The efficacy of fluoxetine combined with a heterocyclic antidepressant in treatment-resistant depression: a retrospective analysis

J Clin Psychiatry. 1995 Aug;56(8):338-43.


Background: Treatment-resistant depression is a common clinical challenge that often requires the use of innovative pharmacologic treatments. Recent reports suggest the efficacy of the combination of a serotonin selective reuptake inhibitor and a heterocyclic antidepressant (HCA) in depressed patients who fail monotherapy with either agent alone. We present our clinical experience with the use of fluoxetine combined with an HCA in a group of 25 treatment-resistant depressed subjects.

Method: Twenty-five depressed subjects who failed to adequately respond to at least 4 weeks of open-label fluoxetine treatment (mean dose = 73 mg/day) had an HCA added to their fluoxetine. The dose of the HCA was increased to maximize efficacy and minimize side effects. Efficacy was measured using the 21-item Hamilton Rating Scale for Depression (HAM-D-21) score and the Clinical Global Impressions-Global Improvement (CGI) scale.

Results: Response to treatment was defined as a 50% or greater drop in the HAM-D-21 score and a CGI of either very much improved or moderately improved from the start of the HCA. Seven (35%) of 20 subjects who demonstrated a poor or partial response to fluoxetine responded when an HCA was added to the fluoxetine. Five (71%) of the responders had previously failed to respond to monotherapy with the HCA that they responded to when used with fluoxetine. Additionally, 5 subjects who demonstrated significant improvement with fluoxetine but who had mild, residual depressive symptoms experienced at least partial further improvement with the addition of an HCA.

Conclusion: The results suggest that the addition of an HCA to fluoxetine may be an effective treatment in treatment-resistant depressed patients who have failed to adequately respond to monotherapy with fluoxetine. Additional controlled trials are warranted to further explore the efficacy of this treatment combination in patients who demonstrate a poor or partial response to monotherapy. When using this drug combination, the clinician is cautioned to prescribe low doses of the HCA and monitor serum levels closely since fluoxetine can raise serum HCA levels.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / psychology
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Fluoxetine / therapeutic use*
  • Heterocyclic Compounds / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Psychiatric Status Rating Scales
  • Retrospective Studies
  • Treatment Outcome


  • Antidepressive Agents
  • Heterocyclic Compounds
  • Fluoxetine