Management of insomnia symptoms in depressed patients treated with agomelatine, mirtazapine and trazodone: A systematic review and meta-analysis.

The diagnosis of insomnia rests on self-report of difficulty initiating or maintaining sleep. However, subjective reports may be unreliable, and possibly may vary by the method of inquiry. We investigated this possibility by comparing within-individual response to direct versus indirect time queries after overnight polysomnography. We obtained self-reported sleep-wake times via morning questionnaires in 879 consecutive adult diagnostic polysomnograms. Responses were compared within subjects (direct versus indirect query) and across groups defined by apnea-hypopnea index and by self-reported insomnia symptoms in pre-sleep questionnaires. Direct queries required a time duration response, while indirect queries required clock times from which we calculated time durations. Direct and indirect queries of sleep latency were the same in only 41% of cases, and total sleep time queries matched in only 5.4%. For both latency and total sleep, the most common discrepancy involved the indirect value being larger than the direct response. The discrepancy between direct and indirect queries was not related to objective sleep metrics. The degree of discrepancy was not related to the presence of insomnia symptoms, although patients reporting insomnia symptoms showed underestimation of total sleep duration by direct response. Self-reported sleep latency and total sleep time are often internally inconsistent when comparing direct and indirect survey queries of each measure. These discrepancies represent substantive challenges to effective clinical practice, particularly when diagnosis and management depends on self-reported sleep patterns, as with insomnia. Although self-reported sleep-wake times remains fundamental to clinical practice, objective measures provide clinically relevant adjunctive information.

Introduction Depression is associated with poor subjective sleep on Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI), and with polysomnographic (PSG) sleep disturbances. However, how physiological variables relate to self-reported sleep remains unclear. This analysis compares PSG and self-reported sleep measures between patients with vs. without depression history, and correlates self-reported and PSG measures. Methods From 1666 consecutive clinical baseline adult PSG studies, 201 patients were selected who had ≥120 minutes of total sleep time (TST), AHI< 5.0, no history of shift work or significant pain, neurological, cardiac, pulmonary, endocrine and psychiatric diagnoses, except depression (with or without anxiety). Only 18 patients (10 women, 16 white) with depression met other inclusion criteria; 17 of them were taking various mood stabilizers. MANCOVA, with sex, age and BMI covariates, was used to compare patients with vs. without depression history on PSQI, ISI, Center for Epidemiological Studies Depressions Scale Revised (CESDR), TST, N1%, N3%, REM%, SL, REM latency (REMLat) sleep efficiency (SE), WASO, number of awakenings (AW) and total arousal index (TAI). PSG variables showing between-group differences were used to predict ISI and PSQI in multiple regression models. Results Depression group had higher CESDR (M[Depression]=28.8±16.6 vs. M[No-Deprression]=12.7±10.6, p< 0.001), ISI (M[Deprression]=17.4±6.1 vs. M[No-Deprression]=12.1±6.4, p=0.001), PSQI (M[Deprression]=11.4±4.8 vs. M[No-Deprression]=8.7±3.7, p=0.009), more frequent AW (M[Deprression]=32.7±23.2 vs. M[No-Deprression]=28.0±12.0, p=0.02) and TAI (M[Deprression]=29.5±19.1 vs. M[No-Deprression]=22.4±12.7, p=0.01), lower N3% (M[Deprression]=14.1±9.1 vs. M[No-Deprression]=19.6±6.4, p< 0.001), longer REMLat (M[Deprression]=164.6±110.3 vs. M[No-Deprression]=107.7±62.3, p=0.006) and marginally longer SL (M[Deprression]=47.9±38.6 vs. M[No-Deprression]=29.9±32.2, p=0.055). In multiple regressions, no PSG variables predicted ISI or PSQI in either group or in both groups combined (all p values >0.09). Conclusion This small sample of depressed patients without major medical or psychiatric comorbidities evidenced both subjective and objective sleep disturbance, in comparison with non-depressed patients. However, PSG variables do not appear to account for subjective sleep disturbance as measured by ISI and PSQI. These results suggest a complex relationship between depression and different measures of sleep. Effect of depression on subjective sleep may be mediated by factors other than PSG variables, including antidepressant use and daytime symptoms. Support (if any) none

The Role of Duloxetine in the Treatment of Depression and Associated Painful Physical Symptoms.

To assess the sleep detection and staging validity of a non-contact, commercially available bedside bio-motion sensing device (S+, ResMed) and evaluate the impact of algorithm updates. Polysomnography data from 27 healthy adult participants was compared epoch-by-epoch to synchronized data that were recorded and staged by actigraphy and S+. An update to the S+ algorithm (common in the rapidly evolving commercial sleep tracker industry) permitted comparison of the original (S+V1) and updated (S+V2) versions. Sleep detection accuracy by S+V1 (93.3%), S+V2 (93.8%), and actigraphy (96.0%) was high; wake detection accuracy by each (69.6%, 73.1%, and 47.9%, respectively) was low. Higher overall S+ specificity, compared to actigraphy, was driven by higher accuracy in detecting wake before sleep onset (WBSO), which differed between S+V2 (90.4%) and actigraphy (46.5%). Stage detection accuracy by the S+ did not exceed 67.6% (for stage N2 sleep, by S+V2) for any stage. Performance is compared to previously established variance in polysomnography scored by humans: a performance standard which commercial devices should ideally strive to reach. Similar limitations in detecting wake after sleep onset (WASO) were found for the S+ as have been previously reported for actigraphy and other commercial sleep tracking devices. S+ WBSO detection was higher than actigraphy, and S+V2 algorithm further improved WASO accuracy. Researchers and clinicians should remain aware of the potential for algorithm updates to impact validity. A commentary on this article appears in this issue on page 935.

This archival cross-sectional investigation examined the impact of mood, reproductive status (RS), and age on polysomnographic (PSG) measures in women. PSG was performed on 73 normal controls (NC) and 64 depressed patients (DP), in the course of studies in menstruating, pregnant, postpartum, and peri- and postmenopausal women. A two-factor, between-subjects multivariate analysis of variance (MANOVA) was used to test the main effects of reproductive status (RS: menstrual vs pregnant vs postpartum vs menopausal) and diagnosis (NC vs DP), and their interaction, on PSG measures. To further refine the analyses, a two-factor, between subjects MANOVA was used to test the main effects of age (19 to 27 vs 28 to 36 vs 37 to 45 vs 46+ years) and diagnosis on the PSG data. Analyses revealed that in DP women, rapid eye movement (REM) sleep percentage was significantly elevated relative to NC across both RS and age. Significant differences in sleep efficiency, Stage 1%, and REM density were associated with RS; differences in total sleep time, Stage 2 percentage, and Stage 4 percentage were associated with differences in age. Both RS and age were related to differences in sleep latency, Stage 3 percentage, and Delta percentage. Finally, wake after sleep onset time, REM percentage, and REM latency did not vary with respect to RS or age. Overall, this investigation examined three major variables (mood, RS, and age) that are known to impact sleep in women. Of the variables, age appeared to have the greatest impact on PSG sleep measures, reflecting changes occurring across the lifespan.

Sleep quality in patients studied with laboratory-based polysomnography may differ from sleep quality in patients studied at home but remains clinically relevant and important to describe. We assessed objective sleep quality and explored factors associated with poor sleep in patients undergoing laboratory-based polysomnography. We reviewed diagnostic polysomnography studies from a 10-year period at a single sleep center. Total sleep time (TST) and sleep efficiency (SE) were assessed as markers of sleep quality. Poor sleep was defined as TST ≤ 4 hours or SE ≤ 50%. Multivariable analysis was performed to determine associations between objective sleep quality as an outcome and multiple candidate predictors including age, sex, race, body mass index, comorbidities, severity of obstructive sleep apnea, and central nervous system medications. Among 4957 patients (age 53 ± 15 years), average TST and median SE were 5.8 hours and 79%, respectively. There were 556 (11%) and 406 (8%) patients who had poor sleep based on TST and SE, respectively. In multivariable analysis, those who were older (per 10 years: 1.48 [1.34, 1.63]), male (1.38 [1.14,1.68]), and had severe obstructive sleep apnea (1.76 [1.28, 2.43]) were more likely to have short sleep. Antidepressant use was associated with lower odds of short sleep (0.77 [0.59,1.00]). Older age (per 10 years: 1.48 [1.34, 1.62]), male sex (1.34 [1.07,1.68]), and severe obstructive sleep apnea (2.16 [1.47, 3.21]) were associated with higher odds of poor SE. We describe TST and SE from a single sleep center cohort. Multiple demographic characteristics were associated with poor objective sleep in patients during laboratory-based polysomnography. Harrison EI, Roth RH, Lobo JM, et al. Sleep time and efficiency in patients undergoing laboratory-based polysomnography. J Clin Sleep Med. 2021;17(8):1591-1598.

This study presents polysomnographic data and psychiatric history for parents and siblings of probands with unipolar depression and short REM latency, probands with unipolar depression and normal REM latency, and normal comparison probands. Parents and adult siblings (N = 252) of probands (N = 64) were evaluated for lifetime history of psychiatric disorders and were studied in the sleep laboratory for 3 nights. REM latency predicted lifetime history of major depression. Short REM latency was also associated with slow wave sleep deficits. Rate of short REM latency in relatives of depressed probands with short REM latency quadrupled the rate in relatives of both depressed probands with normal REM latency and normal probands. Lifetime risk of depression was almost twice as high in relatives of depressed probands with short REM latency as in relatives of depressed probands with normal REM latency. Short REM latency and slow wave sleep deficits are familial. Short REM latency is associated with increased risk of major depression beyond the familial risk associated with a depressed proband. Polysomnographic abnormalities also occurred in unaffected relatives. Although the data can be considered only suggestive, these findings indicate that polysomnographic abnormalities may precede the clinical expression of depression and may be useful in identifying those at highest risk for the illness.

Respiratory-related leg movements (RRLMs) may contribute to the cardiovascular risk associated with obstructive sleep apnea (OSA). Selective serotonin reuptake inhibitors (SSRIs), but not bupropion, increase periodic leg movements in sleep. This study examines whether patients with OSA using SSRIs have more RRLMs than those taking bupropion or no antidepressant. Patients with an apnea-hypopnea index (AHI) of at least 10 events/h during a full-night diagnostic study or split-night study, who were taking bupropion (n = 32), an SSRI (n = 31), or no antidepressant (n = 31), were selected from a database of prestudy questionnaires. RRLMs were scored according to World Association of Sleep Medicine 2016 standards. Patients using SSRIs had significantly greater overall RRLM% (defined as the percentage of respiratory events associated with a leg movement, including apneas, hypopneas, and respiratory effort-related arousals), RRLM index, and periodic limb movement index relative to patients using bupropion and control patients. The difference between the RRLM% in the SSRI and bupropion groups was limited to patients undergoing split-night studies, and that of the SSRI and control groups was limited to patients undergoing full-night diagnostic studies. The greater number of RRLMs and PLMs in the SSRI group may contribute to treatment-emergent insomnia often seen with SSRI use. Fragmented sleep and elevated autonomic nervous system activation associated with increased RRLMs in patients with OSA taking SSRIs might also limit the tolerability of antidepressant treatment, as well as increase the risk for cardiovascular disease.

Objective: The present study aimed to observe the effect of bi-level positive airway pressure on sleep structure in patients with overlap syndrome (OS). Method: Forty patients with OS were randomly divided into control and experimental groups, respectively, with 20 cases in each group. Patients in both the control and experimental groups were given anti-infection, dilating bronchi, expectoration, and oxygen inhalation treatment according to the conditions. Bi-level positive airway pressure was conducted in patients in the experimental group for approximately 10 hr a day over a one-week therapeutic course. Polysomnography, Sleep questionnaire survey was performed before treatment and after one week of treatment in both the control and experimental groups to measure sleep structure to investigate the drowsiness and quality of life of the patients. Results: (1) Prior to treatment, differences in the total sleep time, sleep latency, rapid eye movement (REM) latency, sleep efficiency, phase I, II, and III sleep, REM phase sleep and sleep questionnaire survey was not statistically significant between the two groups (P > 0.05). (2) One week after treatment, compared with the control group, the REM latency in the experimental group was shortened, the percentage of REM sleep and Rem sleep in total sleep time was prolonged, the second stage sleep time and the percentage of second stage sleep in total sleep time were shortened, and the scores of Epworth drowsiness, fatigue, dizziness, lack of energy and anxiety decreased in the sleep questionnaire. There was no significant difference in other indexes (P > 0.05). After treatment in the experimental group, REM latency was shortened, REM sleep time and the percentage of Rem sleep in total sleep time were prolonged, second-stage sleep time and second-stage sleep in total sleep time were shortened. Sleep questionnaire survey showed that Epworth drowsiness score, fatigue, dizziness, mental in concentration and anxiety symptoms decreased. There was no significant difference in other indexes (P > 0.05). The sleep questionnaire in the control group after treatment showed that the score of fatigue symptoms decreased, and the difference was statistically significant (P < 0.05). There was no significant difference in other indexes (P > 0.05). Conclusion: Bi-level positive airway pressure can potentially shorten REM latency, prolong REM sleep, and shorten phase II sleep, alleviate the symptoms of drowsiness, fatigue, dizziness, distraction and anxiety, and improve the quality of life in patients with OS.

Subjective and objective measures of poor sleep in alcoholic insomniacs predict relapse to drinking. Nonalcoholic insomniacs underestimate their total sleep time (TST) and overestimate their sleep onset latency (SOL) and wake time after sleep onset (WASO) compared with polysomnography (PSG). This study evaluated 3 hypotheses: (1) subjective SOL would predict frequency of future drinking; (2) participants would overestimate SOL and WASO and underestimate TST; and (3) higher amounts of over- and underestimates of sleep at baseline would predict worse drinking outcomes prospectively. Participants (N=18), mean age 44.6 years (+/-13.2), underwent an adaptation night and then 2 nights of PSG 3 weeks apart. They also provided morning estimates of SOL, WASO, TST, and sleep efficiency (SE). Following the baseline PSG, participants were followed over 12 weeks. A 2-way ANOVA (night x method of measuring sleep) compared results and regression analyses predicted drinking. Drinking outcomes were defined as number of days drinking (DD) and number of heavy-drinking days (HDD) during 2 consecutive 6-week follow-up periods. Most participants (72%) overestimated SOL by a mean of 21.3 (+/-36) minutes compared with PSG [F(1, 14)=7.1, p<0.03]. Unexpectedly, 89% underestimated WASO by a mean difference of 48.7 (+/-49) minutes [F(1, 14)=15.6, p<0.01]. Drinking during the first 6-week study period was predicted by both subjective estimates of WASO and their accuracy, whereas drinking during the second 6-week period was predicted by both subjective estimations of sleep and rapid eye movement sleep latency. Greater subjective accuracy of wakefulness at night provided by the patient predicted drinking during the study. Unlike nonalcoholic insomniacs, this alcoholic sample significantly underestimated WASO compared with PSG values. The predictive ability of sleep parameters depended on the selected measure of drinking outcomes and when outcomes were measured. Subjective sleep measures were better predictors of future drinking than corresponding PSG measures.

Brief arousals have been systematically scored during sleep for more than 20 years. Despite significant knowledge concerning the importance of arousals for the sleep process in normal subjects and patients, comprehensive age norms have not been published. Seventy-six normal subjects (40 men) without sleep apnea or periodic limb movements of sleep, aged 18 to 70 years, slept in the sleep laboratory for 1 or more nights. Sleep and arousal data were scored by the same scorer for the first night (comparable to clinical polysomnograms) and summarized by age decade. There were no statistically significant differences for sex or interaction of sex by age (p > .5 for both). The mean arousal index increased as a function of age. Newman-Keuls comparisons (.05) showed arousal index in the 18- to 20-year and 21- to 30-year age groups to be significantly less than the arousal index in the other 4 age groups. Arousal index in the 31-to 40-year and 41-to 50-year groups was significantly less than the arousal index in the older groups. The arousal index was significantly negatively correlated with total sleep time and all sleep stages (positive correlation with stage 1 and wake). Brief arousals are an integral component of the sleep process. They increase with other electroencephalographic markers as a function of age. They are highly correlated with traditional sleep-stage amounts and are related to major demographic variables. Age-related norms may make identification of pathologic arousal easier.

The literature investigating the relationship between objective and subjective sleep in depressed patients is limited and the results are inconsistent. Furthermore, many factors that influence the aforementioned relationship have not been investigated. The present study was carried out to clarify the characteristics of self-estimation of sleep in depressed patients. Sleep was estimated concurrently using a sleep log and polysomnography for 5 consecutive days to investigate the relationship between subjective sleep estimation and objective sleep estimation in 23 patients with major depression (Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised; DSM-III-R). Factors related to a discrepancy between both types of estimation were identified. The subjective total sleep time showed a significant, but moderate, positive correlation (correlation coefficient: 0.63) with the objective total sleep time. The degree of discrepancy was significantly correlated with various objective sleep variables and severity of depression. In the underestimation group in which the subjective total sleep time was shorter than the objective total sleep time, the objective total sleep time and slow-wave sleep time were shorter, age was greater and the extroversion score (Maudsley Personality Inventory) was lower than in the overestimation group in which the subjective total sleep time was longer than the objective total sleep time. The data suggest that subjective sleep estimation in depressed patients is influenced by their objective sleep, severity of depression, age and personality.

Chronic sleeplessness is a primary clinical symptom of vascular depression (VaDep). We investigated the efficacy and safety of escitalopram plus tandospirone citrate for patients with VaDep and chronic insomnia and the potential correlation of insomnia severity with neurotransmitter indexes, including serotonin (5-HT), serotonin 2C receptor (5-HT2CR), serotonin 7 receptor (5-HT7R) in platelets, and plasma 5-HT. This double-blind, randomized controlled study randomized patients with VaDep and chronic insomnia [Hamilton depression rating scale (HAMD) > 17 points] into a monotherapy group [escitalopram (10 mg once daily) plus placebo] or combined group [escitalopram (10 mg once daily) plus tandospirone citrate (10 mg three times daily)] by using a 1:1 assignment algorithm generated by SPSS 25.0 software. The primary endpoint was the change in sleep quality from baseline to week 12, evaluated by the Pittsburgh Sleep Quality Index (PSQI), polysomnography (PSG), Epworth Sleepiness Scale, and Asen Self-Rating Insomnia Scale (AIS). Secondary outcomes were the changes in depression and anxiety assessment and the levels of peripheral blood neurotransmitters from baseline to week 12, including HAMD, the Hamilton anxiety scale (HAMA), 5-HT, 5-HT2CR, 5-HT7R in platelets, and plasma 5-HT. The levels of 5-HT, 5-HT2CR, and 5-HT7R were detected with the enzyme-linked immunosorbent assay kits. The safety assessment included the Treatment-Emergent Symptom Scale and clinical and laboratory variables. The therapeutic improvement was analyzed by a generalized estimation equation. A total of 123 subjects (30.89% male) were included, with a mean age of 70.56 ± 6.37 (mean ± standard deviation, SD) years. In the monotherapy group, the baseline HAMD and PSQI scores (n = 61 for both) were 28.84 ± 2.49 and 14.16 ± 1.86, respectively. In the combined group, the baseline HAMD and PSQI scores (n = 62 for both) were 28.81 ± 2.51 and 14.21 ± 1.87, respectively. The HAMA and HAMD scores in both groups were significantly lower at weeks 4, 8, and 12 after treatment than before treatment (P < 0.001). Compared with the monotherapy counterpart, the combined group displayed significantly lower PSQI and AIS scores at weeks 4, 8, and 12 and improved PSG sleep macrostructure at week 12, including total sleep time (TST), sleep latency, sleep efficiency, sleep maintenance rate (SMT), wake time after sleep onset, and percentage of sleep in each phase. Platelet 5-HT, plasma 5-HT, and platelet 5-HT7R decreased in both groups at the end of weeks 4, 8, and 12 of treatment. Platelet 5-HT7R was moderately negatively correlated with the percentage of nonrapid eye movement 3 sleep time (N3). Plasma 5-HT was moderately positively correlated with PSQI and AIS and negatively with TST, SMT, nonrapid eye movement 2 sleep time (N2), and percentage of N2 sleep time. No statistical difference in the total incidence of adverse events was found between the two groups (P = 0.842). The statistically significant changes in PSG, PSQI, and AIS may indicate that the combination of escitalopram and tandospirone may improve, with a reasonable safety profile, the sleep quality of patients with VaDe. The clinical results observed were associated with changes in measures of plasma 5-HT and platelet 5HT7R; these findings suggest that a possible role of central serotonergic function in the mechanism of action of the drug combination in this trial could be a relevant subject of future studies. ChiCTR2300075407.

The effects of serotonergic agents on respiration neuromodulation may vary according to differences in the serotonin system, such as those linked to depression. This study investigated how sleep-related respiratory disturbances relate to depression and the use of medications commonly prescribed for depression. Retrospective polysomnography was collated for all 363 individuals who met selection criteria out of 2,528 consecutive individuals referred to a specialized sleep clinic (Ottawa, Canada) between 2006 and 2016. The apnea-hypopnea index (AHI), oxygen saturation nadir, and oxygen desaturation index during REM and NREM sleep were analyzed using mixed analyses of covariance comparing 3 main groups: (1) medicated individuals with depressive disorders (antidepressant group; subdivided into the selective serotonin reuptake inhibitor and norepinephrine-dopamine reuptake inhibitor subgroups), (2) non-medicated individuals with depressive disorders (non-medicated group), and (3) mentally healthy control patients (control group). Individuals with depressive disorders (on antidepressants or not) had significantly higher AHIs compared to control patients (both P ≤ .007). The antidepressant group had a lower NREM sleep oxygen saturation nadir and a higher NREM sleep oxygen desaturation index than the control and non-medicated groups (all P ≤ .009). Within individuals with depressive disorders, independent of depression severity, the selective serotonin reuptake inhibitor group had a lower oxygen saturation nadir and a higher oxygen desaturation index during NREM sleep than the norepinephrine-dopamine reuptake inhibitor (both P ≤ .045) and non-medicated groups (both P < .001) and a higher NREM sleep AHI than the non-medicated group (P = .014). These findings suggest that the use of selective serotonin reuptake inhibitors may be associated with impaired breathing and worse nocturnal oxygen saturation in individuals with depressive disorders and sleep complaints, but this needs to be confirmed by prospective studies.

Introduction Mood progressively deteriorates over consecutive days of sleep restriction. The neurobiological processes active during sleep that influence the risk of mood disturbance are unknown. This study investigated the relationships between physiological sleep parameters (i.e., slow-wave activity (SWA), slow-wave energy (SWE), rapid eye-movement (REM) sleep duration and latency), and self-reported measures of mood across sleep restriction. Methods N=181 healthy participants (48.1% female; 30±6.8 yrs) had valid polysomnography (PSG) and mood data. The study design included two baseline nights (8h time in bed [TIB]) followed by five nights of 4h TIB. PSG (EEG derivations C3-A2, Fz-A1, O2-A1) was collected on the second baseline night (B2), first night of 4h TIB (SR1), and the fifth night of 4h TIB (SR5). The Profile of Mood States was assayed on days following PSG. Power spectral analysis for SWE and SWA was conducted (delta power; band: 0.5-4.5 Hz). General linear regression models were used to independently assess the slope of SWE, SWA, percent REM of total sleep time (TST), and REM latency on mood disturbance across sleep restriction. Results At baseline, higher SWE (unadjusted; r=0.21; P=0.004) and SWA (unadjusted; r=0.19; P=0.007) were associated with greater mood disturbance; these relations were attenuated when adjusted for age and sex. No relation was found between mood and REM latency or REM percent of TST. The slope of mood disturbance from B2 to SR5 was associated with greater percentage increases in C3 SWA on SR5 relative to B2 (β=0.039; P=0.008); this association was not observed for SWE (β=-0.016; P=0.48). The slope of REM latency and REM percent of TST were not associated with the slope of mood disturbance. Conclusion Our results indicate that greater SWA due to sleep restriction was associated with greater mood disturbance, suggesting that less SWA may confer resilience to mood disturbances resulting from sleep restriction. Support This work was supported by National Institute of Health NIH R01NR004281 and National Space and Biomedical Research Institute NSRBI NCC 5-98.