Effect of Psychological and Medication Therapies for Insomnia on Daytime Functions: A Randomized Clinical Trial.

Importance: Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted. Objectives: To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted. Design, Setting, and Participants: In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023. Interventions: Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone). Main Outcomes and Measures: Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components. Results: Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, -3.5 [95% CI, -4.7 to -2.3] vs -4.3 [95% CI, -5.7 to -2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, -4.7 [95% CI, -7.3 to -2.2] vs -5.2 [95% CI, -7.9 to -2.5]), functional impairments (Work and Social Adjustment Scale mean score change, -5.0 [95% CI, -6.7 to -3.3] vs -5.1 [95% CI, -7.2 to -2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, -4.1 [95% CI, -5.8 to -2.4] vs -1.2 [95% CI, -3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, -3.8 [95% CI, -7.1 to -0.4]; zolpidem plus trazodone, -3.7 [95% CI, -6.3 to -1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, -3.7 [95% CI, -6.4 to -1.0]; zolpidem plus trazodone, -3.3 [95% CI, -5.9 to -0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences. Conclusions and Relevance: In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions. Trial Registration: ClinicalTrials.gov Identifier: NCT01651442.

Association between insomnia patients' pre-treatment characteristics and their responses to distinctive treatment sequences.

STUDY OBJECTIVES: It is common to provide insomnia patients a second treatment when the initial treatment fails, but little is known about optimal treatment sequences for different patient types. This study examined whether pre-treatment characteristics/traits predict optimal treatment sequences for insomnia patients. METHODS: A community sample of 211 adults (132 women; Mage = 45.6 ± 14.9 years) with insomnia were recruited. Patients were first treated with behavioral therapy (BT) or zolpidem (Zol). Non-remitting BT recipients were randomized to a second treatment with either Zol or cognitive therapy; non-remitting Zol recipients underwent BT or Trazodone as a second treatment. Remission rates were assessed at the end of the first and second 6-week treatments. We then compared the remission rates of dichotomous groups formed on the basis of gender, age, pretreatment scores on SF36 and Multidimensional Fatigue Scale, the presence/absence of psychiatric/medical comorbidities or pain disorders, and mean subjective sleep duration and efficiency within and across treatment sequences. RESULTS: Lower remission rates were noted for those: with a pain disorder, poor mental health perceptions, high MFI fatigue scores, and lower sleep times and efficiencies. Patients with a pain disorder responded best to the BT-to-Zol sequence, whereas patients with more mental impairment, severe fatigue, short sleep, and low sleep efficiency responded poorly to treatment starting with BT. CONCLUSIONS: Pain, fatigue, poor mental health status, and subjective sleep duration and efficiency all affect response to different insomnia treatment sequences. Findings may guide clinicians in matching insomnia treatments to their patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01651442, Protocol version 4, April 20, 2011, registered June 26, 2012, https://clinicaltrials.gov/ct2/show/NCT01651442?rslt=With&type=Intr&cond=Insomnia&cntry=US&state=US%3ACO&city=Denver&age=12&draw=2&rank=1.

Effectiveness of Sequential Psychological and Medication Therapies for Insomnia Disorder: A Randomized Clinical Trial.

Importance: 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. Objective: 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. Results: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01651442.

Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial.

CONTEXT: Cognitive behavioral therapy (CBT) and hypnotic medications are efficacious for short-term treatment of insomnia, but few patients achieve complete remission with any single treatment. It is unclear whether combined or maintenance therapies would enhance outcome. OBJECTIVES: To evaluate the added value of medication over CBT alone for acute treatment of insomnia and the effects of maintenance therapies on long-term outcome. DESIGN, SETTING, AND PATIENTS: Prospective, randomized controlled trial involving 2-stage therapy for 160 adults with persistent insomnia treated at a university hospital sleep center in Canada between January 2002 and April 2005. INTERVENTIONS: Participants received CBT alone or CBT plus 10 mg/d (taken at bedtime) of zolpidem for an initial 6-week therapy, followed by extended 6-month therapy. Patients initially treated with CBT attended monthly maintenance CBT for 6 months or received no additional treatment and those initially treated with combined therapy (CBT plus 10 mg/d of zolpidem) continued with CBT plus intermittent use of zolpidem or CBT only. MAIN OUTCOME MEASURES: Sleep onset latency, time awake after sleep onset, total sleep time, and sleep efficiency derived from daily diaries (primary outcomes); treatment response and remission rates derived from the Insomnia Severity Index (secondary outcomes). RESULTS: Cognitive behavioral therapy used singly or in combination with zolpidem produced significant improvements in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy (all P<.001); a larger increase of sleep time was obtained with the combined approach (P = .04). Both CBT alone and CBT plus zolpidem produced similar rates of treatment responders (60% [45/75] vs 61% [45/74], respectively; P = .84) and treatment remissions (39% [29/75] vs 44% [33/74], respectively; P = .52) with the 6-week acute treatment, but combined therapy produced a higher remission rate compared with CBT alone during the 6-month extended therapy phase and the 6-month follow-up period (56% [43/74 and 32/59] vs 43% [34/75 and 28/68]; P = .05). The best long-term outcome was obtained with patients treated with combined therapy initially, followed by CBT alone, as evidenced by higher remission rates at the 6-month follow-up compared with patients who continued to take zolpidem during extended therapy (68% [20/30] vs 42% [12/29]; P = .04). CONCLUSION: In patients with persistent insomnia, the addition of medication to CBT produced added benefits during acute therapy, but long-term outcome was optimized when medication is discontinued during maintenance CBT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00042146.

Hypnotic taper with or without self-help treatment of insomnia: a randomized clinical trial.

This study aimed to assess the efficacy of a minimal intervention focusing on hypnotic discontinuation and cognitive-behavioral treatment (CBT) for insomnia. Fifty-three adult chronic users of hypnotics were randomly assigned to an 8-week hypnotic taper program, used alone or combined with a self-help CBT. Weekly hypnotic use decreased in both conditions, from a nearly nightly use at baseline to less than once a week at posttreatment. Nightly dosage (in lorazepam equivalent) decreased from 1.67 mg to 0.12 mg. Participants who received CBT improved their sleep efficiency by 8%, whereas those who did not remained stable. Total wake time decreased by 52 min among CBT participants and increased by 13 min among those receiving the taper schedule alone. Total sleep time remained stable throughout withdrawal in both CBT and taper conditions. The present findings suggest that a systematic withdrawal schedule might be sufficient in helping chronic users stop their hypnotic medication. The addition of a self-help treatment focusing on insomnia, a readily available and cost-effective alternative to individual psychotherapy, produced greater sleep improvement.

Long-Term Maintenance of Therapeutic Gains Associated With Cognitive-Behavioral Therapy for Insomnia Delivered Alone or Combined With Zolpidem.

Study objectives: To document the long-term sleep outcomes at 12 and 24 months after patients with chronic insomnia were treated with cognitive-behavioral therapy (CBT), either singly or combined with zolpidem medication. Methods: Participants were 160 adults with chronic insomnia. They were first randomized for a six-week acute treatment phase involving CBT alone or CBT combined with nightly zolpidem, and randomized for a six-month extended treatment phase involving CBT, no additional treatment, CBT combined with zolpidem as needed, or CBT with zolpidem tapered. This paper reports results of the 12- and 24-month follow-ups on the main outcome measures derived from the Insomnia Severity Index and sleep diaries. Results: Clinical improvements achieved 6 months following the end of treatment were well-maintained in all four conditions, with insomnia remission rates ranging from 48% to 74% at the 12-month follow-up, and from 44% to 63% at the 24-month follow-up. Participants receiving CBT with zolpidem taper in the extended treatment phase had significantly better results than those receiving CBT with continued zolpidem as needed. The magnitude of improvements on sleep diary parameters was similar between conditions, with a slight advantage for the CBT with zolpidem taper condition. The addition of extended CBT did not alter the long-term outcome over improvements obtained during the initial 6-week CBT. Conclusions: The results suggest that CBT for insomnia, when delivered alone or in combination with medication, produce durable sleep improvements up to two years after completion of treatment. These long-term results indicate that even if a combined CBT plus medication approach provide an added benefit immediately after treatment, extending CBT while tapering medication produce better sustained improvements compared to continued use of medication as needed.

Cognitive-behavior therapy singly and combined with medication for persistent insomnia: Impact on psychological and daytime functioning.

While impairment of daytime functioning due to poor sleep is often the main determinant for seeking treatment, few studies have examined the clinical impact of insomnia therapies on daytime outcomes. The main objective of this study was to evaluate the impact of cognitive-behavior therapy (CBT), alone and combined with medication, on various indices of daytime and psychological functioning. Participants were 160 individuals with chronic insomnia who received CBT alone or CBT plus medication (zolpidem) for an initial six-week therapy, followed by an extended six-month therapy. Participants treated with CBT initially received maintenance CBT or no additional treatment and those treated with combined therapy initially continued with CBT plus intermittent medication (prn) or CBT without medication (taper). Measures of anxiety and depressive symptoms, fatigue, quality of life, and perceived impact of sleep difficulties on various indices of daytime functioning were completed at baseline, after each treatment stage, and at six-month follow-up. Following acute treatment, significant improvements of fatigue, quality of life (mental component), anxiety, and depression were obtained in the CBT alone condition but not in the combined CBT plus medication condition. Following extended treatment, further improvements were noted for the subgroup receiving extended CBT relative to that with no additional treatment, and for the subgroup receiving CBT and intermittent medication relative to that with CBT but no medication. Improvements were well maintained at the 6-month follow-up. These findings indicate that insomnia-specific therapy is effective at improving daytime and psychological functioning in the short term, and that maintenance therapy produces an added value to optimize long-term outcomes. TRIAL REGISTRATION: www.clinicaltrials.gov (#NCT 00042146).

Sequential combinations of drug and cognitive behavioral therapy for chronic insomnia: an exploratory study.

This study explores the efficacy of sequential treatments involving medication and cognitive behavioral treatment (CBT) for primary insomnia. Seventeen participants took part in a multiple baseline design and were assigned to: (a) medication for 5 weeks, followed by combined medication plus CBT for 5 weeks; (b) combined treatment for 5 weeks, followed by CBT alone; or (c) CBT alone. Each treatment sequence produced significant sleep improvements, but at different points in time. For the first sequence, most of the sleep improvement was obtained after the introduction of CBT, while for the other sequence and CBT alone, improvement appeared during the first weeks. These results suggest that sleep improvement seems affected by the way treatments are combined. Also, a sequence beginning with a combined treatment followed by CBT alone seems to produce the best outcome. Additional research should be conducted with larger samples to determine the most effective sequence.

Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia.

OBJECTIVE: This study evaluated the effectiveness of a supervised benzodiazepine taper, singly and combined with cognitive behavior therapy, for benzodiazepine discontinuation in older adults with chronic insomnia. METHOD: Seventy-six older adult outpatients (38 women, 38 men; mean age of 62.5 years) with chronic insomnia and prolonged use (mean duration of 19.3 years) of benzodiazepine medication for sleep were randomly assigned for a 10-week intervention consisting of a supervised benzodiazepine withdrawal program (N=25), cognitive behavior therapy for insomnia (N=24), or supervised withdrawal plus cognitive behavior therapy (N=27). Follow-up assessments were conducted at 3 and 12 months. The main outcome measures were benzodiazepine use, sleep parameters, and anxiety and depressive symptoms. RESULTS: All three interventions produced significant reductions in both the quantity (90% reduction) and frequency (80% reduction) of benzodiazepine use, and 63% of the patients were drug-free within an average of 7 weeks. More patients who received medication taper plus cognitive behavior therapy (85%) were benzodiazepine-free after the initial intervention, compared to those who received medication taper alone (48%) and cognitive behavior therapy alone (54%). The patients in the two groups that received cognitive behavior therapy perceived greater subjective sleep improvements than those who received medication taper alone. Polysomnographic data showed an increase in the amount of time spent in stages 3 and 4 sleep and REM sleep and a decrease in total sleep time across all three conditions from baseline to posttreatment. Initial benzodiazepine reductions were well maintained up to the 12-month follow-up, and sleep improvements became more noticeable over this period. No significant withdrawal symptoms or adverse events were associated with benzodiazepine tapering. CONCLUSIONS: A structured, time-limited intervention is effective in assisting chronic users of benzodiazepine medication to discontinue or reduce their use of medication. The addition of cognitive behavior therapy alleviates insomnia, but sleep improvements may become noticeable only after several months of benzodiazepine abstinence.

Speed and trajectory of changes of insomnia symptoms during acute treatment with cognitive-behavioral therapy, singly and combined with medication.

OBJECTIVES: To examine the speed and trajectory of changes in sleep/wake parameters during short-term treatment of insomnia with cognitive-behavioral therapy (CBT) alone versus CBT combined with medication; and to explore the relationship between early treatment response and post-treatment recovery status. METHODS: Participants were 160 adults with insomnia (mean age, 50.3 years; 97 women, 63 men) who underwent a six-week course of CBT, singly or combined with 10 mg zolpidem nightly. The main dependent variables were sleep onset latency, wake after sleep onset, total sleep time, sleep efficiency, and sleep quality, derived from sleep diaries completed daily by patients throughout the course of treatment. RESULTS: Participants treated with CBT plus medication exhibited faster sleep improvements as evidenced by the first week of treatment compared to those receiving CBT alone. Optimal sleep improvement was reached on average after only one week for the combined treatment compared to two to three weeks for CBT alone. Early treatment response did not reliably predict post-treatment recovery status. CONCLUSIONS: Adding medication to CBT produces faster sleep improvement than CBT alone. However, the magnitude of early treatment response is not predictive of final response after the six-week therapy. Additional research is needed to examine mechanisms involved in this early treatment augmentation effect and its impact on long-term outcome.

Comparison of subjective and objective sleep quality in menopausal and non-menopausal women with insomnia.

BACKGROUND: Insomnia affects midlife women as they approach and experience menopause at a rate higher than most other stages of life. Insomnia is considered one of the climacteric symptoms of menopause, which can be controlled with hormone replacement therapy (HRT). This study examined the relationship between menopause and sleep in women with insomnia and compared the sleep quality of menopausal women with and without HRT. METHODS: A total of 74 women (age range=40-59 years old) with insomnia who were either pre or peri/post menopause were evaluated at Laval University's Sleep Disorders Center as part of ongoing clinical trials of insomnia therapies. All participants completed daily sleep diaries for a 2-week period and a series of psychological and insomnia questionnaires, followed by three consecutive nights of polysomnographic evaluation (PSG). A detailed medical history interview was taken by the study physician. RESULTS: PSG measures showed that menopausal women had significantly longer total wake time (TWT, 84.2 vs. 63.2 min, Cohen's d=0.504) and lower sleep efficiency (SE, 81.8% vs. 86.0%, d=0.487) than the non-menopausal women. Women using HRT did not show significantly better sleep compared to those who did not use HRT. No significant difference was observed between menopausal groups on subjectively assessed sleep parameters. CONCLUSION: Menopause may contribute to specific aspects of sleep disturbances in midlife women with insomnia. Use of HRT for menopausal symptoms does not seem to attenuate such disturbances, although further investigation using hormonal level dosing and a larger sample size is warranted.

Sequential treatment for chronic insomnia: a pilot study.

This article explores the efficacy of sequential treatment involving medication and cognitive behavioral treatment (CBT) for insomnia. In a multiple baseline across-subjects design, 6 participants with primary chronic insomnia received 1 of the following treatment sequences: (a) concurrent combination of medication and CBT for the 10-week treatment duration (Combined); (b) medication for the first 5 weeks, with introduction of CBT at week 4 and medication withdrawal after the 5th week resulting in treatment overlap during weeks 4 and 5 (Overlapping: Medication --> Combined --> CBT); and (c) medication alone for the first 5 weeks followed by CBT alone for an additional 5 weeks (Medication --> CBT). Each sequence led to significant sleep improvements, but these improvements occurred at different times during the intervention. Participants in the Combined and in the Overlapping sequences improved their sleep during the 1st phase of treatment, whereas those in the Medication --> CBT sequence improved mostly during the 2nd phase of treatment. These preliminary results suggest that a sequential treatment is effective for chronic insomnia. In addition, the results suggest that sleep improvements are more likely to emerge when CBT is introduced, with an Overlapping sequence showing a slight advantage over the other sequences. Additional clinical trials should be conducted with larger samples to replicate these preliminary findings.