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Tuesday, July 29, 2025

Paroxetine


Generic Name: Paroxetine
Brand Names: Paxil (USA), Seroxat (UK), Aropax (AU), Brisdelle (for menopausal hot flashes), Pexeva, ParoGen, among others


Drug Class: Selective Serotonin Reuptake Inhibitor (SSRI)
Pharmaceutical Category: Antidepressant; Anxiolytic
Formulations: Immediate-release tablets, controlled-release tablets, oral suspension
Route of Administration: Oral

1. Pharmacological Classification

Paroxetine is a potent selective serotonin reuptake inhibitor (SSRI) used primarily to treat mood and anxiety disorders. It works by increasing the levels of serotonin (5-HT) in the synaptic cleft, which improves communication between neurons involved in mood regulation.

Compared to other SSRIs, paroxetine has a shorter half-life and stronger anticholinergic properties, making its withdrawal profile more pronounced and its use more sedating in some cases.

2. Mechanism of Action

Paroxetine selectively inhibits the presynaptic reuptake of serotonin (5-HT) by blocking the serotonin transporter (SERT), leading to:

  • Increased serotonin levels in the synaptic cleft

  • Enhanced serotonergic neurotransmission

  • Gradual improvement in mood, anxiety, and obsessive-compulsive behaviors

At higher doses, paroxetine may also exhibit weak inhibition of norepinephrine reuptake and possess anticholinergic and histaminergic properties, contributing to side effects like dry mouth and sedation.

3. Therapeutic Indications

Paroxetine is approved or used for:

A. Mood Disorders

  • Major Depressive Disorder (MDD)

  • Dysthymia (off-label)

B. Anxiety Spectrum Disorders

  • Generalized Anxiety Disorder (GAD)

  • Panic Disorder

  • Social Anxiety Disorder (SAD)

  • Post-Traumatic Stress Disorder (PTSD)

  • Obsessive-Compulsive Disorder (OCD)

C. Premenstrual and Menopausal Disorders

  • Premenstrual Dysphoric Disorder (PMDD)

  • Vasomotor symptoms of menopause (Brisdelle formulation, low-dose paroxetine 7.5 mg)

D. Other Off-label Uses

  • Premature Ejaculation

  • Chronic headache and neuropathic pain

  • Hot flashes in breast cancer survivors

4. Dosage and Administration

Adults

IndicationInitial DoseMaintenance RangeMaximum
Depression20 mg/day20–50 mg/day50 mg/day
Panic Disorder10 mg/day20–40 mg/day60 mg/day
OCD20 mg/day40–60 mg/day60 mg/day
GAD / SAD20 mg/day20–50 mg/day50 mg/day
PTSD20 mg/day20–50 mg/day50 mg/day
PMDD12.5 mg/day (CR)12.5–25 mg/day25 mg/day
Hot flashes (Brisdelle)7.5 mg/day—7.5 mg/day



ّ* Take once daily, usually in the morning, with or without food

  • Controlled-release (CR) formulations reduce gastrointestinal and peak-related side effects

  • Elderly or renal/hepatic impairment: start at lower doses (10 mg)

5. Pharmacokinetics

  • Absorption: Rapid oral absorption; peak plasma levels in 5–6 hours

  • Bioavailability: ~50% due to first-pass metabolism

  • Metabolism: Extensive hepatic metabolism via CYP2D6

  • Elimination: Primarily urine (metabolites); less than 2% unchanged

  • Half-life: ~21 hours (longer in elderly or hepatic impairment)

6. Contraindications

  • Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping either agent

  • Use with pimozide or thioridazine (QT prolongation risk)

  • Known hypersensitivity to paroxetine or formulation components

  • Pregnancy (Brisdelle formulation) is contraindicated due to teratogenicity

7. Precautions and Warnings

  • Suicidality: Increased risk in children, adolescents, and young adults during early treatment phases

  • Serotonin Syndrome: Risk increased with other serotonergic agents (e.g., triptans, tramadol, MAOIs)

  • Withdrawal syndrome: Rebound symptoms (dizziness, anxiety, electric-shock sensations) due to short half-life—taper gradually

  • QT prolongation: Rare, but caution with cardiac risk

  • Hyponatremia: Especially in elderly or those taking diuretics

  • Bone fracture risk: Observed with chronic use in elderly

  • Bleeding: Caution in patients on NSAIDs, antiplatelets, or anticoagulants

8. Adverse Effects

Common (>10%)

  • Nausea

  • Somnolence

  • Sexual dysfunction (delayed ejaculation, anorgasmia, decreased libido)

  • Headache

  • Insomnia

  • Dry mouth

  • Constipation or diarrhea

  • Sweating

Moderate (1–10%)

  • Appetite/weight change

  • Anxiety or nervousness

  • Dizziness

  • Tremor

  • Blurred vision

  • Fatigue

  • Increased risk of bruising

Rare but Serious (<1%)

  • Suicidal thoughts or behavior

  • Serotonin syndrome

  • Mania or hypomania

  • Severe hyponatremia

  • QT prolongation, arrhythmia

  • Angle-closure glaucoma (due to pupil dilation)

  • Withdrawal symptoms on abrupt cessation

9. Drug Interactions

Serotonergic Drugs

  • SSRIs, SNRIs, MAOIs, linezolid, tramadol, St. John’s wort → Serotonin syndrome

CYP2D6 substrates

  • Paroxetine inhibits CYP2D6, affecting:

    • Tamoxifen (↓ efficacy)

    • Codeine (↓ conversion to morphine)

    • Beta-blockers (e.g., metoprolol)

    • Antipsychotics (e.g., risperidone)

Antiplatelet/Anticoagulants

  • Increased bleeding risk with NSAIDs, aspirin, warfarin, DOACs

Pimozide, thioridazine

  • Risk of cardiac arrhythmia, QT prolongation

Enzyme inducers/inhibitors

  • CYP3A4 inducers (e.g., carbamazepine): ↓ levels

  • CYP inhibitors: May increase paroxetine toxicity

10. Pregnancy and Lactation

Pregnancy

  • Paroxetine is Category D (USA)

  • Associated with congenital heart defects, especially first trimester exposure

  • Alternative SSRIs (e.g., fluoxetine or sertraline) preferred

  • Use only when benefits outweigh risks

Lactation

  • Paroxetine is excreted into breast milk

  • Considered relatively safe for nursing infants

  • Monitor infant for irritability or feeding issues

11. Withdrawal and Discontinuation

Due to its short half-life and potent SERT inhibition, paroxetine has one of the highest risks for withdrawal symptoms among SSRIs.

Common Discontinuation Symptoms

  • Dizziness, nausea

  • Insomnia

  • Anxiety or agitation

  • “Electric shock” sensations (“brain zaps”)

  • Tremors

  • Mood instability

Tapering is strongly recommended—decrease dose over several weeks or months, especially for long-term users.

12. Clinical Comparisons

DrugSedationWeight GainSexual DysfunctionWithdrawal Risk
ParoxetineHighModerateHighHigh
SertralineLowLowModerateModerate
FluoxetineLowLowModerateLow
EscitalopramLowLowModerateLow
CitalopramModerateModerateModerateLow

  • Paroxetine is more sedating, weight-promoting, and anticholinergic than other SSRIs

  • Has greater efficacy in anxiety spectrum disorders, but more side effects

  • Preferred short-term for acute anxiety, but less favored for chronic depression due to adverse profile

13. Monitoring Parameters

  • Suicidal ideation: Especially during the first 1–2 months of therapy

  • Mood and anxiety symptoms (efficacy)

  • Sexual side effects

  • Serotonin syndrome signs

  • Sodium levels in elderly

  • INR/PT in patients on warfarin

  • Weight and appetite over time

14. Available Formulations

  • Paroxetine Hydrochloride (HCl): Tablets (10, 20, 30, 40 mg), Suspension (10 mg/5 mL)

  • Paroxetine CR (controlled release): 12.5 mg, 25 mg, 37.5 mg

  • Paroxetine Mesylate: Pexeva formulation

  • Brisdelle: 7.5 mg capsule (non-depression indication only)

15. Patient Counseling

  • Take once daily, preferably in the morning to reduce insomnia

  • May take 1–4 weeks for initial symptom improvement; full benefit in 6–8 weeks

  • Do not stop suddenly; tapering is essential

  • Report signs of serotonin syndrome, suicidal ideation, mania, or bleeding

  • Avoid alcohol, caution with driving until side effects are known

  • Monitor for sexual or mood changes




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