The Effect of Melatonin on Depression, Anxiety, Cognitive Function and Sleep Disturbances in Breast Cancer Patients (MELODY)

The purpose of this study is to investigate the effect of 6 mg melatonin daily for 1 week preoperatively to 12 weeks postoperatively on depressive symptoms, anxiety, cognitive function and sleep disturbances in breast cancer patients. Furthermore the investigators will examine whether a specific clock-gene (HPER3) is correlated with an increased risk of depression, sleep disturbances or cognitive dysfunction.

Study Overview

• Status: Terminated
• Conditions: Depression; Breast Cancer
• Intervention / Treatment: Drug: Melatonin (N-acetyl-5-methoxytryptamine); Drug: Placebo

Detailed Description

About 1.4 million women are diagnosed with breast cancer every year. Breast cancer is the most common malignancy among women worldwide constituting about 1/5 of all cancer types. Breast cancer diagnosis and treatment, and the months following primary therapy are stressful times for most women. Aside from the actual "cancer threat" many women experience various degrees of depression, anxiety, sleep disturbances and memory/concentration problems (cognitive dysfunction). Naturally these factors influence the quality of life but also contribute to morbidity and mortality.

Melatonin is a regulatory circadian hormone having, among others, hypnotic, sedative, anxiolytic and possibly anti-depressive effects. It has very low toxicity and very few adverse effects.

The purpose of this project is to test melatonin (6 mg daily for 1 week preoperatively to 12 weeks postoperatively) on breast cancer patients and hopefully hereby be able to prevent depression, anxiety, sleep disturbances and cognitive dysfunction. On an overall perspective this will hopefully contribute to improving the quality of life for these patients and extend their lifetime. Furthermore the investigators will be examining whether a specific gene called a clock-gene (HPER3) is correlated with an increased risk of depression, sleep disturbances or cognitive dysfunction. If this is the case it could become possible to identify women with an increased risk and provide prophylactic treatment for those with a risk of developing a depression, sleep disturbances or cognitive disturbances.

Sample size calculations were based on our primary outcome parameter. Using a conservative estimate for the incidence of depression, the investigators expect to find a reduction from 30% to 15% with melatonin treatment. Sample size is sufficient to include our secondary and tertiary outcome parameters as well. The sample size calculations were calculated with a power of 80%, a type I error of 5% and a type II error of 20%.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2730
    • Herlev Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Women, age 30-75, with breast cancer who are admitted for a lumpectomy or mastectomy at Herlev Hospital
• ASA score I-III
• No sign of depression measured my Major Depression Inventory (MDI)
• Not pregnant

Exclusion Criteria:

• Neoadjuvant chemotherapy
• Treatment with SSRI, Warfarin or other anticoagulants (except 75 mg ASA daily), MAO inhibitors or calcium blockers
• Rotor or Dubin-Johnson syndrome
• Epilepsy
• Known allergic reaction to melatonin
• Known and treated sleep apnea
• Diabetes Mellitus - insulin treated
• Ongoing or previous medically treated depression or bipolar disorder
• Known autoimmune diseases - systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and sclerose
• Incompensated liver cirrhosis
• Severe kidney disease
• Previous or current cancer
• Known medically treated sleep-disorder (insomnia, restless legs etc)
• Shift-work and night-work
• Daily alcohol intake of more than 5 units
• Pre-operative treatment with psychopharmacological drugs, opioids or anxiolytics (including all sleeping pills)
• Predicted bad compliance
• Pregnant or breast-feeding
• Pre-operative Mini Mental State Evaluation (MMSE) score less than 24

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Melatonin; 6 mg oral melatonin daily	Drug: Melatonin (N-acetyl-5-methoxytryptamine); 6 mg oral melatonin daily 1 hour before bedtime; Other Names: Melatonin; N-acetyl-5-methoxytryptamin
Placebo Comparator: Placebo; 6 mg oral placebo daily	Drug: Placebo; 6 mg oral placebo daily 1 hour before bedtime

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Depression Inventory (MDI)- Depression at One Point in the Study	MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument. For inclusion we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale. Diagnostic scale using the ICD-10 algorithm: Mild depression: 2 core symptoms and 2 other symptoms Moderate depression: 2 core symptoms and 4 other symptoms Severe depression: 3 core symptoms and 5 other symptoms Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50	Depression at one point in the study (not including baseline) out of 4 measurements at app. day 21, day 35, day 63 and day 91 of the study.
Per Protocol - Depression at One Point in the Study Period	MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument. For inclusion we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50 This analysis includes only patients who have taken study medication as planned.	Per protocol - depression at one point in the study period (not baseline)
Intention to Treat (Underestimate) - Depression at One Point in the Study Period	MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument. For inclusion we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50 For this analysis all missing MDI data have been analyzed as "NO" depression.	Intention to treat (underestimate) - depression at one point in the study period (not baseline)
Intention to Treat (Overestimate) - Depression at One Point in the Study Period	MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument. For inclusion we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale. Rating scale: No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50 For this analysis all missing MDI data have been analyzed as "YES" for depression.	Intention to treat (overestimate) - depression at one point in the study period (not baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) for VAS Data on Anxiety - Immediate Postoperative Period	Anxiety measured by VAS (visual analog scale). A subjective feeling of anxiety was registered on a VAS going from "no anxiety", equivalent to 0mm to "worst possible anxiety", equivalent to 100mm. Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively. Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %	Daily - from inclusion till 8 days postoperatively
Area Under the Curve (AUC) for VAS Data on Anxiety - Long-term Postoperative Period	Anxiety measured by VAS (visual analog scale). Completed every 14th day. A subjective feeling of anxiety was registered on a VAS going from "no anxiety", equivalent to 0mm to "worst possible anxiety", equivalent to 100mm. Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day). Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %	App. 14 days postoperatively till 10 weeks postoperatively
Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Immediate Postoperative Period	Sleepiness measured by Karolinska Sleepiness Scale. KSS is a 9-point scale from 1 (very awake) to 9 (very sleepy) where a score of 7 or more reflects pathological sleepiness. Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively. Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %	Daily from inclusion till 8 days postoperatively
Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Long-term Postoperative Period	Sleepiness measured by Karolinska Sleepiness Scale. KSS is a 9-point scale from 1 (very awake) to 9 (very sleepy) where a score of 7 or more reflects pathological sleepiness. Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day). Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %	App. 14 days postoperatively till 10 weeks postoperatively
Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period	Fatigue on a Visual Analog Scale - filled out daily. A subjective feeling of fatigue was registered on a VAS going from "no fatigue", equivalent to 0mm to "worst possible fatigue", equivalent to 100mm. Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively. Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %	Daily from inclusion till 8 days postoperatively
Area Under the Curve (AUC) for VAS Data on Fatigue - Long-term Postoperative Period	Fatigue on a Visual Analog Scale - filled out every 14th day. A subjective feeling of fatigue was registered on a VAS going from "no fatigue", equivalent to 0mm to "worst possible fatigue", equivalent to 100mm. Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day). Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %	App. 14 days postoperatively till 10 weeks postoperatively
Area Under the Curve (AUC) for Data on General Well-being - Immediate Postoperative Period	General well-being on a Visual Analog Scale - filled out daily. A subjective feeling of general well-being was registered on a VAS going from "very high well-being", equivalent to 0mm to "very low well-being", equivalent to 100mm. Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively. Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %	Daily from inclusion till 8 days postoperatively
Area Under the Curve (AUC) for VAS Data on General Well-being - Long-term Postoperative Period	General well-being on a Visual Analog Scale - filled out every 14th day. A subjective feeling of general well-being was registered on a VAS going from "very high well-being", equivalent to 0mm to "very low well-being", equivalent to 100mm. Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day). Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %	App. 14 days postoperatively till 10 weeks postoperatively
Area Under the Curve (AUC) for VAS Data on Pain - Immediate Postoperative Period	Pain on a Visual Analog Scale - filled out daily. A subjective feeling of pain was registered on a VAS going from "no pain", equivalent to 0mm to "worst possible pain", equivalent to 100mm. Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively. Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %	Daily from inclusion till 8 days postoperatively
Area Under the Curve (AUC) for VAS Data on Pain - Long-term Postoperative Period	Pain on a Visual Analog Scale - filled out every 14th day. A subjective feeling of pain was registered on a VAS going from "no pain", equivalent to 0mm to "worst possible pain", equivalent to 100mm. Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day). Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %	App. 14 days postoperatively till 10 weeks postoperatively
Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period	Subjective sleep score on Visual Analog Scale. Subjective sleep quality was registered on a VAS going from "best possible sleep", equivalent to 0mm to "worst possible sleep", equivalent to 100mm. Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively. Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %	Daily from inclusion till 8 days postoperatively
Area Under the Curve (AUC) for VAS Data on Sleep Quality - Long-term Postoperative Period	Subjective sleep on a Visual Analog Scale. Subjective sleep quality was registered on a VAS going from "best possible sleep", equivalent to 0mm to "worst possible sleep", equivalent to 100mm. Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day). Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %	App. 14 days postoperatively till 10 weeks postoperatively
Sleep Architecture	Actigraphy (total minutes asleep, sleep effectiveness, sleep latency, awakenings). A wrist actigraph will be worn from inclusion till 14 days postoperatively.	From inclusion till 14 days postoperatively
HPER3 Genotype	A blood sample will be taken at inclusion and analysed for HPER3 genotype (4/4, 4/5, 5/5) and this will be investigated for a correlation with sleep, cognitive function and depressive symptoms 7 patients did not give blood samples	At inclusion = day-7
Incidence of Postoperative Cognitive Dysfunction (POCD) App. 2 Weeks Postoperatively.	Calculations for POCD were based on normative data from 133 females aged 40-60 years. We evaluated changes from the preoperative baseline to the 2 postoperative test sessions. In controls we calculated mean and standard deviations (SD) of these differences. The mean change in this group may be taken as estimated learning effects. For the individual patients, we compared baseline scores with the 2- and 12-week postoperative test results, subtracted the average learning effect from the changes and divided the result by the SD of the control group to obtain a Z score for the 7 individual test outcomes. A large positive Z score indicated deterioration in cognitive function from baseline in patients. We defined a composite Z score as the sum of the 7 Z scores and normalized this using the SD for that sum in the controls. POCD was defined as a combined Z score >1.96 or a Z score >1.96 in at least 2 of the 7 subtests. Units of measure = % of patients with YES to POCD	App. 2 weeks postoperatively
Incidence of Postoperative Cognitive Dysfunction (POCD) App. 10 Weeks Postoperatively	Calculations for POCD were based on normative data from 133 females aged 40-60 years. We evaluated changes from the preoperative baseline to the 2 postoperative test sessions. In controls we calculated mean and standard deviations (SD) of these differences. The mean change in this group may be taken as estimated learning effects. For the individual patients, we compared baseline scores with the 2- and 12-week postoperative test results, subtracted the average learning effect from the changes and divided the result by the SD of the control group to obtain a Z score for the 7 individual test outcomes. A large positive Z score indicated deterioration in cognitive function from baseline in patients. We defined a composite Z score as the sum of the 7 Z scores and normalized this using the SD for that sum in the controls. POCD was defined as a combined Z score >1.96 or a Z score >1.96 in at least 2 of the 7 subtests. Units of measure = % of patients with YES to POCD	App. 10 weeks postoperatively

Collaborators and Investigators

• Sponsor: Melissa Voigt Hansen
• Collaborators: Rigshospitalet, Denmark; University of Copenhagen; Pharma Nord
• Investigators: Principal Investigator: Melissa V Hansen, MD, Herlev Hospital

Publications and helpful links

General Publications

• Hansen MV, Madsen MT, Andersen LT, Hageman I, Rasmussen LS, Bokmand S, Rosenberg J, Gogenur I. Effect of Melatonin on Cognitive Function and Sleep in relation to Breast Cancer Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial. Int J Breast Cancer. 2014;2014:416531. doi: 10.1155/2014/416531. Epub 2014 Aug 27.

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: May 13, 2011
• First Submitted That Met QC Criteria: May 17, 2011
• First Posted (Estimate): May 18, 2011

Study Record Updates

• Last Update Posted (Estimate): May 6, 2014
• Last Update Submitted That Met QC Criteria: April 4, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Depression; Anxiety; Melatonin; Cognitive function; Sleep disturbances; Breast cancer surgery
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Nervous System Diseases; Skin Diseases; Mood Disorders; Neoplasms; Sleep Wake Disorders; Neoplasms by Site; Breast Diseases; Depression; Depressive Disorder; Breast Neoplasms; Dyssomnias; Parasomnias; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: MVH-03; 2010-022460-12 (EudraCT Number); 2007-58-0015/HEH.750.89-12 (Other Identifier: The Danish Data Protection Agency); H-4-2011-007 (Other Identifier: The Danish Ethics Committee)