A double-blind, randomized, placebo-controlled trial of suvorexant for the treatment of vasomotor symptom-associated insomnia disorder in midlife women

Study Objectives The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS. Methods In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 minutes of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10-20 mg (n=27) or placebo (n=29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race. Results Mean baseline ISI scores were 18.1 (95% CI, 16.8-19.4) and 18.3 (95% CI, 17.2-19.5) in the suvorexant and placebo groups, respectively (p=0.81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant [-8.1 (95% CI, -10.2 to -6.0)] compared to placebo [-5.6 (95% CI, -7.4 to -3.9), p=0.04]. Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p<0.01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparison. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated. Conclusion These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia.

Interaction of Gut Microbiota and Brain Function in Patients With Chronic Insomnia: A Regional Homogeneity Study

Recent studies have shown that the human gut microbiota (GM) plays a critical role in brain function and behavior via the complex microbiome–gut–brain axis. However, knowledge about the underlying relationship between the GM and changes in brain function in patients with chronic insomnia (CI) is still very limited. In this prospective study, 31 CI patients and 30 healthy controls were recruited. Resting-state functional magnetic resonance imaging scans were performed and brain functional alterations in CI patients were evaluated using the regional homogeneity (ReHo) method. We collected fecal samples of CI patients and used 16S rDNA amplicon sequencing to assess the relative abundance (RA) and alpha diversity of the GM. We also performed extensive sleep, mood, and cognitive assessments. Then, we tested for potential associations between the GM profile, ReHo alterations, and neuropsychological changes in CI patients. Our results showed associations between the RA of Lactobacilli, ReHo values in the left fusiform gyrus, and depression scores in CI patients. We also found some bacterial genera related to ReHo values of the right triangular inferior frontal gyrus. In addition, the RA of genus Coprobacter was correlated with ReHo values of the left angular gyrus and with specific cognitive performance. These findings revealed complex relationships between GM, brain function, and behavior in patients with CI.

Association Between Z Drugs Use and Risk of Cognitive Impairment in Middle-Aged and Older Patients With Chronic Insomnia

Background: Benzodiazepines (BZDs) and Non-BZDs (NBZDs) have been widely used for patients with chronic insomnia. Long-term uses of BZDs may cause cognitive impairment and increase the risk for dementia in older patients. NBZD as an agonist of the GABAA receptor complex includes eszopiclone, zopiclone, zolpidem, and zaleplon, also collectively known as Z drugs. However, evaluations for an association between cognitive impairment and Z drug use have been limitedly performed. This study aimed to investigate the association between the risk of cognitive decline and exposure to Z drugs in middle-aged and older patients with chronic insomnia.Methods: Investigations were performed on patients with chronic insomnia who visited the outpatient Department of Neurology, Beijing Friendship Hospital, and were assessed for the global cognitive function (MoCA) and memory (AVLT), executive function (TMT-B), visuospatial ability (CDT), verbal function (BNT-30), and attention (DST). Multiple regression analysis was conducted to determine the independent factors of cognition and evaluated the effect of Z drug use (zolpidem and zopiclone) on cognition.Results: A total of 120 subjects were identified. In our analysis, BZD exposure density (P = 0.025, OR = 1.43, 95% CI, 1.25–1.86) was an independent risk factor of cognitive impairment in middle-aged and older patients with chronic insomnia. Neither Z drug use (P = 0.103) nor Z drug exposure density (P = 0.765) correlated with global cognitive function. Moreover, there was a positive association between Z drug use and attention [(P = 0.002, OR = 0.42, 95% CI, 0.24–0.73)]. Additionally, income level (P = 0.001, OR = 0.23, 95% CI, 0.10–0.53), severity of insomnia (P = 0.019, OR = 1.20, 95% CI, 1.03–1.40) and age (P = 0.044, OR = 1.07, 95% CI, 1.00–1.14) were also independent factors of global cognitive function.Conclusion: BZD exposure density was an independent risk factor of cognitive impairment in middle-aged and older patients with chronic insomnia, but no correlation was found between Z drug use and cognitive impairment. Moreover, the use of Z drugs seemed to be associated with protection for attention. The use for prescription of BZDs, in this case, should be avoided or limited to low doses. Due to the addiction and tolerance, Z drugs should also be prescribed with great caution in middle-aged and elderly patients.

Abnormalities in Cutaneous Microcirculation in Patients with Alzheimer’s Disease, Mild Cognitive Impairment, and Chronic Insomnia Disorder

Impaired sympathetic response is frequently observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). On the other hand, chronic insomnia disorder (CID) is also often accompanied by activation of sympathetic nerves. Considering that cutaneous microcirculation reflects sympathetic tone, we hypothesized that baseline cutaneous microcirculation in fingers, as detected by laser Doppler flowmetry (LDF), differs among patients with mild cognitive impairment (MCI), AD, and CID. As light therapy is one of the adjunctive treatments for AD and CID, we designed a randomized controlled cross-over trial of light therapy through eyes for 12 weeks with red light as treatment and green light as control limb, and examined if light therapy has an impact on cutaneous microcirculation. Before light therapy, patients with AD had significantly lower baseline cutaneous perfusion than those with CID in left and right first to fourth fingers. After red light therapy, however, cutaneous perfusion of fingers in CID patients significantly decreased (right fingers, before vs. after = 227.25 ± 62.00 vs. 162.00 ± 49.34, p = 0.007; left fingers, before vs. after = 228.99 ± 58.80 vs. 177.41 ± 59.41, p = 0.003) while cutaneous perfusion of fingers in CID patients did not significantly change after green light therapy. Light therapy with red light also significantly increased cutaneous finger perfusion in patients with AD (right fingers, before vs. after = 130.13 ± 49.82 vs. 172.38 ± 38.32, p = 0.043). Our results suggest that cutaneous perfusion is a useful tool to detect sympathetic dysfunction in patients with CID and AD, and that light therapy with red light is a potential therapeutic intervention to reverse impaired sympathetic function in patients with CID and patients with AD.

Correlation between Serum Levels of Sympathetic Nerve Activity Markers and Sleep Quality and Cognitive Function in Patients with Chronic Insomnia Disorder

Objectives: To explore the changes of the serum levels of copeptin and α-amylase and the correlations with sleep quality and cognition function in the patients with chronic insomnia disorder (CID). Methods: Fifty-seven CID patients and thirty healthy controls were enrolled continuously. Pittsburgh Sleep Quality Index (PSQI), polysomnography (PSG) and Pre-Sleep Arousal Scale (PSAS) were used to assess the insomnia severity and cognitive and somatic manifestations of arousal experienced at bedtime. Montreal Cognitive Assessment scale (MoCA) and Nine-Box Maze were used to respectively assess general cognition and memories. The serum levels of copeptin and α-amylase were detected using Enzyme-Linked ImmunoSorbent Assay. Results: Compared to the controls, the CID patients had increased PSQI and PSAS scores (Z=‒7.678 and ‒7.350; Ps<0.001), decreased MoCA score (t=‒4.625, P<0.001), increased numbers of errors in the object working, spatial working and object recognition (Z=‒2.099, ‒3.935 and ‒2.266; Ps<0.05) memories, and elevated serum levels of copeptin and α-amylase (t=5.414 and 5.597, P <0.001). In the CID patients，the level of copeptin positively correlated with PSQI and PSAS scores (r=0.338 and 0.316; Ps<0.05), and PSG sleep latency, wake time and N1% (r=0.324, 0.325 and 0.278, Ps<0.05), and negatively correlated with PSG N 2% (r=‒0.279, Ps<0.05). Alpha-amylase was positively correlated with waking numbers in PSG (r=0.293, P< 0.05). Multiple linear regression analysis showed that copeptin level affected PSQI score and PSG sleep latency (P<0.05). Conclusions: The serum levels of copeptin and α-amylase elevated in the CID patients, and the serum levels of copeptin may be associated with the poor sleep quality, especially in the individuals of initial sleep difficulties.

Polysomnographic Characteristics of the Patients Having Chronic Insomnia and Obstructive Sleep Apnea: Evidence for Paradoxical Insomnia and Comorbid Insomnia with OSA (COMISA)

Background: Sleep state misperception (SSM) is seen among patients with obstructive sleep apnea (OSA) as well as those having insomnia. Moreover, OSA and insomnia can also be comorbid. This study aims at finding the proportion of SSM and “Comorbid Insomnia with OSA” (COMISA) among patients of OSA and chronic insomnia. Macroachitecture of sleep was also compared across groups. Methods: This study utilized the retrospective laboratory and medical records of two groups of patients: chronic insomnia and OSA. Sleep disorders were diagnosed according to standard criteria. Daytime sleepiness was examined using the Epworth Sleepiness Scale. Diagnosis of SSM was based on the difference between subjective and objective sleep onset latency (Subjective SOL > 1.5 × Objective SOL). Results: Sixteen adult subjects were included in each group. Based on the difference between subjective and objective sleep onset latency, SSM was reported by 62.5% subjects of chronic insomnia and 56.25% subjects having OSA (OR = 1.29; 95% CI = 0.31–5.33; P = 0.79). The proportion of COMISA in subjects with chronic insomnia was 18% and among subjects with OSA, it was 43%. Effect size for the proportion was calculated as odds ratio (33.96; 95% CI = 7.48–154.01; P < 0.0002). Thus, the odds for COMISA were higher among subjects with OSA than those with chronic Insomnia. The three groups (OSA, COMISA and Chronic Insomnia) were comparable with regard to the macro-architecture of sleep. Conclusion: SSM is common among subjects with OSA and chronic insomnia. COMISA was commoner among patients with OSA compared to those with chronic insomnia. Macro-architecture of sleep is comparable among groups.

IgLON5 autoimmunity tested positive in patients with isolated chronic insomnia disease

In the patients with neurological autoimmune diseases such as anti-IgLON5 disease, insomnia symptoms are very common. Clinical diagnosis of the anti-IgLON5 disease is usually made when neurodegenerative processes have occurred. To find the early signs of anti-IgLON5 disease, we evaluate the presence of IgLON5 autoantibodies in the serum of patients with chronic insomnia disease. Based on video-polysomnography, twenty-two individuals with isolated chronic insomnia disease were found. A control group of twenty-two healthy people was chosen using the PSQI. An indirect immunofluorescence cell-based test of serum anti-IgLON5 antibodies was used to investigate IgLON5 autoimmunity. Anti-IgLON5 antibodies were detected in the serum of four of these patients with the titer of 1/10. The presence of IgLON5 autoantibodies in some patients with chronic insomnia disease can be considered a causing factor of insomnia which can be effective in more specific treatments of these patients. Moreover, the recognition of anti-IgLON5 disease in the early stages and before the progression of tauopathies can be useful in effective and timely treatment.