The primary objective of the present study is to examine whether the combination of the antidepressant duloxetine and chronoterapeutic methods (including sleep deprivation, light therapy and maintaining a regular sleep-wake rhythm)in patient with major depression, will induce an immediate improvement form depression and whether this antidepressive effect will be maintained in the long term (29 weeks). Patient will be randomised to the above mentioned treatment or to an active groups receiving exercise.

Condition	Intervention
Major depression	Procedure: Sleep deprivation  Procedure: Light therapy  Procedure: Diurnal rhythms

Further Study Details: 

Primary Outcomes: Hamilton score during the 29 weeks trial
Secondary Outcomes: Cortisol measurements; Depression self rating by the Preskorn scale
Expected Total Enrollment:  100

PROTOCOL SYNOPSIS

Background The Psychiatric Research Unit at Frederiksborg General Hospital, with professor Per Bech as the driving force, has been working with sleep in relation to affective disorders for many years. During the last 4 years we have performed and been involved in several light therapy studies in depression, both in seasonal affective disorder (SAD), with light as an augmention strategy in nonseasonal depression, in post-stroke depression and in Tourette''''s syndrome.

In relation to the dissemination of results from Klaus Martiny’ Ph.D. thesis on bright light therapy as an augmenting strategy in major depression (Martiny 2004a), our research unit has achieved close collaboration with some of the world''''s leading experts in chronoterapeutics: Professor Anna Wirz-Justice in Basel, Switzerland, Franscesco Benedetti in Milano, Italy, Michael Terman in New York, Mathias Berger in Freiburg, Germany and Joseph Wu at the University of California Irvine (see Wirz-Justice 2004). The basic idea of the present study comes from this group which over many years has performed and reported clinical studies in chronoterapeutics.We hope that our research unit will be able to conduct this study, as required, in a large patients sample and under the guidance of this group.

The study will fulfil the research unit''''s ambition to investigate antidepressive treatment algorithms with the propensity to lead to an earlier and sustained onset of action and a higher remission rate. Remission from depression does not only restore the patients'''' normal social functioning, but also reduces the risk of recurrence of depression. To attain this goal we regard the combination of new and powerful antidepressive drugs and non-pharmacological therapies most interesting and promising. This study has full support from the hospital administration who welcomes the active involvement of the nursing staff in the chronoterapeutic part.

The present study incorporates the combination of duloxetine and chronoterapeutics: sleep deprivation, sleep phase advance and light therapy.

Duloxetine is a new dual action antidepressant drug that has shown an early onset of action and a high remission rate, with acceptable side effects (Detke 2002, Raskin 2003). It is thus a promising drug for new studies.

Chronotherapeutic approaches such as total or partial sleep deprivation, phase advance of the sleep-wake cycle and light therapy have been investigated over the last thirty years.

Total or partial sleep deprivation in the second half of the night and phase advance of the sleep-wake cycle have shown to have rapid and profound effects on depressed mood in all diagnostic subgroups (Schilgen and Tölle 1987, Kuhs and Tölle 1991). Sleep deprivation attains an immediate response in around 60% of the cases and smaller reported studies using combinations of sleep deprivation with lithium, antidepressant drugs, pindolol, sleep phase advance or morning light therapy have indicated that the response after initial sleep deprivation can be maintained (Neumeister 1996, Fritzsche 2001). Light treatment has become an accepted and effective treatment of seasonal affective disorder (SAD), and recent studies have document accelerated and augmented response in non-seasonal, and even in chronic depression (as adjunctive treatment to medication) (Martiny 2004a, Martiny 2004b, Benedetti, 2003).

The combination of the effect of chronoterapeutics and new powerful antidepressant drugs thus is a very interesting and promising approach. While light treatment is widely used, sleep deprivation and sleep phase advance are therapies that are in need of studies with sufficient numbers of patients to evaluate their applicability and efficacy.

Objectives Duloxetine, a new dual action drug, has shown promising efficacy with an early onset of action and a high remission rate both in short- and long-term treatment. Thus, Raskin (2003) found an impressive remission rate of 50.8% after six weeks and 81.8% after 52 weeks of treatment. The primary objective of the present study is to examine whether the combination of duloxetine and chronoterapeutic methods induces higher remission rates at an earlier time point and obtains a 50% percent remission rate after three weeks of treatment.

Patients

Inclusion criteria:

• A diagnosis of major depression according to DSM-IV • Patient with major depression as part of a bipolar disorder should be in adequate mood stabilizing therapy at entry to the study • Age of 18 or above • A score on the Hamilton Depression Scale,17 items version of at least 18

Exclusion criteria:

• Primary psychotic disorder • Psychotic depression • Drug or alcohol abuse • Severe organic brain disease • Severe suicidal ideation (a score of 2 or above on the Hamilton Depression Scale, 17-items version) • Mental retardation • Pregnancy or lactation period

Study design Please see enclosure 1 (flow sheet). The study will be a randomised controlled, semi-blind (rater-blind) trial with a fixed dosage trial length of nine weeks. Within this nine weeks period study drugs will be given at a dose of 60 mg duloxetine. Patients will be randomized and start medication with duloxetine one week before starting the chronoterapeutic intervention. This is a precaution not to cause any distress in patients (as could be expected with new possible side-effects and the chronoterapeutic intervention introduced at the same time). The following chronoterapeutic intervention covers one week (seven days) where patients will be admitted to an open ward. If improved sufficiently patients can be discharged at this time point.

Subsequently patients will be seen monthly in an uncontrolled follow-up period ending with a last visit at 6 month after inclusion into the study. In this follow-up period starting from week nine, patients will have the opportunity to alter dosage of study drug or to shift into other medication. The only intervention in this follow up period will be to encourage the patients to keep the daily time structure as instructed during their admittance to the ward.

Patients randomised to group A will be treated with a combination of duloxetine 60 mg per day for 29 weeks and a chronoterapeutic intervention of one weeks duration (see below). Patients randomised to group B will be treated with duloxetine in a dose of 60 mg per day for 29 weeks and individual exercise instructed by a psysiotherapist. Patients will be informed that the two intervention groups are based on different time-structuring regimes. The placebo condition has been chosen to secure an similar expectancy rate in the two treatment conditions.

Group A. Duloxetine treatment with 60 mg per day for 29 weeks plus chronoterapeutic intervention of 1 weeks duration.

• Duloxetine Dosage will be 60 mg daily with the possibility of increasing dosage to 90 or 120 mg at week nine for patients with incomplete response.

• Chronoterapeutic intervention

1. Light treatment: Light treatment will be given with 10.000 lux for 1 hour, individually timed according to the MEQ score.
2. Sleep deprivation and sleep phase advance: Sleep will be scheduled as shown below Day one to two: Total sleep deprivation I Day two to three: from 9 pm to 7 am. Sleep-phase-advance I Day three to four: Total sleep deprivation II Day four to five: from 9 pm to 7 am. Sleep phase advance II Day five to six: Total sleep deprivation III Day six to seven: from 9 pm to 7 am. Sleep phase advance III Group B Duloxetine treatment with 60 mg per day for nine weeks plus chronoterapeutic intervention with moderate time structure and exercise of 1 weeks duration.

• Duloxetine Dosage will be 60 mg daily with the possibility of increasing dosage to 90 or 120 mg at week nine for patients with incomplete response.

From day seven and on, sleep is regulated according to two rules:

1. Not taking naps in the daytime
2. Getting out of bed by 8 am at the latest. Concomitant medication Oxazepam is allowed for severe agitation and sleep disturbances (except at days of sleep deprivation) in daily doses as mentioned earlier.

Psychometrics The diagnosis of major depression will be made by the Mini International Neuropsychiatric Interview (M.I.N.I.). Severity of depression will be assessed by weekly ratings using the interview-based Hamilton Depression Rating scales (17- and 6-items versions, Bech et al 2000) and the newly developed 6-item self-assessment Hamilton scale. Patients will fill in the Global Rating Scale (Preskorn) daily. Side effects will be monitored weekly by the UKU scale. At baseline, the Morningness Eveningness Questionnaire (MEQ) will be used to calculate the individual timing of light (Terman, Benedetti 2003).

Time line The study starts in september 2005.The inclusion period is 2 years and data will be published in a 6 months'''' period thereafter.

Efficacy measures Primary outcome criteria will be response and remission. Secondary outcome criteria will be the mean of weekly Hamilton ratings (17-items and 6-items versions).

Tertiary outcome criterion will be the time until discharge.

Regulations The study will follow the Good Clinical Practice Guidelines and has obtained approval from the local ethical committee, the Danish Data Protection Agency and the Danish Medicines Agency. Patients will sign informed consent forms after written and oral descriptions of the study.

Safety All Events, serious Events, Adverse drug reactions and Suspected Unexpected Serious Adverse Reactions will be reported according to the regulatory authorities’ rules. Side effects will be monitored.

References Bech P, Cialdella P, Haugh MC, Birkett MA, Hours A, Boissel JP, Tollefson GD. Meta-analysis of randomised controlled trials of fluoxetine v. placebo and tricyclic antidepressants in the short-term treatment of major depression.

Br J Psychiatry. 2000 May;176:421-8. Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita, M, Smeraldi E. Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. J Clin Psychiatry 2003; 64, 648-653.

Detke MJ, Lu Y, Goldstein DJ, McNamara RK, Demitrack MA. Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. J Psychiatr Res 2002; 36: 383-390.

Fritzsche M, Heller R, Hill H, Kick H. Sleep deprivation as a predictor of response to light therapy in major depression. J Aff Disord 2001; 62, 207-215.

Kuhs H, Tölle R. Sleep deprivation therapy. Biol Psychiatry 1991; 29:1129-1148.

Martiny K, Lunde M, Undén M, Dam H, Bech P. Adjunctive bright light in non-seasonal major depression (2004, in review).

Martiny K, Lunde M, Simonsen C, Clemmesen L, Poulsen DL, Solstad K, Bech, P. Relapse prevention with citalopram in SAD patients responding to one week of bright light treatment. Acta Psychiatr Scand 2004; 109: 230-234.

Neumeister A, Goessler R, Lucht M, Kapitany T, Bamas C, Kasper S. Bright light therapy stabilizes the antidepressant effect of partial sleep deprivation. Biological Psychiatry 1996; 3: 16-21.

Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry 2003; 64: 1237-1244.

Schilgen B, Tölle R. Partial sleep deprivation as therapy for depression. Arch Gen Psychiatry 1987; 37: 267-271.

Terman M, White TM, Jacobs J. Automated Morningness-Eveningness Questionnaire. Self-assessment version. Center for Environmental Therapeutics, Norwood, NJ. Available at: http://www.cet.org.

Wirz-Justice A, Terman M, Oren DA, Goodwin FC, Kripke DF, Whybrow PC, Wisner KL, Wu JC, Lam RW, Berger M, Danilenko KV, Kasper S, Smeraldi E, Takahashi K, Thompson C, Hoofdakker R (2004). Brightening depression (letter to the editor). Science, 303: 467-468.

Ages Eligible for Study:  18 Years   -   70 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• A diagnosis of major depression according to DSM-IV
• Patient with major depression as part of a bipolar disorder should be in adequate mood stabilizing therapy at entry to the study
• Age of 18 or above
• A score on the Hamilton Depression Scale,17 items version of at least 18

Exclusion Criteria:

• Primary psychotic disorder
• Psychotic depression
• Drug or alcohol abuse
• Severe organic brain disease
• Severe suicidal ideation (a score of 2 or above on the Hamilton Depression Scale, 17-items version)
• Mental retardation
• Pregnancy or lactation period

Please refer to this study by ClinicalTrials.gov identifier  NCT00149110

Klaus Martiny, MD Ph.D.      +45 48 29 33 15    kmar@fa.dk
Per Bech, Professor      +45 48 29 32 53    pebe@fa.dk

Denmark
      Psychiatric Research Unit, Hilleroed Hospital, Hilleroed,  3400,  Denmark

Study chairs or principal investigators

Klaus Martiny Martiny, MD Ph.D.,  Principal Investigator,  Psychiatric Research Unit, Hilleroed Hospital, Denmark   

Study ID Numbers:  2005-001855-39 Eudra CT number
Last Updated:  September 7, 2005
Record first received:  September 6, 2005
ClinicalTrials.gov Identifier:  NCT00149110
Health Authority: Denmark: Danish Medicines Agency
ClinicalTrials.gov processed this record on 2005-09-13