PharmacologyTier 1Medical Sciences concept

Antidepressant pharmacokinetics (half-life comparison, active metabolites)

Core concept

Half-life governs three practical things: time to steady state, washout before switching, and discontinuation syndrome risk
Fluoxetine is the outlier at both ends
- Parent t-half 1-4 days; active metabolite norfluoxetine 7-15 days
- -> steady state takes ~4-5 weeks, and interactions persist for weeks after stopping

Drug	t-half	Active metabolite	Note
Fluoxetine	1-4 d (norfluoxetine 7-15 d)	Yes	Longest; self-tapering; potent CYP2D6 inhibitor
Sertraline	~26 h	Weak (desmethylsertraline)	Fewest interactions of the SSRIs
Citalopram / escitalopram	~33 h / ~30 h	No	QT prolongation, dose cap 20 mg over 65
Paroxetine	~21 h	No	Potent CYP2D6 inhibitor, antimuscarinic, worst discontinuation syndrome
Venlafaxine	~5 h (ODV ~11 h)	O-desmethylvenlafaxine	Worst discontinuation; inc BP at high dose
Desvenlafaxine	~11 h	(is the metabolite)	Minimal CYP involvement
Duloxetine	~12 h	No	Hepatotoxicity
Mirtazapine	20-40 h	No	Sedating and orexigenic at low dose
Amitriptyline	~20 h	Nortriptyline	Nortriptyline is the active metabolite and a drug in its own right
Vortioxetine	~66 h	No
Agomelatine	1-2 h	No	LFT monitoring

Discontinuation syndrome - dizziness, "brain zaps", flu-like symptoms, insomnia, irritability, within days of stopping
- Risk is inversely proportional to half-life: venlafaxine and paroxetine worst, fluoxetine effectively self-tapers
- Not withdrawal in the dependence sense - no craving, no dose escalation
Washout before an MAOI: 2 weeks for most SSRIs, 5 weeks for fluoxetine; 2 weeks after an MAOI before an SSRI
CYP2D6 inhibition - fluoxetine and paroxetine potent; relevant to tamoxifen, codeine, metoprolol, TCAs, risperidone
- Sertraline, citalopram, escitalopram and venlafaxine are the safe choices alongside tamoxifen
Fluvoxamine - potent CYP1A2 inhibitor -> inc clozapine, theophylline, caffeine
Antidepressant effect appears at 2-4 weeks regardless of half-life; adequate trial is 4-6 weeks at therapeutic dose

Switching
- Fluoxetine -> another serotonergic drug: allow the long washout or expect additive serotonergic effect
- Cross-taper for short half-life agents; direct swap is safer for long ones
Poor adherence with paroxetine or venlafaxine produces withdrawal that mimics relapse - ask about missed doses before escalating
Renal or hepatic impairment: desvenlafaxine and sertraline are the safer choices; avoid duloxetine below CrCl 30
Elderly - hyponatraemia (SIADH) within the first 2-4 weeks of any SSRI/SNRI, check Na at 2 weeks
SSRIs inc bleeding risk (platelet serotonin depletion), amplified by NSAIDs and anticoagulants -> co-prescribe a PPI
Long half-life is an advantage in poor adherence and a disadvantage in overdose or interaction

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