Circadian Reinforcement Therapy in Combination With Electronic Self-Monitoring to Facilitate a Safe Postdischarge Period for Patients With Major Depression: Randomized Controlled Trial.

BACKGROUND: Patients with major depression exhibit circadian disturbance of sleep and mood, and when they are discharged from inpatient wards, this disturbance poses a risk of relapse. We developed a circadian reinforcement therapy (CRT) intervention to facilitate the transition from the inpatient ward to the home for these patients. CRT focuses on increasing the zeitgeber strength for the circadian clock through social contact, physical activity, diet, daylight exposure, and sleep timing. OBJECTIVE: In this study, we aimed to prevent the worsening of depression after discharge by using CRT, supported by an electronic self-monitoring system, to advance and stabilize sleep and improve mood. The primary outcome, which was assessed by a blinded rater, was the change in the Hamilton Depression Rating Scale scores from baseline to the end point. METHODS: Participants were contacted while in the inpatient ward and randomized 1:1 to the CRT or the treatment-as-usual (TAU) group. For 4 weeks, participants in both groups electronically self-monitored their daily mood, physical activity, sleep, and medication using the Monsenso Daybuilder (MDB) system. The MDB allowed investigators and participants to simultaneously view a graphical display of registrations. An investigator phoned all participants weekly to coinspect data entry. In the CRT group, participants were additionally phoned between the scheduled calls if specific predefined trigger points for mood and sleep were observed during the daily inspection. Participants in the CRT group were provided with specialized CRT psychoeducation sessions immediately after inclusion, focusing on increasing the zeitgeber input to the circadian system; a PowerPoint presentation was presented; paper-based informative materials and leaflets were reviewed with the participants; and the CRT principles were used during all telephone consultations. In the TAU group, phone calls focused on data entry in the MDB system. When discharged, all patients were treated at a specialized affective disorders service. RESULTS: Overall, 103 participants were included. Participants in the CRT group had a significantly larger reduction in Hamilton Depression Scale score (P=.04) than those in the TAU group. The self-monitored MDB data showed significantly improved evening mood (P=.02) and sleep quality (P=.04), earlier sleep onset (P=.009), and longer sleep duration (P=.005) in the CRT group than in the TAU group. The day-to-day variability of the daily and evening mood, sleep offset, sleep onset, and sleep quality were significantly lower in the CRT group (all P<.001) than in the TAU group. The user evaluation was positive for the CRT method and the MDB system. CONCLUSIONS: We found significantly lower depression levels and improved sleep quality in the CRT group than in the TAU group. We also found significantly lower day-to-day variability in daily sleep, mood parameters, and activity parameters in the CRT group than in the TAU group. The delivery of the CRT intervention should be further refined and tested. TRIAL REGISTRATION: ClinicalTrials.gov NCT02679768; https://clinicaltrials.gov/study/NCT02679768. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-019-2101-z.

Circadian reinforcement therapy in combination with electronic self-monitoring to facilitate a safe post-discharge period of patients with depression by stabilizing sleep: protocol of a randomized controlled trial.

BACKGROUND: The transition phase from inpatient to outpatient care for patients suffering from Major Depressive Disorder represents a vulnerable period associated with a risk of depression worsening and suicide. Our group has recently found that the sleep-wake cycle in discharged depressive patients became irregular and exhibited a drift towards later hours, associated with worsening of depression. In contrast, an advancement of sleep phase has earlier been shown to have an antidepressant effect. Thus, methods to prevent drift of the sleep-wake cycle may be promising interventions to prevent or reduce worsening of depression after discharge. METHODS: In this trial, we apply a new treatment intervention, named Circadian Reinforcement Therapy (CRT), to patients discharged from inpatient psychiatric wards. CRT consists of a specialized psychoeducation on the use of regular time signals (zeitgebers): daylight exposure, exercise, meals, and social contact. The aim is to supply stronger and correctly timed zeitgebers to the circadian system to prevent sleep drift and worsening of depression. The CRT is used in combination with an electronic self-monitoring system, the Monsenso Daybuilder System (MDB). By use of the MDB system, all patients self-monitor their sleep, depression level, and activity (from a Fitbit bracelet) daily. Participants can inspect all their data graphically on the MDB interface and will have clinician contact. The aim is to motivate patients to keep a stable sleep-wake cycle. In all, 130 patients referred to an outpatient service will be included. Depression rating is blinded. Patients will be randomized 1:1 to a Standard group or a CRT group. The intervention period is 4 weeks covering the transition phase from inpatient to outpatient care. The primary outcome is score change in interviewer rated levels of depression on the Hamilton Depression Rating Scale. A subset of patients will be assessed with salivary Dim Light Melatonin Onset (DLMO) as a validator of circadian timing. The trial was initiated in 2016 and will end in 2020. DISCUSSION: If the described intervention is beneficial it could be incorporated into usual care algorithms for depressed patients to facilitate a better and safer transition to outpatient treatment. TRIAL REGISTRATION: Posted prospectively at ClinicalTrials.gov at February 10, 2016 with identifier NCT02679768 .

Usability, Acceptability, and Adherence to an Electronic Self-Monitoring System in Patients With Major Depression Discharged From Inpatient Wards.

BACKGROUND: Patients suffering from depression have a high risk of relapse and readmission in the weeks following discharge from inpatient wards. Electronic self-monitoring systems that offer patient-communication features are now available to offer daily support to patients, but the usability, acceptability, and adherence to these systems has only been sparsely investigated. OBJECTIVE: We aim to test the usability, acceptability, adherence, and clinical outcome of a newly developed computer-based electronic self-assessment system (the Daybuilder system) in patients suffering from depression, in the period from discharge until commencing outpatient treatment in the Intensive Outpatient Unit for Affective Disorders. METHODS: Patients suffering from unipolar major depression that were referred from inpatient wards to an intensive outpatient unit were included in this study before their discharge, and were followed for four weeks. User satisfaction was assessed using semiqualitative questionnaires and the System Usability Scale (SUS). Patients were interviewed at baseline and at endpoint with the Hamilton depression rating scale (HAM-D17), the Major Depression Inventory (MDI), and the 5-item World Health Organization Well-Being Index (WHO-5). In this four-week period patients used the Daybuilder system to self-monitor mood, sleep, activity, and medication adherence on a daily basis. The system displayed a graphical representation of the data that was simultaneously displayed to patients and clinicians. Patients were phoned weekly to discuss their data entries. The primary outcomes were usability, acceptability, and adherence to the system. The secondary outcomes were changes in: the electronically self-assessed mood, sleep, and activity scores; and scores from the HAM-D17, MDI, and WHO-5 scales. RESULTS: In total, 76% of enrolled patients (34/45) completed the four-week study. Five patients were readmitted due to relapse. The 34 patients that completed the study entered data for mood on 93.8% of the days (872/930), sleep on 89.8% of the days (835/930), activity on 85.6% of the days (796/930), and medication on 88.0 % of the days (818/930). SUS scores were 86.2 (standard deviation [SD] 9.7) and 79% of the patients (27/34) found that the system lived up to their expectations. A significant improvement in depression severity was found on the HAM-D17 from 18.0 (SD 6.5) to 13.3 (SD 7.3; P<.01), on the MDI from 27.1 (SD 13.1) to 22.1 (SD 12.7; P=.006), and in quality of life on the WHO-5 from 31.3 (SD 22.9) to 43.4 (SD 22.1; P<.001) scales, but not on self-assessed mood (P=.08). Mood and sleep parameters were highly variable from day-to-day. Sleep-offset was significantly delayed from baseline, averaging 48 minutes (standard error 12 minutes; P<.001). Furthermore, when estimating delay of sleep-onset (with sleep quality included in the model) during the study period, this showed a significant negative effect on mood (P=.03). CONCLUSIONS: The Daybuilder systems performed well technically, and patients were satisfied with the system and had high adherence to self-assessments. The dropout rate and the gradual delay in sleep emphasize the need for continued clinical support for these patients, especially when considering sleep guidance.

Acetate kinase isozymes confer robustness in acetate metabolism.

Acetate kinase (ACK) (EC no: 2.7.2.1) interconverts acetyl-phosphate and acetate to either catabolize or synthesize acetyl-CoA dependent on the metabolic requirement. Among all ACK entries available in UniProt, we found that around 45% are multiple ACKs in some organisms including more than 300 species but surprisingly, little work has been done to clarify whether this has any significance. In an attempt to gain further insight we have studied the two ACKs (AckA1, AckA2) encoded by two neighboring genes conserved in Lactococcus lactis (L. lactis) by analyzing protein sequences, characterizing transcription structure, determining enzyme characteristics and effect on growth physiology. The results show that the two ACKs are most likely individually transcribed. AckA1 has a much higher turnover number and AckA2 has a much higher affinity for acetate in vitro. Consistently, growth experiments of mutant strains reveal that AckA1 has a higher capacity for acetate production which allows faster growth in an environment with high acetate concentration. Meanwhile, AckA2 is important for fast acetate-dependent growth at low concentration of acetate. The results demonstrate that the two ACKs have complementary physiological roles in L. lactis to maintain a robust acetate metabolism for fast growth at different extracellular acetate concentrations. The existence of ACK isozymes may reflect a common evolutionary strategy in bacteria in an environment with varying concentrations of acetate.