Do Evidence-Based Treatments for Circadian Rhythm Sleep-Wake Disorders Make the GRADE? Updated Guidelines Point to Need for More Clinical Research

INTRODUCTION

This issue of the Journal of Clinical Sleep Medicine contains updated clinical practice guidelines for the treatment of intrinsic circadian rhythm sleep-wake disorders (CRSWDs).¹ Use of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system of analysis represents a major change in comparison to the previously published CRSWD practice parameters,² and future American Academy of Sleep Medicine (AASM) guidelines will be subject to the same rigorous assessment criteria.

The use of the GRADE approach to assess the quality of evidence and determine the strength of recommendations is associated with significant changes.³ The Strengths of Recommendations are now dichotomized into two categories, “Strong” and “Weak,” either FOR or AGAINST specific patient-care strategies. A strong recommendation applies to actions that clinicians always should take for the specified CRSWD. Accordingly, a strong recommendation AGAINST a patient-care strategy indicates a treatment that clinicians should NOT use. Weak recommendations reflect a lower degree of certainty in the appropriateness of the patient-care strategy for all patients, and require that the clinician use his or her knowledge and experience, and consider the patient's individual values and preferences, to determine the best course of treatment. A weak recommendation for a patient-care strategy suggests that the majority of—but not all—patients would choose the reviewed treatment. A weak recommendation against suggests that a majority of patients would not choose this patient-care strategy; however, a small percentage of patients would nevertheless choose to do so. Thus, weak recommendations are conditional, based on the individual circumstances of the patient and clinician.

A conspicuous aspect of the new guideline is the paucity of relevant new studies since the previous CRSWD practice parameters were published in 2007 and, by relation, an abundance of therapies for which there is “No Recommendation.” This does not mean that particular treatments should not be employed but reflects the fact that, in the absence of sufficient and conclusive evidence, the Task Force did not feel sufficiently confident to make a recommendation for or against a treatment. As always, clinicians should use their best judgment prior to implementing a particular therapy. Affirmative or negative recommendations should serve to provide clinicians with heightened confidence in prescribing (or refraining from prescribing) select treatments and, equally importantly, the document should serve as a roadmap for future studies that will propel higher quality, more sophisticated CRSWD treatments.

A major implication of the use of the GRADE system is that the new treatment recommendations cannot be compared to the previous practice parameters since different assessment criteria were used. Thus, this guideline represents a replacement rather than an update of the previously published practice parameters.² Previous recommendations, however, are indicated in corresponding sections for the same treatment to provide a reader with more complete information. Furthermore, recommendations for a particular treatment or disorder each stand alone and are not meant to be compared or generalized relative to the other CRSWDs or treatments. As the AASM continues to incorporate the GRADE rating system into future guideline updates, we anticipate the increased rigor will improve treatment of sleep disorders and provide an impetus for research in clinical sleep medicine.

The circadian rhythms literature includes an impressive body of basic science studies performed with healthy individuals, but there is a relative dearth of research on patients suffering from CRSWDs. Thus, larger, more rigorously designed studies that include CRSWD patients and utilize International Classification of Sleep Disorders-adherent diagnostic criteria are required.⁴ Detailed therapeutic information needs to be provided consistently (e.g., method and means of treatment delivery, relationship of treatment timing with respect to a defined physiologic circadian phase marker or other sleep parameters, inclusion/exclusion of adjunctive behavioral interventions), so that results can be compared and replicated across centers. Field-based studies are sorely needed, lest tightly-controlled bench research prematurely dictate clinical treatment.

From the standpoint of outcomes, similar clinically relevant sleep-related measures are required for inter-study comparative purposes (e.g., polysomnography versus actigraphy versus subjective reports, phase markers), along with systematic measures of treatment compliance, to accurately inform clinical practice. Arguments may be made for investigation of outcome measures not addressed with this update (e.g., daytime alertness, rest-activity cycle variations), as these may be more relevant to patients with CRSWDs. Optimal inter-study medication comparisons will require equivalent dosing, formulation, timing, and treatment durations to accurately gauge benefit.

Research on long-term outcomes and potential risks related to circadian-based interventions is needed to determine the minimum required duration of specific treatments (or to determine that they are required indefinitely), and to develop maintenance treatment schedules. Demonstration of superiority (or lack thereof) of circadian versus clock-hour time of administration (TOA) for interventions should engender studies that aim to explore demonstrable benefits of phase assessments in the clinical setting. If importance of circadian TOA is demonstrated, it will be necessary to determine relevant light and melatonin phase response curves (PRCs) for adult populations afflicted with CRSWDs, and to determine the same for both afflicted and healthy pediatric/adolescent populations. Complicating matters, alterations in phase relationships between the circadian timing system and the timing of sleep among those with CRSWDs may impact the ability of interventions to exert benefits, even with knowledge of the PRC. Conflicting data have been presented in this regard.^5–11

Present guidelines predominantly reflect presumed biological underpinnings associated with CRSWDs. Studies are needed to improve understanding of predominant exogenous and endogenous contributors to the development and perpetuation of CRSWDs, so that different subtypes (and possibly different treatment/prophylactic regimens) can be identified. The associated development of clinical profiles would enable clinicians to better ascertain which patients might respond to suggested treatments. Although not the focus of the updated guideline, a lack of sophisticated diagnostics (e.g., a lack of a physiologic marker of CRSWDs for clinical purposes) may be responsible for the inability to identify various CRSWD phenotypes and to employ tailored treatments. Future investigations that demonstrate the utility of physiologic phase assessments from both a diagnostic and treatment standpoint would be of enormous benefit.

The major obstacle to overcoming all stated deficiencies is a lack of clinical research funding. Given the immense impact of circadian misalignment on myriad aspects of physical and mental health¹² and the common nature of select CRSWDs,⁴ prioritization of research dollars is needed. The nascent state of clinical research also appears to have a direct impact on CRSWD patients' confidence and satisfaction with their health practitioners. The Circadian Sleep Disorders Network ( www.circadiansleepdisorders.org), a nonprofit patient advocacy group, reports members' concerns regarding recognition of their conditions (even among sleep specialists), and related difficulties with access to care [personal communication].

On a more encouraging note, investigations specifically oriented to the pediatric/adolescent and other “special” populations have emerged with this updated guideline. Inclusion of the former group in particular should be of interest to those accustomed to treating delayed sleep-wake phase disorder. In addition, although much work remains, significant progress has been made in the overall recognition of CRSWDs since the inception of Sleep Medicine as a unique medical discipline. In closing, the dual aim of the present guideline is to provide clinicians with up-to-date information to make properly informed treatment decisions, while simultaneously providing an impetus to address clinical research deficiencies, and to ultimately provide effective, evidence-based therapies.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

CITATION

Auger RR, Burgess HJ, Emens JS, Deriy LV, Sharkey KM. Do evidence-based treatments for circadian rhythm sleep-wake disorders make the GRADE? Updated guidelines point to need for more clinical research. J Clin Sleep Med 2015;11(10):1079–1080.

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