Increasing the Effectiveness of Antidepressants

In-depth look at increasing the effectiveness of antidepressants, treatment strategies for treatment-resistant depression.

In-depth look at increasing the effectiveness of antidepressants for relief of depression symptoms, treatment strategies for treatment-resistant depression.

Importance of Continuation of Treatment

There is a period of time following the relief of depression symptoms during which discontinuation of the antidepressant treatment would likely result in a depression relapse. The NIMH Depression Collaboration Research Program found that four months of treatment with antidepressant medication or cognitive behavioral and interpersonal psychotherapy is insufficient for most depressed patients to fully recover and enjoy lasting remission. Their 18-month follow-up after a course of treatment found depression relapses of between 33 and 50 percent of those initially responding to a short-term treatment.

The currently available data on the continuation of treatment indicate that patients treated for the first episode of uncomplicated depression who exhibit a satisfactory response to an antidepressant should continue to receive a full therapeutic dose of that antidepressant medication for at least 6-12 months after achieving full remission. The first eight weeks after symptom resolution is a period of particularly high vulnerability to relapse. Patients with recurrent depression, dysthymia or other complicating features may require a more extended course of treatment.

Refractory Depression, Treatment-Resistant Depression

Refractory depression (aka treatment-resistant depression) occurs in as many as 10 to 30 percent of depressive episodes, affecting nearly a million patients. Katherine A. Phillips, M.D. (a 1992 NARSAD Young Investigator) has found that failure to provide adequate doses of medication for sufficient periods of time is perhaps the most common cause of apparent treatment resistance. Once the clinician has determined that a patient is truly treatment-refractory, many treatment approaches can be tried. Phillips recommends the following treatment strategies for refractory depression:

  • Augmentation with lithium, and perhaps other agents
  • Combining antidepressants
  • Switching antidepressants

Antidepressant Augmentation Strategy

Lithium: Efficacy has been reported when lithium is added to existing antidepressants, with a reported response rate of 30 to 65 percent. However, what constitutes an adequate dose and blood level is unclear.

Thyroid hormone: It appears that triiodothyronine (T3) sometimes accelerates response to, and increases the efficacy of tricyclic antidepressants, with a reported response rate of about 25%.

Psychostimulants: Although evidence for the efficacy of this strategy is weak, stimulants are of value in depressed patients with adult attention-deficit hyperactivity disorder a diagnosis that can easily be missed and they may be of value in yet-to-be-defined subpopulations of patients with refractory depression, such as the medically ill and elderly.

Combining Antidepressants Strategy

SSRIs with tricyclics: Several studies have shown a good response when fluoxetine is added to tricyclics and when tricyclics are added to fluoxetine. It is important to monitor tricyclic levels because fluoxetine can raise tricyclic levels by 4- to 11- fold and thereby cause tricyclic toxicity.

SSRIs with trazodone: Trazodone may be worth trying either alone or in combination with fluoxetine or tricyclics if other approaches have failed.

Switching Antidepressants

When switching antidepressants, it is probably best to switch from one antidepressant class to another since most patients who fail to respond to one adequate tricyclic trial will be resistant to other tricyclics. There are many treatment strategies for refractory depression, but relatively few are derived from controlled studies. In particular, studies that compare different treatment strategies are limited. At this time, treatment approaches for refractory patients are based largely on clinical experience and must be highly individualized.


There has been impressive progress in the understanding and treatment of depression in the past three decades; however, a number of important issues remain. Although we have gained important clues as to the causes and mechanisms underlying depression, the precise biological and psychological determinants are unknown. In 20 to 30 percent of patients, current treatments are inadequate, and even among patients who respond initially, relapse is not uncommon.

NOTE: You should always check with your doctor before making any changes in your medications.

Source: Information for this article came from "Practice Guidelines for Major Depressive Disorder in Adults", in the Supplement of the American Journal of Psychiatry.

APA Reference
Gluck, S. (2022, January 4). Increasing the Effectiveness of Antidepressants, HealthyPlace. Retrieved on 2024, June 22 from

Last Updated: January 11, 2022

Medically reviewed by Harry Croft, MD

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