This study will determine whether selective serotonin reuptake inhibitors (SSRI) exacerbate opioid induced respiratory depression in patients initiating treatment for underlying conditions such as depression or an anxiety disorder. Next to paroxetine which has been evaluated in a previous study in healthy volunteers sertraline, citalopram and escitalopram will be evaluated with regards to its influence on opioid induced respiratory depression.

Primary Objective:

To determine the effect of low-dose (10 mg) oxycodone versus placebo in individuals that use paroxetine on ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg at 1 week (4-10 days) of SSRI treatment.

Secondary objectives:

To determine the effect of low-dose (10 mg) oxycodone versus placebo in individuals that either use sertraline, citalopram or escitalopram on ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg at 1 week (4-10 days) of SSRI treatment.

To determine the effect of low dose (10 mg) oxycodone versus placebo in individuals that either use paroxetine, sertraline, citalopram or escitalopram on ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg following at 1 month (25- 45 days) following initiation of SSRI treatment.

To determine whether the effects of SSRI on opioid induced respiratory depression alter during the course of treatment.

To determine the effect of low-dose oxycodone versus placebo in individuals that use and SSRI on pupil diameter.

To determine the effect of paroxetine on the pharmacokinetics of oxycodone.

Study design:

The design of the study is double-blind, placebo-controlled and cross over.

two groups will be studied: Time 1: individuals that use an SSRI for 1 week (day 4-10 after initiation of treatment); Time 2: (the same) individuals that use an SSRI for 1 month (day 25-45 after initiation of treatment); Subjects from Time 1 may transition to time 2 (preferably).

This is a crossover study. Subjects will be randomized (placebo vs oxycodone) with at least 2days in-between study days.

Subjects will be asked to take their antidepressant on t = 0 h, and will then dose the oxycodone on t = 2 h. Primary endpoint is ventilation measured at an extrapolated end-tidal PCO2 of 55 mmHg (VE55) at t = 4 h.

Prior to any antidepressant intake (t = 0) and at 1 h intervals following drug intake, the ventilatory response to hypercapnia will be measured for 6 hours. If VE55 is below 20% of baseline a further 1 or 2 measurements will be obtained

In between respiratory measurements, pupil diameter will be measured the using a handheld pupilometer. Additionally, subjects will be queried the at 1 h intervals for sedation,lightheadedness, nausea/vomiting using 11-point Likert scale from 0 (no effect) to 10 (max. possible effect).

In all subjects, a blood sample will be draw to determine the state of the CYP 2C8/3A4/2D6 gene to determine the metabolic state of the antidepressant among the subjects and relate this as covariate to our results. Additionally, 10 venous blood samples will be drawn for pharmacokinetic oxycodon analysis by Ardena (Assen). Blood will be drawn for a venipuncture in the arm or via an access line in the cubital vein. Blood sampling will be at t = 0 (blank), t = 15 min, 30 min, t = 45 min, t = 60 min, t = 120 min, t = 180 min, t = 240 min en t = 300 min.

SSRIs: the following SSRIs are planned to be studied :

• Paroxetine, dose at least 20 mg (Primary endpoint)
• Citalopram , dose at least 20 mg
• Escilatopram, dose at least 10 mg,
• Sertraline, dose at least 50 mg

Inclusion Criteria:

• Signed the informed consent form (ICF) and able to comply with the study requirements and restrictions listed therein;
• Male and female subjects, age 18 to 75 years, inclusive;
• Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 month after the last dose of study drug;
• Body Mass Index (BMI) 18 to 35 kg/m2, inclusive;
• Stable as defined by the Investigator, based on a medical evaluation that includes the subject's medical and surgical history, physical examination, vital signs;
• Using sertraline (minimal dose 50 mg), paroxetine minimal dose 20 mg), citalopram (minimal dose 20 mg) or escitalopram (minimal dose 10 mg).

Exclusion Criteria:

• Currently meet the criteria for diagnosis of moderate or severe substance use disorder according to the DSM-5 criteria on any substances other than caffeine, or nicotine;
• Any active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;
• Consume, on average, >27 units/week of alcohol in men and >20 units/week of alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);
• Currently receiving medication-assisted treatment for the treatment of opioid-use disorder;
• Require on-going prescription or over-the-counter medications that are clinically relevant CYP P450 3A4 or CYP P450 2C8 inducers or inhibitors (e.g., rifampicin, azole antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]);
• Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
• History of substance use disorder;
• History of suicidal ideation within 30 days prior to informed consent or history of a suicide attempt in the 6 months prior to informed consent;
• Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;
• History or presence of allergic response to study medication;
• Treatment with another investigational drug within 3 months prior to dosing or having participated in more than 4 investigational drug studies within 1 year prior to screening;
• Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.
• Current use of any opioid.
• Opioid use less than 4 weeks prior to dosing with oxycodone in the current study.

Double (Participant, Outcomes Assessor)