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

Study Overview
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Brief Summary
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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.

Detailed Description
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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%.

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

Conditions
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Depression, Breast Cancer

Intervention / Treatment
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* Drug: Melatonin (N-acetyl-5-methoxytryptamine)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep disturbances, Breast cancer surgery, Melatonin, Depression, Anxiety, Cognitive function