Effect of early morning awakening in major depressive disorder

Background Patients with major depressive disorder (MDD) usually manifest sleep disturbance. Early morning awakening is more closely related to MDD than other sleep disturbances. Aim The aim of this study was to assess the effect of early morning awakening in the treatment of patients with MDD. Methods Eligible patients were randomly assigned into two groups: early morning awakening and non-early morning awakening group. All patients were assessed using Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores at baseline and the fourth week. Results Twenty-one men and 31 women (mean age 25.13 ±10.67 years) were enrolled. There is a signicant main effect of early morning awakening in HAMD (P =0.04) and HAMA (P =0.01) at fourth week after escitalopram treatment. Discussion This trial suggests that early morning awakening may result in statistically and clinically signicant delay in the recovery of the MDD but cognitive impairment.


Introduction
Major depressive disorder (MDD) is a complex disease, which affects individual health with an enormous toll [1]. The clinical symptoms display a wide variation as affected individuals. It is a chronic psychiatric condition characterized by changes in the emotional states, such as reduction of positive emotions, cognitive impairments, and memory di culties [2]. Currently, 30-50% of patients with MDD are resistant to the current treatment [3]. In addition, it has a considerable economic impact.
Sleep disturbance a icts nearly a quarter of the population in the world. People with perennial sleep problems are more likely to suffer from mental disorders, especially for MDD [4]. In many cases, sleep disturbance is the main symptom of MDD. Sleep neurophysiological changes in patients with MDD are often observed [5]. In the past, sleep disturbance was regarded as a concomitant symptom of MDD. It is generally believed that sleep disturbance can be alleviated as symptoms related to the treatment of MDD. Now it has been found that depressed patients with sleep disturbance may have more serious symptoms and treatment di culties [6]. In addition, insomnia is a common residual symptom in patients with MDD.
It is considered to be an important predictor of MDD recurrence and may lead to unpleasant clinical outcomes [7]. It has been known that insomnia is an independent diagnostic entity that may lead to the onset of MDD. However, in clinical practice, only about half of patients with MDD will seek treatment [8].
Insomnia in young people may lead to a risk of MDD for at least 30 years. Studies have con rmed the importance of insomnia as a risk factor for MDD and the necessity of early treatment of insomnia [9].
The diagnosis of insomnia is based on four different symptoms: early morning awakening, di culty in falling asleep, di culty in maintaining sleep, and non-restorative sleep. In addition, patients with MDD usually manifest sleep disturbance and early morning awakening [10]. It has been reported that about half of depressed patients have early morning awakening [11]. Furthermore, early morning awakening is more closely related to MDD than other sleep disturbances [12]. Hence, studying early morning awakening in depressed patients remains critically important. Moreover, examining early morning awakening plays an important role in evaluating the treatment of MDD in the current clinical trial.
The aim of this study was to assess the effect of early morning awakening in the treatment of patients with MDD. First, we evaluated the Hamilton depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as a predictor of the effect of early morning awakening on MDD. Second, we compared the results of HAMD, HAMA, RBANS scores and evaluated the effect of early morning awakening at the fourth week post-treatment follow-up.

Method Study design and participants
Patients were recruited from psychiatric inpatients at the department of psychiatry, the third people's hospital of Foshan, China. Patients between 17-60 years of age, with a diagnosis of MDD based on the Diagnostic and Statistical Manual-5 (DSM-5).
Standard clinical assessment of patients, including psychiatric assessment, structured diagnostic interview, and medical history. According to the sleep monitoring of the polysomnography (SOMNOscreen plus, somnomedics, ed), group according to whether patients wake up at 2-4 a.m. Eligible patients were randomly assigned into two groups: early morning awakening and non-early morning awakening group.

Intervention
All patients received daily escitalopram (H.Lundbeck A/S, Denmark) treatment for 4 weeks, which start with 5mg/d, 5mg weekly increase, and up to 15mg/d. Patients with trouble falling asleep were treated with oxazepam (Beijing Yimin Pharmaceutical Co., Ltd.) 15-30mg/night. Escitalopram has little effect on sleep and is taken during the day. Oxazepam is a sleep adjuvant medication with short action time. It is a medication to promote sleep and has relatively little effect on sleep structure.

Outcome
All patients were assessed using HAMD, HAMA, and RBANS scores at baseline and at the fourth week. The patients were rated by two senior psychiatrists, and the internal reliability of HAMD and HAMA was > 90%. We used HAMD and HAMA (the fourth week) scores to assess remission and remission rates. We assessed neuropsychological states using RBANS scores.

Statistical Analysis
For comparisons between the baseline of early morning awakening and non-early morning awakening group, one sample t test was used. The student's t-tests of paired samples were used to compare the values of pre-and post-intervention values. Regarding the predictive effect of early morning awakening on MDD recovery, we performed 2way ANOVA using the difference between baseline and the fourth week scores as HAMD, HAMA, and RBANS scores. P < 0.05 was considered as statistically signi cant, and the data are presented as mean ± standard deviation (SD). All data were analyzed with the SPSS Statistics, version 21.0 for Windows (IBM Corporation, Armonk, USA).

Result Participant characteristics
Twenty-one men and 31 women (mean age 25.13 ±10.67 years) were enrolled. There were no signi cant differences between the two groups regard to age (P = 0.76) or duration of illness on HAMD (P = 0.86), HAMA (P = 0.89). The education level of both groups was higher than 9 years. In addition, the baseline of  Table 1.

Outcomes
The rehabilitative effects of early morning awakening on MDD patients observed during the trial are showed in Figure 1. There is a signi cant main effect of early morning awakening in HAMD (P =0.04) at the fourth week after escitalopram treatment. Similarly, regarding HAMA scores, we observed a signi cant main effect in HAMA (P =0.01). The results suggest that early morning awakening leads to delay of rehabilitation during the trial.
In terms of neuropsychological status in the patients, the RBANS scores separately considering details and integrity are achieved by immediate memory, visuospatial construction, language, attention, and delayed memory. In addition, the characteristics of the participants from baseline to the fourth week were not signi cantly different between the early morning awakening and non-early morning awakening groups ( Figure 2).

Discussion
This study demonstrates the inhibitory effect of early morning awakening on treatment in patients with MDD. According to HAMD and HAMA scores, depressed patients with early morning awakening had poor recovery in depressive and anxious symptoms after the treatment on the fourth week. In addition, there is no signi cant change in neuropsychological states (as the RBANS score). To our knowledge, this is the rst study to demonstrate that early morning awakening is a determinant tolerant for treatment in patients with MDD.
Insomnia is a syndrome. Its diagnosis relies on the patient's subjective report, which is de ned as di culty in falling asleep, maintaining sleep, non-restorative sleep, or early morning awakening [13]. It has been reported that approximately 30% of the population have some insomnia symptoms, and 10% experience chronic and persistent insomnia symptoms [14]. The consequences associated with insomnia include fatigue, drowsiness, memory de cits, mood disorders, and impaired attention [15]. Insomnia is a condition caused by other diseases, completely independent of these diseases, and can also cause coexisting diseases. Mental disorders (depression and anxiety), circadian rhythm disorders (phase delay syndrome), or other sleep disorders (sleep-related respiratory disorders) may be the disorders [13]. In this study, as many as 51.9% of patients have early morning awakening complaints. It has been reported that as many as 24% to 58% of patients with sleep disturbance meet the criteria of MDD [16]. As a subtype of sleep disturbance, early morning awakening is frequent in patients with MDD. In the treatment of MDD and anxiety, this may be of great signi cance to prevent the onset or recurrence of the disorder.
Insomnia can affect the trajectory of MDD and increase the severity and duration of this disorder. Poor subjective sleep quality before the treatment may indicate a reduced treatment response. A previous study reported that women with interpersonal therapy have higher pre-treatment sleep quality scores than women with no remission of MDD, signi cantly improved mood [17]. Furthermore, poor sleep quality is associated with poor response to depressed pharmacotherapy and psychotherapy [18]. Depressed patients with suicidal tendencies have poor sleep quality and a higher incidence of insomnia and hypersomnia [19]. As many as 42% of the elderly report sleep-related troubles [20]. A review reported that the prevalence of MDD is approximately 9% and insomnia is about 17% [21]. Studies assessing sleep quality in the elderly have found that insomnia increases the risk of MDD [22]. In addition, it has been reported that the severity of insomnia is one of the clinical features predicting suicide within 1 year, and this connection has been reported in adolescence [23]. Adolescents with insomnia have the most severe MDD, and those with insomnia have more severe MDD than those without sleep disturbance [24]. Sleep disturbances is also associated with an increased risk of suicide in adolescents [25]. The patients have a mean age of 24.67 years and ranged in age from 17 to 60 years in this study. It may indicate that the risk factor of early morning awakening is not particularly for the elderly, but for depressed patients of all ages.
Insomnia can lead to sleep disturbance symptoms and excessive performance in patients with MDD, and vice versa [16]. Our results showed that after 4 weeks of antidepressant treatment, although antiinsomnia treatment is carried out for early morning awakening patients, the treatment effect is not obvious. The symptoms of insomnia and MDD re ect a bidirectional relationship. Previous studies have shown that there is a close relationship between depressive and insomnia symptoms, and insomnia is correlated with poor treatment results. Sleep disturbance strongly affects the development of MDD. Sleep disturbance-related symptoms may be important and modi able risk factors for preventing MDD and/or achieving and maintaining MDD remission. For patients with insomnia, early morning awakening, combined with other medical or mental disorders and pharmacotherapy side effects should be considered. Furthermore, sleep disruption is associated with behavioral, emotional, and cognitive disorders [26]. Our results suggested that early morning awakening did not cause signi cant cognitive changes, which may be related to the limitations related to the measurement time.
Based on the above ndings, clinicians must carefully evaluate the sleep symptoms of patients with MDD. The emerging view is that insomnia commonly coexists with MDD, rather than secondary to MDD. It suggests that insomnia and MDD need require speci c treatment. Although there are few trials for insomnia complicated with MDD, the existing evidence indicates that attention should be paid to insomnia, especially early morning awakening, while treating MDD.

Conclusions
The project was inspired to assess early morning awakening as a comorbid disorder for patients with MDD, which may bring uncertain treatment consequences to these patients. This trial suggests that early morning awakening may result in statistically and clinically signi cant delays in the recovery of the MDD. Whether the effect of early morning awakening on MDD needs to be in large clinical trials, which will be of great correlation with public health.

Declarations
Funding This research was supported by the project of Foshan Science and Technology Bureau (1920001001018) and the High-level Hospital Development Program for Foshan "Climbing" Project (DF-04-02-002).

Authors' contributions
Guohong Xu and Jiaquan Liang made substantial contributions to the conception or design of the work as well as the acquisition, analysis, or interpretation of data; they aided in drafting the work, gave nal approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Declarations
Ethics approval and consent to participate We obtained written informed consent from all patients. This study was approved by the ethics committee of the Third People's Hospital of Foshan, China and the experiments were conducted following the declaration of Helsinki.

Consent for publication
Not applicable.

Competing Interest
The authors have no potential or actual con icts of interest.

Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available due to con dentiality but are available from the corresponding author on reasonable request.

Figure 1
Scores on the HAMD and HAMA in time of baseline and the fourth week.