Journal Mobile Options
Table of Contents
Vol. 71, No. 4, 2002
Issue release date: July–August 2002
Psychother Psychosom 2002;71:190–194

Treatment Approaches to Major Depressive Disorder Relapse

Part 1: Dose Increase

Schmidt M.E. · Fava M. · Zhang S. · Gonzales J. · Raute N.J. · Judge R.
aLilly Research Laboratories, Indianapolis, Ind., and bDepression Clinical and Research Program, Massachusetts General Hospital, Boston, Mass., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Objective: Although continuing antidepressant treatment after patients have responded to medication has been shown to greatly reduce the risk of relapse, this risk is not eliminated. A number of theories have been proposed to account for this apparent loss of efficacy. A common initial approach to managing relapse is to increase the dose of antidepressant. We prospectively evaluated the likelihood of response to increasing the fluoxetine doses in patients relapsing during a long-term efficacy study of two fluoxetine dosing regimens. Method: Patients meeting the DSM-IV criteria for major depressive disorder with modified HAMD17 scores ≧18 and CGI-severity scores ≧4 were treated for 13 weeks with open-label 20 mg/day fluoxetine in a multicenter US study. Responders (n = 501) were randomized to 20 mg fluoxetine daily, placebo, or 90 mg enteric-coated fluoxetine weekly for 25 weeks of double-blind continuation treatment. If the patients relapsed during the continuation phase, they were offered a 25-week optional rescue treatment phase during which the study medication dose was increased as follows: (1) patients on placebo had treatment with fluoxetine 20 mg/day reinitiated, (2) patients on fluoxetine 20 mg/day had their dose increased to 40 mg/day, and (3) patients on a 90-mg weekly dose had their dose increased to 90 mg twice a week. The results of the rescue phase for the latter two groups who relapsed while on continuation treatment with fluoxetine are reported. Response was defined as a 50% reduction in the modified HAMD17 score since time of relapse and a CGI-severity score ≤2. Additional efficacy analyses included HAMD and CGI-severity changes from baseline to endpoint. Safety measures included assessment of treatment-emergent adverse events, vital signs, and laboratory measures. Results: Overall, patients relapsing during the continuation treatment responded to an increased dose (57% of the 40-mg-daily group and 72% of the enteric-coated 90-mg-twice-weekly group). Mean modified HAMD17 scores decreased from a mean of approximately 20 to below 8 and were maintained for up to 6 months in the responders. Thirty-five percent of patients either did not respond or initially responded but again relapsed after augmentation of medication. Conclusions: The patients relapsing after initially responding to fluoxetine can benefit from an increase in fluoxetine dose. These results also generally support increasing dose as a first-line treatment strategy for a patient who has relapsed while taking a previously effective dose of an antidepressant. Increasing enteric-coated fluoxetine 90 mg once weekly to twice weekly appeared to be as well-tolerated and effective in restoring response as increasing a daily fluoxetine dose from 20 to 40 mg.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Agency for Health Care Policy and Research: Treatment of major depression; in Agency for Health Care Policy and Research (ed): Clinical Practice Guideline No 5 – Depression in Primary Care, vol 2. Rockville, Agency for Health Care Policy and Research, 1993.
  2. World Health Organization Mental Health Collaborating Centres: Pharmacotherapy of depressive disorders: A consensus statement. J Affect Disord 1989;17:197–198.
  3. American Psychiatric Association: Practice guidelines for major depressive disorder in adults. Am J Psychiatry 1993;150:1–26.
  4. Frank E, Kupfer DJ, Perel JM, Cornes C, Jarrett DB, Mallinger AG, Thase ME, McEachran AB, Grochocinski VJ: Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990;47:1093–1099.
  5. Rush AJ: Strategies and tactics in the management of maintenance treatment for depressed patients. J Clin Psychiatry 1999;60(suppl 14):21–26.
  6. Byrne S, Rothschild AJ: Loss of antidepressant efficacy during maintenance therapy: Possible mechanisms and treatments. J Clin Psychiatry 1998;59:279–288.
  7. Fava M, Rappe SM, Pava JA, Nierenberg AA, Alpert JE, Rosenbaum JF: Relapse in patients on long-term fluoxetine treatment: Response to increased fluoxetine dose. J Clin Psychiatry 1995;56:52–55.
  8. Schmidt ME, Fava M, Robinson J, Judge R: The efficacy and safety of a new enteric-coated formulation of fluoxetine given once weekly during the continuation treatment of major depressive disorder. J Clin Psychiatry 2000;61:851–857.

    External Resources

  9. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, American Psychiatric Association, 1994.
  10. Fredman SJ, Fava M, Kienke AS, White CN, Nierenberg AA, Rosenbaum JF: Partial response, nonresponse, and relapse with selective serotonin reuptake inhibitors in major depression: A survey of current ‘next-step’ practices. J Clin Psychiatry 2000;61:403–408.
  11. Nierenberg AA, Alpert JE: Depressive breakthrough. Psychiatr Clin North Am 2000;23:731–742.

    External Resources

  12. Jarrett RB, Kraft D, Schaffer M, Witt-Browder A, Risser R, Atkins DH, Doyle J: Reducing relapse in depressed outpatients with atypical features: A pilot study. Psychother Psychosom 2000;69:232–239.
  13. Fava M: Management of nonresponse and intolerance: Switching strategies. J Clin Psychiatry 2000;61(suppl 2):10–12.
  14. Fava M: New approaches to the treatment of refractory depression. J Clin Psychiatry 2000;61(suppl 1):26–32.
  15. Cohen BM, Baldessarini RJ: Tolerance to therapeutic effects of antidepressants. Am J Psychiatry 1985;142:489–490.

    External Resources

  16. Mann JJ: Loss of antidepressant effect with long-term monoamine oxidase inhibitor treatment without loss of monoamine oxidase inhibition. J Clin Psychopharmacol 1983;3:363–366.

    External Resources

  17. Stewart JW, Quitkin FM, McGrath PJ, Amsterdam J, Fava M, Fawcett J, Reimherr F, Rosenbaum J, Beasley C, Roback P: Use of pattern analysis to predict differential relapse of remitted patients with major depression during 1 year of treatment with fluoxetine or placebo. Arch Psychiatry 1998;55:334–343.
  18. Mischoulon D, McColl-Vuolo R, Howarth S, Lagomasino IT, Alpert JE, Nierenberg AA, Fava M: Management of major depression in the primary care setting. Psychother Psychosom 2001;70:103–107.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50