Timing matters: Endogenous cortisol mediates benefits from early-day psychotherapy
Introduction
Exposure therapy – systematic and controlled confrontation with feared situations or sensations – facilitates fear extinction through acquisition of new, fear-discordant information (Bouton, 2002, Milad et al., 2006). Therapeutic success of exposure therapy for fear-based avoidance is well-established treatment for anxiety disorders (McNally, 2007). However, a significant number of patients experience limited recovery or a return of fear following exposure (Meuret et al., 2012a, Loerinc et al., 2015). Identification of moderators and mediators that can facilitate corrective learning is of great scientific and clinical interest (Hermans et al., 2006, Graham and Milad, 2011). However, few if any reliable ways of enhancing treatment outcome exist (Schneider et al., 2015; for a review), and no “simple” determinant of enhanced learning has been identified. Both psychophysiological and contextual indices of extinction, such as fear reactivity (activation, within- and between-session habituation of fear levels) and exposure characteristics (variation of stimulus, session spacing and duration), show varying results (Meuret et al., 2012b, Craske et al., 2008, for a review).
One biological factor associated with enhanced extinction learning is cortisol. Research over the last decades has provided growing evidence for a beneficial effect of glucocorticoids on extinction learning. A dual mechanism is assumed by which cortisol reduces the retrieval of aversive memories, and thereby partially interrupts the vicious cycle of spontaneous retrieving, re-experiencing and (re)consolidating of aversive memories, while simultaneously enhances fear extinction by means of facilitating the storage of corrective experiences. The latter process is thought to be active in exposure techniques taught in cognitive-behavioral therapy (de Quervain et al., 2009; review). In recent findings from laboratory-based exposure protocols show that higher levels of cortisol (exogenous and endogenous) during exposure sessions are linked to lower, concurrent stimulus-induced fear and enhanced approach behaviors (Soravia et al., 2006, Soravia et al., 2014, de Quervain et al., 2011), and to attenuated negative emotional arousal during and following response to acute stress (Het et al., 2012). The observed “fear-buffering” effects of cortisol have been ascribed to the ability of glucocorticoids to inhibit the retrieval of aversive memories, while simultaneously enhancing extinction learning (Roozendaal et al., 2006, Bentz et al., 2010, de Quervain et al., 2009). Two naturalistic exposure studies further documented cortisol-related enhancement of extinction learning, but without direct links between cortisol and concurrent fear levels. Siegmund et al. (2011) showed greater clinical improvements (trend level) in panic patients with higher cortisol levels undergoing in-vivo exposure. Higher cortisol levels during exposures were also associated with enhanced clinical improvement in a multi-session in-vivo exposure protocol for panic disorder and agoraphobia (Meuret et al., 2015). In the latter study, greater cortisol awakening responses on exposure day also predicted treatment gains. A potential link between time of treatment session and treatment gains was not examined in those analyses, but if higher cortisol enhances the beneficial impact of exposure treatment, and normal diurnal variation in cortisol levels produces the highest levels in the morning, morning sessions may be advantageous.
The diurnal rhythm of cortisol is well established (Kirschbaum and Hellhammer, 1989), with a morning peak followed by a steady decline throughout day, and a nadir in the evening. While the function of the acute rise in cortisol triggered by morning awakening remains undetermined, the rise is thought to facilitate performance and orientation to the day’s upcoming demands (Fries et al., 2009, Chida and Steptoe, 2009). Indeed, preliminary evidence supports the link between circadian factors, cortisol, and extinction learning. Using a fear conditioning and extinction paradigm in healthy young adult males, Pace-Schott and colleagues demonstrated enhanced extinction learning in participants assigned to the “morning” (7–10 a.m.) versus “evening” group (7–10 p.m). The evening group had significantly lower salivary cortisol levels at time of training than the morning group (Pace-Schott et al., 2013), but the investigators did not perform a mediation analysis to determine if cortisol mediatedthe superior morning results. Furthermore, spider-phobic adults assigned to receive a single-session laboratory-based exposure at 8 a.m. (versus 8 p.m.), had higher cortisol levels during the exposure and showed greater approach behavior and a trend toward lower subjective fear of spiders at post-treatment and 3-months later (Lass-Hennemann and Michael, 2014). Again, no mediation analysis was undertaken.
These early findings may give rise to a simple, clinical hypothesis: exposure sessions are most effective in the morning, since the higher cortisol in the morning will maximize memory consolidation of new information and hence ultimately lead to better clinical outcomes. It is notable that time-of-day recommendations are common standard for psychotropic drug treatment, largely due to the handling of side-effects. However, such recommendations have not yet been explored for psychotherapy treatment. Though intriguing, the existing evidence for optimal exposure session timing is still modest and prior designs have not allowed for the direct testing of cortisol as a mediator of the time-of-day effects, to determine whether greater cortisol levels, independent of time-of-day, are responsible for improved clinical outcomes, or conversely, whether time-of-day enhances fear-learning independent of cortisol level. Sorting out the contributing factors may allow us to more optimally design exposure exercises.
Here we examined the role of time-of-day as a simple and practical predictor of therapeutic gains from exposure, examining patients undergoing multi-session in-vivo exposure therapy for panic disorder and agoraphobia. Using a cross-lagged analytic approach, we were also able to examine the role of cortisol levels as a mediator between time of day and therapeutic gains, hypothesizing that exposure sessions performed earlier in the day would result in greater clinical benefits, mediated by the enhancing effects of the higher levels of cortisol usually seen in the earlier part of the day.
Section snippets
Participants
Data came from a prior study that examined psychophysiological predictors of exposure treatment outcomes (Meuret et al., 2012b). Twenty-four outpatients with Panic Disorder (PD) with agoraphobia were recruited through an academic clinic and local advertisements. Patients were primarily white (95.8%), female (87.5%), married (n = 45.8%), well educated (M = 15.7 years, SD = 2.4), and employed (75.0%). The mean age was 32.4 years (SD = 9.1). Inclusion criteria were current principal diagnosis of PD and
Clinical changes
As reported previously (Meuret et al., 2012b), exposure therapy resulted in significant improvements in all measures over time (threat misappraisal [ASI], avoidance behaviors [MQA], perceived control [ACS], and panic symptom severity [PDSS]), as demonstrated by significant slopes of change over time (b = −0.12, t(24) = −4.61, p < 0.001, d = 1.88; b = −0.14, t(22) = −5.71, p < 0.001, d = 2.44; b = 0.20, t(21) = 7.08, p < 0.001, d = 3.09; and b = −0.21, t(31) = −5.60, p < 0.001, d = 2.01, respectively).
Effect of time-of-day on clinical improvement and cortisol
Controlling for severity
Discussion
This study examined the effects of time-of-day on indexes of extinction learning in patients with panic disorder and agoraphobia undergoing exposure therapy. Preliminary evidence from cross-sectional, laboratory studies has suggested that extinction learning is more effective with morning exposures. It has also been independently suggested that higher cortisol levels are associated with better outcomes. Here, we examined whether the time-of-day benefits of early exposure sessions are mediated
Conflict of interests
None of the authors have any actual or potential conflict of interests related to the findings of this study.
Contributions
All authors contributed to the design and implementation of the study or analysis and interpretation of the study results. All authors contributed to the review and interpretation of the results, report preparation, and approved the final version.
Role of funding source
The study was supported by the Behavior Therapy Research Foundation (PI Meuret). The Behavior Therapy Research Foundation had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report.
Acknowledgements
We would like to thank Dr. Berhard Dahme and Alex Fessler for his helpful input.
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