Shared and distinct effect mediators in exposure-based and traditional cognitive behavior therapy for fibromyalgia: Secondary analysis of a randomized controlled trial.

Fibromyalgia is a chronic pain condition associated with substantial suffering and societal costs. Traditional cognitive behavior therapy (T-CBT) is the most evaluated psychological treatment, but exposure therapy (Exp-CBT) has shown promise with a pronounced focus on the reduction of pain-related avoidance behaviors. In a recent randomized controlled trial (N = 274), we found that Exp-CBT was not superior to T-CBT (d = -0.10) in reducing overall fibromyalgia severity. This study investigated pain-related avoidance behaviors, pain catastrophizing, hypervigilance, pacing, overdoing and physical activity as potential mediators of the treatment effect. Mediation analyses were based on parallel process growth models fitted on 11 weekly measurement points, and week-by-week time-lagged effects were tested using random intercepts cross-lagged panel models. Results indicated that a reduction in avoidance behaviors, pain catastrophizing, and hypervigilance were significant mediators of change in both treatments. An increase in pacing and a reduction in overdoing were significant mediators in T-CBT only. Physical activity was not a mediator. In the time-lagged analyses, an unequivocal effect on subsequent fibromyalgia severity was seen of avoidance and catastrophizing in Exp-CBT, and of overdoing in T-CBT. Exposure-based and traditional CBT for fibromyalgia appear to share common treatment mediators, namely pain-related avoidance behavior, catastrophizing and hypervigilance.

An investigation of the role of estradiol in fear reduction during a single session of exposure therapy.

Research suggests that estradiol may moderate fear extinction. It is unclear whether these results generalize to exposure therapy. The aim of the current study was to determine whether estradiol moderates outcomes in exposure therapy among women with anxiety disorders. Participants were 35 women with a primary diagnosis of an anxiety disorder who participated in the study as part of routine care at an anxiety specialty clinic. Endogenous estradiol was assessed via saliva. They provided subjective distress ratings before (pre) and after (post) an exposure session, as well as after a brief delay (recall). Contrary to predictions, there were no significant differences in exposure outcomes between the high and low estradiol groups. However, among participants with primary obsessive-compulsive disorder (OCD), results were partially consistent with the hypotheses. Women with lower estradiol initially demonstrated more improvement in subjective distress from pre- to post-exposure, but after the delay, significantly greater distress (attenuated extinction recall). Results suggest that women with lower estradiol may respond less favorably to exposure therapy for OCD relative to women with higher estradiol. These findings await replication in larger samples with longer recall delays. Should replication occur, these results may inform the use of estradiol to augment exposure therapy.

Effect of exposure-based vs traditional cognitive behavior therapy for fibromyalgia: a two-site single-blind randomized controlled trial.

ABSTRACT: Fibromyalgia is a debilitating pain condition for which treatment effects are typically modest. The most evaluated psychological treatment is traditional cognitive behavior therapy (T-CBT), but promising effects have recently been seen in exposure-based cognitive behavior therapy (Exp-CBT). We investigated whether Exp-CBT was superior to T-CBT in a randomized controlled trial. Self-referred participants with fibromyalgia (N = 274) were randomized (1:1) to 10 weeks of Exp-CBT or T-CBT. Treatments were delivered online and presented as "CBT for fibromyalgia." Participants were assessed at baseline, weekly during treatment, posttreatment, and at 6- and 12-month follow-up. Primary outcome was the difference in reduction in fibromyalgia severity as measured using the Fibromyalgia Impact Questionnaire (FIQ) over 11 assessment points from baseline to posttreatment, modelled within an intention-to-treat framework using linear mixed effects models fitted on multiple imputed data. Approximately 91% of weekly FIQ scores were collected over the main phase. There was no significant difference between Exp-CBT and T-CBT in the mean reduction of fibromyalgia severity from pretreatment to posttreatment (b = 1.3, 95% CI -3.0 to 5.7, P = 0.544, d = -0.10). Minimal clinically important improvement was seen 60% in Exp-CBT vs 59% in T-CBT. Effects were sustained up to 12 months posttreatment. This well-powered randomized trial indicated that Exp-CBT was not superior to T-CBT for fibromyalgia. Both treatments were associated with a marked reduction in fibromyalgia severity, and the online treatment format might be of high clinical utility. T-CBT can still be regarded a reference standard treatment that remains clinically relevant when compared to novel treatment approaches.

Virtual reality cue exposure therapy for tobacco relapse prevention: a comparative study with standard intervention.

BACKGROUND: Successful interventions have been developed for smoking cessation although the success of smoking relapse prevention protocols has been limited. Cognitive behavioural therapy (CBT) in particular has been hampered by a high relapse rate. Because relapse can be due to conditions associated with tobacco consumption (such as drinking in bars with friends), virtual reality cue exposure therapy (VRCE) can be a potential tool to generate 3D interactive environments that simulate risk situations for relapse prevention procedures. METHODS: To assess the effectiveness of VRCE with CBT, a comparative trial involving 100 smoking abstinent participants was designed with all required virtual environments (VE) created with an inexpensive graphic engine/game level editor. RESULTS: Outcome measures confirmed the immersive and craving eliciting effect of these VEs. Results demonstrated that more participants in the VRCE group did not experience smoking relapse and that VRCE is at least as efficacious as traditional CBT in terms of craving reduction and decrease in nicotine dependence. Dropout and relapse rate in the VRCE group was noticeably lower than the CBT group. Aside from mood scores, no significant differences were found regarding the other scales. CONCLUSION: The present clinical trial provides evidence that VRCE was effective in preventing smoking relapse. Improvement in technology and methodology for future research and applications is delineated.

Change in posttraumatic stress disorder-related thoughts during treatment: Do thoughts drive change when pills are involved?

Posttraumatic negative thoughts about one's self and the world are related to posttraumatic stress disorder (PTSD) symptom severity and change in cognitive behavioral treatment (CBT), but little is known about this association when CBT is delivered with medication. The current study presents a planned comparison of changes in negative posttraumatic thoughts during (a) prolonged exposure (PE) plus pill placebo (PE+PLB), (b) sertraline plus enhanced medication management (SERT+EMM), and (c) PE plus sertraline (PE+SERT) as part of a randomized clinical trial in a sample of 176 veterans. Lagged regression modeling revealed that change in posttraumatic negative thoughts was associated with PTSD symptom change in the conditions in which participants received sertraline, ds = 0.14-0.25, ps = 0.04-.001). However, contrary to previous research, the models that started with symptom change were also statistically significant, d = 0.23, p < .001, for the lagged effect of symptoms on negative thoughts about self in the SERT+EMM condition, indicating a bidirectional association between such thoughts and PTSD symptoms. In the PE+PLB condition, no significant association between posttraumatic thoughts and PTSD symptoms emerged in either direction. These results suggest that the previously demonstrated role of change in posttraumatic thoughts leading to PTSD symptom reduction in PE may be altered when combined with pill administration, either active or placebo.

A Close Look Into Coping Cat: Strategies Within an Empirically Supported Treatment for Anxiety in Youth.

The Coping Cat protocol has shown both efficacy and effectiveness in the treatment of youth anxiety across numerous randomized controlled trials (RCTs), leading to its designation as an empirically supported treatment. The treatment is completed in two phases. In the first phase, children are taught a series of coping skills outlined using the FEAR plan acronym. The FEAR plan is then practiced in exposure tasks during the second phase of treatment. To illustrate implementation of both phases, and highlight core treatment components (i.e., exposure, flexibility within fidelity), a case description is presented. Directions for future research are discussed.

Approach as a key for success: Reduced avoidance behaviour mediates the effect of exposure therapy for fibromyalgia.

Fibromyalgia (FM) is a prevalent chronic pain disorder associated with large suffering and substantial societal costs. Pain-related avoidance behaviour and hypervigilance to bodily symptoms are common in FM and contribute in maintaining and exacerbating the disorder. Exposure therapy targeting avoidance behaviours and hypervigilance has shown promise in the treatment of FM. The present study investigated mediators of treatment outcome in exposure therapy for FM. We used data from a randomised trial, where 140 participants were allocated to 10-week internet-delivered exposure therapy or to a waiting-list control condition. The main outcome variable (FM symptoms) and the hypothesized mediators (FM-related avoidance behaviour, mindful non-reactivity and FM-related worry) were measured weekly throughout treatment. Mediation analyses were conducted using linear mixed effects models with bootstrap replication and time-lagged analysis. Results indicated that all three process variables were significant mediators of FM severity. However, in the time-lagged analyses, only FM-related avoidance behaviour displayed a unidirectional relationship over time with FM symptoms, suggesting a causal effect. Thus, results illustrate that changes in avoidance behaviour mediate the outcome of exposure on FM symptoms, which implies that avoidance behaviour is an important treatment target in exposure therapy.

Effects of Delay Discounting and Other Predictors on Smoking Relapse.

Despite the substantial decrease in the prevalence of tobacco smoking and the availability of effective smoking cessation treatments, smoking relapse after formal treatments remains extremely high. Evidence regarding clinical predictors of relapse after quitting is essential to promote long-term abstinence among those who successfully quit. This study aimed to explore whether baseline delay discounting (DD) rates and other sociodemographic, psychological, and smoking-related variables predicted relapse to smoking at six-month follow-up. Participants were 188 adult smokers (mean age = 42.9, SD = 12.9; 64.4% females) who received one of three treatment conditions: 6-weeks of cognitive-behavioral treatment (CBT) alone; or combined with contingency management (CBT + CM); or combined with cue exposure treatment (CBT+CET). Smoking status was biochemically verified. Logistic regression was conducted to examine prospective predictors of smoking relapse at six months after an initial period of abstinence. Greater DD rates (OR: 0.18; 95% CI [0.03, 0.93]), being younger (OR: 0.96; 95% CI [0.94, 0.99]), high nicotine dependence (OR: 1.34; 95% CI [1.13, 1.60]), and a higher number of previous quit attempts (OR: 4.47; 95% CI [1.14, 17.44]) increased the likelihood of smoking relapse at six-month follow-up. Besides sociodemographic and smoking-related characteristics, greater DD predisposes successful quitters to relapse back to smoking. These results stress the relevance of incorporating specific treatment components for reducing impulsivity.

A placebo-controlled randomized trial of D-cycloserine augmentation of cue exposure therapy for smoking cessation.

Recent studies underscore the importance of studying d-cycloserine (DCS) augmentation under conditions of adequate cue exposure treatment (CET) and protection from reconditioning experiences. In this randomized trial, we evaluated the efficacy of DCS for augmenting CET for smoking cessation under these conditions. Sixty-two smokers attained at least 18 hours abstinence following 4 weeks of smoking cessation treatment and were randomly assigned to receive a single dose of DCS (n=30) or placebo (n=32) prior to each of two sessions of CET. Mechanistic outcomes were self-reported cravings and physiologic reactivity to smoking cues. The primary clinical outcome was 6-week, biochemically-verified, continuous tobacco abstinence. DCS, relative to placebo, augmentation of CET resulted in lower self-reported craving to smoking pictorial and in vivo cues (d = 0.8 to 1.21) in a relevant subsample of participants who were reactive to cues and free from smoking-related reconditioning experiences. Select craving outcomes were correlated with smoking abstinence, and DCS augmentation was associated with a trend toward a higher continuous abstinence rate (33% vs. 13% for placebo augmentation). DCS augmentation of CET can significantly reduce cue-induced craving, supporting the therapeutic potential of DCS augmentation when applied under appropriate conditions for adequate extinction learning.

Therapist-led and self-led one-session virtual reality exposure therapy for public speaking anxiety with consumer hardware and software: A randomized controlled trial.

Public speaking anxiety (PSA) is a common condition which can be treated effectively with exposure therapy. However, inherent difficulties in stimuli presentation and control limits dissemination and the therapeutic potential. Virtual Reality (VR) technology has the potential to resolve these issues and provide a scalable platform for self-help interventions. No previous study has examined whether this can be achieved using the first generation of consumer VR hardware and software. In the current trial, n = 25 + 25 participants were randomized to either one-session therapist-led VR exposure therapy for PSA followed by a four-week internet-administered VR to in-vivo transition program, or a waiting-list. Linear mixed effects modeling revealed significant, large (within Cohen's d = 1.67) decreases in self-reported PSA. The waiting-list was then given access to an internet-administered, self-led version of the same VR exposure therapy to be conducted at home, followed by the same transition program. Dual-slope mixed effects modeling revealed significant, large (d = 1.35) decreases in self-reported PSA. Results were maintained or improved at six- and twelve-month follow-ups. We show for the first time that low-cost, off-the-shelf consumer VR hardware and software can be used to conduct exposure therapy for PSA, both in the traditional, previously impractical one-session format, and in a novel self-led, at-home format.

D-cycloserine nasal formulation development for anxiety disorders by using polymeric gels.

D-cycloserine (DCS), a partial agonist at N-methyl-D-aspartate (NMDA) receptors, is used as an enhancer of exposure therapy for anxiety disorders. The purpose of the present study was to investigate the feasibility of using polymeric gels to increase the viscosity of the formulation and thereby increase the nasal residence time and sustained release of DCS in vitro. Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and methyl cellulose (MC) were prepared at concentrations of 0.5 to 5% w/v. Pluronic F-127 (PF-127) was prepared at concentrations of 15 to 35% w/v. pH, viscosity and in vitro DCS release behavior of the formulated gels were analyzed. All four gels that were tested, demonstrated sustained DCS release behavior over a 24-hour period, but with different rates. Based on the results of this study, HPMC, HPC, MC, and PF-127 are capable of increasing the viscosity of nasal gel formulations and of releasing DCS in sustained manner. Therefore, these polymeric gels can be suitable carriers for DCS nasal gel formulation.

The association between estradiol levels, hormonal contraceptive use, and responsiveness to one-session-treatment for spider phobia in women.

Preclinical studies have demonstrated that conditioned fear extinction is impaired in females with low endogenous levels of the sex hormone estradiol, due to menstrual fluctuations or hormonal contraceptive use. As fear extinction is a laboratory model of exposure therapy for anxiety and trauma disorders, here we assessed the hypothesis that treatment outcomes may be diminished when exposure therapy occurs during periods of low estradiol. 90 women with spider phobia (60 cycling and 30 using hormonal contraceptives) underwent a one-session exposure treatment for spider phobia, following which, serum estradiol levels were assessed. A median split in estradiol level was used to divide cycling participants into two groups; lower and higher estradiol. Behavioral avoidance and self-reported fear of spiders were measured pre-treatment, post-treatment, and at a 12 week follow-up assessment. Women using hormonal contraceptives exhibited a significantly slower rate of improvement across treatment, greater behavioral avoidance at post-treatment and follow-up, and fewer self-initiated post-treatment exposure tasks, relative to both groups of cycling women, who did not differ. No group differences in self-reported fear were evident. Correlational analyses revealed that across the whole sample, lower estradiol levels were associated with slower rates of improvement across treatment, and greater self-reported fear and behavioral avoidance at post-treatment, but not follow-up. These results provide the first evidence of an association between endogenous estradiol, hormonal contraceptive use, and exposure therapy outcomes in spider phobic women. Hormonal profile may partly account for variability in responsiveness to psychological treatments for anxiety and trauma disorders in women.

Changing disgust through imagery rescripting and cognitive reappraisal in contamination-based obsessive-compulsive disorder.

Contamination-related obsessive-compulsive disorder (C-OCD) is characterized by strongly experienced disgust and fear, in response to potentially contaminating stimuli. Both emotions differ in their susceptibility for change by habituation and extinction, which are important processes for the success of exposure therapy. Even though the response rates for exposure therapy for C-OCD are very good, it seems promising to test additional therapeutic techniques which target disgust more directly. Therefore, imagery rescripting and cognitive reappraisal were evaluated for their potential to change levels of disgust (within-subject), in the two-session laboratory study with 30 participants, with diagnosed C-OCD, and 30 matched, healthy controls (between-subject), presented. The results show that both emotion-regulation strategies reduced disgust better than a non-intervention control task (counting fishes), across all the participants. Therefore, both strategies seem to be applicable and effective for reducing disgust, in the short term, in participants with diagnosed C-OCD. The implications of these findings for the experimental approach and for the clinical treatment of C-OCD, are discussed.

Cue exposure therapy reduces overeating of exposed and non-exposed foods in obese adolescents.

BACKGROUND AND OBJECTIVES: This study tested whether two sessions of food cue exposure therapy reduced eating in the absence of hunger (EAH), specified for exposed and non-exposed food, in overweight and obese adolescents, and whether habituation of food cue reactivity and reduced CS-US expectancies predicted a decrease in EAH. METHODS: 41 overweight adolescents (aged 12-18 years) were randomly assigned to a cue exposure intervention or a lifestyle intervention (control condition). Habituation of food cue reactivity (self-reported desire to eat and salivation) and CS-US expectancy were measured during both sessions, and EAH was measured at the end of session two. RESULTS: Compared to the control condition, the cue exposure condition showed less EAH for the exposed food item as well as for the non-exposed food items. Larger within-session (WSH) and between-session habituation (BSH) of cue reactivity were not related to less EAH, change in CS-US expectancy was unrelated to EAH. LIMITATIONS: The study was underpowered, and compliance to homework instructions between sessions was poor, intervention effects might have been larger when participants adhered to daily homework exercises. CONCLUSIONS: Food cue exposure was effective to reduce EAH of exposed and non-exposed food items, indicating generalisability of the exposure effect. In line with exposure effects in anxiety disorders, habituation was not found to benefit outcome, though the present data do also not provide evidence that CS-US expectancy violation predicts EAH.

Internet-Delivered Exposure Therapy for Fibromyalgia: A Randomized Controlled Trial.

BACKGROUND: Fibromyalgia (FM) is a common and disabling chronic pain disorder, for which existing pharmacological and psychological treatments have yet yielded insufficient effects. Previous literature has shown that exposure therapy may be an effective treatment for chronic pain. This study constitutes the first randomized controlled trial evaluating exposure therapy for FM. METHODS: A total of 140 participants with diagnosed FM were randomized to a 10-week Internet-delivered exposure treatment (iExp; n=70) or a waitlist control condition (WLC; n=70). Primary outcome measure were FM symptoms and impact, and secondary outcome measures were fatigue, disability, quality of life, pain-related distress and avoidance behaviors, insomnia, depression, and anxiety. RESULTS: Data retention was high (100% data completion at posttreatment for primary outcome, 96% at 6-month follow-up and 94% at 12-month follow-up). Results showed that participants in the iExp group made large and superior improvements compared with WLC on FM symptoms and impact (B, -1.93; z, -10.14; P<0.001, between-group Cohen d=0.90), as well as all secondary outcomes (between-group Cohen d ranging from 0.44 to 1.38) with sustained results. CONCLUSIONS: We conclude that iExp seems to be an efficacious treatment for FM compared with no treatment, and the results also highlight the potential increase of accessibility by using the Internet format to deliver psychological treatments for these patients. Future trials with active control conditions are warranted.

Intensive prolonged exposure treatment for adolescent complex posttraumatic stress disorder: a single-trial design.

BACKGROUND: The current study evaluated the effectiveness and safety of intensive prolonged exposure (PE) targeting adolescent patients with complex posttraumatic stress disorder (PTSD) and comorbid disorders following multiple interpersonal trauma. METHODS: Ten adolescents meeting full diagnostic criteria for PTSD were recruited from a specialized outpatient mental health clinic and offered a standardized intensive PE. The intensive PE consisted of three daily 90-min exposure sessions delivered on five consecutive weekdays, followed by 3 weekly 90-min booster sessions. In a single-trial design, the participants were randomly allocated to one of five baseline lengths (4-8 weeks) before starting the intensive PE. Before, during, and after intensive PE completion, self-reported PTSD symptom severity was assessed weekly as a primary outcome (a total of 21 measurements). Furthermore, clinician-administered PTSD diagnostic status and symptom severity (primary outcome), as well as self-reported comorbid symptoms (secondary outcomes), were assessed at four single time points (baseline-to-6-month follow-up). RESULTS: Time-series analyses showed that self-reported PTSD symptom severity significantly declined following treatment (p = .002). Pre-postgroup analyses demonstrated significant reductions of clinician-administered PTSD symptom severity and self-reported comorbidity that persisted during the 3- and 6-month follow-ups (all ps < .05), where 80% of adolescents had reached diagnostic remission of PTSD. There was neither treatment dropout nor any adverse events. CONCLUSIONS: The results of this first proof of concept trial suggest that intensive PE can be effective and safe in an adolescent population with complex PTSD, although the gains achieved need to be confirmed in a randomized controlled trial.

Concurrent varenicline and prolonged exposure for patients with nicotine dependence and PTSD: A randomized controlled trial.

BACKGROUND: Prevalence of smoking among individuals with posttraumatic stress disorder (PTSD) is disproportionately high, and PTSD is associated with especially poor response to smoking cessation treatment. OBJECTIVE: The current study examined whether integrating treatments for smoking cessation (varenicline plus smoking cessation counseling; VARCC) and PTSD (prolonged exposure therapy; PE) enhances smoking outcomes among smokers diagnosed with PTSD. METHOD: 142 adults with nicotine dependence (ND) and PTSD were randomized to a treatment program consisting of varenicline, smoking cessation counseling, and PE (VARCC + PE) or to VARCC only. Seven-day point prevalence abstinence (PPA) at posttreatment (3-months postquit day) and follow-up (6-months postquit day), verified by serum cotinine levels and exhaled carbon monoxide, was the primary smoking outcome. Psychological outcomes were PTSD and depression severity. Mixed effects models included baseline PTSD severity as a moderator of treatment condition effects. RESULTS: Overall, VARCC + PE participants did not show greater PPA than VARCC participants. However, treatment effects were moderated by baseline PTSD severity. For participants with moderate and high PTSD severity, VARCC + PE led to significantly higher PPA than VARCC alone (ps<.05). No differences between treatment conditions emerged for participants with low baseline PTSD severity. Participants who received PE showed significantly greater reduction of PTSD and depression symptoms than those who did not receive PE. CONCLUSIONS: Integrating psychological treatment for PTSD and smoking cessation treatment enhances smoking cessation for participants with moderate or severe PTSD symptom severity, but does not enhance smoking cessation for participants with low baseline PTSD severity. (PsycINFO Database Record

Exposure reduces negative bias in self-rated performance in public speaking fearful participants.

BACKGROUND AND OBJECTIVES: Individuals with public speaking anxiety (PSA) under-rate their performance compared to objective observers. The present study examined whether exposure reduces the discrepancy between self and observer performance ratings and improved observer-rated performance in individuals with PSA. METHODS: PSA participants gave a speech in front of a small audience and rated their performance using a questionnaire before and after completing repeated exposures to public speaking. Non-anxious control participants gave a speech and completed the questionnaire one time only. Objective observers watched videos of the speeches and rated performance using the same questionnaire. RESULTS: PSA participants underrated their performance to a greater degree than did controls prior to exposure, but also performed significantly more poorly than did controls when rated objectively. Bias significantly decreased and objective-rated performance significantly increased following completion of exposure in PSA participants, and on one performance measure, anxious participants no longer showed a greater discrepancy between self and observer performance ratings compared to controls. LIMITATIONS: The study employed non-clinical student sample, but the results should be replicated in clinical anxiety samples. CONCLUSIONS: These findings indicate that exposure alone significantly reduces negative performance bias among PSA individuals, but additional exposure or additional interventions may be necessary to fully correct bias and performance deficits.

Utilizing measure-based feedback in control-mastery theory: A clinical error.

Clinical errors and ruptures are an inevitable part of clinical practice. Often times, therapists are unaware that a clinical error or rupture has occurred, leaving no space for repair, and potentially leading to patient dropout and/or less effective treatment. One way to overcome our blind spots is by frequently and systematically collecting measure-based feedback from the patient. Patient feedback measures that focus on the process of psychotherapy such as the Patient's Experience of Attunement and Responsiveness scale (PEAR) can be used in conjunction with treatment outcome measures such as the Outcome Questionnaire 45.2 (OQ-45.2) to monitor the patient's therapeutic experience and progress. The regular use of these types of measures can aid clinicians in the identification of clinical errors and the associated patient deterioration that might otherwise go unnoticed and unaddressed. The current case study describes an instance of clinical error that occurred during the 2-year treatment of a highly traumatized young woman. The clinical error was identified using measure-based feedback and subsequently understood and addressed from the theoretical standpoint of the control-mastery theory of psychotherapy. An alternative hypothetical response is also presented and explained using control-mastery theory. (PsycINFO Database Record

Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats.

Current treatments for stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), are inadequate. Cognitive behavioral psychotherapies, including exposure therapy, are an alternative to pharmacotherapy, but the neurobiological mechanisms are unknown. Preclinical models demonstrating therapeutic effects of behavioral interventions are required to investigate such mechanisms. Exposure therapy bears similarity to extinction learning. Thus, we investigated the therapeutic effects of extinction learning as a behavioral intervention to model exposure therapy in rats, testing its effectiveness in reversing chronic stress-induced deficits in cognitive flexibility and coping behavior that resemble dimensions of depression and PTSD. Rats were fear-conditioned by pairing a tone with footshock, and then exposed to chronic unpredictable stress (CUS) that induces deficits in cognitive set-shifting and active coping behavior. They then received an extinction learning session as a therapeutic intervention by repeated exposure to the tone with no shock. Effects on cognitive flexibility and coping behavior were assessed 24 h later on the attentional set-shifting test or shock-probe defensive burying test, respectively. Extinction reversed the CUS-induced deficits in cognitive flexibility and coping behavior, and increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex (mPFC) of stress-compromised rats, suggesting a role for activity-dependent protein synthesis in the therapeutic effect. Inhibiting protein synthesis by microinjecting anisomycin into mPFC blocked the therapeutic effect of extinction on cognitive flexibility. These results demonstrate the utility of extinction as a model by which to study mechanisms underlying exposure therapy, and suggest these mechanisms involve protein synthesis in the mPFC, the further study of which may identify novel therapeutic targets.