Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs

J Clin Psychiatry. 1999 May;60(5):326-35. doi: 10.4088/jcp.v60n0511.


Background: The significant morbidity and mortality associated with severe depression and its psychotic or melancholic subtypes necessitate effective and well-tolerated therapy. This review evaluates antidepressant treatments for patients with severe depression.

Data sources: Comparative clinical trials conducted on patients with severe depression were found by an English-language MEDLINE search (1985 to present). Additional studies were identified in article bibliographies. Search terms included depressive disorders, depression and severe, hospitalized, melancholic or melancholia, psychotic, and endogenous.

Study findings: Evidence for efficacy of SSRIs in severe or melancholic depression comes from a small but growing number of controlled studies with adequate samples, as well as meta-analyses and retrospective subgroup analysis of premarketing trials. In studies that defined response as a 50% or greater reduction in Hamilton Rating Scale for Depression (HAM-D) scores, response rates ranged from 53% to 64% for SSRIs and 43% to 70% for TCAs. In separate trials on severe depression, venlafaxine and mirtazapine were both more effective than placebo and an active comparator. Nefazodone and bupropion were each found to be more effective than placebo in studies of severe depression. Venlafaxine and mirtazapine have been found to be more effective than fluoxetine.

Conclusion: SSRIs and TCAs are comparably effective for the treatment of severe or melancholic depression. SSRIs and other newer agents appear to be better tolerated than TCAs, specifically lacking adverse anticholinergic and cardiovascular effects that may limit the use of TCAs. Emerging data with venlafaxine and mirtazapine in severely depressed patients with or without melancholia support the efficacy of these treatments. Nefazodone and bupropion were found to be effective in hospitalized depressed patients. Electroconvulsive therapy (ECT) or combined antidepressant therapy may be useful in some patients with severe depression. Patients with severe psychotic depression may respond better to an antipsychotic-antidepressant combination.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aged
  • Ambulatory Care
  • Antidepressive Agents / therapeutic use*
  • Antidepressive Agents, Tricyclic / therapeutic use*
  • Clinical Trials as Topic
  • Cyclohexanols / therapeutic use
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / psychology
  • Drug Therapy, Combination
  • Electroconvulsive Therapy
  • Hospitalization
  • Humans
  • Multicenter Studies as Topic
  • Serotonin Uptake Inhibitors / therapeutic use*
  • Severity of Illness Index
  • Treatment Outcome
  • Venlafaxine Hydrochloride


  • Antidepressive Agents
  • Antidepressive Agents, Tricyclic
  • Cyclohexanols
  • Serotonin Uptake Inhibitors
  • Venlafaxine Hydrochloride