What are Selective Serotonin Reuptake Inhibitors (SSRIs)?

Selective Serotonin Reuptake Inhibitors (SSRIs): Mechanism, Uses, and Considerations

SSRIs are medications that inhibit the presynaptic reuptake of serotonin in the brain, thereby increasing serotonin availability at the synaptic cleft, which is effective for treating depression, anxiety disorders, and other psychiatric conditions. 1, 2

Mechanism of Action

• SSRIs selectively block serotonin reuptake transporters, leading to increased serotonin levels in synaptic clefts
• This blockade eventually leads to downregulation of inhibitory serotonin autoreceptors, heightening serotonergic neuronal firing rates 1
• The multi-step process explains the delayed onset of therapeutic effects 1
• Unlike older antidepressants, SSRIs have minimal effects on other neurotransmitter systems (norepinephrine, dopamine) and negligible affinity for adrenergic, cholinergic, GABA, histaminergic, or benzodiazepine receptors 2

FDA-Approved SSRIs

• Currently available SSRIs include:
  • Fluoxetine (Prozac)
  • Sertraline (Zoloft)
  • Paroxetine (Paxil)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluvoxamine (Luvox)
  • Vilazodone (Viibryd) 1, 3

Clinical Applications

SSRIs are first-line treatments for:

• Major depressive disorder 3
• Anxiety disorders:
  • Generalized anxiety disorder
  • Social anxiety disorder
  • Panic disorder
  • Obsessive-compulsive disorder (OCD) 1
  • Post-traumatic stress disorder 4
• Other conditions:
  • Bulimia nervosa
  • Premenstrual dysphoric disorder 1, 5

Pharmacokinetics

• Most SSRIs have long half-lives allowing once-daily dosing 3
  • Exception: Fluoxetine has the longest half-life due to its active metabolite 1
• Undergo extensive first-pass metabolism, primarily through cytochrome P450 enzymes 2
  • Sertraline undergoes N-demethylation as its principal metabolic pathway 2
  • Paroxetine is extensively metabolized by CYP2D6 1
• Steady-state plasma levels typically achieved after approximately one week of once-daily dosing 2

Efficacy

• SSRIs demonstrate moderate superiority to placebo for depression treatment 3
• For anxiety disorders, SSRIs improve primary anxiety symptoms, response rates, remission rates, and global function 1
• In OCD, SSRIs are considered first-line pharmacotherapy alongside cognitive-behavioral therapy 1
• For social anxiety disorder, SSRIs are suggested as first-line pharmacotherapy 1

Side Effects and Safety

• Approximately 63% of patients experience at least one adverse effect 3

• Common side effects include:

  • Gastrointestinal: nausea, diarrhea, dry mouth
  • Neurological: dizziness, headache, tremor
  • Sleep disturbances: insomnia or somnolence
  • Sexual dysfunction: decreased libido, ejaculatory disturbance, orgasmic disturbance
  • Other: fatigue, sweating, weight changes 3, 6, 5

• Sexual side effects are particularly common:

  • Males: decreased libido (6-15%), ejaculatory disturbance (13-28%), impotence (2-9%)
  • Females: decreased libido (0-9%), orgasmic disturbance (2-9%) 6

• Safety considerations:

  • Black box warning for increased suicidality in adolescents and young adults 1
  • Risk of discontinuation syndrome with abrupt cessation 7
  • Potential for serotonin syndrome when combined with other serotonergic medications

Special Populations

• Children and adolescents:

  • SSRIs are recommended for anxiety disorders in patients 6-18 years old 1
  • Fluoxetine is FDA-approved for major depression in children/adolescents aged 8+ 1
  • Careful monitoring for suicidality is essential 1

• Pregnancy:

  • Newborns exposed prenatally to SSRIs may experience symptoms including irritability, tremors, feeding difficulties, and sleep disturbances 3
  • Risk-benefit assessment is crucial

Duration of Treatment

• For depression: Continue treatment for at least 6-12 months after remission to prevent relapse
• For anxiety disorders: Longer treatment durations are often needed
• The decision to continue or discontinue should be revisited periodically, assessing the risk-benefit ratio 7

Pharmacogenetic Considerations

• CYP2D6 and CYP2C19 genetic variations can affect metabolism of certain SSRIs 1
• Pharmacogenetic testing may help guide dosing in some cases, though its routine use remains controversial 1

Practical Prescribing Tips

• Start at low doses and titrate gradually to minimize initial side effects
• Most side effects are transient and diminish within 2-4 weeks
• Some side effects (nausea, dizziness) show adaptation over 4-6 weeks, while others (dry mouth, somnolence) may persist 6
• When discontinuing, taper gradually to minimize discontinuation symptoms
• Consider drug interactions, particularly with other medications metabolized by CYP enzymes

SSRIs have revolutionized psychiatric treatment due to their efficacy, tolerability, and safety compared to older antidepressants, making them the cornerstone of pharmacotherapy for depression and anxiety disorders.