Sleep Disturbance Severity is Associated With Cognitive Impairment in Patients With First-episode, Treatment-naïve Major Depressive Disorders

by age,sex, and depression severity in different domains.To evaluate the presence and degree of cognitive impairment, we used a battery of comprehensive, cognitive measurement tests, which have proved sensitive in identifying impaired cognition in mental disorders. Our results indicate that sleep disorder is associated with impaired executive functioning and delayed information processing speed in rst-episode, treatment-naïve patients with MDD.Certain patients, including women between the ages of 30 and 45 years or patients with moderate depression, may be more likely to exhibit the symptoms of cognitive impairment.Sleep disorders can be important symptoms for physicians in clinical practice and can aid in recognizing cognitive impairment in patients with MDD.


Abstract
Background Sleep disorders and cognitive impairment are common in patients with major depressive disorder (MDD), though the relationship between the two remains unclear. We investigated this association in rstepisode, treatment-naïve patients with MDD.

Method
We analyzed data from 242 patients withMDD. We divided the patients into 2 groups based on sleep disturbance severity and compared the cognitive impairment odds ratios in different domains between the groups.

Limitations
The cross-sectional data on the relationship between sleep disorders and cognitive impairment were weak. Our study population was restricted to Chinese adults aged 18 to 65 years, so the results may not be generalizable to other populations.Because our sample size was limited, some variables were not included in the study.

Conclusions
Sleep disturbance is associated with cognitive impairment in the domains of executive functioning and information processing speed in rst-episode, treatment-naïve patients with MDD. Sleep problems can be important symptoms for physicians in clinical practice and can aid in recognizing cognitive impairment in patients with MDD. Further study is required to con rm our results.

Background
Major depressive disorder (MDD) is a disabling disease with signi cant social and economic consequences, including decreased work productivity and poor psychosocial outcomes [1,2]. MDD has been associated with cognitive impairment in several domains, including attention, memory, executive functioning, and information processing speed [3], and approximately 90% of patients with MDD complain about impaired cognition [4].
Patients with rst-episode MDD can suffer from impaired cognition [5]. Cognitive dysfunction is associated with a high risk of relapse and a low rate of remission [6,7], increasing the risk of treatmentresistant MDD, so it is imperative to intervene early during the course of the rst episode of MDD.
Treatment should not just focus on the remission of affective symptoms but also on improving the patient's quality of life and recovering social functioning [8,9]. Cognitive de cits are barriers to full resolution of depressive symptoms and restoration of social functioning, so cognition is an important treatment target in patients with MDD.
Sleep disturbances are common complaints in patients who are depressed [10], and they, in turn, increase the risk of developing a depressive disorder [11,12]. Sleep disorders are manifest in different ways, including di culty falling asleep, frequent nocturnal awakenings, and waking early in the morning, unable to go back to sleep. Several studies have explored the relationship between sleep and cognitive functioning [13,14], and a recent meta-analysis concluded that insomnia has a profound effect on a wide range of cognitive domains [15].  19], and MDD subtype [20]. Most studies have focused on recurrent depressive disorders or cognitive impairment in late-onset depression [21]. Some risk factors are unmodi able, such as age, and others are potentially modi able, such as MDD severity. Though previous studies have explored the negative consequences of sleep disturbances in patients with MDD or cognitive impairment [12,22,23], it is still not known about the role, if any, of sleep disturbances play in the development of cognitive impairment in patients with MDD.
Previous studies have included patients with both rst-episode and recurrent depressive disorders, and the in uence of antidepressants has not been clari ed. So, we aimed to examine whether sleep disturbance severity can be a risk factor for cognitive impairment in unmedicated patients with MDD. If so, then treating sleep disturbances may be an option in reducing cognitive impairment in a clinical setting. Here we report on the relationship between sleep disturbances and cognitive impairment in the setting of a clinical trial.

Method
Participants Between December 2013 and December 2016, researchers recruited Chinese adults to participate in the multicenter, multistage, prospective study Objective Diagnostic Indicators and Individualized Drug Intervention of Major Depressive Disorder (OIMDD), project No. 2013CB531305. We conducted a secondary, cross-sectional analysis using the baseline data from OIMDD for participants diagnosed with MDD. Nine hospitals in China participated in the study. All participants provided written consent, and the study protocol was approved by the research ethics board of the institution where it was performed.
Study participants included patients between the ages of 18 and 65 years who had been diagnosed with their rst episode of MDD, did not receive any antidepressant treatment in the acute phase of the disease, and had a total score of ≥14 on the 17-item Hamilton Rating Scale for Depression (HAMD-17) [24].
Patients were excluded if they had severe somatic diseases, such as severe heart disease, malignant tumors, or a history of epilepsy. Pregnant or lactating women were also excluded [25].

Depression Diagnosis and Clinical Assessment
Using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), psychiatrists made a diagnosis of MDD and then conducted structured clinical interviews with the prospective participants using the Mini-International Neuropsychiatric Interview (MINI), Chinese Version 5.0.0 [26]. After the interviews, HAMD-17 was used to assess depressive symptoms, evaluating functioning in 5 subscales: cognitive impairment, retardation, anxiety or somatization, sleep disturbance, and weight change [27]. Sleep disturbance severity was assessed by evaluating the followingmetrics on the HAMD-17 scale: item 4, di culty falling asleep; item 5, waking in the middle of the night for any reason except to void; and item 6, waking early in the morning and unable to go back to sleep. Each item could be rated from 0 (no di culty) to 2 (nightly di culty), with a total possible score of 6. A sleep subscale score >4 was de ned as a serious sleep disorder, and patients in this category were assigned into Group 1; the remainder, were assigned into Group 2. The Hamilton Anxiety Rating Scale (HAMA) was used to assess 2 areas of somatic anxiety: muscular (pains and aches, twitching, stiffness, myoclonic jerks, grinding of teeth, unsteady voice, and increased muscular tone)and sensory (tinnitus, blurring of vision, hot and cold ushes, feelings of weakness, and pricking sensation) [28,29].

Cognitive Tests
A battery of cognitive tests were performed to evaluate 5 cognitive domains: attention (vigilance), assessed by the Continuous Performance Test (CPT); speed of information processing, assessed by the Animal Verbal Fluency Scale (AVFS), Digit Symbol Coding Test (DSCT), and Color Trial Test (CTT); learning, assessed by the immediate recall of Brief Visual Memory Test-Revised (BVMT-R) and Hopkins Verbal Learning Test-Revised (HVLT-R); memory, assessed by delayed recall of Brief Visual Memory Test-Revised (BVMT-R) and Hopkins Verbal Learning Test-Revised (HVLT-R); executive functioning,assessed by the Stroop Color Word Test (SCWT, which assessed executive inhibition) and color line II (which assessed executive-shifting). We selected the cognitive test battery in our study from the MCCB (MATRICS Consensus Cognitive Battery) of the MATRICS (the Measurement and Treatment Research to Improve Cognition in Schizophrenia) study. The MCCB has been widely used to evaluate the cognitive function of patients with mental disorders. The test scores for each domain were transferred into global de cit scores (GDS) , which were adjusted for age, sex, and education level. A global de cit score≥0.5 was de ned as cognitive impairment [30,31].

Confounding Covariables
In addition to gathering basic demographic data-marital status, living situation (whether the subject lives alone or with others), religious a liation, work status, the type of work (whether it requires ental labor, physical labor, or both), independence (degree to which the subject depends on someone else for life's basics), and body mass index (BMI), we obtained information on potential confounding covariables that could alter a person's risk for cognitive impairment. Some comorbid conditions are known to increase the risk of cognitive impairment, including cardiovascular disease and diabetes. Other suspected risk factors include duration of disorder, severity of depression and/or anxiety, family history of psychiatric disorders, history of alcohol abuse, smoking history, and childhood trauma [1].
We collected previous disease history at baseline, including hyperlipidemia, hypertension, and diabetes.
Childhood trauma was assessed using the childhood trauma questionnaire (CTQ), which evaluates the subject's experience of abuse and/or neglect before the age of 18 years. The CTQ includes domains of emotional, physical, and sexual abuse, as well as of emotional and physical neglect. Items are rated from 1 ("never true") to 5 ("very often true") according to the frequency with which each event occurred in childhood. We considered the history of trauma as a dichotomic variable (yes/no) if the person rated items as moderate or severe according to the subscale cutoff criteria in at least one type of trauma [32].

Statistical Analyses
Summary statistics were presented as mean ± standard deviation for variables that conformed to a normal distribution, as medians and quartile for data did not conform to a normal distribution, and as percentages for categorical variables. To make the 2 groups more comparable, we performed propensity score matching.Propensity scores were estimated using a logistic regression model that contained known or suspected covariates that were unbalanced between the 2 groups. To perform the propensity score matching, we included the type of work, marital status, religion, alcohol use, and HAMD-17 weight subscale. Because the independent-variable global de cit scores are functions converted fromstandard scores corrected by age, sex, and education, we did not include these variables in the propensity score matching. Subjects were matched 1:1 without replacement, using a 0.00 caliper width. Effect size was calculated to estimate the balance of the baseline data between the 2 groups. Cohen d was calculated using a t test and φ(phi) or φc (Cramer's phi) was calculated using the chi-square test. Effect size >0.20 was considered to be an imbalance between the 2 groups.
Statistical analyses were conducted using SPSS 25.0 (SPSS Inc, Chicago, Illinois, USA) and version R 3.3.3(Foundation for Statistical Computing,Vienna, Austria). The R package of MatchIt was used forthe propensity score analysis. Logistic regression analysis was used to estimate the odds ratios for the global de cit scores for each cognitive domain and their corresponding 95% con dence intervals (CIs).

Results
Of the 296 patients included in our analysis, 121 had symptoms of serious sleep disorders. Chi-square analysis and nonparametric test of the demographic and clinical characteristics between the 2 groups revealed signi cant differences in the groups' social demographics (see Table 1), including type of work (10.924, P = 0.004), marital status (17.072, P < 0.001), living situation (19.919, P < 0.001), religion (4.457, P = 0.035), alcohol use (14.284, P = 0.001), and HAMD weight subscale (P = 0.001). Because the 2 groups were so heterogeneous, we performed propensity score matching and the variables above were included into matching, after which the baseline characteristics of the 2 groups were highly comparable and we were able to successfully match 121 pairs of participants (average age 39.42 ± 10.07, 70.2% female). No differences in the other variables were observed between the 2 groups, with the exception of age ( Table 2). The effects of sleep symptom severity between the 2 groups were similar before and after propensity score matching, with the exception of word uency (Tables 3 and 4).     (Tables 3 and 4).

Subgroup and Sensitivity Analyses
We analyzed the effects of sleep disorder symptoms in Group 1 by age, sex, and depression severity in the domains of attention, learning, memory, and word uency ( We performed additional subgroup analyses in Group 1 of the effects of sleep disorders on executive functioning, executive shifting, executive inhibition, and the speed of information processing (

Discussion
In this study, we evaluated the effects of seriously disordered sleep on cognitive functioning in treatmentnaïve patients with rst-episode MDD and found a link between serious sleep disorders and impaired executive functioning and information processing speed. We found signi cant differences in strati cation by sex, age, and depression severity between Groups 1 and 2.
The baseline characteristics of the 2 groups had signi cant heterogeneity, so we performed propensity score matching to reduce bias, which reduced the sample size to 242 participants and enabled us to perform between-group comparisons, though the statistical power was decreased because the sample was somewhat smaller. There was a difference in the effect size of age between the 2 groups, though we had already considered the effect of age when we calculated the global de cit scores.
Previous studies have demonstrated that disordered sleep can affect cognitive functioning in various groups of people [33,34]. Moreover, several types of sleep disturbances have been shown to affect cognitive functioning. Some longitudinal studies found that insomnia is a risk factor for mild cognitive impairment and dementia [13,21,35]. In patients with multiple sclerosis, sleep disorders have been shown to impair cognitive functioning, especially in executive functioning [36]. Conversely, other studies have not found any relationship between sleep disorders and cognitive impairment. Astudy of 50 patients with chronic fatigue syndrome and 50 healthy controls found impaired executive functioning, but it was not related to sleep di culties [37].
In our study, sleep disorders impaired cognition in the domains of executive functioning and information processing speed in patients with MDD. Other studies of patients with MDD have reported that sleep disturbances affect different cognitive domains. One study of 34 patients with MDD patients and 29 healthy controls found that poor sleep is an independent predictor of impaired executive functioning and especially visual-motor processing speed in patients with MDD [34]. A meta-analysis concluded that insomnia may affect a wide range of cognitive domains, including episodic memory, alertness and complex attention, manipulation in working memory, problem-solving, and perceptual functions [15]. The affected cognitive domains were different from those in our study, as were the methods for testing cognitive functioning.
Previous studies have explored the mechanisms underlying cognitive impairment in patients with MDD.
Researchers have shown that sleep can affect both cognitive functioning and emotional processingby altering neural networks and decreasing brain-derived neurotrophic factor (BDNF); [38][39][40]. Executive functioning has been identi ed as one of the main impaired cognitive domains in patients with MDD, and impaired cognition has been suggested as one of the main barriers to functional recovery in these patients [1,41]. Information processing speed has also consistently been found to be impaired in patients with MDD [1,42]. Neural networks, including the prefrontal cortex, cingulate gyrus, subcortical regions in the striatum and thalamus, and temporal lobe structures, including the amygdala and hippocampus, have been found to be functionally altered in patients in a depressive state [43]. De cits in executive functioning have been associated with pathophysiology in the lateral aspects of the prefrontal cortex. Functional alterations in the prefrontal cortex, cingulate gyrus, and subcortical regions, combined with de cits in executive functioning, have been observed in patients with sleep disorders [44]. The prefrontal cortex is the region responsible for executive functioning, and the subcortical regions are responsible for information processing speed. Another mechanism reportedly underlying cognitive impairment secondary to disordered sleep is related to the decrease of BDNF. One study conducted in a Chinese population found a lower level of BDNF in patients with clinical insomnia and cognitive impairment. Patients with MDD who had lower BDNF levels in the central nervous system had evidence of neural death and decreased brain volume, which led to cognitive impairment [45,46]. Rahmani and colleagues concluded that insomnia and depression arelinked to the down-regulation of hippocampal BDNF along with disrupted BDNF expression in the prefrontal cortex [47].
We strati ed study participants by age, sex, and severity of MDD and analyzed the effects of sleep disturbances in different cognitive domains. Our results showed that patients who fell into discrete categories of age, sex, and depression severity were more impaired by sleep disorders. Speci cally, we found that patients between the ages of 30 and 45 were more likely to have de cits in the domains of attention, learning, memory, executive functioning, and information processing speed. Patients younger than 30 years were more likely to experience cognitive impairment in the domains of executive shifting and word uency. The correlation between sleep disturbances and impairment in word uency domain was not signi cant after we performed propensity score matching, because the matching process eliminated some younger participants who did not have serious sleep disorders. We did observe a difference by sex. Sleep disorders were more likely to affect women in the domains of attention, memory, and executive functioning (especially executive shifting). For men, sleep disorders were more likely to affect information processing speed.
Cognitive impairment has also been reported to be related to MDD severity. Patients with mild to moderate depression have been shown to be more likely to experience cognitive impairment in the domains of attention, memory, executive functioning, and information processing speed. A sensitivity analysis conducted as part of a meta-analysis summarizing cognitive impairment in rst-episode MDD patients concluded that neither age nor severity of depression was related to impaired cognition in the domains of attention, learning, memory, executive functioning, or information processing speed. These results are different from our ndings, which may re ect the fact that the study participants included patients treated with medication, and that they were compared with normal controls [5].
Our study had some limitations. The cross-sectional study data we accessed had a weak cause-andeffect relationship. Future longitudinal studies will be essential in evaluating the link between sleep disturbance remission and cognitive impairment in MDD patients. Our sample population was restricted to Chinese adults aged 18 to 65 years, so our results may not be generalizable to other populations.Because our sample size was so small, we were not able to include some variables that can be risk factors for cognitive impairment in people with MDD. Also, the ages of the participants in our study varied so widely that a between-group imbalance in age ranges remained after propensity score matching. Finally, we used the HAMD sleep subscale to estimate sleep disorder severity. More speci c measurement tools will be necessary to evaluate the effects of the stages of sleep in patients with MDD.

Conclusions
We explored the link between symptoms of disordered sleep and cognitive impairment in rst-episode, treatment naïve patients with MDD,and strati ed the effect of sleep disturbance symptoms by age,sex, and depression severity in different domains.To evaluate the presence and degree of cognitive impairment, we used a battery of comprehensive, cognitive measurement tests, which have proved sensitive in identifying impaired cognition in mental disorders.
Our results indicate that sleep disorder is associated with impaired executive functioning and delayed information processing speed in rst-episode, treatment-naïve patients with MDD.Certain patients, including women between the ages of 30 and 45 years or patients with moderate depression, may be more likely to exhibit the symptoms of cognitive impairment.Sleep disorders can be important symptoms for physicians in clinical practice and can aid in recognizing cognitive impairment in patients with MDD.
Therefore, sleep problems should be considered in depression management. Future longitudinal studies are warranted to con rm the effects of sleep disorders on cognitive functioning in patients with MDD.

Availability of data and materials
The dataset analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interest
The authors declare that they have no competing interests. Yu Huang designed the database for this study.
Tianmei Si and Xin Yu designed the study and registered the project, and had oversight over all research activities as the principal investigators of this multicenter study.
All authors approved the nal version to be published.
All persons who have made substantial contributions to the work reported in this manuscript, including those who provided editing and writing assistance but who are not authors, are named in the acknowledgement section of the manuscript and have given their permission to be named.