Pharmacology · CNS

Selective Serotonin Reuptake Inhibitors

Module 2 — Chapter 17: Antidepressant Drugs

All six SSRIs share the same primary mechanism — SERT blockade — but differ in ways that matter clinically: half-life determines discontinuation syndrome risk (fluoxetine's norfluoxetine metabolite makes it nearly immune; paroxetine's short half-life makes it the highest risk), and CYP inhibition profile determines drug interaction burden across the class.
Two agents carry especially consequential interaction warnings the table flags in red: paroxetine is the most potent CYP2D6 inhibitor in the class, contraindicated with tamoxifen because it blocks conversion to active endoxifen; fluvoxamine is a potent CYP1A2 inhibitor and is effectively contraindicated with clozapine (5- to 10-fold level increase) and tizanidine (severe hypotension).
Fluoxetine's norfluoxetine active metabolite creates a unique practical problem at MAOI transitions: while all other SSRIs require a 2-week washout before starting an MAOI, fluoxetine requires 5 weeks — a rule that is routinely missed and can produce fatal serotonin syndrome.
Serotonin syndrome and neuroleptic malignant syndrome can both present with hyperthermia and altered mental status, but the distinguishing neuromuscular finding is clonus and hyperreflexia in serotonin syndrome versus lead-pipe rigidity and bradyreflexia in NMS — getting this right determines whether you reach for cyproheptadine or dantrolene.
QTc prolongation is a class-specific risk concentrated in citalopram (FDA dose-capped at 40 mg; 20 mg in elderly and hepatic impairment) and escitalopram at high doses — both are the S-enantiomer pair, and this risk is not shared across the class, so switching within the class to sertraline or fluoxetine avoids it.

Abbreviations: SSRI = selective serotonin reuptake inhibitor · SERT = serotonin transporter · MAOI = monoamine oxidase inhibitor · CYP = cytochrome P450 · NMS = neuroleptic malignant syndrome · QTc = corrected QT interval · FDA = Food and Drug Administration · OCD = obsessive-compulsive disorder

The Six Selective Serotonin Reuptake Inhibitors — Key Distinctions

Agent	Half-Life Tier	Cytochrome P450 Inhibition	Key Distinguishing Feature
Fluoxetine	Very long (norfluoxetine)	Potent 2D6; moderate 3A4, 2C19	Active metabolite norfluoxetine — minimal discontinuation syndrome; 5-week monoamine oxidase inhibitor washout; approved for children age 8 and older
Sertraline	Moderate	Weak 2D6 at standard doses	Broadest FDA approval; preferred in cardiac patients and pregnancy; cleanest interaction profile after escitalopram
Paroxetine	Short — no active metabolite	Potent 2D6 (most potent in class)	Highest discontinuation syndrome risk; anticholinergic (muscarinic blockade); avoid in pregnancy and with tamoxifen
Escitalopram	Moderate	Minimal — all isoforms	Cleanest interaction profile — preferred in polypharmacy; QTc risk at high doses (cap 20 mg in elderly/hepatic); approved age 12 and older
Citalopram	Moderate	Minimal 2D6	Greatest QTc prolongation risk — FDA dose cap 40 mg; 20 mg in elderly/hepatic/CYP2C19 poor metabolizers
Fluvoxamine	Moderate-short	Potent 1A2, 2C19; moderate 3A4	Primary indication: obsessive-compulsive disorder; avoid with clozapine (dramatic level increase) and tizanidine (contraindicated)

High-Yield Drug Interactions

Cytochrome P450 2D6 Inhibitors

Paroxetine and Fluoxetine

Tricyclic antidepressants: levels double or triple → toxicity
Tamoxifen: reduced activation to endoxifen → reduced anticancer efficacy (avoid both agents)
Antipsychotics (haloperidol, risperidone): elevated levels
Codeine: reduced conversion to morphine → reduced analgesia

Cytochrome P450 1A2 Inhibitor

Fluvoxamine Only

Clozapine: 5- to 10-fold level increase → toxicity
Theophylline: narrow therapeutic index → toxicity risk
Olanzapine: 2- to 3-fold level increase
Tizanidine: contraindicated — severe hypotension

Serotonin Syndrome — Clinical Recognition

Clinical Triad

Serotonin Syndrome

Neuromuscular: clonus (key finding), hyperreflexia, myoclonus, tremor
Autonomic: hyperthermia, diaphoresis, tachycardia, hypertension
Mental status: agitation, confusion, anxiety
Onset: within 24 hours of precipitant
Treatment: stop all serotonergic drugs; cyproheptadine; benzodiazepines

Comparison

Neuroleptic Malignant Syndrome

Neuromuscular: lead-pipe rigidity, bradyreflexia (no clonus)
Autonomic: hyperthermia, diaphoresis, labile blood pressure
Mental status: confusion, stupor
Onset: 24 to 72 hours or more; caused by dopamine antagonists
Treatment: stop offending drug; bromocriptine; dantrolene

Monoamine Oxidase Inhibitor Washout Rules

Before starting monoamine oxidase inhibitor after selective serotonin reuptake inhibitor: wait 2 weeks for most agents — wait 5 weeks after fluoxetine (norfluoxetine active metabolite). Before starting any selective serotonin reuptake inhibitor after monoamine oxidase inhibitor: always wait 2 weeks. Combining a selective serotonin reuptake inhibitor with a monoamine oxidase inhibitor is absolutely contraindicated.

Suggested References

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Brunton LL, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed.	McGraw-Hill; 2023
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Kelly CM, Juurlink DN, Gomes T, et al.	Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study.	BMJ. 2010;340:c693
U.S. Food and Drug Administration.	FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses.	FDA.gov; 2012
Boyer EW, Shannon M.	The serotonin syndrome.	N Engl J Med. 2005;352(11):1112–1120
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Rush AJ, Trivedi MH, Wisniewski SR, et al.	Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.	Am J Psychiatry. 2006;163(11):1905–1917
Stahl SM.	Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 5th ed. Chapter 8.	Cambridge University Press; 2021