Initial treatment choices for long term remission of insomnia disorder in adults: a systematic review and network meta-analysis

Background Cognitive behavioral therapy for insomnia (CBT-I), pharmacotherapy and their combination are effective for insomnia. However, it remains unclear which treatment is more likely to lead to favorable long-term outcomes when used as the initial treatment. We aimed to evaluate the comparative efficacy and acceptability of CBT-I, pharmacotherapy, and their combination in the long- and short-terms among adults with insomnia disorder. Methods We searched PubMed, CENTRAL, PsycINFO and WHO ICTRP from database inception to Dec 27, 2023, to identify published and unpublished randomized controlled trials. We included trials in hypnotic-free adults with insomnia disorder comparing at least two of the following: CBT-I with at least one effective component (sleep restriction, stimulus control, cognitive restructuring, and third wave components), pharmacotherapy, or their combination. We assessed the confidence in evidence using CINeMA. The primary outcome was long-term remission (longest follow-up between 3 to 12 months). Secondary outcomes included all-cause dropout and self-reported sleep continuity measures at long-term follow-up, and the same outcomes at the end of the acute treatment phase. We performed frequentist random-effects network meta-analyses. We used odds ratio (OR) for dichotomous outcomes and mean difference for continuous outcomes, expressed in minutes and percent. This study is registered in PROSPERO (CRD42024505519). Findings We identified 13 trials, including 823 randomized participants (mean age, 47.8 years, 60% women). Results suggested that CBT-I was more beneficial than pharmacotherapy in the long-term (remission OR 1.82 [95% Confidence Interval (CI), 1.15 to 2.87; certainty of evidence: high]), while there was weaker evidence of benefit of combination against pharmacotherapy (OR 1.71 [95%CI, 0.88 to 3.30: moderate]) and no clear evidence of difference of CBT-I against combination (OR 1.07 [95%CI, 0.63 to 1.80: moderate]). CBT-I was associated with less dropouts than pharmacotherapy in the long-term. Short-term outcomes also favored CBT-I over pharmacotherapy except total sleep time. Given the average long-term remission rate in the pharmacotherapy-initiating arms of 28%, CBT-I resulted in a long-term remission rate of 41% (95% CI: 31% to 53%) and combination 40% (95% CI: 25% to 56%). Interpretation This study found that starting with CBT-I for the treatment of adults with chronic insomnia leads to better outcomes than starting with pharmacotherapy. Combination therapy may be better than pharmacotherapy alone, but unlikely to be worth the additional burden over CBT-I alone. ### Competing Interest Statement YF has received consultancy fee from Panasonic and lecture fee from Otsuka outside the submitted work. MS reports personal fee from SONY outside submitted work. TAF reports personal fees from Boehringer-Ingelheim, Daiichi Sankyo, DT Axis, Kyoto University Original, Shionogi, SONY and UpToDate, and a grant from DT Axis and Shionogi, outside the submitted work; In addition, TAF has a patent 7448125, and a pending patent 2022-082495, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. MP wrote treatment manuals and books for CBT-I, teaches CBT-I, and is a founder of Hypknowledge LLC. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Databases such as PubMed, CENTRAL, PsycINFO and WHO ICTRP I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Codes for all analyses will be available in a repository on GitHub (https://github.com/ykfrkw/W2I) after publication.