SSRI

Selective Serotonin Reuptake Inhibitors (SSRIs) are among the most commonly prescribed medications for mood and anxiety disorders, including depression, generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD). While these medications share a common mechanism, increasing serotonin availability in the brain, they differ significantly in pharmacological profiles, side effects, metabolism, and clinical application.

All SSRIs work by inhibiting the serotonin transporter (SERT), thereby increasing serotonin in the synaptic cleft and enhancing serotonergic neurotransmission. Over time, this helps regulate mood, reduce anxiety, and modulate obsessive thoughts (Stahl, 2013). However, differences in receptor binding, half-life, and secondary effects give each SSRI a distinct therapeutic personality.

1. Fluoxetine (Prozac)
● Mechanism: Inhibits SERT; weak 5-HT2C receptor antagonism, which may increase dopamine and norepinephrine in the prefrontal cortex (Stahl, 2013).
● Half-life: 2–4 days; active metabolite norfluoxetine has a half-life of 7–15 days (Hiemke et al., 2018).
● FDA-approved for: Major depression, OCD, panic disorder, bulimia nervosa, bipolar depression.
● Preferred when: Low energy or poor medication adherence is a concern.
● Use caution when: Insomnia or agitation is prominent; CYP2D6 inhibition can cause drug interactions.
● Citation: Hiemke, C., et al. (2018). AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry. Pharmacopsychiatry, 51(1), 9–62. https://doi.org/10.1055/s-0043-116492

2. Sertraline (Zoloft)
● Mechanism: Inhibits SERT; weak dopamine transporter (DAT) inhibition may enhance motivation (Stahl, 2013).
● Half-life: ~26 hours.
● FDA-approved for: Depression, OCD, PTSD, panic disorder, social anxiety, PMDD.
● Preferred when: Treating OCD, PTSD, or depression with fatigue.
● Use caution when: GI side effects are intolerable (common early in treatment).
● Citation: Preskorn, S. H. (1997). Clinically relevant pharmacology of SSRIs. Clinical Pharmacokinetics, 32(1), 1–21.

3. Escitalopram (Lexapro)
● Mechanism: Pure S-enantiomer of citalopram; highly selective for SERT with minimaloff-target activity.
● Half-life: ~27–32 hours.
● FDA-approved for: Major depression, GAD.
● Preferred when: Clean receptor profile is desired (e.g., elderly, polypharmacy patients).
● Use caution when: QT prolongation is a concern, especially in high doses.
● Citation: Owens, M. J., Knight, D. L., & Nemeroff, C. B. (2001). Second-generation SSRIs: Human monoamine transporter binding profile. Biological Psychiatry, 50(5), 345–350.

4. Citalopram (Celexa)
● Mechanism: Racemic mixture of R- and S-enantiomers; inhibits SERT.
● Half-life: ~35 hours.
● FDA-approved for: Major depressive disorder.
● Preferred when: Cost or insurance issues limit access to escitalopram.
● Contraindicated when: QTc >500 ms or patient is on other QT-prolonging meds.
● Citation: FDA (2011). Celexa (citalopram) drug safety communication. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-celexa-citalopram

5. Paroxetine (Paxil)
● Mechanism: Inhibits SERT; notable anticholinergic activity and mild norepinephrine reuptake inhibition.
● Half-life: ~21 hours; no active metabolite.
● FDA-approved for: Depression, OCD, panic disorder, social anxiety, GAD, PTSD, PMDD.
● Preferred when: Anxiety with sleep disturbance, or severe GAD.
● Avoid when: Pregnancy (Category D), discontinuation concerns, or cognitive blunting risk.
● Citation: Louik, C., et al. (2007). First-trimester use of SSRIs and risk of birth defects. NEJM, 356(26), 2675–83. https://doi.org/10.1056/NEJMoa064378

6. Fluvoxamine (Luvox)
● Mechanism: Potent SERT inhibition; sigma-1 receptor agonism, which may contribute to cognitive enhancement and neuroplasticity (Hashimoto, 2009).
● Half-life: ~15–20 hours.
● FDA-approved for: OCD (in both children and adults).
● Preferred when: Treating OCD or ASD with repetitive thoughts/behaviors.
● Use caution when: Polypharmacy is a concern; fluvoxamine is a strong CYP1A2/2C19 inhibitor.
● Citation: Hashimoto, K. (2009). Sigma-1 receptors and fluvoxamine: Clinical
implications. CNS Drugs, 23(11), 963–971. https://doi.org/10.2165/11310960-000000000-00000

While SSRIs all work by boosting serotonin, their differences in receptor activity, metabolism, and side effect profiles make them far from interchangeable. Choosing the right SSRI means considering the patient’s full clinical picture, including symptom type, lifestyle, medical history, and medication interactions.

Educating patients on these nuances fosters informed, collaborative decision-making and ultimately leads to better outcomes.

 

Written By Ivy Stevens- Bowdoin College

Reviewed By Nicolas Sikaczowski, DO Board Certified Adult & Child Psychiatrist

References:
1. Stahl, S. M. (2013). Stahl’s Essential Psychopharmacology: Neuroscientific Basis and
Practical Applications (4th ed.). Cambridge University Press.
2. Hiemke, C., et al. (2018). AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry. Pharmacopsychiatry, 51(1), 9–62.
3. Preskorn, S. H. (1997). Clinically Relevant Pharmacology of SSRIs. Clinical Pharmacokinetics, 32(1), 1–21.
4. Owens, M. J., Knight, D. L., & Nemeroff, C. B. (2001). Second-generation SSRIs and
transporter binding. Biological Psychiatry, 50(5), 345–350.
5. FDA. (2011). Celexa (citalopram) and QT prolongation. https://www.fda.gov
6. Louik, C., et al. (2007). First-trimester SSRI use and birth defects. NEJM, 356(26), 2675–83.
7. Hashimoto, K. (2009). Sigma-1 receptors and fluvoxamine. CNS Drugs, 23(11), 963–971.
8. Yonkers, K. A., et al. (2009). Management of depression during pregnancy. General Hospital Psychiatry, 31(5), 403–413.