Drug–drug interactions involving antidepressants: focus on desvenlafaxine

Figures & data

Figure 1 Prevalence of depression in patients with chronic physical conditions.

Notes: Data from: Dumbreck et al 2015³⁵ (diabetes, heart failure), Guthrie et al 2012⁴⁹ (atrial fibrillation, chronic pain, CAD, dementia, hypertension, stroke), Kalaydjian and Merikangas⁵⁹ (migraine), Ng et al¹⁰⁷ (cancer), Tao et al⁷⁵ (HIV), Tellez-Zenteno et al⁵⁴ (epilepsy), and Weinstein et al¹⁰⁰ (chronic liver disease).
Abbreviation: CAD, coronary artery disease.

Table 1 Antidepressants and CYP enzymes

Antidepressants	Major elimination pathway	Other elimination pathways	Inhibitory effect on CYP isoenzyme
SSRI
Citalopram	CYP2C19	CYP3A4, CYP2D6	CYP1A2, CYP2B6, CYP2C19, CYP2D6
Escitalopram	CYP2C19	CYP3A4, CYP2D6	CYP2D6, CYP2C9
Fluoxetine (active metabolite norfluoxetine)	CYP2D6	CYP2C9, CYP2C19, CYP3A4	CYP2D6,** CYP2C9,* CYP2C19,* CYP3A4,* CYP1A2
Fluvoxamine	CYP1A2, CYP2D6		CYP1A2,** CYP2C19,** CYP2C9,* CYP3A4,* CYP2D6
Paroxetine	CYP2D6	CYP3A4	CYP2D6,** CYP1A2, CYP2C9, CYP2C19, CYP3A4
Sertraline	CYP2B6	CYP2C19, CYP2C9, CYP3A4, CYP2D6	CYP2D6,* CYP1A2, CYP2C9, CYP2C19, CYP3A4
SNRI
Desvenlafaxine	Renal	UGT, CYP3A4	None
Duloxetine	CYP1A2	CYP2D6	CYP2D6*
Levomilnacipran	Renal	CYP3A4, CYP2C8, CYP2C19, CYP2D6, CYP2J2, UGT	None
Milnacipran	Renal	UGT, CYP3A4	CYP3A4
Venlafaxine (active metabolite desvenlafaxine)	CYP2D6	CYP3A4	CYP2D6, CYP3A4
Others
Agomelatine	CYP1A2	CYP2C9, CYP2C19	None
Bupropion (active metabolite hydroxybupropion)	CYP2B6		CYP2D6*
Mirtazapine	CYP2D6, CYP3A4	CYP1A2, UGT	None
Reboxetine	CYP3A4		None
Vilazodone	CYP3A4	CYP2C19, CYP2D6, carboxylesterase	CYP2C8?
Vortioxetine	CYP2D6	CYP3A4, CYP2C19, CYP2C9, CYP2A6, CYP2C8, CYP2B6	None

Notes:

** Potent;

* moderate;

? undetermined; no symbol, weak. Data from Flockhart,³³ Gelenberg et al,²³ and Spina et al.³⁴

Abbreviations: CYP, cytochrome P450; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin-reuptake inhibitor; UGT, uridine diphosphate glucuronosyltransferases.

Table 2 Summary of potential DDIs with desvenlafaxine

Therapeutic class/drugs	Pharmacologic profile of polypharmacy agents	Potential DDI with desvenlafaxine
Cardiovascular conditions
β-blockers (eg, propranolol, timolol, metoprolol, carvedilol)	Substrate of CYP2D6^Citation39	No interaction expected,a but caution is still advised, as elevation in blood pressure, heart rate, and cholesterol levels was observed in clinical studies^Citation18
CCBs, statins (eg, lovastatin, simvastatin, atorvastatin), rivaroxaban, apixaban	Substrate of CYP3A4^Citation10,Citation39,Citation44	No interaction expected,a but caution is still advised, as elevation in blood pressure, heart rate, and cholesterol levels was observed in clinical studies^Citation18
Antiarrhythmic agents (eg, quinidine, disopyramide, lignocaine, mexiletine, flecainide, amiodarone, dronedarone)	Substrate, inducer, or inhibitor of various CYP enzymes^Citation41	Potent CYP3A4 inhibitors may result in higher levels of desvenlafaxine^Citation18 Effect of CYP3A4 induction is unknownb
Warfarin	Substrate of CYP3A4, CYP1A2 and CYP2C9; induction of CYP3A4 and CYP2C9^Citation42	Risk of abnormal bleeding, caution with concomitant aspirin, antiplatelet drugs, or other drugs that affect coagulation^Citation10,Citation18 Effect of CYP3A4 induction is unknown, but may decrease levels of desvenlafaxineb
Diabetes mellitus
Sulfonylureas (eg, tolbutamide, glipizide), nateglinide	Substrate of CYP2C9^Citation14	No interaction expected,a but caution is still advised, as hypoglycemic events reported with other antidepressants^Citation45
Neurological conditions
Dementia
Donepezil, galantamine	Substrate of CYP2D6 and CYP3A4^Citation51	No interaction expecteda
Memantine	Renally excreted by tubular secretion^Citation52	Effect on tubular secretion is unknownb
Epilepsy
Carbamazepine, phenobarbital, phenytoin, primidone	Induction of CYP enzymes (eg, CYP1A2, CYP3A4) and UGTs (eg, UGT1A1, UGT2B7, and UGT2B15)^Citation34	Interaction not studied, but unlikely to be relevant according to CYP involvement in metabolism^Citation34 Effect of UGT induction is unknown, but may decrease levels of desvenlafaxineb
Valproic acid	Inhibition of CYPs (eg, CYP2C9, CYP2C19 and CYP3A4), some UGTs (eg, UGT1A4 and UGT2B7)^Citation34	Potent CYP3A4 inhibitors may result in higher levels of desvenlafaxine^Citation18,b
Carbamazepine, phenytoin, phenobarbital, primidone	Substrate of CYP3A4 or CYP2C9^Citation34	No interaction expecteda
Lamotrigine, topiramate	Induction of UGTs and/or CYP3A4^Citation34	Effect of CYP3A4 and UGT induction is unknown, but may decrease levels of desvenlafaxineb
Bupropion, TCAs	Strong proconvulsive properties^Citation53,Citation57	Possibility of seizures, caution in patients with seizure disorder^Citation18
Migraine
Triptans	Affinity for 5HT1 receptor (serotonergic property)^Citation66	Possibility of serotonin syndrome, caution when coadministered with serotonergic agents^Citation18,Citation67
Sumatriptan, zolmitriptan	Substrate of MAOA^Citation61	No interaction expecteda
Frovatriptan, eletriptan	Substrate of CYP1A2 or CYP3A4^Citation61,Citation62	No interaction expecteda
Schizophrenia
FGAs (eg, phenothiazines), asenapine (SGA)	Inhibition of CYP2D6^Citation69,Citation72	No interaction expected, abut caution for serotonin syndrome when coadministered with antidopaminergic agents^Citation18
SGAs, apart from amisulpride	Substrate of various CYP enzymes (eg, CYP2D6, CYP3A4) and UGTs^Citation69	No PK DDI was shown between desvenlafaxine and aripiprazole^Citation18
Clozapine	Associated with hypertension^Citation69	Increased risk for tachycardia and/or hypertension when administered with desvenlafaxine^Citation69,b
HIV
Protease inhibitors (eg, ritonavir)	Inhibition of CYP3A4 and/or CYP2D6^Citation77,Citation78	Potent CYP3A4 inhibitors may result in higher levels of desvenlafaxine^Citation18,b
Efavirenz	Inhibition of CYP2C19; induction of CYP3A4 and CYP2D6^Citation77	No interaction expecteda
Nevirapine	Substrate and inducer of CYP3A4 and CYP2B6^Citation82	Effect of CYP3A4 induction is unknown, but may decrease levels of desvenlafaxineb
Indinavir	Substrate and inhibitor of CYP3A4^Citation80	No PK DDI was shown between desvenlafaxine and indinavir^Citation81
Chronic pain
Opioids
Codeine, fentanyl, methadone, morphine, oxycodone, pethidine, tramadol	Substrate of CYP3A4 and/or CYP2D6^Citation86,Citation87	No interaction expecteda
Fentanyl, methadone, pethidine, tramadol	Inhibition of serotonin reuptake (serotonergic property)^Citation63	Possibility of serotonin syndrome, caution when coadministered with serotonergic agents^Citation18,Citation63
NSAIDs
Ibuprofen, naproxen, diclofenac, celecoxib, etoricoxib	Substrate of several CYP enzymes including CYP3A4, CYP2C9, or CYP2D6^Citation91^–^Citation96	No interaction expecteda
Ibuprofen, indomethacin, diclofenac, meloxicam, celecoxib	Inhibition of CYP2C9 or CYP2C8/2D6^Citation91	No interaction expecteda
Ibuprofen, diclofenac	Inhibition of UGT^Citation91	Effect of UGT inhibition unknown, but may increase levels of desvenlafaxineb
All NSAIDs	Risk of gastrointestinal bleeding^Citation91	Caution for abnormal bleeding with concomitant aspirin, antiplatelet drugs, or other drugs that affect coagulation^Citation18
Chronic liver disease
IFNα	Inhibition of CYP1A2^Citation103	No interaction expecteda
Direct-acting antivirals, such as ritonavir, boceprevir, simeprevir	Inhibition of CYP3A4^Citation104,Citation105	Potent CYP3A4 inhibitors may result in higher levels of desvenlafaxine^Citation18,b
Simeprevir, asunaprevir	Substrate of CYP3A4/5^Citation128,Citation129	No interaction expecteda
Ombitasvir, dasabuvir, paritaprevir	Inhibition of UGTs^Citation104	May increase desvenlafaxine levels (clinical significance unknown); monitor and titrate dose according to clinical response^Citation106
Cancer
Antiemetic agents
5HT3-receptor antagonists (ondansetron, tropisetron, dolasetron, palonosetron)	Substrate of CYP2D6^Citation111	No interaction expecteda
Granisetron, corticosteroids (dexamethasone, methylprednisolone, prednisolone, prednisone)	Substrate of CYP3A4^Citation109,Citation111	No interaction expecteda
Dexamethasone, prednisone	Induction of CYP3A4^Citation109	Effect of CYP3A4 induction is unknown, but may decrease levels of desvenlafaxineb
Anticancer agents
Vinca alkaloids (eg, vincristine, vinblastine, vinorelbine), taxanes (eg, docetaxel, paclitaxel), tyrosine-kinase inhibitors(eg, erlotinib, gefitinib, imatinib), irinotecan	Substrate of CYP3A4^Citation111,Citation112,Citation115,Citation116,Citation126	No interaction expecteda
Erlotinib	Substrate of CYP1A2^Citation115	No interaction expecteda
Cyclophosphamide, ifosfamide	Substrate of CYP3A4 and CYP2B6^Citation119	No interaction expecteda
Doxorubicin	Substrate of CYP3A4 and CYP2D6^Citation120	No interaction expecteda
Tamoxifen	Substrate of CYP2D6^Citation121	No interaction documented; desvenlafaxine may representa safe and effective treatment unlikely to alter the efficacy of tamoxifen^Citation125
Imatinib, gefitinib, irinotecan	Inhibition of CYP3A4/5, CYP2D6, and/or CYP2C9^Citation111,Citation116,Citation117,Citation126	Potent CYP3A4 inhibitors may result in higher levels of desvenlafaxine^Citation18,b

Notes: This table is not exhaustive, and serves only as a guide to potential DDIs with desvenlafaxine.

a No interaction expected, based on known PK characteristics of desvenlafaxine;¹⁸

b no documented evidence in current literature.

Abbreviations: 5HT, 5-hydroxytryptamine; AE, adverse event; CCB, calcium-channel blocker; CYP, cytochrome P450; DDI, drug–drug interaction; FGA, first-generation antipsychotic; MAOA, monoamine oxidase A; NSAID, nonsteroidal anti-inflammatory drug; PK, pharmacokinetic; SGA, second-generation antipsychotic; TCA, tricyclic antidepressant; UGT, uridine diphosphate glucuronosyltransferases.

DumbreckSFlynnANairnMDrug-disease and drug-drug interactions: systematic examination of recommendations in 12 UK national clinical guidelinesBMJ2015350h94925762567

 PubMed Web of Science ®Google Scholar

GuthrieBPayneKAldersonPMcMurdoMEMercerSWAdapting clinical guidelines to take account of multimorbidityBMJ2012345e634123036829

 PubMed Web of Science ®Google Scholar

KalaydjianAMerikangasKPhysical and mental comorbidity of headache in a nationally representative sample of U.S. adultsPsychosom Med200870777378018725426

 PubMed Web of Science ®Google Scholar

NgCGBoksMPMZainalNZde WitNJThe prevalence and pharmacotherapy of depression in cancer patientsJ Affect Disord20111311–31720732716

 PubMed Web of Science ®Google Scholar

TaoJVermundSHQianHZAssociation between depression and antiretroviral therapy use among people living with HIV: a meta-analysisAIDS Behav Epub2017424

 Web of Science ®Google Scholar

Tellez-ZentenoJFPattenSBJetteNWilliamsJWiebeSPsychiatric comorbidity in epilepsy: a population-based analysisEpilepsia200748122336234417662062

 PubMed Web of Science ®Google Scholar

WeinsteinAAKallman PriceJStepanovaMDepression in patients with nonalcoholic fatty liver disease and chronic viral hepatitis B and CPsychosomatics201152212713221397104

 PubMed Web of Science ®Google Scholar

FlockhartDADrug interactions: defining genetic influences on pharmacologic responses – cytochrome P450 drug interaction table2007 Available from: http://medicine.iupui.edu/clinpharm/ddisAccessed June 7, 2017

 Google Scholar

GelenbergAFreemanMMarkowitzJCPractice Guideline for the Treatment of Patients with Major Depressive Disorder3rd edArlington (VA)American Psychiatric Association2010

 Google Scholar

SpinaEPisaniFde LeonJClinically significant pharmacokinetic drug interactions of antiepileptic drugs with new antidepressants and new antipsychoticsPharmacol Res2016106728626896788

 PubMed Web of Science ®Google Scholar

FlockhartDATanus-SantosJEImplications of cytochrome P450 interactions when prescribing medication for hypertensionArch Intern Med2002162440541211863472

 PubMed Web of Science ®Google Scholar

Pristiq (desvenlafaxine) extended release tablets [prescribing information]SingaporePfizer2016

 Google Scholar

ScheenAJCytochrome P450-mediated cardiovascular drug interactionsExpert Opin Drug Metab Toxicol2011791065108221810031

 PubMed Web of Science ®Google Scholar

WalengaJMAdiguzelCDrug and dietary interactions of the new and emerging oral anticoagulantsInt J Clin Pract201064795696720584229

 PubMed Web of Science ®Google Scholar

TrujilloTCNolanPEAntiarrhythmic agents: drug interactions of clinical significanceDrug Saf200023650953211144659

 PubMed Web of Science ®Google Scholar

HolbrookAMPereiraJALabirisRSystematic overview of warfarin and its drug and food interactionsArch Intern Med2005165101095110615911722

 PubMed Web of Science ®Google Scholar

ManolopoulosVGRagiaGAlevizopoulosGPharmacokinetic interactions of selective serotonin reuptake inhibitors with other commonly prescribed drugs in the era of pharmacogenomicsDrug Metabol Drug Interact2012271193122718622

 PubMedGoogle Scholar

DerijksHJHeerdinkERDe KoningFHJanknegtRKlungelOHEgbertsACThe association between antidepressant use and hypoglycaemia in diabetic patients: a nested case-control studyPharmacoepidemiol Drug Saf200817433634418302302

 PubMed Web of Science ®Google Scholar

PasqualettiGTogniniSCalsolaroVPoliniAMonzaniFPotential drug–drug interactions in Alzheimer patients with behavioral symptomsClin Interv Aging2015101457146626392756

 PubMed Web of Science ®Google Scholar

KornhuberJKennepohlEMBleichSMemantine pharmacotherapy: a naturalistic study using a population pharmacokinetic approachClin Pharmacokinet200746759961217596105

 PubMed Web of Science ®Google Scholar

TrivediMHKurianBTManaging depressive disorders in patients with epilepsyPsychiatry (Edgmont)2007412634

 PubMedGoogle Scholar

RamasubbuRTaylorVHSamaanZThe Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and select comorbid medical conditionsAnn Clin Psychiatry20122419110922303525

 PubMed Web of Science ®Google Scholar

Imigran (sumatriptan) film-coated tablet [prescribing information]SingaporeGlaxoSmithKline2015

 Google Scholar

EvansRWThe FDA alert on serotonin syndrome with combined use of SSRIs or SNRIs and triptans: an analysis of the 29 case reportsMedGenMed20079348

 PubMedGoogle Scholar

RolanPEDrug interactions with triptansCNS Drugs2012261194995723018546

 PubMed Web of Science ®Google Scholar

TepperSAllenCSandersDGreeneABoccuzziSCoprescription of triptans with potentially interacting medications: a cohort study involving 240 268 patientsHeadache2003431444812864757

 PubMed Web of Science ®Google Scholar

SpinaEde LeonJMetabolic drug interactions with newer antipsychotics: a comparative reviewBasic Clin Pharmacol Toxicol2007100142217214606

 PubMed Web of Science ®Google Scholar

UrichukLPriorTIDursunSBakerGMetabolism of atypical antipsychotics: involvement of cytochrome p450 enzymes and relevance for drug-drug interactionsCurr Drug Metab20089541041818537577

 PubMed Web of Science ®Google Scholar

HillLLeeKCPharmacotherapy considerations in patients with HIV and psychiatric disorders: focus on antidepressants and antipsychoticsAnn Pharmacother2013471758923341158

 PubMed Web of Science ®Google Scholar

Norvir (ritonavir) film-coated tablet [prescribing information]SingaporeAbbVie2016

 Google Scholar

de MaatMMHuitemaADMulderJWDrug interaction of fluvoxamine and fluoxetine with nevirapine in HIV-1-infected individualsClin Drug Investig20032310629637

 PubMed Web of Science ®Google Scholar

Crixivan (indinavir) capsules [prescribing information]SingaporeMSD Pharma2012

 Google Scholar

JannMWSpratlinVMomaryKLack of a pharmacokinetic drug-drug interaction with venlafaxine extended-release/indinavir and desvenlafaxine extended-release/indinavirEur J Clin Pharmacol201268571572122173281

 PubMed Web of Science ®Google Scholar

LotschJSkarkeCTegederIGeisslingerGDrug interactions with patient-controlled analgesiaClin Pharmacokinet20024113157

 PubMed Web of Science ®Google Scholar

PergolizziJVJrMaLFosterDRThe prevalence of opioid-related major potential drug-drug interactions and their impact on health care costs in chronic pain patientsJ Manag Care Spec Pharm201420546747624761818

 PubMed Web of Science ®Google Scholar

AnsariHKoutiLDrug interaction and serotonin toxicity with opioid use: another reason to avoid opioids in headache and migraine treatmentCurr Pain Headache Rep20162085027457368

 PubMed Web of Science ®Google Scholar

SolomonDHNSAIDs: therapeutic use and variability of response in adults2017 Available from: https://www.uptodate.com/contents/nsaids-therapeutic-use-and-variability-of-response-in-adultsAccessed June 13, 2017

 Google Scholar

Aleve (naproxen) film-coated tablet [prescribing information]SingaporeBayer2015

 Google Scholar

Pegasys (PEG-interferon α2a) subcutaneous injection [prescribing information]SingaporeRoche2017

 Google Scholar

SmoldersEJde KanterCTde KnegtRJvan der ValkMDrenthJPBurgerDMDrug–drug interactions between direct-acting antivirals and psychoactive medicationsClin Pharmacokinet201655121471149427317413

 PubMed Web of Science ®Google Scholar

Victrelis (boceprevir) capsule [prescribing information]SingaporeMSD Pharma2017

 Google Scholar

Sunvepra (asunaprevir) capsule [prescribing information]SingaporeBristol-Myers Squibb2016

 Google Scholar

Olysio (simprevir) capsule [prescribing information]SingaporeJohnson & Johnson2017

 Google Scholar

SockalingamSTsengAGiguerePWongDPsychiatric treatment considerations with direct acting antivirals in hepatitis CBMC Gastroenterol2013138623672254

 PubMed Web of Science ®Google Scholar

BlowerPde WitRGoodinSAaproMDrug-drug interactions in oncology: why are they important and can they be minimized?Crit Rev Oncol Hematol200555211714215890526

 PubMed Web of Science ®Google Scholar

ChanANgTRYapKYClinically-relevant anticancer-antidepressant drug interactionsExpert Opin Drug Metab Toxicol20128217319922191471

 PubMed Web of Science ®Google Scholar

BeijnenJHSchellensJHMDrug interactions in oncologyLancet Oncol20045848949615288238

 PubMed Web of Science ®Google Scholar

Tarceva (erlotinib) film-coated tablet [prescribing information]SingaporeRoche2016

 Google Scholar

Iressa (gefitinib) film-coated tablet [prescribing information]SingaporeAstraZeneca2017

 Google Scholar

Campto (irinotecan) intravenous injection [prescribing information]SingaporePfizer2014

 Google Scholar

BoddyAVYuleSMMetabolism and pharmacokinetics of oxazaphosphorinesClin Pharmacokinet200038429130410803453

 PubMed Web of Science ®Google Scholar

Adriamycin (doxorubicin) intravenous injection [prescribing information]SingaporePfizer2015

 Google Scholar

CaraciFCrupiRDragoFSpinaEMetabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and Hypericum extractCurr Drug Metab201112657057721395523

 PubMed Web of Science ®Google Scholar

NicholsAILubaczewskiSLiangYMatschkeKBraleyGRameyTOpen-label, 2-period sequential drug interaction study to evaluate the effect of a 100-mg dose of desvenlafaxine on the pharmacokinetics of tamoxifen when coadministered in healthy postmenopausal female subjectsInt J Clin Pharmacol Ther2014521083084125138680

 PubMed Web of Science ®Google Scholar

YapKYTayWLChuiWKChanAClinically relevant drug interactions between anticancer drugs and psychotropic agentsEur J Cancer Care2011201632

 PubMed Web of Science ®Google Scholar