Skip to main content

Advertisement

Log in

Clinically Significant Drug Interactions with Newer Antidepressants

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone.

In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at usual therapeutic concentrations and are not expected to affect the disposition of concomitantly administered medications.

Although drug interactions with newer antidepressants are potentially, but rarely, clinically significant, the use of antidepressants with a more favourable drug interaction profile is advisable. Knowledge of the interaction potential of individual antidepressants is essential for safe prescribing and may help clinicians to predict and eventually avoid certain drug combinations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
€34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Table I
Table II
Table III

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Stahl S. Antidepressants. In: Stahl S, editor. Stahl’s essential psychopharmacology. 3rd ed. New York: Cambridge University Press, 2008: 511–666

    Google Scholar 

  2. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry 2007; 8: 67–1004

    PubMed  Google Scholar 

  3. Preskorn S, Werder S. Detrimental antidepressant drug-drug interactions: are they clinically relevant? Neuropsychopharmacology 2006; 31: 1605–12

    PubMed  CAS  Google Scholar 

  4. Spina E, Perucca E. Newer and older antidepressants: a comparative review of drug interactions. CNS Drugs 1994; 2: 479–97

    Google Scholar 

  5. Lane RM. Pharmacokinetic drug interaction potential of selective serotonin reuptake inhibitors. Int Clin Psychopharmacol 1996; 11 Suppl. 5: 31–61

    PubMed  Google Scholar 

  6. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther 2000; 85: 11–28

    PubMed  CAS  Google Scholar 

  7. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 2002; 3: 13–37

    PubMed  CAS  Google Scholar 

  8. Nemeroff CB, Preskorn S, Devane CL. Antidepressant drug-drug interactions: clinical relevance and risk management. CNS Spectr 2007; 12 Suppl. 7: 1–13

    PubMed  Google Scholar 

  9. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther 2008; 30: 1206–27

    PubMed  CAS  Google Scholar 

  10. Caraci F, Crupi R, Drago F, et al. Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract. Curr Drug Metab 2011; 12: 570–7

    PubMed  CAS  Google Scholar 

  11. Dalton SO, Sorensen HT, Johansen C. SSRIs and upper gastrointestinal bleeding: what is known and how should it influence prescribing? CNS Drugs 2006; 20: 143–51

    PubMed  Google Scholar 

  12. Van Walraven C, Mamdani MM, Wells PS, et al. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. Br Med J 2001; 323: 2354–8

    Google Scholar 

  13. Meijer WE, Heerdink ER, Nolen WA, et al. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004; 164: 2367–70

    PubMed  Google Scholar 

  14. Vidal X, Ibanez L, Vendrell L, et al. Risk of upper gastrointestinal bleeding and the degree of serotonin reuptake inhibition by antidepressants: a case-control study. Drug Saf 2008; 31: 159–68

    PubMed  CAS  Google Scholar 

  15. Dall M, Schaffalitzky de Muckadell OB, Lassen AT, et al. An association between selective serotonin reuptake inhibitor use and serious upper gastrointestinal bleeding. Clin Gastroenterol Hepatol 2009; 7: 1314–21

    PubMed  CAS  Google Scholar 

  16. De Abajo FJ, Rodriguez LAG, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. Br Med J 1999; 319: 1106–9

    Google Scholar 

  17. Dalton SO, Johansen C, Mellemkjaer L, et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding. Arch Intern Med 2003; 163: 59–64

    PubMed  CAS  Google Scholar 

  18. Tata LJ, Fortun PJ, Hubbard RB, et al. Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Aliment Pharmacol Ther 2005; 22: 175–81

    PubMed  CAS  Google Scholar 

  19. de Jong J, van der Berg PB, Tobi H, et al. Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects. Br J Clin Pharmacol 2002; 55: 591–5

    Google Scholar 

  20. Targownik LE, Bolton JM, Metge CJ, et al. Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Am J Gastroenterol 2009; 104: 1475–82

    PubMed  CAS  Google Scholar 

  21. Bak S, Tsiropoulos I, Kjaersgaard JO, et al. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke 2002; 33: 1465–73

    PubMed  CAS  Google Scholar 

  22. Douglas I, Smeeth L, Irvine D. The use of antidepressants and the risk of haemorrhagic stroke: a nested case control study. Br J Clin Pharmacol 2011; 71: 116–20

    PubMed  Google Scholar 

  23. Woolfrey S, Gammack N, Dewar M, et al. Fluoxetinewarfarin interaction [letter]. Br Med J 1993; 307: 241

    CAS  Google Scholar 

  24. Dent LA, Orrock MW. Warfarin-fluoxetine and diazepamfluoxetine interaction. Pharmacotherapy 1997; 17: 170–2

    PubMed  CAS  Google Scholar 

  25. Duncan D, Sayal K, McConnell H, et al. Antidepressant interactions with warfarin. Int Clin Psychopharmacol 1998; 13: 87–94

    PubMed  CAS  Google Scholar 

  26. Yap KB, Low ST. Interaction of fluvoxamine with warfarin in an elderly woman. Singapore Med J 1999; 40: 480–2

    PubMed  CAS  Google Scholar 

  27. Sayal KS, Duncan-McConnell DA, McConnell HW, et al. Psychotropic interactions with warfarin. Acta Psychiatr Scand 2000; 102: 250–2

    PubMed  CAS  Google Scholar 

  28. Limke KK, Shelton AR, Elliott ES. Fluvoxamine interaction with warfarin. Ann Pharmacother 2002; 36: 1890–2

    PubMed  Google Scholar 

  29. Wallerstedt SM, Gleerup H, Sundstrom A, et al. Risk of clinically relevant bleeding in warfarin-treated patients: influence of SSRI treatment. Pharmacoepidemiol Drug Saf 2009; 18: 412–6

    PubMed  CAS  Google Scholar 

  30. Hauta-Aho M, Tirkkonen T, Vahlberg T, et al. The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients. Ann Med 2009; 41: 619–28

    PubMed  CAS  Google Scholar 

  31. Schalekamp T, Klungel OH, Souverei PC, et al. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med 2008; 168: 180–5

    PubMed  Google Scholar 

  32. De Abajo FJ, Montero D, Garcia-Rodriguez LA, et al. Antidepressants and risk of upper gastrointestinal bleeding. Basic Clin Pharmacol Ther 2006; 98: 304–10

    Google Scholar 

  33. Mort JR, Aparasu RR, Baer RK. Interaction between selective serotonin reuptake inhibitors and nonsteroidal anti-inflammatory drugs: review of the literature. Pharmacotherapy 2006; 26: 1307–13

    PubMed  CAS  Google Scholar 

  34. Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2008; 27: 31–40

    PubMed  CAS  Google Scholar 

  35. Boyer EW, Shannon M. The serotonin syndrome. New Engl J Med 2005; 352: 1112–20

    PubMed  CAS  Google Scholar 

  36. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician 2008; 54: 988–92

    PubMed  Google Scholar 

  37. Tepper S, Allen C, Sanders D, et al. Coprescription of triptans with potentially interacting medications: a cohort study involving 240,268 patients. Headache 2003; 43: 44–8

    PubMed  Google Scholar 

  38. Fleishaker JC, Ryan KK, Carel BJ, et al. Evaluation of the potential pharmacokinetic interaction between almotriptan and fluoxetine in healthy volunteers. J Clin Pharmacol 2001; 41: 217–23

    PubMed  CAS  Google Scholar 

  39. Buchan P, Keywood C, Wade A, et al. Clinical pharmacokinetics of frovatriptan. Headache 2002; 42: S54–62

    PubMed  Google Scholar 

  40. FDA Alert. July 19, 2006. Combined use of 5-hydro-xytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/ norepinephrine reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm124349.htm [Accessed 2011 Oct 13]

  41. Shapiro RE, Tepper SJ. The serotonin syndrome, triptans and the potential for drug-drug interactions. Headache 2007; 47: 266–9

    PubMed  Google Scholar 

  42. Wappler F, Fiege M, Schulte am Esch J. Pathophysiological role of the serotonin system in malignant hyperthermia. Br J Anaesth 2001; 87: 793–7

    Google Scholar 

  43. Isbister GK, Whyte IM. Serotonin toxicity and malignant hyperthermia: role of 5-HT2 receptors. Br J Anaesth 2002; 88: 603–4

    PubMed  CAS  Google Scholar 

  44. Evans RW, Tepper SJ, Shapiro RE, et al. The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American Headache Society position paper. Headache 2010; 50: 1089–99

    PubMed  Google Scholar 

  45. Spina E. Drug interactions. In: Shorvon S, Perucca E, Engel J, editors. Treatment of epilepsy, 3rd ed. Oxford: Wiley-Blackwell Publishing Ltd, 2009: 361–77

    Google Scholar 

  46. Cozza KL, Armstrong SC, Oesterheld JR. Concise guide to drug interaction principles for medical practice: cytochrome P450s, UGTs, P-glycoproteins. 2nd ed. Washington (DC): American Psychiatric Association, 2003

    Google Scholar 

  47. Lin JH. Transporter-mediated drug interactions: clinical implications and in vitro assessment. Exp Opin Drug Metab Toxicol 2007; 3: 81–92

    CAS  Google Scholar 

  48. Zhang L, Huang SM, Lesko LJ. Transporter-mediated drug-drug interactions. Clin Pharmacol Ther 2011; 89: 481–4

    PubMed  CAS  Google Scholar 

  49. Weiss J, Dorman SM, Martin-Facklam M, et al. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 2003; 305: 197–204

    PubMed  CAS  Google Scholar 

  50. Ehret MJ, Levin GM, Narasimhan M, et al. Venlafaxine induces P-glycoprotein in human Caco-2 cells. Hum Psychopharmacol 2007; 22: 49–53

    PubMed  CAS  Google Scholar 

  51. Bachmeier CJ, Beaulieu-Abdelahad D, Ganey NJ, et al. Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine. Biopharm Drug Dispos 2011; 32: 233–44

    PubMed  CAS  Google Scholar 

  52. Dhillon S, Scott LJ, Plosker GL. Escitalopram: a review of its use in the management of anxiety disorders. CNS Drugs 2006; 20: 763–90

    PubMed  CAS  Google Scholar 

  53. Garnock-Jones KP, McCormack PL. Escitalopram: a review of its use in the management of major depressive disorder in adults. CNS Drugs 2010; 24: 769–96

    PubMed  CAS  Google Scholar 

  54. Rao N. The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet 2007; 46: 281–90

    PubMed  CAS  Google Scholar 

  55. Von Moltke LL, Greenblatt DJ, Giancarlo GM, et al. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos 2001; 29: 1102–9

    Google Scholar 

  56. Malling D, Poulsen MN, Sogaard B. The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects. Br J Clin Pharmacol 2005; 60: 287–90

    PubMed  CAS  Google Scholar 

  57. Rocha A, Coelho EB, Sampaio SA, et al. Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers. Br J Clin Pharmacol 2010; 70: 43–51

    PubMed  CAS  Google Scholar 

  58. Gutierrez MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interactions between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther 2003; 25: 1200–10

    PubMed  CAS  Google Scholar 

  59. Bondolfi G, Chautems C, Rochat B, et al. Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation. Psychopharmacology 1996; 128: 421–5

    PubMed  CAS  Google Scholar 

  60. Lexapro® oral tablet, oral solution; escitalopram oxalate tablet, oral solution [product information]. St. Louis (MO): Forest Pharmaceuticals, Inc., 2005 Feb

  61. Nikolic M, Noorani A, Park G. Interaction between clonidine and escitalopram. Br J Anaesth 2009; 102: 567–8

    PubMed  CAS  Google Scholar 

  62. Huska MT, Catalano G, Catalano MC. Serotonin syndrome associated with the use of escitalopram. CNS Spectr 2007; 12: 270–4

    PubMed  Google Scholar 

  63. Lessard E, Yessine MA, Hamelin BA, et al. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol 2001; 21: 175–84

    PubMed  CAS  Google Scholar 

  64. Hynninen VV, Olkkola KT, Bertilsson L, et al. Effect of terbinafine and voriconazole on the pharmacokinetics of the antidepressant venlafaxine. Clin Pharmacol Ther 2008; 83: 342–8

    PubMed  Google Scholar 

  65. Lindh JD, Annas A, Meurling L, et al. Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol 2003; 59: 401–6

    PubMed  CAS  Google Scholar 

  66. Albers LJ, Reist C, Vu RL, et al. Effect of venlafaxine on imipramine metabolism. Psychiatry Res 2000; 20: 235–43

    Google Scholar 

  67. McCue RE, Joseph M. Venlafaxine- and trazodone-induced serotonin syndrome. Am J Psychiatry 2001; 158: 2088–9

    PubMed  CAS  Google Scholar 

  68. Effexor XR(R) extended-release oral capsules (venlafaxine hydrochloride extended-release oral capsules) [US prescribing information]. Philadelphia (PA): Wyeth Pharmaceuticals, Inc., 2009

  69. Patat A, Baird-Bellaire S, Behrle J. Lack of clinically relevant effect of pharmacokinetic interaction between ketoconazole and desvenlafaxine-SR pharmacokinetics [abstract no. PII-50]. Clin Pharmacol Ther 2007 Mar; 81 Suppl. 1: S64

    Google Scholar 

  70. Nichols AI, Fatato P, Shenouda M, et al. The effects of desvenlafaxine and paroxetine on the pharmacokinetics of the cytochrome P450 2D6 substrate desipramine in healthy adults. J Clin Pharmacol 2009; 49: 219–28

    PubMed  CAS  Google Scholar 

  71. Patroneva A, Connolly SM, Fatato P, et al. An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects. Drug Metab Dispos 2008; 36: 2484–91

    PubMed  CAS  Google Scholar 

  72. PRISTIQ(TM) oral extended-release tablets (desvenlafaxine oral extended-release tablets) [US prescribing information]. Philadelphia (PA): Wyeth Pharmaceuticals Inc., 2008

  73. Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003; 73: 170–7

    PubMed  CAS  Google Scholar 

  74. Lobo ED, Bergstrom RF, Reddy S, et al. In vitro and in vivo evaluations of cytochrome P4501A2 interactions with duloxetine. Clin Pharmacokinet 2008; 47: 191–202

    PubMed  CAS  Google Scholar 

  75. CYMBALTA(R) delayed-release oral capsules (duloxetine HCl delayed-release oral capsules) [US prescribing information]. Indianapolis (IN): Eli Lilly and Company, 2008

  76. Hua TC, Pan A, Cha C, et al. Effect of duloxetine on tolterodine pharmacokinetics in healthy volunteers. Br J Clin Pharmacol 2004; 57: 652–6

    PubMed  CAS  Google Scholar 

  77. Preskorn SH, Greenblatt DJ, Flockhart D, et al. Comparison of duloxetine, escitalopram, and sertraline effects on cytochrome P450 2D6 function in healthy volunteers. J Clin Psychopharmacol 2007; 27: 28–34

    PubMed  CAS  Google Scholar 

  78. Santoro V, D’Arrigo C, Micò U, et al. Effect of adjunctive duloxetine on the plasma concentrations of clozapine, olanzapine and risperidone in patients with psychotic disorders. J Clin Psychopharmacol 2010; 30: 634–6

    PubMed  Google Scholar 

  79. Glueck CJ, Khalil Q, Winiarska M, et al. Interaction of duloxetine and warfarin causing severe elevation of international normalized ratio. JAMA 2006; 295: 1517–8

    PubMed  CAS  Google Scholar 

  80. Puozzo C, Leonard BE. Pharmacokinetics of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 1996; 11 Suppl. 4: 15–27

    PubMed  Google Scholar 

  81. Sitsen JM, Maris FA, Timmer CJ. Concomitant use of mirtazapine and cimetidine: a drug-drug interaction study in healthy male subjects. Eur J Clin Pharmacol 2000; 56: 389–94

    PubMed  CAS  Google Scholar 

  82. Anttila AK, Rasanen L, Leinonen EV. Fluvoxamine augmentation increases serum mirtazapine concentration three- to fourfold. Ann Pharmacother 2001; 35: 1221–3

    PubMed  CAS  Google Scholar 

  83. Demers JC, Malone M. Serotonin syndrome induced by fluvoxamine and mirtazapine. Ann Pharmacother 2001; 35: 1217–20

    PubMed  CAS  Google Scholar 

  84. Sitsen J, Maris F, Timmer C. Drug-drug interaction studies with mirtazapine and carbamazepine in healthy male subjects. Eur J Drug Metab Pharmacokinet 2001; 26: 109–21

    PubMed  CAS  Google Scholar 

  85. Spaans E, van den Heuvel MW, Schnabel PG, et al. Concomitant use of mirtazepine and phenytoin: a drug-drug interactions study in healthy male subjects. Eur J Clin Pharmacol 2002; 58: 423–9

    PubMed  CAS  Google Scholar 

  86. Kim SW, Shin IS, Kim JM, et al. Factors potentiating the risk of mirtazapine-associated restless legs syndrome. Hum Psychopharmacol Clin Exp 2008; 23: 615–20

    Google Scholar 

  87. Herman BD, Fleishaker JC, Brown MT. Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans. Clin Pharmacol Ther 1999; 66: 374–9

    PubMed  CAS  Google Scholar 

  88. Helland A, Spigset O. Low serum concentrations of reboxetine in 2 patients treated with CYP3A4 inducers. J Clin Psychopharmacol 2007; 27: 308–10

    PubMed  Google Scholar 

  89. Turpeinen M, Tolonen A, Uusitalo J, et al. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther 2005; 77: 553–9

    PubMed  CAS  Google Scholar 

  90. Ketter TA, Jenkins JB, Schroeder DH, et al. Carbamazepine but not valproate induces bupropion metabolism. J Clin Psychopharmacol 1995; 15: 327–33

    PubMed  CAS  Google Scholar 

  91. Loboz KK, Gross AS, Williams KM, et al. Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: effect of induction by rifampin and ethnicity. Clin Pharmacol Ther 2006; 80: 75–84

    PubMed  CAS  Google Scholar 

  92. Hogeland GW, Swindells S, McNabb JC, et al. Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects. Clin Pharmacol Ther 2007; 81: 69–75

    PubMed  CAS  Google Scholar 

  93. Kharasch ED, Mitchell D, Coles R, et al. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother 2008; 52: 1663–9

    PubMed  CAS  Google Scholar 

  94. Park J, Vousden M, Brittain C, et al. Dose-related reduction in bupropion plasma concentrations by ritonavir. J Clin Pharmacol 2010; 50: 1180–7

    PubMed  CAS  Google Scholar 

  95. Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: pharmacokinetic and formulations considerations. Clin Ther 2005; 27: 1685–95

    PubMed  CAS  Google Scholar 

  96. Weintraub D. Nortriptyline toxicity secondary to interaction with bupropion sustained-release. Depress Anxiety 2001; 13: 50–2

    PubMed  CAS  Google Scholar 

  97. Kennedy SH, McCann SM, Masellis M, et al. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry 2002; 63: 181–6

    PubMed  CAS  Google Scholar 

  98. Paslakis G, Gilles M, Deuschle M. Clinically relevant pharmacokinetic interaction between venlafaxine and bupropion: a case series. J Clin Psychopharmacol 2010; 30: 473–4

    PubMed  Google Scholar 

  99. McCollum DL, Greene JL, McGuire DK. Severe sinus bradycardia after initiation of bupropion therapy: a probable drug interaction with metoprolol. Cardiovasc Drug Ther 2004; 18: 329–30

    CAS  Google Scholar 

  100. Desmerais JE, Looper KJ. Interactions between tamoxifen and antidepressants via cytochrome P450 2D 6. J Clin Psychiatry 2009; 70: 1688–97

    Google Scholar 

  101. Valdoxan (agomelatine): summary of product characteristics [online]. Servier Laboratories Ltd., 2009. Available from URL: http://emc.medicines.org.uk/medicine/21830/SPC/Valdoxan/ [Accessed 2010 Jan 29]

  102. VIIBRYD(R) oral tablets (vilazodone HCl oral tablets) [US prescribing information]. New Haven (CT): Trovis Pharmaceuticals, LLC, 2011

  103. Noher-Jensen L, Zwisler ST, Larsen F, et al. Escitalopram is a weak inhibitor of the CYP2D6-catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain. Clin Pharmacol Ther 2009; 86: 626–33

    Google Scholar 

  104. Waade RB, Christensen H, Rudberg I, et al. Influence of comedication on serum concentrations of aripiprazole and dehydroaripiprazole. Ther Drug Monit 2009; 31: 233–8

    PubMed  CAS  Google Scholar 

  105. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs 2009; 69: 1777–98

    PubMed  CAS  Google Scholar 

  106. Hilli J, Korhonen T, Laine K. Lack of clinically significant interactions between concomitantly administered rasagiline and escitalopram. Prog Neuro-Psychopharmacol Biol Psychiatr 2009; 33: 1526–32

    CAS  Google Scholar 

  107. Covyeou JA, Jackson CW. Hyponatremia associated with escitalopram. N Engl J Med 2007; 356: 94–5

    PubMed  CAS  Google Scholar 

  108. Frazer A. Serotonergic and noradrenergic reuptake inhibitors: prediction of clinical effects from in vitro potencies. J Clin Psychiatry 2001; 62 Suppl. 12: 16–23

    PubMed  CAS  Google Scholar 

  109. Wellington K, Perry CM. Venlafaxine extended-release: a review of its use in the management of major depression. CNS Drugs 2001; 15: 643–69

    PubMed  CAS  Google Scholar 

  110. Otton SV, Ball SE, Cheung SW, et al. Venlafaxine oxidation in vitro is catalyzed by CYP2D 6. Br J Clin Pharmacol 1996; 41: 149–56

    PubMed  CAS  Google Scholar 

  111. Fogelman SM, Schmider J, Venkatakrishnan K, et al. O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology 1999; 20: 480–90

    PubMed  CAS  Google Scholar 

  112. Nichols AI, Lobello K, Guico-Pabia CJ, et al. Venlafaxine metabolism as a marker of cytochrome P450 enzyme 2D6 metabolizer status. J Clin Psychopharmacol 2009; 29: 383–6

    PubMed  CAS  Google Scholar 

  113. Ball SE, Ahern D, Scantina J, et al. Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRI’s, and effects on human hepatic CYP3A4, CYP2C9, and CYP1A 2. Br J Clin Pharmacol 1997; 42: 619–26

    Google Scholar 

  114. Von Moltke LL, Duan SX, Greenblatt DJ, et al. Venlafaxine and metabolites are weak inhibitors of human cytochrome P450-3A isoforms. Biol Psychiatry 1997; 41: 377–80

    Google Scholar 

  115. Troy SM, Rudolph R, Mayersohn M, et al. The influence of cimetidine on the disposition kinetics of the antidepressant venlafaxine. J Clin Pharmacol 1998; 38: 467–74

    PubMed  CAS  Google Scholar 

  116. Eap C, Lessard E, Bauman P, et al. Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics 2003; 13: 39–47

    PubMed  CAS  Google Scholar 

  117. Amchin J, Zarycransky W, Taylor KP, et al. Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine. J Clin Pharmacol 1999; 39: 252–9

    PubMed  CAS  Google Scholar 

  118. Troy SM, Lucki I, Peirgies AA, et al. Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and diazepam. J Clin Pharmacol 1995; 35: 410–9

    PubMed  CAS  Google Scholar 

  119. Amchin J, Zarycransky W, Taylor KP, et al. Effect of venlafaxine on the pharmacokinetics of alprazolam. Psychopharmacol Bull 1998; 34: 211–9

    PubMed  CAS  Google Scholar 

  120. Levin GM, Nelson LA, DeVane CL, et al. A pharmacokinetic drug-drug interaction study of venlafaxine and indinavir. Psychopharmacol Bull 2001; 35: 62–71

    PubMed  CAS  Google Scholar 

  121. Amchin J, Zarycransky W, Taylor KP, et al. Effect of venlafaxine on the pharmacokinetics of risperidone. J Clin Pharmacol 1999; 39: 297–309

    PubMed  CAS  Google Scholar 

  122. Repo-Tiihonen E, Eloranta A, Hallikainen T, et al. Effects of venlafaxine treatment on clozapine plasma levels in schizophrenic patients. Neuropsychology 2005; 51: 173–6

    CAS  Google Scholar 

  123. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, anti-depressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005; 97: 30–9

    PubMed  CAS  Google Scholar 

  124. Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implications for optimization of breast cancer treatment. Clin Pharmacol Ther 2006; 80: 61–74

    PubMed  CAS  Google Scholar 

  125. Mekler G, Woggon B. A case of serotonin syndrome caused by venlafaxine and lithium. Pharmacopsychiatry 1997; 30: 272–3

    PubMed  CAS  Google Scholar 

  126. Adan-Manes J, Novalbos J, López-Rodríguez R, et al. Lithium and venlafaxine interaction: a case of serotonin syndrome. J Clin Pharm Ther 2006; 31: 397–400

    PubMed  CAS  Google Scholar 

  127. Prost N, Tichadou L, Rodor F, et al. St Johns wortvenlafaxine interaction. Presse Med 2000; 29: 1285–6

    PubMed  CAS  Google Scholar 

  128. De Abajo FJ, Garcia-Rodriguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008; 65: 795–803

    PubMed  Google Scholar 

  129. Opatrny L, Delaney JA, Suissa S. Gastro-intestinal haemorrhage risks of selective serotonin receptor antagonist therapy: a new look. Br J Clin Pharmacol 2008; 66: 76–81

    PubMed  CAS  Google Scholar 

  130. Yang LP, Plosker GL. Desvenlafaxine extended-release. CNS Drugs 2008; 22: 1061–9

    PubMed  CAS  Google Scholar 

  131. Perry R, Cassagnol M. Desvenlafaxine: a new serotonin-norepinephrine reuptake inhibitor for the treatment of adults with major depressive disorder. Clin Ther 2009; 31: 1374–404

    PubMed  CAS  Google Scholar 

  132. Oganesian A, Shilling AD, Young-Sciame R, et al. Desvenlafaxine and venlafaxine exert minimal in vitro inhibition of human cytochrome P450 and P-glycoprotein activities. Psychopharmacol Bull 2009; 42: 47–63

    PubMed  Google Scholar 

  133. Frampton JE, Plosker GL. Duloxetine: a review of its use in the treatment of major depressive disorder. CNS Drugs 2007; 21: 581–609

    PubMed  CAS  Google Scholar 

  134. Carter NJ, McCormack PL. Duloxetine: a review of its use in the treatment of generalized anxiety disorder. CNS Drugs 2009; 23: 523–41

    PubMed  CAS  Google Scholar 

  135. Lantz RJ, Gillespie TA, Rash TJ, et al. Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. Drug Metab Dispos 2003; 31: 1142–50

    PubMed  CAS  Google Scholar 

  136. Knadler MP, Lobo E, Chappell J, et al. Duloxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet 2011; 50: 281–94

    PubMed  CAS  Google Scholar 

  137. Fric M, Pfuhlmann B, Laux G, et al. The influence of smoking on the serum level of duloxetine. Pharmacopsychiatry 2008; 41: 151–5

    PubMed  CAS  Google Scholar 

  138. Hendset M, Molden E, Enoksen TB, et al. The effect of coadministration of duloxetine on steady-state serum concentration of risperidone and aripiprazole: a study based on therapeutic drug monitoring data. Ther Drug Monit 2010; 32: 787–90

    PubMed  CAS  Google Scholar 

  139. Chappell J, He J, Knadler MP, et al. Effects of duloxetine on the pharmacodynamics and pharmacokinetics of warfarin at steady-state in healthy subjects. J Clin Pharmacol 2009; 49: 1456–66

    PubMed  CAS  Google Scholar 

  140. Spencer CM, Wilde MI. Milnacipran: a review of its use in depression. Drugs 1998; 56: 405–27

    PubMed  CAS  Google Scholar 

  141. Pae CU, Marks DM, Shah M, et al. Milnacipran: beyond a role of antidepressant. Clin Neuropharmacol 2009; 32: 355–63

    PubMed  CAS  Google Scholar 

  142. Puozzo C, Panconi E, Deprez D. Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol 2002; 17 Suppl. 1: S25–35

    PubMed  Google Scholar 

  143. Puozzo C, Lens S, Reh C, et al. Lack of interaction of milnacipran with the cytochrome p450 isoenzymes frequently involved in the metabolism of antidepressants. Clin Pharmacokinet 2005; 44: 977–88

    PubMed  CAS  Google Scholar 

  144. Puozzo C, Hermann P, Chassard D. Lack of pharmacokinetic interaction when switching from fluoxetine to milnacipran. Int Clin Psychopharmacol 2006; 21: 153–8

    PubMed  Google Scholar 

  145. Paris BL, Ogilvie BW, Scheinkoenig JA, et al. In vitro inhibition and induction of human liver cytochrome P450 enzymes by milnacipran. Drug Metab Dispos 2009; 37: 2045–54

    PubMed  CAS  Google Scholar 

  146. SAVELLA(R) oral tablets (milnacipran HCL oral tablets) [US prescribing information]. St Louis (MO): Forest Pharmaceuticals, 2009

  147. Croom KF, Perry CM, Plosker GL. Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS Drugs 2009; 23: 427–52

    PubMed  CAS  Google Scholar 

  148. Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000; 38: 461–74

    PubMed  CAS  Google Scholar 

  149. Stormer E, von Moltke LL, Shader RI, et al. Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6, and 3A 4. Drug Metab Dispos 2000; 28: 1168–75

    PubMed  CAS  Google Scholar 

  150. Sennef C, Timmer CJ, Sitsen JMA. Mirtazapine in combination with amitriptyline: a drug-drug interaction studies in healthy subjects. Hum Psychopharmacol 2003; 18: 91–101

    PubMed  CAS  Google Scholar 

  151. Ruwe FJL, Smulders RA, Kleijn HJ, et al. Mirtazapine and paroxetine: a drug-drug interaction study in healthy subjects. Hum Psychopharmacol 2001; 16: 449–59

    PubMed  CAS  Google Scholar 

  152. Loonen AJ, Doorschot CH, Oostelbos MC, et al. Lack of drug interaction between mirtazapine and risperidone in psychiatric patients. Eur Neuropsychopharmacol 1999; 10: 51–7

    PubMed  CAS  Google Scholar 

  153. Zoccali R, Muscatello MR, La Torre D, et al. Lack of pharmacokinetic interaction between mirtazapine and the newer antipsychotics clozapine, risperidone and olanzapine in patients with chronic schizophrenia. Pharmacol Res 2003; 48: 411–4

    PubMed  CAS  Google Scholar 

  154. Lind AB, Reis M, Bengtsson F, et al. Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour. Clin Pharmacokinet 2009; 48: 63–70

    PubMed  CAS  Google Scholar 

  155. Dimellis D. Serotonin syndrome produced by a combination of venlafaxine and mirtazapine. World J Biol Psychiatry 2002; 3: 167

    PubMed  Google Scholar 

  156. Hernandez JL, Ramos FJ, Infante J, et al. Severe serotonin syndrome induced by mirtazapine monotherapy. Ann Pharmacother 2002; 36: 641–3

    PubMed  Google Scholar 

  157. Ubogu EE, Katirji B. Mirtazapine-induced serotonin syndrome. Clin Neuropharmacol 2003; 26: 54–7

    PubMed  Google Scholar 

  158. Houlihan DJ. Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine. Ann Pharmacother 2004; 38: 411–3

    PubMed  Google Scholar 

  159. Isbister GK, Whyte IM. Adverse reactions to mirtazapine are unlikely to be serotonin toxicity. Clin Neropharmacol 2003; 26: 287–8

    Google Scholar 

  160. Gillman PK. A review of serotonin toxicity: implications for the mechanisms of antidepressant drug action. Biol Psychiatry 2006; 59: 1046–51

    PubMed  CAS  Google Scholar 

  161. Shioda K, Nisijima K, Yoshino T, et al. Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome. Neurosci Lett 2010; 482: 216–9

    PubMed  CAS  Google Scholar 

  162. Rottach KG, Schaner BM, Kirch MH, et al. Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res 2009; 43: 70–5

    Google Scholar 

  163. Hajos M, Fleishaker JC, Filipiak-Reisner JK, et al. The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile. CNS Drug Rev 2004; 10: 23–44

    PubMed  CAS  Google Scholar 

  164. Fleishaker JC. Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression. Clin Pharmacokinet 2000; 39: 413–27

    PubMed  CAS  Google Scholar 

  165. Wienkers LC, Allievi C, Hauer MJ, et al. Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metab Dispos 1999; 27: 1334–40

    PubMed  CAS  Google Scholar 

  166. Fleishaker JC, Herman BD, Pearson LK. Evaluation of the potential pharmacokinetic/pharmacodynamic interaction between fluoxetine and reboxetine in healthy volunteers. Clin Drug Invest 1999; 18: 141–50

    CAS  Google Scholar 

  167. Avenoso A, Facciolà G, Scordo MG, et al. No effect of the new antidepressant reboxetine on CYP2D6 activity in healthy volunteers. Ther Drug Monit 1999; 21: 577–9

    PubMed  CAS  Google Scholar 

  168. Spina E, Avenoso A, Scordo MG, et al. No effect of reboxetine on plasma concentrations of clozapine, risperidone and their active metabolites. Ther Drug Monit 2001; 23: 675–8

    PubMed  CAS  Google Scholar 

  169. Kerr JS, Powell J, Hindmarch I. The effects of reboxetine and amitriptyline, with and without alcohol, on cognitive function and psychomotor performance. Br J Clin Pharmacol 1996; 42: 239–41

    PubMed  CAS  Google Scholar 

  170. Cooper-Kazaz R, Cohen A, Lerer B. Noradrenergic adverse effects due to combined treatment with reboxetine and triiodothyronine. J Clin Psychopharmacol 2010; 30: 211–2

    PubMed  Google Scholar 

  171. Dhillon S, Yag LPH, Curra MP. Bupropion: a review of its use in the management of major depressive disorder. Drugs 2008; 68: 653–89

    PubMed  CAS  Google Scholar 

  172. Hesse LM, Venkatakrishnan K, Court MH, et al. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 2000; 28: 1176–83

    PubMed  CAS  Google Scholar 

  173. Kotlyar M, Brauer LH, Tracy TS, et al. Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol 2005; 25: 226–9

    PubMed  CAS  Google Scholar 

  174. Richter T, Mürdter TE, Heinkele G, et al. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther 2004; 308: 189–97

    PubMed  CAS  Google Scholar 

  175. Turpeinen M, Nieminen R, Juntunen T, et al. Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro. Drug Metab Dispos 2004; 32: 626–31

    PubMed  CAS  Google Scholar 

  176. Guo Z, Raeissi S, White RB, et al. Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos 1997; 25: 390–3

    PubMed  Google Scholar 

  177. Reese MJ, Wurm RM, Muir KT, et al. An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction. Drug Metab Dispos 2008; 36: 1198–201

    PubMed  CAS  Google Scholar 

  178. Wellbutrin XL(TM) bupropion hydrochloride extended-release tablets [US prescribing information]. Research Triangle Park (NC): GlaxoSmithKline, 2003

  179. Enns MW. Seizure during combination of trimipramine and bupropion. J Clin Psychiatry 2001; 62: 476–7

    PubMed  CAS  Google Scholar 

  180. Shin YW, Erm TM, Choi EJ, et al. A case of prolonged seizure activity after combined use of bupropion and clomipramine. Clin Neuropharmacol 2004; 27: 192–4

    PubMed  Google Scholar 

  181. De Bodinat C, Guardiola-Lemaitre B, Mocaer E, et al. Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov 2010; 9: 628–42

    PubMed  Google Scholar 

  182. McAllister-Williams RH, Baldwin DS, Haddad PM, et al. The use of antidepressants in clinical practice: focus on agomelatine. Hum Psychopharmacol 2010; 25: 95–102

    PubMed  CAS  Google Scholar 

  183. Green B. Focus on agomelatine. Curr Med Res Opin 2011; 27: 745–9

    PubMed  CAS  Google Scholar 

  184. Khan A. Vilazodone, a novel dual-acting serotonergic antidepressant for managing major depression. Expert Opin Investig Drug 2009; 18: 1753–64

    CAS  Google Scholar 

  185. Dawson LA, Watson JM. Vilazodone: a 5-HT1A receptor agonist/serotonin transporter inhibitor for the treatment of affective disorders. CNS Neurosci Ther 2009; 15: 107–17

    PubMed  CAS  Google Scholar 

  186. Frampton JE. Vilazodone in major depression. CNS Drugs 2011; 25: 615–27

    PubMed  CAS  Google Scholar 

  187. Trifirò G, Barbui C, Spina E, et al. Antidepressant drugs: prevalence, incidence and indications of use in general practice of Southern Italy during the years 2003—2004. Pharmacoepidemiol Drug Saf 2007; 16: 552–9

    PubMed  Google Scholar 

  188. Mark TL, Joish VN, Hay JW, et al. Antidepressant use in geriatric populations: the burden of side effects and interactions and their impact on adherence and costs. Am J Geriatr Psychiatry 2011; 19: 211–21

    PubMed  Google Scholar 

  189. Schellander R, Donnerer J. Antidepressants: clinically relevant drug interactions to be considered. Pharmacology 2010; 86: 203–15

    PubMed  CAS  Google Scholar 

  190. DeVane CL. Antidepressant-drug interactions are potentially but rarely clinically significant. Neuropsychopharmacology 2006; 31: 1594–604

    PubMed  CAS  Google Scholar 

  191. Tamblyn R, Huang A, Perreault R, et al. The medical office of the 21st century (MOXXI): effectiveness of computerized decision-making support in reducing inappropriate prescribing in primary care. CMAJ 2003; 169: 549–56

    PubMed  Google Scholar 

  192. Dallenbach MF, Bovier PA, Desmeules J. Detecting drug interactions using personal digital assistants in an outpatient clinic. QJM 2007; 100: 691–7

    PubMed  Google Scholar 

Download references

Acknowledgements

The preparation of this review was not supported by any external funding. Prof. Spina has previously received honoraria for speaking and consultation from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Janssen, Lundbeck and Pfizer. The other authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Edoardo Spina.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spina, E., Trifirò, G. & Caraci, F. Clinically Significant Drug Interactions with Newer Antidepressants. CNS Drugs 26, 39–67 (2012). https://doi.org/10.2165/11594710-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11594710-000000000-00000

Keywords