Skip to content
2000
Volume 23, Issue 10
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Introduction/Objective

Esketamine is administered intranasally in combination with at least another antidepressant in patients with treatment-resistant depression. Some of these antidepressants might affect ketamine’s pharmacokinetic profile by inhibiting cytochrome-P (CYP) isoforms. Our aim was to establish how different types of combined antidepressants affect serum and salivary levels of esketamine at the time of maximum plasma concentrations and afterward in TRD patients receiving esketamine in a real-world context.

Methods

Serum and salivary samples were collected from 53 patients receiving intranasal esketamine (56 mg) at baseline, after 20 min (roughly corresponding to ), 7 hours (corresponding to the t value), 24, and 72 hours. Patients were stratified according to the combined antidepressant medication.

Results

Salivary esketamine levels were several-fold higher than the corresponding serum levels at all time points, and showed high inter-individual variability. Serum 20-min post-esketamine levels and AUC levels were significantly higher in patients on antidepressants known to inhibit different isoforms of CY (paroxetine, fluoxetine, duloxetine, venlafaxine), with respect to levels detected in patients on sertraline, citalopram, escitalopram, vortioxetine. These changes in the pharmacokinetic profile of esketamine did not affect the clinical outcome of esketamine. However, changes in systolic blood pressure in response to esketamine positively correlated with serum esketamine levels, suggesting a reduction of esketamine dose in patients with cardiovascular comorbidity under treatment with paroxetine, fluoxetine, duloxetine, venlafaxine.

Conclusion

The CYP-related status of co-administered antidepressants may affect esketamine levels. However, the small sample sizes of the co-administered drug subgroups and multiple prescriptions do not allow for drawing strong conclusions.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cn/10.2174/011570159X356952241216172603
2025-04-07
2025-09-11

  • From This Site

    /content/journals/cn/10.2174/011570159X356952241216172603
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. KimJ. FarchioneT. PotterA. ChenQ. TempleR. Esketamine for treatment-resistant depression - First FDA-approved antidepressant in a new class.N. Engl. J. Med.201938111410.1056/NEJMp1903305 31116916
     [Google Scholar]
  2. FedgchinM. TrivediM. DalyE.J. MelkoteR. LaneR. LimP. VitaglianoD. BlierP. FavaM. LiebowitzM. RavindranA. GaillardR. AmeeleH.V.D. PreskornS. ManjiH. HoughD. DrevetsW.C. SinghJ.B. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: Results of a randomized, double-blind, active-controlled study (TRANSFORM-1).Int. J. Neuropsychopharmacol.2019221061663010.1093/ijnp/pyz039 31290965
     [Google Scholar]
  3. DalyE.J. TrivediM.H. JanikA. LiH. ZhangY. LiX. LaneR. LimP. DucaA.R. HoughD. ThaseM.E. ZajeckaJ. WinokurA. DivackaI. FagioliniA. CubalaW.J. BitterI. BlierP. SheltonR.C. MoleroP. ManjiH. DrevetsW.C. SinghJ.B. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial.JAMA Psychiatry201976989390310.1001/jamapsychiatry.2019.1189 31166571
     [Google Scholar]
  4. McIntyreR.S. RosenblatJ.D. NemeroffC.B. SanacoraG. MurroughJ.W. BerkM. BrietzkeE. DoddS. GorwoodP. HoR. IosifescuD.V. Lopez JaramilloC. KasperS. KratiukK. LeeJ.G. LeeY. LuiL.M.W. MansurR.B. PapakostasG.I. SubramaniapillaiM. ThaseM. VietaE. YoungA.H. ZarateC.A.Jr StahlS. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation.Am. J. Psychiatry2021178538339910.1176/appi.ajp.2020.20081251 33726522
     [Google Scholar]
  5. ReifA. BitterI. BuyzeJ. CebullaK. FreyR. FuD.J. ItoT. KambarovY. LlorcaP.M. Oliveira-MaiaA.J. MesserT. Mulhern-HaugheyS. RiveB. von HoltC. YoungA.H. GodinovY. ESCAPE-TRD Investigators. Esketamine nasal spray versus quetiapine for treatment-resistant depression.N. Engl. J. Med.2023389141298130910.1056/NEJMoa2304145 37792613
     [Google Scholar]
  6. MarwahaS. PalmerE. SuppesT. ConsE. YoungA.H. UpthegroveR. Novel and emerging treatments for major depression.Lancet20234011037114115310.1016/S0140‑6736(22)02080‑3 36535295
     [Google Scholar]
  7. Smith-ApeldoornS.Y. VeraartJ.K.E. SpijkerJ. KamphuisJ. SchoeversR.A. Maintenance ketamine treatment for depression: A systematic review of efficacy, safety, and tolerability.Lancet Psychiatry202291190792110.1016/S2215‑0366(22)00317‑0 36244360
     [Google Scholar]
  8. ZanosP. GouldT.D. Mechanisms of ketamine action as an antidepressant.Mol. Psychiatry201823480181110.1038/mp.2017.255 29532791
     [Google Scholar]
  9. PsiukD. NowakE.M. DychaN. ŁopuszańskaU. KurzepaJ. SamardakiewiczM. Esketamine and psilocybin-The Comparison of two mind-altering agents in depression treatment: Systematic review.Int. J. Mol. Sci.202223191145010.3390/ijms231911450 36232748
     [Google Scholar]
  10. CapuzziE. CaldiroliA. CapellazziM. TagliabueI. MarcatiliM. ColmegnaF. ClericiM. BuoliM. DakanalisA. Long-term efficacy of intranasal esketamine in treatment-resistant major depression: A systematic review.Int. J. Mol. Sci.20212217933810.3390/ijms22179338 34502248
     [Google Scholar]
  11. Moda-SavaR.N. MurdockM.H. ParekhP.K. FetchoR.N. HuangB.S. HuynhT.N. WitztumJ. ShaverD.C. RosenthalD.L. AlwayE.J. LopezK. MengY. NellissenL. GrosenickL. MilnerT.A. DeisserothK. BitoH. KasaiH. ListonC. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation.Science20193646436eaat807810.1126/science.aat8078 30975859
     [Google Scholar]
  12. RiggsL.M. GouldT.D. Ketamine and the future of rapid-acting antidepressants.Annu. Rev. Clin. Psychol.202117120723110.1146/annurev‑clinpsy‑072120‑014126 33561364
     [Google Scholar]
  13. BuchmayerF. KasperS. Overcoming the myths of esketamine administration: Different and not difficult.Front. Psychiatry202314127965710.3389/fpsyt.2023.1279657 38076689
     [Google Scholar]
  14. Perez-RuixoC. RossenuS. ZannikosP. NandyP. SinghJ. DrevetsW.C. Perez-RuixoJ.J. Population pharmacokinetics of esketamine nasal spray and its metabolite noresketamine in healthy subjects and patients with treatment-resistant depression.Clin. Pharmacokinet.202160450151610.1007/s40262‑020‑00953‑4 33128208
     [Google Scholar]
  15. YanagiharaY. KariyaS. OhtaniM. UchinoK. AoyamaT. YamamuraY. IgaT. Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes.Drug Metab. Dispos.2001296887890 11353758
     [Google Scholar]
  16. HijaziY. BoulieuR. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes.Drug Metab. Dispos.200230785385810.1124/dmd.30.7.853 12065445
     [Google Scholar]
  17. LangmiaI.M. JustK.S. YamouneS. MüllerJ.P. StinglJ.C. Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant - Implications for precision dosing in a global perspective.Br. J. Clin. Pharmacol.202288125149516510.1111/bcp.15467 35863300
     [Google Scholar]
  18. KowalskaM. NowaczykJ. FijałkowskiŁ. NowaczykA. Paroxetine-Overview of the molecular mechanisms of action.Int. J. Mol. Sci.2021224166210.3390/ijms22041662 33562229
     [Google Scholar]
  19. MargolisJ.M. O’DonnellJ.P. MankowskiD.C. EkinsS. ObachR.S. (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes.Drug Metab. Dispos.2000281011871191 10997938
     [Google Scholar]
  20. HarveyA.T. PreskornS.H. Fluoxetine pharmacokinetics and effect on CYP2C19 in young and elderly volunteers.J. Clin. Psychopharmacol.200121216116610.1097/00004714‑200104000‑00007 11270912
     [Google Scholar]
  21. HaduchA. WójcikowskiJ. DanielW.A. Effect of selected antidepressant drugs on cytochrome P450 2B (CYP2B) in rat liver. An in vitro and in vivo study.Pharmacol. Rep.2008606957965 19211989
     [Google Scholar]
  22. PreskornS.H. NicholsA.I. PaulJ. PatronevaA.L. HelznerE.C. Guico-PabiaC.J. Effect of desvenlafaxine on the cytochrome P450 2D6 enzyme system.J. Psychiatr. Pract.200814636837810.1097/01.pra.0000341891.43501.6b 19057238
     [Google Scholar]
  23. ParisB.L. OgilvieB.W. ScheinkoenigJ.A. Ndikum-MofforF. GibsonR. ParkinsonA. In vitro inhibition and induction of human liver cytochrome p450 enzymes by milnacipran.Drug Metab. Dispos.200937102045205410.1124/dmd.109.028274 19608694
     [Google Scholar]
  24. ChanC.Y. NewL.S. HoH.K. ChanE.C.Y. Reversible time-dependent inhibition of cytochrome P450 enzymes by duloxetine and inertness of its thiophene ring towards bioactivation.Toxicol. Lett.2011206331432410.1016/j.toxlet.2011.07.019 21839818
     [Google Scholar]
  25. CallejaS. ZubiaurP. OchoaD. Villapalos-GarcíaG. Mejia-AbrilG. Soria-ChacarteguiP. Navares-GómezM. de MiguelA. RománM. Martín-VílchezS. Abad-SantosF. Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine.Front. Pharmacol.202314111046010.3389/fphar.2023.1110460 36817149
     [Google Scholar]
  26. VenturaJ. LukoffD. NuechterleinK.H. LibermanR.P. GreenM.F. ShanerA. Training and quality assurance with the brief psychiatric rating scale.Int. J. Methods Psychiatr. Res.19933221244
     [Google Scholar]
  27. RonconeR. VenturaJ. ImpallomeniM. FalloonI.R.H. MorosiniP.L. ChiaravalleE. CasacchiaM. Reliability of an Italian standardized and expanded brief psychiatric rating scale (BPRS 4.0) in raters with high vs. low clinical experience.Acta Psychiatr. Scand.1999100322923610.1111/j.1600‑0447.1999.tb10850.x 10493090
     [Google Scholar]
  28. MontgomeryS.A. ÅsbergM. A new depression scale designed to be sensitive to change.Br. J. Psychiatry1979134438238910.1192/bjp.134.4.382 444788
     [Google Scholar]
  29. HamiltonM. A rating scale for depression.J. Neurol. Neurosurg. Psychiatry1960231566210.1136/jnnp.23.1.56 14399272
     [Google Scholar]
  30. HamiltonM. The assessment of anxiety states by rating.Br. J. Med. Psychol.1959321505510.1111/j.2044‑8341.1959.tb00467.x 13638508
     [Google Scholar]
  31. YoungR.C. BiggsJ.T. ZieglerV.E. MeyerD.A. A rating scale for mania: Reliability, validity and sensitivity.Br. J. Psychiatry1978133542943510.1192/bjp.133.5.429 728692
     [Google Scholar]
  32. GuyW. ECDEU assessment manual for psychopharmacology, revised. US Department of Health, Education, and Welfare PublicationNational Institute of Mental HealthRockville, MD1976218222
     [Google Scholar]
  33. BeckA.T. SteerR.A. BrownG. Beck Depression Inventory–II (BDI-II).San Antonio, TXPsychological Corporation199610.1037/t00742‑000
     [Google Scholar]
  34. BeckA.T. RushA.J. ShawB.F. EmeryG. Cognitive Therapy of Depression.New YorkGuilford Press1987
     [Google Scholar]
  35. Development of the World Health Organization WHOQOL-BREF quality of life assessment.Psychol. Med.199828355155810.1017/S0033291798006667 9626712
     [Google Scholar]
  36. BattagliaJ. LindborgS.R. AlakaK. MeehanK. WrightP. Calming versus sedative effects of intramuscular olanzapine in agitated patients.Am. J. Emerg. Med.200321319219810.1016/S0735‑6757(02)42249‑8 12811711
     [Google Scholar]
  37. BremnerJ.D. KrystalJ.H. PutnamF.W. SouthwickS.M. MarmarC. CharneyD.S. MazureC.M. Measurement of dissociative states with the clinician-administered dissociative states scale (CADSS).J. Trauma. Stress199811112513610.1023/A:1024465317902 9479681
     [Google Scholar]
  38. MazzilliR. CurtoM. De BernardiniD. OlanaS. CapiM. SalernoG. CipollaF. ZamponiV. SantiD. MazzilliF. SimmacoM. LionettoL. Psychotropic drugs levels in seminal fluid: A new therapeutic drug monitoring analysis?Front. Endocrinol. (Lausanne)20211262093610.3389/fendo.2021.620936 33776918
     [Google Scholar]
  39. HarrisC.R. MillmanK.J. van der WaltS.J. GommersR. VirtanenP. CournapeauD. WieserE. TaylorJ. BergS. SmithN.J. KernR. PicusM. HoyerS. van KerkwijkM.H. BrettM. HaldaneA. del RíoJ.F. WiebeM. PetersonP. Gérard-MarchantP. SheppardK. ReddyT. WeckesserW. AbbasiH. GohlkeC. OliphantT.E. Array programming with NumPy.Nature2020585782535736210.1038/s41586‑020‑2649‑2 32939066
     [Google Scholar]
  40. FeidtD.M. KleinK. HofmannU. RiedmaierS. KnobelochD. ThaslerW.E. WeissT.S. SchwabM. ZangerU.M. Profiling induction of cytochrome p450 enzyme activity by statins using a new liquid chromatography-tandem mass spectrometry cocktail assay in human hepatocytes.Drug Metab. Dispos.20103891589159710.1124/dmd.110.033886 20551241
     [Google Scholar]
  41. MartinottiG. VitaA. FagioliniA. MainaG. BertolinoA. Dell’OssoB. SiracusanoA. ClericiM. BellomoA. SaniG. d’AndreaG. ChiaieR.D. ConcaA. BarlatiS. Di LorenzoG. De FazioP. De FilippisS. NicolòG. RossoG. ValcheraA. NuciforaD. Di MauroS. BassettiR. MartiadisV. OlivolaM. BellettiS. AndriolaI. Di NicolaM. PettorrusoM. McIntyreR.S. di GiannantonioM. Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study).J. Affect. Disord.202231964665410.1016/j.jad.2022.09.043 36167246
     [Google Scholar]
  42. CastroM. WilkinsonS.T. Al JurdiR.K. PetrilloM.P. ZakiN. BorentainS. FuD.J. TurkozI. SunL. BrownB. CabreraP. Efficacy and safety of esketamine nasal spray in patients with treatment-resistant depression who completed a second induction period: Analysis of the ongoing SUSTAIN-3 Study.CNS Drugs202337871572310.1007/s40263‑023‑01026‑3 37558912
     [Google Scholar]
  43. ZakiN. ChenL. LaneR. DohertyT. DrevetsW.C. MorrisonR.L. SanacoraG. WilkinsonS.T. PopovaV. FuD.J. Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression: Interim results of the SUSTAIN-3 study.Neuropsychopharmacology20234881225123310.1038/s41386‑023‑01577‑5 37173512
     [Google Scholar]
  44. WilliamsonD.J. GogateJ.P. Kern SliwaJ.K. ManeraL.S. PreskornS.H. WinokurA. StarrH.L. DalyE.J. Longitudinal course of adverse events with esketamine nasal spray: A post hoc analysis of pooled data from phase 3 trials in patients with treatment-resistant depression.J. Clin. Psychiatry20228362110.4088/JCP.21m14318
     [Google Scholar]
  45. HauserJ. SarlonJ. LiwinskiT. BrühlA.B. LangU.E. Listening to music during intranasal (es)ketamine therapy in patients with treatment-resistant depression correlates with better tolerability and reduced anxiety.Front. Psychiatry202415132759810.3389/fpsyt.2024.1327598 38322143
     [Google Scholar]
  46. ZhornitskyS. TourjmanV. PelletierJ. AssafR. LiC.S.R. PotvinS. Acute effects of ketamine and esketamine on cognition in healthy subjects: A meta-analysis.Prog. Neuropsychopharmacol. Biol. Psychiatry202211811057510.1016/j.pnpbp.2022.110575 35568275
     [Google Scholar]
  47. MannaC.K. RanjanR. KumarP. AhmadS. NathS. Effect of vortioxetine versus venlafaxine on cognitive functions in adults with major depressive disorder: A randomized-controlled trial.Indian J. Psychiatry202365881582410.4103/indianjpsychiatry.indianjpsychiatry_160_23 37736222
     [Google Scholar]
  48. ZhangY. LaiS. ZhangJ. WangY. ZhaoH. HeJ. HuangD. ChenG. QiZ. ChenP. YanS. HuangX. LuX. ZhongS. JiaY. The effectiveness of vortioxetine on neurobiochemical metabolites and cognitive of major depressive disorders patients: A 8-week follow-up study.J. Affect. Disord.202435179980710.1016/j.jad.2024.01.272 38311073
     [Google Scholar]
  49. BertilssonL. Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19.Clin. Pharmacokinet.199529319220910.2165/00003088‑199529030‑00005 8521680
     [Google Scholar]
  50. HerrlinK. MasseleA.Y. RimoyG. AlmC. RaisM. EricssonO. BertilssonL. GustafssonL.L. Slow chloroguanide metabolism in Tanzanians compared with white subjects and Asian subjects confirms a decreased CYP2C19 activity in relation to genotype.Clin. Pharmacol. Ther.200068218919810.1067/mcp.2000.108583 10976550
     [Google Scholar]
  51. DandaraC. SwartM. MpetaB. WonkamA. MasimirembwaC. Cytochrome P450 pharmacogenetics in African populations: Implications for public health.Expert Opin. Drug Metab. Toxicol.201410676978510.1517/17425255.2014.894020 24588448
     [Google Scholar]
/content/journals/cn/10.2174/011570159X356952241216172603
Loading
The Potential Influence of Associated Antidepressants on the Pharmacokinetic Profile of Esketamine in Patients Affected by Treatment-resistant Depression
Curr. Neuropharmacol. 23, 1301 (2025); https://doi.org/10.2174/011570159X356952241216172603
/content/journals/cn/10.2174/011570159X356952241216172603
/content/journals/cn/10.2174/011570159X356952241216172603
Loading

Data & Media loading...

Supplements

file format download Download

  • Article Type:     Research Article
Keyword(s): antidepressant drugs; cytochrome P450 isoenzymes; depression; Esketamine; pharmacokinetics; treatment-resistant

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test