Paroxetine: A Comprehensive Pharmacology Review for Clinicians

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is one of the most prescribed antidepressants worldwide. Yet, its unique pharmacokinetic profile and high affinity for serotonin transporters make it a double‑edged sword—offering robust efficacy in certain disorders while posing a higher risk for drug–drug interactions and withdrawal phenomena. Consider a 45‑year‑old woman with major depressive disorder who is also taking a selective serotonin reuptake inhibitor and an antipsychotic; the overlapping serotonin pathways can precipitate serotonin syndrome if paroxetine is added without careful monitoring. This article dissects paroxetine’s pharmacology to equip clinicians with the knowledge needed to maximize benefit and minimize harm.

Introduction and Background

Paroxetine was first synthesized in the 1970s by the pharmaceutical company Eli Lilly and introduced to the market in 1991 under the brand name Paxil. It belongs to the phenylpiperidine class of SSRIs, distinct from the tricyclic and newer serotonin–norepinephrine reuptake inhibitors (SNRIs). Epidemiologically, paroxetine accounts for roughly 8–10% of all SSRI prescriptions in the United States, a figure that has declined slightly in recent years due to its side‑effect burden and drug–interaction profile.

SSRIs target the serotonin transporter (SERT), inhibiting reuptake of 5‑hydroxytryptamine (5‑HT) from the synaptic cleft and thereby increasing serotonergic neurotransmission. Paroxetine’s potency is among the highest of SSRIs, with a dissociation constant (K_d) for SERT in the low nanomolar range. This high affinity translates into a steeper dose–response curve and a greater likelihood of serotonergic side effects at lower doses compared with other agents such as sertraline or fluoxetine.

Beyond its primary pharmacologic target, paroxetine also exhibits weak inhibition of norepinephrine (NET) and dopamine transporters (DAT), and modest antagonism at alpha‑1 adrenergic and histamine H1 receptors. These off‑target effects contribute to its sedative properties, weight gain potential, and risk of orthostatic hypotension, differentiating it from other SSRIs that are more selective.

Mechanism of Action

Serotonin Reuptake Inhibition

At the cellular level, paroxetine binds to the extracellular binding site of SERT, blocking the reuptake of serotonin into presynaptic neurons. This blockade increases extracellular 5‑HT concentration, enhancing activation of postsynaptic 5‑HT1A, 5‑HT1B, and 5‑HT2 receptors. The net effect is a reduction in depressive symptoms, anxiety, and obsessive–compulsive behaviors. The high affinity of paroxetine for SERT results in a prolonged occupancy time, meaning that therapeutic effects may persist even after plasma levels fall.

Weak NET and DAT Inhibition

While paroxetine’s inhibition of norepinephrine and dopamine transporters is modest (IC_50 values > 1 µM), it can still influence mood and cognition in susceptible individuals. The slight NET inhibition may explain the mild antidepressant augmentation seen in some patients with comorbid anxiety disorders. DAT inhibition, though weak, may contribute to the drug’s modest analgesic effects in neuropathic pain trials.

Off‑Target Receptor Antagonism

Paroxetine antagonizes alpha‑1 adrenergic receptors, leading to vasodilation and potential orthostatic hypotension. Its H1 antagonism promotes sedation and weight gain, while mild muscarinic blockade can cause dry mouth and constipation. These off‑target effects are clinically relevant when prescribing paroxetine to patients with cardiovascular disease or those prone to orthostatic dizziness.

Clinical Pharmacology

Absorption: Paroxetine is well absorbed orally with a bioavailability of approximately 60–70%. Peak plasma concentrations (T_max) are reached 1–2 hours post‑dose. Food does not significantly alter absorption, allowing flexible dosing schedules.

Distribution: The drug is highly protein‑bound (~95%), primarily to albumin. The volume of distribution (V_d) ranges from 1.5 to 2.5 L/kg, indicating moderate tissue penetration. Paroxetine readily crosses the blood–brain barrier, achieving brain concentrations comparable to plasma levels.

Metabolism: Metabolism occurs almost exclusively via hepatic cytochrome P450 2D6 (CYP2D6) to inactive metabolites (paroxetine N‑oxide, paroxetine glucuronide). Genetic polymorphisms in CYP2D6 (poor, intermediate, extensive, ultra‑rapid metabolizers) can profoundly affect plasma concentrations, with poor metabolizers experiencing up to 3‑fold higher systemic exposure.

Excretion: Approximately 90% of the dose is eliminated renally as metabolites, with a terminal half‑life (t_½) of 21–24 hours in extensive metabolizers. In poor metabolizers, the half‑life extends to 40–50 hours, necessitating dose adjustment or extended tapering schedules.

Pharmacodynamics: The therapeutic dose range is 10–40 mg/day, with most patients achieving efficacy at 20 mg/day. The dose–response relationship is relatively linear, but the steepness of the curve can lead to dose‑related side effects at higher concentrations. The therapeutic window is narrow; plasma trough concentrations above 200 ng/mL correlate with increased adverse events without proportional benefit.

Therapeutic Applications

• Major Depressive Disorder – 10–40 mg/day, titrate to 20 mg/day for most patients.
• Generalized Anxiety Disorder – 10–20 mg/day; effective in reducing anxiety severity scores.
• Obsessive‑Compulsive Disorder – 20–60 mg/day; often combined with CBT.
• Panic Disorder – 10–40 mg/day; effective in reducing panic attack frequency.
• Post‑Traumatic Stress Disorder (PTSD) – 10–40 mg/day; evidence supports use as adjunctive therapy.
• Premenstrual Dysphoric Disorder (PMDD) – 10–20 mg/day during luteal phase.
• Off‑label: Chronic Pain, Pruritus, and Migraine Prophylaxis – 10–40 mg/day; limited evidence but used in practice.

Special Populations

• Pediatrics – Approved for ages 12 and older; dosing starts at 10 mg/day and may increase to 20 mg/day.
• Geriatrics – Start at 10 mg/day; monitor for orthostatic hypotension and sedation.
• Renal Impairment – Dose reduction to 10 mg/day in severe CKD; monitor serum creatinine.
• Hepatic Impairment – Reduce dose to 10 mg/day in moderate liver disease; avoid in severe hepatic failure.
• Pregnancy – Category C; limited data suggest low teratogenic risk but avoid during first trimester if possible.
• Breastfeeding – Paroxetine is excreted in milk; advise against nursing during therapy.

Adverse Effects and Safety

Common Side Effects (incidence 5–20%):

• Gastrointestinal upset (nausea, diarrhea) – 10–15%
• Sexual dysfunction (decreased libido, anorgasmia) – 15–25%
• Weight gain – 5–10%
• Somnolence, dizziness – 8–12%
• Headache – 6–9%

Serious/Black Box Warnings

• Serotonin syndrome – particularly when combined with MAOIs, tramadol, or St. John’s wort.
• Withdrawal syndrome – abrupt discontinuation can lead to anxiety, tremor, paresthesia; requires tapering over 4–6 weeks.
• QT interval prolongation – rare but documented; contraindicated in patients with congenital long QT or on other QT‑prolonging agents.
• Increased risk of suicidal ideation in adolescents and young adults – monitor closely during first 6 months.

Major Drug Interactions

Monitoring Parameters

• Baseline and periodic liver function tests (ALT, AST) in patients on long‑term therapy.
• Serum creatinine and eGFR in patients with renal impairment.
• ECG in patients with known QT prolongation risk or on other QT‑prolonging drugs.
• Weight and BMI monitoring annually.
• Assessment for suicidal ideation at each visit for patients <25 years old.

Contraindications

• Concurrent use with MAO inhibitors.
• Known hypersensitivity to paroxetine or any excipient.
• Severe hepatic impairment (Child‑Pugh C).
• Pregnancy category C with high risk of fetal harm (e.g., uncontrolled hypertension).

Clinical Pearls for Practice

• Start low, go slow. Begin at 10 mg/day and titrate by 10 mg increments every 2 weeks to minimize withdrawal and side effects.
• Watch for serotonin syndrome. In patients on tramadol or St. John’s wort, consider alternative analgesics or discontinue herbal supplements.
• Plan a taper. To avoid withdrawal, reduce the dose by 5 mg every 2 weeks for 3–4 weeks after discontinuation.
• Consider CYP2D6 genotype. Poor metabolizers may require a 50% dose reduction to prevent toxicity.
• Use caution in the elderly. Monitor for orthostatic hypotension and sedation; start at the lowest effective dose.
• Pregnancy & lactation. Counsel patients that paroxetine is excreted in breast milk and advise against nursing during therapy.
• Mnemonic: “P.A.R.O.” – Paroxetine’s Adverse Reactions: Pruritic, Anorectal, Restlessness, Orthostatic.