Elsevier

Journal of Psychiatric Research

Volume 84, January 2017, Pages 90-97
Journal of Psychiatric Research

Specific expectancies are associated with symptomatic outcomes and side effect burden in a trial of chamomile extract for generalized anxiety disorder

https://doi.org/10.1016/j.jpsychires.2016.09.029Get rights and content

Abstract

Objective

Patient expectancies are hypothesized to contribute to the efficacy and side effects of psychiatric treatments, but little research has investigated this hypothesis in the context of psychopharmacological therapies for anxiety. We prospectively investigated whether expectancies predicted efficacy and adverse events in oral therapy for Generalized Anxiety Disorder (GAD), controlling for confounding patient characteristics correlating with outcomes.

Methods

Expectancies regarding treatment efficacy and side effects were assessed at baseline of an eight week open-label phase of a trial of chamomile for Generalized Anxiety Disorder (GAD). The primary outcome was patient-reported GAD-7 scores, with clinical response and treatment-emergent side-effects as secondary outcomes. Expectancies were used to predict symptomatic and side-effect outcomes.

Results

Very few baseline patient characteristics predicted either type of expectancy. Controlling for a patient's predicted recovery based on their baseline characteristics, higher efficacy expectancies at baseline predicted greater change on the GAD-7 (adjusted β = −0.19, p = 0.011). Efficacy expectancies also predicted a higher likelihood of attaining clinical response (adjusted odds ratio = 1.69, p = 0.002). Patients with higher side effect expectancies reported more side effects (adjusted log expected count = 0.26, p = 0.038). Efficacy expectancies were unrelated to side effect reports (log expected count = −0.05, p = 0.680), and side effect expectancies were unrelated to treatment efficacy (β = 0.08, p = 0.306).

Conclusions

Patients entering chamomile treatment for GAD with more favorable self-generated expectancies for the treatment experience greater improvement and fewer adverse events. Aligning patient expectancies with treatment selections may optimize outcomes.

Registration

Trial Number NCT01072344 at ClinicalTrials.gov.

Introduction

Patient expectancies for treatment have been identified as a key contributor to therapeutic effects and experience of side effects in both clinical practice and clinical trials (Bingel, 2014, Horing et al., 2014, Mora et al., 2011). For example, the higher the probability of being randomized to an active drug versus placebo arm of a randomized trial, the greater the observed magnitude of placebo effects in adult depression (Rutherford et al., 2009b, Rutherford et al., 2010, Rutherford et al., 2014b). Experimentally altering patients' beliefs about whether they are taking an active medication has sometimes been found to enhance the effects of placebos (Vase et al., 2002). Similarly, side effect profiles in the placebo arms of clinical trials often resemble those of the active drug comparator (Mora et al., 2011, Rojas-Mirquez et al., 2014) (i.e., a nocebo effect), and manipulating patients’ side effect expectations affects their reports of side effects (Mondaini et al., 2007, Wise et al., 2009).

However, it is less known as to how a patient's own positive and negative expectancies for a particular treatment shape their experiences while on that specific treatment. Across medical disciplines, prior studies have frequently measured patients' general health optimism or pessimism rather than their expectancy that a particular treatment would be helpful for their condition or be likely to cause side effects (Barefoot et al., 2011, Enck et al., 2013, Nestoriuc et al., 2010). While these studies have been cited as providing evidence for expectancy effects in treatments, specific expectancies for treatment are psychometrically distinguishable from health optimism and pessimism (Haanstra et al., 2015).

Expectancy research in psychopharmacology has primarily concerned the treatment of depression (Krell et al., 2004, Leuchter et al., 2014, Mora et al., 2011, Rutherford et al., 2010, Rutherford et al., 2013, Rutherford et al., 2014b, Rutherford and Roose, 2013, Sotsky et al., 1991, Weimer et al., 2015), in which naturalistic and manipulated expectancies are typically found to relate to depression treatment outcomes on placebo and often on active medications (though not always; Leuchter et al., 2014). However, negative expectancies are typically not assessed (Colagiuri et al., 2013). Furthermore, no study to our knowledge has assessed positive and negative expectancies in tandem, and often little is done to disentangle expectancies from confounding patient characteristics. For example, the number of prior treatments a patient has had for a condition could relate to both a patient's belief that they can get better on a treatment, and how treatment-resistant their illness is.

Moreover, for anxiety disorders—and generalized anxiety disorder (GAD) in particular—there has been very limited research into the role of patient-held expectancies in psychopharmacological treatment. This is unfortunate, as anxiety disorders as a class may evidence a less strong response to placebo or “common factors” interventions compared to unipolar depression (Cuijpers et al., 2012, Hofmann and Smits, 2008). Thus, it is possible that expectancy-driven responses differ in the treatment of anxiety as compared to depressive disorders, and that expectancies may have less or no relationship to outcomes for this disorder class.

On the other hand, a recent meta-analysis of psychopharmacological treatment of anxiety found that improvement on active medication was significantly greater in active-comparator studies (e.g., Drug A vs. Drug B) relative to placebo-controlled studies, replicating findings in depression (Rutherford et al., 2015). Patients have a higher expectancy for improvement in active-comparator designs relative to placebo-controlled designs (Gaudiano et al., 2013, Rutherford et al., 2009a), and these heightened expectancies are hypothesized to contribute to effects observed in active-comparator trials. Supportively, a recent randomized controlled trial treating depression reported a superiority of randomization to open-label citalopram versus placebo-controlled citalopram, and found that increases in expectancy in the open-label group mediated this superiority (Rutherford et al., 2016). Thus, it is possible that expectancy effects enhance treatment response in anxiety as they do in depression (Rutherford et al., 2009b, Rutherford et al., 2016). Ultimately, however, the relevance of the full body of depression-focused expectancy research in psychopharmacology to anxiety treatment is unclear. Observation of a relationship between patient-held expectancies and anxiety outcomes on a drug would further support an expectancy-based account of this meta-analytic finding (Rutherford et al., 2015).

Direct evidence does exist concerning the predictive value of patient expectancies in the psychotherapeutic treatment of anxiety. Early treatment expectancies have been found to correlate positively with outcomes in evidence-based psychotherapies for GAD (Borkovec and Costello, 1993, Newman and Fisher, 2010), social anxiety (Chambless et al., 1997, Safren et al., 1997), simple phobia (Price et al., 2008), and mixed anxiety disorders (Brown et al., 2014, Westra et al., 2007). Nevertheless, given that expectancies may act differently in a psychotherapy as compared to pill treatment—for example, as a motivation to engage in psychotherapeutic procedures such as exposures to feared stimuli or completing homework (Westra et al., 2007)—the transferability of this research to the psychopharmacology context is uncertain.

To help elucidate the role that particular expectancies may play in predicting symptomatic and side effect outcomes in psychopharmacological treatments for anxiety, we prospectively evaluated treatment-specific patient expectancies during a clinical trial of chamomile treatment for GAD. Expectancies for treatment efficacy and side effect emergence were assessed separately. We hypothesized that higher expectancy for treatment response would predict greater improvements in core anxiety symptoms and well-being. We also hypothesized that higher expectancy of side effect emergence would predict more reports of treatment-related side effects during treatment. Furthermore, we hypothesized that these relationships would be specific to their respective outcomes, and would not reflect general optimism or pessimism. Finally, we aimed to clarify whether any observed effects of expectancies were potentially attributable to their correlation with baseline patient characteristics that predict outcome (e.g., number of prior treatments), and hypothesized that expectancies would uniquely predict variance in outcomes even when adjusting for these baseline characteristics.

Section snippets

Patients

Patients were adults (≥18 years) with a DSM-IV diagnosis of GAD as a primary disorder recruited from a psychiatric clinic at a major research hospital and from primary care practices. All diagnoses were determined using the MINI-SCID/P (First et al., 2001) structured interview to assess for the presence of specific DSM-IV Axis I disorders. Discrepancies in diagnostic assessment for inclusion into the study were resolved by conferencing and consensus between the investigators of the trial.

Results

Between March 2010 and September 2014, we enrolled a total of 179 participants. Seven did not have baseline expectancy assessments and were therefore not included in the analyses. Demographic and clinical information on the sample is reported in Table 1. The mean participant age was 45.4 (SD 15.4), and 115 (66.9%) of participants were female. The mean baseline GAD-7 score was 15.1 (SD 3.1), reflecting moderate to severe GAD symptoms. The average participant reported having been in their current

Discussion

In this open-label study of oral chamomile extract for generalized anxiety disorder, participants with higher expectancy for positive outcomes experienced greater reduction of anxiety symptoms and were more likely to meet criteria for clinically significant response to treatment. In addition, patients who expected more side effects reported a higher number of side effects during treatment, relative to those who expected very few side effects. Our results suggest that expectancies can be

Author contributions

JJM designed the study and managed trial and data collection processes. JRK performed data analysis and data interpretation. JA obtained the funding. QSL performed data management. IS evaluated patients. RD provided expertise in psychological assessment and statistical analyses. All authors participated in study design, writing, revision, and approving the final manuscript.

Funding source

This study is supported by grant from the National Institutes of Health/National Center for Complementary and Integrative Health R01 AT005074. This study is in part supported by an NCI P30 Cancer Center Core Grant to Craig B. Thompson. The funding agencies had no role in the design or conduct of the study. Dr. Mao has full access to all the data in the study and had final responsibility for the decision to submit for publication.

Institutional approval

This study has been approved by the Institutional Review Board (Federalwide Assurance # 00004028) at the University of Pennsylvania. The protocol title is “Long-Term Chamomile Therapy of Generalized Anxiety Disorder” and the protocol number is 809780. All study participants have signed informed consent forms before participating in any study related activities.

Conflicts of interests

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that they have no conflicts of interest to report.

Acknowledgements

We thank all of the clinical coordinators and research assistants for their dedication to clinical trial coordination, data collection and management. We also thank Dr. Kenneth Rockwell and the staff at the Penn Investigational Drug Service for their contrition. We thank the Swedish Herbal Institute for processing, producing, and providing the standardized oral chamomile extract product. We also thank our Data Safety and Monitoring Board members Drs. Andy Nierenberg and Sara Ratcliffe for

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