What is paroxetine (selective serotonin reuptake inhibitor)?

What is Paroxetine?

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) antidepressant that works by potently and selectively blocking the neuronal reuptake of serotonin in the central nervous system. 1

Chemical Structure and Formulation

• Paroxetine hydrochloride is chemically identified as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate, a phenylpiperidine derivative. 1
• It is available as film-coated tablets (10 mg, 20 mg, 30 mg, 40 mg) and as an oral suspension (10 mg per 5 mL). 1
• A controlled-release formulation (paroxetine CR) was developed to improve gastrointestinal tolerability. 2

Mechanism of Action

• Paroxetine is the most potent inhibitor of serotonin reuptake among all currently available SSRIs. 3, 2
• It has very weak effects on norepinephrine and dopamine reuptake, with minimal affinity for muscarinic, alpha-adrenergic, beta-adrenergic, dopaminergic, and histaminergic receptors. 1
• This selectivity results in fewer anticholinergic, sedative, and cardiovascular side effects compared to tricyclic antidepressants. 3

Pharmacokinetics

• Paroxetine is completely absorbed after oral administration with an elimination half-life of approximately 21 hours, supporting once-daily dosing. 1
• It undergoes extensive first-pass metabolism that is partially saturable, leading to nonlinear pharmacokinetics with increasing doses. 1
• Steady-state concentrations are achieved after approximately 10 days in most patients, though this may take substantially longer in some individuals. 1
• The drug is metabolized primarily by cytochrome P450 2D6 (CYP2D6), and paroxetine itself inhibits this enzyme. 4
• Approximately 95% of paroxetine is bound to plasma proteins, and it distributes throughout the body including the CNS. 1

FDA-Approved Indications

Paroxetine has the broadest range of FDA-approved indications among SSRIs, covering both depressive and anxiety disorders: 4

• Major depressive disorder
• Obsessive-compulsive disorder (OCD)
• Panic disorder
• Social anxiety disorder (social phobia)
• Generalized anxiety disorder (GAD)
• Posttraumatic stress disorder (PTSD)
• Premenstrual dysphoric disorder (paroxetine CR formulation) 2

Notably, paroxetine is the only SSRI approved for treatment of social anxiety disorder and GAD, making it the only drug in its class indicated for all five anxiety disorders in addition to major depression. 5, 6

Clinical Efficacy

• In 6- to 24-week trials, paroxetine 10-50 mg/day was significantly more effective than placebo and at least as effective as tricyclic antidepressants and other SSRIs for major depressive disorder. 5, 7
• For anxiety disorders, paroxetine 20-60 mg/day demonstrated superior efficacy to placebo after 8-12 weeks of treatment. 5
• Long-term data show paroxetine prevents relapse or recurrence of depression for up to 1 year and maintains therapeutic response in OCD for 1 year and panic disorder for up to 6 months. 5, 2
• Higher dosing strategies (60 mg daily) have shown superior efficacy for OCD treatment compared to lower doses. 4

Important Safety Considerations

Black box warnings have been issued for treatment-emergent suicidality, particularly in adolescents and young adults. 4

Common Adverse Effects

• The most frequently reported adverse events include nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor, and decreased appetite. 4, 5
• Nausea and vomiting are the most common reasons for treatment discontinuation. 4

Specific Concerns with Paroxetine

• Paroxetine has higher rates of sexual dysfunction compared to fluoxetine, fluvoxamine, nefazodone, or sertraline. 4
• Paroxetine is associated with a higher risk of discontinuation syndrome compared to other SSRIs, characterized by dizziness, fatigue, nausea, sensory disturbances, anxiety, and agitation. 4
• Paroxetine causes more weight gain than sertraline, trazodone, or venlafaxine. 4
• Paroxetine tends to be more sedating and constipating than other SSRIs, possibly due to its anticholinergic activity. 2

Drug Interactions

• Concomitant use with monoamine oxidase inhibitors (MAOIs) is contraindicated due to risk of serotonin syndrome. 4
• Paroxetine may interact with drugs metabolized by CYP2D6, including reducing conversion of tamoxifen to its active metabolite endoxifen. 4
• Caution is needed when combining with other serotonergic drugs due to serotonin syndrome risk. 4

Special Population Considerations

• The American Family Physician recommends avoiding paroxetine in older adults due to higher rates of adverse effects, preferring citalopram, escitalopram, or sertraline instead. 8
• Higher plasma concentrations and slower elimination occur in elderly patients and those with severe renal or hepatic impairment. 3
• Wide inter-individual variation exists in paroxetine pharmacokinetics across all age groups. 3

Clinical Positioning

Given the high degree of psychiatric comorbidity between depression and anxiety, paroxetine represents an important first-line option when treating patients with major depressive disorder who also have comorbid anxiety disorders, particularly social anxiety disorder or GAD where it has unique FDA approval among SSRIs. 5, 6 However, clinicians should weigh its broader indication profile against its higher propensity for discontinuation syndrome, sexual dysfunction, and adverse effects in elderly patients when selecting among SSRIs. 4, 8