افزایش مواجهه درمانی برای اختلالات اضطرابی با گلوکوکورتیکوئیدها: از مکانیسم های پایه یادگیری عاطفی با کاربردهای بالینی

Current neurophysiological and psychological accounts view exposure therapy as the clinical analog of extinction learning that results in persistent modifications of the fear memory involved in the pathogenesis, symptomatology, and maintenance of anxiety disorders. Evidence from studies in animals and humans indicate that glucocorticoids have the potential to facilitate the processes that underlie extinction learning during exposure therapy. Particularly, glucocorticoids can restrict retrieval of previous aversive learning episodes and enhance consolidation of memory traces relating to non-fearful responding in feared situations. Thus, glucocorticoid treatment especially in combination with exposure therapy might be a promising approach to optimize treatment of anxiety disorders. This review examines the processes involved in aversive conditioning, fear learning and fear extinction, and how glucocorticoids might enhance restructuring of fear memories during therapy.

The most effective psychotherapy for anxiety disorders, such as specific phobia, social phobia, and posttraumatic stress disorder (PTSD), is exposure therapy (Chambless & Ollendick, 2001). Its core element is to expose patients to fear-provoking stimuli in a repeated and systematic manner in order for them to acquire a sense of safety in the presence of the formerly feared stimuli (e.g., Öst, 1997). Besides this cognitive-behavioral treatment (CBT) strategy, pharmacotherapy with anxiolytic agents such as monoamine oxidase inhibitors, tricyclic antidepressants, and benzodiazepines has been proven to be an effective treatment for anxiety disorders (Gould et al., 1997 and Gould et al., 1995). Meta-analyses comparing CBT and psychopharmacological therapy for anxiety disorders indicate that both treatments have similar efficacy in treating acute fear symptoms, but that CBT shows better stability of treatment gains after the end of treatment (e.g., Gould et al., 1995 and Gould et al., 1997). The stand-alone success of both exposure therapy and psychopharmacotherapy has led to the idea of combining these interventions to boost the effectiveness of either treatment method. Although it seems reasonable to assume that the combination of two effective interventions would maximize treatment gains, this approach has not been very successful, in particular with respect to long-term outcome. Studies of combined treatment regimes indicate that a combination of the two methods can be advantageous in the short and intermediate term, but that the effect typically reverses in the long term (e.g., Coldwell et al., 2007, Foa et al., 2002, Otto et al., 2005 and Wilhelm and Roth, 1997). It is generally assumed that the high rate of relapse after medication discontinuation both with monotherapy and combined therapy may be explained by the mechanism by which anxiolytic psychotropics unfold their activity. Common to all anxiolytic psychotropics is that they attenuate fear symptoms elicited by the fear-provoking stimulus, albeit via different brain pathways. Such attenuation of the anxiety response seems to work only as long as psychotropics are given (e.g., Noyes et al., 1989 and Noyes et al., 1991). In contrast, CBT regimes for anxiety disorders are not just aimed at attenuating fear symptoms but are aimed at emotional learning processes that are believed to lead to persistent modifications of neuronal networks in specific brain areas associated with the pathogenesis and maintenance of anxiety disorders. For example, LeDoux (2002) believes that “Psychotherapy is fundamentally a learning process for its patients, and as such is a way to rewire the brain. In this sense, psychotherapy ultimately uses biological mechanisms to treat mental illness.” This perspective on psychotherapy has important implications for the combination of psychopharmacologic and psychotherapeutic treatment methods. If psychotherapy changes central nervous system structures and subsequently central nervous system processes associated with fear responding it is logical to ask the following questions: What is the underlying central nervous system mechanism of successful psychotherapy for anxiety disorders?, and, Is there any medication that can directly enhance this mechanism? Procedurally, exposure therapy parallels extinction training within a model of learning and unlearning of conditioned responses. In this model, the patient's decline of fear within an exposure session is the result of continuous decrements in the conditioned response seen over successive extinction trials. Thus, extinction of fear responses is generally assumed to be the most important underlying mechanisms of exposure therapy. This implies that pharmacological enhancers of psychological treatments for anxiety disorders should focus on facilitation of extinction and on stabilization of treatment gains after extinction. It has been argued that extinction of conditioned responses and consolidation processes that stabilize extinction are both amenable to pharmacologic manipulations (Myers & Davis, 2002). Thus, deeper knowledge about behavioral and molecular mechanisms leading to extinction and consolidation will present opportunities for creating new effective treatment approaches that combine psychopharmacologic and psychotherapeutic treatments. The aim of this review is to present administration of glucocorticoids as a promising approach that intends to enhance extinction learning and facilitate consolidation of extinction memory into long-term memory. We begin by elucidating the underlying mechanisms of acquisition and extinction of fear and then translate basic knowledge from the field of neuroscience into a novel clinical application.

Scientific understanding of the processes involved in exposure therapy has undergone several revisions in the past decades and new findings continue to contribute to reconceptualizations. In this review we discussed historical and recent accounts to lay the foundation for integrating the action of GCs on exposure treatment of anxiety. We reviewed evidence indicating that exposure therapy is the clinical analog of extinction learning. Exposure leads to persistent modifications of the fear memory that is involved in the pathogenesis, symptomatology and maintenance of anxiety disorders. We reviewed the literature on fear acquisition and fear extinction to find out what the underlying mechanisms of successful exposure treatment are. All pathways of fear acquisition are emotional learning processes that create a stimulus-associated fear memory and retrieval of this fear memory plays an important role in the symptomatology of anxiety disorders. Through extinction learning, an alternative set of memory associations develop. This additional non-fear structure (extinction memory) competes with the original fear memory associations (inhibitory learning) but does not erase them. The growing knowledge about learning and memory processes involved in exposure therapy opened up a new research avenue for the development of psychobiological approaches combining exposure therapy with the administration of memory-modulatory drugs. We reviewed recent evidence, which indicates that GCs have the potential to facilitate the processes that lead to enhanced extinction learning during exposure therapy. The differential memory-modulatory effects of GCs and the lacking side effects make these hormones an ideal candidate for therapeutic use. As an underlying mechanism, we hypothesize that GCs impede retrieval of the former fear memory trace and enhance long-term consolidation of corrective experiences (extinction memory). We conclude that GCs have the potential to enhance the effectiveness of exposure therapy. GC treatment in combination with exposure therapy may be a promising approach for treating anxiety disorders, but further research is needed to elucidate the underlying mechanisms and clinical outcome.