SSRIs (selective serotonin reuptake inhibitors)
Target: Serotonin transporter (SERT, SLC6A4)
- 0-6 wk
- time to clinical response
- ~0%
- response rate in MDD trials (vs ~30% placebo)
- $0-15/mo
- generic cash price floor
- 0-20%
- discontinuation due to side effects
What are ssris (selective serotonin reuptake inhibitors)?
SSRIs are the first-line pharmacologic treatment for major depressive disorder and most anxiety disorders. They block reuptake of serotonin into presynaptic neurons, increasing synaptic 5-HT availability over weeks. The class includes fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine — six molecules with broadly similar efficacy and meaningfully different side-effect, half-life, and interaction profiles.
How do ssris (selective serotonin reuptake inhibitors) work?
By inhibiting SERT, SSRIs raise extracellular serotonin in cortical and limbic synapses. The immediate biochemical effect happens within hours, but clinical antidepressant effect lags 2-6 weeks — a gap that current models attribute to downstream receptor desensitization, BDNF signaling, and neuroplastic adaptations rather than synaptic 5-HT levels alone. Anxiety can paradoxically worsen during the first 1-2 weeks as the system adapts.
History of ssris (selective serotonin reuptake inhibitors)
Fluoxetine (Prozac) launched in 1987 and became the first blockbuster antidepressant — credited with destigmatizing depression treatment. Sertraline (Zoloft, 1991), paroxetine (Paxil, 1992), and citalopram (Celexa, 1998) followed. Escitalopram (Lexapro, 2002), the S-enantiomer of citalopram, is the most prescribed SSRI in the US as of 2025. All six molecules are available as generics; cash prices are $4-15/month at most pharmacies.
Drugs in this class
Other drug classes
GLP-1 receptor agonists
GLP-1 receptor agonists are a class of injectable and oral medications that mimic the incretin hormone GLP-1. Originally developed for type
edPDE5 inhibitors
Phosphodiesterase type 5 (PDE5) inhibitors are the first-line oral treatment for erectile dysfunction. They work by blocking PDE5 from break
hair loss5-alpha reductase inhibitors
5-alpha reductase inhibitors slow the conversion of testosterone to dihydrotestosterone (DHT), the androgen primarily responsible for male-p
skincareTopical retinoids
Topical retinoids are vitamin A derivatives applied to the skin to accelerate cell turnover, reduce comedonal acne, and reverse photodamage.
cholesterolStatins (HMG-CoA reductase inhibitors)
Statins are the cornerstone of pharmacologic LDL-cholesterol lowering and the most widely prescribed cardiovascular drug class in the world.
high blood pressureACE inhibitors
ACE inhibitors are first-line therapy for hypertension, heart failure with reduced ejection fraction, post-MI, and diabetic nephropathy. The
Related topics
Sources
Primary sources cited above. FDA labeling, peer-reviewed trials, and specialty-society guidelines only.
- Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder (network meta-analysis) · The Lancet, 2018 · PMID 29477251
- Practice Guideline for the Treatment of Patients With Major Depressive Disorder, 3rd Edition · American Psychiatric Association, 2010
- STAR*D: Sequenced Treatment Alternatives to Relieve Depression · American Journal of Psychiatry, 2006 · PMID 17074942
- Antidepressant withdrawal effects: review of the evidence · Addictive Behaviors, 2019 · PMID 30292574
People also ask
Which SSRI is best — sertraline, escitalopram, or fluoxetine?
Network meta-analyses (Cipriani 2018) put escitalopram and sertraline modestly ahead on the combined efficacy-acceptability axis, but the differences are small. Choice usually comes down to side-effect profile, drug interactions, and half-life. Fluoxetine's long half-life makes it forgiving of missed doses and easier to discontinue. Sertraline has the fewest pharmacokinetic interactions. Escitalopram is the cleanest in terms of receptor selectivity. Paroxetine is the worst for discontinuation syndrome and weight gain.
How long until SSRIs start working?
Some patients notice improved sleep or energy within 1-2 weeks, but the antidepressant effect typically requires 4-6 weeks at a therapeutic dose. Anxiety disorders can take 6-12 weeks. Side effects often appear first and improve over the same window — counterintuitive but expected.
Do SSRIs cause weight gain?
Paroxetine is the worst offender (mean +1-3 kg over 12 months). Mirtazapine (not an SSRI but in the same neighborhood) is worse. Sertraline, escitalopram, and fluoxetine are weight-neutral on average in trials, though individual responses vary widely. Long-term observational data shows modest weight gain across the class, partly attributable to recovery from depression-driven appetite suppression.
What is SSRI discontinuation syndrome?
Stopping an SSRI abruptly — especially paroxetine, sertraline, or fluvoxamine, all with shorter half-lives — can trigger dizziness, electric-shock sensations ('brain zaps'), GI upset, irritability, and flu-like symptoms lasting 1-3 weeks. Fluoxetine's long half-life (active metabolite ~7-15 days) makes it the easiest to discontinue. Tapering over 4-8 weeks is standard; some patients need hyperbolic tapers over months.
Are SSRIs safe in pregnancy?
Untreated depression itself carries fetal risk, so the calculus is comparative rather than absolute. Sertraline is the most-studied and generally preferred in pregnancy. Paroxetine has a Category D label due to associations with cardiac malformations and is usually avoided. Decisions should be individualized with OB/perinatal psychiatry input.
Can SSRIs cause sexual side effects?
Yes — reduced libido, delayed orgasm, and anorgasmia affect 25-70% of patients depending on the molecule and how you ask. Paroxetine is worst; bupropion (an NDRI, not an SSRI) has the lowest sexual side-effect burden among antidepressants and is sometimes added or substituted. PSSD (post-SSRI sexual dysfunction) — persistent symptoms after discontinuation — is recognized by EMA and FDA labels but remains poorly characterized.