The mechanisms of tolerance in antidepressant action.

There is increasing awareness that, in some cases, long-term use of antidepressant drugs (AD) may enhance the biochemical vulnerability to depression and worsen its long-term outcome and symptomatic expression, decreasing both the likelihood of subsequent response to pharmacological treatment and the duration of symptom-free periods. A review of literature suggesting potential side effects during long treatment with antidepressant drugs was performed. Studies were identified electronically using the following databases: Medline, Cinahl, PsychInfo, Web of Science and the Cochrane Library. Each database was searched from its inception date to April 2010 using "tolerance", "withdrawal", "sensitization", "antidepressants" and "switching" as key words. Further, a manual search of the psychiatric literature has been performed looking for articles pointing to paradoxical effects of antidepressant medications. Clinical evidence has been found indicating that even though antidepressant drugs are effective in treating depressive episodes, they are less efficacious in recurrent depression and in preventing relapse. In some cases, antidepressants have been described inducing adverse events such as withdrawal symptoms at discontinuation, onset of tolerance and resistance phenomena and switch and cycle acceleration in bipolar patients. Unfavorable long-term outcomes and paradoxical effects (depression inducing and symptomatic worsening) have also been reported. All these phenomena may be explained on the basis of the oppositional model of tolerance. Continued drug treatment may recruit processes that oppose the initial acute effect of a drug. When drug treatment ends, these processes may operate unopposed, at least for some time and increase vulnerability to relapse. Antidepressant drugs are crucial in the treatment of major depressive episodes. However, appraisal and testing of the oppositional model of tolerance may yield important insights as to long-term treatment and achievement of enduring effects.