Paroxetine
Paroxetine
Generic Name
Paroxetine
Mechanism
- Selective serotonin reuptake inhibition:
- Blocks the serotonin transporter (SERT) on presynaptic neurons, increasing synaptic 5‑HT levels.
- Produces enhanced serotonergic neurotransmission in corticolimbic pathways related to emotion regulation.
- Minor noradrenergic effect:
- Weak inhibition of norepinephrine reuptake contributes to anxiolytic properties but is not the primary action.
- Pharmacodynamic profile
- Affinity for SERT > 30× that of noradrenaline transporter (NET); thus, its antidepressant effect arises mainly from serotonin.
- Effective in reducing neuroendocrine secretion of cortisol, partly explaining its stress‑modulating benefits.
Pharmacokinetics
| Parameter | Typical value (adult) | Notes |
| Absorption | ~100 % | Rapid, peak (Cmax) 2–4 h post‑dose |
| Bioavailability | 43 % | Food increases bioavailability by ~25 % |
| Distribution | Vd 1.8 L/kg | Highly bound to plasma proteins (≈95 %) |
| Metabolism | Primarily CYP2D6‑predominant | Extensive first‑pass extraction; reluctance to dose‑adjust in poor metabolizers |
| Elimination half‑life | 6–9 h (steady state 12–16 h) | Dependent on CYP2D6 activity |
| Excretion | 55 % renal, 30 % biliary | Metabolite excretion rate-modulated by CYP2D6 phenotype |
Drug interactions: strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine itself) prolong exposure; concomitant P‑gp inhibitors slightly augment bioavailability. Psychostimulants and MAO‑I leading to serotonin syndrome risk.
Indications
| Primary Indication | Dosing Guideline |
| Major Depressive Disorder (MDD) | 10‑20 mg/day (titrated up to 60 mg/day, usually 20 mg/day for maintenance) |
| Generalized Anxiety Disorder (GAD) | 10‑20 mg/day (max 30 mg/day) |
| Panic Disorder | 10‑20 mg/day (up to 30 mg/day) |
| Obsessive‑Compulsive Disorder (OCD) | 10‑20 mg/day (max 60 mg/day) |
| Social Anxiety Disorder (SAD) | 10‑20 mg/day |
| Premenstrual Dysphoric Disorder (PMDD) | 10‑30 mg/day (daily or continuous dosing) |
| Chronic Diabetic Neuropathy | 20 mg/day (secondary benefit) |
Note: FDA‑approved only for MDD, GAD, OCD, panic disorder, SAD, and PMDD in the U.S.; extended indication for diabetic neuropathic pain is off‑label.
Contraindications
| Category | Key Points |
| Absolute contraindication | Concomitant use with *serotonin‑enhancing* agents (MAO‑I, triptans, linezolid) – serotonin syndrome. |
| Absolute contraindication | Severe hepatic impairment; lawful to limit use. |
| Caution | In patients with QTc prolongation; moderate risk is possible due to weak effects on CYP3A4. |
| Warnings | Became active in withdrawal (paroxetine). Manage by gradually tapering over 4–6 weeks. |
| Pregnancy/Lactation | Category C; limited data suggest potential fetal risk (preeclampsia); avoid in early pregnancy. |
| Pediatric | Use with caution in depression/anxiety; dosing starts low (2.5–10 mg/day). |
| Bipolar Disorder | Risk of mood switch; not first‑line antidepressant. |
Dosing
- Start low, go slow:
- Adult MDD/GAD: 10 mg PO daily; titrate by 10 mg increments every 2–3 weeks.
- OCD: 10 mg to 20 mg PO; may increase to 60 mg/day in resistant cases.
- Timing: Once daily; best taken in the evening due to constipation and insomnia risk.
- Extemporaneous formulation: Avoid crushing tablets – can alter release properties.
- Renal/Hepatic impairment: No dose adjustment needed in mild–moderate hepatic disease; monitor for accumulation in severe hepatic impairment.
- Tapering: Reduce by 10 mg every 4–7 days to prevent withdrawal symptoms (somatic and affective).
Monitoring
- Baseline: CBC, CMP, serum electrolytes, lipid panel, liver enzymes (AST/ALT), ECG if cardiac disease suspected, and psychiatric assessment.
- During therapy:
- CBC and CMP at 4 weeks, then every 6–12 months.
- Monitor weight, appetite.
- Screen for SIADH or hyponatremia in elderly.
- Taper/withdrawal: Evaluate for withdrawal syndrome; counsel patients on expected symptoms.
Clinical Pearls
- CYP2D6 Poor Metabolizer Myth: Around 15–20 % of Caucasians are poor metabolizers; they will experience *higher* plasma levels and may require a lower dose or slower titration.
- “Paroxetine = the six‑finger drug”: Due to its ^6‑carbon side chain, paroxetine’s side‑chain length correlates with its superior potency vs. older SSRIs.
- Sleep & REM suppression: Its anticholinergic and antihistaminic profile can *reduce REM latency*, which may paradoxically worsen anxiety during daytime. Consider evening dosing or discontinuation if insomnia persists.
- Switching people: Paroxetine’s high affinity for SERT makes *rapid cross‑titration* from fluoxetine to paroxetine hard; increase wash‑out interval by 3–4 weeks to avoid serotonin syndrome.
- Pregnancy “no‑sex”: Invasive monitoring may be unnecessary if risk‑benefit analysis flags paroxetine; consider switch to sertraline for better safety profile.
- Tapering tip: A *weekly duloxetine reduction* of 10 mg often produces less abrupt withdrawal; low‑dose 10 mg after 2 weeks can mitigate the withdrawal heat.
- Sexual dysfunction: Many patients tolerate sugammadex‑like *non‑serotonergic adjuncts* (e.g., phosphodiesterase‑5 inhibitors) as a bridge while continuing paroxetine.
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• *For detailed prescribing guidelines and drug interactions, refer to the U.S. FDA label, British National Formulary, and the latest version of the American Psychiatric Association Practice Guideline for the Pharmacologic Treatment of Depression.*