The efficacy of a transdiagnostic sleep intervention for outpatients with sleep problems and depression, bipolar disorder, or attention deficit disorder: study protocol for a randomized controlled trial.

BACKGROUND: Patients with mental disorders have a higher prevalence of sleep problems than the general population. Sleep problems may include insomnia, circadian rhythm disorders, or hypersomnia. A transdiagnostic approach combining cognitive behavioral therapy for insomnia (CBT-I) with chronotherapy addressing a broad range of sleep problems has shown promising results in a limited number of studies. The aim of the study is to investigate the efficacy of a transdiagnostic sleep intervention for patients with sleep problems comorbid to bipolar disorder, unipolar depression, or attention deficit disorders. The primary hypothesis is that the intervention improves sleep quality compared with a control group. The secondary hypotheses are that the intervention increases subjective and objective sleep efficiency, reduces sleep onset latency, wake after sleep onset, number of awakenings, and severity of insomnia; and that it improves well-being, personal recovery, work ability, and consumption of sleep medication compared with a control group. METHODS: The study is a randomized controlled trial enrolling 88 outpatients with bipolar disorder, major depression, or attention deficit disorder with symptoms of various sleep problems (insomnia, circadian rhythm disorders, or hypersomnia). Patients are allocated to either an intervention group receiving six sessions of transdiagnostic sleep treatment or to a control group receiving a single session of sleep hygiene education. Assessments are made at baseline, at week two, and after 6 weeks in both groups. Actigraphy is performed continuously throughout the 6-week study period for all patients. The primary outcome is changes in the subjective appraisal of sleep quality (Pittsburgh Sleep Quality Index). The secondary outcomes are changes in sleep efficiency, sleep onset latency, wake after sleep onset, number of nocturnal awakenings (based on actigraph and sleep diary data), changes in insomnia severity (Insomnia Severity Index), well-being (WHO-5 Well-Being Index), personal recovery (INSPIRE-O), work ability (Work Ability Index), and consumption of sleep medication (sleep-diaries). DISCUSSION: The study was initiated in 2022 and the inclusion period will continue until mid-2024. The results may have implications for the development and implementation of additional treatment options for patients with mental disorders and comorbid sleep problems. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05406414. Registered on June 6, 2022.

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.

[Light therapy for depression].

Artificial light has been used as a treatment for depression since the 1980s. The indications have since broadened from seasonal depression to non-seasonal depression including bipolar, geriatric, and chronic depression. Light acts through retinohypothalamic connections from specialised retinal neurons to central nuclei involved in circadian and emotional regulation. This review illuminates the current strategies directed towards utilising natural daylight or electric lighting mimicking the dynamic spectrum and intensity of daylight to improve treatment in modern hospital settings.

Treatment of difficult-to-treat depression - clinical guideline for selected interventions.

BACKGROUND: Difficult-to-treat-depression (DTD) is a clinical challenge. The interventions that are well-established for DTD are not suitable or effective for all the patients. Therefore, more treatment options are highly warranted. We formulated an evidence-based guideline concerning six interventions not well-established for DTD in Denmark. METHODS: Selected review questions were formulated according to the PICO principle with specific definitions of the patient population (P), the intervention (I), the comparison (C), and the outcomes of interest (O), and systematic literature searches were performed stepwise for each review question to identify relevant systematic reviews/meta-analyses, and randomized controlled trials. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the methodological quality of the included studies. Clinical recommendations were formulated based on the evidence, the risk-benefit ratio, and perceived patient preferences. RESULTS: We found sufficient evidence for a weak recommendation of repetitive transcranial magnetic stimulation (rTMS) and cognitive behavioural analysis system of psychotherapy (CBASP). The use of bright light therapy in DTD was not sufficiently supported by the evidence, but should be considered as good clinical practice. The interventions should be considered in addition to ongoing antidepressant treatment. We did not find sufficient evidence to recommend intravenous ketamine/esketamine, rumination-focused psychotherapy, or cognitive remediation to patients with DTD. CONCLUSION: The evidence supported two of the six reviewed interventions, however it was generally weak which emphasizes the need for more good quality studies. This guideline does not cover all treatment options and should be regarded as a supplement to relevant DTD-guidelines.

Light therapy for seasonal affective disorder in visual impairment and blindness - a pilot study.

OBJECTIVE: Seasonal and non-seasonal depression are prevalent conditions in visual impairment (VI). We assessed the effects and side effects of light therapy in persons with severe VI/blindness who experienced recurrent depressive symptoms in winter corresponding to seasonal affective disorder (SAD) or subsyndromal SAD (sSAD). RESULTS: We included 18 persons (11 with severe VI, 3 with light perception and 4 with no light perception) who met screening criteria for sSAD/SAD in a single-arm, assessor-blinded trial of 6 weeks light therapy. In the 12 persons who completed the 6 weeks of treatment, the post-treatment depression score was reduced (p < 0.001), and subjective wellbeing (p = 0.01) and sleep quality were improved (p = 0.03). In 6/12 participants (50%), the post-treatment depression score was below the cut-off set for remission. In four participants with VI, side effects (glare or transiently altered visual function) led to dropout or exclusion. CONCLUSION: Light therapy was associated with a reduction in depressive symptoms in persons with severe VI/blindness. Eye safety remains a concern in persons with residual sight.

Dynamic LED light versus static LED light for depressed inpatients: results from a randomized feasibility trial.

BACKGROUND: Retrospective studies conducted in psychiatric wards have indicated a shorter duration of stay for depressed inpatients in bright compared to dim daylight-exposed rooms, pointing to a possible antidepressant effect of daylight conditions. Dynamic LED lighting, aiming to mimic daylight conditions, are currently been installed in several hospitals, but their feasibility is poorly investigated. METHODS: To investigate the feasibility of these systems, we developed and installed a LED-lighting system in four rooms in a psychiatric inpatient ward. The system could function statically or dynamically regarding light intensity and colour temperature. The system consisted of (A) a large LED luminaire built into the window jamb mimicking sunlight reflections, (B) two LED light luminaires in the ceiling and (C) a LED reading luminaire. In the static mode, the systems provided constant light from A and B. In the dynamic mode, the system changed light intensity and colour temperature using A, B and C. Patients with unipolar or bipolar depression were randomised to dynamic or static LED lighting for 4 weeks, in addition to standard treatment. Primary outcome was the rate of patients discontinuing the trial due to discomfort from the lighting condition. Secondary outcomes were recruitment and dropout rates, visual comfort, depressive symptoms and suicidal ideation. RESULTS: No participants discontinued due to discomfort from the LED lighting. Recruitment rate was 39.8%, dropout from treatment rates were 56.3% in the dynamic group and 33.3% in the static group. 78.1% in the dynamic group were satisfied with the lighting compared with 71.8% in the static group. Discomfort from the light (glare) was reported by 11.5% in the dynamic group compared to 5.1% in the static group. Endpoint suicidal scores were 16.8 (10.4) in the dynamic and 16.3 (14.9) in the static group. The lighting system was 100% functional. The light sensor system proved unstable. CONCLUSION: Dropout from treatment was high primarily due to early discharge and with a lack of endpoint assessments. The feasibility study has influenced an upcoming large-scale dynamic lighting efficacy trial where we will use a shorter study period of 3 weeks and with more emphasis on endpoint assessments. The lighting was well tolerated in both groups, but some found intensity too low in the evening. Thus, we will use higher intensity blue-enriched light in the morning and higher intensity amber (blue-depleted) light in the evening in the upcoming study. The light sensor system needs to be improved. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03363529.

Dynamic LED-light versus static LED-light for depressed inpatients: study protocol for a randomised clinical study.

INTRODUCTION: Retrospective studies conducted in psychiatric inpatient wards have shown a relation between the intensity of daylight in patient rooms and the length of stay, pointing to an antidepressant effect of ambient lighting conditions. Light therapy has shown a promising antidepressant effect when administered from a light box. The emergence of light-emitting diode (LED) technology has made it possible to build luminaires into rooms and to dynamically mimic the spectral and temporal distribution of daylight. The objective of this study is to investigate the antidepressant efficacy of a newly developed dynamic LED-lighting system installed in an inpatient ward. METHODS AND ANALYSIS: In all, 150 inpatients with a major depressive episode, as part of either a major depressive disorder or as part of a bipolar disorder, will be included. The design is a two-arm 1:1 randomised study with a dynamic LED-lighting arm and a static LED-lighting arm, both as add-on to usual treatment in an inpatient psychiatric ward. The primary outcome is the baseline adjusted score on the 6-item Hamilton Depression Rating Scale at week 3. The secondary outcomes are the mean score on the Suicidal Ideation Attributes Scale at week 3, the mean score on the 17-item Hamilton Depression Rating Scale at week 3 and the mean score on the World Health Organisation Quality of Life-BREF (WHOQOL-BREF) at week 3. The spectral distribution of daylight and LED-light, with a specific focus on light mediated through the intrinsically photosensitive retinal ganglion cells, will be measured. Use of light luminaires will be logged. Assessors of Hamilton Depression Rating Scale scores and data analysts will be blinded for treatment allocation. The study was initiated in May 2019 and will end in December 2021. ETHICS AND DISSEMINATION: No ethical issues are expected. Results will be published in peer-reviewed journals, disseminated electronically and in print and presented at symposia. TRIAL REGISTRATION NUMBER: NCT03821506; Pre-results.

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology.

AIMS: To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. METHODS: PRISMA-based systematic review of the literature. RESULTS: The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. CONCLUSIONS: The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered.

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 .

[Psychiatry and circadian rhythms].

Circadian and seasonal rhythm disturbances are prominent in patients with psychiatric disorders. Properly timed and dosed light of specific spectral composition stabilises mood and sleep through serotonergic mechanisms and through input to the master circadian clock in the hypothalamus. Correctly administered, light can be used as an effective treatment for seasonal and non-seasonal depression and for stabilising the sleep-wake cycle. Blocking blue light in the evening may provide a non-pharmacological anti-manic tool. Current developments use dynamic lighting built into somatic and psychiatric hospitals to maximise the beneficial effects of light.

Predictors of response to combined wake and light therapy in treatment-resistant inpatients with depression.

There is growing evidence for combined chronotherapeutic interventions as adjunctive treatments for major depression. However, as the treatments can be demanding, we need to identify predictors of response. This study aimed to describe predictors of response, remission and deterioration in the short-term phase, as well as predictors of long-term response. The predictors investigated were gender, type of depression, severity of depression, treatment resistance, quetiapine use, general self-efficacy, educational level and positive diurnal variation. Follow-up data from 27 inpatients with moderate-to-severe depression participating in a chronotherapeutic intervention were analysed. As a supplement to standard treatment, they completed 3 wake therapy sessions in the first week, 30 min daily light treatment and sleep-time stabilisation in the entire 9-week study period. Patients had a significant decrease of depressive symptoms during the first 6 days measured by HAM-D6. At Day 6, 41% of the patients responded to the treatment and 19% fulfilled the criteria of remission. Deterioration by the end of wake therapy sessions was however not uncommon. In the short-term phase, mild degree of treatment resistance was associated with remission and low educational level associated with deterioration. Positive diurnal variation (mood best in the evening) was a predictor of both short-term and long-term response to combined wake and light therapy. Furthermore, patients with evening chronotypes (measured with morningness-eveningness score) were more responsive. Our results suggest that targeting the combined chronotherapeutic intervention at patients with positive diurnal variation and evening types is a viable option.

Novel Augmentation Strategies in Major Depression.

Hypothesis The hypotheses of all the four included studies share the common idea that it is possible to augment the effect of antidepressant drug treatment by applying different interventions and with each intervention attain a clinically meaningful better effect compared to a control condition, and with minor side effects, thus improving the short- and medium-term outcome in major depression. Procedures Study design The basic study design has been the double blind randomised controlled trial (RCT). In the light therapy study, all patients were treated with sertraline for the whole of the study duration. In the first five weeks of the study, patients were randomised to treatment with either 60 minutes of bright white or 30 minutes of dim red light (sham condition). In the four weeks follow-up period, patients were treated with sertraline alone. In the Pindolol study, all patients were treated with venlafaxine and randomised to augmentation with either active or placebo matching pindolol tablets. In the PEMF study patients were continued on ongoing medication and randomised to augmentation with active or inactive (sham) 30 minutes daily PEMF treatment on weekdays. In the Chronos study all patients were treated with duloxetine and randomized to either a combination of three wake therapies with daily bright light treatment and sleep time stabilisation (wake group) or to daily exercise of minimum 30 minutes as an active control intervention (exercise group). The Chronos study was divided into: (1) a one-week run-in phase where duloxetine were started (and continued for the whole 29 week study period), (2) a one-week inpatient intervention phase where patient in the wake group did three wake therapies (sleep abstinence for the whole night and the following day until evening) in combination with daily light therapy and guidance on sleep time stabilisation and patients in the exercise group started a daily exercise program, (3) a seven week continuation phase where patient in the wake group continued light therapy and sleep time stabilisation and patients in the exercise group continued an individual exercise program, and (4) a 20 week follow-up phase with the same treatment elements but where duloxetine dosage could be adjusted or changed to other antidepressants. Recruitment Patients recruited for these studies were allocated from general practitioners, psychiatric specialist practices and for the lesser part from open psychiatric wards. Only a few patients were re-cruited through advertisements (in the PEMF and Chronos studies).   Inclusion criteria Inclusion criteria were major depression according to the DSM-IV, including a depressive episode as part of a bipolar disorder. For the PEMF study, treatment resistance was a specific inclusion criterion. Duration of studies Study duration was nine weeks for the light therapy study, 19 days for the Pindolol study, five weeks for the PEMF study, and 29 weeks for the Chronos study. Assessments In all studies, assessments were done with clinician rated scales, patient self-assessment scales, including quality of life scales and a side effect scale. As clinician rated scales we used the Hamilton depression rating scale: the HAM-D17 and its 6 item subscale: the HAM-D6, the Bech Rafaelsen Melancholia scale (MES), and the Bech Rafaelsen Mania scale (MAS). As self-assessment scales we used the Major Depression Inventory (MDI), the Symptom Check-list (SCL-92), and the Preskorn scale. For side effects we used the UKU scale. Further scales used are mentioned in the specific study sections. Assessments in the light therapy study were done weekly for the first six weeks and finally after nine weeks; at four time points in the Pindolol study (baseline, days 6, 11 and 19), weekly for five weeks in the PEMF study and weekly for the first nine weeks of the Chronos study and thereafter every four weeks. The clinical setting for evaluation has been the Psychiatric Research Unit at Mental Health Centre North Zealand. For the Bright Light study, Pindolol and PEMF study patients were also seen at a psychiatric specialist practice in Copenhagen. Biochemical measures In the Light therapy study saliva cortisol was collected at baseline before start of light therapy and sertraline and blood was drawn for thyroid analysis. In the Chronos study saliva and 24 hour urine cortisol was collected in the patients randomised to the exercise group. Main results The main results from the Bright Light study covering the first five weeks of the study are given in the PhD thesis "Adjunctive bright light in nonseasonal major depression" defended and awarded on the 18 November 2004 at the University of Copenhagen. Results from the cortisol measurement and for the four weeks extension period were published in separate papers after the PhD thesis and are included in this thesis. Results from the Bright Light study Analysis of the saliva cortisol measurements taken at baseline of the study as cortisol awakening profiles (CAR) showed that patients responded differentially to light treatment according to their CAR levels (dichotomized to high or low about the mean). Thus, in the bright light group HAM-D17 scores were reduced by 15.7 (4.2) points for patients with a low CAR (below mean), and 11.4 (4.8) points for patients with a high CAR (above mean). In the dim light group the corresponding values were 11.1 (5.2) for patients with a low CAR and 11.3 (5.3) for patients with a high CAR. This interaction between CAR and treatment group was statistically significant (p = 0.006). Survival analysis, for the first five weeks of the study period, showed a statistically significant higher response rate (χ2= 9.6, p =0.002) and higher remission rate (χ2 = 12.5, p = 0.0004) for the bright light treated group versus the dim light treated group. At end of the five weeks of light treatment response rates were 66.7% versus 40.7 % and remission rates were 41.7 % versus 14.8 % for the bright versus dim light treated group. In the subsequent publication that covered the four weeks extension period where light treatment was discontinued, data showed that the attained differences in response and remission rates between groups were not sustained. The offset of effect was nearly complete after four weeks of continued treatment on sertraline only. Thus, at end-point, response rates were 79.2 % versus 75.9 % and remission rates were 60 .4 % versus 55.6% in the bright versus dim light groups. The conclusion reached was that bright light in non-seasonal depression should be used to achieve an earlier antidepressant response and that light therapy probably should be of longer duration. Results from the Pindolol study The results from the Pindolol study showed that pindolol did not augment the effect of venlafaxine for the whole sample. However, for those patients classified as slow metabolizers, based on their O-desmethylvenlafaxine/venlafaxine ratio (ODV/V), pindolol did augment the antidepressant effect. For patients classified as fast metabolizers, pindolol worsened the outcome. This interaction between ODV/V ratio and treatment group was statistically significant (p = 0.01). Results from the PEMF study The results from the PEMF Study showed that treatment with active versus sham PEMF augmented the effect of the ongoing anti-depressant medication treatment. Thus, patients in the active PEMF group attained a statistically significant greater score reduction from week one and at all subsequent assessments compared to the sham treated group (p < 0.01). Response and remission rates in the active PEMF group were also larger than in the sham treated group with response rates at endpoint of 61.0 % versus 12.9 % (p < 0.01) and remission rates of 33.9 % versus 4.1 % (p < 0.05). Results from the Chronos study The Chronos study, published in three papers, covers a one-week intervention phase, a seven weeks continuation phase, and a 20 weeks follow-up phase. Results from the intervention week showed that patient treated in the wake group, from the day after the first wake therapy, had en clinically and statistically significant better antidepressant effect compared to the exercise group. On the HAM-D6 scale (which does not contains sleep items), patients in the wake group had a response rate after the first wake therapy of 58.7% versus 13.7% i the exercise group (p <0.0001) and a remission rate of 38.6% versus 2.9% (p <0.0001). After the second recovery sleep (the night after the second wake therapy = dag 5) patients in the wake group had a response rate of 75.0% versus 25.1% in the exercise group (p <0.0001) and remission rates of 58.6% versus 6.0% (p <0.0001). Results from the continuation phase showed, on the HAM-D17 scale which was used at all the following assessments, at week two response rates of 41.4% in the wake group and 12.8% in the exercise group (p = 0.003) and remission rates of 23.9% versus 5.4% (p = 0,004). This clinically relevant and statistically significant difference between the wake and exercise groups was maintained at all the subsequent assessments with response rates of 71.4% versus 47.3% (p = 0.04) and remission rates of 45.6% versus 23.1% (p = 0.04), at week nine. Results from the 20 weeks follow-up phase showed a continued better effect in the wake group at all visits with HAM-D17 depression scored at week 29 of 7.5 (SE = 0.9) in the wake group versus 10.1 (SE = 0.9), (p = 0.02) in the exercise group. Remission rates were higher in the wake group with endpoint rates of 61.9% versus 37.9% (p = 0.01) in the exercise group. Response rates was only numerically, but not statistically, higher in the wake group with 74.6% versus 64.4% in the exercise group (p = 0.22). The sleep diary data showed a statistically smaller day-to-day variation in sleep onset, sleep midpoint, sleep offset and sleep duration in the wake group compared to the exercise group as asign of better day-to-day sleep-wake cycle control in the wake group (p < 0.01). In the first nine weeks of the study patients in the wake group had a moderate sleep phase advance that diminished during the follow-up period. The hypothesised predictors for response to wake therapy were confirmed. Thus, in the wake group, a positive diurnal variation (morning worst, evening best) was associated with a better out-come, after the wake therapies, compared to a negative diurnal variation (morning best, evening worst). In the exercise group, the reverse was found, as a positive diurnal variation was associated with worse outcome, compared to a negative diurnal variation. This interaction between group and diurnal variation was statistically significant (p = 0.0004). The positive predictive value of response to the first wake therapy (i.e. maintaining response also at week two) was 56.3 % and the negative predictive value of non-response to the first wake therapy (i.e. maintaining no response also at week two) was 75.0 %. The impact of naps on depression severity was examined. In the wake group, patients who napped on the days after wake therapy compared to those patients not napping, had a more severe deterioration at the following assessment at week two (p = 0.02). Patients in the exercise group were able to perform exercise with a mean of 63.0 minutes/day (55.3) for the first eight weeks.

Experiences of wake and light therapy in patients with depression: A qualitative study.

Wake therapy can reduce depressive symptoms within days, and response rates are high. To sustain the effect, it is often combined with light therapy. Few studies have focussed on factors related to patients' adherence to the regime, and none has used qualitative methods to examine their experience of these combined interventions. Therefore, the aim of the present study was to illuminate patients' experiences with wake and light therapy and factors related to adherence. Thirteen inpatients with depression were included. They participated in an intervention consisting of three wake therapies during the first week, 30 min of daily light treatment for the entire 9 weeks, and ongoing psychoeducation regarding good sleep hygiene. Patients kept a diary, and individual semistructured interviews were conducted. Data were analysed using qualitative content analysis. The participants' overall experience with the treatment was positive. Some experienced a remarkable and rapid antidepressant effect, whereas others described more long-term benefits (e.g. improved sleep and diurnal rhythm). Yet recovery was fragile, and patients were only cautiously optimistic. Social support was important for maintaining the motivation to stay awake and receive daily light therapy. Overall, participants found the treatment worthwhile and would recommend it to others with depression. The study revealed a lack of knowledge among participants about the connection between regular sleep patterns and depression. In conclusion, this study provides insight into patients' experiences, and knowledge that can contribute to guidelines for future adherence-promoting organization of wake and light therapy.

Psychometric analysis of the Melancholia Scale in trials with non-pharmacological augmentation of patients with therapy-resistant depression.

OBJECTIVE: The Melancholia Scale (MES) consists of the psychic core items of the Hamilton Depression Scale (HAM-D6) (depressed mood, interests, psychic anxiety, general somatic, guilt feelings, and psychomotor retardation) and the neuropsychiatric items of the Cronholm-Ottossen Depression Scale. Patients resistant to anti-depressant medication (therapy-resistant depression) have participated in our trials with non-pharmacological augmentation. On the basis of these trials, we have evaluated to what extent the neuropsychiatric subscale of the MES (concentration difficulties, fatigability, emotional introversion, sleep problems, and decreased verbal communication) is a measure of severity of apathia when compared with the HAM-D6 subscale of the MES. METHODS: We have focused on rating sessions at baseline (week 0) and after 2 and 4 weeks of therapy in four clinical trials on therapy-resistant depression with the following augmentations: electroconvulsive therapy, bright light therapy, transcranial magnetic stimulation or pulsed electromagnetic fields, and wake therapy. The item response theory model constructed by Mokken has been used as the psychometric validation of unidimensionality. For the numerical evaluation of transferability, we have tested item ranks across the rating weeks. RESULTS: In the Mokken analysis, the coefficient of homogeneity was above 0.40 for both the HAM-D subscale and the apathia subscale at week 4. The numerical transferability across the weeks was statistically significant (p < 0.05) for both subscales. CONCLUSION: The apathia subscale is a unidimensional scale with acceptable transferability for the measurement of treatment-resistant symptoms, analogue to the psychic core subscale (HAM-D6).

The day-to-day acute effect of wake therapy in patients with major depression using the HAM-D6 as primary outcome measure: results from a randomised controlled trial.

BACKGROUND: This paper reports day-to-day data for from a one-week intervention phase, part of a 9-weeks randomised parallel study with patient having major depression (data from weekly visits have been reported). Wake therapy (sleep deprivation) has an established antidepressant effect with onset of action within hours. Deterioration on the following night's sleep is, however, common, and we used daily light therapy and sleep time stabilisation as a preventive measure. In particular, we evaluated the day-to-day acute effect of and tolerance to sleep deprivation and examined predictors of response. METHODS: Patients were assessed at psychiatric inpatient wards. In the wake group (n = 36), patients did three wake therapies in combination with light therapy each morning together with sleep time stabilisation. In the exercise group (n = 38), patients did daily exercise. Hamilton subscale scores were primary outcome (not blinded), secondary outcome was self-assessment data from the Preskorn scale and sleep. RESULTS: Patients in the wake therapy group had an immediate, large, stable, and statistically significant better antidepressant effect than patients in the exercise group with response rates at day5 of 75.0%/25.1% and remission rates of 58.6%/6.0%, respectively. The response and remission rates were diminished at day8 with response rates of 41.9%/10.1% and remission rates of 19.4%/4.7%, respectively. Patients and ward personnel found the method applicable with few side effects. Positive diurnal variation (mood better in the evening) predicted a larger response to wake therapy. In the wake group napping on days after intervention predicted greater deterioration on day8. CONCLUSIONS: The intervention induced an acute antidepressant response without relapse between wake nights but with a diminishing effect after intervention. Development is still needed to secure maintenance of response. Avoiding napping in the days after wake therapy is important. TRIAL REGISTRATION: Clinical trials.gov NCT00149110.

A 9-week randomized trial comparing a chronotherapeutic intervention (wake and light therapy) to exercise in major depressive disorder patients treated with duloxetine.

OBJECTIVE: The onset of action of antidepressants often takes 4 to 6 weeks. The antidepressant effect of wake therapy (sleep deprivation) comes within hours but carries a risk of relapse. The objective of this study was to investigate whether a new chronotherapeutic intervention combining wake therapy with bright light therapy and sleep time stabilization could induce a rapid and sustained augmentation of response and remission in major depressive disorder. METHOD: 75 adult patients with DSM-IV major depressive disorder, recruited from psychiatric wards, psychiatric specialist practices, or general medical practices between September 2005 and August 2008, were randomly assigned to a 9-week chronotherapeutic intervention using wake therapy, bright light therapy, and sleep time stabilization (n = 37) or a 9-week intervention using daily exercise (n = 38). Patients were evaluated at a psychiatric research unit. The study period had a 1-week run-in phase in which all patients began treatment with duloxetine. This phase was followed by a 1-week intervention phase in which patients in the wake therapy group did 3 wake therapies in combination with daily morning light therapy and sleep time stabilization and patients in the exercise group began daily exercise. This phase was followed by a 7-week continuation phase with daily light therapy and sleep time stabilization or daily exercise. The 17-item Hamilton Depression Rating Scale was the primary outcome measure, and the assessors were blinded to patients' treatment allocation. RESULTS: Both groups responded well to treatment. Patients in the wake therapy group did, however, have immediate and clinically significantly better response and remission compared to the exercise group. Thus, immediately after the intervention phase (week 2), response was obtained in 41.4% of wake therapy patients versus 12.8% of exercise patients (odds ratio [OR] = 4.8; 95% CI, 1.7-13.4; P = .003), and remission was obtained in 23.9% of wake therapy patients versus 5.4% of exercise patients (OR = 5.5; 95% CI, 1.7-17.8; P = .004). These superior response and remission rates obtained by the wake therapy patients were sustained for the whole study period. At week 9, response was obtained in 71.4% of wake therapy patients versus 47.3% of exercise patients (OR = 2.8; 95% CI, 1.1-7.3; P = .04), and remission was obtained in 45.6% of wake therapy patients and 23.1% of exercise patients (OR = 2.8; 95% CI, 1.1-7.3, P = .04). All treatment elements were well tolerated. CONCLUSIONS: Patients treated with wake therapy in combination with bright light therapy and sleep time stabilization had an augmented and sustained antidepressant response and remission compared to patients treated with exercise, who also had a clinically relevant antidepressant response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00149110.

Transcranial low voltage pulsed electromagnetic fields in patients with treatment-resistant depression.

BACKGROUND: Approximately 30% of patients with depression are resistant to antidepressant drugs. Repetitive transcranial magnetic stimulation (rTMS) has been found effective in combination with antidepressants in this patient group. The aim of this study was to evaluate the antidepressant effect of a new principle using low-intensity transcranially applied pulsed electromagnetic fields (T-PEMF) in combination with antidepressants in patients with treatment-resistant depression. METHODS: This was a sham-controlled double-blind study comparing 5 weeks of active or sham T-PEMF in patients with treatment-resistant major depression. The antidepressant treatment, to which patients had been resistant, was unchanged 4 weeks before and during the study period. Weekly assessments were performed using both clinician-rated and patient-rated scales. The T-PEMF equipment was designed as a helmet containing seven separate coils located over the skull that generated an electrical field in tissue with orders of magnitude weaker than those generated by rTMS equipment. RESULTS: Patients on active T-PEMF showed a clinically and statistically significant better outcome than patients treated with sham T-PEMF, with an onset of action within the first weeks of therapy. Effect size on the Hamilton 17-item Depression Rating Scale was .62 (95% confidence interval .21-1.02). Treatment-emergent side effects were few and mild. CONCLUSION: The T-PEMF treatment was superior to sham treatment in patients with treatment-resistant depression. Few side effects were observed. Mechanism of the antidepressant action, in light of the known effects of PEMF stimulation to the brain, is discussed.

[Physical therapies for depression--light, exercise, TMS and sleep deprivation]. / Fysiske behandlingsmetoder ved depression: lysbehandling, motion, magnetisme og søvnmanipulation.

This paper reviews the status of some physical therapies for depression. Light is the treatment of choice for seasonal affective disorder. Light is also effective in non-seasonal depression as mono-therapy and as add-on to drug therapy. Exercise is effective in moderate depression, but onset of action, duration and compliance need to be examined. TMS treatment has a moderate, albeit transient effect on depression, but further development is needed before it can be used as a standard treatment. Sleep deprivation has the fastest known antidepressant effect, but the risk of relapse limits its use. New regimens including drugs and light may sustain the response.