Lara Kierlin’s research while affiliated with University of California, Los Angeles and other places

Importance Placebo effects are commonly observed in benzodiazepine receptor agonist hypnotic clinical trials. Clinical guidelines recommend discontinuing benzodiazepine receptor agonist hypnotics (particularly in older adults) and administering cognitive behavioral therapy for insomnia (CBTI) as first-line therapy for insomnia. It is unknown whether a novel intervention that masks the daily dose of benzodiazepine receptor agonist during tapering and augments CBTI with novel cognitive and behavioral exercises targeting placebo effect mechanisms improves benzodiazepine receptor agonist discontinuation. Objective To compare a masked benzodiazepine receptor agonist taper plus augmented CBTI vs an unmasked taper plus standard CBTI. Design, Setting, and Participants This randomized clinical trial conducted at an academic medical center and a Department of Veterans Affairs medical center included adults aged 55 years or older who had used lorazepam, alprazolam, clonazepam, temazepam, and/or zolpidem for current or prior insomnia, at doses of less than 8-mg diazepam–equivalent 2 or more nights per week for at least 3 months. Data were collected between December 2018 and November 2023. Data analyses were conducted between November 2023 and July 2024. Interventions Masked taper plus cognitive behavioral therapy-augmented program (MTcap); standard CBTI plus supervised (unmasked) gradual taper (SGT). Main Outcomes and Measures The primary efficacy outcome was percentage achieving benzodiazepine receptor agonist discontinuation 6 months after treatment ended (6-month; intention-to-treat) measured with 7-day self-reported medication logs and for a subset, urine tests. Secondary outcomes were Insomnia Severity Index scores at 1 week posttreatment and 6 months posttreatment, percentage of participants that have discontinued benzodiazepine receptor agonist use at 1 week posttreatment, and benzodiazepine receptor agonist dose and the Dysfunctional Beliefs About Sleep-Medication subscale at 1 week and 6 months posttreatment. Results Of 338 participants who underwent in-depth screening, 188 participants (mean [SD] age, 69.8 [8.3] years, 123 male [65.4%] and 65 female [35.6%]) were randomly assigned to MTcap (n = 92) or SGT (n = 96). Compared with SGT, MTcap resulted in greater benzodiazepine receptor agonist discontinuation at 6 months (MTcap = 64 [73.4%], SGT = 52 [58.6%]; odds ratio [OR], 1.95; 95% CI 1.03-3.70; P = .04) and 1 week posttreatment (MTcap = 76 [88.4%], SGT = 62 [67.4%]; OR, 3.68; 95% CI, 1.67-8.12; P = .001) and reduced frequency of benzodiazepine receptor agonist use (nights/week) at 1 week posttreatment (−1.31; 95% CI, −2.05 to −0.57; P < .001). Insomnia Severity Index improved with no significant between-group difference at follow-up (baseline to 1 week posttreatment, 1.38; P = .16; baseline to 6 months, 0.16; P = .88). Conclusions and Relevance This randomized clinical trial found that a program combining masked tapering with novel cognitive and behavioral exercises targeting placebo mechanisms improved the percentage of long-term benzodiazepine receptor agonist discontinuation compared with standard CBTI plus an unmasked taper. Trial Registration ClinicalTrials.gov Identifier: NCT03687086

Introduction Benzodiazepines and benzodiazepine receptor agonists (BZRAs) are not recommended as first-line therapy for insomnia in older adults due to adverse events (e.g., falls). Although guidelines recommend cognitive behavioral therapy for insomnia (CBTI) and BZRA discontinuation, discontinuing BZRAs is challenging. To improve discontinuation success, we developed and tested a novel intervention (grounded in the science of known placebo effects of BZRAs), masked taper plus cognitive behavioral therapy-augmented program (MTcap), which masks the daily BZRA dose during tapering and adds novel cognitive and behavioral exercises targeting placebo effects to CBTI. We hypothesized that MTcap would increase BZRA discontinuation 1 week (PTX) and 6 months post-treatment (6M) compared to standard CBTI plus supervised (unmasked) gradual taper (SGT). Methods In a multi-site randomized trial, adults (>= 55 years) who use lorazepam, alprazolam, clonazepam, temazepam, and/or zolpidem at doses <= 8 mg diazepam-equivalent 2+ nights/week for >= 3 months for insomnia were randomized to MTcap versus SGT. Blinded research staff conducted PTX and 6M assessments including one-week medication logs and Insomnia Severity Index (ISI). Effects of MTcap versus SGT on BZRA discontinuation (primary outcome) were modeled with logistic regression. Using two-level mixed-effects models, we predicted additional outcomes (frequency [#days/week taken], dose, ISI) as a function of treatment group, site, treatment-site interaction, and time. Results 188 participants (mean age 69.2 years, 34.6% female, mean frequency 5.9 days/week BZRA use, mean diazepam-equivalent 3.9 mg, mean ISI 14.0) were randomized (MTcap n=92, SGT n=96), with PTX and 6M follow-up rates of 94.7% and 93.6%, respectively. BZRA discontinuation for MTcap was superior to SGT at both PTX (MTcap=0.884, SGT=0.674; odds ratio [OR] 3.683, 95% CI 1.670, 8.122, p=.001) and 6M (MTcap=0.734, SGT=0.586; OR 1.955, 95% CI 1.033, 3.700, p=.039). Change in BZRA frequency was lower in MTcap than SGT at PTX (-1.32, 95% CI -2.07, -0.57, p<.001), but not 6M. ISI did not differ between these two active treatment groups at PTX or 6M. Conclusion Adding a masked taper and novel cognitive and behavioral exercises targeting placebo effects to traditional unmasked tapering plus CBTI results in markedly improved long-term BZRA discontinuation, with similar improvement in symptoms of insomnia. Support (if any) VAIIR 17-234, NIAR01AG057929, UL1TR001881

Chronic use of hypnotic medications such as benzodiazepines is associated with adverse consequences including increased risk of falls. Efforts to help patients discontinue these medications have had varying levels of success. We developed a blinded (masked) tapering protocol to help patients taper off hypnotics. In this blinded protocol, patients consented to a drug taper but agreed to forego knowledge about the specific tapering schedule or the actual dose each night until the end of the taper. Blinded tapering aims to reduce negative expectancies for withdrawal effects that may impair a patient’s successful discontinuation of hypnotics. In preparation for a randomized trial, we tested the feasibility of adding a blinded tapering component to current best evidence practice [supervised hypnotic taper combined with cognitive behavioral therapy for insomnia (CBTI)] in 5 adult patients recruited from an outpatient mental health practice in Oregon. A compounding pharmacy prepared the blinded capsules for each patient. During the gradual blinded taper, each participant completed CBTI. Measures collected included feasibility/process (e.g., recruitment barriers), hypnotic use, the Dysfunctional Beliefs and Attitudes about Sleep Scale, Insomnia Severity Index, Epworth Sleepiness Scale, and Patient Health Questionnaire-9 (depressive symptoms). The intervention was feasible, and participants reported high satisfaction with the protocol and willingness to follow the same treatment again. All five participants successfully discontinued their hypnotic medication use post-treatment. Dysfunctional beliefs/attitudes about sleep and insomnia severity improved. Blinded tapering is a promising new method for improving hypnotic discontinuation among patients treated with a combination of hypnotic tapering plus CBTI.

Studies have found that depictions of unhealthy behaviors (e.g., illicit substance use, violence) are common in popular music lyrics; however, we are unaware of any studies that have specifically analyzed the content of music lyrics for unhealthy sleep-related behaviors. We sought to determine whether behaviors known to perpetuate insomnia symptoms are commonly depicted in the lyrics of popular music. We searched three online lyrics sites for lyrics with the word "insomnia" in the title and performed content analysis of each of the lyrics. Lyrics were analyzed for the presence/absence of the following perpetuating factors: extending sleep opportunity, using counter fatigue measures, self-medicating, and engaging in rituals or anti-stimulus control behaviors. We analyzed 83 music lyrics. 47% described one or more perpetuating factor. 30% described individual(s) engaging in rituals or antistimulus control strategies, 24% described self-medicating, 7% described engaging in counter fatigue measures, and 2% described extending sleep opportunity (e.g., napping during daytime). Maladaptive strategies known to perpetuate insomnia symptoms are common in popular music. Our results suggest that listeners of these sleep-related songs are frequently exposed to lyrics that depict maladaptive coping mechanisms. Additional studies are needed to examine the direct effects of exposing individuals to music lyrics with this content.

Diagnosis of insomnia disorder by the Diagnostic and Statistical Manual (DSM)-IV, and as proposed by the DSM-V, includes criteria for impairment in occupational- or social functioning due to sleep complaints. This study evaluated the clinical and polysomnographic correlates of impairment in daytime functioning in older adults with insomnia. In older adults with DSM-IV chronic insomnia (n=68), clinical and demographic information, and measures of health functioning, medical co-morbidity, and polysomnographic sleep were obtained. Four questions that evaluated difficulties or distress in occupational- or social functioning related to sleep complaints were used to code DSM threshold criteria for impairment in daytime functioning. Stepwise regression was used to identify predictors of impairment in daytime functioning. Impairment in daytime functioning was significantly associated with younger age (p<0.05), and the amount of wake time after sleep onset as assessed by polysomnography (p<0.001), controlling for health functioning and minority racial status. Amount of wake time after sleep onset uniquely contributes to criteria symptoms of impairment in daytime functioning among older adults with insomnia. Treatments that target sleep maintenance have the potential to improve social and occupational functioning in older adults with sleep complaints.

There exists a varying level of evidence linking the use of antidepressant medication to the parasomnias, ranging from larger, more comprehensive studies in the area of REM sleep behavior disorder to primarily case reports in the NREM parasomnias. As such, practice guidelines are lacking regarding specific direction to the clinician who may be faced with a patient who has developed a parasomnia that appears to be temporally related to use of an antidepressant. In general, knowledge of the mechanisms of action of the medications, particularly with regard to the impact on sleep architecture, can provide some guidance. There is a potential for selective serotonin reuptake inhibitors, tricyclic antidepressants, and serotonin–norepinephrine reuptake inhibitors to suppress REM, as well as the anticholinergic properties of the individual drugs to further disturb normal sleep architecture.

Licht et al1 discuss a relationship between depression and heart rate variability in their sample, which was also studied for the presence of other health-related variables, including heart disease and chronic medical conditions. Not specifically mentioned in their report is the presence of sleep-related breathing disorders (including sleep apnea) as a potential confounder, which is surprising given the evidence that exists linking these conditions to both diminished heart rate variability2 and depression.3

Insomnia is a complaint of patients seen in many medical settings, but it is particularly prevalent in patients who present to mental health practitioners. When choosing an intervention for insomnia, physicians often turn to pharmacological management options as their primary strategy, with other modalities only considered secondarily, if at all. Medications for insomnia, which include benzodiazepines, nonbenzodiazepines, and antihistamines, have been found to have both varying degrees of efficacy as well as side-effect profiles that may limit their use. In recent years, the American Academy of Sleep Medicine has studied nonpharmacologic interventions for insomnia and found evidence to support their use in achieving sustained improvements in sleep parameters over time. Methods such as cognitive-behavioral therapy, stimulus-control therapy, relaxation, paradoxical intention, and sleep restriction are efficacious treatments that mental health practitioners can consider in the treatment of insomnia. Researchers are only beginning to review evidence concerning complementary and alternative medicine therapies (CAM); however, given the preponderance of patients who may be employing these techniques for insomnia, it is important that clinicians be familiar with these approaches, which merit further study. This article reviews nonpharmacologic treatments for insomnia that are available to mental health practitioners as well as primary care providers, either via direct application of the techniques or by referral. The evidence for each of these modalities is presented in an effort to expand the treating physician's armamentarium beyond sole use of the medications traditionally used to treat insomnia.