study demonstrates the feasibility of a prospective clinical trial in patients with epilepsy to evaluate whether fluoxetine modifies the HCVR slope. Future studies that utilize different doses and/or durations of treatment may be necessary to ascertain the effect on HCVR slope in patients with epilepsy.

Financial support and sponsorship

This study was supported by Citizens United for Research in Epilepsy (CURE) (award number: 411673), and the National Institute of Health CTSA (program grant: UL1TR002537).

Conflicts of interest

There are no conflicts of interest.

 » References Top

Sveinsson O, Andersson T, Carlsson S, Tomson T. The incidence of SUDEP: A nationwide population-based cohort study. Neurology 2017;89:170-7.  Back to cited text no. 1
Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): A retrospective study. Lancet Neurol 2013;12:966-77.  Back to cited text no. 2
Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: The pathway to prevention. Nat Rev Neurol 2014;10:271-82.  Back to cited text no. 3
Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: Analysis of incidence, severity and risk factors. Brain 2008;131:3239-45.  Back to cited text no. 4
Bermeo-Ovalle AC, Kennedy JD, Schuele SU. Cardiac and autonomic mechanisms contributing to SUDEP. J Clin Neurophysiol 2015;32:21-9.  Back to cited text no. 5
Richerson GB. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 2004;5:449-61.  Back to cited text no. 6
Buchanan GF, Richerson GB. Central serotonin neurons are required for arousal to CO2. Proc Natl Acad Sci U S A 2010;107:16354-9.  Back to cited text no. 7
Sainju RK, Dragon DN, Winnike HB, Nashelsky MB, Granner MA, Gehlbach BK, et al. Ventilatory response to CO 2 in patients with epilepsy. Epilepsia 2019;60:508-17.  Back to cited text no. 8
Bateman LM, Li CS, Lin TC, Seyal M. Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxemia in medically refractory partial epilepsy. Epilepsia 2010;51:2211-4.  Back to cited text no. 9
Lacuey N, Martins R, Vilella L, Hampson JP, Rani MRS, Strohl K, et al. The association of serotonin reuptake inhibitors and benzodiazepines with ictal central apnea. Epilepsy Behav 2019;98:73-9.  Back to cited text no. 10
Bocola V, Trecco MD, Fabbrini G, Paladini C, Sollecito A, Martucci N. Antipanic effect of fluoxetine measured by CO2 challenge test. Biol Psychiatry 1998;43:612-5.  Back to cited text no. 11
Hodges MR, Echert AE, Puissant MM, Mouradian GC. Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats. Respir Physiol Neurobiol 2013;186:221-8.  Back to cited text no. 12
Gehlbach BK, Sainju RK, Tadlock DK, Dragon DN, Granner MA, Richerson GB. Tolerability of a comprehensive cardiorespiratory monitoring protocol in an epilepsy monitoring unit. Epilepsy Behav 2018;85:173-6.  Back to cited text no. 13
Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994;15:220-6.  Back to cited text no. 14
Patrick JM, Howard A. The influence of age, sex, body size and lung size on the control and pattern of breathing during CO2 inhalation in Caucasians. Respir Physiol 1972;16:337-50.  Back to cited text no. 15
Zhang X, Cui L, Lin W. Cardiac Arrest in Frontal Lobe Epilepsy: A Potential Cause of Sudden Unexpected Death in Epilepsy. Neurol India 2021;69:737-9.  Back to cited text no. 16
[PUBMED]  [Full text]  
Meenakshi-Sundaram S, Sankaranarayanan M. Epilepsy, Phenytoin, and Atherogenic Risk-Current Perspectives. Neurol India 2021;69:962-3.  Back to cited text no. 17
[PUBMED]  [Full text]  
Murthy J, Jaiswal SK, Reddy MP, Srikrishna S. Incidence Study of Epilepsy using the ILAE 2017 Classification of Epilepsies in a Cohort of School Children Accessing Education in Government Primary Schools in South India. Neurol India 2020;68:1389-93.  Back to cited text no. 18
[PUBMED]  [Full text]  
Abokrysha NT, Kishk NA, Nawito AM, Mounir N. Effect of Low-Dose Naltrexone on Egyptian Children with Intractable Epilepsy: A Case Series Study. Neurol India 2021;69:1781-4.  Back to cited text no. 19
[PUBMED]  [Full text]  
Kaur T, Diwakar A, Kirandeep Mirpuri P, Tripathi M, Chandra PS, Gandhi TK. Artificial Intelligence in Epilepsy. Neurol India 2021;69:560-6.  Back to cited text no. 20
[PUBMED]  [Full text]  
Doddamani RS, Samala R, Subianto H, Ramanujam B, Tripathi M, Chandra PS. Robotic-Guided Stereoelectroencephalography for Refractory Epilepsy: Technique and Nuances. Neurol India 69:587-91.  Back to cited text no. 21
Garg K. Prevalence of Major Mental and Neurological Disorders in India. Neurol India 2021;69:302-3.  Back to cited text no. 22
[PUBMED]  [Full text]  


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  [Table 1], [Table 2]


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