Clinical trial NCT00971815: Effects of 3 Months of Selective Serotonin Reuptake Inhibitor (SSRI)-Treatment on Metabolism and Hypothalamic-pituitary-adrenal (HPA)-Axis in Young Men Born With Low Birth Weight
Official title: Effects of 3 Months of SSRI-Treatment on Metabolism and HPA-axis in Young Men Born With Low Birth Weight - a Randomized, Double Blinded and Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Insulin Resistance
Low Birth Weight
Type 2 Diabetes
Cardiovascular Disease
Melancholic Depression
Anxiety Disorders
Keywords: HPA-axis
fetal programming
Lead sponsor: University of Aarhus
Sponsor class: OTHER
First posted: 2009-09-04
Enrollment: 60
Sex: MALE
Minimum age (years): 20
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Chronic stress has been proposed to be involved the development of western life-style diseases such as cardiovascular disease and type 2 diabetes (T2DM). At the same time chronic stress is also believed to cause psychiatric disease such as melancholic depression (MD)and anxiety disorders.

Accordingly, humans born with low birth weight (LBW) (ei. less than 5,0 LB) display an increased risk for T2DM and MD. Studies suggest stress and adrenal stress hormones (glucocorticoids) (GCC) might be involved in the development of both of these conditions.

Recent studies of animals born LBW suggest, that SSRI-compounds, usually employed in the treatment of MD-related diseases, reduces stress-responses and levels of stress hormones such adrenal steroids and at the same time has a positive influence on glucose metabolism.

In present study, the investigators aim to measure levels of GCC and stress and assess glucose metabolism in healthy young men (20-35 years) born LBW (40 subjects). The volume and structure of a certain brain area (ie. hippocampus) involved in regulation of adrenal GCC and known to be malfunctioning in chronically stressed individuals will be assessed by magnetic resonance imaging (MRI). Further metabolic examination will be accompanied by MRI spectroscopy of liver and muscle fat content as well as total fat content (Dexa-scanning) and contents of fat in the abdomen (by MRI) . Psychiatric well-ness and symptoms will be characterized by well-established questionnaires such as MDI and SCL-92 and responses as regards blood pressure, heart rate and changes in basal plasma concentrations of GCC and Epinephrine will be assessed while performing a Stroop Stress Test. Finally, a 24 hour blood pressure profile test will be included.

After this extensive examination program, subjects will be randomized to 3-4 months of treatment with either Escitalopram (an SSRI-compound) or Placebo. Subsequently, at the end of the treatment, the whole examination program will be repeated to detect potential beneficial changes.

A group of young normal birth weight men (20 subjects) will serve as a healthy baseline group for comparison and will not be exposed to any medical treatment.

This trial will add understanding to the mechanism underlying the development of type 2 diabetes and depression in LBW. Additionally, present trial might be capable of proposing a novel treatment strategy to prevent the development of these diseases in LBW man.


Eligibility criteria: Inclusion Criteria:

1. Healthy men 20-35 years old.
2. birth weight \<2500g.
3. Born at gestational week 38- 40 (42).

Exclusion Criteria:

1. Diabetes, insulin-resistance or precursors in first degree relatives or maternal gestational diabetes.
2. Small parents(mother \<160cm and/or father \<170cm).
3. History of abuse of alcohol, medicine og drugs in the mother during pregnancy.
4. Liver of renal failure : s-ALAT \> 2.5 normal upper limit (\>175μM) or s-creatinine \>125 μmol/l.
5. Co-morbidity that after at medical examination is considered to be a problem.
6. BMI\>25.5
7. Smoking that is considered to be an issue as regards completing the study.
8. Treatment with a MAO-inhibitor.
9. Born before gestational week 38.
10. Participation in larger X-ray examinations such CT-scans during the last 12 months.
11. Participation in medical experiments or treatments involving intravenous administration of radioactive substances during the last
12. Ongoing medical treatment that will be considered a issue for completing the study.
13. Allergy towards the substance Escitalopram.
14. Metal parts in the body that contra-indicates MRI.
15. Ongoing medical treatment thrombocyte inhibiting substances such as NSAIDS.
16. Previous gastrointestinal bleeding or gastro-duodenal ulcers.
17. Depression during examination or treatment

16/05-2011: Criterias updated - added 17 and adjusted 6. from BMI \>25 to BMI \>25.5

Primary outcomes:
measure: Changes in rate of glucose dissappearance
timeFrame: Changes in LBW-subjects from baseline vs. post-treatment after 3 months treatment with placebo or Escitalopram
measure: Changes in the 24-hour AUC of free plasma cortisol
timeFrame: Changes in LBW-subjects from baseline vs. post-treatment after 3 months treatment with placebo or Escitalopram
Secondary outcomes:
measure: 24 hour basal plasma cortisol/ACTH profile as measured every 3rd hour.
timeFrame: before and after 3 months of treatment with placebo or Escitalopram
measure: hippocampic volume and structure as assessed by MRI
timeFrame: before and after 3 months of treatment with placebo or Escitalopram
measure: 24 hour bloodpressure profile
timeFrame: before and after 3 months of treatment with placebo or Escitalopram
measure: MRI spectroscopy of fat in skeletal muscle tissue
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: MRI spectroscopy of fat in liver
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Abdominal fat as assessed by MRI
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: MDI questionnaire scores
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: SCL-92 questionnaire scores
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Fasting blood lipid profile
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Ratio between insulin and glucose concentrations in blood during an oral glucose tolerance test (OGTT)
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Whole body fat content as assessed by a dexa scanning
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Hepatic insulin sensitivity as assessed suppression of endogenous glucose production (calculated by infusion of 3H-labelled glucose)
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: 10 pm to midnight basal plasma ACTH/cortisol concentration ratio as measured by blood sampling every 10th minute.
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: increase in blood pressure and heart rate during Stroops Stress test
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Increase in plasma ACTH, cortisol and epinephrine concentrations during Stroops Stress Test
timeFrame: before and after 3 months of treatment with placebo or Escitalopram
measure: SRPAS questionnaire scores
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Actigraph GT3X activity monitoring
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Whole body bone mass density and T-/Z-scores as assessed by a dexa scanning
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
measure: Plasma-Inflammation markers
timeFrame: Before and after 3 months of treatment with placebo or Escitalopram
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Medical Dep M, Diabetes and Endocrinology Aarhus University Hospital, Aarhus Sygehus
Study officials:
References:
citation: Buhl CS, Stodkilde-Jorgensen H, Videbech P, Vaag A, Moller N, Lund S, Buhl ES. Escitalopram Ameliorates Hypercortisolemia and Insulin Resistance in Low Birth Weight Men With Limbic Brain Alterations. J Clin Endocrinol Metab. 2018 Jan 1;103(1):115-124. doi: 10.1210/jc.2017-01438.