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Serotonin modulator antidepressants: Pharmacokinetics

Drug	Bioavailability (%)	Time to peak plasma concentration (hours)	Metabolism and pharmacokinetic interactions*	Major effects on metabolism of co-administered drugs	Elimination half-life (hours)	Active metabolite(s)
Trazodone	65 (taken without food) Up to 100 (taken with food)	1 (unfed) 2 (fed)	Hepatic via CYP3A4 If taken with a strong CYP3A4 inhibitor, a dose reduction of trazodone may be warranted If taken with a strong CYP3A4 inducer for more than 7 to 14 days, a dose increase of trazodone may be considered Monitor clinical effect and tolerability; a list of CYP3A4 inhibitors and inducers is provided as a separate table in UpToDate	None	5 to 9	Yes (m-chlorophenylpiperazine)
Vilazodone	72 (taken with food) Decreased if taken on empty stomach	4 to 5	Hepatic via CYP3A4 If taken with a strong inhibitor of CYP3A4, label recommends specific dose reduction of vilazodone If taken with a strong inducer of CYP3A4 for >14 days, label suggests considering a vilazodone dose increase For specific recommendations refer to clinical topic and drug interactions program; a list of CYP3A4 inhibitors and inducers is provided as a separate table in UpToDate	None	25	No
Vortioxetine	75 (not affected by food)	7 to 11	Hepatic via CYP2D6 and other CYP enzymes (eg CYP3A4) If taken with a strong inhibitor of CYP2D6, label recommends specific dose reduction of vortioxetine If taken with a strong CYP inducer for >14 days, label suggests considering a vortioxetine dose increase^¶ For specific recommendations refer to drug interactions program; a list of CYP2D6 inhibitors is provided as a separate table in UpToDate	None	66	No
Nefazodone^Δ	20 (may be decreased if taken with food)	0.5 to 2 (delayed by food)	Hepatic via CYP3A4 Dose adjustment of nefazodone may be warranted if taken with either a strong CYP3A4 inhibitor or inducer. The safety of such combinations has not been established and avoidance of coadministration should be considered, if appropriate; approach should be individualized. A list of strong CYP3A4 inhibitors and inducers is provided as a separate table in UpToDate	Nefazodone is a strong inhibitor of CYP3A4; it can significantly elevate levels of co-administered medications that are dependent on CYP3A4 metabolism for clearance	2 to 5 (parent) 2 to 33 (active metabolites)	Yes (triazoledione, hydroxynefazodone and m-chlorophenylpiperazine [mCPP])

CYP: cytochrome P450; Pgp: P-glycoprotein efflux transporter.
* The metabolism and clearance of serotonin modulators may be altered by co-administration of medications that inhibit or induce CYP450 hepatic drug metabolism. Prior to initiating treatment with a serotonin modulator or adjusting comedications, drug interactions should be analyzed using the drug interactions program included within UpToDate. Serotonin modulators are not dependent upon kidney function for a significant amount of clearance of unchanged (ie, active) drug.
¶ Although there are no drugs that are known to be specific inducers of CYP2D6, drugs that induce other CYP enzymes that are coadministered for 14 days or more can reduce vortioxetine levels; refer to the drug interactions program to determine specific interactions and management suggestions.
Δ Nefazodone is not a first- or second-line choice. Rare reports of fatal hepatotoxicity have led to market withdrawal in many countries. Avoid use in setting of liver disease and/or elevated transaminases.

Spina E, Trifirò G, Caraci F. Clinically significant drug interactions with newer antidepressants. CNS Drugs 2012; 26:39.
Frampton JE. Vilazodone: in major depressive disorder. CNS Drugs 2011; 25:615.
Zhang J, Mathis MV, Sellers JW, et al. The US Food and Drug Administration's perspective on the new antidepressant vortioxetine. J Clin Psychiatry 2015; 76:8.

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