CNS Drugs

, Volume 18, Issue 13, pp 911–932

A Comparison of the Direct Costs and Cost Effectiveness of Serotonin Reuptake Inhibitors and Associated Adverse Drug Reactions

  • Patrick W. Sullivan
  • Robert Valuck
  • Joseph Saseen
  • Holly M. MacFall
Original Research Article


Background: The economic burden of depression is known to be high and was estimated to be $US83.1 billion in 2000. Serotonin reuptake inhibitors (SRIs), including both selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), have a superior adverse effect and safety profile relative to traditional agents (e.g. TCAs), and as a result have demonstrated superior cost effectiveness. Although efficacy across the SRIs is similar, the incidence of adverse drug reactions (ADRs) within SRIs remains significant and varies by agent. Patients who experience ADRs from SRIs may seek medical care, require additional treatment, and even discontinue treatment altogether, leading to increased utilisation and cost of therapy.

Objective: This study estimates the direct cost and cost effectiveness, taking into account the impact of treatment-related ADRs, of eight currently marketed SRIs (citalopram, escitalopram, generic fluoxetine, paroxetine, paroxetine controlled release [CR], sertraline, venlafaxine and venlafaxine extended release [XR]) used as initial treatment for depression.

Methods: A decision analytic model with a 6-month treatment goal was used to estimate the direct cost and cost effectiveness of treatment from the managed care/ payer perspective. Estimates of SRI-related ADRs, associated treatments and costs were derived from the US FDA-approved prescribing information and published literature. Efficacy was assumed to be similar across all SRIs. Effectiveness was measured using quality-adjusted life years (QALY) based on EuroQol EQ-5D scores derived from the 2000 Medical Expenditure Panel Survey (MEPS). Censored least absolute deviations (CLAD) regression analysis was used to derive age-adjusted estimates of utility for all health states. Univariate and Bayesian second-order multivariate probabilistic sensitivity analyses were conducted to examine the impact of uncertainty in the parameter estimates.

Results: The expected direct cost and cost effectiveness of treatment from least to most expensive were: escitalopram ($US3891; 0.341), citalopram ($US3938; 0.340), generic fluoxetine ($US4034; 0.335), venlafaxine XR ($US4226; 0.336), sertraline ($US4250; 0.335), generic paroxetine ($US4385; 0.332), paroxetine CR ($US4440; 0.332) and venlafaxine ($US4613; 0.326). Monte Carlo simulation results suggested that escitalopram was the most likely (77%) to be cost effective for a willingness to pay ≤$US50 000 per QALY, followed by citalopram (22%), generic fluoxetine (0.3%) and all other SRIs (0%). Sensitivity analyses indicated that the results of the study were robust to the assumptions underpinning the model.

Conclusions: SRI-related ADRs have a significant impact on the direct cost and cost effectiveness of treatment. Escitalopram, with the lowest ADR rate of the SRIs, had the lowest expected treatment cost and greatest effectiveness when compared with citalopram, generic fluoxetine, generic paroxetine, paroxetine CR, sertraline, venlafaxine and venlafaxine XR.


  1. 1.
    Greenberg PE, Stiglin LE, Finkelstein SN, et al. The economic burden of depression in 1990. J Clin Psychiatry 1993 Nov; 54(11): 405–18PubMedGoogle Scholar
  2. 2.
    Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry 2003 Dec, 64 (12)Google Scholar
  3. 3.
    Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 2000; 58(1): 19–36PubMedCrossRefGoogle Scholar
  4. 4.
    Song F, Freemantle N, Sheldon TA, et al. Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. BMJ 1993 Mar 13; 306(6879): 683–7PubMedCrossRefGoogle Scholar
  5. 5.
    Geddes JR, Freemantle N, Mason J, et al. SSRIs versus other antidepressants for depressive disorder. Cochrane Database Syst Rev 2000; (2): CD001851Google Scholar
  6. 6.
    Peretti S, Judge R, Hindmarch I. Safety and tolerability considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl 2000; 403: 17–25Google Scholar
  7. 7.
    American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. Am J Psychiatry 2000; 157(4 Suppl.): 1–45Google Scholar
  8. 8.
    Fry RN, Avey SG, Sullivan SD. The Academy of Managed Care Pharmacy Format for Formulary Submissions: an evolving standard. A Foundation for Managed Care Pharmacy Task Force report. Value Health 2003 Sep; 6(5): 505–21Google Scholar
  9. 9.
    Tai-Seale M, Croghan TW, Obenchain R. Determinants of antidepressant treatment compliance: implications for policy. Med Care Res Rev 2000; 57(4): 491–512PubMedCrossRefGoogle Scholar
  10. 10.
    Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27(1): 85–102PubMedCrossRefGoogle Scholar
  11. 11.
    Anderson IM, Tomenson BM. Treatment discontinuation with selective serotonin reuptake inhibitors compared with tricyclic antidepressants: a meta-analysis. BMJ 1995; 310(6992): 1433–8PubMedCrossRefGoogle Scholar
  12. 12.
    Montgomery SA, Henry J, McDonald G, et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994; 9(1): 47–53PubMedCrossRefGoogle Scholar
  13. 13.
    Barbui C, Hotopf M, Freemantle N, et al. Selective serotonin reuptake inhibitors versus tricyclic and heterocyclic antidepressants: comparison of drug adherence. Cochrane Database Syst Rev 2000; (4): CD002791Google Scholar
  14. 14.
    Panzarino PJ, Nash DB. Cost-effective treatment of depression with selective serotonin reuptake inhibitors. Am J Manag Care 2001; 7(2): 173–84PubMedGoogle Scholar
  15. 15.
    Wilde MI, Whittington R. Paroxetine: a pharmacoeconomic evaluation of its use in depression. Pharmacoeconomics 1995; 8(1): 62–81PubMedCrossRefGoogle Scholar
  16. 16.
    Wilde MI, Benfield P. Fluoxetine: a pharmacoeconomic evaluation of its use in depression. Pharmacoeconomics 1998; 13(5): 543–61PubMedCrossRefGoogle Scholar
  17. 17.
    Davis R, Wilde MI. Sertraline: a pharmacoeconomic evaluation of its use in depression. Pharmacoeconomics 1996; 11(4): 377–80Google Scholar
  18. 18.
    Burke W. Selective versus multi-transmitter antidepressants: are two mechanisms better than one? J Clin Psychiatry 2004; 65Suppl. 4: 37–45PubMedGoogle Scholar
  19. 19.
    Olver JS, Burrows GD, Norman TR. Third-generation antidepressants: do they offer advantages over the SSRIs? CNS Drugs 2001; 15(12): 941–54PubMedCrossRefGoogle Scholar
  20. 20.
    Croom KF, Plosker GL. Escitalopram: a pharmacoeconomics review of its use in depression. Pharmacoeconomics 2003; 21(16): 1185–209PubMedCrossRefGoogle Scholar
  21. 21.
    Valuck R. Selective serotonin reuptake inhibitors: a class review. P&T 2004; 29(4): 234–43Google Scholar
  22. 22.
    Rascati K, Godley P, Pham H. Evaluation of resources used to treat adverse events of selective serotonin reuptake inhibitor use. J Manag Care Pharm 2001; 7(5): 402–6Google Scholar
  23. 23.
    Kroenke K, West SL, Swindle R, et al. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial. JAMA 2001; 286(23): 2947–55PubMedCrossRefGoogle Scholar
  24. 24.
    Eli Lilly and Company. Prozac [package insert]. Indianapolis (IN), 2003 NovGoogle Scholar
  25. 25.
    GlaxoSmithKline. Paxil [package insert]. Research Triangle Park (NC), 2004 AprGoogle Scholar
  26. 26.
    Glaxo Smith Kline. Paxil CR [package insert]. Research Triangle Park (NC), 2004 MarGoogle Scholar
  27. 27.
    Pfizer. Zoloft [package insert]. New York, 2003Google Scholar
  28. 28.
    Wyeth Pharmaceuticals. Effexor [package insert]. Philadelphia (PA), 2001 MarGoogle Scholar
  29. 29.
    Wyeth Pharmaceuticals. Effexor XR [package insert]. Philadelphia (PA), 2003 DecGoogle Scholar
  30. 30.
    Forest Pharmaceuticals. Citalopram [package insert]. St Louis (MO), 2004 JanGoogle Scholar
  31. 31.
    Forest Pharmaceuticals. Escitalopram [package insert]. St Louis (MO), 2004 DecGoogle Scholar
  32. 32.
    World Health Organization. International drug monitoring: the role of the hospital. Technical report series: No. 425. Geneva: World Health Organization, 1996Google Scholar
  33. 33.
    Bates DW, Boyle DL, Vander Vliet MB, et al. Relationship between medication errors and adverse drug events. J Gen Intern Med 1995; 10(4): 199–205PubMedCrossRefGoogle Scholar
  34. 34.
    Rodriguez-Monguio R, Otero M, Rovira J. Assessing the economic impact of adverse drug effects. Pharmacoeconomics 2003; 21(9): 623–50PubMedCrossRefGoogle Scholar
  35. 35.
    National Committee for Quality Assurance. The health plan employer data and information set (HEDIS®) 2003. Washington, DC: National Committee for Quality Assurance, 2003Google Scholar
  36. 36.
    Depression Guideline Panel. Clinical practice guideline, number 5. Depression in primary care: volume 2: treatment of major depression. AHCPR Publication No. 93-0551. Rockville (MD): US Department of Health and Human Services, Agency for Healthcare Policy and Research, 1993Google Scholar
  37. 37.
    Lenox-Smith A, Conway P, Knight C. Cost effectiveness of representatives of three classes of antidepressants used in major depression in the UK. Pharmacoeconomics 2004; 22(5): 311–9PubMedCrossRefGoogle Scholar
  38. 38.
    Boyer P, Danion JM, Bisserbe JC, et al. Clinical and economic comparison of sertraline and fluoxetine in the treatment of depression: a 6-month double-blind study in a primary-care setting in France. Pharmacoeconomics 1998; 13 (1 Pt 2): 157–69PubMedCrossRefGoogle Scholar
  39. 39.
    Claxton AJ, Chawla AJ, Kennedy S. Absenteeism among employees treated for depression. J Occup Environ Med 1999; 41(7): 605–11PubMedCrossRefGoogle Scholar
  40. 40.
    Sclar DA, Skaer TL, Robison LM, et al. Economic appraisal of citalopram in the management of single-episode depression. J Clin Psychopharmacol 1999; 19(5 Suppl. 1): 47S–54SPubMedCrossRefGoogle Scholar
  41. 41.
    Simon GE, Fishman P. Cost implications of initial antidepressant selection in primary care. Pharmacoeconomics 1998; 13 (1 Pt 1): 61–70PubMedCrossRefGoogle Scholar
  42. 42.
    François C, Toumi M, Aakhus AM, et al. A pharmacoeconomic evaluation of escitalopram, a new selective serotonin reuptake inhibitor. Eur J Health Econ 2003; 4(1): 9–12Google Scholar
  43. 43.
    Valuck R. Treatment of depression with citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine in managed care: part 1. Drug selection, dosing, and utilization. Drug Benefit Trends 2002; 14(7): 23–30Google Scholar
  44. 44.
    Gold MR, Siegel JE, Russell LB, et al., editors. Cost-effectiveness in health and medicine. New York: Oxford University Press, 1996Google Scholar
  45. 45.
    Physician’s desk reference. 57th ed. Montvale (NJ): Medical Economics, 2003Google Scholar
  46. 46.
    Fredman SJ, Fava M, Kienke AS, et al. Partial response, nonresponse, and relapse with selective serotonin reuptake inhibitors in major depression: a survey of current “next-step” practices. J Clin Psychiatry 2000; 61(6): 403–8PubMedCrossRefGoogle Scholar
  47. 47.
    Croghan TW, Lair TJ, Engelhart L, et al. Effect of antidepressant therapy on health care utilization and costs in primary care. Psychiatr Serv 1997; 48(11): 1420–6PubMedGoogle Scholar
  48. 48.
    Bull SA, Hunkeler EM, Lee JY, et al. Discontinuing or switching selective serotonin-reuptake inhibitors. Ann Pharmacother 2002; 36(4): 578–84PubMedCrossRefGoogle Scholar
  49. 49.
    Hensley PL, Nurnberg HG. Formulary restriction of selective serotonin reuptake inhibitors for depression: potential pitfalls. Pharmacoeconomics 2001; 19(10): 973–82PubMedCrossRefGoogle Scholar
  50. 50.
    Brown WA, Harrison W. Are patients who are intolerant to one serotonin selective reuptake inhibitor intolerant to another? J Clin Psychiatry 1995; 56(1): 30–4PubMedGoogle Scholar
  51. 51.
    Curkendall SM, Goehring EL, She D. Comparison of treatment cost for depression between fluoxetine, paroxetine, sertraline and venlafaxine using managed care claims data. Value Health 2002 May–Jun; 5(3): 119CrossRefGoogle Scholar
  52. 52.
    Crown WH, Finkelstein SN, Berndt ER, et al. The impact of treatment-resistant depression on healthcare utilization and costs. J Clin Psychiatry 2002; 63: 963–71PubMedCrossRefGoogle Scholar
  53. 53.
    Masand PS. Tolerability and adherence issues in antidepressant therapy. Clin Ther Aug 2003; 25(8): 2289–304CrossRefGoogle Scholar
  54. 54. Pharmacy [online]. Available from URL: [Accessed 2004 May 14]
  55. 55.
    Department of Health and Human Services, Health Care Financing Administration. Medicare program: revisions to payment policies under the physician fee schedule for calendar year 2003. Fed Regist 2003; 68(40): 9567Google Scholar
  56. 56.
    Baker CB, Woods SW. Cost of treatment failure for major depression: direct costs of continued treatment. Adm Policy Ment Health 2001; 28(4): 263–77PubMedCrossRefGoogle Scholar
  57. 57.
    McCombs JS, Nichol MB, Stimmel GL, et al. The cost of antidepressant drug therapy failure: a study of antidepressant use patterns in a Medicaid population. J Clin Psychiatry 1990; 51 Suppl.: 60–69; discussion 70–61PubMedGoogle Scholar
  58. 58.
    Agency for Healthcare Research and Quality, Center for Cost and Financing Studies. MEPS HC-052. 2000 medical conditions, June 2003 [online]. Available from URL: [Accessed 2003 Nov 10]Google Scholar
  59. 59.
    Agency for Healthcare Research and Quality. Computing standard errors for MEPS estimates [online]. Available from URL: [Accessed 2003 Sep]Google Scholar
  60. 60.
    Brooks RG, Jendteg S, Lindgren B, et al. EuroQol: health-related quality of life measurement. Results of the Swedish questionnaire exercise. Health Policy 1991; 18(1): 37–48Google Scholar
  61. 61.
    Dolan P. Modeling valuations for EuroQol health states. Med Care 1997; 35(11): 1095–108PubMedCrossRefGoogle Scholar
  62. 62.
    McDowell I, Newell C. Measuring health: a guide to rating scales and questionnaires. 2nd ed. New York: Oxford University Press, 1996Google Scholar
  63. 63.
    EuroQol [online]. Available from URL: [Accessed 2003 Nov 11]Google Scholar
  64. 64.
    Health Care Financing Administration. The International classification of diseases, 9th rev., clinical modification: ICD-9-CM, 2nd ed. Washington (DC): US Government Printing Office, 1980Google Scholar
  65. 65.
    Elixhauser A, Andrews RM, Fox S. Clinical classifications for health policy research: discharge statistics by principal diagnosis and procedure. AHCPR Publication No. 93-0043. Rockville (MD): Agency for Health Policy and Research, 1993Google Scholar
  66. 66.
    Grootendorst P. Censoring in statistical models of health status: what happens when one can do better than ‘1’. Qual Life Res 2000; 9(8): 911–4PubMedCrossRefGoogle Scholar
  67. 67.
    Green WH. Econometric Analysis. 4th ed. Upper Saddle River (NJ): Prentice Hall, 2000Google Scholar
  68. 68.
    Maddala GS. Limited-dependent and qualitative variables in econometrics. Cambridge: Cambridge University Press, 1999Google Scholar
  69. 69.
    Powell J. Least absolute deviations estimation for the censored regression model. J Econometrics 1984; 25: 303–25CrossRefGoogle Scholar
  70. 70.
    Austin PC. A comparison of methods for analyzing health-related quality-of-life measures. Value Health 2002 Jul–Aug; 5(4): 329–37PubMedCrossRefGoogle Scholar
  71. 71.
    Fryback DG, Stout NK, Rosenberg MA. An elementary introduction to Bayesian computing using WinBUGS. Int J Technol Assess Health Care 2001; 17(1): 98–113PubMedCrossRefGoogle Scholar
  72. 72.
    Briggs AH. Handling uncertainty in cost-effectiveness models. Pharmacoeconomics 2000; 17(5): 479–500PubMedCrossRefGoogle Scholar
  73. 73.
    Briggs AH, Goeree R, Blackhouse G, et al. Probabilistic analysis of cost-effectiveness models: choosing between treatment strategies for gastroesophageal reflux disease. Med Decis Making 2002 Jul–Aug; 22(4): 290–308PubMedGoogle Scholar
  74. 74.
    François C, Sintonen H, Toumi M. Introduction of escitalopram, a new SSRI in Finland: comparison of cost-effectiveness between the other SSRIs and SNRI for the treatment of depression and estimation of the budgetary impact. J Med Econ 2002; 5: 91–107CrossRefGoogle Scholar
  75. 75.
    François C, Henriksson F, Toumi M, et al. A Swedish pharmacoeconomic evaluation of escitalopram, a new SSRI: comparison of cost-effectiveness between escitalopram, citalopram, fluoxetine and venlafaxine [abstract]. Value Health 2002; 5(3): 230CrossRefGoogle Scholar
  76. 76.
    Wade A, McCrone P, Anderson I, et al. Cost-effectiveness of escitalopram, a new SSRI, in the treatment of major depressive disorder in the UK [abstract plus poster]. 1st Asia Pacific Conference for Pharmacoeconomic and Outcomes Research 2003 Sep 1–3, KobeGoogle Scholar
  77. 77.
    Demyttenaere K, Rachidi S, Van Dijck P, et al. Cost-effectiveness of escitalopram compared to brand and generic SSRI (citalopram and fluoxetine), and venlafaxine in the treatment of depression in Belgium. Paris: Lundbeck A/S, 2003 (Data on file)Google Scholar
  78. 78.
    Montgomery SA, Fernandez JL, François C. Treatment of depression: escitalopram has similar efficacy but lower costs compared to venlafaxine XR [abstract no. PMH42]. Value Health 2003; 6(3): 358CrossRefGoogle Scholar
  79. 79.
    Naglie G, Krahn MD, Naimark D, et al. Primer on medical decision analysis. Part 3: estimating probabilities and utilities. Med Decis Making. 1997 Apr–Jun; 17(2): 136–41Google Scholar
  80. 80.
    Prieto L, Sacristan JA. Problems and solutions in calculating quality-adjusted life years (QALYs). Health Qual Life Outcomes. 2003 Dec 19; 1(1): 80PubMedCrossRefGoogle Scholar
  81. 81.
    Gorman JM, Korotzer A, Su G. Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectr 2002; 7 Suppl. 4: 40–4Google Scholar
  82. 82.
    Weinstein MC, Toy EL, Sandberg EA, et al. Modeling for health care and other policy decisions: uses, roles, and validity. Value Health 2001 Sep–Oct; 4(5): 348–61PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Informotion BV 2004

Authors and Affiliations

  • Patrick W. Sullivan
    • 1
  • Robert Valuck
    • 1
  • Joseph Saseen
    • 2
  • Holly M. MacFall
    • 3
  1. 1.Pharmaceutical Outcomes Research Program, Department of Clinical Pharmacy, School of PharmacyUniversity of Colorado Health Sciences CenterDenverUSA
  2. 2.Department of Clinical Pharmacy, School of PharmacyUniversity of Colorado Health Sciences CenterDenverUSA
  3. 3.Department of Pharmacy PracticeMUSC Drug Information CenterCharlestonUSA
  4. 4.School of PharmacyUniversity of Colorado Health Sciences CenterDenverUSA

Personalised recommendations