Paroxetine - Drug Monograph

Introduction

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) antidepressant medication approved by the FDA in 1992. It is widely prescribed for the treatment of major depressive disorder, anxiety disorders, and other psychiatric conditions. As one of the most potent SSRIs, paroxetine exhibits strong serotonin reuptake inhibition with minimal effects on other neurotransmitter systems.

Mechanism of Action

Paroxetine exerts its therapeutic effects primarily through potent inhibition of serotonin reuptake at the presynaptic neuronal membrane. The drug binds with high affinity to the serotonin transporter (SERT), blocking serotonin reuptake and increasing synaptic concentrations of serotonin in the central nervous system. This enhanced serotonergic activity is believed to mediate its antidepressant and anxiolytic effects. Paroxetine also exhibits weak anticholinergic properties and demonstrates moderate affinity for muscarinic cholinergic receptors.

Indications

FDA-approved indications:

• Major depressive disorder (MDD)
• Panic disorder with or without agoraphobia
• Social anxiety disorder (social phobia)
• Generalized anxiety disorder (GAD)
• Obsessive-compulsive disorder (OCD)
• Post-traumatic stress disorder (PTSD)
• Premenstrual dysphoric disorder (PMDD)

Off-label uses include:

• Vasomotor symptoms associated with menopause
• Diabetic neuropathy
• Chronic tension-type headache

Dosage and Administration

• Depression: 20 mg once daily in morning
• Panic disorder: 10 mg once daily initially
• OCD: 20 mg once daily
• Social anxiety: 20 mg once daily
• GAD: 20 mg once daily

• May increase by 10 mg/day increments at weekly intervals
• Maximum dose: 50-60 mg/day for depression, 60 mg/day for OCD

• Elderly: Start with 10 mg daily, maximum 40 mg/day
• Hepatic impairment: Reduced initial dose recommended
• Renal impairment (CrCl <30 mL/min): Initial dose 10 mg daily, maximum 40 mg/day

• Administer with or without food
• Swallow tablets whole; do not crush or chew
• Take at same time each day

Pharmacokinetics

Contraindications

• Hypersensitivity to paroxetine or any component of formulation
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI therapy
• Concurrent use with thioridazine or pimozide
• Use of paroxetine oral suspension in patients taking disulfiram (due to alcohol content)

Warnings and Precautions

• Increased risk of suicidal thinking and behavior in children, adolescents, and young adults
• Not approved for use in pediatric patients except for OCD

• Serotonin syndrome risk, especially with other serotonergic drugs
• Discontinuation syndrome (taper gradually)
• Activation of mania/hypomania in bipolar disorder
• Increased risk of bleeding abnormalities
• SIADH and hyponatremia
• QTc prolongation at higher doses
• Angle-closure glaucoma
• Seizure risk (0.1-0.2% incidence)

Drug Interactions

• MAOIs: Risk of serotonin syndrome (contraindicated)
• Thioridazine, pimozide: Increased QTc prolongation risk
• Warfarin: Increased anticoagulant effect
• Tamoxifen: Reduced efficacy (CYP2D6 inhibition)
• Triptans: Increased serotonin syndrome risk
• NSAIDs, aspirin: Increased bleeding risk

• Reduced metabolism of beta-blockers, antiarrhythmics, TCAs, antipsychotics
• Dose adjustments needed for metoprolol, propafenone, flecainide

• Strong CYP2D6 inhibitors may increase paroxetine levels
• Phenobarbital, phenytoin: Decreased paroxetine levels

Adverse Effects

• Nausea (26%)
• Somnolence (23%)
• Headache (18%)
• Dry mouth (18%)
• Asthenia (15%)
• Insomnia (13%)
• Sweating (11%)
• Dizziness (13%)

• Constipation
• Decreased appetite
• Tremor
• Anxiety
• Sexual dysfunction (anorgasmia, decreased libido)
• Weight changes

• Serotonin syndrome
• Suicidal ideation
• Seizures
• Mania
• Hyponatremia
• Bleeding events
• Angle-closure glaucoma
• Discontinuation syndrome

Monitoring Parameters

• Comprehensive metabolic panel
• CBC with platelets
• ECG in patients with cardiac risk factors
• Mood assessment (PHQ-9, GAD-7)
• Suicide risk assessment

• Therapeutic response assessment (weeks 4-8)
• Adverse effects monitoring
• Weight changes
• Signs of serotonin syndrome
• Mood changes, especially in first few months
• Bleeding signs
• Hyponatremia symptoms in elderly

• Periodic reassessment of continued need
• Bone density monitoring in chronic use

Patient Education

• Take medication at same time each day
• Do not stop abruptly due to withdrawal risk
• Therapeutic effects may take 4-8 weeks
• Report worsening depression or suicidal thoughts immediately
• Avoid alcohol during treatment
• Use caution when driving or operating machinery
• Report unusual bleeding or bruising
• Inform all healthcare providers of paroxetine use
• Use effective contraception (Pregnancy Category D)
• Notify provider if pregnancy is planned or occurs
• Avoid St. John's Wort and other serotonergic supplements

References

1. FDA Prescribing Information: Paroxetine Hydrochloride. 2022 2. Stahl SM. Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013 3. Hiemke C, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018;51(1-2):9-62 4. Shelton RC. Steps Following Attainment of Remission: Discontinuation of Antidepressant Therapy. Prim Care Companion J Clin Psychiatry. 2001;3(4):168-174 5. Boyer EW, Shannon M. The Serotonin Syndrome. N Engl J Med. 2005;352(11):1112-1120 6. Fava GA, et al. Effects of Gradual Discontinuation of Selective Serotonin Reuptake Inhibitors in Panic Disorder with Agoraphobia. Am J Psychiatry. 2007;164(6):959-962 7. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2D6 and CYP2C19 Genotypes and Dosing of SSRIs. Clin Pharmacol Ther. 2015;98(2):127-134