Paroxetine

Mechanism of Action

As an SSRI class drug, paroxetine's signature mechanism of action is to block the serotonin reuptake transporter (SERT) and thus increase the concentration of synaptic serotonin. Current theory suggests that the diminished serotonin concentration in the depressed brain induces the upregulation of serotonergic receptors. By increasing the synaptic serotonin concentration, paroxetine thus induces the downregulation of the previously upregulated serotonin receptors, thus normalizing the receptor concentration.[2] Furthermore, in a radioligand study, paroxetine showed some affinity for muscarinic, adrenergic (alpha and beta), dopaminergic (D2), serotonergic (5-HT2), and histaminergic (H1) receptors.[3] These receptors have also appeared to contribute to its antidepressant effects and its side effect profile. 

Administration

Paroxetine is administered orally. The medication should be titrated based on the patient's symptoms and tolerance to dosage. The drug can be taken with or without food. In addition to regular tablets, it is available in a controlled-release tablet and liquid form. Paroxetine may be administered at any time of the day, depending on toleration.

Metabolism

The steady-state mean value of T1/2 is 21 hours. Paroxetine undergoes metabolism via hepatic CYPP450 2D6. The urine excretes 2%, 62% metabolized over a 10-day post-dosing period, 36% excreted in the feces. Paroxetine inhibits CYP2D6 and, thus, its own metabolism; plasma concentrations can potentially double following dosage increases of 50%.[4]

For Major Depression [1]

Immediate-release formulas

• Adults: start with 20 mg by mouth daily and increase by 10 mg weekly with a max of 50 mg per day.
• Geriatric adults: start with 10 mg by mouth daily and then increase by 10 mg weekly with a max dose of 40 mg per day orally.

Controlled-release formulas:

• Adults: Start with 25 mg by mouth daily, then increase by 12.5 mg weekly with a max of 62.5 mg.
• Geriatrics: Start with 12.5 mg by mouth once daily, then increase to 12.5 if needed weekly.

Generalized Anxiety Disorder [1]

Immediate release formulas

• Adults: 20 mg by mouth once daily. Titrate the dose by 10 mg per day at weekly intervals if required with a max dose of 60 mg per day.
• Geriatric Adults: 10 mg by mouth once daily and titrate 10 mg per day at weekly intervals. Usually effective at 20 mg by mouth daily but can increase up to 40 mg per day.

Premenstrual Dysphoric Disorders [1]

Controlled-release tablet

• Adult Females: 12.5 mg per day orally. Effective doses were between 12.5 to 25 mg per day.

Immediate-release formulation

• Adult females: 5 mg per day to 30 mg per day.

Vasomotor Disorder Secondary to Menopause [1]

Controlled release tablets: 12.5 mg by mouth daily and titrated to 25 mg by mouth weekly.

Obsessive-Compulsive Disorder [1]

Immediate release formulation

• Adult: 20 mg once daily and increase by 10 mg per day weekly intervals if tolerated. Titrate the dose include 40 mg orally once daily with a max of 60 mg per day.
• Geriatric: 10 mg once daily. If needed, increase to 10 mg per day at weekly intervals with a max dose of 40 mg per day.
• Children and adolescents seven years and older: 10 to 50 mg by mouth; 10 mg per day increase at intervals of a week with a max of 50 mg per day. 

Panic Disorder [1]

Immediate-release formulation

• Adult: 10 mg orally once daily and increase the dose to 10 mg per day at weekly intervals with a target dose of 40 mg per day with a max dose of 60 mg per day.
• Geriatrics: 10 mg orally once daily and increase 10 mg per day at weekly intervals with a target dose of 40 mg per day. Max dose is 40 mg per day.
• Children and adolescents seven years and older: 10 mg orally; max dose 40 mg per day.

Controlled-release tablets

• Adults: 12.5 mg orally once daily and increase by 12.5 mg at weekly intervals. The effective dose range is 12.5 to 75 mg per day with a max dose of 75 mg daily.
• Geriatrics Adults: 12 mg by mouth daily and increase by 12.5 mg at weekly intervals. The effective dose is 12.5 to 75 mg per day. The recommended maximum dose is 50 mg per day.

Post Traumatic Stress Disorder [1]

Immediate-release formulation

• Adults: 20 mg by mouth daily. Effective doses range from 20 to 50 mg per day. With a max dose of 60 mg per day.
• Geriatrics: 10 mg by mouth once daily and increase by 10 mg per day at a weekly interval. Max dose of 40 mg per day orally.

Social Phobias [1]

Immediate release formulation

• Adult: 20 mg per day orally; Effective dose range is 20 to 60 mg per day; Titrate to 10 mg per day weekly; Max dose of 60 mg per day.
• Geriatric adults: 10 mg orally and titrate by 10 mg per day; target the dose 20 mg per day with a max dose of 40 mg per day.
• Children and adolescents eight years and older: 10 mg per day and titrate 10 mg per day at a weekly interval; The maximum dose of 50 mg per day orally.

Controlled release formulation

• Adult: 12.5 mg per day orally and titrate at intervals of at least one week and an increase of 12.5 mg per day; Max dose of 37.5 mg per day orally.

Renal Impairment: Adults [1]

For patients with renal impairment, the dosage is based on creatinine clearance, as shown below.

• If the CrCL is 30 to 60 ml per minute: No need to change the dosing.
• If CrCl is less than 30 ml per minute:
  • Immediate release formulation: 10 mg per day; increase if needed by 10 mg per day increments at an interval of at least a week; maximum dose: 40 mg per day.
  • Controlled release formulation: 12.5 mg per day; increase if needed by 12.5 mg per day increments at interval one week; maximum dose: 50 mg per day.

Hepatic Impairment Adults [1]

In hepatic impairment, plasma concertation of two times normal can occur.

• If mild to moderate: no change in dosage.
• If severe
  • Immediate-release formulations: 10 mg per day and, if needed, increase by 10 mg per day at intervals of 1 week; maximum dose of 40 mg per day.
  • Controlled release formulation: 12.5 mg per day; increase if needed by 12.5 mg per day increments at intervals of 1 week; maximum dose is 50 mg per day.

Adverse Effects

Many of the side effects of paroxetine are dose-dependent. The most common side effects include drowsiness, dry mouth, loss of appetite, sweating, sleep disturbance, and sexual side effects. Clinicians can address sexual side effects medications like sildenafil). Discontinuation syndrome is more common and more severe with paroxetine than with other SSRIs; this may be due in part to the fact that it inhibits its own metabolism. Withdrawal symptoms from discontinuation include dizziness, lethargy, nausea, vomiting, headache, fever, chills, vivid dreams, electric shock-like-sensation, dyskinesia, anxiety, crying, irritability, and depersonalization.[5]

Other Adverse Effects

• Psychiatric: Apathy and emotional flattening (indirect decrease of dopamine), hypomania, or mania (1%). In children and adolescents, and young adults (18 to 24 years of age), paroxetine can increase the risk of suicide.
  • Induction of agitation or manic state may represent an underlying bipolar condition that requires the addition of a mood stabilizer, lithium, an atypical antipsychotic, and/or the discontinuation of paroxetine.
• Nervous system: Extrapyramidal symptoms, dizziness, headache, tremor
• Metabolic: hyponatremia (SIADH), weight gain
• Cardiovascular: Edema, chest pain, palpitations, tachycardia, vasodilation
• Dermatologic: Alopecia, eczema, photosensitivity, purities
• Gastrointestinal: Constipation, diarrhea, nausea

Contraindications

There are only a few absolute contraindications for the use of paroxetine. Absolute contraindications include concurrent use of monoamine oxidase inhibitors (MAOIs), thioridazine, and pimozide. Concomitant use of MAOIs and paroxetine can precipitate serotonin syndrome. Concurrent use of thioridazine and paroxetine can induce cardiac arrhythmias; similar effects can occur with pimozide and paroxetine.[6] 

Precautions that should be acknowledged when prescribing paroxetine include concurrent tricyclic antidepressant (TCA) use, concomitant tamoxifen use, and drugs affecting hepatic metabolism. Paroxetine inhibits TCA metabolism, leading to possible TCA toxicity. Tamoxifen is active once metabolized by CYP4502D6; thus, paroxetine essentially inactivates tamoxifen. 

Paroxetine is not recommended for use during pregnancy or if breastfeeding. Based on epidemiological studies, infants exposed to paroxetine during the first trimester had an increased risk for cardiovascular malformations.[6]

Monitoring

Patients initiated on paroxetine should initially receive close observation and be monitored for worsening clinical symptoms, behavior changes (mania, social function, anxiety), or suicidal ideations. Labs should include serum sodium concentration to rule out SIADH.[7] Vital signs should be monitored for signs of serotonergic hyperactivity. Serotonin syndrome precipitates via the manifestation of changes in mental status, autonomic instability, gastrointestinal symptoms, hyperreflexia, and myoclonus. Serotonin syndrome is treated by discontinuing any of the offending agents. If symptoms continue to escalate, the clinician can administer cyproheptadine.[8]

Toxicity

Though it is rarely lethal in overdose by itself, patients can develop somnolence, nausea, tremor, heart rhythm disturbances, confusion, vomiting, dizziness, and mydriasis. During toxicity, a patient’s airway, oxygenation, and ventilation require evaluation first. The treatment for overdose includes symptomatic supportive treatment. There is no specific treatment for paroxetine toxicity.[9]

Enhancing Healthcare Team Outcomes

Interprofessional teamwork can impact a patient's outcome positively. This team starts with the prescribing clinicians (MD, DO, PA, NP), who will make the initial determination for using paroxetine. Open communication between various disciplines, such as pharmacy and psychiatry, can benefit the patient.[10] Each department acknowledges what the patients' needs and implement the plan. The pharmacist can provide the dosing for the patient and monitor toxicity levels and consult with the prescriber for changes. Each patient is unique; some may require a different dosage because of renal or hepatic dysfunction. This approach allows the patient to have a correct dosage based on their co-morbid conditions. Nursing should be alert to signs of adverse drug events, improvement in status, or the need for further evaluation and report such to the clinician. The psychiatrist can also monitor the patient clinically for improvement, or if needed, make changes in the medication. This interprofessional paradigm can improve patient outcomes through enhanced treatment strategies and information sharing. [Level 5]