CNS Drugs

, Volume 4, Issue 5, pp 341–350

Practical Guidelines for Combination Drug Therapy of Treatment-Resistant Depression

  • Stephen T. H. Sokolov
  • Russell T. Joffe
Practical Therapeutics


Although antidepressants are effective in many individuals with major depression, there remains a significant proportion of patients who do not respond to initial treatment. Recent evidence suggests that the persistence of major depressive symptoms increases the risk of developing a chronic depressive illness, and emphasises the importance of pursuing effective therapies for patients who fail to respond to initial treatment.

Classically, approaches to antidepressant failure have included: (i) optimisation of current therapy; (ii) substitution with a second antidepressant; (iii) combination of antidepressant agents; and (iv) augmentation (combination) with a second medication that alone does not possess inherent antidepressant properties. These strategies are discussed in the present article. Emphasis is placed on the discussion of the latter 2 strategies, which may offer advantages including reasonable efficacy, tolerability and ease of introduction.

Of the strategies presented, augmentation with lithium or liothyronine are the best evaluated. However, these drugs have only been assessed systematically in patients who have failed to respond to tricyclic antidepressants. Their value in patients who have not responded to other classes of antidepressants is supported by anecdotal case reports only. Furthermore, although it is known that these agents produce a response within several weeks, the required duration of treatment once a response is achieved is not known.

Despite these limitations, augmentation approaches have substantial inherent value because of their efficacy and rapid onset of effect. This latter feature is particularly important given recent evidence suggesting that chronicity of illness may be preventable by obtaining an early response.


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Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Stephen T. H. Sokolov
    • 1
  • Russell T. Joffe
    • 1
  1. 1.Department of PsychiatryMcMaster UniversityHamiltonCanada
  2. 2.Mood Disorders ClinicHamilton Psychiatric HospitalHamiltonCanada

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