Are Bright Lights and Regulated Sleep Effective Treatment for Depression.
Phase: NA
Conditions: Sleep Phase Rhythm Disturbance, Sleep Deprivation
Sponsor: New York State Psychiatric Institute

Signed copy on file at IRB 
 
             v. 11/15/13 
New York State Psychiatric Institute 
Institutional Review Board 
 
November 30, 2016 
 
 
To: 
 
Dr. Jonathan Stewart 
From:  
Dr. Edward Nunes, Co-Chairman 
 
 
Dr. Laurence Greenhill, Co-Chairman 
 
 
 
 
 
Subject: 
Approval Notice 
 
 
  
 
 
 
 
Your protocol # 7361entitled: ARE BRIGHT LIGHTS AND REGULATED SLEEP EFFECTIVE 
TREATMENT FOR DEPRESSION? Protocol version date 11/30/2016 and consent forms have been 
approved by the New York State Psychiatric Institute - Columbia University Department of 
Psychiatry Institutional Review Board from November 30, 2016 to November 20, 2017. (Reviewed 
at the Full Board meeting on November 21, 2016.) 
 
Consent requirements: 
      Not applicable:  
    45CFR46.116 (d) alteration of consent to obtain verbal consent for the telephone interview   
     √  Signature by the person(s) obtaining consent is required to document the consent process 
      Documentation of an independent assessment of the participant’s capacity to consent is also 
required. 
Approved for recruitment of subjects who lack capacity to consent: √ No  Yes    
 
 
Field Monitoring Requirements: √ Routine Special: ___________________  
 
 
  Only copies of consent documents that are currently approved by the IRB may be used to obtain 
consent for participation in this study. 
  A progress report and application for continuing review is required 2 months prior to the 
expiration date of IRB approval. 
  Changes to this research may not be initiated without the review and approval of the IRB except 
when necessary to eliminate immediate hazards to participants.  
  All serious and/or unanticipated problems or events involving risks to subjects or others must be 
reported immediately to the IRB.  Please refer to the PI-IRB website at http://irb.nyspi.org for 
Adverse Event Reporting Procedures and additional reporting requirements.    
 
Cc: 
RFMH Business Office (grant) 
 
Encl:  Independent Evaluator, CF, cover sheet, adherence, questionnaire, HIPAA 
 
EN/LG/alw 

Protocol Summary Form
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Stewart, Jonathan
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Protocol Title:
Are bright lights and regulated sleep 
effective treatment for depression?
Protocol Number:
7361
First Approval:
11/30/2016
Expiration Date:
Not yet accepted
Version Date:
11/30/2016
Clinic:
Depression Evaluation Service
Contact Principal Investigator:
Jonathan Stewart, MD
Email: jws6@columbia.edu
Telephone: 646-774-8070
Co-Investigator(s):
David Hellerstein, MD
Research Chief:
B. Timothy Walsh, MD
Cover Sheet
Choose from the following that is applicable to your study
I am submitting a new protocol
Division & Personnel
Division
What Division/Department does the PI belong to?
Therapeutics
Within the division/department, what Center or group are you affiliated with, if any? 
Depression Evaluation Service
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 
State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.
None

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Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Use of Placebo or Sham Treatment
   Medication-Free Period or Treatment Washout
   Somatic Treatment or Intervention
   Internet-based Data Collection or Transmission
Population
Indicate which of the following populations will be included in this research
   Adults
   Adults over 50
   Employees or Students
   Individuals with HIV/AIDS
Research Support/Funding
Will an existing internal account be used to support the project?
Yes
Describe internal account
Any DES account from which project expenses can be drawn (specifically, light boxes, activity monitors, 
amber and clear goggles, and melatonin collection/analysis costs)
Is the project externally funded or is external funding planned?
No
Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
   Other Columbia University Medical Center Facilities
This protocol describes research conducted by the PI at other facilities/locations
Yes
   Other Facilities
Other Facilities
Type in location(s)

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3 Columbus Circle
Lay Summary of Proposed Research 
Lay Summary of Proposed Research
Research Question: Is Chronotherapy (i.e., missing a night of sleep, shifting sleep time and bright morning 
lights to adjust the biological clock) effective treatment for non-bipolar depression?
 
Antidepressant medications do not result in quick remissions and they produce side effects.  "Jet lag" can be 
thought of as resulting from the internal clock being out of sync with external time; as the internal clock 
aligns with sun time, the symptoms of jet lag lessen.  Preliminary data suggest some depressed patients act 
as if their internal biological clock is out of sync with the outside world and re-aligning their clock with the 
timing of sunlight lessens their depressed mood and accompanying depressive symptoms.  This 
"chronotherapy" may produce remission during the first week of treatment while causing minimal 
problems.  This study aims to demonstrate the efficacy of chronotherapy by comparing its efficacy to an 
alternative protocol we consider unlikely to produce the same effects.  Whether a given patient will be 
instructed to use chronotherapy or the alternative protocol will be determined randomly (i.e., by chance, 
essentially a computerized flip of a coin).  Prior to determination of which protocol a patient will follow, 
each patient will declare their desired sleep time (for example, 11 p.m. to 7 a.m.).  All patients will be 
assigned specific times to sleep and sit in front of bight lights wearing clear (Chronotherapy) or amber 
(alternative protocol) goggles.  Those assigned Chronotherapy will miss a night of sleep while those in the 
alternative protocol will not; assigned sleep times will also differ between groups using different strategies 
to shift the timing of their sleep from their ideal sleep time as determined by their MEQ score to their 
desired sleep time.  All subjects will be rated daily by telephone for the first week after their Wake Night 
(those assigned Chronotherapy) or for the first week following randomization (those assigned the alternative 
protocol), and then weekly for an additional five weeks.  Whenever possible, weekly visits will be in person, 
although telephone visits will be allowed.  All subjects will be rated at baseline, 1 week and 6 weeks by an 
Independent Evaluator blind to treatment assignment.  After the six week post-randomization evaluation, all 
subjects will be offered six months of continued treatment and be rated monthly.  Treatment during this six 
month period may consist of Chronotherapy or conventional antidepressants as the patient and doctor 
determine.  Standard ratings of depression, over-all illness and functioning will be obtained; melatonin, 
sleep logs and activity monitoring will measure the timing of the biological clock.  Change in the symptom 
measures will determine whether chronotherapy is as effective as, less effective than or more effective than 
the alternative treatment.  Chronotherapy will be judged effective if it is more effective than the alternative 
treatment. Secondary analyses will analyze timing of melatonin rise, timing of sleep and activity to 
determine whether the timing of the biological clock changes, and if so whether clock changes correlate 
with improvement.  Measures of functioning will determine whether functioning improves coincident with, 
independent of or subsequent to mood improvement. 
Background, Significance and Rationale

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Background, Significance and Rationale
While chronotherapy (variously including some number of nights without sleep coupled with early morning 
bright lights and set times for sleep with or without an advance in the timing of allowed sleep) has some 
degree of acceptance as effective treatment for affective disorders, the majority of the literature addresses 
bipolar illness.  We found three studies that address depressed patients who do not have bipolar disorder.  
One concluded that chronotherapy is more effective for and is more quickly effective in depressed patients 
with bipolar disorder than those without a bipolar history, but conclusions as to whether this treatment is 
effective for nonbipolar patients cannot be made as there was no comparison condition (Barbini, 1998).  
Two studies (Martiny, 2012; Sahlem, 2014) included nonbipolar depressed subjects but neither separately 
reported response by polarity, although one stated that the nonbipolar subjects' response "did not differ".  
Both, however, also gave patients standard antidepressant treatment; i.e., chronotherapy was used as an add-
on or augmentation rather than as the only treatment.  Thus, Chronotherapy for nonbipolar depression 
appears to us to be insufficiently studied to judge its efficacy in this population.  Our preliminary work (IRB 
#5491 and #6938) suggest our version of chonotherapy may be effective alone for nonbipolar depression.  
To date, we have treated 18 such patients; 10 (56%) were remitted at 1 week and 10 (56%) were remitted at 
6 weeks.  These results compare favorably to antidepressant medications.  Szegedi (see uploads), for 
example, compiled data from 41 randomized, controlled trials; no drug resulted in increased remissions at 
week one relative to placebo.  Rapidly titrated mirtazapine resulted in significantly more remissions than 
placebo at week 2 (13% vs 7%), while all other drugs including usual dose mirtazapine, venlafaxine, 
selective serotonin re-uptake inhibitors, tricyclic antidepressants, trazodone and matprotyline separated from 
placebo at week 3 or later.  Even at week 6, the highest remission rate was TCA at 40%.  So, even 
considering the 95% confidence limits of 10 out of 18 range from 31-78%, these two open pilot studies raise 
the possibility that some patients can improve quickly, even in days, rather than the weeks it takes 
antidepressant medications to produce remissions.  Definitive studies demonstrating the ability of 
chronotherapy to produce rapid remissions have not been conducted.  This study aims to fill that void.
Specific Aims and Hypotheses
Specific Aims and Hypotheses
Research Question
Is Chronotherapy effective treatment for nonbipolar depression?
 
Specific Aim #1: Demonstrate that Chronotherapy is effective treatment for nonbipolar depressive illness 
after one week of treatment.
 
Specific Aim #2: Demonstrate that Chronotherapy is effective treatment for nonbipolar depressive illness 
after six weeks.
 
Specific Aim #3: Demonstrate that Chronotherapy shifts the biological clock.
 
Hypothesis #1: Patients assigned Chronotherapy will be more likely to be remitted at week 1 than those 
assigned alternative treatment.
 

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Hypothesis #2: Patients assigned Chronotherapy will be more likely to be remitted at week 6 than those 
assigned alternative treatment.
 
Hypothesis #3: Shift (earlier) of the onset of night-time melatonin secretion levels will be greater in 
chonotherapy-treated patients than in those receiving alternative treatment.
Description of Subject Population
Sample #1
Specify subject population
nonbipolar depression
Number of completers required to accomplish study aims
60
Projected number of subjects who will be enrolled to obtain required number of completers
75
Age range of subject population
18-65
Gender, Racial and Ethnic Breakdown
We anticipate our study population will consist of roughly:
 
Females 60%
 
Hispanics 15%
 
Race
Caucasian 65%
African-American/Black 15%
Asian 15%
Other/Mixed/Unstated 5%
Description of subject population
As above
Recruitment Procedures
Describe settings where recruitment will occur

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Depression Evaluation Service: 3rd Floor New York State Psychiatric Institute, 1051 Riverside Dr., New 
York, New York
 
3 Columbus Circle: 14th floor, Suite 1408, 3 Columbus Circle, New York, New York 
How and by whom will subjects be approached and/or recruited? 
We anticipate that most patients will be approached and recruited by the clinician interviewing patients in 
IRB Protocol #6669R once it has been presumptively determined that all inclusion and no exclusion criteria 
have been met. 
 
Additional patients initially recruited for another DES study may be suggested for this study once they 
complete any treatment portion of the other study (patients in the post-treatment follow-up phase of the 
other study will be eligible for recruitment into this protocol assuming they meet all inclusion and no 
exclusion criteria, agree to and sign consent for this protocol).  Such patients from other protocols will either 
be recruited by their clinician in the other study (if that clinician is authorized to obtain consent for this 
protocol) or referred by the other study's clinician to a DES clinician authorized to obtain informed consent 
for this protocol.  
 
Patients referred from other NYSPI clinicians and from CUMC will be interviewed and recruited through 
Protocol #6669R.
How will the study be advertised/publicized? 
We do not envision advertising this study at this time.  However, should we decide to advertise, any text 
and/or pictures will be submitted to the IRB for approval prior to their use, which will occur only after IRB 
approval.  Non-advertising publicity may occur from time to time in the form of publicized interviews such 
as appearances on talk shows or news reports and print media articles based on interviews.
Do you have ads/recruitment material requiring review at this time? 
No
Does this study involve a clinical trial?
Yes
YOU MUST REGISTER AT ClinicalTrials.gov IMMEDIATELY UPON RECEIPT OF IRB APPROVAL 
AND PRIOR TO ENROLLMENT OF THE FIRST SUBJECT. YOU WILL BE PROVIDED WITH A NCT 
REGISTRATION NUMBER ON REGISTRATION. PLEASE REVISE THIS SECTION OF THE 
PROTOCOL SUMMARY FORM TO INCLUDE THE NCT NUMBER AND RE-SUBMIT AS AN 
AMENDMENT TO THE IRB.
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement

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Stewart, Jonathan
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Protocol #7088 involves a single blood draw to analyze for epigenetic markers; this blood draw may occur 
while patients participate in this protocol
 
Protocol #6669R is the DES Screening Protocol which most patients entering this study will complete prior 
to entry to this protocol
 
Protocol #5768 is a study of Cognitive Behavior Therapy; patients who do not remit upon completion of 
that protocol may be offered participation in this protocol, while non-remitters in this protocol may be 
offered treatment in #5768
 
We are still following some participants in Study #6457 (which compared desvenlafaxine to placebo) and 
#6263 (AKA #7160R) (which compared sertraline to placebo, non-responders crossed to bupropion or 
sertraline, respectively).  While unlikely, should any such patients be eligible for this study, we would 
approach them.  We would not endeavor to make them eligible, for example, by stopping current treatment 
in order to produce eligibility.
Inclusion/Exclusion Criteria
Name the subject group/sub sample
nonbiopolar depression
Create or insert table to describe the inclusion criteria and methods to ascertain them
1. Age 18-65                                                           1. Ask patient and compare stated age to reported 
                                                                                    DOB
 
2. Currently depressed                                            2. Has an affective disorder diagnosis per SCID 
                                                                                    interview (i.e., major depression, persistent 
                                                                                    depressive disorder, unspecified depressive 
                                                                                    disorder)
 
3. In reasonably good physical health                    3. No active medical problem not under good control
                                                                                    (e.g., someone with hypertension whose current 
                                                                                    blood pressure is in the normal range, someone 
                                                                                    with diabetes having a hemoglobin A1C < 7;       
                                                                                    abnormal thyroid tests [low TSH in someone 
                                                                                    taking thyroid medication is OK); so, medical
                                                                                    history (from patient), labs, and when indicated
                                                                                    discussion with primary care physician
Create or insert table to describe the exclusion criteria and methods to ascertain them
1. Bipolar disorder (I, II or unspecified)                1. SCID interview
 

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2. History of psychosis                                           2. SCID interview
 
3. Unstable medical condition                                3. medical history, labs, physical examination
 
4. Current (past six months) drug or alcohol use   4. SCID interview; urine toxicology
    disorder
 
5. Need for hospitalization                                     5. Clinician's judgment based on depression severity,
                                                                                    suicidality or any other reason
 
6. Treating clinician determination not to include 6. Clinician's judgment
    patient in this protocol
 
7. Currently taking medication approved              7. Patient report
    for the treatment of depression
 
8. Un- or poorly controlled hypertension              8. BP on repeated readings of >= 150 systolic or >=
                                                                                  100 diastolic
 
9. Pregnancy                                                          9. Patient report; lab test
Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
No
Waiver of parental consent 
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB # 
6669R
Describe Study Consent Procedures
The consenting clinician after determining the patient is presumptively eligible (e.g., prior to lab results 

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returning) will explain the study procedures as well as alternatives, risks and possible benefits, answer any 
questions and offer the IRB approved study consent, watch the patient read the consent, answer any further 
queries and then watch while the patients signs the consent.
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
   Information Sheet
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Hellerstein, David, MD
Stewart, Jonathan, MD
Type in the name(s) not found in the above list
Study Procedures
Describe the procedures required for this study
Potential participants will be interviewed under Protocol #6669R.  Those meeting all Inclusion Criteria and 
no Exclusion Criteria will be offered participation in the study.  For clarification purposes, no otherwise 
eligible subject will be offered participation in this study who is currently taking approved antidepressant 
medication and the DES will not suggest or recommend discontinuation of such medication in order to 
create an eligible subject.  Informed consent will be obtained prior to any procedures specific to this 
protocol.  If labs and physical have been done within three months, these will be obtained and reviewed; 
potentially exclusionary labs will either exclude the subject or be repeated to determine eligibility vs. 
exclusion; such recent labs and physical examinations will not be repeated unless the consenting physician 
deems a repeat appropriate; urine for pregnancy and drug testing will be obtained from all potential subjects 
whether recent such tests exist or not.  All other patients who sign consent will have blood drawn, urine 
collected, EKG obtained and physical examination performed.  Blood analyses will include SMA-25 (which 
assesses kidney and liver function, several electrolytes such as calcium, sodium and potassium and some 
other bodily functions), TSH (assessing thyroid function); urinalysis measures kidney and bladder function; 
other analyses of urine will test for commonly abused substances and pregnancy (if appropriate).  
Electrocardiogram assesses heart function.  The Mini-Mental Status Examination (given to those over 60 
years of age) assesses cognitive function (such as memory).  Patients and doctors will complete a variety of 
ratings to assess mood, over-all symptoms, the timing of their biological clock and psychosocial functioning 
(see Table in "Uploads" for schedule of when ratings are done and by whom, and "Assessment Instruments" 
below for names, acronyms and descriptions of the assessment scales).  Patients will be given an activity 
monitor to wear and sleep/activity/mood logs to complete daily.  They will return in 1-2 weeks (although at 
patient's discretion, this time will be allowed to last up to 30 days) at which time mood symptoms will be 
reassessed.  Those who do not remain depressed will not receive further treatment through the protocol 
although they will be offered three months of "open treatment" (i.e, they can consult with a DES psychiatrist 
who will prescribe whatever treatment the patient and doctor agree upon and available to the DES 
psychiatrist to use).  Those still depressed will be randomly assigned to treatment with Chronotherapy or 

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alternative treatment (see below for descriptions). Prior to randomization, all patients will declare what time 
they desire to end up sleeping ("desired sleep time").
 
Chronotherapy
Patients assigned chronotherapy will determine which night during the ensuing week they will be able to 
miss a night of sleep ("Wake Night"); their chronotherapy protocol will begin that night.  Followign their 
Wake Night, they will be instructed to sleep 8 hours at specific times; their first allowed sleep will be on the 
evening following their Wake Night starting at six hours prior to their desired sleep onset time.  Their 
second allowed 8 hours of sleep time will be the following night starting three hours prior to their desired 
sleep onset time.  Those whose desired sleep time is within two hours of the times determined by their 
responses to the Morningness-Eveningness Questionnaire (MEQ) will thereafter be instructed to sleep only 
at their desired sleep time.  Subjects whose desired sleep time is more than two hours earlier than their MEQ 
derived ideal sleep time will be given instructions to sleep desired minus six and desired minus 3 hours the 
initial two allowed sleep nights; thereafter their allowed sleep will be later and later in maximal 3 hour 
increments until allowed sleep coincides with MEQ determined sleep times; thereafter, their allowed sleep 
will shift half an hour earlier every two-four days (depending on their ability to waken earlier) until their 
allowed sleep coincides with their desired sleep time.  Whichever allowed sleep paradigm is followed, once 
sleep is at the desired time, their allowed sleep time will remain their desired sleep time thereafter.  Patients 
whose desired sleep time is within two hours of their MEQ-determined ideal sleep time will sit in front of 
the bright lights wearing clear goggles throughout at their desired wake-up time beginning the morning 
following their Wake Night.  Those whose MEQ-determined ideal sleep time is more than two hours 
different from their ideal sleep time will initially sit in front of the bright lights at their MEQ-determined 
ideal wake-up time, also beginning the morning following their Wake Night; as wake-up times shift earlier, 
time in front of the bright lights will shift with their allowed wake-up time.  For the six weeks following 
randomization, whenever they sit in front of the light box, patients will be instructed to wear clear goggles.
 
To date, the longest time from wake-up prior to institution of a "Wake Night" until post-Wake Night 
allowed sleep has been 42 hours.  Should time from prior wake-up to six hours earlier than desired sleep 
onset time project to more than 42 hours, first allowed sleep time will be shifted earlier so that first allowed 
sleep time is no more than 42 hours after their previous day's wake-up time.  An additional day or days of 
shifting sleep will be added such that three hour per day increments (likely shorter on the last night) in 
allowed sleep time ends at their desired sleep time.
 
Should any patient have difficulty getting to sleep at the assigned time and/or waking at the prescribed time, 
they will enter a remedial protocol.  This protocol will allow such patients to go to sleep when they feel tired 
and spontaneously waken for two nights, using the bright lights at the time they spontaneously waken (or at 
the previously assigned time if spontaneous wakening is earlier than the assigned time).  The mean go to 
sleep and wake-up times of these two nights will determine their allowed sleep onset and wake-up times and 
the resulting wake-up time will be their new time to sit in front of the bright lights.  They will then shift 
their allowed sleep and light use times half hour forward or back as appropriate until they are sleeping at 
their desired time and using the bright lights at their desired wake-up time.  Should they have trouble 
shifting in half-hour decrements, shorter decrements will be used.
 
Alternative treatment

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Patients randomized to alternative treatment will also be assigned specific allowed 8 hour sleep times and sit 
in front of the bright lights for half an hour each morning.  Patients assigned alternative treatment will NOT 
miss a night of sleep; that is, they will not have a Wake Night.  Their allowed sleep times will start at their 
MEQ-determined ideal sleep time.  Subsequently, allowed sleep will shift in half hour increments or 
decrements as appropriate until allowed sleep coincides with desired sleep.  They will sit in front of the 
bright lights each morning on waking up.  Whenever they sit in front of the light box, they will be instructed 
to wear the amber goggles.  The remedial protocol above will be followed with any patient unable to shift 
their sleep.
 
Ratings and timing of ratings will be identical for all patients.  That is, all will complete the same rating 
scales throughout.  In particular, all subjects will log in for 12 hours out of 24 during their initial 24 hours 
post-randomization, complete daily mood, sleep and energy logs, wear an activity monitor and have call-in 
interviews daily during the first post-randomization week.  All will be interviewed by an independent 
evaluator blind to treatment assignment at baseline and Weeks 1 and 6, with ratings by their study clinician 
daily for the first week and weekly thereafter.  At week 6, remitters will be recommended to continue bright 
light and allowed sleep times, although they will be asked to return their light boxes, goggles and activity 
monitors.  Nonremitters will be offered alternative treatment, including Chronotherapy if assigned to the 
alternative treatment group and standard antidepressants whichever their assigned study treatment.  All 
randomized subjects will continue to be seen at least monthly for six months with continued ratings each 
month.
 
Use of Light Boxes
All fecund women will be instructed to stop using the light box should they become pregnant.  Also, 
regardless of group assignment, patients will be instructed to sit about 18 inches from the light box with 
eyes open but not looking directly at the light; instead they should read or use their computer or other 
sedentary activity.  They should remain 18 inches from the light for 30 minutes.  However, should side 
effects occur (e.g., overstimulation), the time may be decreased.  Tolerance of the light box plus continuing 
depressed mood will trigger the doctor recommending longer light box use in weekly 15 minute increments 
up to 60 minutes total; first available increment would be at the week 2 visit, decrements can occur at any 
time. 
 
Melatonin
All randomized subjects on the night they are randomized will collect saliva to later be analyzed for 
melatonin.  They will be given tubes each of which contains a cotton swab with instructions to place a swab 
in their mouth every half hour (so, nine swabs = over a four hour period), write the date and time each swab 
was collected on the tube, refrigerate until they bring the vials in at their next visit.  This is repeated over a 
three hour period at approximately one week (patients who have difficulty reaching their intended sleeping 
time will delay 2nd salvia collection until they reach their desired sleep time).  In order to prevent ambient 
light from preventing melatonin secretion, all subjects will be issued blue-blocking amber goggles with 
instructions to wear them from an hour prior to start of saliva collection until the last saliva collection on 
each of the two nights during which saliva is collected.
 
Independent Evaluation
All study subjects who are randomized will be evaluated by someone who has no idea what their treatment 
has been, whether treatment has begun or how long treatment has been if currently being treated.  These 

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Independent Evaluations will occur prior to institution of post-randomization procedures (typically on day 
of randomization), at the end of Week 1 and at the end of Week 6 post-randomization.  If possible, this 
evaluation will be in person, but when in person interviewing is not possible these evaluations will be made 
by telephone.  Independent Evaluators will be instructed not to ask any questions about treatment or where 
the interviewee is in the study.  Participants will be instructed not to say anything to the Independent 
Evaluator about whether they are in treatment, or if in treatment what that treatment might be.
 
Independent Evaluators will be individuals trained in use of the Hamilton Rating Scale for Depression.  
They will not know what the study entails or be informed where the individual is in the study, that is, 
whether treatment has begun or what treatment the subject may be receiving.  I have lined up Sudha Raman, 
M.A., as an Independent Evaluator.  She has been trained in the obtaining the necessary information and 
scoring the Hamilton Rating Scale for Depression and has experience rating depressed patients using a 
structure version of the Hamilton Rating Scale for Depression (the SIGH-SAD) and has agreed to act as an 
Independent Evaluator in this study.  I am searching for at least one (preferably two) additional individuals 
to also act as Independent Evaluators.  Preferably such individuals will be already trained and have 
experience using the Hamilton Rating Scale for Depression; however, I will train candidates if necessary.  
 
To assess whether Independent Evaluators are indeed "blind," following each evaluation, the Independent 
Evaluator will complete a form asking about whether they suspect the study subject is receiving treatment 
and if so what that treatment might be and why they think so.
 
Telephone Visits
Ratings on the six days following randomization will be by telephone.  Other ratings will be in person 
whenever possible.  However, we recognize that sometimes in person visits are not possible for patients; 
when this occurs, some evaluations and ratings are better both clinically and scientifically than are missed 
evaluations and ratings.  Therefore, telephone ratings will be allowed at all visits after randomization.  Once 
a patient is randomized to Chronotherapy, should he/she elect to remain awake some night other than the 
night they were randomized, a telephone visit the day they will later remain awake will reassess the ratings.
 
Protocol Violations
I was asked by the IRB Subcommittee to explicitly address what happens clinically and scientifically if 
patients do not adhere to their Wake Night.  Falling asleep, for example, when the individual is assigned to 
remain awake, not logging in at the prescribed times and all other variances from the protocol  will not 
automatically remove the patient from the protocol.  To the extent that it is reasonable and possible, the 
protocol will be continued through Week 6 as if the violation had not occurred.  It is difficult to enumerate 
each and every possible protocol violation with how each would be handled.  The principle will be that from 
the point the violation is noted, the protocol will be resumed as if the violation had not occurred, though 
some violations might require new assigned sleep times.  The only exception would be if the patient 
objected or it makes no clinical sense; an example of the latter would be if a patient was supposed to sleep 
from, say, 6 pm until 2 am, instead slept from noon to 8 pm, we would not insist he/she go back to bed til 2 
am but would ask the patient to continue their 8 am bright lights and try not to sleep again til 9 pm the 
following night (assuming those had been the predetermined times for sleep and lights).  
 
Scientifically, we will record protocol violations (see "Protocol Adherence Form) but all analyses will be 
"intent to treat".  That is, once a patient is randomized, he/she is included in all efficacy analyses out to the 

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point at which there are no more data; missing intermediate data will be estimated by interpolation, missing 
end data will be estimated by last observation carried forward.
 
Treatment after six weeks
Following the six weeks post-randomization period, for reasons best known to the IRB all fecund women 
not already known to be pregnant will provide a urine to be tested for pregnancy.  While we will 
make the request of all fecund women, we will not deny post-study treatment to any who fail for any 
or no reason to supply a post-treatment urine sample.  All patients will be offered continued treatment at 
the DES as determined jointly by patient and DES physician.  In general, those who did well with 
Chronotherapy would have the recommendation they continue a.m. bright lights and regular sleep times, 
though they could opt for alternative treatment or to discontinue these and see how they do having the back-
up of returning to this or instituting different treatment should depressive symptoms return.  Those who do 
well with the alternative protocol will be allowed to continue it, but with the explanation that we think they 
probably improved for reasons other than something specific about the Alternative Protocol; therefore, they 
might best see how things go without the a.m. lights, amber goggles and specific sleep times, reverting to 
these or other standard treatments should symptoms return.  Alternative Treatment subjects who do not 
benefit, will be offered the alternative of Chronotherapy or standard antidepressant medications.  
Nonresponders to Chronotherapy will be offered standard antidepressant medications. 
 
Prior to beginning treatment and again six weeks after randomization, all patients will be told that light 
boxes, goggles, and post-study (i.e., beginning six weeks post-randomization) medications are their 
responsibility and will not be paid for or supplied by the DES or the NYSPI.  They will be informed that the 
light boxes we use in the study cost about $150.  They will receive six months of clinical visits with a DES 
psychiatrist beginning six weeks after randomization.
 
You can upload charts or diagrams if any
Flow Chart.22Nov16.pdf
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
1) patient withdraws consent
 
2) clinician judgment that change in treatment should not wait until end of study (i.e., six week post-
randomization evaluation)
 
3) need for hospitalization
 
4) overt suicidality or clinician judgment that overt suicidality is a significant risk prior to six week post-
randomization evaluation.  
 

Protocol Summary Form
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Stewart, Jonathan
Page 14 of 19
After six weeks, patients receive "open treatment" (that is, patient and doctor negotiate what, if any, 
treatment will be) so following the six week randomized treatment period there is nothing to withdraw, 
although patients throughout can choose not to continue treatment or can choose to continue treatment 
without the ratings being done and circumstances may dictate a change in what the open treatment is.
 
A study doctor (right now that would be Drs. Hellerstein and Stewart, possibly later also Dr. Steinberg) will 
always be available to patients by telephone and patients will be so informed.  In addition, for the first week 
post-randomization, a study doctor will telephone patients each day, obtaining the information needed to 
rate the SIGH-ADS, thereby learning about worsening or other reasons to consider removing the patient 
from the study and/or asking the patient to be seen earlier than next visit or other instruction, such as go to 
nearest Emergency Room.
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
See Flow Chart, below (which should be identical to that uploaded under "Study Procedures").  I have 
included below ratings with which I suspected the IRB might not be familiar.  Should the IRB desire 
additional documents, I will be pleased to provide them.
Please attach copies, unless standard instruments are used
Flow Chart.22Nov16.pdf
Independent Evaluator Treatment Guess.27Oct16.pdf
MEQ.8Apr11.pdf
PATIENT ADHERENCE FORM.pdf
MEQ-rev 11_01.pdf
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
Approximately 7 weeks, although delays in obtaining labs, waiting for a 'clean' urine, scheduling, patients 
desire to delay their Wake Night might in some cases delay randomization beyond a week.  Study 
participation concludes after 6 weeks, and the 6 months after study participation is considered clinical 
treatment. Nevertheless, pregnancy testing will be requested from fecund women prior to institution of 
post-study treatment.
Maximum duration of delay to standard care or treatment of known efficacy
Same as above.  As the purpose of this study is to demonstrate the efficacy of Chronotherapy, it cannot be 
considered to have "known efficacy."  Hence, all subjects will be delayed in potentially receiving treatment 
of "known efficacy."
Treatment to be provided at the end of the study
This depends on the definition of "end of the study."  If the end of formal randomizaed treatment, then the 
six months of "open" follow-up is the duration of post-study treatment.  If "end of study" is considered the 

Protocol Summary Form
7361
Stewart, Jonathan
Page 15 of 19
end of rating scales, then there is no further commitment of the DES to treat the patient, as these continue 
through the six months of "open" treatment.  "Open treatment" means the study does not determine what the 
treatment is; instead the treating doctor and the patient together determine what the treatment will be.
Clinical Treatment Alternatives
Clinical treatment alternatives
Standard treatments include about 30 marketed antidepressant medications, several FDA-approved devices, 
including electroconvulsive treatment, transcranial magnetic stimulation and vagal nerve stimulation, and 
several psychotherapies having some degree of evidence of efficacy, including cognitive behavior therapy, 
interpersonal psychotherapy and cognitive behavioral analysis system of psychotherapy.  To our knowledge, 
none has been compared to chronotherapy, so comparative efficacy is unknown. And, as efficacy of 
chronotherapy is unknown, it cannot be considered to be an effective treatment; nor is it a generally 
accepted treatment.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
1. overstimulation - both remaining awake over night and bright lights can be stimulating.  A worry is that 
such stimulation will result in hypomania or even mania.  Most find the overstimulation uncomfortable and 
do not like it (as opposed to hypomania which is generally liked by those experiencing it).  While we have 
occasionally had reports of overstimulation attributable to bright lights, we have not seen mania or 
hypomania.  Benedetti (2012; see Uploads) estimates the risk of switching is 6% in patients with bipolar 
disorder, somewhat less than his estimate of a 15% switch rate during other forms of treatment.  As patients 
with bipolar disorder carry an inherent risk to switch mood states, it is unclear that the 6% switch rate in 
bipolar illness ought to be attributed to the chronotherapy.  And, if there is a risk in non-bipolar illness, it 
ought to be lower than in bipolar disorder, though we are unaware of literature suggesting a frequency of 
"switching" in nonbipolar patients.  
 
2. fatigue - will likely occur following a night of missed sleep.
 
3. eye damage - while this has been listed as a risk, to our knowledge it has never been demonstrated.  
Indeed, the only prospective study of which we are aware (Gallin et al, 1995) found no eye/retinal changes 
after six weeks (N=50) or after 3-6 years (N=17).  Indeed, sunlight is quite safe except for ultraviolet (UV) 
exposure and prolonged exposure to direct bright light; the light boxes we will use in this study do not emit 
significant UV light, nor is the 10,000 lux intensity of the light boxes we will use anywhere near the 
intensity of light known to produce retinal damage.  To our knowledge, no ophthalmologist recommends 
that we avoid going outdoors between 9 a.m. and 4 p.m. when outdoor light is at or greater than 10,000 lux.  
See "Uploads" for the Gallin reference.
 

Protocol Summary Form
7361
Stewart, Jonathan
Page 16 of 19
4. patient's depression may not improve - this, of course, is the risk of any treatment one might choose, or of 
not being treated.  It is unclear, however, whether chronotherapy improves on not being treated or 
approximates/surpasses accepted treatments.
 
5. pregnancy  - while it makes sense that simulated sunlight ought not to adversely affect a pregnancy, to 
our knowledge, this has not been studied so the affect of the bright lights we have patients use in this study 
must be considered of unknown risk to a pregnancy.  We are also unaware of documentation of missed sleep 
or regulated sleep adversely affecting pregnancy, so also consider these to have unknown risk to pregnancy.
Describe procedures for minimizing risks
1. overstimulation - we have not seen overstimulation during Wake Nights, but have occasionally had 
patients report it at the end of a session using bright lights.  Should it be reported during a Wake Night, the 
patient would be instructed to find a quiet dark place in which to sit or lie quietly, try to calm down and not 
worry should they fall asleep.  In the more likely case that it occurs during or following light treatment, the 
patient would be instructed to decrease their light exposure by sitting further away from the lamp or sitting 
in front of the lamp for a shorter time.  In the case of patients who experience overstimulation toward the 
end of their light exposure, they would be instructed to sit in front of the lights for the amount of time prior 
to their experience of overstimulation.  Thus, if overstimulation began after 25 minutes, they would be 
instructed next time to sit in front of the lights for 20 minutes.
 
2. fatigue - reassurance that fatigue will decrease as they recover their sleep in nights subsequent to their 
Wake Night.  Should uncharacteristic (i.e., not present prior to treatment) fatigue continue after apparent 
sleep recovery, this will be take as evidence that the new timing of their sleep is out of sync with their 
biological clock such that a significant portion of their assigned sleep time is occurring when their biological 
clock insists they ought to be awake.  That is, the paradigm has not shifted their clock.  This will trigger a 
new attempt to shift their clock as is outlined for patients whose MEQ-determined ideal sleep time is more 
than two hours different from their desired sleep time.  All patients will be warned re driving and using 
heavy/dangerous equipment during and following missed sleep as well as if significant fatigue occurs at 
other times.
 
3. eye damage  - as damage from light is mainly attributed to exposure to ultraviolet rays and very high 
intensity light, this risk will be minimized by limiting bright light use to devices certified to emit only 
visible light; that is, not to emit UV light.  And at a much lower intensity than used, for example in laser 
surgery or emitted by the noonday sun (> 100,000 lux, or more than 100 times the intensity of the emission 
of the light boxes we use [lux is measured on a logarithmic scale, not a linear scale]) which would damage 
the retina if stared at for too long a time.  That is, the intensity of light used in this study is one the eye often 
experiences and one no one is warned against.
 
4. depression may not improve  - as noted, this is a risk whether one pursues accepted treatment or does 
nothing.  The odds of either treatment approach relieving a patient's depression is unknown and the purpose 
of this protocol is to begin determining those odds.  Attention, a listening (hopefully) ear, activating oneself 
to come to weekly meetings may be expected to produce more benefit than not being engaged in treatment.  
While the protocol will not automatically remove patients whose symptoms do not improve prior to six 
weeks post-randomization, patients and clinicians will always have the option of discontinuing the protocol 

Protocol Summary Form
7361
Stewart, Jonathan
Page 17 of 19
for any reason, including but not limited to the emergence of suicidal ideation/activity and worsening 
symptoms whether such worsening includes suicidal ideation/activity or not.  We will leave it to patient 
preference and treater's clinical judgment, however, whether to continue or remove patients.
 
5. Pregnancy -  all fecund women will be told at their consenting visit that risk of the study procedures to an 
unborn fetus is unknown; therefore, they must discontinue all study procedures if they think they might be 
pregnant until it becomes known they are not pregnant.  And, immediately contact a study physician.  In 
addition, pregnancy testing will be performed at the patient's consenting visit and again following the 
six week experimental treatment immediately prior to "open" treatment, although failure to provide 
urine for pregnancy testing will not lead to denial of "open" treatment.   Failure to provide a 
specimen for pregnancy testing or a positive pregnancy test prior to experimental treatment would 
lead to denial of experimental treatment.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
Confidentiality will be maintained by keeping physical data in locked file cabinets, while electronic data 
will be collected within the HIPAA compiant StudyTRAX system, which when downloaded will be kept 
behind the PI firewall in data files accessible only to authorized staff using a password. We do not anticipate 
sharing data with researchers outside PI, but if this were to occur, only data with identifying information 
(e.g., name, birth date) removed will be sent outside PI, and prior IRB approval would be obtained. Should 
it become necessary for the treating psychiatrist to contact the subject’s primary physician to obtain copies 
of their medical records or release our records to other providers, explicit written agreement for such record 
transfers will be obtained from the patient.
Will the study be conducted under a certificate of confidentiality?
No
Direct Benefits to Subjects  
Direct Benefits to Subjects
Their depression may improve, either with initial treatment, or with subsequent treatment.  If their 
depression improves without use of medication, they may be spared taking medication.
Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
No

Protocol Summary Form
7361
Stewart, Jonathan
Page 18 of 19
Uploads
Upload copy(ies) of unbolded Consent Form(s)
Wake DB CF.unbolded.22Nov16.pdf
Upload copy(ies) of bolded Consent Form(s)
Wake DB CF.bolded.22Nov16.pdf
Upload copy(ies) of unbolded Information Sheet(s)
Cover Sheet for DB Wake.unbolded.15Sept16.pdf
Upload copy(ies) of bolded Information Sheet(s)
Cover Sheet for DB Wake.bolded.15Sept16.pdf
Upload copy(ies) of the HIPAA form
HIPAA.DB Wake.15Sept16.pdf
Upload any additional documents that may be related to this study
Szegedi.Early Onset.JCP2009.pdf
Bennedetti 2012.pdf
Barbini.UP_BP.PsychRes1998.pdf
Martiny.PLOS One.2013.pdf
Sahlem.JPsychRes2014.pdf
IRB Memo.11.07.16.pdf
Negative effect of BL on retina.Gallin 1995 Am J Ophthal.pdf
References
References
Szegedi et al: Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with 
major depressive disorder: A meta-analysis including 6562 patients. J Clin Psychiatry 2009;70(3):344-53. 
 
Benedetti F: Antidepressant chronotherapeutics for bipolar depression. Dialogues in Clinical Neuroscience 
14:401-11;2012.
 
Barbini et al: The unipolar-bipolar dichotomy and the response to sleep deprivation. Psychiatry Research 
79:43-50;1998.
 
Gallin et al: Ophthalmoolgic examination of patients with seasonal affective disorder, before and after 
bright light therapy. Am J Ophthalmology 119:202-210;1995.
 
Martiny K et al: A 9-week randomized trial comparing a chronotherapeutic intervention (wake and light 
therapy) to exercise in major depressive disorder patients treated with duloxetine. J Clin Psychiatry 
73:1234-42;2012.
 

Protocol Summary Form
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Stewart, Jonathan
Page 19 of 19
Sahlem et al: Adjunctive chronotherapy (combined total sleep deprivation, sleep phase adv ance, and bright 
light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot 
study. J Psychiatric Res 59:101-7;2014.
 
 

 
-1- 
 
 
22 November 2016                                                                                                                                      IRB #7361 
CONSENT FORM 
Are Bright Lights and Regulated Sleep Times Effective Treatment for Depression? 
 
Purpose and Overview 
The purpose of this study is to find out whether sleeping only at regulated times and sitting in front of a 
bright light wearing different colored or clear goggles is effective treatment for depression.  You are 
being asked to participate in this study because you are depressed and do not have mood swings 
(bipolar disorder). 
 
Voluntary 
Participation in this research study is voluntary. If you decide not to participate, or if you later decide to 
stop participating, or your doctor removes you from study participation for any reason, you will not lose 
any benefits to which you are otherwise entitled. A decision not to participate or withdraw your 
participation will not affect your current or future treatment at the New York State Psychiatric Institute 
or Columbia University. 
 
Alternatives to Participation 
There are alternatives to your participating in this study. If you previously participated in another 
treatment study, you may be eligible for further treatment without taking part in this study. You can go 
to a private doctor or to a psychiatry clinic where you may receive any of the medications marketed 
for depression. Electroconvulsive treatment and focused psychotherapy are also accepted treatments 
for depression. Electrical stimulation of a nerve in the neck (called the vagus nerve) has also been 
approved by the FDA. 
 
Study Procedures 
In order to find out if you can be treated in this study, you will receive a complete psychiatric evaluation 
by a study psychiatrist. If the study psychiatrist decides you can participate, you will be given this 
consent form to read. If you then agree to participate and are satisfied that your questions have been 
answered, you will then sign the consent form. A member of the research team will then complete 
research rating forms, you will complete self-report ratings, about 15 cc (approximately a tablespoon) of 
blood will be drawn for routine laboratory testing (for example, to make sure your kidneys and liver are 
healthy), a doctor will perform a physical examination (for example, listen to your heart and lungs, look 
into your eyes) and you will provide a urine specimen (to be checked for kidney function, pregnancy if 
you are a woman of child-bearing age, and street drugs such as heroin and cocaine). These tests will 
determine if you have a medical disorder such as low thyroid function that might be the cause of your 
depression or that should be treated prior to your entry into this. If you have one of these medical 
problems, your doctor will discuss this with you at the first visit after it is found, or telephone you if it 
requires quicker attention.   
 
You have been offered participation in this study because you are depressed.  Once you have agreed 
and signed the study consent form, you will be asked to answer questions about your mood, prior 
treatment, the times of the day you like to do things, a variety of common psychiatric symptoms and 
your interest and functioning in several life circumstances, like work and family.  You will wear an 
activity monitor (which looks like a wrist watch) and keep a log of your sleep, mood and energy for 
about seven weeks.  After 1-2 weeks (you can choose to wait up to 30 days before re-evaluation), you 
will be re-evaluated.  If you remain significantly depressed at this re-evaluation, and remain agreeable, 

 
-2- 
you will begin sleeping only at assigned times (regulated sleep therapy) plus sitting in front of bright 
lights wearing goggles.  The timing of your allowed sleep and whether the goggles you wear will be clear 
or amber will  be determined randomly (as if by a flip of a coin). Whatever timing and goggles you are 
assigned you will continue for the next six weeks, initially with daily telephone evaluations and from the 
end of week 1 through the end of week 6 weekly in person.  At the time you are randomized and again 
at weeks 1 and 6 visits you will also be evaluated by a rater who does not know whether you have begun 
treatment or what treatment you may be receiving.  It is important that you not let on whether you 
have begun treatment, or, if you have, what that treatment has been. 
 
Light and Regulated Sleep Therapy 
Treatment will be with bright lights and regulated sleep times.  To help us determine whether this 
approach is effective treatment and which times for sleep and bright lights and how best to use the 
bright lights, by chance different patients will receive different instructions.  All will be given specific 
times they are allowed to sleep and specific times to sit in front of the bright lights.  Time sitting in front 
of the bright lights will begin at 30 minutes, but if you have trouble tolerating the light your doctor may 
tell you to decrease this time shorter (to as little as 10 minutes), and if you tolerate the light but remain 
depressed your doctor may tell you to increase the time (up to 60 minutes).  For some the specific sleep 
times may include a 48 hour period during which they are not allow to sleep as long as 42 hours.  You 
will be provided goggles both to wear in the evening during saliva collection for melatonin and when 
sitting in front of the bright lights.  Some goggles will be clear and some will be amber.  Prior to being 
told your specific times for allowed sleep and use of the bright lights, you will complete the 
Morningness-Eveningness Questionnaire; your answers will suggest where your biologic clock is 
currently set and partially determine the times you will be allowed to sleep and instructed to use the 
bright lights.  You will also report the time you want to be sleeping which will also determine the sleep 
instructions and timing of your bright light use. 
 
Risks and Inconveniences 
General. A general risk is that you may remain depressed. It has not been determined whether the 
combination of wake therapy, light therapy and regular allowed sleep is effective for your disorder. 
Second, suicide is a risk in patients who are depressed.  Patients with bipolar disorder may become 
manic. These risks will be minimized by: (a) exclusion of patients known to have bipolar disorder; (b) not 
participating in the study if you or your doctor consider you to be at significant risk to harm yourself or 
in need of hospitalization; (c) discontinuing study participation should you become significantly worse or 
significantly suicidal; (d) offer of hospitalization in the case of significant worsening/suicidal 
thoughts/behavior; (e) weekly visits and 24 hour phone availability of an experienced research 
psychiatrist.  
 
Remaining awake for long periods. The major risk of remaining awake for long periods is mania. This 
possibility will be minimized by only including patients without a history of mania or hypomania (a 
period of being “high” without being manic), constant availability of access to a research psychiatrist by 
telephone.  An additional risk is being drowsy at times alertness is required, such as driving or operating 
heavy machinery.  Therefore, if assigned extended periods of wakefulness or if you feel sleepy, you 
should not drive or operate heavy machinery. 
 
Light Therapy. Patients may become over-stimulated, and those with bipolar disorder may become 
manic.  As this study will not include patients known to have bipolar disorder, this risk seems minimal, 
but likely not zero, especially since not all patients with bipolar disorder are known to have it.  More 
commonly, over-stimulation is described as “like too much coffee” and can be eliminated by decreasing 

 
-3- 
bright light exposure, either by decreasing the time in front of the light or increasing the distance from 
the light, or both.  Occasionally, light exposure may also cause headache, nausea or eye irritation.  
Again, these will be counteracted by increasing the distance for the light, decreasing the time you sit at 
the light or both.  Long-term research studies have found that light therapy is safe for the 
retina of the eye. Nevertheless, as a precaution, we will examine your retina to see whether there are 
already signs of damage, and you will not receive light therapy if you have retinal conditions such as 
retinitis pigmentosa or macular degeneration. As the lights used are similar to early morning light in 
intensity but without any ultraviolet radiation, they may be considered safer than going outside on a 
sunny day. 
 
Additional Risks 
Participation in this study may involve risks that we currently do not know.  Some discomfort may be 
associated with the drawing of blood samples. A maximum of 1 tablespoon of blood will be taken unless 
there is a medical reason to obtain extra blood.  There is a minor risk of bleeding, bruising, or infection 
at the site of the needle insertion. With any treatment there is the risk that the treatment may not help 
and the depression might become worse. Also, if a treatment is effective or partially effective there is 
the risk of worsening of symptoms if the treatment is stopped or the dose is reduced. 
 
Benefits 
Your depression may improve. 
 
You will be informed if significant new information becomes known about treatment of depression 
or about the treatments used in this study, especially if such information might affect the willingness of 
some subjects to continue their participation. 
 
Confidentiality 
All study information is kept in locked cabinets at the Depression Evaluation service at the New 
York State Psychiatric Institute or in a secure HIPAA compliant computer accessable only by study staff. 
Records will be kept confidential to the extent permitted by law. Your name and other personal 
identifying information will be stored in an electronically secure database at New York Psychiatric 
Institute. Any publications will present only group data and not include information that could identify 
you. Records will be available to research staff, and to Federal, State and Institutional regulatory 
personnel (who may review records as part of routine audits). Also, you should be aware that there are 
legal advocacy organizations that have the authority under New York State law to access otherwise 
confidential subject records, though they cannot re-disclose this information without the subject’s 
consent. Electronically stored/transmitted data will be password protected with access only to study 
personnel. 
 
There are limits to confidentiality. For example: 
 
If your answers indicate a serious problem that may jeopardize your safety or health, then the 
researchers will contact your physician or emergency personnel as seems appropriate to your well-
being.  Also, suspected or known neglect or sexual or physical abuse of a child, or threatened violence to 
self or others will be reported to the appropriate authorities. 
 
Study Compensation 
Tests that are part of the research study are provided free of charge, and neither 

 
-4- 
you nor your insurance company or other third party payer will be billed for these, including 
hospitalization, if at the New York State Psychiatric Institute. Any tests not required by the research will 
be paid for by you or your insurance company.  In addition, following 6 weeks, regardless of initial 
treatment assignment, all participants will continue to be followed and complete monthly ratings for an 
additional six months; during this post-6 week six months, the cost of any prescription, whether for 
medication or light box will be your responsibility.  After this six month post-12 week treatment period, 
should you and your doctor determine that further psychiatric treatment is indicated, your doctor will 
help you find an appropriate treater. 
 
In Case of Injury 
Federal regulations require that we inform participants about our institution's policy with regard to 
compensation and payment for treatment of research-related injuries.  In case of injury, New York State 
Psychiatric Institute will provide short term emergency medical treatment, which has been determined 
to be necessary by New York State Psychiatric Institute's doctors. In addition, we will provide assistance 
in arranging follow up care in such instances.  New York State Psychiatric Institute and Research 
Foundation for Mental Hygiene do not provide compensation or payment for treatment of research 
related injuries. However, you should be aware that you do not give up your legal right to seek such 
compensation through the court by participating in this research. 
 
Questions 
Your study doctor will answer any questions you may have now or in the future to the best of 
his/her ability. If you should have additional questions, you can contact the Principal Investigator, 
Jonathan W. Stewart, M.D., (646-774-8070). 
 
If you have any questions about your rights as a research participant, want to provide feedback, or have 
a complaint, you may call the NYSPI Institutional Review Board (IRB). (An IRB is a committee that 
protects the rights of participants in research studies). You may call the IRB Main Office at (646)774-
7155 during regular office hours.  You will be notified of significant new findings that may relate to your 
willingness to continue to participate. 
 
Women of Child-bearing Age 
While these treatments are considered to be fairly safe during pregnancy, the study excludes women 
who are pregnant.  Therefore, a pregnancy test will be performed and if it is positive, you cannot 
participate.  Also, we ask that you use reasonable precautions not to become pregnant while 
participating and if you choose to be treated with medication after the initial six weeks of treatment.  
Because the safety of missing a night of sleep, keeping specific sleep schedules or bright lights are 
unknown in pregnancy, you should not be pregnant or become pregnant while using these treatments.  
Should you become pregnant, you should immediately contact a study psychiatrist and discontinue any 
treatment until informed otherwise by a study psychiatrist.  After the six weeks research treatment, 
you will again be asked to produce a urine specimen which will be tested for pregnancy.  If do not 
produce a urine at the six week time point, continuing treatment will not be denied. 
 
By signing this form, you are indicating that you have discussed this research study and consent form 
with an investigator, and he/she has answered all of your questions about the study to the best of 
his/her ability. Your study doctor will answer to the best of his/her ability any questions you may have 
about the study, your psychiatric condition or your reaction to the study procedures. If you have any 
further questions, you may call Jonathan W. Stewart, M.D., the Principal Investigator of this study, at 
646-774-8070. 

 
-5- 
 
You will receive a copy of this consent form to keep. 
 
Documentation of Consent 
 
I voluntarily agree to participate in the research study described above. 
 
 
 
Print name: __________________ 
 
 
Signed: _____________________ 
 
 
Date: _______________________ 
 
I have discussed the proposed research with this participant including the risks, benefits, and 
alternatives to participation (including the alternative of not participating in the research). The 
participant has had an opportunity to ask questions and in my opinion is capable of freely consenting to 
participate in this research. 
 
 
 
Print name: ________________ 
 
Person Designated to Obtain Consent 
 
 
 
Signed: ___________________ 
 
Date: _____________________ 

Table - Flow Chart 
 
00 
RZ 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
W2 
W3 
W4 
W5 
W6 
M1 
M2 
M3 
M4 
M5 
M6 
Clinician-Rated Measures 
  - SCID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - HIGH-C 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - SIGH-ADS 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - CGI 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - m-HIGH-C 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  - m-SIGH-ADS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  - m-CGI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  - MMSE* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Independent Evaluator 
  - SIGH-ADS 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
  - CGI 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
  - IE Treatment Guess 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Patient-Rated Measures 
  - QIDS 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- Expectation Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - PGI 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - MEQ 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
  - SCL-90 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
  - sleep log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - m-QIDS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  - m-PGI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory and other 

  - PE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - labs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - saliva for melatonin 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
  - urine for pregnancy** 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
* used only for those aged 60 and above 
** only for fecund women not already known to be pregnant 
 
KEY TO ABBREVIATIONS 
CGI (Clinical Global Impression) - this is a clinician rated global measure of the patient’s over-all psychopathology and  
improvement over the past week, improvement compared to pre-treatment 
HIGH-C (Hypomania Interview Guide including Hyperthymia, Current Assessment Version) - this is a clinician-rated 
measure of manic/hypomanic symptoms rated over the past week 
labs (laboratory examinations) - these include EKG, blood and urine; blood is examined for hematology (e.g., whether the  
patient is anemic) and routine blood chemistry (e.g., whether the patient has problems with their liver, kidney or 
thyroid); analysis of the urine determines whether there is a kidney 
m-CGI - this is identical to the CGI except it measures the past 24 hours 
m-HIGH-C - this is identical to the HIGH-C except modified to measure the past 24 hours 
m-PGI - this is identical to the PGI except it is rated for the past 24 hours 
m-QIDS - this is identical to the QIDS except it omits sleep and weight items and is rated for the past 24 hours 
m-SIGH-ADS - this is identical to the SIGH-ADS except sleep and weight items are removed and ratings are for the past  
24 hours 
MEQ (Morningness-Eveningness Questionnaire) - this is a 19-item patient-rated questionnaire asking the times of the day  
respondents prefer to eat, sleep and perform various functions, like exercise, test-taking and working; answers 
indicate the timing of the individual’s biological clock 
MMSE (Mini-Mental Status Examination) – this is a standard method for evaluating whether someone is cognitively intact 
or demented 
PE - physical examination 
PGI (Patient Global Impression)- this is identical to the CGI except patient-rated, asking patients to rate their over-all  
symptoms over the past week and improvement relative to pre-treatment 
QIDS-SR (Quick Inventory of Depressive Symptoms, Self-Rated) - this is a patient-rated 16-item measure of depressive  
symptoms which has been shown to correlate highly with the clinician-rated 30-item Inventory of Depressive 
Symptoms 
SCID (Structured Clinical Interview for DSM Diagnoses) - this is a standard semi-structured interview enabling assignment  
of the major clinical diagnoses according to the DSM diagnostic system, both current and life-time 
SCL-90 (90 item Symptom Check List) - this instrument includes 90 common psychiatric symptoms covering 9 areas of  
psychopathology, including depression, anxiety, psychosis 

SIGH-ADS (Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Supplement) - this is a 
clinician-rated measure of depressive symptoms which generates scores for the 17, 21 and 25 item Hamilton 
Rating Scale for Depression as well as a score summarizing the 8 items intended to measure symptoms of atypical 
depression 
Sleep Log - The patient completes this daily, 7 days to a page, indicating when sleep occurred, mood and energy each  
day, timing of light exposure and any medications 

Independent Evaluator Treatment Guess 
IE Name: ____________________________ 
Patient Study ID   ________                               
Date __________________ 
____________________________________________________________________ 
Do you think the subject is currently being treated? 
____ Yes 
         No 
 
What treatment has this patient been receiving? (Even if you have no idea, please make 
a wild guess; if you think treatment has not begun, this answer would be “none”) 
                                                                         
 
How long has the patient been receiving this treatment? (If you think treatment has not 
begun, the answer would be “0")
 
_____ Days Weeks Months Years (insert # and circle the time period 
 
Why did you guess the patient was not being treated, or, if treated, what that treatment 
might be? 

MORNINGNESS-EVENINGNESS QUESTIONNAIRE (revised)1
Name: _____________________________ Date: ________________________
For each question, please select the answer that best describes you by checking the
corresponding box.  Make your judgments based on how you have felt in recent
weeks.
1. Approximately what time would you get up if you were entirely free to plan
your day?
q 5:00 a.m. – 6:30 a.m.
             5
q 6:30 a.m. – 7:45 a.m.
             4
q 7:45 a.m. – 9:45 a.m.
        
3
q 9:45 a.m. – 11:00 a.m.
             2
q 11:00 a.m. – 12 noon
        
1
2. Approximately what time would you go to bed if you were entirely free to plan
your evening?
q 8:00 p.m. – 9:00 p.m.
                                       
5
q 9:00 p.m. – 10:15 p.m. 
        
4
q 10:15 p.m. – 12:30 a.m.
                   
3
q 12:30 a.m. – 1:45 a.m.
        
2
q 1:45 a.m. – 3:00 a.m.
        
1
3. If you usually have to get up at a specific time in the morning, how much do
you depend on an alarm clock?
q Not at all 
4
q Slightly 
3
q Somewhat
2
q Very much
1
                                                
1Some stem questions and item choices have been rephrased from the original instrument (Horne and Östberg, 1976)
to conform with spoken American English.  Discrete item choices have been substituted for continuous graphic scales.
Prepared by Terman M, Rifkin JB, Jacobs J, and White TM. New York State Psychiatric Institute, 1051 Riverside Drive,
Unit 50, New York, NY, 10032.  Supported by NIH Grant MH42931. See also:
automated version (AutoMEQ) at www.cet.org.
Horne JA and Östberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian
rhythms.  International Journal of Chronobiology, 1976: 4, 97-100.
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MORNINGNESS-EVENINGNESS QUESTIONNAIRE
                                Page 2 
4. How easy do you find it to get up in the morning (when you are not awakened
unexpectedly)?
q Very difficult
1
q Somewhat difficult
2
q Fairly easy
3
q Very easy
4
5. How alert do you feel during the first half hour after you wake up in the
morning?
q Not at all alert
1
q Slightly alert
2
q Fairly alert
3
q Very alert
4
6. How hungry do you feel during the first half hour after you wake up?
q Not at all hungry
1
q Slightly hungry
2
q Fairly hungry
3
q Very hungry
4
7. During the first half hour after you wake up in the morning, how do you feel?
q Very tired
1
q Fairly tired
2
q Fairly refreshed
3
q Very refreshed
4
8. If you had no commitments the next day, what time would you go to bed
compared to your usual bedtime?
q Seldom or never later
4
q Less that 1 hour later
3
q 1-2 hours later
2
q More than 2 hours later
1
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MORNINGNESS-EVENINGNESS QUESTIONNAIRE
                                Page 3 
9. You have decided to do physical exercise.  A friend suggests that you do this
for one hour twice a week, and the best time for him is between 7-8 a.m.
Bearing in mind nothing but your own internal “clock,” how do you think
you would perform?
q Would be in good form
4
q Would be in reasonable form
3
q Would find it difficult
2
q Would find it very difficult
1
10. At approximately what time in the evening do you feel tired, and, as a result, in
 need of sleep?
q 8:00 p.m. – 9:00 p.m.
5
q 9:00 p.m. – 10:15 p.m.
4
q 10:15 p.m. – 12:45 a.m.
3
q 12:45 a.m. – 2:00 a.m.
2
q 2:00 a.m. – 3:00 a.m.
1
11. You want to be at your peak performance for a test that you know is going to be
 mentally exhausting and will last two hours.  You are entirely free to plan your
 day.  Considering only your “internal clock,” which one of the four testing 
 times would you choose?
q 8 a.m. – 10 a.m.
6
q 11 a.m. – 1 p.m.
4
q 3 p.m. – 5 p.m.
2
q 7p.m. – 9 p.m.
0
12. If you got into bed at 11 p.m., how tired would you be?
q Not at all tired
0
q A little tired
2
q Fairly tired
3
q Very tired
5
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MORNINGNESS-EVENINGNESS QUESTIONNAIRE
                                Page 4 
13. For some reason you have gone to bed several hours later than usual, but there
 is no need to get up at any particular time the next morning.  Which one of the
 following are you most likely to do?
q Will wake up at usual time, but will not fall back asleep
4
q Will wake up at usual time and will doze thereafter
3
q Will wake up at usual time, but will fall asleep again
2
q Will not wake up until later than usual
1
14. One night you have to remain awake between 4-6 a.m. in order to carry out a
 night watch.  You have no time commitments the next day.  Which one of the
 alternatives would suit you best?
q Would not go to bed until the watch is over
1
q Would take a nap before and sleep after
 
2
q Would take a good sleep before and nap after
3
q Would sleep only before the watch
4
15. You have two hours of hard physical work.  You are entirely free to plan your
 day.  Considering only your internal “clock,” which of the following times 
 would you choose?
q 8 a.m. – 10 a.m.
4
q 11 a.m. – 1 p.m.
3
q 3 p.m. – 5 p.m.
2
q 7p.m. – 9 p.m.
1
16. You have decided to do physical exercise.  A friend suggests that you do this
 for one hour twice a week.  The best time for her is between 10-11 p.m.
 Bearing in mind only your internal “clock,” how well do you think you would
 perform?
q Would be in good form
1
q Would be in reasonable form
2
q Would find it difficult
3
q Would find it very difficult
4
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MORNINGNESS-EVENINGNESS QUESTIONNAIRE
                                Page 5 
17. Suppose you can choose your own work hours.  Assume that you work a five-
 hour day (including breaks), your job is interesting, and you are paid based on
 your performance.  At approximately what time would you choose to begin?
q 5 hours starting between 4:00 – 8:00 a.m.
5
q 5 hours starting between 8:00 – 9:00 a.m.
4
q 5 hours starting between 9:00 a.m. – 2:00 p.m.
3
q 5 hours starting between 2:00 – 5:00 p.m.
2
q 5 hours starting between 5:00 p.m. – 4:00 a.m.
1
18. At approximately what time of day do you usually feel your best?
q 5:00 a.m. – 8:00 a.m.
5
q 8:00 a.m. – 10:00 a.m.
4
q 10:00 a.m. – 5:00 p.m.
3
q 5:00 p.m. – 10:00 p.m.
2
q 10:00 p.m. – 5:00 a.m.
1
19. One hears about “morning types” and “evening types.”  Which one of these
 types do you consider yourself to be?
q Definitely a morning type
6
q Rather more a morning type than an evening type
4
q Rather more an evening type than a morning type
2
q Definitely an evening type
0
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  Total: ________

Table - Flow Chart 
 
00 
RZ 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
W2 
W3 
W4 
W5 
W6 
M1 
M2 
M3 
M4 
M5 
M6 
Clinician-Rated Measures 
  - SCID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - HIGH-C 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - SIGH-ADS 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - CGI 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - m-HIGH-C 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  - m-SIGH-ADS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  - m-CGI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  - MMSE* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Independent Evaluator 
  - SIGH-ADS 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
  - CGI 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
  - IE Treatment Guess 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Patient-Rated Measures 
  - QIDS 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- Expectation Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - PGI 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - MEQ 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
  - SCL-90 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
  - sleep log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  - m-QIDS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  - m-PGI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory and other 

  - PE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - labs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  - saliva for melatonin 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
  - urine for pregnancy** 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
* used only for those aged 60 and above 
** only for fecund women not already known to be pregnant 
 
KEY TO ABBREVIATIONS 
CGI (Clinical Global Impression) - this is a clinician rated global measure of the patient’s over-all psychopathology and  
improvement over the past week, improvement compared to pre-treatment 
HIGH-C (Hypomania Interview Guide including Hyperthymia, Current Assessment Version) - this is a clinician-rated 
measure of manic/hypomanic symptoms rated over the past week 
labs (laboratory examinations) - these include EKG, blood and urine; blood is examined for hematology (e.g., whether the  
patient is anemic) and routine blood chemistry (e.g., whether the patient has problems with their liver, kidney or 
thyroid); analysis of the urine determines whether there is a kidney 
m-CGI - this is identical to the CGI except it measures the past 24 hours 
m-HIGH-C - this is identical to the HIGH-C except modified to measure the past 24 hours 
m-PGI - this is identical to the PGI except it is rated for the past 24 hours 
m-QIDS - this is identical to the QIDS except it omits sleep and weight items and is rated for the past 24 hours 
m-SIGH-ADS - this is identical to the SIGH-ADS except sleep and weight items are removed and ratings are for the past  
24 hours 
MEQ (Morningness-Eveningness Questionnaire) - this is a 19-item patient-rated questionnaire asking the times of the day  
respondents prefer to eat, sleep and perform various functions, like exercise, test-taking and working; answers 
indicate the timing of the individual’s biological clock 
MMSE (Mini-Mental Status Examination) – this is a standard method for evaluating whether someone is cognitively intact 
or demented 
PE - physical examination 
PGI (Patient Global Impression)- this is identical to the CGI except patient-rated, asking patients to rate their over-all  
symptoms over the past week and improvement relative to pre-treatment 
QIDS-SR (Quick Inventory of Depressive Symptoms, Self-Rated) - this is a patient-rated 16-item measure of depressive  
symptoms which has been shown to correlate highly with the clinician-rated 30-item Inventory of Depressive 
Symptoms 
SCID (Structured Clinical Interview for DSM Diagnoses) - this is a standard semi-structured interview enabling assignment  
of the major clinical diagnoses according to the DSM diagnostic system, both current and life-time 
SCL-90 (90 item Symptom Check List) - this instrument includes 90 common psychiatric symptoms covering 9 areas of  
psychopathology, including depression, anxiety, psychosis 

SIGH-ADS (Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Supplement) - this is a 
clinician-rated measure of depressive symptoms which generates scores for the 17, 21 and 25 item Hamilton 
Rating Scale for Depression as well as a score summarizing the 8 items intended to measure symptoms of atypical 
depression 
Sleep Log - The patient completes this daily, 7 days to a page, indicating when sleep occurred, mood and energy each  
day, timing of light exposure and any medications 

First 2 Weeks Predict Treatment Outcome in MDD
J Clin Psychiatry 70:3, March 2009
345
PSYCHIATRIST.COM
hen a patient with major depressive disorder
(MDD) starts antidepressant drug treatment, the
Early Improvement in the First 2 Weeks
as a Predictor of Treatment Outcome in
Patients With Major Depressive Disorder:
A Meta-Analysis Including 6562 Patients
Armin Szegedi, M.D., Ph.D.; Wim T. Jansen; Arjen P. P. van Willigenburg, M.Sc.;
Egbert van der Meulen, Ph.D.; Hans H. Stassen, Ph.D.; and Michael E. Thase, M.D.
Objective: New evidence indicates that treat-
ment response can be predicted with high sensi-
tivity after 2 weeks of treatment. Here, we assess
whether early improvement with antidepressant
treatment predicts treatment outcome in patients
with major depressive disorder (MDD).
Data Sources: Forty-one clinical trials
comparing mirtazapine with active compar-
ators or placebo in inpatients and outpatients
(all-treated population, N = 6907; intent-to-treat
population, N = 6562) with MDD (DSM-III-R or
DSM-IV Criteria) were examined for early im-
provement (≥20% score reduction from baseline
on the 17-item Hamilton Rating Scale for Depres-
sion [HAM-D-17] within 2 weeks of treatment)
and its relationship to treatment outcome.
Study Selection: Data were obtained from a
systematic search of single- or double-blind clini-
cal trials (clinical trials database, Organon, a part
of Schering-Plough Corporation, Oss, The Neth-
erlands). All included trials (a total of 41) em-
ployed antidepressant treatment for more than
4 weeks and a maximum of 8 weeks. The studies
ranged from March 1982 to December 2003. Tri-
als were excluded if there were no HAM-D-17
ratings available, no diagnosis of MDD, or if the
study was not blinded. Trials were also excluded
if HAM-D-17 assessments were not available at
week 2, week 4, and at least once beyond week 4.
Data Synthesis: Early improvement predicted
stable response and stable remission with high
sensitivity (≥81% and ≥87%, respectively).
Studies utilizing rapid titration vs. slow titration
of mirtazapine demonstrated improved sensitivity
for stable responders (98%, [95% CI = 93% to
100%] vs. 91% [95% CI = 89% to 93%]) and
stable remitters (100%, [95% CI = 92% to 100%]
vs. 93% [95% CI = 91% to 95%]). Negative
predictive values for stable responders and
stable remitters were much higher (range =
82%–100%) than positive predictive values
(range = 19%–60%).
Conclusions: These results indicate that early
improvement with antidepressant medication can
predict subsequent treatment outcome with high
sensitivity in patients with major depressive
disorder. The high negative predictive values
W
indicate little chance of stable response or stable
remission in the absence of improvement within
2 weeks. A lack of improvement during the first
2 weeks of therapy may indicate that changes in
depression management should be considered
earlier than conventionally thought.
J Clin Psychiatry 2009;70(3):344–353
© Copyright 2009 Physicians Postgraduate Press, Inc.
Received Sept. 24, 2007; accepted May 13, 2008. From Organon, a
part of Schering-Plough Corporation, Roseland, N.J. (Dr. Szegedi and
Mr. van Willigenburg), and Oss, The Netherlands (Dr. van der Meulen
and Mr. Jansen); Psychiatric University Hospital, Zurich, Switzerland
(Dr. Stassen); and the University of Pennsylvania School of Medicine,
Philadelphia, the Philadelphia Veterans Affairs Medical Center,
and the University of Pittsburgh Medical Center, Pa. (Dr. Thase).
Financial support for this report was provided by an unrestricted
educational grant from Organon, a part of Schering-Plough Corporation.
Editorial assistance was provided by Complete Healthcare
Communications, Inc., and was funded by Schering-Plough.
Financial disclosure appears at the end of the article.
Corresponding author and reprints: Armin Szegedi, M.D., Ph.D.,
Global Clinical Research CNS, Schering-Plough Research Institute,
56 Livingston Ave., Roseland, NJ 07068
(e-mail: armin.szegedi@spcorp.com).
ability to identify as early as possible those people who
will not benefit from a particular type of treatment could
minimize unnecessary drug exposure, lessen suffering,
and limit resource use. This ability in turn allows for ear-
lier initiation of a treatment adaptation such as alternative
or adjunctive treatment. The early identification of nonre-
sponders is also important because selection of an antide-
pressant agent is still primarily guided by trial and error.
Although the current expert consensus indicates that
antidepressants may have a rapid onset of action in some
individuals,1–4 most current treatment guidelines do not
contain recommendations for adapting an individual’s
treatment during the early course of therapy (e.g., within
the first 2 weeks of treatment). Rather, treatment guide-
lines reflect the outdated belief that antidepressant
response usually appears with a delay of several weeks5
344

Szegedi et al.
346
J Clin Psychiatry 70:3, March 2009
PSYCHIATRIST.COM
and suggest that treatment should be changed if a partial
response has not occurred after 4 to 6 weeks.6–10 This
advice was reinforced by the perception that placebo-
controlled trials do not usually show a significant effect
of treatment before treatment week 3. This perception re-
flected the assumption that early improvement was in-
dicative of a placebo response associated with an irregu-
lar time course of recovery.11–13 To a large extent, these
beliefs are no longer held by experts in the treatment
community.14 However, physicians who follow the most
current treatment guidelines may not consider a medi-
cation change within the first 2 weeks of treatment to
be a useful strategy for improving the management of
depression.
Because most antidepressant treatment guidelines
continue to suggest 4 to 6 weeks of treatment until
nonresponse can be assumed, substantial patience and
adherence is required from depressed patients, partic-
ularly when pessimism and hopelessness dominate the
outlook of these patients. Ineffective treatment is espe-
cially problematic in depression because it can increase
the risk that patients lose confidence in and detach from
their treating physicians, stop taking their prescribed
treatment, or lose hope that their symptoms can be effec-
tively treated. As a result, the risk of serious complica-
tions, such as suicide, is increased. Clearly, early identi-
fication of patients who subsequently will not benefit
from a longer course of antidepressant therapy has im-
mense clinical significance.
The hypothesis that antidepressants have a delayed
onset of action gained support from the way data from
clinical trials are analyzed. Most trials, including pivotal
trials used to demonstrate efficacy for regulatory authori-
ties, use group comparisons to detect significant mean
differences between the antidepressant and placebo. Us-
ing this analytic approach, statistically significant differ-
ences between effective antidepressants and placebo are
usually detected after 3 to 4 weeks of treatment. This ap-
proach assumes that mean differences adequately reflect
changes observed in the individual patient. However, an
examination of data from individuals participating in an-
tidepressant clinical trials reveals a high degree of vari-
ability between patients. This broad range of responses
suggests that individual responsiveness may not be ad-
equately represented by the assumption of the “average”
patient.
The delayed-onset hypothesis for antidepressant ac-
tion is now being challenged. Many studies have not only
reported onset of antidepressant action within the first
2 weeks of treatment,1–3,14–20 but have also substantiated
a close relationship between improvement of depression
symptoms within the first 2 weeks of treatment and the
final treatment response.16–20 For example, Stassen and
colleagues16–19 analyzed the time course of intraindi-
vidual treatment outcomes in patients with depression
by means of survival analyses. In these studies, patients
who improved during the first 2 weeks of antidepressant
treatment, as indexed by a ≥20% reduction in score on the
17-item Hamilton Rating Scale for Depression (HAM-D-
17), showed substantial response at the study endpoint,
as indexed by a ≥50% reduction in HAM-D-17 score.
Stassen and colleagues argued not only that early im-
provement predicted response at study endpoint but also
that lack of improvement was associated with little chance
of response if the treatment strategy remained unchanged.
It is important to note that the criterion of a 20% score re-
duction has been chosen as an early indicator of improve-
ment because it can be reliably measured in clinical trials
and translates into a clinically relevant change in the se-
verity of depressive symptoms in patients (e.g., for a mod-
erately depressed patient with an initial HAM-D-17 score
of 20 points, it means a decrease of 4 points). However, a
change of 20% is not a sensible target for therapeutic in-
tervention and should not be understood as such.
As early as 1987, Katz et al.21 reported that the onset of
improvement occurred within the first 10 days of treat-
ment across several domains in hospitalized patients with
MDD who were being treated with a tricyclic antide-
pressant (TCA). This study did not include a placebo
control group; thus, it could be questioned whether the
early clinical treatment effects observed were due to
drug effects or placebo effects. This issue was addressed
in a subsequent randomized, parallel-group, placebo-
controlled study in which patients were treated with the
selective serotonin reuptake inhibitor (SSRI) paroxetine
or the norepinephrine reuptake inhibitor desipramine.4 In
this study, early treatment-specific behavioral changes
were demonstrated that were not observed in the placebo-
treated group, and these early changes were highly pre-
dictive of ultimate clinical responses to antidepressant
therapy. It was argued that these results could eventually
be directly applied to clinical practice. Nierenberg and
colleagues15 have also reported that more than 50% of
patients who eventually responded to fluoxetine treatment
started to improve during the first 2 weeks of treatment.
This same group has also reported that early nonresponse
to fluoxetine treatment predicted poor 8-week outcomes.22
Clearly, evidence continues to accumulate that indicates
early individual improvement is a key predictor of treat-
ment response.
In 2003, Szegedi et al.20 examined early improvement
with antidepressant treatment in a randomized controlled
trial comparing mirtazapine and paroxetine in patients
with a Diagnostic and Statistical Manual of Mental Dis-
orders (DSM) diagnosis of major depression. Improve-
ment occurred in a majority of patients within 2 weeks of
initiating treatment, and this improvement was a highly
sensitive predictor of later stable response or stable re-
mission for both drugs. Furthermore, negative predictive
value approached maximal values as early as week 2 for
345

First 2 Weeks Predict Treatment Outcome in MDD
J Clin Psychiatry 70:3, March 2009
347
PSYCHIATRIST.COM
mirtazapine and week 3 for paroxetine. Less than 10% of
patients who had not improved after 2 weeks of treatment
became stable responders or remitters over the course of
the study. These results indicate that response or nonre-
sponse to antidepressant treatment can be predicted with
high sensitivity after 2 weeks of therapy. Clearly, such
findings could have significant clinical relevance if ap-
plied in clinical practice. The capacity to predict outcome
during the early stages of treatment could not only shorten
the length of ineffective treatments but could also decrease
morbidity, mortality, and resource use associated with pro-
longed depression.
In the report by Szegedi et al.,20 several caveats were
considered in regard to interpretation of their data. First,
the sample consisted primarily of moderately depressed
outpatients. Although it was noted that this population was
representative of the patients typically encountered in pri-
mary care settings and that their conclusions were fully
appropriate for that patient population, it was unclear if
the conclusions could be generalized to more severely de-
pressed patients. Second, the results were confined to mir-
tazapine and paroxetine, so it was unclear if the results
could be generalized to other antidepressants. Third, the
lack of a placebo group in this study limited the ability to
generalize these observations.16
The objective of the present study was to confirm the
findings of Szegedi et al.20 in a large patient population
with MDD. Data from 6562 patients with MDD who par-
ticipated in randomized, single- or double-blind clinical
trials comparing mirtazapine with active comparators or
placebo from March 1982 to December 2003 were ret-
rospectively examined to determine the time course of
improvement, response, and remission in individual pa-
tients, as well as the predictive capacity of early improve-
ment for later treatment outcome.
METHOD
Inclusion of Studies
Analyses were carried out using data obtained from a
systematic search of single- or double-blind clinical trials
(clinical trials database; Organon, a part of Schering-
Plough Corporation, Roseland, N.J.) comparing mirtaz-
apine with active comparators or placebo in patients with
MDD. The studies ranged from March 1982 to December
2003. The algorithm for trial selection is provided in Fig-
ure 1. Trials were excluded if there were no HAM-D-17
ratings available, no diagnosis of MDD, or if the study was
not blinded. Trials were also excluded if HAM-D-17 as-
sessments were not available at week 2, week 4, and at
least once beyond week 4.
Patient Population
All patients met DSM-III-R or DSM-IV criteria for
the diagnosis of at least 1 major depressive episode. The
HAM-D-17 total score was used to assess the baseline
severity of depressive symptoms (mild = < 22; moder-
ate = 22–25; severe = > 25). Each study was approved by
the institutional review board for the participating site.
Written informed consent was obtained from all partici-
pants prior to participation in the original clinical trials
and all studies were conducted in compliance with the
current revision of the Declaration of Helsinki.
Outcome Measures
For the purpose of this analysis, the following patient
groups were defined:
1. Early improvers: patients having a reduction
in HAM-D-17 score of ≥20% compared with
baseline within the first 2 weeks of treatment.
This threshold represents a clinically meaningful
change in the patient’s state and can be reliably
assessed.
2. Treatment responders: patients having a reduction
in HAM-D-17 score of ≥50% from baseline.
3. Stable responders: patients having a reduction
in HAM-D-17 score of ≥50% from baseline at 4
weeks of treatment and at all subsequent assess-
ments.
4. Symptom remitters: patients having a reduction in
HAM-D-17 score to ≤7 points.
5. Stable remitters: patients having a reduction in
HAM-D-17 score to ≤7 points at week 4 of treat-
ment and at all subsequent assessments.
Statistical Analyses
Analyses of the predictive value of early response for
stable response and remission at 4 weeks were performed
on the intent-to-treat (ITT) population. The method of last
observation carried forward (LOCF) was used for missing
values. The number of early improvers, responders, stable
responders, remitters, and stable remitters was entered
into a contingency table. The following indices, as well as
their respective 95% Fisher exact CIs, were then calcu-
lated:
1. Sensitivity: [Early improvers who became stable
responders or stable remitters/(Early improvers
who became stable responders or stable remit-
ters + Early nonimprovers who became stable re-
sponders or stable remitters)] × 100.
2. Specificity: [Early nonimprovers who did not be-
come stable responders or stable remitters/(Early
nonimprovers who did not become stable respond-
ers or stable remitters + Early improvers who did
not become stable responders or stable remit-
ters)] × 100.
3. Positive predictive value: (Early improvers who
became stable responders or stable remitters/All
improvers) × 100.
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4. Negative predictive value (Early nonimprovers
who did not become stable responders or stable
remitters/All nonimprovers) × 100.
5. False positives: 100% – Specificity.
6. False negatives: 100% – Sensitivity.
All statistical analyses were performed using SAS
analytic software (SAS Institute Inc., Cary, N.C.).
RESULTS
Studies Included
A total of 145 trials were identified (Figure 1). Trials
were excluded from the analysis if there were no HAM-
D-17 ratings (N = 71), no MDD diagnosis (N = 3), or if
the study was not blinded (N = 19). An additional 11 tri-
als were excluded because a valid HAM-D-17 assess-
ment was not available at week 2, week 4, and at least
once beyond week 4.
A total of 41 single- or double-blind clinical trials in
patients with MDD were included in the analyses. The
majority consisted of a 6-week antidepressant treatment
period (N = 37). The remaining trials consisted of 5-week
(N = 2) or 8-week (N = 2) antidepressant treatment peri-
ods. All studies used common inclusion/exclusion crite-
ria, but varied in the criterion for depression severity re-
quired for enrollment.
Demographic Characteristics
The all-treated and ITT populations consisted of 6907
and 6562 patients, respectively. Demographic character-
istics for the ITT population are presented in Table 1. As
indexed by mean HAM-D-17 scores, a majority of pa-
tients (68%) met criteria for moderate or severe depres-
sion at baseline. In 20 studies, data on previous episodes
of depression were available; the majority of patients
(63%) in these studies had a history of previous episodes
of depression. In 27 studies, data on the duration of cur-
rent MDD were available. In these studies, the duration
of the current MDD exceeded 1 month in more than 90%
of patients (< 1 month, 9%; 1–6 months, 44%; 6 months
to 1 year, 20%; > 1 year, 27%).
The noradrenergic and specific serotonergic antide-
pressant (NaSSA) mirtazapine was used in all studies.
The classes of antidepressants that were active compara-
tors included the serotonin-norepinephrine reuptake in-
hibitor (SNRI) venlafaxine; the SSRIs (paroxetine, fluox-
etine, citalopram, sertraline, and fluvoxamine); the TCAs
(amitriptyline, doxepin, and clomipramine); the tetracy-
clic antidepressant maprotiline, and trazodone (chemi-
cally unrelated to other antidepressants). Fifty-two per-
cent of patients were taking mirtazapine. The percentages
of patients taking other antidepressants or placebo were
SSRI = 21%; TCA = 11%; placebo = 10%; trazodone or
maprotiline = 4%; and venlafaxine = 3%. In 2 trials that
focused on rapid dose titration, mirtazapine and venlafax-
ine were studied head to head. The results from these 2 tri-
als for mirtazapine patients (3% of the all-treated popula-
tion) are also discussed.
Treatment Response
The majority of patients had at least a 20% reduction in
HAM-D-17 total score by week 2 of treatment (Table 2).
Of these, the highest proportion of improvers was ob-
served across all weeks for patients who had rapid titra-
tion with mirtazapine.
The numbers of responders, stable responders, remit-
ters, and stable remitters across treatment weeks demon-
strate that responses to treatment follow a similar time
course (Table 3). More than one half of patients taking
active treatment became stable responders, and more than
one third of patients taking active treatment became stable
remitters at the end of treatment.
Figure 1. Systematic Review of Clinical Trialsa
aA total of 145 clinical trials from March 1982 to December 2003
were reviewed for inclusion in the analyses. Trials were
systematically excluded from the analysis if there were no HAM-D-
17 ratings, no diagnosis of MDD, if the study was not blinded, and if
the study did not have a HAM-D-17 assessment at week 2, week 4,
and at least once beyond week 4.
Abbreviations: HAM-D-17 = 17-item Hamilton Rating Scale for
Depression, MDD = major depressive disorder.
All Clinical Trials,
N = 145
HAM-D-17 Rating
Available,
N = 74
No HAM-D-17
Rating Available,
N = 71
Diagnosis of MDD,
N = 71
No Diagnosis of
MDD/Other,
N = 3
Single Blind,
N = 4
Double Blind,
N = 48
Not Blinded/
Open Label,
N = 19
No Valid
Assessments,
N = 11
Week 5,
N = 2
Week 8,
N = 2
Week 6,
N = 37
Valid Assessments,
N = 41
Last Assessments
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Table 1. Demographic Characteristics at Baseline for the Intent-to-Treat Populationa
Characteristic
Placebo
Mirtazapine
Venlafaxine
SSRI
TCA
Otherb
Total
Sex
Male
394 (62)
2084 (61)
118 (62)
844 (61)
487 (69)
160 (68)
4087 (62)
Female
244 (38)
1318 (39)
72 (38)
535 (39)
217 (31)
77 (33)
2463 (38)
Data unavailable
3 (1)
4 (< 1)
0 (0)
0 (0)
5 (1)
0 (0)
12 (< 1)
Race
Asian
4 (1)
178 (5)
0 (0)
167 (12)
3 (< 1)
1 (< 1)
353 (5)
Black
30 (5)
71 (2)
0 (0)
27 (2)
5 (1)
0 (0)
133 (2)
White
509 (79)
1790 (53)
116 (61)
845 (61)
268 (38)
45 (19)
3573 (54)
Other
22 (3)
55 (2)
0 (0)
26 (2)
4 (1)
1 (< 1)
108 (2)
Data unavailable
76 (12)
1312 (39)
74 (39)
314 (23)
429 (61)
190 (80)
2395 (37)
Age, y
< 18
85 (13)
165 (5)
0 (0)
0 (0)
0 (0)
0 (0)
250 (4)
18–24
39 (6)
156 (5)
10 (5)
105 (8)
28 (4)
3 (1)
341 (5)
25–44
284 (44)
1393 (41)
79 (42)
595 (43)
295 (42)
67 (28)
2713 (41)
45–59
158 (25)
1129 (33)
81 (43)
442 (32)
248 (35)
111 (47)
2169 (33)
≥60
72 (11)
559 (16)
20 (11)
237 (17)
133 (19)
56 (24)
1077 (16)
Data unavailable
3 (1)
4 (< 1)
0 (0)
0 (0)
5 (1)
0 (0)
12 (< 1)
Mean (SD), y
38.9 (15.8)
44.3 (15.1)
44.5 (11.6)
45.3 (14.5)
47.3 (13.6)
50.4 (12.0)
44.5 (14.9)
HAM-D-17 total score,
22.8 (4.3)
24.0 (4.7)
26.5 (3.5)
24.0 (4.3)
24.4 (4.7)
26.0 (4.9)
24.1 (4.6)
Mean (SD)
HAM-D-17 severity score
Mildc
261 (41)
1145 (34)
10 (5)
429 (31)
208 (29)
45 (19)
2098 (32)
Moderated
221 (35)
1085 (32)
71 (37)
482 (35)
236 (33)
66 (28)
2161 (33)
Severee
158 (25)
1167 (34)
108 (56)
464 (34)
265 (37)
126 (53)
2288 (35)
Data unavailable
1 (< 1)
9 (< 1)
1 (1)
4 (< 1)
0 (0)
0 (0.0)
15 (< 1)
aAll data presented as N (%) unless otherwise noted.
bOther = trazodone or maprotiline.
cBaseline HAM-D-17 total score < 22.
dBaseline HAM-D-17 total score ≥22 and ≤25.
eBaseline HAM-D-17 total score > 25.
Abbreviations: HAM-D-17 = 17-item Hamilton Rating Scale for Depression, SSRI = selective serotonin reuptake inhibitor,
TCA = tricyclic antidepressant.
Predictive Value of Early Improvement
The predictive values of early improvement for treat-
ment outcome (stable response and stable remission) are
presented in Table 4. Across all treatments, early im-
provement was a highly sensitive predictor of stable
response (range = 81%–98%) and stable remission
(range = 87%–100%). However, early improvement was
not a highly specific predictor for stable response
(range = 43%–60%) or stable remission (range = 30%–
53%). Furthermore, negative predictive values for stable
response (range = 82%–96%) and stable remission
(range = 95%–100%) were higher than positive predic-
tive values for these groups (ranges = 43%–60% and
19%–28%, respectively).
In the 2 head-to-head trials that focused on rapid dose
titration, the predictive value of early improvement was
enhanced (Table 4). In these studies, rapid dose titration
of mirtazapine was associated with the highest sensitivity
for predicting later stable responders (98%, 95% CI =
93% to 100%) and stable remitters (100%, 95% CI =
92% to 100%). These 2 studies also had the highest posi-
tive and negative predictive values for stable responders
(60%, 95% CI = 52% to 68% and 96%, 95% CI = 86% to
100%, respectively) and stable remitters (28%, 95%
CI = 21% to 36% and 100%, 95% CI = 93% to 100%), as
well as the lowest false-negative rates (stable responder:
2%, 95% CI = 0.3% to 8%; stable remitter: 0%, 95%
CI = 0% to 8%). A direct comparison of slow versus rapid
dose titration for venlafaxine was not possible. However,
rapid titration of venlafaxine was associated with high
sensitivity for predicting later stable responders (96%,
95% CI = 89% to 99%) and stable remitters (100%, 95%
CI = 89% to 100%), high positive and negative predictive
values for stable responders (56%, 95% CI = 47% to 64%
and 94%, 95% CI = 84% to 99%, respectively) and stable
remitters (23%, 95% CI = 17% to 31% and 100%, 95%
CI = 93% to 100%), and low false-negative rates (stable
responder: 4%, 95% CI = 1% to 11%; stable remitter: 0%,
95% CI = 0% to 11%).
Outcomes of Early Improvement
We examined the percentage of early improvers and
those without early improvement who later became stable
responders (Figure 2) and stable remitters (Figure 3). By
the end of treatment, 2285 (53%) early improvers were
stable responders and 1084 (25%) were stable remitters.
As such, early improvers constituted 90% (2285 of 2544)
and 92% (1084 of 1177) of all stable responders and
stable remitters, respectively. These results clearly show
that patients who improve within the first 2 weeks of anti-
depressant therapy are highly likely to achieve stable re-
sponse and stable remission after 4 weeks or longer of
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continued treatment. In contrast, only 11% and 4.1%
of patients, respectively, who did not improve within
the first 2 weeks became stable responders or stable re-
mitters. These results appear to be very robust. Similar
analyses of early improvement predicting treatment re-
sponse in data from a subset of patients for whom data
from the Montgomery-Asberg Depression Rating Scale
(MADRS) were available yielded similar results (data
not presented).
DISCUSSION
The results of this analysis confirm that early improve-
ment in depressive symptoms is frequently observed dur-
ing the course of treatment with various antidepressant
therapies, including mirtazapine, and that early improve-
ment heralds a greater likelihood of stable response to
medication and stable remission of symptoms. Impor-
tantly, the lack of early improvement is associated with
low rates of medication response and symptom remission.
These data thus provide further evidence against the
delayed-onset hypothesis for antidepressant treatment re-
sponse.23–25 and further enforce the notion that an early
improvement during treatment is expected with various
antidepressant drugs. Thus a lack of early improvement
may warrant the need for a change in treatment strategy. It
should be noted that prospective and direct comparisons
of response and remission rates in nonimprovers who
continue treatment compared to those who changed treat-
ment is needed to validate this recommendation. How-
ever, if found to be true, such an approach will have far-
reaching implications for clinical practice.
The most immediate and practical consequence of this
analysis is that a patient’s individual early improvement
may predict that individual’s later stable response or re-
mission with high sensitivity. Most prominently, a lack of
early response to treatment at 2 weeks was highly predic-
tive of a lack of stable response or stable remission. This is
consistent with previous findings that indicated that the
presence or absence of early improvement during mirtaz-
apine or paroxetine treatment was highly predictive of
therapeutic outcome.20 In addition, in patients treated with
Hypericum extracts, a reduction of depressive symptoms
during the first 2 weeks of treatment was a sensitive pre-
dictor of sustained response.26 The current analysis ex-
tends these findings to a variety of widely used antidepres-
sants with different pharmacologic profiles. Furthermore,
the finding that early individual improvement can predict
sustained response is consistent with the finding that the
response trajectory early during treatment is a useful pre-
dictor of response to antidepressants.27 In fact, the criterion
set forth in the current analysis (i.e., 20% improvement
over 2 weeks) represents a favorable response trajectory.
It should be noted that there are important methodologi-
cal differences between the approach of Quitkin and col-
leagues13 and the strategy examined herein. Specifically,
they measured outcome using the Clinical Global Impres-
sions scale and required that patients be rated as “much
improved” or “very much improved” to be counted as re-
sponders. In addition, they studied treatment with TCAs
Table 2. HAMD-17 Improversa by Treatment Week for the Intent-to-Treat Population
Treatment, N (%)b
Week 1
Week 2
Week 3c
Week 4
Beyond Week 4
Placebo (N = 641)
No
388 (69)
306 (48)
231 (41)
244 (38)
216 (34)
Yes
176 (31)
334 (52)
333 (59)
396 (62)
424 (66)
Mirtazapine (N = 3406)
No
1415 (53)
1088 (32)
464 (25)
700 (21)
569 (17)
Yes
1240 (47)
2309 (68)
1414 (75)
2697 (79)
2828 (83)
Mirtazapine (rapid titration, N = 202)
No
84 (42)
48 (24)
31 (25)
32 (16)
28 (14)
Yes
118 (58)
154 (76)
94 (75)
170 (84)
174 (86)
Venlafaxine (rapid titration, N = 190)
No
100 (53)
52 (28)
28 (24)
43 (23)
37 (20)
Yes
89 (47)
137 (72)
87 (76)
146 (77)
152 (80)
SSRI (N = 1378)
No
829 (63)
503 (37)
252 (31)
318 (23)
248 (18)
Yes
477 (37)
872 (63)
574 (69)
1057 (77)
1127 (82)
TCA (N = 709)
No
251 (62)
219 (31)
66 (22)
137 (19)
103 (15)
Yes
153 (38)
490 (69)
240 (78)
572 (81)
606 (85)
Otherd (N = 237)
No
105 (64)
95 (40)
19 (29)
46 (19)
41 (17)
Yes
59 (36)
142 (60)
46 (71)
191 (81)
196 (83)
aImprovers were defined as having a ≥20% reduction in HAM-D-17 total score.
bPercentages are based on the total number of patients actually assessed at a given study week.
cWeek 3 was not a scheduled assessment in all studies.
dOther = trazodone or maprotiline.
Abbreviations: HAM-D-17 = 17-item Hamilton Rating Scale for Depression, SSRI = selective serotonin reuptake inhibitor,
TCA = tricyclic antidepressant.
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(predominantly imipramine) and monoamine oxidase in-
hibitors (predominantly phenelzine). These agents must
be started at subtherapeutic doses and titrated upwards
during the first 2 weeks of treatment to improve tolerabil-
ity. Thus, the association of early improvement with pla-
cebo response in their analyses could reflect both the re-
quirement of a more substantial level of improvement and
the fact that therapeutic doses of TCAs and monoamine
oxidase inhibitors were generally not achieved until the
end of the first 2 weeks of therapy.13
It is important to note that high sensitivity does not
mean that the presence of early improvement invariably
leads to stable response or remission, as indicated by
the limited specificity of early improvement. In fact, the
Table 3. Respondersa and Remittersb by Treatment Week for the Intent-to-Treat Population
Responders
Stable Responders
Beyond
Beyond
Treatment, N (%)
Week 1
Week 2
Week 3d
Week 4
Week 4
Week 1
Week 2
Week 3d
Week 4
Week 4
Placebo (N = 641)
No
530 (94)
532 (83)
429 (76)
447 (70)
370 (58)
550 (98)
567 (89)
479 (85)
477 (75)
397 (62)
Yes
34 (6)
108 (17)
135 (24)
193 (30)
270 (42)
14 (2)
73 (11)
85 (15)
163 (25)
243 (38)
Mirtazapine (N = 3406)
No
2372 (89)
2522 (74)
1168 (62)
1806 (53)
1349 (40) 2476 (93) 2721 (80) 1315 (70)
1984 (58)
1422 (42)
Yes
283 (11)
875 (26)
710 (38)
1591 (47)
2048 (60)
179 (7)
676 (20)
563 (30)
1413 (42)
1975 (58)
Mirtazapine
(rapid titration, N = 202)
No
164 (81)
118 (58)
64 (51)
91 (45)
79 (39)
167 (83)
135 (67)
73 (58)
108 (53)
84 (42)
Yes
38 (19)
84 (42)
61 (49)
111 (55)
123 (61)
35 (17)
67 (33)
52 (42)
94 (47)
118 (58)
Venlafaxine
(rapid titration, N = 190)
No
177 (94)
135 (71)
77 (67)
100 (53)
91 (48)
179 (95)
148 (78)
80 (70)
110 (58)
93 (49)
Yes
12 (6)
54 (29)
38 (33)
89 (47)
98 (52)
10 (5)
41 (22)
35 (30)
79 (42)
96 (51)
SSRI (N = 1378)
No
1215 (93)
1080 (79)
571 (69)
812 (59)
542 (39) 1246 (95)
1160 (84)
636 (77)
884 (64)
571 (42)
Yes
91 (7)
295 (21)
255 (31)
563 (41)
833 (61)
60 (5)
215 (16)
190 (23)
491 (36)
804 (58)
TCA (N = 709)
No
378 (94)
542 (76)
204 (67)
369 (52)
247 (35)
387 (96)
582 (82)
227 (74)
401 (57)
265 (37)
Yes
26 (6)
167 (24)
102 (33)
340 (48)
462 (65)
17 (4)
127 (18)
79 (26)
308 (43)
444 (63)
Othere (N = 237)
No
151 (92)
201 (85)
49 (75)
138 (58)
92 (39)
156 (95)
212 (89)
53 (82)
147 (62)
97 (41)
Yes
13 (8)
36 (15)
16 (25)
99 (42)
145 (61)
8 (5)
25 (11)
12 (18)
90 (38)
140 (59)
Remitters
Stable Remitters
Beyond
Beyond
Treatment, N (%)
Week 1
Week 2
Week 3b
Week 4
Week 4
Week 1
Week 2
Week 3b
Week 4
Week 4
Placebo (N = 641)
No
547 (97)
597 (93)
501 (89)
533 (83)
460 (72)
561 (99)
621 (97)
529 (94)
562 (88)
490 (77)
Yes
17 (3)
43 (7)
63 (11)
107 (17)
180 (28)
3 (1)
19 (3)
35 (6)
78 (12)
150 (23)
Mirtazapine (N = 3406)
No
2568 (97)
3048 (90)
1536 (82)
2572 (76)
2072 (61) 2609 (98) 3165 (93) 1649 (88)
2722 (80)
2141 (63)
Yes
87 (3)
349 (10)
342 (18)
825 (24)
1325 (39)
46 (2)
232 (7)
229 (12)
675 (20)
1256 (37)
Mirtazapine
(rapid titration, N = 202)
No
194 (96)
175 (87)
100 (80)
151 (75)
132 (65)
196 (97)
182 (90)
107 (86)
159 (79)
135 (67)
Yes
8 (4)
27 (13)
25 (20)
51 (25)
70 (35)
6 (3)
20 (10)
18 (14)
43 (21)
67 (33)
Venlafaxine
(rapid titration, N = 190)
No
186 (98)
177 (94)
102 (89)
150 (79)
133 (70)
188 (99)
182 (96)
104 (90)
157 (83)
135 (71)
Yes
3 (2)
12 (6)
13 (11)
39 (21)
56 (30)
1 (1)
7 (4)
11 (10)
32 (17)
54 (29)
SSRI (N = 1378)
No
1285 (98)
1273 (93)
719 (87)
1110 (81)
845 (61) 1292 (99) 1307 (95)
755 (91)
1158 (84)
866 (63)
Yes
21 (2)
102 (7)
107 (13)
265 (19)
530 (39)
14 (1)
68 (5)
71 (9)
217 (16)
509 (37)
TCA (N = 709)
No
396 (98)
650 (92)
261 (85)
541 (76)
428 (60)
401 (99)
667 (94)
278 (91)
565 (80)
437 (62)
Yes
8 (2)
59 (8)
45 (15)
168 (24)
281 (40)
3 (1)
42 (6)
28 (9)
144 (20)
272 (38)
Othere (N = 237)
No
163 (99)
229 (97)
62 (95)
200 (84)
163 (69)
164 (100) 235 (99)
63 (97)
206 (87)
166 (70)
Yes
1 (1)
8 (3)
3 (5)
37 (16)
74 (31)
0 (0)
2 (1)
2 (3)
31 (13)
71 (30)
aResponders were defined as having a reduction in HAM-D-17 score of ≥50% from baseline. Stable responders were defined as having a reduction
in HAM-D-17 score of ≥50% from baseline at 4 weeks of treatment and at study endpoint.
bRemitters were defined as having a reduction in HAM-D-17 score to ≤7 points. Stable remitters were defined as having a reduction in HAM-D-17
score to = 7 points at week 4 of treatment and at all subsequent assessments.
cPercentages are based on the total number of patients actually assessed at a given study week.
dWeek 3 was not a scheduled assessment in all studies.
eOther = trazodone or maprotiline.
Abbreviations: HAM-D-17 = 17-item Hamilton Rating Scale for Depression, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic
antidepressant.
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consistently higher negative predictive values in relation
to the positive predictive values indicate that the absence
of early improvement is more predictive of a later lack
of stable response or stable remission with continued
treatment. Early improvement was a clinical predictor of
treatment success in roughly 50% of early improvers.
However, unsuccessful treatment outcome was predicted
for roughly 90% of those who did not experience early
treatment improvement.
In further regard to the predictive value of a lack of
early improvement, it should be noted that it is unclear
whether these results would change if the treatment dura-
tion were extended. The possibility that some portion of
week 2 nonimprovers may have demonstrated sustained
response or remission if treatment was extended should
be acknowledged. However, based on our analyses, we
would argue that the number of patients doing so would
be small. Furthermore, the overall response and remission
rates reported in this analysis (51%–63% and 29%–37%,
respectively) are comparable to those of other published
reports, including the first step of the Sequenced Treat-
ment Alternatives to Relieve Depression (STAR*D)
Table 4. Predictive Value of Early Improvementa for the Intent-to-Treat Population
Sensitivity
Specificity
Positive Predictive
Negative Predictive
False-Positive
False-Negative
Treatment
(95% CI)b
(95% CI)b
Value (95% CI)b
Value (95% CI)b
Rate (95% CI)b
Rate (95% CI)b
Stable Responder Rates
Placebo (N = 640)
88 (82 to 93)
60 (56 to 93)
43 (38 to 49)
94 (91 to 96)
40 (35 to 44)
12 (7 to 18)
Mirtazapine (N = 3397)
91 (89 to 93)
48 (46 to 51)
56 (54 to 58)
88 (86 to 90)
52 (49 to 54)
9 (8 to 11)
Mirtazapine (rapid titration N = 202)
98 (93 to 100)
43 (33 to 53)
60 (52 to 68)
96 (86 to 100)
57 (48 to 67)
2 (0.3 to 8)
Venlafaxine (rapid titration, N = 189)
96 (89 to 99)
45 (35 to 54)
56 (47 to 64)
94 (84 to 99)
56 (46 to 65)
4 (1 to 11)
SSRI (N = 1375)
88 (85 to 91)
50 (47 to 54)
50 (46 to 53)
86 (85 to 91)
50 (46 to 53)
12 (9 to 15)
TCA (N = 709)
89 (85 to 92)
46 (41 to 51)
56 (51 to 60)
84 (79 to 89)
54 (49 to 59)
11 (8 to 15)
Other (N = 237)c
81 (72 to 89)
53 (45 to 61)
51 (43 to 60)
82 (73 to 89)
47 (39 to 55)
19 (11 to 29)
Stable Remitter Rates
Placebo (N = 640)
91 (82 to 96)
53 (49 to 57)
21 (17 to 26)
98 (95 to 99)
47 (43 to 51)
9 (4 to 18)
Mirtazapine (N = 3397)
93 (91 to 95)
38 (36 to 40)
27 (25 to 29)
96 (94 to 97)
62 (60 to 64)
7 (5 to 10)
Mirtazapine (rapid titration N = 202) 100 (92 to 100)
30 (23 to 38)
28 (21 to 36)
100 (93 to 100)
70 (62 to 77)
0 (0 to 8)
Venlafaxine (rapid titration N = 189) 100 (89 to 100)
33 (26 to 41)
23 (17 to 31)
100 (93 to 100)
67 (59 to 74)
0 (0 to 11)
SSRI (N = 1375)
90 (86 to 94)
42 (39 to 45)
23 (20 to 25)
96 (94 to 97)
58 (56 to 61)
10 (6 to 14)
TCA (N = 709)
92 (86 to 96)
37 (33 to 41)
27 (23 to 31)
95 (91 to 97)
63 (59 to 67)
8 (4 to 14)
Other (N = 237)c
87 (70 to 96)
44 (37 to 51)
19 (13 to 26)
96 (90 to 99)
56 (49 to 63)
13 (4 to 30)
aEarly improvement was defined as having a ≥20% reduction of HAM-D-17 total score within the first 2 weeks of antidepressant therapy.
bFischer exact CI.
cOther = trazodone or maprotiline.
Abbreviations: HAM-D-17 = 17-item Hamilton Rating Scale for Depression, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic
antidepressant.
Figure 2. Patient Flow for Stable Respondersa
aThe number and percentage of patients who became stable responders
were determined from patients who improved with treatment at
week 2 and from those who initially did not improve but did so at
week 4 and at the end of treatment. All treatments, including
placebo, are represented.
Abbreviation: ITT = intent-to-treat.
All Patients (ITT),
N = 6562
Improvers,
N = 4284,
65% of ITT Patients
Nonimprovers,
N = 2263,
35% of ITT Patients
Week 2
Stable Responders,
N = 2544,
39% of ITT Patients
No Stable Responders,
N = 4003,
61% of ITT Patients
Week 4 +
Subsequent
Assessments
53%
of Improvers
11%
of Nonimprovers
89%
of Nonimprovers
47%
of Improvers
Figure 3. Patient Flow for Stable Remittersa
aThe number and percentage of patients who became stable remitters
were determined from patients who improved with treatment at
week 2 and from those who initially did not improve but did so at
week 4 and at the end of treatment. All treatments, including
placebo, are represented.
Abbreviation: ITT = intent-to-treat.
All Patients (ITT)
N = 6562
Improvers,
N = 4284,
65% of ITT Patients
Nonimprovers,
N = 2263,
35% of ITT Patients
Week 2
Stable Remitters,
N = 1177,
18% of ITT Patients
No Stable Remitters,
N = 5370,
82% of ITT Patients
Week 4 +
Subsequent
Assessments
25%
of Improvers
4%
of Nonimprovers
96%
of Nonimprovers
75%
of Improvers
351

First 2 Weeks Predict Treatment Outcome in MDD
J Clin Psychiatry 70:3, March 2009
353
PSYCHIATRIST.COM
study,28 which reported a 48.6% response rate at 5.5
weeks and a 36.8% remission rate at 6.3 weeks. This
outcome suggests that any further additional improve-
ment in the treatment groups would probably be minimal.
It should also be noted that, because the current analysis
primarily included patients with acute MDD, it is unclear
how the predictive indices might change in patients with
chronic depression or a complicated treatment course.
It is also important to note that our contention that
early improvement is a critical factor that can be used to
predict treatment response still implies that in a majority
of patients, full treatment benefit will require continued
treatment of several weeks. Clearly, substantial addi-
tional improvement in depressive symptoms can be ob-
served after treatment periods exceeding 8 weeks.1,2,29–31
This notion is again supported by the results from the
STAR*D trial.29 Furthermore, a meta-analysis published
by Taylor et al.2 concluded that improvement in depres-
sive symptoms can be observed after 1 week of treat-
ment, but improvement continues for at least 6 weeks
after treatment initiation. Our data would suggest that im-
provement, or the lack thereof, that is observed at later
time points can be predicted by improvement under treat-
ment at week 2. That is, most individuals meeting criteria
for response or remission at later time points would dem-
onstrate some evidence of improvement, even if full re-
sponse or remission is not attained, at week 2.
Treatment regimen can be a mitigating factor that in-
fluences the onset of antidepressant action. In fact, re-
sponse to many agents,31,32 but not all,33,34 is facilitated by
dose escalation in previously nonresponsive patients.
Bernardo et al.32 reported that fast titration with venlafax-
ine produced more rapid improvement in depressive
symptoms than did slow titration, a finding that is consis-
tent with results of the present analysis. In addition, rapid
mirtazapine dose titration during the first week of treat-
ment enhanced all indices of predictive value. It should
be noted that the effectiveness of dose escalation is not
limited to the early treatment period. Heiligenstein et al.31
reported that dose escalation of the SSRI fluoxetine im-
proved depressive symptoms at treatment week 10 in
more than two thirds of patients who had not responded
at week 4.
The high negative predictive value and low false-
negative rates we observed indicate that the absence of
early improvement should prompt clinicians to consider
changing the treatment regimen after 2 weeks of treat-
ment, because nonimprovers at week 2 are unlikely to
benefit from their current treatment. Early identification
of potential treatment failures could help alter the treat-
ment management approach to one with a higher likeli-
hood of success. It is hoped that early monitoring and
modification of depression therapy will reduce patient
distress, resource utilization, medication noncompliance,
and risk of suicide.
Monitoring of early improvement as a predictor of
treatment outcome is of further clinical value because it
can be easily implemented in the clinical setting. It does
not require an expensive technical investment and can be
applied worldwide. Implementation requires only an as-
sessment of depression severity at baseline and at weekly
intervals with an adequate scale. In our experience, the
choice of the HAM-D-17 or MADRS scale did not sig-
nificantly influence the results, which argues in favor of
the robustness of early improvement as a predictor of
later clinical outcome. Given the potential for saving time
and costs by using early improvement as a predictor of
later outcome, a weekly investment of 20 to 30 minutes
for the rating of depressive symptoms in the clinical set-
ting seems reasonable.
On the basis of the findings from this analysis of pre-
dominantly 6-week clinical trials, we recommend the fol-
lowing clinical guidelines for antidepressant therapy: (1)
before starting treatment, a baseline assessment of the
severity of depressive symptoms should be performed us-
ing a validated scale, such as the HAM-D-17, MADRS,
Quick Inventory of Depressive Symptomatology–Self-
Report, or 9-item Patient Health Questionnaire; (2) as-
sessments should be made on a weekly basis to monitor
changes in depressive symptoms during the course of
treatment; and (3) antidepressant medications should be
titrated rapidly within the first week, if possible, until
therapeutic response is seen or the highest tolerated dose
is achieved. It should be noted that it is unclear if the re-
sults of this analysis and the treatment guidelines outlined
above can be generalized to longer duration trials. How-
ever, in the context of 4- to 6-week trials, using such
a strategy to identify patients with early improvement
would indicate that the treatment strategy should be
continued without adaptation and monitored for contin-
ued efficacy; subsequent response or remission at 4 to 8
weeks can be expected in a large percentage of patients. If
early improvement is not observed within the first 2
weeks of therapy, there is a substantially smaller chance
of stable response or remission, and individual treatment
adaptations should be made as early as possible and can
be tailored to the patient’s needs.
Drug names: citalopram (Celexa and others), clomipramine
(Anafranil and others), desipramine (Norpramin and others),
doxepin (Sinequan, Zonalon, and others), fluoxetine (Prozac and
others), fluvoxamine (Luvox and others), imipramine (Tofranil and
others), mirtazapine (Remeron and others), paroxetine (Paxil, Pexeva,
and others), phenelzine (Nardil), sertraline (Zoloft and others), venla-
faxine (Effexor and others).
Financial disclosure: Dr. Szegedi and Mr. van Willigenburg
are employees of Organon, a part of Schering-Plough Corporation
(Roseland, N.J., U.S.A.). Mr. Jansen is an employee of Organon, a
part of Schering-Plough Corporation (Oss, The Netherlands). Dr. van
der Meulen was an employee of Organon, a part of Schering-Plough
Corporation (Oss, The Netherlands) at the time this research was
conducted and is currently an employee of Ferring Pharmaceuticals
A/S. During the past 3 years, Dr. Thase is or has been an advisor/
352

Szegedi et al.
354
J Clin Psychiatry 70:3, March 2009
PSYCHIATRIST.COM
consultant to AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli
Lilly, Forest, GlaxoSmithKline, Janssen, MedAvante, Neuronetics,
Novartis, Organon (Schering-Plough), sanofi-aventis, Sepracor, Shire
US, Supernus, Transcept, and Wyeth; has received grant/research sup-
port from Eli Lilly, GlaxoSmithKline, and Sepracor; has received
honoraria for talks sponsored by AstraZeneca, Bristol-Myers Squibb,
Cyberonics, Eli Lilly, GlaxoSmithKline, Organon (Schering-Plough),
and Wyeth; has equity holdings in MedAvante; and receives income
from royalties from American Psychiatric Publishing, Guilford Publi-
cations, and Herald House. Dr. Stassen reports no additional financial
or other relationship relevant to the subject of this article.
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353

401
The need for chronotherapeutics
hronotherapeutics refers to treatments based
on the principles of circadian rhythm organization and
sleep physiology,1,2 which control the exposure to envi-
ronmental stimuli that act on biological rhythms, in order
to achieve therapeutic effects in the treatment of psy-
chiatric conditions.3 These nonpharmaceutical and bio-
logically based clinical interventions include manipula-
tions of the sleep-wake cycle such as sleep deprivation
(SD) and sleep phase advance (SPA), and controlled
exposure to light and dark. The use of these techniques
in everyday clinical practice is almost exclusively limited
to the treatment of mood disorders, offering mental
health practitioners a set of nonpharmaceutical, rapid,
and effective antidepressant modalities for monother-
apy or as adjuvants to conventional medication.1,4
Interest in the clinical use of these techniques stemmed
from their efficacy, rapidity of action, and lack of side
effects, and also from the possibility of achieving long-
lasting therapeutic effects by combining the different
chronotherapeutic interventions among themselves or
with conventional psychiatric treatments.5 Clinical treat-
ment algorithms in everyday psychiatric settings that
include chronotherapeutic techniques and the monitor-
ing of chronobiological variables proved to be useful to
predict outcomes, speed up recovery, shorten hospital-
ization, and reduce the clinical need for changes in drug
prescriptions.6-9 The results observed in clinical trials pro-
C l i n i c a l  r e s e a r c h
Copyright © 2012 LLS SAS.  All rights reserved
www.dialogues-cns.org
Antidepressant chronotherapeutics for 
bipolar depression
Francesco Benedetti, MD
C
Keywords: bipolar disorder; antidepressant; sleep deprivation; light therapy; sleep
phase advance; dawn simulation; serotonin; glutamate; dopamine; noradrenaline 
Author affiliations: Department of Clinical Neurosciences, Scientific Institute and
University Vita-Salute San Raffaele, Milan, Italy 
Address for correspondence: Francesco Benedetti, MD, Istituto Scientifico
Universitario Ospedale San Raffaele, Dipartimento di Neuroscienze Cliniche, San
Raffaele Turro, Via Stamira d’Ancona 20, 20127 Milano, Italy 
(e-mail: benedetti.francesco@hsr.it)
Chronotherapeutics refers to treatments based on the
principles of circadian rhythm organization and sleep
physiology, which control the exposure to environmental
stimuli that act on biological rhythms, in order to achieve
therapeutic effects in the treatment of psychiatric condi-
tions. It includes manipulations of the sleep-wake cycle
such as sleep deprivation and sleep phase advance, and
controlled exposure to light and dark. The antidepressant
effects of chronotherapeutics are evident in difficult-to-
treat conditions such as bipolar depression, which has been
associated with extremely low success rates of antidepres-
sant drugs in naturalistic settings and with stable antide-
pressant response to chronotherapeutics in more than half
of the patients. Recent advances in the study of the effects
of chronotherapeutics on neurotransmitter systems, and
on the biological clock machinery, allow us to pinpoint its
mechanism of action and to transform it from a neglected
or “orphan” treatment to a powerful clinical instrument
in everyday psychiatric practice.
© 2012, LLS SAS
Dialogues Clin Neurosci. 2012;14:401-411.

duced a positive answer to early doubts about the ther-
apeutic usefulness of chronotherapeutics10 and about the
temporary nature of the achieved benefits.11
These effects of chronotherapeutics have been particularly
evident in difficult-to-treat conditions such as bipolar
depression, which has been associated with extremely low
success rates of antidepressant drugs in naturalistic set-
tings.12 Bipolar patients spend a substantial proportion of
their time ill,13 with depression representing their pre-
dominant abnormal mood state,14 but with the repeated
use of antidepressant drugs being related to poor prospec-
tive response to naturalistic treatment.15 The clinical need
for treatment of their disabling condition and the interplay
between the risk of treatment-emergent mania16,17 and the
risk of relapse when discontinuing drug treatments18 often
leads to prolonged and highly complex medication regi-
mens to achieve a sustained response.19 Nevertheless, there
is still a real clinical need for fast-acting antidepressant
effects to counteract the rapid breakthrough depression
experienced by the patients: hence the interest in
chronotherapeutics, which act without the delay inherent
to traditional antidepressant treatments.3,20
Paralleling these clinical achievements in recent years, basic
research in the last decade has substantially improved
knowledge about the biological mechanisms that control
the molecular machinery of the master clock,21 and link it
with the neurotransmitter systems that are involved in
mood regulation and targeted by antidepressant drugs.22
Confirming the classical belief that man and his environ-
ment are inseparable, it is now established that exposure to
environmental stimuli that act on the transcription of clock
genes will lead to major changes in the same brain neuro-
transmitter function involved in psychiatric conditions,3 and
that from a clinical point of view the choice will be
restricted between the potentially detrimental random
exposure to these stimuli, which could even precipitate
bipolar illness episodes,23,24 and the direct control by the psy-
chiatrist in order to achieve a therapeutic effect.
The present review focuses on recent achievements in
the chronotherapeutic treatment of bipolar depression
and on the recently discovered molecular mechanisms
that clearly link chronotherapeutics with the usual anti-
depressant drug treatments of this disorder.
Techniques
The first studies published in clinical samples used sin-
gle chronotherapeutic techniques to treat depression,
but the clinical need for rapid and sustained improve-
ment of patients prompted the combination of different
techniques among themselves and with usual antide-
pressant drug treatments.
Sleep deprivation
Antidepressant effects of sleep deprivation were first
reported in 1959,25 but the first experimental trials to test
its clinical efficacy were performed in the 1970s.26,27 The
amazingly rapid effects of the treatment, which is usu-
ally able to restore euthymia in the morning soon after
a single night awake, are closely linked to the wake
period and are usually rapidly lost after restoring an
undisturbed night sleep.11 To achieve the best results the
wake period includes the extension of daytime wakeful-
ness into the night, and lasts about 36 hours until the
evening of the day after (total sleep deprivation), but it
can also be limited to the second half of the night and
the following day, thus allowing sleep during the first half
of the night,28 with little disadvantage29: in both cases, the
mood amelioration is obtained during the prolonged
wake, and in the presence of light.30 This link between
mood and wake, together with the observation that dur-
ing the nights of undisturbed sleep patients sleep better
and deeper than usual,31 justified the recent use of the
term “wake therapy” to refer to this treatment.2
In the absence of combined treatments, not more than
5% of responders to wake will maintain a stable
euthymia in the days of subsequent normal sleep,20 thus
limiting the diffusion of this technique alone.32 Soon in
the early studies, however, SD was observed to produce
rapid benefits in the broadly defined depressive syn-
drome: in endogenous, reactive, unipolar, bipolar, sec-
ondary, and schizoaffective depression; in the elderly and
in children; in depression secondary to Parkinson’s dis-
ease or schizophrenia; or associated with pregnancy and
postpartum and premenstrual dysphoric disorder,10,20 and
with better effects observed in endogenous primary
depression compared with reactive and/or secondary
depression, and in the treatment of Bipolar Disorder
compared with Primary Depressive Disorder.33
In order to prevent the relapse into depression after SD,
single-night SD or repeated SD was combined with sero-
tonergic antidepressants, lithium salts, or other
chronotherapeutic techniques.4 The simple repetition of
SD over time has been tested for many schedules, includ-
ing twice in 1 week,34 or twice a week for 3 weeks35,36 or
C l i n i c a l  r e s e a r c h
402

for a month,37 or for twice in 1 week followed by partial
SD twice,38 etc. Repeated SD once a week has also been
proposed as a prophylactic treatment: preliminary stud-
ies in small samples showed that SD reduced the fre-
quency of relapses and increased the duration of nor-
mothymia in roughly one half of the patients.39,40
Our group developed a treatment schedule based on
repeated total SD, three times during 1 week, resulting in
a lengthening of the sleep-wake period from the usual 24
to 48 hours.41-49 When combined with light therapy and
with lithium salts, the mainstay for the long-term treat-
ment of bipolar disorder, this therapy is able to trigger an
acute response also in patients drug resistant to both
serotonergic and tricyclic antidepressants, and to lead to
a stable euthymia for 9 months in roughly 60% of bipo-
lar patients without a history of drug resistance.47 Despite
early concerns due to the close link between sleep loss
and the onset of mania,50 this result is achieved with a risk
of switch which is around 6% and leads to easily con-
trolled manic reactions,51 thus comparable to the reported
switch rate for placebo. Considering the 15%-to-25% risk
of treatment-emergent mania linked with antidepressant
drug treatment in bipolar patients,16,17 and the 30% of
responders mantaining euthymia when discontinuing
drug treatments before 6 months,18 these data warrant the
highest clinical interest in using these techniques as first-
choice treatments for bipolar depression. 
Light therapy
The scientific approach to the treatment of depression
with bright light started in the 1980s.52-54 Early on, anti-
depressant bright light therapy (LT) was administered 1
to 2 hours before the usual time of awakening.55 This
phase-advancing administration of light in the early
morning was then proven to have better antidepressant
effects than the simple increase of the subjective pho-
toperiod obtained by exposing the patients to light in the
evening.56 A correlation was then observed between the
magnitude of phase advances to morning LT and
improvement in depression ratings, with maximum
effects with phase advances of 1.5 to 2.5 hours (about 7.5
to 9 hours after the dim-light melatonin onset the
evening before).57 Since scores on the Morningness-
Eveningness Questionnaire (MEQ) are strongly corre-
lated with sleep midpoint and melatonin secretion, a pre-
dictive algorithm based on MEQ scores was then
developed to define the individual optimal timing of LT
administration,58 and proven successful even when used
in common clinical settings, and when giving light in
combination with antidepressants.59 Over the years, other
treatment algorithms have been proposed,60 and
research is currently identifying the most effective treat-
ment schedule as a function of seasonality and other
individual characteristics.61
Given that LT is, however, useful, even when given at
midday,62 the clinical use of LT followed a pattern of
evolving applications in any kind of depressive syn-
drome.63 The APA Committee on Research on
Psychiatric Treatments64 and a Cochrane review65 con-
cluded that light treatment for nonseasonal major
depression is efficacious, with effect sizes equivalent to
those in most antidepressant pharmacotherapy trials.
When combined with standard antidepressant drug
treatments LT hastens recovery, with benefits that can
be perceived by the patients during the first week of
treatment.59,66 After 1 month of treatment, patients
treated with light show a net benefit, in respect to
placebo, that can be quantified in a approximately 30%
better reduction in the severity of depression: remark-
ably, these values are very similar for early studies per-
formed with the combination of light and tricyclic anti-
depressants, and for new studies combining light and
selective serotonergic drugs.59,66,67 The benefit is also clin-
ically evident in drug-resistant patients, when adding
light to ongoing albeit ineffective antidepressants.68
Similar to SD, LT in nonseasonal major depression does
not show a sustained effect after discontinuation, with a
complete offset of effect after 1 month,69 but the relapse
can be easily prevented when combining LT with com-
mon antidepressant drugs.70 Again, similarly to SD, LT
caused marked benefits in the broadly defined depres-
sive syndrome, including very different psychopatho-
logical conditions such as antepartum depression71 as
well as post-stroke depression in the elderly.72
In the case of bipolar depression, the efficacy of LT
alone is questioned, with studies showing either better
benefits than in unipolar patients,73 or worse effects,74 but
the combination of LT with other chronotherapeutic
techniques and with lithium salts was proven to lead to
stable mood ameliorations and euthymia, even in drug-
resistant patients.45,47 Moreover, some observations sug-
gested that bipolar patients could be sensitive to the
antidepressant properties of light at intensities as low as
300 to 500 lux,45,73 far below the usual 10000-lux standard
used in LT of unipolar patients: a finding in agreement
Chronotherapeutics for bipolar depression - Benedetti
Dialogues in Clinical Neuroscience - Vol 14 . No. 4 . 2012
403

with the proposed supersensitivity of the biological clock
to the effects of light as a possible trait marker for bipo-
lar disorder.75
Other studies explored the interaction of LT with the cir-
cadian changes of sensitivity of the biological clock to
the effects of light and defined “dawn simulation” pro-
tocols based on the administration of low intensity (400
lux) LT during the last period of the patient’s sleep
episode, a treatment with a comparable efficacy to that
of bright white LT.76,77
Sleep phase advance and combined treatments
Antidepressant effects of sleep phase-advance (SPA)
have been predicted by chronobiological studies of
depression (suggesting a misalignment between the bio-
logical clock, biological rhythms, and the sleep-wake
rhythms) and first described in 197978: the simple act of
going to bed and waking up 5 hours earlier leads to a
sustained marked improvement of mood in a bipolar
depressed patient, an effect then confirmed in unipolar
endogenous depression.79 Remarkably, recent studies on
large samples in the general population showed that ear-
lier parental set bedtimes are a protective factor against
depression and suicidal ideation during adolescence,80
thus suggesting a major role for the disruption of the cir-
cadian timing in the pathophysiology of depression.81
Probably because of the difficult match of a phase-
advanced sleep schedule with social and environmental
cues and expectations, SPA has never spread into clinical
settings. When combined with a previous SD, SPA is how-
ever able to sustain its effects and prevent the relapse
that might occur after restoring night sleep.82 A short SPA
protocol, performed over 3 days, has been shown to be
sufficient to achieve this effect and to be synergistic with
lithium salts in sustaining a stable euthymia in bipolar
depressed patients.83 This protocol can easily be associ-
ated with antidepressant medications,84 and more recent
pilot trials explored the possibility of a “triple
chronotherapeutics” for bipolar depression: SD followed
by SPA and combined with morning LT, given as adjunc-
tive treatment to lithium and antidepressants, signifi-
cantly enhanced antidepressant response.85
Mechanisms of action
The mechanism of action of chronotherapeutics has
been widely explored for SD, and suggests convergence
of effects between SD and all known antidepressant
strategies. Many effective antidepressant treatments tar-
get several mechanisms, and a multitarget approach to
treatment could overall be better suited for a multifac-
torial illness such as depression86: chronotherapeutics is
no exception, and is able to influence the same mecha-
nisms that are targets for other antidepressants. 
Brain monoamines and glutamate
SD potentiates all the monoaminergic systems that are tar-
geted by antidepressant drugs and that have been involved
in the pathogenesis of depression, and effects of SD on
monoamines are part of its mechanism of action. Research
on this topic directly measured changes in monoaminer-
gic neurotransmission in animal models, or studied SD
effects in humans with challenge methods, brain imaging,
or pharmacogenetic approaches. These methods allowed
definition of convergent effects in animal and humans,
either healthy or depressed, of SD on serotonin (5-HT),
noradrenaline (NA), and dopamine (DA). 
In animal models, SD increase 5-HT neurotransmission87
by enhancing the activity of 5-HT neurons in the dorsal
raphé nucleus,88 increasing brain extracellular 5-HT89 and
5-HT turnover,90-92 reducing the sensitivity of 5-HT1A
inhibitory autoreceptors,88,93 and increasing the behav-
ioral responsiveness to 5-HT precursors.94 In a similar
way, SD was shown to increase synaptic levels of NA95
and tyrosine hydroxylase and NA transporter mRNA in
the locus coeruleus,96 and to increase DA activity and
behavioral response to DA agonists,97,98 with an increase
of DA receptor binding sites during the early stages of
SD (following 12 to 24 hours awake)99 and a subsequent
subsensitivity after more prolonged wake,100 suggesting
downregulation after prolonged stimulation.
Clinical psychobiology confirmed these effects in
depressed humans and linked them with the efficacy of
chronotherapeutics. SD increased the prolactin response
to intravenous tryptophan infusion101 and decreased
plasma levels of prolactin, which is inhibited by DA ago-
nists, thus suggesting DA hyperactivity during SD.102,103
D2 receptor occupancy decreased in responders to SD,
thus suggesting an enhanced DA release in responders,104
levels of homovanillic acid in the spinal fluid predicted
the clinical effects of SD,105 and eye-blink rate after SD
increased in responders, suggesting DA activation.106 The
NA metabolites 3-methoxy-4-hydroxyphenylglycol
(MHPG) and MHPG sulfate107 increased after SD pro-
C l i n i c a l  r e s e a r c h
404

portionally to severity of depression108 and clinical
response to treatment.109 Human pharmacogenetics con-
firmed that gene variants that improve neurotransmis-
sion by increasing receptor or transporter density, or
decreasing neurotransmitter degradation, also improve
the clinical efficacy of SD in bipolar depression when
given alone or combined with bright light therapy. This
was proven for genotypes influencing the density of the
5-HT transporter110-112 and of the 5-HT2A receptor,113 or
the efficiency of the catechol-O-methyltransferase
(COMT) in clearing NA and DA from the synapse.114
Interestingly, the role of these genetic influences has
effect sizes comparable to those observed on response
to antidepressant drugs,115-117 thus strongly suggesting a
shared mechanism of action of chronotherapeutics and
monoaminergic drugs.
Following this line of reasoning, the most striking con-
firmations of shared influences on monoamines come
from combined treatments with chronotherapeutics and
drugs. SD showed synergistic interactions with drugs that
increase the activity of brain 5-HT,42,43,85 NA,118 and DA46
systems; conversely, DA antagonists block the behav-
ioral119 and antidepressant120 effects of SD. Similar syn-
ergistic effects have been described for light therapy,
which significantly potentiates serotonergic antidepres-
sants,59,66 is influenced by genotypes influencing the den-
sity of the 5-HT transporter,112 and can prevent the
mood-lowering effect of acute tryptophan depletion,
which reduces brain 5-HT.121
Finally, an increasing interest on glutamatergic neuro-
transmission in depression stemmed from trials report-
ing antidepressant effects of the NMDA antagonists ket-
amine122 and the glutamatergic modulator riluzole.123
Glutamatergic neurotransmission follows a strict circa-
dian rhythm, and in animal models it is first enhanced
and then markedly depressed during SD.124 In vivo sin-
gle proton magnetic resonance spectroscopy (1H-MRS)
indicated that glutamatergic transmission is altered by
SD, as shown by reduced glutamate concentrations, the
changes being proportional to both perceived and
observed mood amelioration in bipolar depression.125
Remarkably, these effects were observed in the anterior
cingulate cortex, a brain area which has been widely
implicated in providing a neural basis for mood-congru-
ent cognitive biases in depression,126 and where
chronotherapeutics was shown to profoundly change
metabolism127,128 and neural reactivity to stimulus words48
in responders to treatment. 
Biological clock and long-lasting effects on biological
rhythms
The hypothesis that several psychiatric conditions may
involve primary or secondary changes in biological
clocks,129 and the observations that biological rhythms
show a range of abnormalities in mood disorders,130
make the biological clock a primary candidate to explain
the mechanism of action of chronotherapeutic tech-
niques. The molecular machinery which constitutes the
biological master clock in the suprachiasmatic nuclei
(SCN) is being elucidated,131 but the systematic study of
the relationship between clock and therapeutic inter-
ventions in psychiatry is just beginning.132
Growing evidence supports the hypothesis that changes
in brain monoaminergic functioning influence the func-
tion of the biological clock molecular machinery, and the
clock and the control of biological rhythms are emerg-
ing targets for antidepressant drug treatment.133,134 New
animal models have been used to test the interactions
between circadian genes and mood-related neurotrans-
mitter systems, and, conversely, to explore the effects of
light on brain circuitries and of antidepressant and
mood-stabilizing drugs on the clock.22 Serotonin modu-
lates the response of the circadian system to light and
mediates modification of the period and phase of the
central clock by behavioral arousal, while, in turn, the
biological clock gene network is expressed in seroton-
ergic raphe neurons,135 with a close interplay between the
two systems leading to strong circadian and seasonal
rhythms in serotonergic function.136 Dopaminergic activ-
ity also follows a strong rhythm, and manipulations of
clock genes within brain dopaminergic structures leads
to abnormal animal behaviors that closely resemble
human bipolar disorder,137-139 while some genetic variants
of the same clock genes are associated with a worse
bipolar phenotype in human patients.140,141 The locus
coeruleus produces a relatively constant tonic nora-
drenergic firing throughout all behavioral states, except
during rapid eye movement (REM) sleep when NA dis-
charge is absent,142 and it was hypothesized that modifi-
cations of NA activity during chronotherapeutics could
be necessary for its effects.99,143
Remarkably, all antidepressant chronotherapeutic inter-
ventions cause a phase advance of biological rhythms.
Light therapy in the morning is the main environmental
synchronizer of the internal clock and influences timing
and entrainment of the SCN circadian clock by inducing
Chronotherapeutics for bipolar depression - Benedetti
Dialogues in Clinical Neuroscience - Vol 14 . No. 4 . 2012
405

406
C l i n i c a l  r e s e a r c h
CREB.144 The circadian pacemaker is sensitive to short-
duration light pulses with a nonlinear relationship
between light duration and the amount of resetting, and
a 1-hour bright white light pulse phase shifts the circadian
pacemaker following a clear-cut phase-response curve145:
phase advances are obtained when administering light in
the morning, and phase delays when administering it in
the evening (the so-called type I phase response).146 SD
directly targets the sleep-wake rhythm and can influence
SCN function by modifying vigilance state transitions and
sleep states,147 specifically modifies the binding of the mol-
ecular components of the biological clock,148 and is clini-
cally synergistic with the administration of phase-advanc-
ing morning light149: in agreement with these findings, an
actimetric advance of the activity-rest circadian cycle cor-
relates with positive antidepressant response to SD.49
Surprisingly, very little data are available on the effects of
antidepressant drugs on the biological clock, but a single
study showed that fluoxetine induces a phase advance of
the SCN in rats,150 while the antidepressant agomelatine
can induce a phase advance in normal humans,151 thus sup-
porting the hypothesis that chronotherapeutics and drug-
induced changes on monoaminergic function may result
in similar long-lasting effects on the master clock of
depressed patients, possibly correcting yet poorly under-
stood abnormalities in the phase-angle relationships
between biological rhythms.81,152
Brain plasticity and metabolism
Genes of the biological clock are expressed in many
brain structures other than in the SCN153,154 and their
genetic variants can bias “non-clock” brain functions
such as information processing and decision making in
bipolar depression.155 Several findings suggest that at the
cellular level clock genes could provide a mechanism for
the control of circadian gene expression and of respon-
siveness to stimuli,156 which in psychiatric conditions may
influence the complex relationship between susceptibil-
ity and precipitating factors for depression, thus biasing
core characteristics of the illness such as age at onset,157
recurrence of illness,158 or its occurrence in specific risk
periods such as the postpartum period.159
The close link between the clock machinery and core
metabolic cellular processes is confirmed by the study of
protein modulators such as glycogen synthase kinase 3-
β (GSK3-β), which is a core constituent of the mam-
malian circadian clock and affects circadian rhythm gen-
eration by modifying the stability of circadian clock mol-
ecules.160 This kinase is also an essential element of the
Wnt/beta-catenin pathway, which is involved in the con-
trol of gene expression, cell behavior, cell adhesion, and
cell polarity, and plays major roles in neurodevelopment
and in regulation of neuronal polarity, neuronal plastic-
ity, and cell survival.161 It regulates the activity of many
targets including transcriptional factors, enzymes, and
cytoskeletal proteins,162 and is considered a primary reg-
ulator in a range of cellular processes including differen-
tiation, growth, motility, and apoptosis.163 GSK-3 influ-
ences the susceptibility of neurons to harmful stimuli
(neuronal resilience), because increasing GSK-3 activity
increases apoptosis in neuronal cells, while inhibiting
GSK has neuroprotective effects,164 and because its inhi-
bition occurs in response to brain-derived neurotrophic
factor (BDNF) and other neurotrophins.165
These mechanisms provide a target for the convergent
effects of chronotherapeutics and antidepressant drugs
on the biological clock and on neurotransmitter systems.
Control of the phosphorylation/activity status of GSK-
3β is considered an important mechanism of serotonin
(5-HT) and dopamine (DA) action on brain and behav-
ior,166 because GSK3-β is inhibited by lithium, valproate,
and several antidepressants such as selective serotonin
reuptake inhibitors, monoamine oxidase inhibitors, and
tricyclic antidepressants.165,167 Confirming the role of
these mechanisms for bipolar disorder and chronother-
apeutics, promoter gene variants were associated with
less detrimental clinical features, including a delayed
onset of illness,168 a better clinical response to lithium,169,170
and a better response to sleep deprivation171: this effect
was so strong as to overcome the detrimental influence
on SD response of genotypes negatively affecting sero-
tonergic function.111,172
Molecular mechanisms involved in brain plasticity are
likely to play a major role in antidepressant response
and long-term mood stabilization of bipolar patients.173
Accumulating evidence suggests then that plastic
processes occurring during wakefulness result in a net
increase in synaptic strength in many brain circuits, and
that synaptic strength is downscaled to baseline levels
during sleep,174 when effective cortico-cortical connec-
tivity is broken down.175 In agreement with the predic-
tions of this “synaptic homeostasis hypothesis” of
sleep,176 a recent study showed that in healthy humans
prolonged wakefulness is associated with significant
changes in the state of cortical circuits involving a steady

Cronoterapia antidepresiva para la depre-
sión bipolar
La cronoterapia se refiere a los tratamientos basa-
dos en los principios de la organización del ritmo
circadiano y de la fisiología del sueño, mediante el
control de la exposición a los estímulos ambienta-
les que actúan sobre los ritmos biológicos con el fin
de conseguir efectos terapéuticos en el tratamiento
de los cuadros psiquiátricos. Esta terapia incluye
manipulaciones del ciclo sueño-vigilia como la pri-
vación de sueño y el avance de fase, junto con la
exposición controlada a la luz y a la oscuridad. Los
efectos antidepresivos de la cronoterapia son evi-
dentes en cuadros de difícil tratamiento como la
depresión bipolar, la cual se ha asociado con resul-
tados de éxito extremadamente bajos para los fár-
macos antidepresivos en estudios naturalísticos y
con una respuesta antidepresiva estable a la cro-
noterapia en más de la mitad de los pacientes.
Avances recientes en el estudio de los efectos de la
cronoterapia en los sistemas de neurotransmisión y
en la maquinaria del reloj biológico, permiten iden-
tificar su mecanismo de acción y transformarla
desde un rechazo o un “tratamiento huérfano” a
un poderoso instrumento clínico en la práctica psi-
quiátrica cotidiana. 
Chronothérapie antidépressive pour la
dépression bipolaire
La chronothérapie se rapporte aux traitements dont
les principes reposent sur l’organisation des rythmes
circadiens et la physiologie du sommeil, qui contrô-
lent l’exposition aux stimuli environnementaux
agissant sur les rythmes biologiques, afin de pou-
voir traiter les pathologies psychiatriques. Elle com-
prend des manipulations du cycle veille-sommeil
comme la privation de sommeil et l’avance de
phase du sommeil ainsi qu’une exposition contrô-
lée à la lumière et à la nuit. Les effets antidépres-
seurs de la chronothérapie sont évidents dans des
pathologies difficiles à traiter comme la dépression
bipolaire, qui a été associée à des taux de succès
extrêmement faibles des antidépresseurs dans les
échantillons naturalistes et à une réponse antidé-
pressive stable à la chronothérapie chez plus de la
moitié des patients. Des progrès récents dans
l’étude des effets de la chronothérapie sur les neu-
rotransmetteurs et sur l’horloge biologique nous
permettent d’identifier son mécanisme d’action et
de faire de ce traitement « orphelin » ou négligé un
instrument clinique puissant en pratique psychia-
trique quotidienne. 
407
Chronotherapeutics for bipolar depression - Benedetti
Dialogues in Clinical Neuroscience - Vol 14 . No. 4 . 2012
increase in the excitability of human cortical circuits that
is rebalanced during sleep.177 These effects have been
related with the circadian rhythms of glutamatergic neu-
rotransmission and with increased synaptic weights in
animal models,178 thus supporting the hypothesis that
these mechanisms could provide a new basis in concep-
tualizing the link between chronotherapeutics and brain
homeostasis in bipolar depression. 
Conclusion
In conclusion, chronotherapeutics has now been proven
to be a powerful clinical instrument for the treatment of
depression in everyday clinical practice. Rapidity of
effects and lower rates of switch into mania with respect
to available antidepressant drugs make chronothera-
peutic combinations a first-choice option for the hospi-
tal treatment of patients with a major depressive episode
in the course of bipolar disorder. Antidepressant efficacy
in nearly one half of drug-resistant patients makes it
mandatory for the clinician to prescribe these treatments
to these difficult-to-treat patients. Single techniques, such
as light therapy, can be easily prescribed to outpatients
in combination with the usual antidepressant drug treat-
ments. In all cases, chronotherapeutic techniques should
be combined with mood-stabilizing treatments, such as
lithium salts, which are the mainstay of the long-term
psychiatric management of bipolar disorder and which
can enhance and sustain the acute antidepressant effects
of chronotherapeutics. ❏

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Ž
.
Psychiatry Research 79 1998 43]50
The unipolar]bipolar dichotomy and the response
to sleep deprivation
Barbara Barbini, Cristina Colombo, Francesco BenedettiU, Euridice Campori,
Laura Bellodi, Enrico Smeraldi
IRCCS Istituto Scientiﬁco Ospedale San Raffaele, Department of Neuropsychiatric Sciences, Uni¨ersity of Milan,
School of Medicine, Via Prinetti 29, 20127 Milano, Italy
Received 25 August 1997; revised 2 February 1998; accepted 24 February 1998
Abstract
Fifty-one inpatients affected by a major depressive episode were divided into four groups according to mood
Ž
disorder diagnosis and previous clinical history bipolar disorder type I; bipolar disorder type II; major depressive
.
disorder with at least three previous depressive episodes; and single depressive episode patients and administered
Ž
.
three consecutive total sleep deprivation TSD cycles. Mood changes were rated with a reduced version of the
Hamilton Depression Rating Scale and with self-administered visual analogue scales. TSD caused better clinical
effects in bipolar and single-episode patients; in particular, unipolar patients lacked effects in perceived mood after
the ﬁrst TSD and showed worse Hamilton ratings in respect to the other groups after the three TSD treatments.
Discriminant function analysis could correctly classify 80% of bipolar patients, post hoc, based on TSD response.
Further researches on the clinical efﬁcacy of TSD must take into account the heterogeneity of depression and of its
biological substrate.
Q 1998 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Depression; Mania; Antidepressants; Nosography
1. Introduction
Ž
.
Total sleep deprivation TSD is an alternative
Ž
somatic treatment for major depression Ameri-
.
can Psychiatric Association, 1995 with a response
Ž
rate of approximately 60% Leibenluft and Wehr,
UCorresponding author. Tel.: q39 2 26433229; fax: q39 2
26433265; e-mail: affetti@rsisi.hsr.it
.
1992 and with an 85% short-term relapse rate in
Ž
.
unmedicated responders Wu and Bunney, 1990 .
Several strategies have been applied in order to
sustain this transient effect: serial repetition of
TSD and its association with antidepressant drugs
Ž
and other non-pharmacologic treatments
e.g.
Baxter et al., 1986; Shelton and Loosen, 1993;
Szuba et al., 1994; Kuhs et al., 1996; Benedetti et
.
al., 1997; Berger et al., 1997
are some of the
techniques proposed with promising results.
0165-1781r98r$19.00
Q 1998 Elsevier Science Ireland Ltd. All rights reserved.
Ž
.
P I I S0 1 6 5 - 1 7 8 1 9 8 0 0 0 2 0 - 1

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)
B. Barbini et al. rPsychiatry Research 79 1998 43]50
44
A major problem in the literature is the diag-
nostic heterogeneity of the samples treated with
TSD, due to the inclusion in the study groups of
patients
with
endogenous,
reactive,
unipolar,
bipolar, secondary and schizoaffective depression
Ž
.
Leibenluft and Wehr, 1992 . Depression can in-
deed be considered as a heterogeneous condition,
the different subtypes of which may be classiﬁed
Ž
by longitudinal course
e.g. Merikangas et al.,
.
1994 : sleep]wake rhythm manipulations could
exert different clinical effects depending on the
different mood disorder diagnoses of patients and
then on the possibly different biological subs-
trates of their clinically similar depressive syn-
dromes. As an example, sleep loss can effectively
Ž
trigger the onset of mania in bipolar patients e.g.
.
Wehr et al., 1987; Barbini et al., 1996 but has
little or no euphorogenic effects in other diagnos-
tic categories and in normal subjects, so that an
euphorogenic response to TSD has been success-
fully used as a diagnostic tool in uncertain cases
Ž
.
of mood disorder Strouse et al., 1992 . Moreover,
differences in response to TSD have been pro-
posed as a diagnostic tool in differentiating mood
disorders and dementia with depressive symptoms
Ž
.
e.g. Buysse et al., 1988; Williams et al., 1994 .
Diagnosis could then be considered a poor
predictor of the clinical effect of TSD in patients
affected by a major depressive episode, leading to
a relative uncertainty and to sometimes contrast-
Ž
ing reports in the literature
see review in Wu
.
and Bunney, 1990; Leibenluft and Wehr, 1992 .
The topic is controversial: in agreement with the
hypothesis, polarity of depression was found to
Ž
inﬂuence the response by some authors e.g. Kvist
.
and Kirkegaard, 1980; Szuba et al., 1991 , but not
Ž
by others e.g. Svendsen, 1976; Elsenga and Van
.
den Hoofdakker, 1987 ; however, the presence of
Ž
a variety of concomitant medications
including
antidepressants,
lithium,
carbamazepine,
neu-
.
roleptics and benzodiazepines hampers the eval-
uation of these reports. The aim of the present
study was to clarify this topic by evaluating the
clinical effect of TSD in diagnostic subgroups of
drug-free patients affected by a major depressive
Ž
episode i.e. bipolar disorder type I, bipolar dis-
order type II, major depressive disorder and sin-
.
gle-episode patients .
2. Methods
2.1. Subjects
Fifty-one inpatients affected by a major depres-
sive
episode,
according
to
DSM-IV
criteria
Ž
.
American Psychiatric Association, 1994 , were
studied. A written informed consent was obtained
after complete description of the study to the
subjects. Inclusion criteria were: absence of other
diagnoses on Axis I; absence of mental retarda-
tion on Axis II; absence of pregnancy, history of
epilepsy, and major medical and neurological dis-
orders; no treatment with lithium salts or long-
acting neuroleptic drugs in the last 6 months
before admission; no treatment with neuroleptics
or irreversible MAOIs in the last month before
admission; and absence of a history of drug or
alcohol dependency or abuse within the last 6
months. Previous antidepressant drug treatments
were stopped 1 week before admission. Physical
examinations, laboratory tests and electrocardio-
grams were performed at admission.
Patients were divided in four groups according
to their Axis I diagnosis and previous psychiatric
history: Group 1, patients affected by bipolar
Ž
.
disorder, type I
ns17 ; Group 2, patients af-
Ž
.
fected by bipolar disorder, type II ns8 ; Group
3, patients affected by major depressive disorder
with at least three previous episodes in their
clinical history and without a family history of
Ž
.
bipolar disorder in ﬁrst-degree relatives
ns17 ;
Group 4, patients affected by major depression,
Ž
.
single episode
ns9 . Restricted inclusion crite-
ria for Group 3 were chosen in order to enhance
the stability of unipolar diagnosis, since longitudi-
nal studies have shown that family history of
bipolar disorder and a low number of previous
depressive episodes are risk factors for the devel-
opment of manic episodes in previously unipolar
Ž
patients
see review in Goodwin and Jamison,
.
1990 . Patients underwent a 7-day run-in period,
during which semi-structured interviews based on
DSM-IV for Axis I diagnoses were completed.
Ž
The agreement of two independent raters chosen
.
among the authors of the study was required to
conﬁrm the diagnosis. Family history was evalu-
ated by interviewing all probands and at least two

(
)
B. Barbini et al. rPsychiatry Research 79 1998 43]50
45
Ž
ﬁrst-degree relatives
Andreasen et al., 1977;
.
Smeraldi et al., 1984 .
2.2. Treatment and data collection
After a 7-day placebo run-in period, all subjects
were administered three TSD cycles, composed of
a night of TSD followed by a recovery night. On
days 1, 3 and 5, patients were totally sleep-de-
prived and had to stay awake for 36 h, from 07.00
h until 19.00 h of the following day. They were
then allowed to sleep during the nights of days 2,
4 and 6. Compliance of the subjects with the TSD
procedure was ensured by the nursing staff. No
concurrent psychotropic medication was adminis-
tered.
Changes in mood over time were rated on the
mornings of days 1, 2 and 7 by trained psychia-
trists blind to the group assignment on a modiﬁed
version of the 21-item Hamilton Depression Rat-
Ž
.
ing Scale Hamilton, 1960 from which items that
could not be meaningfully rated due to the TSD
procedure and to the time frame were excluded
Ži.e. weight changes and insomnia: items a4]6
. Ž
.
and 16
HDRS-NOW; Leibenluft et al., 1993 .
Changes in perceived mood were rated on days
1]3 and 7 at 08.00 h on a self-administered
Ž
.
12.5-cm visual analogue scale, VAS Aitken, 1969 .
Patients
were instructed
to rate their mood
Ž
.
between ‘very sad’ on the left and ‘very happy’
Ž
.
on the right , with a median ‘normal’ point.
Patients could not see, when administered the
VAS, their previous self-ratings. Raw VAS data
Ž
were then converted to a 0]100 rating scale with
0, 50 and 100 denoting extreme depression, eu-
.
thymia and euphoria
and normalized with re-
spect to baseline values by expressing them as the
square root of the ratio between the score on
each day from day 2 to day 7 and the score at day
Ž
. Ž
.
1 baseline
Benedetti et al., 1996 .
2.3. Statistics
Clinical and demographic characteristics were
compared between the four groups with one-way
analysis of variance and chi-square tests. Levene’s
test of homogeneity of variances was performed
on HDRS-NOW scores at day 1. To assess the
clinical effects of treatment, a two-way repeated
measures analysis of variance with post-hoc New-
man]Keuls test was performed on ratings, with
time and diagnosis as independent factors and
Ž
current age and duration of illness
i.e. current
.
Ž
age minus age at onset as covariates Roy-Byrne
.
et al., 1984a . To determine if the response to
TSD discriminated diagnostic subgroups, a dis-
criminant function analysis was performed, with
diagnosis as the grouping variable and improve-
Ž
ment after TSD i.e. difference between HDRS-
.
NOW scores at day 1 and at day 7 as the inde-
pendent variable.
Computerized analyses were performed with a
commercially
available
statistical
package
Ž
.
Statistica, 1993 .
3. Results
Clinical and demographic characteristics of the
subjects are shown in Table 1. Groups differed
Ž
signiﬁcantly in age bipolar I and unipolar patients
were older than bipolar II and single episode
.
Ž
patients and duration of illness longer in bipolar
.
I than in bipolar II patients . No patient switched
polarity during the TSD treatment.
Homogeneity of variances before the TSD
treatment was successfully tested for HDRS-
Ž
.
NOW scores
Fs0.11, d.f.s3,47, Ps0.998 . A
two-way repeated measures analysis of covariance
Ž
.
on HDRS-NOW scores
see Table 2
showed a
Ž
highly signiﬁcant time effect
Fs68.16, d.f.s
.
2,94, P-0.0001 , a non-signiﬁcant group effect
Ž
.
Fs1.34, d.f.s3,45, Ps0.271 and a signiﬁcant
Ž
time=group interaction
Fs2.52, d.f.s6,94,
.
Ps0.0265 . This interaction was also signiﬁcant
with univariate test and Greenhouse]Geisser cor-
Ž
.
rection
es0.95, d.f.s5.70, 89.37, Ps0.0269 .
Covariates showed a marginal effect on HDRS
Ž
scores after the ﬁrst TSD
Fs2.87, d.f.s2,45,
.
Ps0.067 and no other relevant effect. Post-hoc
comparisons showed non-signiﬁcant differences
between groups at days 1 and 2; at day 7, Groups
1, 2 and 4 did not signiﬁcantly differ among
themselves, but all showed signiﬁcantly better
Ž
scores than Group 3
Ps0.026, Ps0.013 and
.
Ps0.007, respectively . All patients showed sig-
Ž
niﬁcantly better day-7 than day-1 scores Group

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)
B. Barbini et al. rPsychiatry Research 79 1998 43]50
46
Table 1
Clinical and demographic characteristics of the subjects
Group 1
Group 2
Group 3
Group 4
Analysis of variance
Ž
.
Ž
.
Ž
.
Ž
.
bipolar I
bipolar II
unipolar
single episode
F
d.f.
P
Ž
.
Ž
.
Ž
.
Ž
.
ns17
ns8
ns17
ns9
Sex distribution
6 m, 11 f
2 m, 6 f
5 m, 12 f
1 m, 8 f
}
a
Ž
.
Age years
47.29"11.30
37.38"10.63
50.06"10.13
34.11"10.02
5.91
3.47
0.00
Ž
.
Age of onset years
29.82"8.73
29.88"8.25
35.29"8.23
34.11"10.02
1.45
3.47
0.23
Ž
.
Duration of illness years
17.47"9.96
7.50"5.83
14.76"10.09
}
3.07
2.39
0.05
Number of previous depressive episodes
4.41"3.57
3.13"0.64
3.76"1.68
}
0.74
2.39
0.48
b
Number of previous manic episodes
3.00"3.79
1.63"1.19
}
}
0.98
1.23
0.33
Ž
.
Duration of current episode weeks
15.06"11.16
8.50"5.83
13.29"10.51
18.00"14.76
1.13
3.47
0.34
aNewman]Keuls post-hoc comparisons: Grp 1 vs. 2, Ps0.034; Grp 1 vs. 4, Ps0.013; Grp 2 vs. 3, Ps0.021; Grp 3 vs. 4, Ps0.004.
bNumber of previous hypomanic episodes.
Values are presented as mean"S.D.
Table 2
Changes in HDRS-NOW scores during treatment
Day 1
Day 2
Day 7
Ž
.
Ž
.
Ž
.
Baseline
After the ﬁrst TSD
Endpoint
Ž
.
Ž
.
Ž
.
Ž
.
Group 1 bipolar I
22.24"4.22 15
11.00"6.51 27
11.53"7.19 23
Ž
.
Ž .
Ž
.
Ž
.
Group 2 bipolar II
21.13"3.23 8
8.25"4.86 17
9.25"8.91 26
Ž
.
Ž
.
Ž
.
Ž
.
Group 3 unipolar
22.00"3.91 14
11.65"6.83 27
16.29"7.67 28
Ž
.
Ž
.
Ž
.
Ž
.
Group 4 single episode
21.22"4.18 13
13.78"7.18 22
8.89"8.75 21
Ž
.
Values are means"S.D. range .
1, Ps0.0001; Group 2, Ps0.0002; Group 3,
.
Ps0.0050; Group, 4 Ps0.0001 .
Normalized VAS scores are plotted in Fig. 1. A
two-way repeated measures analysis of variance
Ž
showed a highly signiﬁcant time effect
Fs6.86,
.
d.f.s3,138, Ps0.0002 , a non-signiﬁcant group
Ž
.
effect
Fs1.22, d.f.s3,46, Ps0.31 and a non-
Ž
signiﬁcant
time =group interaction
F s1.26,
.
d.f.s9,138, Ps0.26 . Inspection of Fig. 1 shows
Ž
that all subjects but unipolar depressives Group
.
3 exhibited a marked improvement in perceived
mood after the ﬁrst TSD, with a subsequent re-
lapse after the recovery night; Student‘s t-tests
conﬁrmed that Group 1 had signiﬁcantly better
Ž
.
t s 2.18,
d.f.s 31,
P s 0.037
and
Group
4
Ž
.
marginally better
ts1.96, d.f.s24, Ps0.062
scores than Group 3 at day 2.
Discriminant
function
analysis
showed that
Ž
HDRS-NOW rated mood improvement i.e. day-1
.
score minus day-7 score
signiﬁcantly discrimi-
Ž
nated between diagnostic subgroups
Wilks’ls
.
0.848, Fs2.81, d.f.s3,47, Ps0.049 . However,
when the above-described diagnostic classiﬁcation
was used in four groups, 65% of bipolar type I
Ž
.
Ž
.
Group 1 and 65% of unipolar Group 3 patients
were correctly classiﬁed, while none of the bipolar
Ž
.
Ž
.
type II
Group 2 and single episode Group 4
patients were assigned to the proper group; in
Ž
.
particular, six out of eight
75%
bipolar II
patients were assigned to the bipolar I group.
When bipolar types I and II patients were pooled
together in one group, the discriminant power
Ž
increased
Wilks’ls0.851, Fs4.21, d.f.s2,48,
.
Ps0.021 : 80% of bipolar and 53% of unipolar
patients were correctly classiﬁed; again, single-ep-
isode patients were assigned either to the bipolar
Ž
.
Ž
.
7r9 or to the unipolar 2r9 group.
4. Discussion
Our study showed that in patients affected by a
major depressive episode TSD caused different

(
)
B. Barbini et al. rPsychiatry Research 79 1998 43]50
47
Fig. 1. Mean transformed VAS scores in the four groups. TSD, total sleep deprivation; R, recovery night.
clinical effects depending on mood disorder diag-
noses. After TSD, mood levels improved in all
diagnostic subgroups, but Hamilton ratings of
unipolar patients were signiﬁcantly worse than
those
of
bipolar
I,
bipolar
II
and
single-
episode
patients.
The
signiﬁcance
of
the
unipolarrbipolar dichotomy in respect to TSD
effects was conﬁrmed by discriminant function
analysis which, based on the clinical response to
sleep deprivation, failed to separate bipolar I and
II patients while it signiﬁcantly discriminated
between
bipolar
and
unipolar
patients.
All
patients showed signiﬁcantly higher mood levels
after the three TSD cycles than at baseline; this
ﬁnding disagrees with patterns of decreasing re-
sponses to TSD following repeated TSD treat-
Ž
ments reported by some authors e.g. Roy-Byrne
.
Ž
et al., 1984b , but not by others e.g. Benedetti et
.
al., 1996 .
The present data conﬁrm previous reports of a
better effect of TSD in bipolar than in unipolar
Ž
.
depression e.g. Szuba et al., 1991 , but also sug-
gest a difference in patterns of perceived mood
changes after TSD in the two diagnostic sub-
Ž
.
groups Fig. 1 . Some speculations on the possible
biological substrates of these differences are pos-
sible, though no deﬁnite conclusions on this sub-
ject can yet be drawn from our data or from the
literature.
Ž
.
Wehr et al.
1987
hypothesized that abrupt
changes in the sleep]wake rhythm can trigger
manic or hypomanic phases in bipolar patients
through a self-reinforcing mechanism of sleep
loss and progressive mood improvement; prelimi-
nary ﬁndings on the patterns of sleep and wake
during the onset of mania are in agreement with
Ž
this
hypothesis
Wehr,
1989;
Wright,
1993;
.
Nowlin-Finch et al., 1994; Barbini et al., 1996 .
This phenomenon is by deﬁnition absent
in
unipolar subjects, thus suggesting the presence of
different biological substrates in the two diagnos-
tic groups. In bipolar patients TSD seems to exert
its effect by acting on the same mechanisms which
Ž
can cause the switch into a manic phase
e.g.
.
Wehr, 1992 : the susceptibility to develop mania
could involve a different sensitivity to the neu-
rochemical changes induced by sleep deprivation
Že.g. Gerner et al., 1979; Ebert et al., 1994; Salo-
.
mon et al., 1994; Asikainen et al., 1995 , or sleep
deprivation could cause different neurobiological
effects in bipolar and unipolar patients. More-
over, since we did not measure sleep during the
recovery nights, we cannot exclude the possibility
that differences among diagnostic groups in timing

(
)
B. Barbini et al. rPsychiatry Research 79 1998 43]50
48
and architecture of sleep during the recovery
Ž
nights could have inﬂuenced the results
e.g.
.
Berger et al., 1997 .
The
attempt
to
discriminate
unipolar
and
bipolar patients on the basis of biological vari-
ables has not yet proved successful. In agreement
Ž
.
with the permissive hypothesis of serotonin 5-HT
dysfunction, platelet 5-HT uptake was found to
Ž
be lower in bipolar than in unipolar patients see
.
review in Goodwin and Jamison, 1990 . A recent
review of the available data, however, pointed out
that none of the variables examined appeared to
Ž
differentiate the two groups consistently Yatham
.
et al., 1997 . Moreover, the occurrence of mania,
which discriminates the two diagnostic groups,
seems to be related to alterations in dopaminer-
Ž
gic function
e.g. Post et al., 1980; Bunney and
.
Garland, 1982 , with CSF homovanillic levels rais-
Ž
ing before the switch into a manic phase Wehr
.
and Goodwin, 1981 and urinary dopamine levels
Ž
.
predicting manic mood Joyce et al., 1995 .
Interestingly, current hypotheses on the neu-
rochemical mechanisms of action of TSD focus
on the same neurotransmitters considered for a
biological differentiation of unipolar and bipolar
illness. Several ﬁndings suggested an involvement
of the brain dopaminergic system: lower levels of
homovanillic acid in the spinal ﬂuid before TSD
were associated with better clinical effects of TSD
Ž
.
Gerner et al., 1979 ; plasma levels of prolactin,
Ž
.
which is inhibited by dopamine
DA
agonists,
Ž
were reported to decrease after TSD Kasper et
.
al., 1988; Baumgartner et al., 1990 with a differ-
ent prolactin response to sulpiride in TSD re-
Ž
.
sponders and non-responders Ebert et al., 1993 ;
single photon emission computed tomography be-
fore and after TSD showed a signiﬁcantly differ-
ent D
receptor occupancy in responders and
2
non-responders, thus suggesting an enhanced do-
Ž
.
pamine release in responders Ebert et al., 1994 ;
and animal research suggested a major role for
enhanced DA activity in the behavioral effects of
Ž
sleep deprivation Zwicker and Calil, 1986; Gessa
.
et al., 1995 . The involvement of the 5-HT system
is suggested by preclinical research: sleep depri-
vation induces an increase in the electrophysio-
logical activity of brain 5-HT neurons in cats
Ž
.
Gardner et al., 1997 ; an increase in brain 5-HT
Ž
turnover in rats and hamsters Hery et al., 1970;
.
Cramer et al., 1973; Asikainen et al., 1995 with
an increase in behavioral responsiveness to 5-HT
Ž
.
precursors
Santos and Carlini, 1983 ; and an
enhanced prolactin response to tryptophan in hu-
Ž
.
man females Salomon et al., 1994 .
To clarify the topic with sounder evidence,
however, further research is needed to try to link
the different effects of TSD on mood of bipolar
and unipolar patients with different changes in
biological parameters. It should be noted that a
more precise deﬁnition of this subject could be
very useful in choosing the appropriate pharma-
cological strategy to sustain the transient effects
of TSD.
Whatever the answer to these issues, we can
say with conﬁdence that further research on the
clinical effects of TSD cannot ignore the possibil-
ity of a differential effect in unipolar and bipolar
depressed patients. It is arguable that differences
in response due to this diagnostic heterogeneity
could be responsible for the sometimes conﬂict-
Ž
.
ing literature data Leibenluft and Wehr, 1992 .
Finally, discriminant function analysis failed to
recognize single-episode patients as a distinct cat-
egory but, based on the response to TSD, as-
signed them either to the bipolar or to the
unipolar group. Longitudinal naturalistic studies
show that at least 50% of patients affected by an
initial major depressive episode will have one or
more further mood disorder episodes during their
Ž
.
lifespan e.g. NIMH-NIH, 1985; Angst, 1992 and
that a not negligible percentage of patients with a
diagnosis of unipolar depression will develop
Ž
manic or hypomanic episodes
Akiskal et al.,
.
1995 . TSD has been proposed as a diagnostic
Ž
tool to classify uncertain clinical cases e.g. Buysse
et al., 1988; Strouse et al., 1992; Leibenluft and
.
Wehr, 1992; Williams et al., 1994 : the presence
of a ‘bipolar-like’ or a ‘unipolar-like’ response to
TSD could be useful in predicting the further
evolution of single-episode patients. The follow-up
data of our sample and further studies using
discriminant function analysis to classify indepen-
dent and larger samples will help to clarify this
point.

(
)
B. Barbini et al. rPsychiatry Research 79 1998 43]50
49
Acknowledgements
We thank Mrs P. Erba and the nursing staff of
our psychiatric ward for their valuable assistance
in the sleep deprivation procedure.
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Cover Sheet for “Are Bright Lights and Regulated Sleep Times Effective Treatment for 
Depression?” (IRB #7361)  
Overview: This outline is a guide for you to use while considering whether to participate in 
this research study. The consent that follows includes much more information about the 
study and its risks, which you will need to make a decision. Please read this outline and the 
consent carefully, and only sign it if you are comfortable doing so.  
● You are being asked to participate in a research treatment study because you are 
depressed.                                                                                                                               
● Your treatment will involve keeping specified sleep times and sitting in front of 
bright lights wearing tinted or untinted goggles..  
Type of treatment: The treatment portion of this study will last up 6 weeks followed by six 
month during which helpful treatment can be continued or other treatment can be tried. Prior 
to treatment, blood and urine tests as well as a heart test and physical examination will 
determine whether you are healthy and not pregnant (if you are a fertile female).  
Treatment will be with bright lights and specific changes to your sleep, partially 
determined by how you answer questions about when you do or like to do things and 
partially by when you would like to be asleep.  The specific timing and manipulation 
of allowed sleep, bright lights and use of goggles will be randomly (like flipping a 
coin) determined.  In order to manipulate your sleep, varying amounts of time 
remaining awake between allowed sleep will be required, for some patients required 
wake time might reach as long as 42 hours on a single occasion. During the first week 
you will complete rating forms and speak with a study doctor by telephone daily and 
then weekly for the remainder of 6 weeks. Thereafter, your study doctor will continue to 
treat you for an additional six months during which there will be monthly determinations of 
how you are doing.  During this time, while your study doctor will manage your treatment, 
you or your insurance will pay for any medicine or other treatment such as a light box.  After 
this six months, if psychiatric treatment is still needed, your doctor will help you find further 
treatment.  
Alternatives to participation: You do not have to participate in this research study to receive 
treatment for depression. If you decide not to participate, the doctor who evaluated you will 
help you find an alternative.  
Risks: There are risks and discomforts associated with participating in this study (please 
read the “Risks” section of the detailed consent for a complete listing and explanation of 
risks). These include:                                                                                                               
● Your depression may not improve                                                                                                    
● Bright light can over-stimulate some people and can cause patients with bipolar disorder 
to switch from being depressed to being “high” (that is, hypomanic or manic)                        
● Missing sleep can also over-stimulate and induce switching to a “high” mood                             
Compensation: None                                                                                                  
Voluntary Participation: Participation in this study is entirely voluntary. You do not have to 
participate if you do not want to and can stop participating at any time. 

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
Klaus Martiny1*, Else Refsgaard2, Vibeke Lund2, Marianne Lunde2, Lene Sørensen2, Britta Thougaard3,
Lone Lindberg2, Per Bech2
1 Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, 2 Psychiatric Research Unit, Mental Health Centre North
Zealand, Copenhagen University Hospital, Copenhagen, Denmark, 3 Child and Adolescent Psychiatric Centre, Bispebjerg, Copenhagen University Hospital, Copenhagen,
Denmark
Abstract
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
Citation: Martiny K, Refsgaard E, Lund V, Lunde M, Sørensen L, et al. (2013) 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. PLoS ONE 8(6): e67264. doi:10.1371/journal.pone.0067264
Editor: Marianna Mazza, Catholic University of Sacred Heart of Rome, Italy
Received December 26, 2012; Accepted May 14, 2013; Published June 28, 2013
Copyright:  2013 Martiny et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors acknowledge financial support and the receipt of duloxetine from Eli Lilly, Copenhagen Denmark (https://www.eli-lilly.dk/); The Danish
Agency for Science, Technology and Innovation, Denmark (http://www.fi.dk/); The Danish Medical Research Council, Eastern Region Research Foundation (no
website); The Olga Bryde Nielsen Foundation, Denmark (http://www.hillerodhospital.dk); and The Frederiksborg General Hospital Research Grant, Denmark
(http://www.hillerodhospital.dk/topmenu/Kontakt/). AstraZeneca, Copenhagen, Denmark provided funding for a travel grant (http://www.astrazeneca.dk/home/).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: We have the following interests: This study received financial support and duloxetine from Eli Lilly, Copenhagen Denmark (https://www.
eli-lilly.dk/), and AstraZeneca, Copenhagen, Denmark provided funding for a travel grant. Duloxetine is manufactured and marketed by Eli Lilly. Klaus Martiny has
had part of his salary for working with the study paid by funding from Eli Lilly, Denmark and has occasionally served as a speaker for pharmaceutical companies
with an interest in the drug treatment of affective disorders (Servier and Eli Lilly). Else Refsgaard has had part of her salary for working with the study paid by
funding from Eli Lilly Denmark. Per Bech, until August 2008, occasionally received funding from and was a speaker or member of advisory boards for
pharmaceutical companies with an interest in the drug treatment of affective disorders (Astra-Zeneca, Lilly, H Lundbeck A/S, and Organon). There are no further
patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and
materials, as detailed online in the guide for authors.
* E-mail: klaus.martiny@regionh.dk
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Introduction
The objective of this study was to investigate if a chronother-
apeutic intervention combining sleep deprivation (wake therapy)
with light therapy and sleep time stabilisation could induce a rapid
and augmented antidepressant response and remission in patients
with major depression. The medium-term effect over a nine week
period has been published elsewhere [1], whereby the wake
therapy group manifested a sustained better response and
remission than the exercise group. The present paper reports
data from the one-week study period where patients were
randomised to either wake therapy or exercise in an inpatient
setting. In this study period patients had daily ratings of depression
severity and did self-evaluation of sleep in order to reflect a timely
assessment of any mood fluctuation and sleep changes. This was
important as wake therapy is known to induce mood swings and
alterations in sleep quality, length and phase.
Systematic clinical investigation has been performed on various
aspects of the acute response to wake therapy for more than 40
years, and a large evidence base confirms the rapid antidepressant
effect [2], [3], [4], [5]. The term wake therapy is used synonymous
to sleep deprivation but has a more positive image for the patient.
Deterioration or relapse after the first nights sleep after wake
therapy (termed ‘‘recovery sleep’’) has been and still is a problem,
and several new methods have been tested, mainly in bipolar
depressed patients. These include the use of wake therapy in
combination with: bright light therapy [6], bright light therapy
and sleep phase advance [7], bright light therapy and lithium [8],
pindolol [9], bright light therapy and transcranial magnetic
stimulation [10]. A manual [11] and an instruction chapter [12]
assist clinicians in the practical details of chronotherapy with an
emphasis on preventing relapse. The prevention of deterioration
or relapse during a course of wake therapy is important with
respect to its applicability, safety and acceptance. A fast response
to an antidepressant intervention is very desirable but a steep
relapse is equally undesirable. What we want from antidepressant
therapy is a rapid and stable improvement.
The effect of wake therapy is linked to the phenomenon of
diurnal variation [13], [14]. Slight alterations of sleep timing can
cause dramatically changes in mood and at the extreme end of this
is the positive response to an entire night of sleep deprivation. As
the antidepressant improvement gained over night has been
known to be unstable, the present protocol aimed at inducing day-
to-day stability through the use of sleep time stabilisation and light
therapy. Our earlier report of the results showed that this was
attained as we found a smaller day-to-day variation of sleep
parameters [1]. Napping is know from the literature to be
depressiogenic after wake therapy [15] and was thus advised
against.
This paper thus focuses on the acute effect of the interventions
used in the one-week intervention phase as assessed throughout the
intervention days on the inpatient ward, and on testing potential
predictors of wake therapy response.
As the acute changes during or after wake therapy is very
important for safety and tolerance we designed the intervention phase
so as to be able to detect rapid changes in depression severity.
Thus the first objective regarding the intervention phase was:
N To investigate whether the combination of wake therapy, light
therapy and sleep time stabilisation can prevent any deterio-
ration between wake nights and/or after the end of the series of
3x wake therapy.
As some discrepancy exists regarding the impact of diurnal
variation on the effect of wake therapy response, patient self-
assessed their mood over the course of the day for 6 days prior to
the intervention week. Thus we were able to test our second
objective:
N To investigate if the acute effect of wake therapy was
influenced by the presence of diurnal variation of mood as
assessed prior to the intervention?
As the literature shows that napping after sleep deprivation is
depressiogenic we sampled information regarding napping during
the intervention days to test our third objective:
N To investigate to what extent daytime napping in the intervention
phase caused deterioration of any achieved improvement?
Methods
General
The protocol for this trial and supporting CONSORT checklist
are available as supporting information; see Checklist S1 and
Protocol S1.
Methods have been described in detail in [1] which presented
the medium-term results from weekly visits from a 9-weeks study
period. Patients diagnosed with major depression were rando-
mised in a ratio of 1:1 into two parallel groups: the wake group or
the exercise group. Inclusion criteria were: age above 18, major
depressive episode, patients with bipolar disorder to be in mood
stabilising treatment for at least one month in a recommended
dosage and a HAM-D17 score $13. Exclusion criteria were:
psychotic disorder, organic brain disorder, mental retardation,
alcohol or drug abuse, pregnancy or insufficient contraception,
light-induced migraine or epilepsy, retinal blindness or severe
cataract, glaucoma, retinal diseases, antipsychotic drugs treatment,
marked suicidal ideation, and severe agitation.
The study started with a one-week run-in phase where medication
with duloxetine was begun and diurnal variation assessed.
Then followed a one-week intervention phase where all patients
were admitted to an in-patient ward on a Monday (day1). Patients
randomised to the wake group carried out (A) three wake therapies
alternating with recovery sleep nights, (B) daily morning bright
light therapy and (C) sleep timing control. Patients randomised to
the exercise group were also admitted on a Monday (day1) and
started a daily exercise program instructed by physiotherapists.
Patients were all discharged on the following Saturday (day6) when
patients in the wake group had carried out all 3 wake therapies.
During each of the five days of the inpatient stay we assessed
patients at the ward in the morning. After discharge patients were
seen at the psychiatric research unit on the following Monday
(day8).
This was followed by a 7-week continuation phase where patient in
the wake group continued with sleep time stabilisation, daily
morning light therapy and duloxetine 60 mg daily dosage and
patients in the exercise group continued with an individual exercise
program of at least 30 minutes duration and duloxetine in a daily
dosage of 60 mg. In this paper we report data from the one-week
intervention phase.
The individual study days in the intervention phase and their
relation to study procedures are named as shown in Figure 1:
Monday is day1, Tuesday is day2, Wednesday is day3, Thursday is
day4, Friday is day5, Saturday is day6, Sunday is day7, and the next
day, Monday, is day8.
The intervention phase has, for the purpose of data analyses,
been subdivided into a admittance period signifying the period from
being admitted to the in-patients ward on a Monday (day1) and till
Acute Effect of Wake Therapy
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being discharged on a Saturday (day6), and a discharge period
signifying the period from discharge on a Saturday (day6) till
assessments at the psychiatric research unit on the following
Monday (day8).
Wake Therapy
Wake therapies were scheduled for Mondays (day1), Wednes-
days (day3) and Fridays (day5). Patients were instructed to stay up
the entire wake nights and were encouraged not to sleep on the
following day until 8 pm. Patients were allowed to walk freely in
and outside the ward, take baths, talk to the staff, watch television,
cook meals, listen to music, read, use the computer, and drink
coffee etc. The ward staff was instructed to encourage patients to
stay awake but without putting any pressure onto them. On
Tuesday, Thursday and Saturday nights (recovery sleep I, II and
III), patients were scheduled to go to sleep no later than 8 pm and
to wake up no later than 8 am. This was used as a precaution,
because oversleeping in the morning on recovery nights is known,
from the literature, to worsen mood [16]. This adjustment to early
sleep was intended to act like a milder version of a sleep phase
advance, as this has been shown to facilitate antidepressant
response [17].
Light Therapy
Daily light therapy was administered daily for 30 minutes while
on the in-patient ward; using a light box (SMIFA Biolamp, giving
10.000 lux white light at 40 cm distance from the screen).
Individual timing was scheduled from an algorithm based on the
patient’s score on the Morningness-Eveningness Questionaire
(MEQ) [18] (but limited to 7 AM in the morning as the earliest).
At 4 AM patients were administered 30 minutes of light to
alleviate tiredness. Oral and written information on the light
therapy procedure was given.
Sleep Time Stabilisation
Guidance for sleep time stabilisation was based on daily entries
in the sleep logs of sleep onset, sleep offset, subjective sleep quality
(range 0 to 10 and 10 = best) and daytime naps and entries were
used at daily and weekly visits to guide patients to keep a stable
sleep-wake cycle. Patients who needed to take naps were instructed
to schedule these at around 4 pm and not to exceed 30 minutes.
Exercise
A daily exercise programme was started on admittance to the
inpatient ward. Each participant planned a daily exercise program
of minimum 30 minutes duration with the physiotherapist.
Patients filled in daily logs with name of activity, perceived
exertion [19] and duration of exercise. Patients in this group
followed the ordinary bedtime and sleep length regime in the open
ward. At the hospital, exercise was taken between 9 am and 4 pm.
Medication
Patient received a fixed daily dosage of 60 mg duloxetine in the
morning, begun at the run-in phase, a week prior to admittance to
the in-patient ward.
Structure of Reporting
Reporting followed the Consort guideline (Figure 2) [20].
Figure 1. Consort diagram of subject flow.
doi:10.1371/journal.pone.0067264.g001
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Approval, Monitoring and Ethics
Approvals were given by the committee on Biomedical
Research Ethics, the Danish Medicines Agency and the Danish
Central Data Register. Monitoring was done by the national GCP
unit in Copenhagen. The study was carried out according to the
declaration of Helsinki and the ICH-GCP guidelines [21].Written
study information and oral description of the study were given to
the patients before written informed consent was obtained.
Recruitment
Patients were recruited from general practitioners and psychi-
atrists, open wards at the local mental health centre and a few
patients through advertisements.
Random Allocation Sequence
A randomisation list was made by an external statistician who
by computer generated a random list with a block size of four
(block size was blinded). A GCP qualified research coordinator
labelled envelopes with consecutive numbers and inserted group
specific instruction letters according to the randomization list (kept
locked up). The envelope was handed over to the patient after
signing the informed consent form.
Blinding
Blinding of assessors at the daily assessments on the ward was
not possible, as patients in the wake group would show signs of not
having slept during wake nights. Assessments on the ward were
Figure 2. Flow chart and description of study procedures in the intervention phase.
doi:10.1371/journal.pone.0067264.g002
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thus done by other raters than assessments at weekly visits that
were done by Hamilton raters blinded to treatment assignment.
Sample Size
Sample size for the whole 9-week study was calculated from an
expected reduction in HAM-D17 scores of 14 points from 24 to10
points (wake group) and of 11 points from 24 to 13 points (exercise
group), and with a standard deviation of 6 points, a power of 80%
to detect a significant difference (p = 0.05, two sided), in all 64
patients were needed in each group. This corresponds to an effect
size of 0.50 (difference between groups/pooled standard devia-
tion). As the expected difference between groups was hypothesized
to emerge immediately when the wake and light therapy was given
in the intervention phase, the sample size calculation from the main
study also applied to this paper.
Interim Analysis
No interim analyses were planned or performed.
Stopping Rules
Criteria for discontinuation of study treatment was: a wish to
discontinue treatment, intolerable or clinically significant side
effects, a score of 15 or more on the Mania Scale (MAS),
continued clinical worsening of depression, change of mood
stabilizer in bipolar patients, and non-compliance with elements of
the study.
Study Registration
Study
is
registered
at
ClinicalTrials.gov
with
identifier
NCT00149110.
Outcomes
Outcome measures are described in detail in [1]. To assess
depression severity we used the clinician-reported Hamilton
depression rating scale 17 items version (HAM-D17). In the
present analysis, focusing on the intervention phase, we have used the
HAM-D6 [22], [23], [24], [25] subscale. This is a validated and
unidimensional depression scale without any sleep items. Sleep
items would be inaccessible in a wake therapy trial. The HAM-D6
contains six core items of depression from the HAM-D17, namely
depressed mood, guilt feelings, work and interests, psychomotor
retardation, psychic anxiety, and somatic general (tiredness and
pain). The total score of the HAM-D6 can theoretically go from 0
(not depressed) to 22 (extremely depressed): a score of 12 equal
severe depression, a score of 9 equals moderate depression.
Remission on the HAM-D6 was defined as a score of 4 or less [26],
response was defined as a reduction of 50% or more from baseline
(day1) [27]. Deterioration rates were defined as scores equal to or
above score values at day1. Deterioration was used as a measure of
instability of depression severity. This HAM-D6 subscale does not
include sleep items, making it appropriate for assessing depression
severity over a course of wake therapies. The HAM-D6 interviews
were performed at the ward in the morning on day1 till day5 and at
the research unit on day8. The self-assessment scales (Preskorn and
sleep logs) were administered on all days in the intervention phase.
The Preskorn scale, constructed as a VAS scoring from 0 (no
depression) to 10 (worst depression ever), was used to self-monitor
mood changes during the day at the run-in phase and from day to
day in the intervention phase. The Bech-Rafaelsen Mania scale (MAS)
[22] was used to monitor any emergence of manic symptoms and
was used on the same days as the HAM-D6.
Patients in the wake group filled in daily light therapy logs, daily
sleep logs with sleep onset, sleep offset, and self-perceived quality
of sleep [28], and the Stanford Sleepiness Scale [29], [30] for every
hour of the wake nights.
Hospital staff filled in semi-qualitative evaluations of treatment
elements during the intervention phase and patients did a similar
evaluation at the following post intervention visit (day8).
During the run-in phase, patient self-assessed their mood on the
Preskorn scale shortly after wake-up, then at 9 am, noon, 3 pm,
6 pm, 9 pm, and just before lights out - over a period of six days.
The rating window (time frame covered by the scale) [26] is for
the HAM-D6 traditionally the past three days and this was used for
assessment on day1 and day8. On day2 till day5 the window for the
HAM-D6 was limited to the past hour to improve sensitivity to
changes in depression severity. The Preskorn scale was self-
assessed at noon on all study days in the intervention phase (to
minimize influence from diurnal variation).
Hamilton assessors were not blinded to patient’s treatment
allocation. Assessors were certified for good inter-rater and test-
retest reliability.
In the intervention phase we expected a rapid reduction in
depression severity in the wake group and a more gradual
reduction on the exercise group. The day-to-day variation in
depression severity was unknown but thought to be of interest, as a
large variation would be considered a substantial burden and
hazard to patients.
The Morningness-Eveningness Questionaire (MEQ) was used to
time light therapy according to individual patient chronotype [31].
In this paper we used it to examine any relation with depression
outcome.
Patients were asked, at the beginning of the run-in phase, if in
their present depressive episode retrospectively they had experi-
enced a significant drop in mood after daytime naps, in order to
investigate this as a predictor for effect of wake therapy.
Data Analysis
All patients with data from any days of the intervention phase were
included in analyses. Available data from HAM-D6 and Preskorn
scales were computed within a Mixed Model Repeated Measures
analysis [32]. This included for continuous endpoints (depression
scores) a Random-effects Regression Model (RRM) and for
dichotomous
endpoint
(response,
remission, deterioration) a
Generalized Estimation Equation model (GEE). Thus, for RRM,
the model included depression score as output variable and
baseline, day, treatment group, the interaction between day and
treatment group as covariates. For GEE, the model included
response, remission or deterioration fractions as output variables
and baseline, day and treatment group as covariates. For tables
and graphs estimated scores are presented. Baseline values (day1)
are used to calculate estimated scores at subsequent days. Baseline
values are mean scores from all patients, and are thus presented in
tables as a single value for both groups. The model gives p-values
for the whole of the intervention phase and post-hoc p-values for each
day.
In this paper we have used day1 of the intervention phase as
baseline for analysis of days of the intervention phase (day1 till 5). The
presented results from day8 were calculated with week0 (see
Figure 1) as baseline with the model specified in [1] because
day8 is not part of the intervention phase.
To facilitate comparisons with other studies the unbiased effect
size (Cohen’s) was calculated as described by Hegdes and Olkin
[33]. For the Cohen effect size we used the method of last
observation carried forward (LOCF) whereas in the RRM and
GEE available data were used.
Analyses of diurnal variation of mood, based on Preskorn data
from 7 times a day each day for 6 days self- assessed in the run-in
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phase, have been analysed in a similar mixed model with Preskorn
scores as outcome variable and patient and interaction of patient
with time as covariates. The resultant parameter estimate for time
is used to represent the degree of diurnal variation and is in turn
used in a RRM model as a covariate to analyse the influence of
diurnal variation on depression scores. A positive diurnal variation
of mood (with mood better in the evening) is defined as a time
parameter estimate of less than zero (score reduction on the
Preskorn scale = improvement) and a negative diurnal variation of
mood (with mood worse in the evening) is defined as a parameter
estimate of time greater than zero (score increase on the Preskorn
scale = deterioration) both on the Preskorn scale. The MEQ sum
score was entered as a covariate to examine its influence on
depression outcome. Sleep parameters were analysed in a general
linear model (GLM) with values at day1 as baseline covariates
except for the effect of sleep quality and napping that was analysed
in a RRM model.
For the analyses of the impact of diurnal variation and naps on
HAM-D6 scores at day8 we included a separate covariate for day8
as available data showed a non-linear deviation from other
intervention days.
Primary outcome was remission rates at day5 based on the
HAM-D6 and outcomes for the other days are considered post-
hoc. Secondary outcomes were response rates, deterioration rates
and mean scores on the MAS, Preskorn and sleep parameters.
Analyses were performed by SAS 9.2 software. All time points
are shown in the format of hour: minutes. Brackets after numbers
are standard deviations unless otherwise stated. The level of
statistical significance was set at a 5% level, two-sided.
Results
General
Patients were included from September 2005 to August 2008,
last patient last visit March 2009. In all, 100 patients were
screened and 75 patients were included in the study with 37
patients randomised to the wake group and 38 patients to the
exercise group. Inclusion was stopped at 75 patients due to time
constraints and funding limits. In the wake group one patient was
kept waiting for the intervention, due to a nurse’s strike, and was in
remission when the strike ended, and was thus discontinued and is
not included in analysis. One patient in the wake group decided at
visit two, before being admitted to the inpatient ward, not to go
through with the wake therapies and was discontinued from the
study but is included in analyses. One patient in the wake group did
not fill in sleep logs and left the inpatient ward after one wake
therapy due to perceived uneasiness on the ward but is included in
the analyses. Thus 36 of the patients allocated to the wake group
and all 38 patients allocated to the exercise group were included in
the data analyses. In the wake therapy group only 34 patients had
available sleep data. Due to logistic reasons the number of patients
assessed with the HAM-D6 in the exercise group was fewer on
days 4 and 5. Numbers are given in tables. No patients
discontinued in the exercise group. The number of performed sleep
deprivations in the intervention phase was 35 for wake I, 34 for wake
II and 28 for wake III. Thus overall 97 wake therapy nights were
carried out in the intervention phase. Patient performed exercise with
a mean duration of 51.2 (SD = 45.0) minutes/day. The mean Borg
scale score was 13.1 (SD = 6.1) corresponding to moderate
exertion.
Deterioration and Depression Outcome
The fraction of patients having a deterioration defined as a
HAM-D6 scale score above the entry level of 12 points, at any of
the assessed days, was very low and below 4.2% in the exercise
group and 1.8% in the wake group. The difference in deterioration
between groups was statistically non-significant for the whole
period.
Table 1 shows estimated post day1 remission and response rates
for assessed intervention days. Clinically relevant and statistically
significant larger response and remission rates were seen in the
wake compared to the exercise group from day2 and reaching a
maximum at day5 with response rates in the wake/exercise groups
of 75.0%/25.1% and remission rates of 56.8%/6.0%. The
difference between groups was statistically significant (response:
Odds ratio 9.0; CL 3.7–21.8, p,.0001 and, remission: Odds ratio
20.8; CL 5.6–77.1, p,.0001) and post hoc for each assessed day
(see Table 1).
The response rates at day8 ( = week2), as analysed on the 9-
weeks dataset was reduced to 41.9%/10.1% in the wake/exercise
groups and remission rates were reduced to 19.4%/4.7%.The
difference between groups at day8 was statistically significant
response: Odds ratio 6.4; CL 2.3–17.4, p = .0002 and, remission:
Odds ratio 4.9; CL 1.4–17.0, p = .01).
Table 2 shows estimated post day1 HAM-D6 scores for assessed
intervention days. A significant and clinically larger reduction in
scores was seen in the wake group compared to the exercise group
from day2 (the day after the first wake therapy night) with a score
difference of 2.5 (SE 0.7), (95% CL, 1.1–3.9, p = .0007) and the
score differences increased on the following days to a maximum of
4.6 (SE 0.6) on day5 (95% CL, 3.4–5.9,p,.0001) solely due to a
further reduction in scores in the wake group, whereas the scores in
the exercise group were unchanged. The scores at day5 were 4.1 (SE
0.4) in the wake group and 8.7 (SE 0.5) in the exercise group. The
difference in HAM-D6 scores between groups was significant for
the interaction between groups and days (F181 = 8.8, p = .004) and
post hoc for each assessed day. The post hoc scores, estimated
from the nine weeks dataset, at day8 were 7.5 (SE 0.5) in the wake
group and 9.7 (SE 0.4) in the exercise group (F529 = 3.4,
p,0.0007), (see Table S2). The difference between groups had
an effect size (Cohen’s) of 1.43 (CL 0.92–1.94) at day5 and 0.53
(CL 0.06–0.99) at day8.
Table 3 shows estimated baseline-adjusted Preskorn scale
scores. A better outcome was seen in the wake group compared
to the exercise group from day1 through till day8 and in contrast to
results from the HAM-D6 scale, no tapering of the difference
between groups or deterioration from day5 till day8 was seen. The
difference between scores in the groups was significant for the
whole period (F69 = 11.5, p = .001) and post hoc for all days.
MAS scale scores (excluding item five, sleep) showed that no
patient reached any level of mania. The maximum score was
below 5 (below cut-off for mild mania).
Significantly more of those patient that had obtained response
at day two were also in response at day eight compared to patients
non-responding at day two (Fisher’s Exact test; p = 0.05). The
positive predictive value (the probability that patients responding
after the first wake therapy maintained the response at day eight)
was 56.3% and the negative predictive value (the probability that
patients not responding after the first wake therapy did also not
respond at day eight) was 75.0%.
Diurnal Variation, Mood and Chronotype
Data on diurnal variation of mood, as assessed by the Preskorn
scale, was present for 72 patients from the run-in week (reduced
scores indicates improvement in the Preskorn scale). A statistically
significant variation of mood was found for time of day (F344 = 4.9,
p,.0001) with no significant differences between treatment
groups. The diurnal variation (mean of 6 days) ranged from a
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maximum score increase of 3.8 points (worsening during the day)
to a maximum score reduction of 3.6 (improvement during the
day). When dividing into positive or negative diurnal variation we
found that positive diurnal variation (morning worst) was present
in 58.3% of patient and negative diurnal variation (evening worst)
scores was present in 41.7% of patients.
We analysed whether diurnal variation of mood at the run-in
phase was predictive of the HAM-D6 depression scores during the
intervention phase and found that the degree of diurnal variation
had a significantly differential impact on scores in the two groups
(F63 = 14.2, p = 0.0004 for the interaction).
We then examined the magnitude of impact of diurnal variation
of mood separately for the two groups, by using the 1. Quartile
(positive diurnal variation), the median, and the 3. Quartile
(negative diurnal variation) values of the diurnal parameter
estimate
range
(Q1 = –0.1976,
median = 0.0363,
and
Q3 = 0.1001) as covariates in the model with day1 as baseline. At
day5 patients in the wake group with positive diurnal variation (Q1)
had an estimated HAM-D6 score of 3.5 (SE 0.5), patients with a
Table 1. Estimated Post-Day1 mean Response and Remission rates based on HAM-D6 scores for Each Treatment Group by day.
Response Per cent (n)
Wake %
Exercise %
Odds Ratio
95% CL
P Value
(n)
(n)
Day1(baseline)
0 (0/36)
0 (0/38)
1
-
-
Day2 (after wake I)
58.7 (16/31)
13.7 (8/35)
Day3 (after recovery sleep I)
64.6 (23/35)
16.9 (3/34)
9.0*
3.7–21.8
,.0001
Day4 (after wake II)
70.1 (21/31)
20.7 (6/26)
Day5 (after recovery sleep II)
75.0 (24/30)
25.1 (4/22)
Remission Per cent (n)
Wake %
Exercise %
Odds Ratio
95% CL
P Value
(n)
(n)
Day1 (baseline)
0 (0/36)
0 (0/38)
1
-
-
Day2 (after wake I)
38.6 (11/31)
2.9 (1/35)
Day3 (after recovery sleep I)
44.6 (18/35)
3.7 (2/34)
20.8*
5.6–77.1
,.0001
Day4 (after wake II)
50.7 (15/31)
4.7 (2/26)
Day5 (after recovery sleep II)
56.8 (17/30)
6.0 (0/22)
Numbers of patients with response and remission given in parenthesis.
Abbreviations: HAM-D6 = Hamilton Depression Rating Scale subscale, Response as a reduction of more than 50% from day1, Remission was defined as a HAM-D6 score
below 5, CL = confidence limits.
*OR was from the regression model without interaction between day and intervention and the main effect of intervention was reported.
doi:10.1371/journal.pone.0067264.t001
Table 2. Estimated Mean Post-Day1 HAM-D6 scores for Each Treatment Group by day. Numbers of patients given in parenthesis.
Wake (SE)
Exercise (SE)
Difference Between Groups
[n]
[n]
Day
Mean (SE)
Mean (SE)
Score (SE)
CL
P value
Day1
12.1 (0.2)
-
NA
[Wake 37 Exercise 38]
Day2 (after wake I)
6.2 (0.5)
8.7 (0.5)
2.5 (0.7)
1.1–3.9
.0007
[31]
[35]
Day3 (after recovery sleep I)
5.5 (0.4)
8.7 (0.4)
3.2 (0.6)
2.0–4.4
,.0001
[35]
[3]
Day4 (after wake II)
4.8 (0.4)
8.7 (0.4)
3.9 (0.5)
2.8–5.0
,.0001
[31]
[26]
Day5 (after recovery sleep II)
4.1 (0.4)
8.7 (0.5)
4.6 (0.6)
3.4–5.9
,.0001
[30]
[22]
Abbreviations: HAM-D6 = Hamilton Depression Rating Scale, NA = not applicable, SE = standard error, CL = confidence limits.
doi:10.1371/journal.pone.0067264.t002
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small diurnal variation (median) had a score of 4.2 (SE 0.4), and
patients with a negative diurnal variation of mood (Q3) had a
score of 4.7 (SE 0.5).
Correspondingly at day5 patients in the exercise group with
positive diurnal variation (Q1) had a mean score of 9.6 (SE 0.6),
patients with a small diurnal variation (median) has a score of 8.9
(0.5) and patients with a negative diurnal variation (Q3) a score of
8.4 (SE 0.6). Positive diurnal variation thus improved outcome in
the wake group but worsened outcome in the exercise group and
negative diurnal variation worsened outcome in the wake group
and improved outcome in the exercise group, compared to
patients without any clinical diurnal variation of mood (median).
The total scores from the Morningness-Eveningness Question-
naire (MEQ) was analysed as a covariate in the RRM model.
Analysis showed no significant impact on depression scores.
Sleep and Influence of Naps on Depression Outcome
At the start of study patients were asked to rate retrospective
whether they, in their current depressive episode, had experienced
any mood drop after having a daytime nap. Results from this
assessment showed that a ‘‘nap-mood-drop’’ had been present in
47.1% of patient and had lasted a mean of 92.7 (69.5) minutes
after end of nap; equally prevalent in both groups. The presence of
a mood drop after daytime napping had a significantly negative
influence on HAM-D6 scores (F65 = 3.9, p = 0.05) in the interven-
tion phase with no difference between groups.
Results from the sleep logs are given in Table S3. This shows
that, during the intervention phase, sleep onset was advanced in both
treatment groups but significantly more in the wake group with
79.6 (99.4) minutes compared to 39.7 (125.6) minutes in the
exercise group (between groups F1 = 10.1, p = .002). Sleep offset
was advanced in the wake group by 30.0 (89.1) minutes but not in
the exercise group where a slight sleep delay of 3.0 (132.8) minutes
was found (between groups F1 = 0.6, p = 0.43). Sleep duration was
increased in both groups: 49.6 (126.9) minutes in the wake group
and 42.7 (123.0) minutes in the exercise group (between groups:
F1 = 2.6, p = 0.11). The mean sleep duration for patients in the
wake group on nights after wake therapy (recovery sleep nights I,
II, III: night3, night5 and night7), was: night3 with 10:35 (1:11) hour:
minutes, night5 with 10:14 (1:41) hour: minutes and night7 with
9:51 (1:58) hour: minutes. Sleep duration on these nights were
significantly longer than corresponding sleep days in the exercise
group that were: night3 with 7:17 (1:20) hour: minutes (between
groups: F1 = 119.2, p,.0001), night5 with 7:47 (1:35) hour: minutes
(between groups: F1 = 36.0, p,.0001), and night7 with 7:17 (1:48)
hour: minutes (between groups: F1 = 29.4, p,.0001). Scores on
self-perceived quality of sleep increased in both groups but
significantly more in the wake group (F1 = 10.5, p = 0.002). The
total mean sleep length for the eight nights (including sleep for
those not taking the third wake therapy) was 49:45 (6:03) hour:
minutes in the wake group and 60:02 (7:45) hour: minutes in the
exercise group (excluding naps in both groups).
Any change of sleep-offset from end of the admittance period to the
end of the discharge period did not have any significant influence on
HAM-D6 scores at day8 (F71 = 0.08, p = 0.77).
Sleep logs showed that 41.2% (n = 14/34, with a total of
25 naps) of patients in the wake group and 52.6% (20/38, with a
total of 60 naps) of patients in the exercise group napped in the
intervention phase. The mean duration of the 25 naps in the wake
group was 96.0 (65.5) minutes and the mean duration of the
60 naps in the exercise group was 75.3 (45.4) minutes. In the wake
group, the total amount of napping time, during the intervention
phase, was 2400 minutes distributed with 675 minutes (n = 9) in the
admittance period (day1 till day5) and 1725 minutes (n = 9) in the
discharge period (day6 till day8). In the exercise group, the total
amount of napping time was 4520 minutes distributed with 2380
minutes (n = 16) in the admittance period (day1 till day5) and 2140
minutes (n = 15) in the discharge period (day6 till day8). The mean
sleep midpoint of naps was 14:31 (2:55) in the wake group and
13:52 (2:50) in the exercise group. Only 14.7% (n = 5) of patients in
the wake group were napping on the days after a wake night; one
patient after the first wake, three patients after the second wake
night and one patient after the third wake night. All differences
between groups on nap statistics were non-significant.
We then examined the effect of napping on depression outcome
(HAM-D6 scores) in the intervention phase and found that napping
significantly worsened depression scores (F70 = 4.4, p = 0.04) in the
whole group. Further analysis showed that this worsening was
predominantly due to napping in the discharge period where napping
significantly worsened depression outcome (F70 = 9.2, p = 0.003)
where as napping in the admittance period had a small and
nonsignificant worsening effect on depression scores. (F70 = 1.1,
p = 0.3). Furthermore the worsening of depression scores seen in
the discharge period was predominantly in the wake group (F69 = 5.8,
p = 0.02).
Table 3. Estimated Mean Post-Day1 Preskorn scores for Each Treatment Group by day.
Wake
Exercise
Difference Between Groups
Day
Mean (SE)
Mean (SE)
Score (SE)
CL
P value
Day1
5.6 (0.3)[Wake 34 Exercise 38]
-
NA
Day2 (after wake I)
4.1 (0.2) [34]
5.2 (0.2) [38]
Day3 (after recovery sleep I)
4.1 (0.2) [34]
5.1 (0.2) [38]
Day4 (after wake II)
4.0 (0.2) [34]
5.0 (0.2) [38]
Day5 (after recovery sleep II)
3.9 (0.2) [34]
4.9 (0.2) [37]
1.0 (0.3)*
0.4–1.7
0.001
Day6 (after wake III)
3.8 (0.2) [34]
4.9 (0.2) [38]
Day7 (after recovery sleep III)
3.7 (0.3) [34]
4.8 (0.3) [37]
Day 8 (week 2)
3.7 (0.3) [32]
4.7 (0.3) [37]
Numbers of patients given in square brackets.
Abbreviations: NA = not applicable, SE = standard error, CL = confidence limits.
*Score difference was from the regression model without interaction between day and intervention and the main effect of intervention was reported.
doi:10.1371/journal.pone.0067264.t003
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To illustrate the effect of napping in the discharge period on
depression scores in the two treatment groups we calculated the
baseline adjusted (day1) estimated HAM-D6 scores for all days in
the intervention phase for patients who napped (n = 24) and for
patients who did not nap in this period. Results are shown in
Figure 3. The main finding is that patients in the wake group who
napped in the discharge period had a very large deterioration from
day5 till day8 whereas patients not napping in the wake group had a
much smaller deterioration in the same period. Also, in the wake
group, we found that patients napping in the discharge period had a
moderately lesser effect of wake therapy during the admittance period
(F65 = 3.8, p = 0.06) compared to those patients without napping.
Difference in depression scores in the exercise group between
those napping and those not napping were nonsignificant.
Patient and Staff Evaluations
Table 4 shows patients and staffs evaluation of study proce-
dures. In general there was a high level of global satisfaction with
the study procedures. Additional semi-qualitative data (not shown
in Table 4) showed that conversations with investigators were
rated especially beneficial in 37.9% of wake patients and 46.0% of
exercise patients. In the wake group 20.7% found wake therapy
especially beneficial and 48.0% found it difficult. In the exercise
group 35.1% found exercise especially beneficial and 24.3% found
it difficult.
The following supplemental data provide further information
about the study:
Supplemental tables and figures:
Table S1: sociodemographics showing data for antidepressants,
depression history, and age and length of depression in past 5
years. No significant differences were found between groups.
Table S2: baseline-adjusted estimated mean HAM-D6 scores by
treatment group from the medium-term 9-weeks study for
comparison.
The
magnitude
of
difference
between
groups
remained stable for the whole period. The difference in HAM-
D6 scores between groups was significant (F529 = 8.9, p = .003) and
also post hoc for all weeks. The interaction between group and
week was insignificant indicating a parallel reduction in scores in
the two groups;
Figure S1: time course of depression ratings on the HAM-D6
scale for individual patients and days in the interventions phase by
treatment group;
Figure S2: sleepiness as measured on all wake nights by the
Stanford Sleepiness Scale (mean6 standard deviation), LOCF.
Mean sleepiness at 11 PM was 2.3 (1.1) (corresponding to:
‘‘functioning at high levels, but not at peak; able to concentrate’’)
and increased by each hour to a maximum of 4.0 (1.9)
(corresponding to: ‘‘somewhat foggy, let down’’) at 6 PM and
then gradually diminished to 3.3 (1.6) (corresponding to: ‘‘awake,
but relaxed; responsive but not fully alert’’) at 8 PM.
Figure 3. Estimated Mean Post-day1 HAM-D6 scores by napping status in the discharge period (day6 till day8) by treatment group.
doi:10.1371/journal.pone.0067264.g003
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Discussion
The presented results confirm our first hypothesis: that a
combination of wake therapy, light therapy and sleep time
stabilisation can induce a rapid and marked response and
remission without any relapse or deterioration between interven-
tion days. It is thus a replication of the results found by other
authors [34].
By necessity, the rating period during the intervention days is
short and scores cannot be directly compared with scores from
weekly assessments (day1 and day8) where the standard retrospec-
tive rating period of three days has been used. However, there is
no doubt that the marked response and remission rates seen
immediately after the first wake therapy and augmented on the
following intervention days are diminished somewhat on the
following weekly assessment (day8). Thus the full goal of the study
is not accomplished. In this respect it is important to notice that
the dreaded mood fluctuations between wake nights and after
recovery sleep, seen in some earlier studies using wake therapy,
were not seen in this study.
The regime was well tolerated but as mentioned in the previous
report [1] a few patients experienced anxiety attacks following
wake therapy nights. Sleep loss due to wake therapies when
compared to sleep duration in the exercise group was moderate and
confirms that wake therapy does not cause a huge sleep deficit but
is more a reallocation of sleep.
Concerning our second hypothesis, we found, as expected, that
the presence of a positive diurnal variation (better in the evening)
was associated with a better treatment response in the wake group.
It is not established whether the diurnal variation of mood can be
regarded as a continuum, as we implicitly have done, of a single
latent biological parameter or whether there is a more complex
and individual biology at the core of the phenomenon.
Gordijn et al found that variability in itself more than any
definite type of variation predicted response to sleep deprivation
[35]. In our opinion a positive diurnal variation should though still
be recommended as a positive predictor when considering a
patient for wake therapy regimens.
The effect size on day5 of 1.45 is considered very large and
larger than seen in drug therapy trials and comes within 5 days.
Regarding our third hypothesis we could confirm [15] that
napping, after the wake therapy regimen, is associated with a
much greater tendency for deterioration than for patients not
napping. Thus, when using this wake paradigm, advice should be
given and control measures employed to avoid any napping in the
days following wake therapy. We cannot from this study with
certainty conclude that napping by itself was the cause of the
greater deterioration as inherent patient characteristics could play
a role. The finding that patients who did nap after the end of the
wake therapy regimen also had less effect during the wake
therapies, suggests that the tendency to nap may be linked to some
degree to the non-response to wake therapy.
The sleep logs showed a significant advance of the sleep-wake
cycle in the wake group, which might also have contributed to the
antidepressant effect.
Performing a series of three wake therapies is quite demanding
on the patients and even though there is a substantial gain in the
short and a moderate gain after nine weeks it would still be very
useful to be able to predict which patients will benefit the most
from this intervention. Our analysis showing a high negative
predictive value suggests that non-response to an initial wake
therapy gives little hope of response after further wake therapies.
This finding could be useful guiding the clinicians.
It is a limitation of the study that the statistical analysis had to be
performed within a larger dataset and with the use of another
baseline than for the 9-weeks study. As the scores at week 1 (day1)
Table 4. Patient and staff evaluations of procedures (wake, sleep time stabilisation, light and exercise) used in intervention week.
Wake
Exercise
Patients’ evaluation
Per cent (n)
Per cent (n)
Felt global improvement
87.9 (29/33)
81.1 (30/37)
Satisfied with study procedures
81.8 (27/33)
94.6 (35/37)
Did you find any study procedure especially beneficially
87.9 (29/33)
100 (37/37)
Did you find any study procedure especially disagreeable
72.7 (24/33)
70.3 (26/37)
Day-time staff evaluation
Staff evaluated that patient improved during stay at ward
82.6 (19/23)
52.6 (10/19)
Staff evaluated that some of the used study procedures were difficult for patient
73.9 (17/23)
52.6 (10/19)
Staff evaluated that some of the used study procedures were beneficial for patient
86.4 (19/22)
89.5 (17/19)
Staff indicated that study procedures are applicable in ward
95.9 (21/22)
57.9 (11/19)
Staff indication that study procedures could be used in ward as a treatment option for patients with depression
81.8 (18/22)
94.7 (18/19)
Night-watch staff evaluation
Staff evaluated that patient improved during stay at ward
47.4 (9/10)
NA
Staff evaluated that used study procedures were difficult for patient
52.4 (11/21)
NA
Staff evaluated that used study procedures were beneficial for patient
75.0 (15/20)
NA
Staff indicated that study procedures are applicable in ward
70.0 (14/20)
NA
Staff indication that study procedures could be used in ward as a treatment option for patients with depression
85.0 (17/20)
NA
Per cent refers to positive responses.
doi:10.1371/journal.pone.0067264.t004
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were quite similar across groups we do not suspect this to be a
major problem. Fewer patients were assessed in the exercise group
with the HAM-D6 at days 4 and 5 primarily due to logistic reasons
pertaining to exercise training sessions. As this was not related to
depression severity we do not believe this has biased the results.
Due to the rather small sample size statistical significance of sub-
analyses might be due to change findings of multiple testing and
should thus be interpreted with caution.
Depression ratings from the days of the intervention week were
based on a ‘last hour’ time window and this might bias towards
lower scores compared to scores from longer time windows. This
would give an artificially deterioration at end of intervention week
where rating were based on a last ‘three days time’ window.
Some imprecision might come from performing ‘last hour’
rating on slightly different time point of the day.
As patients in this study were predominantly treatment resistant
[1] the findings cannot be generalised to non-treatment resistant
patient and as the majority of patient were unipolar we cannot
generalise findings to bipolar patients.
Supporting Information
Figure S1
Individual patient’s available data from the
HAM-D6 scale for the 8 days of the interventions phase
for each patient by treatment group.
(DOC)
Figure S2
Sleepiness as measured on wake nights by the
Stanford Sleepiness Scale (mean± standard deviation)
for 94 wake nights (data missing from 3 nights), LOCF.
Scoring: 1 = Feeling active, vital, alert, or wide awake, 2 = Func-
tioning at high levels, but not at peak; able to concentrate,
3 = Awake, but relaxed; responsive but not fully alert, 4 = Some-
what foggy, let down, 5 = Foggy; losing interest in remaining
awake; slowed down, 6 = Sleepy, woozy, fighting sleep; prefer to lie
down, 7 = No longer fighting sleep, sleep onset soon; having
dream-like thoughts.
(DOC)
Table S1
Sociodemographics.
(DOC)
Table S2
Baseline-adjusted estimated mean HAM-D6
scores by treatment group from the medium-term 9-
weeks study.
(DOC)
Table S3
Results from the sleep logs.
(DOC)
Checklist S1
Consort checklist.
(DOC)
Protocol S1
Study protocol.
(DOC)
Acknowledgments
We want to thank Associate Professor Lene Theil Skovgaard, Institute of
Public Health, Panum Institute, Copenhagen, Denmark for statistical
support, Professor Morten Møller, University of Copenhagen for guidance
on the topic of chronobiologicaly in the early stages of the project, and
Professor Anna Wirz-Justice, University of Basel for guidance on
chronotherapeutics methods.
Author Contributions
Conceived and designed the experiments: KM ER VL ML LS BT LL PB.
Performed the experiments: KM ER VL ML LS BT LL PB. Analyzed the
data: KM ER VL ML LS BT LL PB. Contributed reagents/materials/
analysis tools: KM ER VL ML LS BT LL PB. Wrote the paper: KM ER
VL ML LS BT LL PB.
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Acute Effect of Wake Therapy
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Adjunctive triple chronotherapy (combined total sleep deprivation,
sleep phase advance, and bright light therapy) rapidly improves mood
and suicidality in suicidal depressed inpatients: An open label pilot
study
Gregory L. Sahlem a, *, Benjamin Kalivas a, b, James B. Fox a, Kayla Lamb a, Amanda Roper a,
Emily N. Williams a, Nolan R. Williams a, c, Jeffrey E. Korte d, Zachary D. Zuschlag a,
Salim El Sabbagh a, Constance Guille a, Kelly S. Barth a, b, Thomas W. Uhde a,
Mark S. George a, c, E. Baron Short a, b
a Departments of Psychiatry, Medical University of South Carolina, 67 President Street, Charleston, SC, USA
b Departments of Medicine, Medical University of South Carolina, 67 President Street, Charleston, SC, USA
c Departments of Neurology, Medical University of South Carolina, 67 President Street, Charleston, SC, USA
d Departments of Public Health Sciences, Medical University of South Carolina, 67 President Street, Charleston, SC, USA
a r t i c l e i n f o
Article history:
Received 26 June 2014
Received in revised form
20 August 2014
Accepted 21 August 2014
Keywords:
Sleep deprivation
Suicidal ideation
Chronotherapy
Depression
Phototherapy
Inpatients
a b s t r a c t
Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase
advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant
effect in acutely depressed individuals. To date no studies have explored the impact of the intervention
on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients
(N ¼ 10, Mean age ¼ 44 ± 16.4 SD, 6F) with unipolar depression. In addition to standard of care, they
received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation
(33e36 h), followed by a three-night sleep phase advance along with four 30-min sessions of bright light
therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton
depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded
at baseline prior to total sleep deprivation, and at protocol completion on day ﬁve. Both HAM17, and
CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean
of 24.7 ± 4.2 SD at baseline to a mean of 9.4 ± 7.3 SD on day ﬁve (p ¼ .002) with six of the ten individuals
meeting criteria for remission. CSSRS scores dropped from a mean of 19.5 ± 8.5 SD at baseline to a mean
of 7.2 ± 5.5 SD on day ﬁve (p ¼ .01). The results of this small pilot trial demonstrate that adjunctive Triple
Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a
small number of participants, an open label design, and the lack of a comparison group. Randomized
controlled studies are needed.
© 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Major depressive disorder is a neuropsychiatric condition that
consists of core symptoms including a persistently depressed
mood, anhedonia, sleep disruption, anergia, poor concentration,
guilt,
hopelessness,
appetite
changes,
and
suicidal
ideation.
Currently there are no commonly used rapid treatments for
depression. Suicide is the 10th leading cause of death in the United
States, and is even higher among younger individuals between the
ages of 10e24, where it is the second leading cause (Heron, 2013).
Untreated depression is known to be associated with suicide risk
with estimates that 60% of all suicides are associated with inade-
quately treated depression (Mann et al., 2005). There is an apparent
stratiﬁed risk of suicide in those who have been admitted to the
inpatient unit for depression, with those who have suicidal
thoughts, or suicide attempts, posing the highest lifetime risk of
committing suicide (Bostwick and Pankratz, 2000). Depression is a
major medical issue both domestically and abroad. Depression is
* Corresponding author. 67 President Street, Charleston, SC, 29425, USA.
Tel.: þ1 843 792 2123; fax: þ1 843 792 5702.
E-mail address: Sahlem@musc.edu (G.L. Sahlem).
Contents lists available at ScienceDirect
Journal of Psychiatric Research
journal homepage: www.elsevier.com/locate/psychires
http://dx.doi.org/10.1016/j.jpsychires.2014.08.015
0022-3956/© 2014 Elsevier Ltd. All rights reserved.
Journal of Psychiatric Research 59 (2014) 101e107

the 4th leading cause of disability in the world and has an
approximate lifetime prevalence of 16.5% in the United States
(Kessler et al., 2003; Murray and Lopez, 1996). Pharmacotherapy,
and psychotherapy are the most commonly used treatments but
only approximately 67% of non treatment resistant depressed in-
dividuals achieve remission with medications or psychotherapy,
taking an average of 5e7 weeks to achieve remission in those who
ﬁnd an effective regimen (Rush et al., 2006). Even electroconvulsive
therapy (ECT), which is our most dependable, and effective treat-
ment, still takes 2e3 weeks for therapeutic beneﬁt, and has limited
availability and cognitive side effects (Sackeim et al., 2007).
Although there are promising newer treatments such as repetitive
transcranial magnetic stimulation (rTMS) (George et al., 2014) and
ketamine (Caddy et al., 2014), there are at this time no commonly
used treatments that rapidly treat depression.
Studies have consistently reported a rapid antidepressant
response to total sleep deprivation in both unipolar and bipolar
depression, ﬁrst studied by Pﬂug and Tolle (1971), and reviewed
extensively by (Wu and Bunney (1990); Wirz-Justice et al. (2005);
Benedetti et al. (2007). The clinical utility of this technique is
limited however, because responders typically relapse rapidly
following
recovery
sleep.
The
addition
of
pharmacotherapy
(Benedetti et al., 2001; Colombo et al., 2000; Smeraldi et al., 1999;
Martiny et al., 2012; Shelton and Loosen, 1993; Szuba et al., 1994;
Wu et al., 2009), sleep phase advance (Riemann et al., 1999;
Echizenya et al., 2013), and bright light therapy (Echizenya et al.,
2013; Martiny et al., 2012, 2013; Neumeister et al., 1996; Wu
et al., 2009) to sleep deprivation have each demonstrated efﬁcacy
in preventing some individuals from relapsing into depression.
Some early studies have reported that combined total sleep
deprivation, sleep phase advance, and bright light therapy, dubbed
Triple Chronotherapy, along with concomitant pharmacotherapy,
produces a rapid improvement in depressive symptoms which
endures for as long as 9 weeks (Echizenya et al., 2013; Martiny et al.,
2012; Wu et al., 2009). If the early, encouraging results of Triple
Chronotherapy hold up to further study, the technique represents a
near ideal inpatient treatment, as it is inexpensive, relatively easy to
carry out, and has minimal side effects.
Despite encouraging early results, only one published report has
attempted to use Triple Chronotherapy in suicidal patients, and in
that trial only bipolar depressed patients were included. That study
used a slightly different variation of chronotherapy that included
three nights of sleep deprivation every other night with three light
therapy sessions, combined with lithium (Benedetti et al., 2014).
The lack of data utilizing Triple Chronotherapy in acutely suicidal
patients signiﬁcantly limits its utility in the United States, where
few non-suicidal patients are admitted to the inpatient unit.
Furthermore, published trials to this point have excluded those
with comorbid illness, which also limits the clinical usefulness of
this intervention to a minority of patients. We subsequently sought
to determine if adjunctive Triple Chronotherapy was safe and
feasible in acutely depressed and suicidal inpatients.
2. Materials and methods
2.1. Participants
We included participants with non-psychotic unipolar, or bi-
polar depression (who were on a therapeutic dose of a mood sta-
bilizer), age 18e75. We excluded patients who were in a mixed
state, had active psychosis, had active panic disorder, were actively
withdrawing from a substance of abuse, had a history of seizures, or
had active unstable medical or neurologic illness.
We recruited participants from inpatient units at the Medical
University of South Carolina (MUSC) Institute of Psychiatry (IOP)
during the months of October 2013eMarch 2014 after referral from
the treating inpatient team. Inpatient teams ﬁrst brieﬂy explained
the chronotherapy intervention to patients who were admitted.
Study team members then met with interested patients to obtain
informed consent. All interested patients who met inclusion
criteria, and did not meet exclusion criteria were included in the
study. A total of 21 potential participants were referred, with three
not being interested in the study, and four meeting exclusion
criteria. Of the remaining referrals, 14 signed written informed
consent, one of which later failed initial screening. The remaining
sample of 13 enrolled in the below described protocol which was
approved by the MUSC intuitional review board (IRB). Of the
included participants one participant withdrew from the study
prior to the ﬁrst sleep deprivation and stated they were no longer
wanting to participate, and two others were excluded from data
analysis due to protocol deviations related to the investigative
team, leaving a ﬁnal sample of 10. Of the two that were withdrawn,
our team missed awakening the ﬁrst following the ﬁrst recovery
sleep night, and our team placed the second in an excessively noisy
room during the ﬁrst recovery night of sleep, and they were unable
to sleep (They have a diagnoses of bipolar type I, and following two
sleepless nights we thought the risk of manic switch outweighed
any possible therapeutic beneﬁt of continuing the protocol) (Fig. 1).
The mean age of participants was 44 ± 16.4, six of whom were
women, and none of whom had bipolar depression (Table 1). All but
one participant carried comorbid Axis I, or Axis II diagnosis, which
consisted of the following: Five participants met criteria for
generalized anxiety disorder, four participants met criteria for
dysthymia, three participants met criteria for borderline person-
ality disorder, three participants met criteria for post traumatic
stress disorder, three met criteria for alcohol dependence in early
remission, two met criteria for social anxiety disorder, and one met
criteria for opiate dependence in early remission. We initially
recruited two participants with a diagnosis of bipolar disorder,
however both of those participants were excluded from analysis
due to protocol deviations as described above. Only three partici-
pants were initially admitted for a suicide attempt, while all pa-
tients were admitted for suicidal ideation.
This was an adjunctive procedure, and with the exception of
holding hypnotics on the night of sleep deprivation, all standard of
care pharmacotherapy was allowed. In addition to pharmacotherapy,
all patients on the unit received milieu therapy, group therapy, and
social work interventions. The group was heterogeneous as far as
treatment resistance. The group had an average of 5.5 ± 5.7 medica-
tions that were either failed or were not tolerated. One participant
previously failed ECT. The medications that were either started or
continued by the treating team were as follows: All participants were
on antidepressants during the study; ﬁve were on serotonin selective
reuptake inhibitors (SSRI)'s, two were on serotonin non-selective
reuptake inhibitors (SNRI)'s, four were on trazodone, three were on
mirtazapine, one was on vilazodone, one was on phenelzine, two
were on cytomel, three were on benzodiazepines, one was on que-
tiapine, one was on gabapentin, one was on belladonna, and one was
on melatonin. Prior to, or during the weeklong protocol, the following
medications were started, or titrated: One had an SNRI titrated, one
had phenelzine started, three had mirtazapine started or titrated, two
had titrations of an SSRI, one had cytomel started, one had quetiapine
started, one had prazosin started, one had a benzodiazepine started,
and one had gabapentin started.
2.2. Triple Chronotherapy procedure
The Triple Chronotherapy procedure we used closely resembled
the one described in the manual written by Wirz-Justice at al
(Wirz-Justice et al., 2013). Recruited participants ﬁlled out the
G.L. Sahlem et al. / Journal of Psychiatric Research 59 (2014) 101e107
102

Morningness-Eveningness
questionnaire
(MEQ)
(Horne
and
Ostberg, 1976), which has been shown to predict optimal light
therapy timing. Participants then underwent one night of total
sleep deprivation (Day 0), followed by a three day sleep phase
advance (Sleep occurred between 6pm, and 1am on day 1, 8pm and
3am on day 2, and 10pm and 5am on day 3). In addition they
received bright light therapy on the mornings of days 1, 2, 3, and 4,
for 30 min at 10,000lux, with the timing set by MEQ. The start time
of light exposure varied between 6am and 8am. Following the four-
day intervention, participants were asked to remain on as close a
schedule as possible to 10pm to 5am (although this was not
monitored as we considered the intervention to have been
completed). We did recommend that they expand their time in bed
to a maximum of 8 h if they were experiencing daytime sleepiness
with 7 h in bed. Light therapy was generally discontinued, however
participants were offered recommendations on the appropriate use
of light therapy if they desired to continue it once they left the
hospital (Fig. 2).
2.3. Data collection
On the day proceeding total sleep deprivation (Day 0), after
participants signed informed consent, we performed a chart review
as well as reviewed pertinent laboratory testing. We then per-
formed a MINI neuropsychiatric examination (Sheehan et al., 1998)
to conﬁrm diagnoses, administered a 17-Item Hamilton depression
rating scale (HAMD17) (Hamilton, 1960), Columbia Suicide Severity
Rating Scale (CSSRS) (Posner et al., 2011), and a Young Mania Rating
scale (YMRS) (Young et al., 1978), inquiring about the previous 7
days. In addition, we collected self report measures at baseline,
including the Inventory of Depressive Symptoms Self Report (IDS-
SR) (Rush et al., 1996), the Patient Health Questionaire-9 (PHQ9)
(Spitzer et al., 1999), the Epworth Sleepiness scale (ESS) (Johns,
1993), the Pittsburgh Sleep Quality Index (PSQI) (Buysse et al.,
1989), and the Scale for Suicidal Ideation (SSI) (Beck et al., 1979).
On the day following total sleep deprivation, and the days following
the ﬁrst two nights of sleep phase advance (Days 1e3), we
administered the 6-item version of the Hamilton Depression Rating
Scale (HAM-D6) (O'Sullivan et al., 1997), the CSSRS, the YMRS, the
IDS-SR, the ESS, and the SSI all asking about the previous day only.
On the day following the third sleep phase advance night (Day4),
we administered the HAM17, CSSRS, and YMRS, and collected the
IDS-SR, ESS, SSI, PHQ9, and PSQI asking about the previous day only.
We deﬁned remission from depression as a HAM17 score of less
than 7. We deﬁned response from either depression (HAM17), or
suicidal ideation (CSSRS) as a greater than 50% drop in score from
baseline.
2.4. Data analysis
Because of the small sample size (n ¼ 10), we chose to use more
valid and more conservative non-parametric statistical tests. We
used Wilcoxon's signed rank test to evaluate the change in outcome
measures throughout the four-day study follow-up. For the HAMD-
17, we compared day 4 to baseline. For other measures collected on
each day, we made pairwise comparisons of the change since
baseline for each day of follow-up. We used SAS Enterprise version
4.3 for all analyses (SAS Institute, Inc., Cary NC).
Fig. 1. Screening and enrollment ﬂowchart.
Table 1
Demographics.
N ¼ 10
Age
Mean ¼ 44 ± 16.4 SD
Gender
4 Male, 6 Female
Race/Ethnicity
9 (90%) Caucasian
1 (10%) African American
Duration of current episode
15.4months ± 13.2 SD
Number of lifetime episodes
7.8 ± 5.8 SD
Number of failed medications/ECT
5.5 ± 5.7 SD
One failure of ECT
G.L. Sahlem et al. / Journal of Psychiatric Research 59 (2014) 101e107
103

3. Results
As compared to baseline there was a statistically and clinically
signiﬁcant decrease in both clinician, and self rated scales of
depression and suicidal ideation. The 17-Item Hamilton depression
scale went from an average of 24.7 ± 4.2 SD at day 0, to a ﬁnal score
of 9.4 ± 7.3 SD on day 4. Six out of ten participants met criteria for
remission on the Ham17 (60%). Sixty-percent met criteria for
response (Figs. 3 and 4). The Columbia Suicide Severity Index went
from an average of 19.5 ± 8.5 SD on day 0 to a ﬁnal score of
7.2 ± 5.5 SD on day 4. Sixty percent of participants met criteria for a
response on the CSSRS (Fig. 5). Self report measures were also
collected each day, having been ﬁlled out while receiving light
therapy, and can be found in Table 2.
4. Discussion
This small, open label pilot study suggests that adjunctive Triple
Chronotherapy is safe and tolerable in acutely suicidal, unipolar
depressed inpatients. These results complement and extend the
recently published study demonstrating safety of another variant of
Chronotherapy in suicidal Bipolar Depressed inpatients (Benedetti
et al., 2014). This conclusion, along with any conclusion regarding
treatment efﬁcacy, must however be made in the context of sig-
niﬁcant experimental limitations, with special attention made to
the small sample size, signiﬁcant medication changes, time in the
structured hospital environment, and the lack of a control group.
It is possible that this small cohort of participants would have
improved even more rapidly and robustly with treatment as usual,
or that the response observed was directly the result of treatment
as usual, a placebo response, or some combination of the two. This
is particularly true considering all patients were on concurrent
pharmacotherapy, and receiving group therapy on the unit. How-
ever, typically neither pharmacotherapy, nor group psychotherapy
has an onset of action that is as rapid as was observed in our cohort.
Furthermore, comparison trials of Chronotherapy in the setting of
medication use demonstrate that groups receiving both Chrono-
therapy and medications have a more rapid, and robust improve-
ment as compared to groups receiving either alone, and response
and remission rates have been consistent with our results
(Benedetti et al., 2001; Colombo et al., 2000; Shelton and Loosen,
1993; Szuba et al., 1994).
It is of note that Chronotherapy was well tolerated by all par-
ticipants who agreed to the procedure. Most participants reported
only transient sleepiness, which was most prominent between the
hours of 3am and 6am on the night of total sleep deprivation, and
Fig. 2. Chronotherapy procedure.
Fig. 3. Hamilton Depression Rating Scale 17-item.
G.L. Sahlem et al. / Journal of Psychiatric Research 59 (2014) 101e107
104

following the ﬁrst night of recovery sleep. There was a small sta-
tistically non-signiﬁcant (p ¼ 0.74) increase in suicidal ideation on
day 2 compared to day 1, however this small increase was mostly
accounted for by our non-responders, was still considerably below
reported suicidal ideation prior to starting the procedure, and not
likely to be clinically signiﬁcant. Only three participants were
withdrawn from the study, one of which withdrew before begin-
ning total sleep deprivation, and the other two of which had to be
withdrawn due to easily correctible study team errors (One we did
not correctly wake up, and the other we placed in a room that was
too close to unit activity).
A further limitation of this study that is particularly noteworthy
is the lack of follow-up of our cohort after hospital discharge (Due
to loss to follow-up). Historic data would suggest the possibility of
rapid relapse (Wu and Bunney, 1990), however recent trials have
demonstrated durability of the antidepressant effect of combined
chronotherapeutic interventions with medications (Benedetti et al.,
2005; Echizenya et al., 2013; Martiny et al., 2012; Wu et al., 2009).
After consideration of the above signiﬁcant limitations, the re-
sults found in this pilot study still expand the potential clinical
group that can undergo this intervention. Given the large effect
size, ease of administration, mild side effects, and inexpensive na-
ture of this intervention, further study is warranted. Although our
ﬁndings in the context of the other literature in the ﬁeld are very
encouraging, we believe further study must take place prior to
widespread clinical adoption. The two areas of study that are most
lacking are data comparing active chronotherapy to an adequate
active sham condition, and further durability data. Controlled trials
would ideally include both an active sham group, and a treatment
as usual group. An active sham could include partial sleep
Fig. 4. Hamilton Depression Rating Scale 6-item.
Fig. 5. Columbia Suicide Severity Rating Scale total.
G.L. Sahlem et al. / Journal of Psychiatric Research 59 (2014) 101e107
105

deprivation (Depriving the ﬁrst part of the nights sleep), a three-
day sleep phase delay, and placebo light therapy. All such sham
interventions
have
been
utilized
previously and
have
been
demonstrated to be safe. Such a sham group could control for
placebo effects related to undergoing a procedure, the added staff
attention included in sleep deprivation, and a rigid sleep wake
schedule. Including a treatment as usual group would control for
improvement based upon pharmacotherapy, psychotherapy, and
the structured hospital environment.
4.1. Conclusion
Based upon the results of our small open label pilot study, Triple
Chronotherapy is safe and feasible to administer in acutely
depressed and suicidal inpatients. Further work is needed to
determine treatment effects in a placebo-controlled trial.
Role of the funding source
Support was provided by the Medical University of South Car-
olina Resident Research Training Program (DART program), which
was funded by National Institute on Drug Abuse (NIDA) R25
DA020537-06 (PI's Back and Brady). Besides providing mentorship
that assisted in experimental design and implementation, the
funding source did not inﬂuence the project.
Author contributions
Gregory L. Sahlem was the Primary investigator of the study. He
contributed in experimental design, regulatory procedures, data
collection, data analysis, and manuscript preparation.
Benjamin Kalivas contributed in experimental design, data
analysis, and manuscript preparation.
James B. Fox contributed in recruitment, and manuscript
preparation.
Kayla Lamb contributed to regulatory procedures, and manu-
script preparation.
Amanda Roper contributed in experimental design, and manu-
script preparation.
Emily N. Williams contributed in experimental design, recruit-
ment, and manuscript preparation.
Nolan R. Williams contributed in experimental design, and
manuscript preparation.
Jeffrey E. Korte was the statistician on the project. He contrib-
uted in data analysis and manuscript preparation.
Zachary D. Zuschlag contributed in recruitment and manuscript
preparation. Salim El Sabbagh contributed in recruitment and
manuscript preparation.
Constance Guille was a mentor for the project and contributed
in experimental design and manuscript preparation.
Kelly S. Barth was a mentor for the project and contributed in
recruitment and manuscript preparation.
Thomas W. Uhde was a mentor for the project and contributed
in experimental design, and manuscript preparation.
Mark S. George was a mentor for the project. He contributed in
experimental design, regulatory procedures, data analysis, and
manuscript preparation.
E.Baron Short was a mentor for the project. He contributed in
experimental design, regulatory procedures, data analysis, and
manuscript preparation.
Conﬂict of interest
There is no Conﬂict of Interest.
Acknowledgments
We would like to thank the acute inpatient team at the Institute
of Psychiatry of the Medical University of South Carolina for their
tireless effort. Without your help this study could not have
occurred. We would also like to thank the Drug Abuse Research
Track (DART) program at the Medical University of South Carolina
with special thanks to Drs.Back and Brady, along with the grant that
supports it (NIDA R25 DA020537-06 (PI's Back and Brady)).
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Measures score (±Standard deviation).
Measure
Baseline
Day 1
Day 2
Day 3
Day 4
HAM-D (17)
24.7(±4.2)
9.4(±7.3)
p ¼ .002
HAM-D (6)
12.3(± 1.8)
7.9(±3.9)
p < .004
6(±4.3)
p ¼ .002
4.5(±4.5)
p ¼ .002
4.1(±3.9)
p < .004
CSSRS
19.5(±8.5)
6.5(±4.3)
p < .004
8.1(±7.4)
p < .01
6.2(±6.3)
p < .004
7.2(±5.5)
p < .01
IDS
52.1(±6.7)
45.4 (±11.5)
p ¼ .07
39.1(±16.8)
p ¼ .06
25.9(±13.5)
p < .004
22.3(±14)
p < .004
SSI
17.2(±9.4)
15(±9.8)
12.2(±10.5)
p < .02
8.5(±8.0)
p < .004
7.4(±7.9)
p < .004
HAM-D, 17-Item and 6-Item Hamilton Rating Scale for Depression; CSSRS,
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G.L. Sahlem et al. / Journal of Psychiatric Research 59 (2014) 101e107
107

 
INSTITUTIONAL REVIEW BOARD 
NEW YORK STATE PSYCHIATRIC INSTITUTE 
 
MEMORANDUM 
 
 
 
 
 
 
 
 
 
 
 
November 07, 2016 
TO: 
 
Dr. Jonathan Stewart 
 
FROM: 
Dr. Edward Nunes, IRB Co-Chair 
 
SUBJECT: 
Protocol #7361: ARE BRIGHT LIGHTS AND REGULATED SLEEP EFFECTIVE 
TREATMENT FOR DEPRESSION? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Full Board reviewed the above protocol on November 07, 2016 and recommended approval 
pending your response to the following items. Please submit (through PRISM) (1) a copy of this 
memo, (2) your point-by-point response (question and answer format), (3) the revised 
Protocol Summary Form (PSF) with revisions bolded, (4) the Consent Forms (CF). 
 
1. Please confirm that either an ophthalmologist or an internist will conduct the funduscopic 
exam, as it was felt that this exam needs to be conducted by a physician experienced in it.  
Although you are the expert in this area, and you included the funduscopic exam in the 
protocol, members of the Board also wondered whether such exam is necessary given the 
likely low risk of light therapy.  However, if you wish to remove the requirement for an 
eye exam, that would require re-review by the Board, and your request would need to be 
accompanied by a review of what is known about the risks of light therapy to the eye.` 
2. Please include in the PSF and CF that a pregnancy test will be conducted both at baseline 
and again at 4 weeks for women of child bearing potential. 
3. Please revise the Delay to Treatment section of the PSF to confirm that study 
participation concludes after 6 weeks, and the 6 months after study participation is 
considered clinical treatment. 
4. Because low thyroid function is mentioned in the CF, please update exclusion criterion 
#3 to state, “Unstable medical condition (such as low thyroid function)”. 
 
 
 
EN/alw 
 
Page 1 of 1 

 
-1- 
 
 
22 November 2016                                                                                                                                      IRB #7361 
CONSENT FORM 
Are Bright Lights and Regulated Sleep Times Effective Treatment for Depression? 
 
Purpose and Overview 
The purpose of this study is to find out whether sleeping only at regulated times and sitting in front of a 
bright light wearing different colored or clear goggles is effective treatment for depression.  You are 
being asked to participate in this study because you are depressed and do not have mood swings 
(bipolar disorder). 
 
Voluntary 
Participation in this research study is voluntary. If you decide not to participate, or if you later decide to 
stop participating, or your doctor removes you from study participation for any reason, you will not lose 
any benefits to which you are otherwise entitled. A decision not to participate or withdraw your 
participation will not affect your current or future treatment at the New York State Psychiatric Institute 
or Columbia University. 
 
Alternatives to Participation 
There are alternatives to your participating in this study. If you previously participated in another 
treatment study, you may be eligible for further treatment without taking part in this study. You can go 
to a private doctor or to a psychiatry clinic where you may receive any of the medications marketed 
for depression. Electroconvulsive treatment and focused psychotherapy are also accepted treatments 
for depression. Electrical stimulation of a nerve in the neck (called the vagus nerve) has also been 
approved by the FDA. 
 
Study Procedures 
In order to find out if you can be treated in this study, you will receive a complete psychiatric evaluation 
by a study psychiatrist. If the study psychiatrist decides you can participate, you will be given this 
consent form to read. If you then agree to participate and are satisfied that your questions have been 
answered, you will then sign the consent form. A member of the research team will then complete 
research rating forms, you will complete self-report ratings, about 15 cc (approximately a tablespoon) of 
blood will be drawn for routine laboratory testing (for example, to make sure your kidneys and liver are 
healthy), a doctor will perform a physical examination (for example, listen to your heart and lungs, look 
into your eyes) and you will provide a urine specimen (to be checked for kidney function, pregnancy if 
you are a woman of child-bearing age, and street drugs such as heroin and cocaine). These tests will 
determine if you have a medical disorder such as low thyroid function that might be the cause of your 
depression or that should be treated prior to your entry into this. If you have one of these medical 
problems, your doctor will discuss this with you at the first visit after it is found, or telephone you if it 
requires quicker attention.   
 
You have been offered participation in this study because you are depressed.  Once you have agreed 
and signed the study consent form, you will be asked to answer questions about your mood, prior 
treatment, the times of the day you like to do things, a variety of common psychiatric symptoms and 
your interest and functioning in several life circumstances, like work and family.  You will wear an 
activity monitor (which looks like a wrist watch) and keep a log of your sleep, mood and energy for 
about seven weeks.  After 1-2 weeks (you can choose to wait up to 30 days before re-evaluation), you 
will be re-evaluated.  If you remain significantly depressed at this re-evaluation, and remain agreeable, 

 
-2- 
you will begin sleeping only at assigned times (regulated sleep therapy) plus sitting in front of bright 
lights wearing goggles.  The timing of your allowed sleep and whether the goggles you wear will be clear 
or amber will  be determined randomly (as if by a flip of a coin). Whatever timing and goggles you are 
assigned you will continue for the next six weeks, initially with daily telephone evaluations and from the 
end of week 1 through the end of week 6 weekly in person.  At the time you are randomized and again 
at weeks 1 and 6 visits you will also be evaluated by a rater who does not know whether you have begun 
treatment or what treatment you may be receiving.  It is important that you not let on whether you 
have begun treatment, or, if you have, what that treatment has been. 
 
Light and Regulated Sleep Therapy 
Treatment will be with bright lights and regulated sleep times.  To help us determine whether this 
approach is effective treatment and which times for sleep and bright lights and how best to use the 
bright lights, by chance different patients will receive different instructions.  All will be given specific 
times they are allowed to sleep and specific times to sit in front of the bright lights.  Time sitting in front 
of the bright lights will begin at 30 minutes, but if you have trouble tolerating the light your doctor may 
tell you to decrease this time shorter (to as little as 10 minutes), and if you tolerate the light but remain 
depressed your doctor may tell you to increase the time (up to 60 minutes).  For some the specific sleep 
times may include a 48 hour period during which they are not allow to sleep as long as 42 hours.  You 
will be provided goggles both to wear in the evening during saliva collection for melatonin and when 
sitting in front of the bright lights.  Some goggles will be clear and some will be amber.  Prior to being 
told your specific times for allowed sleep and use of the bright lights, you will complete the 
Morningness-Eveningness Questionnaire; your answers will suggest where your biologic clock is 
currently set and partially determine the times you will be allowed to sleep and instructed to use the 
bright lights.  You will also report the time you want to be sleeping which will also determine the sleep 
instructions and timing of your bright light use. 
 
Risks and Inconveniences 
General. A general risk is that you may remain depressed. It has not been determined whether the 
combination of wake therapy, light therapy and regular allowed sleep is effective for your disorder. 
Second, suicide is a risk in patients who are depressed.  Patients with bipolar disorder may become 
manic. These risks will be minimized by: (a) exclusion of patients known to have bipolar disorder; (b) not 
participating in the study if you or your doctor consider you to be at significant risk to harm yourself or 
in need of hospitalization; (c) discontinuing study participation should you become significantly worse or 
significantly suicidal; (d) offer of hospitalization in the case of significant worsening/suicidal 
thoughts/behavior; (e) weekly visits and 24 hour phone availability of an experienced research 
psychiatrist.  
 
Remaining awake for long periods. The major risk of remaining awake for long periods is mania. This 
possibility will be minimized by only including patients without a history of mania or hypomania (a 
period of being “high” without being manic), constant availability of access to a research psychiatrist by 
telephone.  An additional risk is being drowsy at times alertness is required, such as driving or operating 
heavy machinery.  Therefore, if assigned extended periods of wakefulness or if you feel sleepy, you 
should not drive or operate heavy machinery. 
 
Light Therapy. Patients may become over-stimulated, and those with bipolar disorder may become 
manic.  As this study will not include patients known to have bipolar disorder, this risk seems minimal, 
but likely not zero, especially since not all patients with bipolar disorder are known to have it.  More 
commonly, over-stimulation is described as “like too much coffee” and can be eliminated by decreasing 

 
-3- 
bright light exposure, either by decreasing the time in front of the light or increasing the distance from 
the light, or both.  Occasionally, light exposure may also cause headache, nausea or eye irritation.  
Again, these will be counteracted by increasing the distance for the light, decreasing the time you sit at 
the light or both.  Long-term research studies have found that light therapy is safe for the 
retina of the eye. Nevertheless, as a precaution, we will examine your retina to see whether there are 
already signs of damage, and you will not receive light therapy if you have retinal conditions such as 
retinitis pigmentosa or macular degeneration. As the lights used are similar to early morning light in 
intensity but without any ultraviolet radiation, they may be considered safer than going outside on a 
sunny day. 
 
Additional Risks 
Participation in this study may involve risks that we currently do not know.  Some discomfort may be 
associated with the drawing of blood samples. A maximum of 1 tablespoon of blood will be taken unless 
there is a medical reason to obtain extra blood.  There is a minor risk of bleeding, bruising, or infection 
at the site of the needle insertion. With any treatment there is the risk that the treatment may not help 
and the depression might become worse. Also, if a treatment is effective or partially effective there is 
the risk of worsening of symptoms if the treatment is stopped or the dose is reduced. 
 
Benefits 
Your depression may improve. 
 
You will be informed if significant new information becomes known about treatment of depression 
or about the treatments used in this study, especially if such information might affect the willingness of 
some subjects to continue their participation. 
 
Confidentiality 
All study information is kept in locked cabinets at the Depression Evaluation service at the New 
York State Psychiatric Institute or in a secure HIPAA compliant computer accessable only by study staff. 
Records will be kept confidential to the extent permitted by law. Your name and other personal 
identifying information will be stored in an electronically secure database at New York Psychiatric 
Institute. Any publications will present only group data and not include information that could identify 
you. Records will be available to research staff, and to Federal, State and Institutional regulatory 
personnel (who may review records as part of routine audits). Also, you should be aware that there are 
legal advocacy organizations that have the authority under New York State law to access otherwise 
confidential subject records, though they cannot re-disclose this information without the subject’s 
consent. Electronically stored/transmitted data will be password protected with access only to study 
personnel. 
 
There are limits to confidentiality. For example: 
 
If your answers indicate a serious problem that may jeopardize your safety or health, then the 
researchers will contact your physician or emergency personnel as seems appropriate to your well-
being.  Also, suspected or known neglect or sexual or physical abuse of a child, or threatened violence to 
self or others will be reported to the appropriate authorities. 
 
Study Compensation 
Tests that are part of the research study are provided free of charge, and neither 

 
-4- 
you nor your insurance company or other third party payer will be billed for these, including 
hospitalization, if at the New York State Psychiatric Institute. Any tests not required by the research will 
be paid for by you or your insurance company.  In addition, following 6 weeks, regardless of initial 
treatment assignment, all participants will continue to be followed and complete monthly ratings for an 
additional six months; during this post-6 week six months, the cost of any prescription, whether for 
medication or light box will be your responsibility.  After this six month post-12 week treatment period, 
should you and your doctor determine that further psychiatric treatment is indicated, your doctor will 
help you find an appropriate treater. 
 
In Case of Injury 
Federal regulations require that we inform participants about our institution's policy with regard to 
compensation and payment for treatment of research-related injuries.  In case of injury, New York State 
Psychiatric Institute will provide short term emergency medical treatment, which has been determined 
to be necessary by New York State Psychiatric Institute's doctors. In addition, we will provide assistance 
in arranging follow up care in such instances.  New York State Psychiatric Institute and Research 
Foundation for Mental Hygiene do not provide compensation or payment for treatment of research 
related injuries. However, you should be aware that you do not give up your legal right to seek such 
compensation through the court by participating in this research. 
 
Questions 
Your study doctor will answer any questions you may have now or in the future to the best of 
his/her ability. If you should have additional questions, you can contact the Principal Investigator, 
Jonathan W. Stewart, M.D., (646-774-8070). 
 
If you have any questions about your rights as a research participant, want to provide feedback, or have 
a complaint, you may call the NYSPI Institutional Review Board (IRB). (An IRB is a committee that 
protects the rights of participants in research studies). You may call the IRB Main Office at (646)774-
7155 during regular office hours.  You will be notified of significant new findings that may relate to your 
willingness to continue to participate. 
 
Women of Child-bearing Age 
While these treatments are considered to be fairly safe during pregnancy, the study excludes women 
who are pregnant.  Therefore, a pregnancy test will be performed and if it is positive, you cannot 
participate.  Also, we ask that you use reasonable precautions not to become pregnant while 
participating and if you choose to be treated with medication after the initial six weeks of treatment.  
Because the safety of missing a night of sleep, keeping specific sleep schedules or bright lights are 
unknown in pregnancy, you should not be pregnant or become pregnant while using these treatments.  
Should you become pregnant, you should immediately contact a study psychiatrist and discontinue any 
treatment until informed otherwise by a study psychiatrist.  After the six weeks research treatment, you 
will again be asked to produce a urine specimen which will be tested for pregnancy.  If do not produce a 
urine at the six week time point, continuing treatment will not be denied. 
 
By signing this form, you are indicating that you have discussed this research study and consent form 
with an investigator, and he/she has answered all of your questions about the study to the best of 
his/her ability. Your study doctor will answer to the best of his/her ability any questions you may have 
about the study, your psychiatric condition or your reaction to the study procedures. If you have any 
further questions, you may call Jonathan W. Stewart, M.D., the Principal Investigator of this study, at 
646-774-8070. 

 
-5- 
 
You will receive a copy of this consent form to keep. 
 
Documentation of Consent 
 
I voluntarily agree to participate in the research study described above. 
 
 
 
Print name: __________________ 
 
 
Signed: _____________________ 
 
 
Date: _______________________ 
 
I have discussed the proposed research with this participant including the risks, benefits, and 
alternatives to participation (including the alternative of not participating in the research). The 
participant has had an opportunity to ask questions and in my opinion is capable of freely consenting to 
participate in this research. 
 
 
 
Print name: ________________ 
 
Person Designated to Obtain Consent 
 
 
 
Signed: ___________________ 
 
Date: _____________________ 

Cover Sheet for “Are Bright Lights and Regulated Sleep Times Effective Treatment for 
Depression?” (IRB #7361)  
Overview: This outline is a guide for you to use while considering whether to participate in 
this research study. The consent that follows includes much more information about the 
study and its risks, which you will need to make a decision. Please read this outline and the 
consent carefully, and only sign it if you are comfortable doing so.  
● You are being asked to participate in a research treatment study because you are 
depressed.                                                                                                                               
● Your treatment will involve keeping specified sleep times and sitting in front of bright lights 
wearing tinted or untinted goggles..  
Type of treatment: The treatment portion of this study will last up 6 weeks followed by six 
month during which helpful treatment can be continued or other treatment can be tried. Prior 
to treatment, blood and urine tests as well as a heart test and physical examination will 
determine whether you are healthy and not pregnant (if you are a fertile female).  Treatment 
will be with bright lights and specific changes to your sleep, partially determined by how you 
answer questions about when you do or like to do things and partially by when you would 
like to be asleep.  The specific timing and manipulation of allowed sleep, bright lights and 
use of goggles will be randomly (like flipping a coin) determined.  In order to manipulate 
your sleep, varying amounts of time remaining awake between allowed sleep will be 
required, for some patients required wake time might reach as long as 42 hours on a single 
occasion. During the first week you will complete rating forms and speak with a study doctor 
by telephone daily and then weekly for the remainder of 6 weeks. Thereafter, your study 
doctor will continue to treat you for an additional six months during which there will be 
monthly determinations of how you are doing.  During this time, while your study doctor will 
manage your treatment, you or your insurance will pay for any medicine or other treatment 
such as a light box.  After this six months, if psychiatric treatment is still needed, your doctor 
will help you find further treatment.  
Alternatives to participation: You do not have to participate in this research study to receive 
treatment for depression. If you decide not to participate, the doctor who evaluated you will 
help you find an alternative.  
Risks: There are risks and discomforts associated with participating in this study (please 
read the “Risks” section of the detailed consent for a complete listing and explanation of 
risks). These include:                                                                                                               
● Your depression may not improve                                                                                                    
● Bright light can over-stimulate some people and can cause patients with bipolar disorder 
to switch from being depressed to being “high” (that is, hypomanic or manic)                        
● Missing sleep can also over-stimulate and induce switching to a “high” mood                             
Compensation: None                                                                                                  
Voluntary Participation: Participation in this study is entirely voluntary. You do not have to 
participate if you do not want to and can stop participating at any time. 

Form #PP2: HIPAA Authorization for Research 4.14.14 
New York State Psychiatric Institute (NYSPI) 
Authorization to Use or Disclose Health Information during a Research Study 
Protocol Number: 
Principal Investigator: 
Name of Study: 
Before researchers can use or share any identifiable health information (“Health Information”) about you as part of the 
above study (the “Research”), the New York State Psychiatric Institute (NYSPI) is required to obtain your authorization. You agree 
to allow the following individuals and entities to use and disclose Health Information about you as described below: 
•
New York State Psychiatric Institute (NYSPI), your doctors and other health care providers, if any, and
•
The Principal Investigator and his/her staff (together “Researchers”).   Researchers may include staff of NYSPI, the New York
State Office of Mental Health (OMH), Research Foundation for Mental Hygiene, Inc. (RFMH), and Columbia University (CU),
provided such staff is a part of the study, and
•
Providers of services for the Research at CU, NYSPI and/or RFMH, such as MRI or PET, or  Central Reference Laboratories 
(NKI), if indicated in the consent form.
1.
The Health Information that may be used and/or disclosed for this Research includes:
All information collected during the Research as told to you in the Informed Consent Form.   
Health Information in your clinical research record which includes the results of physical exams, medical and 
psychiatric history, laboratory or diagnostic tests, or Health Information relating to a particular condition that is related  to 
the Research. 
Additional information may include: 
2.
The Health Information listed above may be disclosed to:
Researchers and their staff at the following organizations involved with this Research: 
The Sponsor of the Research, 
and its agents and contractors (together, “Sponsor”); and  
Representatives of regulatory and government agencies, institutional review boards, representatives of the Researchers 
and their institutions to the level needed to carry out their responsibilities related to the conduct of the research.   
Private laboratories and other persons and organizations that analyze your health information in connection with 
this study 
Other (family members or significant others, study buddies, outside agencies etc.) Specify: 
3.
By giving permission to release your Health Information as described above, you understand that your Health
Information may be disclosed to individuals or entities which are not required to comply with the federal and state privacy laws
which govern the use and disclosure of personal Health Information by NYSPI.   This means that once your Health

Nathan Kline Institute (where the laboratory specimens war analyzed)


Are Bright Lights and Regulated Sleep Times Effective Treatment for Depression?
Jonathan W. Stewart, M.D.
7361

Form #PP2: HIPAA Authorization for Research 4.1.14 
Information has been disclosed to a third party which does not have to follow these laws (e.g., a drug company or the Sponsor 
of the Research), it may no longer be protected under the HIPAA or NYS Mental Hygiene Law requirements but is subject to the 
terms of the consent form and may be subject to other state or federal privacy laws or regulations.  
4.
Please note that:
•
You do not have to sign this Authorization form, but if you do not, you may not be able to participate in the study or
receive study related care.  You may change your mind at any time and for any reason. If you do so, you may no
longer be allowed to participate in the study.  If you withdraw this Authorization the research staff and the Sponsor, if this
is sponsored research, may still use or disclose Health Information containing identifying information they already have
collected about you as needed to maintain the reliability of the research.  Any request to withdraw this Authorization
must be made in writing to (enter name and contact information below):
•
While the Research is going on, you may not be allowed to review the Health Information in your clinical research
record that has been created or collected by NYSPI.   When this research has been completed you may be allowed to see
this information.  If it is needed for your care, your Health Information will be given to you or your Doctor.
5.
This Authorization does not have an end date.
6.
You will be given a copy of this form after you have signed it.
I agree to the use and disclosure of Health Information about me as described above: 
__________________________________________                _____________________ 
Signature of Participant/ Legal Representative    
Date 
______________________________________ 
Printed Name of Participant 
______________________________________ 
Relationship of Legal Representative to Participant (if applicable) 
We also ask you or your legal representative to initial the statements below: 
I have received a copy of the NYSPI/OMH Notice of Privacy Practices. 
Jonathan W. Stewart, M.D.
1051 Riverside Drive
New York, New York 10032

PATIENT ADHERENCE FORM 
Patient ID 
 _______ 
Date _______ 
Visit _____ 
___________________________________________________________________ 
1) Did patient complete self-report forms? 
a) all 
b) not all, but more than half 
c) half or less 
d) none 
 
2) Did patient keep his/her appointment? 
a) yes 
b) if daily phone visits during interval, patient completed most 
c) if daily phone visits during interval, patient completed half or fewer 
d) no 
 
3) Did patient follow assigned sleep times? 
a) all the time 
b) most of the time 
c) half or less 
d) not at all 
 
 
 

4) Did patient use bright lights at the assigned time? 
a) all the time 
b) most of the time 
c) half or less 
d) not at all 
 
5) Did patient use bright lights for the assigned amount of time? 
a) every use 
b) most uses 
c) half or less of the time 
d) patient either did not use bright lights or rarely if at all at the right time 
 
6) Did patient wear goggles at the assigned times? 
a) every use 
b) most uses 
c) half or less of the time 
d) patient either did not use goggles or rarely if at all  
 
7) Did patient collect saliva at the assigned times? 
a) patient collected saliva at all the assigned times 
b) patient collected saliva at most of the assigned times 
c) patient collected saliva at half or fewer of the assigned itmes 
d) patient did not collect saliva or collected at the wrong times 
e) no saliva was to be collected during this interval 
 

8) Did patient wear amber goggles during saliva collection? 
a) always 
b) during most of the collections 
c) during half or less of the collections 
d) patient did not wear goggles or wore the wrong goggles during saliva  
    collections 
e) no saliva was to be collected during this interval 
 
Key 
a = 0 
b = 1 
c = 2 
d = 3 
e = 0 
 
 

 
 
MORNINGNESS-EVENINGNESS QUESTIONNAIRE (revised)1 
 
 
Name: _____________________________  Date: ________________________ 
 
 
For each question, please select the answer that best describes you by checking the        
corresponding box.  Make your judgments based on how you have felt in recent  
weeks. 
 
1. Approximately what time would you get up if you were entirely free to plan  
your day? 
 
 5:00 a.m. – 6:30 a.m. 
 
 
 
 
 
 
 
 
              5 
 6:30 a.m. – 7:45 a.m. 
 
 
 
 
 
 
 
 
              4 
 7:45 a.m. – 9:45 a.m. 
 
 
 
 
 
 
 
 
         3 
 9:45 a.m. – 11:00 a.m. 
 
 
 
 
 
 
 
 
              2 
 11:00 a.m. – 12 noon 
 
 
 
 
 
 
 
 
         1 
 
2. Approximately what time would you go to bed if you were entirely free to plan  
your evening? 
 
 8:00 p.m. – 9:00 p.m. 
 
 
 
 
 
                                        5 
 9:00 p.m. – 10:15 p.m.   
 
 
 
 
 
 
 
         4 
 10:15 p.m. – 12:30 a.m.  
 
 
 
 
 
 
                    3 
 12:30 a.m. – 1:45 a.m. 
 
 
 
 
 
 
 
 
         2 
 1:45 a.m. – 3:00 a.m. 
 
 
 
 
 
 
 
 
         1 
 
3. If you usually have to get up at a specific time in the morning, how much do  
you depend on an alarm clock? 
 
 Not at all  
 
 
 
 
 
 
 
 
 
 
 
4 
 Slightly  
 
 
 
 
 
 
 
 
 
 
 
3 
 Somewhat  
 
 
 
 
 
 
 
 
 
 
2 
 Very much  
 
 
 
 
 
 
 
 
 
 
1 
                                                 
1Some stem questions and item choices have been rephrased from the original instrument (Horne and Östberg, 1976)  
to conform with spoken American English.  Discrete item choices have been substituted for continuous graphic scales.  
Prepared by Terman M, Rifkin JB, Jacobs J, and White TM. New York State Psychiatric Institute, 1051 Riverside Drive,  
Unit 50, New York, NY, 10032.  Supported by NIH Grant MH42931. See also:  
automated version (AutoMEQ) at www.cet.org. 
 
Horne JA and Östberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian  
rhythms.  International Journal of Chronobiology, 1976: 4, 97-100. 
 
 
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MORNINGNESS-EVENINGNESS QUESTIONNAIRE 
 
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4. How easy do you find it to get up in the morning (when you are not awakened  
unexpectedly)? 
 
 Very difficult 
 
 
 
 
 
 
 
 
 
 
1 
 Somewhat difficult 
 
 
 
 
 
 
 
 
 
2 
 Fairly easy  
 
 
 
 
 
 
 
 
 
 
3 
 Very easy 
 
 
 
 
 
 
 
 
 
 
 
4 
 
5. How alert do you feel during the first half hour after you wake up in the  
morning? 
 
 Not at all alert 
 
 
 
 
 
 
 
 
 
 
1 
 Slightly alert 
 
 
 
 
 
 
 
 
 
 
2 
 Fairly alert  
 
 
 
 
 
 
 
 
 
 
3 
 Very alert 
 
 
 
 
 
 
 
 
 
 
 
4 
 
6. How hungry do you feel during the first half hour after you wake up? 
 
 Not at all hungry  
 
 
 
 
 
 
 
 
 
1 
 Slightly hungry 
 
 
 
 
 
 
 
 
 
 
2 
 Fairly hungry 
 
 
 
 
 
 
 
 
 
 
3 
 Very hungry 
 
 
 
 
 
 
 
 
 
 
4 
 
7. During the first half hour after you wake up in the morning, how do you feel? 
 
 Very tired 
 
 
 
 
 
 
 
 
 
 
 
1 
 Fairly tired  
 
 
 
 
 
 
 
 
 
 
2 
 Fairly refreshed 
 
 
 
 
 
 
 
 
 
 
3 
 Very refreshed 
 
 
 
 
 
 
 
 
 
 
4 
 
8. If you had no commitments the next day, what time would you go to bed  
compared to your usual bedtime? 
 
 Seldom or never later 
 
 
 
 
 
 
 
 
 
4 
 Less that 1 hour later 
 
 
 
 
 
 
 
 
 
3 
 1-2 hours later 
 
 
 
 
 
 
 
 
 
 
2 
 More than 2 hours later  
 
 
 
 
 
 
 
 
1 
 
 
 
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MORNINGNESS-EVENINGNESS QUESTIONNAIRE 
 
                                Page 3  
 
 
9. You have decided to do physical exercise.  A friend suggests that you do this  
for one hour twice a week, and the best time for him is between 7-8 a.m.              
Bearing in mind nothing but your own internal “clock,” how do you think  
you would perform? 
 
 Would be in good form  
 
 
 
 
 
 
 
 
4 
 Would be in reasonable form 
 
 
 
 
 
 
 
 
3 
 Would find it difficult 
 
 
 
 
 
 
 
 
 
2 
 Would find it very difficult 
 
 
 
 
 
 
 
 
1 
 
10. At approximately what time in the evening do you feel tired, and, as a result, in  
 need of sleep? 
 
 8:00 p.m. – 9:00 p.m. 
 
 
 
 
 
 
 
 
 
5 
 9:00 p.m. – 10:15 p.m. 
 
 
 
 
 
 
 
 
 
4 
 10:15 p.m. – 12:45 a.m.  
 
 
 
 
 
 
 
 
3 
 12:45 a.m. – 2:00 a.m. 
 
 
 
 
 
 
 
 
 
2 
 2:00 a.m. – 3:00 a.m. 
 
 
 
 
 
 
 
 
 
1 
 
11. You want to be at your peak performance for a test that you know is going to be  
 mentally exhausting and will last two hours.  You are entirely free to plan your  
 day.  Considering only your “internal clock,” which one of the four testing  
 
 times would you choose? 
 
 8 a.m. – 10 a.m. 
 
 
 
 
 
 
 
 
 
 
6 
 11 a.m. – 1 p.m. 
 
 
 
 
 
 
 
 
 
 
4 
 3 p.m. – 5 p.m. 
 
 
 
 
 
 
 
 
 
 
2 
 7p.m. – 9 p.m. 
 
 
 
 
 
 
 
 
 
 
0 
 
12. If you got into bed at 11 p.m., how tired would you be? 
 
 Not at all tired 
 
 
 
 
 
 
 
 
 
 
0 
 A little tired  
 
 
 
 
 
 
 
 
 
 
2 
 Fairly tired  
 
 
 
 
 
 
 
 
 
 
3 
 Very tired 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
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MORNINGNESS-EVENINGNESS QUESTIONNAIRE 
 
                                Page 4  
 
 
13. For some reason you have gone to bed several hours later than usual, but there  
 is no need to get up at any particular time the next morning.  Which one of the   
 following are you most likely to do? 
 
 Will wake up at usual time, but will not fall back asleep  
 
 
 
4 
 Will wake up at usual time and will doze thereafter  
 
 
 
 
3 
 Will wake up at usual time, but will fall asleep again 
 
 
 
 
2 
 Will not wake up until later than usual 
 
 
 
 
 
 
1 
 
14. One night you have to remain awake between 4-6 a.m. in order to carry out a  
 night watch.  You have no time commitments the next day.  Which one of the  
 alternatives would suit you best? 
 
 Would not go to bed until the watch is over  
 
 
 
 
 
1 
 Would take a nap before and sleep after 
 
 
 
 
 
  
2 
 Would take a good sleep before and nap after 
 
 
 
 
 
3 
 Would sleep only before the watch 
 
 
 
 
 
 
 
4 
 
15. You have two hours of hard physical work.  You are entirely free to plan your  
 day.  Considering only your internal “clock,” which of the following times  
 
 would you choose? 
 
 8 a.m. – 10 a.m. 
 
 
 
 
 
 
 
 
 
 
4 
 11 a.m. – 1 p.m. 
 
 
 
 
 
 
 
 
 
 
3 
 3 p.m. – 5 p.m. 
 
 
 
 
 
 
 
 
 
 
2 
 7p.m. – 9 p.m. 
 
 
 
 
 
 
 
 
 
 
1 
 
16. You have decided to do physical exercise.  A friend suggests that you do this  
 for one hour twice a week.  The best time for her is between 10-11 p.m.   
 Bearing in mind only your internal “clock,” how well do you think you would  
 perform? 
 
 Would be in good form  
 
 
 
 
 
 
 
 
1 
 Would be in reasonable form 
 
 
 
 
 
 
 
 
2 
 Would find it difficult 
 
 
 
 
 
 
 
 
 
3 
 Would find it very difficult 
 
 
 
 
 
 
 
 
4 
 
 
 
 
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MORNINGNESS-EVENINGNESS QUESTIONNAIRE 
 
                                Page 5  
 
 
17. Suppose you can choose your own work hours.  Assume that you work a five- 
 hour day (including breaks), your job is interesting, and you are paid based on  
 your performance.  At approximately what time would you choose to begin? 
 
 5 hours starting between 4:00 – 8:00 a.m. 
 
 
 
 
 
 
5 
 5 hours starting between 8:00 – 9:00 a.m. 
 
 
 
 
 
 
4 
 5 hours starting between 9:00 a.m. – 2:00 p.m. 
 
 
 
 
 
3 
 5 hours starting between 2:00 – 5:00 p.m. 
 
 
 
 
 
 
2 
 5 hours starting between 5:00 p.m. – 4:00 a.m. 
 
 
 
 
 
1 
 
18. At approximately what time of day do you usually feel your best? 
 
 5:00 a.m. – 8:00 a.m. 
 
 
 
 
 
 
 
 
 
5 
 8:00 a.m. – 10:00 a.m. 
 
 
 
 
 
 
 
 
 
4 
 10:00 a.m. – 5:00 p.m. 
 
 
 
 
 
 
 
 
 
3 
 5:00 p.m. – 10:00 p.m. 
 
 
 
 
 
 
 
 
 
2 
 10:00 p.m. – 5:00 a.m. 
 
 
 
 
 
 
 
 
 
1 
 
19. One hears about “morning types” and “evening types.”  Which one of these  
 types do you consider yourself to be? 
 
 Definitely a morning type 
 
 
 
 
 
 
 
 
6 
 Rather more a morning type than an evening type  
 
 
 
 
4 
 Rather more an evening type than a morning type  
 
 
 
 
2 
 Definitely an evening type 
 
 
 
 
 
 
 
 
0 
 
 
 
 
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  Total: _________