Official Title

The Effect of Melatonin on Depression, Anxiety, Cognitive Function and Sleep Disturbances in Breast Cancer Patients
  • Phase

    Phase 2/Phase 3
  • Study Type

    Interventional
  • Intervention/Treatment

    melatonin ...
  • Study Participants

    54
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.
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 Started
Jul 31
2011
Primary Completion
Jan 31
2013
Study Completion
Jan 31
2013
Results Posted
May 06
2014
Estimate
Last Update
May 06
2014
Estimate

Drug Melatonin (N-acetyl-5-methoxytryptamine)

6 mg oral melatonin daily 1 hour before bedtime

  • Other names: Melatonin, N-acetyl-5-methoxytryptamin

Drug Placebo

6 mg oral placebo daily 1 hour before bedtime

Melatonin Active Comparator

6 mg oral melatonin daily

Placebo Placebo Comparator

6 mg oral placebo daily

Criteria

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

Summary

Melatonin

Placebo

All Events

Event Type Organ System Event Term Melatonin Placebo

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.

Melatonin

NO

23.0
participants

YES

5.0
participants

Placebo

NO

11.0
participants

YES

15.0
participants

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

Melatonin

NO

24.0
participants

YES

3.0
participants

Placebo

NO

11.0
participants

YES

9.0
participants

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.

Melatonin

NO

24.0
participants

YES

3.0
participants

Placebo

NO

11.0
participants

YES

5.0
participants

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.

Melatonin

NO

25.0
participants

YES

3.0
participants

Placebo

NO

21.0
participants

YES

5.0
participants

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 %

Melatonin

13.0
Units on KSS*2 weeks (Median)
Inter-Quartile Range: 11.0 to 17.0

Placebo

14.0
Units on KSS*2 weeks (Median)
Inter-Quartile Range: 12.0 to 20.0

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 %

Melatonin

307.0
mm*day (Median)
Inter-Quartile Range: 93.0 to 399.0

Placebo

300.0
mm*day (Median)
Inter-Quartile Range: 146.0 to 429.0

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 %

Melatonin

90.0
mm*2 weeks (Median)
Inter-Quartile Range: 58.0 to 147.0

Placebo

88.0
mm*2 weeks (Median)
Inter-Quartile Range: 41.0 to 133.0

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 %

Melatonin

282.0
mm*day (Median)
Inter-Quartile Range: 211.0 to 436.0

Placebo

372.0
mm*day (Median)
Inter-Quartile Range: 180.0 to 450.0

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 %

Melatonin

95.0
mm*2 weeks (Median)
Inter-Quartile Range: 141

Placebo

89.0
mm*2 weeks (Median)
Inter-Quartile Range: 44

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 %

Melatonin

97.0
mm*day (Median)
Inter-Quartile Range: 45.0 to 181.0

Placebo

130.0
mm*day (Median)
Inter-Quartile Range: 46.0 to 421.0

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 %

Melatonin

13.0
mm*2 weeks (Median)
Inter-Quartile Range: 2.0 to 48.0

Placebo

22.0
mm*2 weeks (Median)
Inter-Quartile Range: 8.0 to 76.0

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 %

Melatonin

279.0
mm*day (Median)
Inter-Quartile Range: 203.0 to 466.0

Placebo

355.0
mm*day (Median)
Inter-Quartile Range: 194.0 to 441.0

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 %

Melatonin

101.0
mm*2 weeks (Median)
Inter-Quartile Range: 51.0 to 148.0

Placebo

116.0
mm*2 weeks (Median)
Inter-Quartile Range: 51.0 to 133.0

Sleep Architecture

Actigraphy (total minutes asleep, sleep effectiveness, sleep latency, awakenings). A wrist actigraph will be worn from inclusion till 14 days postoperatively.

Outcome Measure Data Not Reported

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

Melatonin

Placebo

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

Melatonin

4/4 genotype

14.0
Participants

4/5 genotype

10.0
Participants

5/5 genotype

2.0
Participants

Missing

2.0
Participants

Placebo

4/4 genotype

10.0
Participants

4/5 genotype

10.0
Participants

5/5 genotype

1.0
Participants

Missing

5.0
Participants

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

Melatonin

Placebo

6.25
Percentage of patients

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 %

Melatonin

85.0
mm*day (Median)
Inter-Quartile Range: 44.0 to 160.0

Placebo

140.0
mm*day (Median)
Inter-Quartile Range: 46.0 to 341.0

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 %

Melatonin

14.0
mm*2 weeks (Median)
Inter-Quartile Range: 4.0 to 31.0

Placebo

19.0
mm*2 weeks (Median)
Inter-Quartile Range: 8.0 to 100.0

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 %

Melatonin

35.0
Units on KSS*day (Median)
Inter-Quartile Range: 26.0 to 48.0

Placebo

39.0
Units on KSS*day (Median)
Inter-Quartile Range: 31.0 to 55.0

Total

54
Participants

Age, Continuous

56.30
years (Mean)
Standard Deviation: 11.07

Anaesthesia duration

171
Minutes (Median)
Inter-Quartile Range: 139.25 to 196.25

MDI - Major Depression Inventory

7
Scores on a scale (Median)
Inter-Quartile Range: 4.0 to 11.0

Surgery duration

110
Minutes (Median)
Inter-Quartile Range: 85.0 to 141.0

Age, Categorical

Anti-hormone therapy

Menopausal status

Oncological treatment

Region of Enrollment

Sex: Female, Male

Type of surgery

Overall Study

Melatonin

Placebo

Drop/Withdrawal Reasons

Melatonin

Placebo