What should be first-line treatment in the management of insomnia disorder, and is there an added value to providing a second treatment for those who fail initial therapy?
In a randomized clinical trial of 211 adults with insomnia disorder, first-stage treatment involving behavior therapy or zolpidem medication produced similar response and remission rates. Adding a second-stage therapy significantly increased the percentage of responders and remitters among patients treated initially with behavior therapy but not among those treated initially with medication.
Sequential treatments involving cognitive behavioral therapy and medication are an effective strategy for insomnia management.
Despite evidence of efficacious psychological and pharmacologic therapies for insomnia, there is little information about what first-line treatment should be and how best to proceed when initial treatment fails.
To evaluate the comparative efficacy of 4 treatment sequences involving psychological and medication therapies for insomnia and examine the moderating effect of psychiatric disorders on insomnia outcomes.
Design, Setting, and Participants
In a sequential multiple-assignment randomized trial, patients were assigned to first-stage therapy involving either behavioral therapy (BT; n = 104) or zolpidem (zolpidem; n = 107), and patients who did not remit received a second treatment involving either medication (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy [CT]). The study took place at Institut Universitaire en Santé Mentale de Québec, Université Laval, Québec City, Québec, Canada, and at National Jewish Health, Denver, Colorado, and enrollment of patients took place from August 2012 through July 2017.
Main Outcomes and Measures
The primary end points were the treatment response and remission rates, defined by the Insomnia Severity Index total score.
Patients included 211 adults (132 women; mean [SD] age, 45.6 [14.9] years) with a chronic insomnia disorder, including 74 patients with a comorbid anxiety or mood disorder. First-stage therapy with BT or zolpidem produced equivalent weighted percentages of responders (BT, 45.5%; zolpidem, 49.7%; OR, 1.18; 95% CI, 0.60-2.33) and remitters (BT, 38.03%; zolpidem, 30.3%; OR, 1.41; 95% CI, 0.75-2.65). Second-stage therapy produced significant increases in responders for the 2 conditions, starting with BT (BT to zolpidem, 40.6% to 62.7%; OR, 2.46; 95% CI, 1.14-5.30; BT to CT, 50.1% to 68.2%; OR, 2.09; 95% CI, 1.01-4.35) but no significant change following zolpidem treatment. Significant increase in percentage of remitters was observed in 2 of 4 therapy sequences (BT to zolpidem, 38.1% to 55.9%; OR, 2.06; 95% CI, 1.04-4.11; zolpidem to trazodone, 31.4% to 49.4%; OR, 2.13; 95% CI, 0.91-5.00). Although response/remission rates were lower among patients with psychiatric comorbidity, treatment sequences that involved BT followed by CT or zolpidem followed by trazodone yielded better outcomes for patients with comorbid insomnia. Response and remission rates were well sustained through the 12-month follow-up.
Conclusions and Relevance
Behavioral therapy and zolpidem medication produced equivalent response and remission rates. Adding a second treatment produced an added value for those whose insomnia failed to remit with initial therapies.
ClinicalTrials.gov Identifier: NCT01651442
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Charles M. Morin, PhD, École de Psychologie, Université Laval, 2325, rue des Bibliothèques, Québec, QC G1V 0A6, Canada (firstname.lastname@example.org).
Accepted for Publication: April 18, 2020.
Published Online: July 8, 2020. doi:10.1001/jamapsychiatry.2020.1767
Author Contributions: Drs Morin and Edinger had access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Morin and Edinger were principal investigators.
Concept and design: Morin, Edinger, Krystal, Belanger.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Morin, Edinger, Beaulieu-Bonneau, Simmons.
Critical revision of the manuscript for important intellectual content: Morin, Beaulieu-Bonneau, Ivers, Krystal, Guay, Belanger, Cartwright, Lamy, Busby.
Statistical analysis: Ivers.
Obtained funding: Morin, Edinger, Krystal.
Administrative, technical, or material support: Morin, Edinger, Beaulieu-Bonneau, Krystal, Simmons, Lamy.
Supervision: Morin, Edinger, Ivers, Guay, Belanger, Lamy.
Conflict of Interest Disclosures: Dr Morin has served as a consultant for Abbot, Eisai, Merck, Philips, and Weight Watchers and received research support from Idorsia and Canopy Health. Dr Edinger has received research support from Merck and Philips/Respironics. Ms Cartwright received research grant support from the National Institutes of Health, Janssen, Jazz Axsome, and Reveal Biosensors and served as a consultant to Eisai, Ferring, Galderma, Harmony Biosciences, Idorsia, Jazz, Janssen, Takeda, Merck, Neurocrine, Pernix, and Physician’s Seal. Dr Krystal reported grants from the National Institutes of Health, Patient-Centered Outcomes Research Institute, Axsome, and Reveal Biosensors; grants and personal fees from Janssen, Jazz, personal fees from Evecxia; and personal fees from Sage, Ferring, Galderma, Harmony Biosciences, Eisai, Idorsia, Neurocrine, Merck, and Takeda outside the submitted work. No other disclosures were reported.
Funding/Support: This study was funded by the National Institute of Mental Health (MH091053).
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Additional Information: The Data and Safety Monitoring Board (DSMB) was composed of 3 members including Daniel Almirall (Chair), Vaughn McCall, and Richard Bootzin. The DSMB committee was responsible for safeguarding the interests of study participants, assessing the safety and efficacy of study procedures, and monitoring the overall conduct of the study. The DSMB completed an annual review of the trial conduct. This committee was independent from the sponsor and declared no competing interests.
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