<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03821506</url>
  </required_header>
  <id_info>
    <org_study_id>Version 1.7</org_study_id>
    <nct_id>NCT03821506</nct_id>
  </id_info>
  <brief_title>ROOM-LIGHT: Effect of a Dynamic Lighting System in Depressed Inpatients</brief_title>
  <official_title>Dynamic LED-light Versus Usual Care for Depressed Inpatient: A Randomised Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mental Health Centre Copenhagen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Mental Health Services in the Capital Region, Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Toyota-Fonden</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Grosserer L. F. Foghts Fond Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>ELFORSK Danish Energy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Technical University of Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Mental Health Centre Copenhagen</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: despite developments a substantial part of patients with depression will only&#xD;
      recover slowly. Light therapy from light boxes has shown antidepressant effects but have&#xD;
      several limitations: time consuming, only allowing a fixed spectral distribution, only&#xD;
      delivered at a specific time-point, and often with inadequate light intensity delivered at&#xD;
      the retina. Therefore, we developed a new dynamic lighting system using light fixtures that&#xD;
      are built into the room and can change intensity and spectral distribution of light during&#xD;
      the 24-hour day.&#xD;
&#xD;
      Objectives: the objective of this trial is to assess the beneficial and harmful effects of a&#xD;
      newly developed dynamic lighting system using Light Emitting Diodes (LED) -light armatures&#xD;
      aiming to mimic sunlight, when installed in the patient rooms of a psychiatric inpatient&#xD;
      ward, compared with usual care.&#xD;
&#xD;
      Design: the design is a randomised controlled trial with two arms: an active dynamic light&#xD;
      trial arm and a usual care arm with blinding of depression outcome, and data analyses.&#xD;
      Randomisation will be 1:1.&#xD;
&#xD;
      Inclusion criteria: a current episode of a major depressive episode as part of a unipolar or&#xD;
      bipolar disorder. Patients with bipolar depression should be in current and recent (minimum&#xD;
      two months before admission) mood stabilising treatment, age &gt; 18 years, informed consent.&#xD;
&#xD;
      Exclusion criteria: severe suicidality, abuse of alcohol and / or drugs, actual psychotic&#xD;
      state, Young Mania Rating score above 7 or fulfilling diagnostic criteria for a current&#xD;
      hypomanic or manic episode.&#xD;
&#xD;
      Interventions: the experimental intervention is a dynamic LED-light system in 10 separate&#xD;
      patient single rooms with three dynamic lamps: a window jamb built-in light panel, two&#xD;
      ceiling mounted lamps, and a wall mounted lamp. The usual care is constant standard&#xD;
      LED-light.&#xD;
&#xD;
      Primary outcome: score on the Hamilton Depression Rating Scale 6 item version (HAM-D6) scale&#xD;
      at week 3&#xD;
&#xD;
      Secondary outcomes: score on the Suicidal Ideation Attribution Scale (SIDAS ) scale at week&#xD;
      3, and score in the Hamilton. Depression Rating Scale 17 item version (HAM-D17) scale at week&#xD;
      3, and score on the World Health Organisation Quality Of Life questionaire abbreviated&#xD;
      version (WHOQOL-BREF) at week 3.&#xD;
&#xD;
      Trial size: in total, 150 patients.&#xD;
&#xD;
      Time schedule: the trial will be submitted for regulatory approvals January 2019, the first&#xD;
      participant will be included April 2019, the expected last follow-up of the last participant&#xD;
      will be December 2020, the expected last follow-up after 6 months will be June 2021, data&#xD;
      will be analysed from June 2021 till September 2021, manuscripts will be prepared from&#xD;
      December 2020, and we expect to submit first manuscript December 2021.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The participant population: depression is a common disorder with a prevalence of about&#xD;
      150,000 in Denmark. According to WHO depression is a leading cause of disability worldwide&#xD;
      and is a major contributor to the global burden of disease. Society suffers large direct and&#xD;
      indirect losses in terms of lost work, sickness and early retirements. In Denmark, the costs&#xD;
      of depression alone amount to an estimated 14 billion DKK per year. Depression can affect an&#xD;
      individual to the extent that everyday activities and chores are insurmountable, and can&#xD;
      ultimately lead to despair, hopelessness, and suicidal behaviour.&#xD;
&#xD;
      Current treatment: the current treatment of a depressive episode, whether it is part of a&#xD;
      Major Depressive Disorder (MDD) or of a Bipolar Disorder (BD), involves as first line&#xD;
      treatment psychotherapy /psychoeducation, mood stabilisers, and antidepressants. Second line&#xD;
      treatments include neurostimulation (Electroconvulsive treatment), and complementary options&#xD;
      include exercise, chronotherapeutics (light therapy, sleep deprivation), neurostimulation and&#xD;
      other therapies. Recent drug development has not been able to produce compounds with better&#xD;
      antidepressant effect, and despite the ongoing development of new psychotherapeutic&#xD;
      approaches, improvement from depression is often slow and with 10-25% ending up being&#xD;
      treatment resistant. Relapse, readmission, and suicide are also major treatment challenges.&#xD;
&#xD;
      Trial interventions: the present efficacy trial investigates the possible antidepressant&#xD;
      effect of a new form of dynamic lighting in the treatment of a major depressive episode&#xD;
      either as part of a MDD or a BD. The Light-Emitting-Diode (LED) technology provides new&#xD;
      potentials to adjust frequency distribution and intensity of light during the 24 hour-day.&#xD;
      LED-lighting can be adjusted to supply light rich in the blue, short waved region of the&#xD;
      spectral composition in the first part of the day, and warmer light with less blue later in&#xD;
      the day and in the evening. This regulation should, according to our current chronobiological&#xD;
      knowledge, entrain and regulate the sleep-wake cycle, and thereby improve and stabilize mood,&#xD;
      providing an added non-pharmacological treatment of in-patients suffering from depression.&#xD;
&#xD;
      The experimental intervention specifically consists of implementation of a dynamic LED-light&#xD;
      system in patient rooms with three modules:&#xD;
&#xD;
        -  a dynamic &quot;sunlight therapy LED-lighting&quot; that mimics the spectral composition and&#xD;
           intensity of daylight coming through a southeast (SE) facing window at equinox with 12&#xD;
           hours of sunlight and 12 hours of darkness. The fixture is built into the window jamb&#xD;
           (vertical side of the window) and cannot be switched off.&#xD;
&#xD;
        -  Two LED-lighting lamps mounted horizontally in the ceiling providing dynamic spectral&#xD;
           composition and intensity dynamic. Can be switched on/off.&#xD;
&#xD;
        -  A reading LED-light mounted vertically on the wall adjacent to the bed providing dynamic&#xD;
           spectral composition and intensity. Can be switched on/off.&#xD;
&#xD;
      The usual care intervention is standard, constant LED-Light with two elements:&#xD;
&#xD;
        -  Two LED-Lighting lamps mounted horizontally in the ceiling. Spectral composition and&#xD;
           intensity are constant. The ceiling lamps can be switched on/off.&#xD;
&#xD;
        -  A reading LED-lighting lamp mounted vertically on the wall adjacent to the bed. Spectral&#xD;
           composition and intensity are constant. The reading lamp can be switched on/off.&#xD;
&#xD;
      Bright Light Therapy: the effect of light therapy in the treatment of non-seasonal depression&#xD;
      has been studied for several decades. In 2004, Tuunainen and colleagues published the&#xD;
      Cochrane systematic review &quot;Light therapy for non-seasonal depression&quot;. The conclusion was&#xD;
      that light therapy must be regarded as a promising treatment method, but because of the&#xD;
      heterogeneity among the studies, methodological problems and a lack of systematic collection&#xD;
      of adverse events (AE's), the recommendation of light therapy as treatment of depression&#xD;
      should be considered with some caution. In 2007, Even et al found, in a systematic review, an&#xD;
      added antidepressant effect of light therapy when used as augmentation to antidepressant&#xD;
      therapy. In 2016, Perara et al in a systematic review including 20 RCT's using light therapy&#xD;
      for non-seasonal depression. found an overall small antidepressant effect (SMD -0.41; 95% CI&#xD;
      -0.64 to -0.18), but with a high risk of bias and inconsistency between studies. None of the&#xD;
      included subgroup analyses were significant (stand-alone light therapy versus adjunctive&#xD;
      light therapy; morning light therapy versus evening light therapy or other times of day;&#xD;
      light therapy for in- versus outpatients; placebo conditions using some form of light versus&#xD;
      using non-light-based placebo). However, when analysed separately some support was found for&#xD;
      better effect of light when used as monotherapy; in the morning; for outpatients, and when&#xD;
      using non-light-based placebos. Only four of the 20 studies had low risk of bias on all items&#xD;
      on the Cochrane Risk of Bias Tool. The Martiny et al study found a statistically significant&#xD;
      better effect of light therapy plus sertraline compared to placebo light and light therapy,&#xD;
      in 102 outpatients. The Lam et al study compared, in 122 outpatients in four groups: (a)&#xD;
      active light plus active fluoxetine, (b) active light plus placebo fluoxetine, (c) inactive&#xD;
      negative ion generator plus active fluoxetine, (d) inactive negative ion generator plus&#xD;
      placebo fluoxetine. They found a statistically significant better effect in the group&#xD;
      receiving the combination of active light plus active fluoxetine, and in the group receiving&#xD;
      the combination of active light and placebo fluoxetine compared to the group receiving the&#xD;
      combination of inactive negative ion generator plus placebo fluoxetine. The Lieversee et al&#xD;
      study found, in 84 elderly (&gt; 60 years) outpatients with non-seasonal depression, a&#xD;
      statistically significant better effect of active versus placebo light treatment. The Loving&#xD;
      et al study found, in 81 elderly outpatients (&gt; 60 years) with non-seasonal depression,&#xD;
      treated with bright or placebo light (administered at three different time-points), no&#xD;
      difference between groups and a low reduction in depression severity across groups, of 16 %.&#xD;
      A more recent study showed effect of bright light treatment (BLT) compared to dim light&#xD;
      treatment, in 46 patients with bipolar depression, when used as augmentation in patients&#xD;
      receiving mood stabilising medication. A recent review, from Benedetti et al, showed that the&#xD;
      risk of switch from depression to mania, in BP patient treated with light therapy, was no&#xD;
      higher than with antidepressant drug therapy. With conventional light therapy, patients are&#xD;
      placed in front of a light box for 30-60 minutes in the morning. With dynamic lighting,&#xD;
      LED-light is built into the room. This enables the system to provide light in the daytime&#xD;
      that can phase advance the circadian rhythms and provide an alerting effect. During evening&#xD;
      and night, the light system provides low intensity light with low blue wavelength content&#xD;
      with minimal impact on the circadian system. Dynamic lighting has, in some studies, been&#xD;
      found to provide more stable mood and better sleep quality in people suffering from dementia&#xD;
      and a more stable circadian rhythm in patient suffering from depression.&#xD;
&#xD;
      Architecture at Hospitals: the discovery of the non-visual, light sensitive ganglionic cells&#xD;
      in the human retina (the intrinsically photosensitive Retinal Ganglion Cells, ipRGCs), with a&#xD;
      maximum sensitivity for blue light (460 nm - 480 nm), has stimulated research on the effect&#xD;
      of using light with different spectral composition in humans. The ipRGC has been shown to&#xD;
      function as the prime connection to the suprachiasmatic nuclei (SCN), the master clock in the&#xD;
      hypothalamus, and to a range of brain structures known to be involved in depression. The&#xD;
      impact of the signals from the ipRGC is thought to be responsible for the ability of light to&#xD;
      time and stabilise the sleep-wake cycle, and to adjust the seasonal regulation of serotonin.&#xD;
      LED-light can be particularly rich in the blue wavelength spectrum in contrast to&#xD;
      conventional compact fluorescent light (CFL). Thus, LED-light can be tuned to impact the&#xD;
      regulation of the sleep-wake cycle. The dynamic steering of LED-light is important as blue&#xD;
      light in the evening will delay the sleep-wake cycle, which may cause difficulty falling in&#xD;
      sleep (sleep onset insomnia). Blue light in the morning, on the other hand, will advance&#xD;
      sleep and increase alertness, and as patients with depression tend to be late chronotypes,&#xD;
      this should provide a better sleep regulation. Nonresponse in depression has also been linked&#xD;
      to late chronotype, and blue light should help to correct the drift in the sleep-wake cycle&#xD;
      that patients with depression often experience.&#xD;
&#xD;
      Recent studies confirm ancient architectural principles about exposure to morning sun, such&#xD;
      as the late 19th century Nightingale pavilions facing SE aiming at optimising exposure to the&#xD;
      morning sun in the darkest winter season. In a previous pilot project, we documented extreme&#xD;
      differences in daylight exposure between hospital wards facing SE and hospital wards facing&#xD;
      northwest (NW). Measured on a clear day, these differences were 57.000 Lux at summer&#xD;
      solstice, 38.000 Lux at autumn equinox and 19.000 Lux at winter solstice. Also, the spectral&#xD;
      composition of the morning light was richer in the blue region towards SE.&#xD;
&#xD;
      At psychiatric units in hospitals there will always be &quot;a dark side of the building&quot; where&#xD;
      facades will receive very little - if any - morning sun during wintertime. Dynamic&#xD;
      LED-lighting can be an effective alternative to natural sunlight. Today, there is not enough&#xD;
      knowledge on how LED-light can be implemented and used or about the potentially beneficial&#xD;
      effects of LED-light on patients with depression. We lack practical research knowledge in&#xD;
      this field, which combines medical science, architecture, and engineering.&#xD;
&#xD;
      Clinical data on the control intervention: the control intervention as applied in the usual&#xD;
      care arm consists of standard hospital LED lighting fixtures without dynamic or spectral&#xD;
      changes. The lighting setup in the control intervention consists of two ceiling lamps and one&#xD;
      reading lamp, all with LED standard technology.&#xD;
&#xD;
      Handling risks: LED-lights and armatures are approved for use in the psychiatric ward.&#xD;
&#xD;
      Expected side effect: most common side effects are headache, eyestrain, nausea, and&#xD;
      agitation. Evening administrations of very bright light have been shown to be associated with&#xD;
      sleep disturbances and bipolar patients may switch into hypomania during BLT. The risk of&#xD;
      hypomania is, however, considered small, as all patients will be in mood stabilizing drug&#xD;
      therapy, and the risk of switch from depression to mania, with light therapy, has been found&#xD;
      to be small.&#xD;
&#xD;
      Expected benefits: we expect the dynamic LED-lighting system to provide a larger&#xD;
      antidepressant effect than the standard LED-light, better sleep and less use of medication.&#xD;
&#xD;
      Ethical justification and trial rationale: it is in the public and in the patients shared&#xD;
      interest to investigate how and if light administration in patient rooms has a potential in&#xD;
      the treatment of depression. The intervention in not expected to expose participants to&#xD;
      unnecessary risks, because the treatment in the ward will continue as usual and there will be&#xD;
      close monitoring as the intervention runs. The potential side effects of dynamic LED-light&#xD;
      are expected to be mild and rare. The risk of switch from depression to manic state, due to&#xD;
      light therapy is considered small because all participants will receive adequate mood&#xD;
      stabilizing treatment, and because the risk of switch to mania from depression with light&#xD;
      therapy has been shown to be small. We will exclude all patients with manic symptoms. To find&#xD;
      any emergent manic symptoms during the trial, we will rate weekly for manic symptoms and&#xD;
      alert the staff to look out for emergence of manic symptoms.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 15, 2019</start_date>
  <completion_date type="Actual">March 15, 2023</completion_date>
  <primary_completion_date type="Actual">March 15, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Blinding of depression severity assessment</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Hamilton Depression Rating Scale 6 item version</measure>
    <time_frame>Up to 3 weeks</time_frame>
    <description>A scale, consisting of 7 items from the Hamilton depression Rating Scale, measuring severity of depression. Total scores from zero (no depression) to 24 (most severe depression)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Score on the SIDAS scale</measure>
    <time_frame>Up to 3 weeks</time_frame>
    <description>Suicidal Ideation Attributes Scale (SIDAS). A scale measuring suicidal ideation. Total scores from zero (no suicidal ideation) to 50 (highest level of suicidal ideation).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hamilton Depression Rating Scale 17 item version</measure>
    <time_frame>Up to 3 weeks</time_frame>
    <description>A Scale, consisting of 17 items of the Hamilton Depression Rating Scale, measuring severity of depression. Total scores from zero (no depression) to 52 (most severe depression)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>WHOQOL-BREF</measure>
    <time_frame>Up to 3 weeks</time_frame>
    <description>Quality of life scale with four domains. Each scores is transformed to a zero (lowest quality of life) to 100 (highest quality of life) score.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Major Depressive Disorder</condition>
  <arm_group>
    <arm_group_label>Dynamic light</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The experimental intervention is the installation of a dynamic LED-light system in 10 separate patient single rooms. The system includes three elements: a window jamb built-in light panel, two ceiling mounted lamps, and a wall mounted lamp. All lamps will have a dynamic, time dependent frequency distribution and intensity of light.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Usual care</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The usual care is constant standard LED-light with two elements: two ceiling mounted lamps and a wall mounted lamp.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Dynamic Light</intervention_name>
    <description>Dynamic Lighting system</description>
    <arm_group_label>Dynamic light</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Usual care</intervention_name>
    <description>Standard lighting system</description>
    <arm_group_label>Usual care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  A current episode of a major depressive episode (DSM-5) as part of a unipolar or&#xD;
             bipolar disorder.&#xD;
&#xD;
          -  Patients with bipolar depression should be in current and recent (minimum two months&#xD;
             before admission) mood stabilizing treatment&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  Informed consent&#xD;
&#xD;
          -  Danish speaking.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe suicidality&#xD;
&#xD;
          -  Abuse of alcohol and / or drugs&#xD;
&#xD;
          -  Actual psychotic state within last four weeks&#xD;
&#xD;
          -  Actual Young Mania Rating score above 7 or fulfilling diagnostic criteria for a&#xD;
             current hypomanic or manic episode&#xD;
&#xD;
          -  Patient is subject to coercive measures of any kind.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>17 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Klaus Martiny, DMSc</last_name>
    <role>Study Director</role>
    <affiliation>Psychiatic Hospital Copenhagen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Psychiatic Hospital Copenhagen</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <results_reference>
    <citation>Perera S, Eisen R, Bhatt M, Bhatnagar N, de Souza R, Thabane L, Samaan Z. Light therapy for non-seasonal depression: systematic review and meta-analysis. BJPsych Open. 2016 Mar 4;2(2):116-126. doi: 10.1192/bjpo.bp.115.001610. eCollection 2016 Mar.</citation>
    <PMID>27703764</PMID>
  </results_reference>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>January 27, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 29, 2019</study_first_posted>
  <last_update_submitted>April 13, 2023</last_update_submitted>
  <last_update_submitted_qc>April 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>We will make data from this study available on reasonable request once the results are published</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03821506
org study id: Version 1.7
nct id: NCT03821506
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
Background: despite developments a substantial part of patients with depression will only
      recover slowly. Light therapy from light boxes has shown antidepressant effects but have
      several limitations: time consuming, only allowing a fixed spectral distribution, only
      delivered at a specific time-point, and often with inadequate light intensity delivered at
      the retina. Therefore, we developed a new dynamic lighting system using light fixtures that
      are built into the room and can change intensity and spectral distribution of light during
      the 24-hour day.

      Objectives: the objective of this trial is to assess the beneficial and harmful effects of a
      newly developed dynamic lighting system using Light Emitting Diodes (LED) -light armatures
      aiming to mimic sunlight, when installed in the patient rooms of a psychiatric inpatient
      ward, compared with usual care.

      Design: the design is a randomised controlled trial with two arms: an active dynamic light
      trial arm and a usual care arm with blinding of depression outcome, and data analyses.
      Randomisation will be 1:1.

      Inclusion criteria: a current episode of a major depressive episode as part of a unipolar or
      bipolar disorder. Patients with bipolar depression should be in current and recent (minimum
      two months before admission) mood stabilising treatment, age > 18 years, informed consent.

      Exclusion criteria: severe suicidality, abuse of alcohol and / or drugs, actual psychotic
      state, Young Mania Rating score above 7 or fulfilling diagnostic criteria for a current
      hypomanic or manic episode.

      Interventions: the experimental intervention is a dynamic LED-light system in 10 separate
      patient single rooms with three dynamic lamps: a window jamb built-in light panel, two
      ceiling mounted lamps, and a wall mounted lamp. The usual care is constant standard
      LED-light.

      Primary outcome: score on the Hamilton Depression Rating Scale 6 item version (HAM-D6) scale
      at week 3

      Secondary outcomes: score on the Suicidal Ideation Attribution Scale (SIDAS ) scale at week
      3, and score in the Hamilton. Depression Rating Scale 17 item version (HAM-D17) scale at week
      3, and score on the World Health Organisation Quality Of Life questionaire abbreviated
      version (WHOQOL-BREF) at week 3.

      Trial size: in total, 150 patients.

      Time schedule: the trial will be submitted for regulatory approvals January 2019, the first
      participant will be included April 2019, the expected last follow-up of the last participant
      will be December 2020, the expected last follow-up after 6 months will be June 2021, data
      will be analysed from June 2021 till September 2021, manuscripts will be prepared from
      December 2020, and we expect to submit first manuscript December 2021.
The participant population: depression is a common disorder with a prevalence of about
      150,000 in Denmark. According to WHO depression is a leading cause of disability worldwide
      and is a major contributor to the global burden of disease. Society suffers large direct and
      indirect losses in terms of lost work, sickness and early retirements. In Denmark, the costs
      of depression alone amount to an estimated 14 billion DKK per year. Depression can affect an
      individual to the extent that everyday activities and chores are insurmountable, and can
      ultimately lead to despair, hopelessness, and suicidal behaviour.

      Current treatment: the current treatment of a depressive episode, whether it is part of a
      Major Depressive Disorder (MDD) or of a Bipolar Disorder (BD), involves as first line
      treatment psychotherapy /psychoeducation, mood stabilisers, and antidepressants. Second line
      treatments include neurostimulation (Electroconvulsive treatment), and complementary options
      include exercise, chronotherapeutics (light therapy, sleep deprivation), neurostimulation and
      other therapies. Recent drug development has not been able to produce compounds with better
      antidepressant effect, and despite the ongoing development of new psychotherapeutic
      approaches, improvement from depression is often slow and with 10-25% ending up being
      treatment resistant. Relapse, readmission, and suicide are also major treatment challenges.

      Trial interventions: the present efficacy trial investigates the possible antidepressant
      effect of a new form of dynamic lighting in the treatment of a major depressive episode
      either as part of a MDD or a BD. The Light-Emitting-Diode (LED) technology provides new
      potentials to adjust frequency distribution and intensity of light during the 24 hour-day.
      LED-lighting can be adjusted to supply light rich in the blue, short waved region of the
      spectral composition in the first part of the day, and warmer light with less blue later in
      the day and in the evening. This regulation should, according to our current chronobiological
      knowledge, entrain and regulate the sleep-wake cycle, and thereby improve and stabilize mood,
      providing an added non-pharmacological treatment of in-patients suffering from depression.

      The experimental intervention specifically consists of implementation of a dynamic LED-light
      system in patient rooms with three modules:

        -  a dynamic "sunlight therapy LED-lighting" that mimics the spectral composition and
           intensity of daylight coming through a southeast (SE) facing window at equinox with 12
           hours of sunlight and 12 hours of darkness. The fixture is built into the window jamb
           (vertical side of the window) and cannot be switched off.

        -  Two LED-lighting lamps mounted horizontally in the ceiling providing dynamic spectral
           composition and intensity dynamic. Can be switched on/off.

        -  A reading LED-light mounted vertically on the wall adjacent to the bed providing dynamic
           spectral composition and intensity. Can be switched on/off.

      The usual care intervention is standard, constant LED-Light with two elements:

        -  Two LED-Lighting lamps mounted horizontally in the ceiling. Spectral composition and
           intensity are constant. The ceiling lamps can be switched on/off.

        -  A reading LED-lighting lamp mounted vertically on the wall adjacent to the bed. Spectral
           composition and intensity are constant. The reading lamp can be switched on/off.

      Bright Light Therapy: the effect of light therapy in the treatment of non-seasonal depression
      has been studied for several decades. In 2004, Tuunainen and colleagues published the
      Cochrane systematic review "Light therapy for non-seasonal depression". The conclusion was
      that light therapy must be regarded as a promising treatment method, but because of the
      heterogeneity among the studies, methodological problems and a lack of systematic collection
      of adverse events (AE's), the recommendation of light therapy as treatment of depression
      should be considered with some caution. In 2007, Even et al found, in a systematic review, an
      added antidepressant effect of light therapy when used as augmentation to antidepressant
      therapy. In 2016, Perara et al in a systematic review including 20 RCT's using light therapy
      for non-seasonal depression. found an overall small antidepressant effect (SMD -0.41; 95% CI
      -0.64 to -0.18), but with a high risk of bias and inconsistency between studies. None of the
      included subgroup analyses were significant (stand-alone light therapy versus adjunctive
      light therapy; morning light therapy versus evening light therapy or other times of day;
      light therapy for in- versus outpatients; placebo conditions using some form of light versus
      using non-light-based placebo). However, when analysed separately some support was found for
      better effect of light when used as monotherapy; in the morning; for outpatients, and when
      using non-light-based placebos. Only four of the 20 studies had low risk of bias on all items
      on the Cochrane Risk of Bias Tool. The Martiny et al study found a statistically significant
      better effect of light therapy plus sertraline compared to placebo light and light therapy,
      in 102 outpatients. The Lam et al study compared, in 122 outpatients in four groups: (a)
      active light plus active fluoxetine, (b) active light plus placebo fluoxetine, (c) inactive
      negative ion generator plus active fluoxetine, (d) inactive negative ion generator plus
      placebo fluoxetine. They found a statistically significant better effect in the group
      receiving the combination of active light plus active fluoxetine, and in the group receiving
      the combination of active light and placebo fluoxetine compared to the group receiving the
      combination of inactive negative ion generator plus placebo fluoxetine. The Lieversee et al
      study found, in 84 elderly (> 60 years) outpatients with non-seasonal depression, a
      statistically significant better effect of active versus placebo light treatment. The Loving
      et al study found, in 81 elderly outpatients (> 60 years) with non-seasonal depression,
      treated with bright or placebo light (administered at three different time-points), no
      difference between groups and a low reduction in depression severity across groups, of 16 %.
      A more recent study showed effect of bright light treatment (BLT) compared to dim light
      treatment, in 46 patients with bipolar depression, when used as augmentation in patients
      receiving mood stabilising medication. A recent review, from Benedetti et al, showed that the
      risk of switch from depression to mania, in BP patient treated with light therapy, was no
      higher than with antidepressant drug therapy. With conventional light therapy, patients are
      placed in front of a light box for 30-60 minutes in the morning. With dynamic lighting,
      LED-light is built into the room. This enables the system to provide light in the daytime
      that can phase advance the circadian rhythms and provide an alerting effect. During evening
      and night, the light system provides low intensity light with low blue wavelength content
      with minimal impact on the circadian system. Dynamic lighting has, in some studies, been
      found to provide more stable mood and better sleep quality in people suffering from dementia
      and a more stable circadian rhythm in patient suffering from depression.

      Architecture at Hospitals: the discovery of the non-visual, light sensitive ganglionic cells
      in the human retina (the intrinsically photosensitive Retinal Ganglion Cells, ipRGCs), with a
      maximum sensitivity for blue light (460 nm - 480 nm), has stimulated research on the effect
      of using light with different spectral composition in humans. The ipRGC has been shown to
      function as the prime connection to the suprachiasmatic nuclei (SCN), the master clock in the
      hypothalamus, and to a range of brain structures known to be involved in depression. The
      impact of the signals from the ipRGC is thought to be responsible for the ability of light to
      time and stabilise the sleep-wake cycle, and to adjust the seasonal regulation of serotonin.
      LED-light can be particularly rich in the blue wavelength spectrum in contrast to
      conventional compact fluorescent light (CFL). Thus, LED-light can be tuned to impact the
      regulation of the sleep-wake cycle. The dynamic steering of LED-light is important as blue
      light in the evening will delay the sleep-wake cycle, which may cause difficulty falling in
      sleep (sleep onset insomnia). Blue light in the morning, on the other hand, will advance
      sleep and increase alertness, and as patients with depression tend to be late chronotypes,
      this should provide a better sleep regulation. Nonresponse in depression has also been linked
      to late chronotype, and blue light should help to correct the drift in the sleep-wake cycle
      that patients with depression often experience.

      Recent studies confirm ancient architectural principles about exposure to morning sun, such
      as the late 19th century Nightingale pavilions facing SE aiming at optimising exposure to the
      morning sun in the darkest winter season. In a previous pilot project, we documented extreme
      differences in daylight exposure between hospital wards facing SE and hospital wards facing
      northwest (NW). Measured on a clear day, these differences were 57.000 Lux at summer
      solstice, 38.000 Lux at autumn equinox and 19.000 Lux at winter solstice. Also, the spectral
      composition of the morning light was richer in the blue region towards SE.

      At psychiatric units in hospitals there will always be "a dark side of the building" where
      facades will receive very little - if any - morning sun during wintertime. Dynamic
      LED-lighting can be an effective alternative to natural sunlight. Today, there is not enough
      knowledge on how LED-light can be implemented and used or about the potentially beneficial
      effects of LED-light on patients with depression. We lack practical research knowledge in
      this field, which combines medical science, architecture, and engineering.

      Clinical data on the control intervention: the control intervention as applied in the usual
      care arm consists of standard hospital LED lighting fixtures without dynamic or spectral
      changes. The lighting setup in the control intervention consists of two ceiling lamps and one
      reading lamp, all with LED standard technology.

      Handling risks: LED-lights and armatures are approved for use in the psychiatric ward.

      Expected side effect: most common side effects are headache, eyestrain, nausea, and
      agitation. Evening administrations of very bright light have been shown to be associated with
      sleep disturbances and bipolar patients may switch into hypomania during BLT. The risk of
      hypomania is, however, considered small, as all patients will be in mood stabilizing drug
      therapy, and the risk of switch from depression to mania, with light therapy, has been found
      to be small.

      Expected benefits: we expect the dynamic LED-lighting system to provide a larger
      antidepressant effect than the standard LED-light, better sleep and less use of medication.

      Ethical justification and trial rationale: it is in the public and in the patients shared
      interest to investigate how and if light administration in patient rooms has a potential in
      the treatment of depression. The intervention in not expected to expose participants to
      unnecessary risks, because the treatment in the ward will continue as usual and there will be
      close monitoring as the intervention runs. The potential side effects of dynamic LED-light
      are expected to be mild and rare. The risk of switch from depression to manic state, due to
      light therapy is considered small because all participants will receive adequate mood
      stabilizing treatment, and because the risk of switch to mania from depression with light
      therapy has been shown to be small. We will exclude all patients with manic symptoms. To find
      any emergent manic symptoms during the trial, we will rate weekly for manic symptoms and
      alert the staff to look out for emergence of manic symptoms.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: Blinding of depression severity assessment
measure: Hamilton Depression Rating Scale 6 item version
time frame: Up to 3 weeks
description: A scale, consisting of 7 items from the Hamilton depression Rating Scale, measuring severity of depression. Total scores from zero (no depression) to 24 (most severe depression)
measure: Score on the SIDAS scale
time frame: Up to 3 weeks
description: Suicidal Ideation Attributes Scale (SIDAS). A scale measuring suicidal ideation. Total scores from zero (no suicidal ideation) to 50 (highest level of suicidal ideation).
measure: Hamilton Depression Rating Scale 17 item version
time frame: Up to 3 weeks
description: A Scale, consisting of 17 items of the Hamilton Depression Rating Scale, measuring severity of depression. Total scores from zero (no depression) to 52 (most severe depression)
measure: WHOQOL-BREF
time frame: Up to 3 weeks
description: Quality of life scale with four domains. Each scores is transformed to a zero (lowest quality of life) to 100 (highest quality of life) score.
arm group label: Dynamic light
arm group type: Experimental
description: The experimental intervention is the installation of a dynamic LED-light system in 10 separate patient single rooms. The system includes three elements: a window jamb built-in light panel, two ceiling mounted lamps, and a wall mounted lamp. All lamps will have a dynamic, time dependent frequency distribution and intensity of light.
arm group label: Usual care
arm group type: Placebo Comparator
description: The usual care is constant standard LED-light with two elements: two ceiling mounted lamps and a wall mounted lamp.
intervention type: Device
intervention name: Dynamic Light
description: Dynamic Lighting system
arm group label: Dynamic light
intervention type: Device
intervention name: Usual care
description: Standard lighting system
arm group label: Usual care
criteria: 
gender: All
minimum age: 17 Years
maximum age: N/A
healthy volunteers: No
last name: Klaus Martiny, DMSc
role: Study Director
affiliation: Psychiatic Hospital Copenhagen
facility: 
country: Denmark
citation: Perera S, Eisen R, Bhatt M, Bhatnagar N, de Souza R, Thabane L, Samaan Z. Light therapy for non-seasonal depression: systematic review and meta-analysis. BJPsych Open. 2016 Mar 4;2(2):116-126. doi: 10.1192/bjpo.bp.115.001610. eCollection 2016 Mar.
PMID: 27703764
responsible party type: Sponsor
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Major
sharing ipd: Yes
ipd description: We will make data from this study available on reasonable request once the results are published