Effect of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation (NCT05470465)

01

Study summary

This study is designed to evaluate the effects of the coadministration of paroxetine or escitalopram with an opioid on ventilation. Ventilation will be assessed using a rebreathing methodology. This study will evaluate chronic and acute dosing of paroxetine and escitalopram combined with an opioid as well as chronic and acute dosing of the two drugs without coadministration of an opioid.

This study is a 3-period, randomized, placebo-controlled crossover study conducted with 25 healthy participants. Each participant will receive each of the 3 treatments (placebo/oxycodone, paroxetine/oxycodone, escitalopram/oxycodone) in a randomized order.

Read the detailed description

This study is designed to evaluate the effects of the coadministration of paroxetine or escitalopram, two selective serotonin reuptake inhibitors (SSRI), with an opioid on hypercapnic ventilation. Hypercapnic ventilation will be assessed under both hyperoxic and hypoxic conditions using the Duffin rebreathing method. This method allows for critical physiological measurements and thresholds to be captured that can then be used to model the effects of drugs when there are dynamic changes in oxygen partial pressure (PO2) and carbon dioxide partial pressure (PCO2), such as during a real-world opioid overdose.

SSRIs take approximately 3 weeks to reach maximal therapeutic effect, which correlates with the time required for pre-synaptic inhibitory serotonergic receptors to desensitize. Therefore, drug-effects on ventilation should be evaluated under steady state conditions.

This study is randomized, placebo-controlled crossover study which includes three 21-day periods conducted with 25 healthy participants. Participants will receive each of the 3 treatments (placebo/oxycodone, paroxetine/oxycodone, or escitalopram/oxycodone) in a randomized order. Paroxetine dosing will range from 40-60 mg once daily (QD) and escitalopram dosing will range from 20-30 mg QD. Subjects will receive 10 mg oxycodone on three different days each period. Subjects will undergo 6 days of rebreathing and time-matched pupillary assessments along with 3 separate days of ECG assessments each period. Additionally, blood samples will be collected for determination of plasma concentrations for each study drug on days with rebreathing and ECG assessments.

02

Conditions studied

Hypercapnia
Ventilatory Depression

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03

In context

Hypercapnia

156 studies on the registry are indexed under Hypercapnia; 31 are open to participants now.

This study's enrollment of 27 is below the median of 36 across 120 interventional studies indexed under Hypercapnia.

Browse Hypercapnia studies →

Lead sponsor

Food and Drug Administration (FDA) is the lead sponsor of 25 studies on the registry; 2 are open to participants now.

Of its 15 completed or terminated interventional studies of FDA-regulated products, 13 (87%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible: 18 Years to 50 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Subject signs an Institutional Review Board (IRB) approved written and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed.
Subject is a healthy, non-smoking man or woman, 18 to 50 years of age, inclusive, who has a of 18.5 to 33.0 kg/m2, inclusive, at Screening.
Subject has normal medical history findings, clinical laboratory results, vital sign measurements, pulse oximetry, 12-lead results, and physical examination findings at screening or, if abnormal, the abnormality is not considered (as determined and documented by the investigator or designee).
Subject must have a negative test result for alcohol and drugs of abuse at screening and check-in days.
Subject must test negative for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by a rapid antigen test at check-in for all study periods. If a subject's test comes back as invalid, the test can be repeated.
Female subjects must be of non- (confirmed with follicle-stimulating hormone levels > 40 milli-international unit [mIU]/mL) or, if they are of childbearing potential, they must: 1) have been strictly abstinent for 1 month before check-in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1month after the last application of study drug; OR 2) be practicing 2 highly effective methods of (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before check-in (Day -1) until at least 1 month after the end of the study.
Male subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee) from at least 1 month before check-in (Day -1) until at least 1 month after the last dose of study drug.
Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

Exclusion criteria

Exclusion Criteria:

Subject has used any prescription or nonprescription drugs (including aspirin or NSAIDs and excluding oral and acetaminophen) within 14 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug. This includes prescription or nonprescription ophthalmic drugs.
Subject is currently participating in another clinical study of an drug or has been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of the compound.
Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, electronic cigarettes) within 6 weeks of Screening. Subjects must refrain from using these throughout the study.
Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, cola), caffeine, grapefruit, or grapefruit juice within 24 h of check-in. Subjects must refrain from ingesting these throughout the study.
Subject has a history or evidence of a disorder, condition, or disease (e.g., cancer, [HIV], hepatic or renal impairment) that, in the opinion of the investigator would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. This includes subjects with any underlying medical conditions that put subjects at increased risk of severe illness from coronavirus disease 2019 (COVID-19) based on the Centers for Disease Control and Prevention (CDC) guidelines.
Subject has any signs or symptoms at screening or check-in of any study periods that are consistent with COVID-19. Per current CDC recommendations this includes subjects with the symptoms cough or shortness of breath or difficulty breathing, or at least two of the following symptoms: fever, chills, repeated shaking with chills, muscle pain, headache, sore throat or new loss of taste/smell. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator.
Subject has known or suspected allergies or sensitivities to any study drugs.
Subject has clinical laboratory test results (hematology, serum chemistry and urinalysis) at Screening or period check-in that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator. Clinical laboratory results may be repeated once, as needed, for confirming results at Screening and period check-in.
Subject has a positive test result at Screening for HIV 1 or 2 antibody, virus antibodies, or surface antigen.
Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access.
Female subject is currently pregnant or lactating or was within 3 months of before enrollment.
Subject has a history of opioid or psychotropic drugs within 60 days of the start of the study.
Subject has a history of asthma that has required medication within the last five years.
Subject has non-reactive or misshapen pupil(s) or damaged orbit structure or surrounding soft tissue is edematous or has an open lesion.
Subject has a Mallampati score of >2.
Subject's Duffin rebreathing data is of poor quality or subject does not agree to remain clean-shaven for all days when the Duffin rebreathing procedure is performed.
Subject has a history of sleep disorders, Panic disorders, Panic Attacks, Generalized Anxiety Disorder, or any associated diagnosis or condition.
Subject has a history of or currently has hypoventilation syndrome or sleep apnea and is on non-invasive ventilation.
Subject has a history of unexplained syncope, structural heart disease, long syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, Torsades de Pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects will be also excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative to cardiac causes at a young age) or Brugada syndrome.
Subject has a history of suicidal ideation or previous suicide attempts.
Subject has a safety 12-lead result at Screening or check-in at any study period with evidence of any of the following abnormalities:
- QTc using Fridericia correction (QTcF)>430 msec
- PR interval>220 msec or \<120msec
- QRS duration>110 msec
- Second- or third-degree atrioventricular block
- Complete left or right bundle branch block or incomplete right bundle branch block
- Heart rate \<50 or >90 beats per minute
- Pathological Q-waves (defined as Q-wave>40 msec)
- Ventricular pre-excitation
Subject has a skin condition likely to compromise ECG electrode placement.
Any individual with breast implants.

Terms in these criteria, in plain language(12)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Informed consent

Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.

You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.

BMI (body mass index)

Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.

What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.

ECG (electrocardiogram)

A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.

Clinically significant

Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.

Childbearing potential

Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).

Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.

Contraception

Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.

Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.

Investigational drug or device

A drug or device being studied in a clinical trial.

It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.

HIV

The human immunodeficiency virus, which weakens the immune system.

Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.

Hepatitis C tests

Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.

After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.

Hepatitis B tests

Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.

Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.

DSM diagnostic criteria

The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.

QT and QTc

On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.

The study may name a correction formula and a limit in milliseconds, often around 450–480.

05

Study design

Phase: Phase 1
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 27 participants (actual)

Study arms

Placebo comparator
Treatment A: Placebo
Participants will receive placebo on days 1-21 for this treatment period. Oxycodone will be administered on days 6, 12, and 21 of this treatment period.
Drug: Placebo and Oxycodone
Experimental
Treatment B: Paroxetine
Participants will receive paroxetine on days 1-21 for this treatment period. Oxycodone will be administered on days 6, 12, and 21 of this treatment period.
Drug: Paroxetine and Oxycodone
Experimental
Treatment C: Escitalopram
Participants will receive escitalopram on days 1-21 for this treatment period. Oxycodone will be administered on days 6, 12, and 21 of this treatment period.
Drug: Escitalopram and Oxycodone

Interventions

DrugPlacebo and Oxycodone
Participants will receive placebo on days 1-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.
DrugParoxetine and Oxycodone
Drug pages: Paroxetine · Oxycodone
Participants will receive 40 mg paroxetine (2 x 20 mg tablets) on days 1-6 and 60 mg paroxetine (3 x 20 mg tablets) on days 7-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.
DrugEscitalopram and Oxycodone
Drug pages: Escitalopram · Oxycodone
Participants will receive 20 mg escitalopram (2 x 10 mg tablets) on days 1-6 and 30 mg escitalopram (3 x 10 mg tablets) on days 7-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.

06

What researchers measure

Primary outcomes

Minute Ventilation at 55mm Hg End Tidal CO2 (VE55) Under Hyperoxic Conditions on Day 21
Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 21.
Time frame: 5 hours on day 21
VE55 Under Hyperoxic Conditions on Day 20
Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 20.
Time frame: 5 hours on day 20

Secondary outcomes

VE55 Under Hyperoxic Conditions on Day 6
Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 6.
Time frame: 5 hours on day 6
VE55 Under Hyperoxic Conditions on Day 12
Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 12.
Time frame: 5 hours on day 12
VE55 Under Hyperoxic Conditions on Day 5
Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 5.
Time frame: 5 hours on day 5
VE55 Under Hyperoxic Conditions on Day 11
Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 11.
Time frame: 5 hours on day 11

07

Results

Posted May 22, 2025

Limitations and caveats

A limitation of this study was that the breathing assessments were conducted in a controlled experimental setting with healthy volunteers which may not be representative of actual at-risk individuals having an overdose. However, the methods used provide a safe way to assess ventilatory effects of drugs as carbon dioxide levels increase, which reflects the physiology of severe respiratory depression.

Participant flow

Participant flow — Overall Study
Milestone	Treatment Sequence ABC	Treatment ACB	Treatment BAC	Treatment BCA	Treatment CAB	Treatment CBA
Started	5	4	5	5	4	4
Completed	4	4	2	4	4	4
Not completed	1	0	3	1	0	0

Outcome measures

PrimaryMinute Ventilation at 55mm Hg End Tidal CO2 (VE55) Under Hyperoxic Conditions on Day 21

Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 21.

Time frame:: 5 hours on day 21
Reported as:: Mean · L/min

Minute Ventilation at 55mm Hg End Tidal CO2 (VE55) Under Hyperoxic Conditions on Day 21
L/min	Paroxetine + Oxycodone	Escitalopram + Oxycodone	Placebo + Oxycodone
Minute Ventilation at 55mm Hg End Tidal CO2 (VE55) Under Hyperoxic Conditions on Day 21	20.2 (15.8 to 24.6)	21.2 (16.8 to 25.6)	26.7 (22.3 to 31.2)

Statistical analysis

Paroxetine + Oxycodone vs Placebo + Oxycodone · Mixed Models Analysis · p = <0.001 (To demonstrate an effect of oxycodone with paroxetine compared to oxycodone alone, it is necessary that the upper bound of the one-sided 97.5% confidence interval (CI) in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -6.5Comparison was the effect of oxycodone and paroxetine compared to oxycodone and placebo.
Escitalopram + Oxycodone vs Placebo + Oxycodone · Mixed Models Analysis · p = 0.001 (To demonstrate an effect of oxycodone with escitalopram compared to oxycodone alone, it is necessary that the upper bound of the one-sided 97.5% confidence interval (CI) in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -5.5Comparison was the effect of oxycodone and escitalopram compared to oxycodone and placebo.

PrimaryVE55 Under Hyperoxic Conditions on Day 20

Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 20.

Time frame:: 5 hours on day 20
Reported as:: Mean · L/min

VE55 Under Hyperoxic Conditions on Day 20
L/min	Paroxetine	Escitalopram	Placebo
VE55 Under Hyperoxic Conditions on Day 20	30.8 (25.9 to 35.7)	30.4 (25.5 to 35.3)	37.4 (32.4 to 42.3)

Statistical analysis

Paroxetine vs Placebo · Mixed Models Analysis · p = 0.002 (To demonstrate an effect of paroxetine compared to placebo, it is necessary that the upper bound of the one-sided 97.5% confidence interval (CI) in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -6.5Comparison was the effect of paroxetine compared to placebo.
Escitalopram vs Placebo · Mixed Models Analysis · p = 0.003 (To demonstrate an effect of escitalopram compared to placebo, it is necessary that the upper bound of the one-sided 97.5% confidence interval (CI) in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -6.9Comparison was the effect of escitalopram compared to placebo.

SecondaryVE55 Under Hyperoxic Conditions on Day 6

Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 6.

Time frame:: 5 hours on day 6
Reported as:: Mean · L/min

VE55 Under Hyperoxic Conditions on Day 6
L/min	Paroxetine + Oxycodone	Escitalopram + Oxycodone	Placebo + Oxycodone
VE55 Under Hyperoxic Conditions on Day 6	18.5 (14.8 to 22.2)	20.0 (16.4 to 23.7)	25.6 (21.8 to 29.4)

Statistical analysis

Paroxetine + Oxycodone vs Placebo + Oxycodone · Mixed Models Analysis · p = <0.001 (Secondary analyses are not adjusted for multiplicity. To demonstrate an effect of oxycodone and paroxetine compared to oxycodone, the upper bound of the one-sided 97.5% CI in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -7.1Comparison was the effect of oxycodone and paroxetine compared to oxycodone and placebo at day 6 at 5 hours.
Escitalopram + Oxycodone vs Placebo + Oxycodone · Mixed Models Analysis · p = <0.001 (Secondary analyses are not adjusted for multiplicity. To demonstrate an effect of oxycodone and escitalopram compared to oxycodone, the upper bound of the one-sided 97.5% CI in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -5.6Comparison was the effect of oxycodone and escitalopram compared to oxycodone and placebo at day 6 at 5 hours.

SecondaryVE55 Under Hyperoxic Conditions on Day 12

Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 12.

Time frame:: 5 hours on day 12
Reported as:: Mean · L/min

VE55 Under Hyperoxic Conditions on Day 12
L/min	Paroxetine + Oxycodone	Escitalopram + Oxycodone	Placebo + Oxycodone
VE55 Under Hyperoxic Conditions on Day 12	18.1 (14.0 to 22.3)	21.4 (17.3 to 25.5)	28.2 (24.0 to 32.4)

Statistical analysis

Paroxetine + Oxycodone vs Placebo + Oxycodone · Mixed Models Analysis · p = <0.001 (Secondary analyses are not adjusted for multiplicity. To demonstrate an effect of oxycodone and paroxetine compared to oxycodone, the upper bound of the one-sided 97.5% CI in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -10.1Comparison was the effect of oxycodone and paroxetine compared to oxycodone and placebo at day 12 at 5 hours.
Escitalopram + Oxycodone vs Placebo + Oxycodone · Mixed Models Analysis · p = 0.003 (Secondary analyses are not adjusted for multiplicity. To demonstrate an effect of oxycodone and escitalopram compared to oxycodone, the upper bound of the one-sided 97.5% CI in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -6.9Comparison was the effect of oxycodone and paroxetine compared to oxycodone and placebo at day 12 at 5 hours.

SecondaryVE55 Under Hyperoxic Conditions on Day 5

Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 5.

Time frame:: 5 hours on day 5
Reported as:: Mean · L/min

VE55 Under Hyperoxic Conditions on Day 5
L/min	Paroxetine	Escitalopram	Placebo
VE55 Under Hyperoxic Conditions on Day 5	31.1 (26.8 to 35.4)	28.6 (24.3 to 32.9)	42.6 (38.3 to 46.9)

Statistical analysis

Paroxetine vs Placebo · Mixed Models Analysis · p = <0.001 (Secondary analyses are not adjusted for multiplicity. To demonstrate an effect of paroxetine compared to placebo, the upper bound of the one-sided 97.5% CI in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -11.6Comparison was the effect of paroxetine compared to placebo at day 5 at 5 hours.
Escitalopram vs Placebo · Mixed Models Analysis · p = <0.001 (Secondary analyses are not adjusted for multiplicity. To demonstrate an effect of escitalopram compared to placebo, the upper bound of the one-sided 97.5% CI in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -14.0Comparison was the effect of escitalopram compared to placebo at day 5 at 5 hours.

SecondaryVE55 Under Hyperoxic Conditions on Day 11

Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 11.

Time frame:: 5 hours on day 11
Reported as:: Mean · L/min

VE55 Under Hyperoxic Conditions on Day 11
L/min	Paroxetine	Escitalopram	Placebo
VE55 Under Hyperoxic Conditions on Day 11	27.3 (21.8 to 32.9)	32.0 (26.4 to 37.5)	41.4 (35.8 to 47.0)

Statistical analysis

Paroxetine vs Placebo · Mixed Models Analysis · p = <0.001 (Secondary analyses are not adjusted for multiplicity. To demonstrate an effect of paroxetine compared to placebo, the upper bound of the one-sided 97.5% CI in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -14.1Comparison was the effect of paroxetine compared to placebo at day 11 at 5 hours.
Escitalopram vs Placebo · Mixed Models Analysis · p = <0.001 (Secondary analyses are not adjusted for multiplicity. To demonstrate an effect of escitalopram compared to placebo, the upper bound of the one-sided 97.5% CI in the least-square mean VE55 difference between treatments \< 0 L/min.) · Mean difference (final values): -9.5Comparison was the effect of escitalopram compared to placebo at day 11 at 5 hours.

Adverse events

Collected over 106 days. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Treatment A: Placebo	0/27 (0%)	0/27 (0%)	26/27 (96.3%)
Treatment B: Paroxetine	0/27 (0%)	0/27 (0%)	26/27 (96.3%)
Treatment C: Escitalopram	0/27 (0%)	0/27 (0%)	26/27 (96.3%)

Most frequent other events

Showing 10 of 70

Most frequent other events
Event	Treatment A: Placebo	Treatment B: Paroxetine	Treatment C: Escitalopram
DiarrheaGastrointestinal disorders	1/27	7/27	1/27
NauseaGastrointestinal disorders	6/27	4/27	6/27
DizzinessNervous system disorders	5/27	4/27	3/27
HeadacheNervous system disorders	3/27	4/27	1/27
DrowsinessNervous system disorders	4/27	2/27	2/27
InsomniaNervous system disorders	1/27	4/27	1/27
Application site irritationGeneral disorders	3/27	2/27	2/27
Infusion site bruisingSkin and subcutaneous tissue disorders	2/27	1/27	1/27
ContusionSkin and subcutaneous tissue disorders	2/27	1/27	1/27
Brain fogNervous system disorders	1/27	1/27	2/27

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Total
Median	36 (31 to 40.5)

Sex: Female, Male
Sex: Female, Male(Participants)	Total
Female	7
Male	20

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Total
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	7
White	18
More than one race	0
Unknown or Not Reported	2

Body Weight
Body Weight(kg)	Total
Median	77 (66 to 84)

Body Mass Index
Body Mass Index(kg/m2)	Total
Median	24.4 (22.8 to 27.5)

Minute Ventilation
Minute Ventilation(L/min)	Total
Median	9.4 (8.7 to 10.1)

Respiratory Rate
Respiratory Rate(breaths/min)	Total
Median	13.6 (12.0 to 15.2)

Tidal Volume
Tidal Volume(L)	Total
Median	0.79 (0.66 to 0.92)

2 further baseline measures are reported on the registry.

08

Study locations

1 site

Spaulding Clinical Research
West Bend, Wisconsin 53095, United States

09

References and documents

Publications

Xu L, Krishna A, Stewart S, Shea K, Racz R, Weaver JL, Volpe DA, Pilli NR, Narayanasamy S, Florian J, Patel V, Matta MK, Stone MB, Zhu H, Davis MC, Strauss DG, Rouse R. Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat. Clin Transl Sci. 2021 Nov;14(6):2208-2219. doi: 10.1111/cts.13080. Epub 2021 Jun 16. PubMed 34080766 ↗
Rebuck AS. Measurement of ventilatory response to CO2 by rebreathing. Chest. 1976 Jul;70(1 Suppl):118-21. doi: 10.1378/chest.70.1_supplement.118. No abstract available. PubMed 939123 ↗
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van der Schrier R, Roozekrans M, Olofsen E, Aarts L, van Velzen M, de Jong M, Dahan A, Niesters M. Influence of Ethanol on Oxycodone-induced Respiratory Depression: A Dose-escalating Study in Young and Elderly Individuals. Anesthesiology. 2017 Mar;126(3):534-542. doi: 10.1097/ALN.0000000000001505. PubMed 28170358 ↗
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Study documents

Study protocol ↗ · Jul 21, 2022
Statistical analysis plan ↗ · Sep 1, 2022
Informed consent form ↗ · Mar 30, 2023

PDFs hosted by the registry, ClinicalTrials.gov.

10

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on May 22, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

11

Registry details

Key details

Study ID: NCT05470465
Lead sponsor: Food and Drug Administration (FDA)
Collaborators: Spaulding Clinical Research LLC, Leiden University
Responsible party: Sponsor
First posted: Jul 22, 2022
Start date: Sep 1, 2022
Primary completion: Sep 17, 2023
Completion: Sep 17, 2023
Results posted: May 22, 2025
Last update: May 22, 2025

Study contacts

Jan Matousek, D.O.

principal investigator · Spaulding Clinical Research LLC

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

Effect of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation

Study summary

Conditions studied

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In context

Hypercapnia

Lead sponsor

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Inclusion criteria

Exclusion criteria

Study design

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Interventions

What researchers measure

Primary outcomes

Secondary outcomes

Results

Participant flow

Outcome measures

Adverse events

Baseline characteristics

Study locations

References and documents

Publications

Study documents

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Oversight

Not currently enrolling

Follow this study

Discussion

Other studies in this condition

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Effect of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation

Study summary

Conditions studied

Browse trials for

In context

Hypercapnia

Lead sponsor

Who can participate

✓Inclusion criteria

✕Exclusion criteria

Study design

Study arms

Interventions

What researchers measure

Primary outcomes

Secondary outcomes

Results

Participant flow

Outcome measures

Adverse events

Baseline characteristics

Study locations

References and documents

Publications

Study documents

Updates

Registry details

Key details

Study contacts

Oversight

Not currently enrolling

Follow this study

Discussion

Other studies in this condition

Other studies from this sponsor

Inclusion criteria

Exclusion criteria