Sequential psychological and pharmacological therapies for comorbid and primary insomnia: study protocol for a randomized controlled trial.

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BACKGROUND: Chronic insomnia is a prevalent disorder associated with significant psychosocial, health, and economic impacts. Cognitive behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported therapeutic approaches for insomnia management. However, few investigations have directly compared their relative and combined benefits, and even fewer have tested the benefits of sequential treatment for those who do not respond to initial insomnia therapy. Moreover, insomnia treatment studies have been limited by small, highly screened study samples, fixed-dose, and fixed-agent pharmacotherapy strategies that do not represent usual clinical practices. This study will address these limitations. METHODS/DESIGN: This is a two-site randomized controlled trial, which will enroll 224 adults who meet the criteria for a chronic insomnia disorder with or without comorbid psychiatric disorders. Prospective participants will complete clinical assessments and polysomnography and then will be randomly assigned to first-stage therapy involving either behavioral therapy (BT) or zolpidem. Treatment outcomes will be assessed after 6 weeks, and treatment remitters will be followed for the next 12 months on maintenance therapy. Those not achieving remission will be offered randomization to a second, 6-week treatment, again involving either pharmacotherapy (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy (CT)). All participants will be re-evaluated 12 weeks after the protocol initiation and at 3-, 6-, 9-, and 12-month follow-ups. Insomnia remission, defined categorically as a score < 8 on the Insomnia Severity Index, a patient-reported outcome, will serve as the primary endpoint for treatment comparisons. Secondary outcomes will include sleep parameters derived from daily sleep diaries and from polysomnography, subjective measures of fatigue, mood, quality of life, and functional impairments; and measures of adverse events; dropout rates; and treatment acceptability. Centrally trained therapists will administer therapies according to manualized, albeit flexible, treatment algorithms. DISCUSSION: This clinical trial will provide new information about optimal treatment sequencing and will have direct implication for the development of clinical guidelines for managing chronic insomnia with and without comorbid psychiatric conditions. TRIAL REGISTRATION: Identifier: NCT01651442 , Protocol version 4, 20 April 2011, registered 26 June 2012.





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Morin, Charles M, Jack D Edinger, Andrew D Krystal, Daniel J Buysse, Simon Beaulieu-Bonneau and Hans Ivers (2016). Sequential psychological and pharmacological therapies for comorbid and primary insomnia: study protocol for a randomized controlled trial. Trials, 17(1). p. 118. 10.1186/s13063-016-1242-3 Retrieved from

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Andrew Darrell Krystal

Professor Emeritus of Psychiatry and Behavioral Sciences

My research is focused on better understanding the pathophysiology of sleep disorders and mood disorders and developing improved treatments for these conditions. My primary research tools are: electroencepahlography (EEG), polysomnography (PSG), computer signal analysis and modeling, functional magnetic resonance imaging (fMRI), and positron emission tomograophy (PET). Nearly all of my projects have been carried out with humans, however, projects are ongoing with gene knock-out models in mice, and lemurs in collaboration with the Duke Primate Center. A few representative current studies are: 1) Defining physiologic (EEG, PSG, PET, fMRI) correlates of sleep complaints and subtyping insomnia on the basis of the associated pathophysiology, 2) Studying the relationship of EEG data recorded during non-REM sleep, daytime function, and insomnia treatment response, 3) Developing new pharmacologic and non-pharmacologic treatments for insomnia, 4) Studying the relationship of natural sleep and hibernation-like phenomena (torpor), 5) Predicting depression treatment response on the basis of pre-treatment EEG and structural MRI data.

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