The mechanisms of tolerance in antidepressant action Giovanni A. Fava a,b, ⁎, Emanuela Offidani a a Affective Disorders Program, Department of Psychology, University of Bologna, Bologna, Italy b Department of Psychiatry, State University of New York at Buffalo, Buffalo, New York, USA abstract article info Article history: Received 25 May 2010 Received in revised form 27 July 2010 Accepted 27 July 2010 Available online 20 August 2010 Keywords: Antidepressant drugs Oppositional tolerance Relapse Resistance Switch Withdrawal syndrome 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. © 2010 Elsevier Inc. All rights reserved. 1. Introduction The possibility that antidepressant drugs may unfavorably affect the outcome of depression was formulated in 1994 (Fava, 1994). It was suggested that long-term use of antidepressant drugs (AD) may increase, in some cases, the biochemical vulnerability to depression (Harvey et al., 2007; Carlson et al., 2007) and worsen its long-term outcome and symptomatic expression, decreasing both its likelihood of subsequent response to pharmacological treatment and the duration of symptom-free periods. The neurobiologic mechanisms were not detailed in that paper (Fava, 1994), but were developed in a subsequent review that referred to the concept of oppositional tolerance (Fava, 2003). In the meanwhile, several reports had appeared showing that, in some cases, antidepressants may induce relapse upon discontinuation, unfavorable long-term outcomes, symptomatic worsening, withdrawal syndrome, tolerance and resistance phenomena (Fava, 2003). The aim of this paper is to update and extend previous papers (Fava, 1994, 2003), by reviewing the clinical literature and discussing the neurobiological framework for such events. A Medline search of the literature, using “tolerance”, “withdrawal”, “sensitization”, “antidepres- sants” and “switching” as key words was performed. In addition, the Cinahl, PsychInfo, Web of Science databases and the Cochrane Library were also searched using the same terms. Further, a manual search of the psychiatric literature has been performed looking for articles Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 1593–1602 Abbreviations: AD, antidepressant; SSRI, selective serotonin reuptake inhibitor; SNRI, selective norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; IMAO, monoamine oxide inhibitor; MS, mood stabilizer; HAM-D, Hamilton depression rating scale; SAPS, scale for assessment of positive symptoms; DESS, discontinuation emergent signs and symptoms scale; CBT, cognitive behavioral therapy; ACID, antidepressant associate chronic irritable dysphoria; ADRs, adverse drug reactions; MDD, major depressive disorder; SAD, social anxiety disorder; GAD, generalized anxiety disorder; STEP-BD, systematic treatment enhancement program for bipolar disorder; STAR*D, sequenced treatment alternatives to relieve depression study; NIMH, National Institute of Mental Health; NICE, National Institute for Health and Clinical Excellence; HPA, hypothalamic–pituitary–adrenal axis; CRF, corticotropin releasing factor; 5HT, serotonin; ACTH, adreno-corticotropic-hormone. ⁎ Corresponding author. Affective Disorders Program, Department of Psychology, University of Bologna, Bologna, Italy. E-mail address: giovanniandrea.fava@unibo.it (G.A. Fava). 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.07.026 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp