Paxil (Paroxetine): Overview
Paxil (paroxetine) is a selective serotonin reuptake inhibitor (SSRI) antidepressant approved for treating major depressive disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, generalized anxiety disorder, and post-traumatic stress disorder in adults. 1
What is Paxil?
Paroxetine is the most potent inhibitor of serotonin reuptake among all available SSRIs 2. It is a phenylpiperidine derivative with minimal effects on norepinephrine uptake and very weak affinity for dopaminergic, histaminergic, and muscarinic cholinergic receptors compared to tricyclic antidepressants 2. The controlled-release formulation (PAXIL CR) was developed to improve gastrointestinal tolerability 3.
FDA-Approved Indications
Immediate-release paroxetine:
- Major depressive disorder
- Obsessive-compulsive disorder
- Panic disorder
- Social anxiety disorder (social phobia)
- Generalized anxiety disorder
- Post-traumatic stress disorder 1
Paroxetine CR:
- Major depressive disorder
- Social anxiety disorder
- Panic disorder
- Premenstrual dysphoric disorder 3
Dosing
Take PAXIL CR exactly as prescribed, with or without food. Controlled-release tablets must be swallowed whole—never chewed or crushed 1. Steady-state levels are achieved after 4-14 days with an elimination half-life of 21 hours, supporting once-daily dosing 2. For vasomotor symptoms, the recommended dose is 7.5 mg once daily at bedtime 4.
Absolute Contraindications
- Concurrent use with MAOIs or within 14 days of MAOI discontinuation
- Concurrent use with thioridazine
- Concurrent use with pimozide
- Hypersensitivity to paroxetine or any inactive ingredients 1
Do not start paroxetine in patients receiving linezolid or methylene blue due to serotonin syndrome risk 1.
Common Side Effects
The most frequently reported adverse events include 5, 1:
- Nausea (most common reason for discontinuation)
- Sexual dysfunction
- Somnolence
- Sweating
- Constipation
- Dizziness
- Headache
- Insomnia
- Dry mouth
- Decreased appetite
- Weakness
Critical Safety Concerns
Sexual Dysfunction
Paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline 5, 6. This includes decreased libido, ejaculatory disturbance (26% vs 1% placebo in males), and orgasmic disturbance (10% vs <1% placebo in females) 1.
Weight Gain
Paroxetine causes higher weight gain than sertraline, trazodone, or venlafaxine 5.
Suicidality
SSRIs including paroxetine are associated with increased risk for nonfatal suicide attempts (odds ratio 1.57-2.25) compared to placebo, though not completed suicide 5.
Pregnancy Risks
There is an increased risk of birth defects, particularly cardiac defects, with paroxetine use during pregnancy 1. Other risks include persistent pulmonary hypertension in newborns, neonatal withdrawal symptoms, and premature birth 1, 7.
Drug Interactions
Paroxetine has the highest inhibitory constant for cytochrome P450 2D6 of all antidepressants (Ki = 0.065-4.65 micromoles) 8. Critical interactions include:
- Tamoxifen: Paroxetine inhibits tamoxifen metabolism, increasing breast cancer mortality risk over 5 years 8
- Warfarin, aspirin, NSAIDs (bleeding risk)
- Triptans, tramadol, St. John's wort (serotonin syndrome)
- Drugs metabolized by CYP2D6 1, 8
Discontinuation Syndrome
Paroxetine has a higher potential for discontinuation syndrome than other SSRIs 3. Never stop abruptly—taper gradually under physician guidance 1.
Other Serious Adverse Events
Monitor for seizures, cardiovascular effects (blood pressure/heart rate changes), hyponatremia, hepatotoxicity, and serotonin syndrome 5.
Clinical Efficacy
Second-generation antidepressants including paroxetine show no clinically significant differences in efficacy for treating major depressive disorder 5. However, 38% of patients do not achieve treatment response and 54% do not achieve remission during 6-12 weeks of treatment 5. Efficacy is similar across age groups, sex, and race 5.
Key Clinical Pearls
- Paroxetine is the only SSRI approved for all five anxiety disorders plus major depression 9
- Lower doses (7.5 mg) effectively treat vasomotor symptoms with fewer side effects 4
- Therapeutic drug monitoring suggests optimal plasma concentrations of 65-120 ng/mL for MDD, with concentrations above 120 ng/mL associated with more liver injury and weight gain without additional benefit 10
- Early plasma concentration at 4 weeks (≥65 ng/mL) predicts 8-week clinical response 10