Annals of Clinical Psychiatry

, Volume 14, Issue 3, pp 175–182 | Cite as

Long-Term Side Effects of Newer-Generation Antidepressants: SSRIS, Venlafaxine, Nefazodone, Bupropion, and Mirtazapine

  • Prakash S. Masand
  • Sanjay Gupta


Anecdotal reports have suggested that the long-term use of selective serotonin reuptake inhibitors (SSRIs) may be associated with significant weight gain, sexual dysfunction, drug interactions, and discontinuation symptoms. Are these effects inevitable or can they be managed effectively with the appropriate interventions? In reviewing published, controlled clinical trials, it has been noted that many depressed patients experience weight gain during remission with or without treatment. Most antidepressants appear to produce a 3- to 4-kg weight gain after 6–12 months of therapy, which may be managed with nutritional counseling and exercise. The exception is mirtazapine, which appears to be associated with significant weight gain early in therapy. Antidepressant-induced sexual dysfunction is also common but may be managed with the addition of an antidote or substitution. Drug interactions are most common with fluvoxamine, nefazodone, and fluoxetine because these agents are more likely to affect the metabolism of commonly prescribed medications. It may be possible to prevent discontinuation symptoms with a cross taper to another antidepressant or by slowly tapering the antidepressant.

SSRIs adverse events newer-generation antidepressants 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Menting JE, Honig A, Verhey FR, Hartmans M, Rozendaal N, de Vet HC, van Praag HM: Selective serotonin reuptake inhibitors (SSRIs) in the treatment of elderly depressed pa-tients: A qualitative analysis of the literature on their efficacy and side-effects. Int Clin Psychopharmacol 1996; 11:165-175Google Scholar
  2. 2.
    Steffens DC, Krishnan KR, Helms MJ: Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: Ameta-analysis. De-press Anxiety 1997; 6:10-18Google Scholar
  3. 3.
    Masand PS, Gupta S: Selective serotonin-reuptake inhibitors: An update. Harvard Rev Psychiatry 1999; 7:69-84Google Scholar
  4. 4.
    Hyttel J: Pharmacological characterization of selective sero-tonin reuptake inhibitors. Int Clin Psychopharmacol 1994; 9(Suppl. 1):19-26Google Scholar
  5. 5.
    Leonard BE: Pharmacological differences of serotonin reup-take inhibitors and possible clinical relevance. Drugs 1992; 43(Suppl. 2):3-9Google Scholar
  6. 6.
    Hall H, Sällemark M, Wedel I: Acute effects of atypical antide-pressants on various receptors in the rat brain. Acta Pharmacol Toxicol (Copenh) 1984; 54:379-384Google Scholar
  7. 7.
    Béïque JC, de Montigny C, Blier P, Debonnel G: Blockade of 5-hydroxytryptamine and noradrenaline uptake by venlafaxine: A comparative study with paroxetine and desipramine. Br J Pharmacol 1998; 125:526-532Google Scholar
  8. 8.
    Davis R, Whittington R, Bryson HM. Nefazodone: A review of its pharmacology and clinical efficacy in the management of major depression. Drugs 1997; 53:608-636Google Scholar
  9. 9.
    Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC, Golden RN, Martin P, Potter WZ, Richelson E. Bupropion: A review of its mechanism of antidepressant ac-tivity. J Clin Psychiatry 1995; 56:395-401Google Scholar
  10. 10.
    Stimmel GL, Dopheide JA, Stahl SM: Mirtazapine: Anantide-pressant with noradrenergic and specific serotonergic effects. Pharmacotherapy 1997; 17:10-21Google Scholar
  11. 11.
    Stahl SM: Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry 1998; 59(Suppl. 4):5-14Google Scholar
  12. 12.
    Masand PS: Weight gain associated with psychotropic drugs. Exp Opin Pharmacother 2000; 1:377-389Google Scholar
  13. 13.
    Kawachi I: Physical and psychological consequences of weight gain. J Clin Psychiatry 1999; 60(Suppl. 21):5-9Google Scholar
  14. 14.
    Benazzi F: Weight gain in depression remitted with antidepres-sants: Pharmacological or recovery effect? Psychother Psycho-som 1998; 67:271-274Google Scholar
  15. 15.
    Michelson D, Amsterdam JD, Quitkin FM, Reimherr FW, Rosenbaum JF, Zajecka J, Sundell KL, Kim Y, Beasley CM: Jr. Changes in weight during a 1-year trial of fluoxetine. Am J Psychiatry 1999; 156:1170-1176Google Scholar
  16. 16.
    Goodnick PJ, Kremer C, Wingard P: Weight change during mirtazapine therapy. Prim Psychiatry 1999; 6:103-108Google Scholar
  17. 17.
    Rosen RC, Lane RM, Menza M: Effects of SSRIs on sex-ual function: A critical review. J Clin Psychopharmacol 1999; 19:67-85Google Scholar
  18. 18.
    Laumann EO, Paik A, Rosen RC: Sexual dysfunction in the United States: Prevalence and predictors. JAMA 1999; 281:537-544Google Scholar
  19. 19.
    Finger WW, Lund M, Slagle MA: Medications that contribute to sexual disorders: A guide to assessment and treatment in family practice. J Fam Pract 1997; 44:33-43Google Scholar
  20. 20.
    Angst J: Sexual problems in healthy and depressed persons. Int Clin Psychopharmacol 1998; 13(Suppl. 6):S1-S4Google Scholar
  21. 21.
    Montejo-González AL, Llorca G, Izquierdo JA, Ledesma A, Bousono M, Calcedo A, Carrasco JL, Ciudad J, Daniel E, De la Gandara J, Derecho J, Franco M, Gomez MJ, Macias JA, Martin T, Perez V, Sanchez JM, Sanchez S, Vicens E: SSRI-induced sexual dysfunction: Fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997; 23:176-194Google Scholar
  22. 22.
    Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM: Antidepressant-induced sexual dysfunction during treat-ment with moclobemide, paroxetine, sertraline, and venlafax-ine. J Clin Psychiatry 2000; 61:276-281Google Scholar
  23. 23.
    Clayton AH, Pradko JF, Croft HA, Montano CB, Leadbet-ter RA, Bolden-Watson C, Bass KI, Donahue RM, Jamerson BD, Metz A: Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 2002; 63:357-366Google Scholar
  24. 24.
    Hirschfeld RM: Management of sexual side effects of antide-pressant therapy. J Clin Psychiatry 1999; 60(Suppl. 14):27-30Google Scholar
  25. 25.
    Gelenberg AJ, McGahuey C, Laukes C, Okayli G, Moreno F, Zentner L, Delgado P: Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry 2000; 61:356-360Google Scholar
  26. 26.
    Segraves RT, Kavoussi R, Hughes AR, Batey SR, Johnston JA, Donahue R, Ascher JA: Evaluation of sexual function-ing in depressed outpatients: A double-blind comparison of sustained-release bupropion and sertraline treatment. J Clin Psychopharmacol 2000; 20:122-128Google Scholar
  27. 27.
    Masand PS, Ashton A, Gupta S, Bradford F: Sustained-release bupropion for SSRI-induced sexual dysfunction: A random-ized double-blind placebo-controlled, parallel group study. Am J Psychiatry 2001; 158:805-807Google Scholar
  28. 28.
    Clayton AH, Pradko JF, Croft HA, Montano CB, Leadbetter RA, Bolden-Watson C, Bass KI, Donahue RM, Jamerson BD, Metz A: Prevalence of sexual dysfunction among newer an-tidepressants. J Clin Psychiatry 2002; 63:357-366.Google Scholar
  29. 29.
    Ashton AK, Ahrens K, Gupta S, Masand PS: Ginkgo biloba: Efficacy in SSRI-induced sexual dysfunction. Am J Psychiatry 2000; 157(5):836-837Google Scholar
  30. 30.
    Masand PS, Anand V, Tanquary J: Psychostimulant augmen-tation of second generation antidepressants: Acase series. De-press Anxiety 1998; 7:89-91Google Scholar
  31. 31.
    Michelson D, Bancroft J, Targum S, Kim Y, Tepner R: Female sexual dysfunction associated with antidepressant administration: A randomized, placebo-controlled study of pharmacologic intervention. Am J Psychiatry 2000; 157:239-243Google Scholar
  32. 32.
    Landen M, Eriksson E, Agren H, Fahlen T: Effect of buspirone on sexual dysfunction in depressed patients treated with se-lective serotonin reuptake inhibitors. J Clin Psychopharmacol 1999; 19:268-271Google Scholar
  33. 33.
    Nelson EB, Shah VN, Welge JA, Keck PE Jr: A placebo-controlled, crossover trial of granisetron in SRI-induced sexual dysfunction. J Clin Psychiatry 2001; 62:469-473Google Scholar
  34. 34.
    Nurnberg HG, Gelenberg A, Hargreave TB, Harrison WM, Siegel RL, Smith MD: Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking sero-tonin reuptake inhibitors. Am J Psychiatry 2001; 158:1926-1928Google Scholar
  35. 35.
    Richelson E: Pharmacokinetic interactions of antidepressants. J Clin Psychiatry 1998; 59(Suppl 10):22-26Google Scholar
  36. 36.
    DeVane CL. Pharmacogenetics and drug metabolism of newer antidepressant agents. J Clin Psychiatry 1994; 55(Suppl 12):38-45Google Scholar
  37. 37.
    Barbhaiya RH, Shukla UA, Kroboth PD, Greene DS: Coad-ministration of nefazodone and benzodiazepines. II: Pharma-cokinetic interaction study with triazolam. J Clin Psychophar-macol 1995; 15:320-326Google Scholar
  38. 38.
    Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI: Drug interactions with newer antidepressants: Role of hu-man cytochromes P450. J Clin Psychiatry 1998; 59(Suppl 15): 19-27Google Scholar
  39. 39.
    Greden JF: Antidepressant maintenance medications: When to discontinue and how to stop. J Clin Psychiatry 1993; 54(Suppl 8):39-45Google Scholar
  40. 40.
    Brown WA, Harrison W: Are patients who are intolerant to one serotonin selective reuptake inhibitor intolerant to an-other? J Clin Psychiatry 1995; 56:30-34Google Scholar

Copyright information

© American Academy of Clinical Psychiatrists 2002

Authors and Affiliations

  • Prakash S. Masand
    • 1
  • Sanjay Gupta
    • 2
    • 3
  1. 1.Department of PsychiatryDuke University Medical CenterDurham
  2. 2.SUNY Upstate Medical UniversitySyracuse
  3. 3.Buffalo School of Medicine and Biomedical SciencesBuffalo

Personalised recommendations