DepressionPhase 1NCT01648998
Fludrocortisone and Information Processing in Healthy Volunteers
A Phase 1 study testing Fludrocortisone in people with Depression, run by Leiden University Medical Center at 1 site in Netherlands.
Trial summary
Stimulating the mineralocorticoid receptor (MR) may restore a disturbed balance as seen in depression. In this double-blind, randomized, placebo-controlled trial the investigators will test the effects of a single dose (500mg) fludrocortisone, an MR-agonist, on the information processing in healthy female volunteers… Read more about this study
- Who is it for?
- Ages 18 to 35 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Depression
- What is being tested?
- Fludrocortisone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteNetherlands
- Study dates
- May 2012to Dec 2013
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Fluent in Dutch
- Age 18-35 yrs
- BMI 18 to 30 kg/m2
- Northwestern European ancestry
Who cannot join
- Known contra-indications for fludrocortisone use:
- Allergy to fludrocortisone.
- Ulcus ventriculi et duodeni.
- Acute infectious processes; viral infections
- Tropical worm infections.
- Vaccination with living virus
Show all 16Show fewer
- Major physical illness, such as diabetes, thyroid disease, epilepsy, multiple sclerosis, pituitary disease, or any other serious medical condition.
- Hypertension or history of stroke. Increased blood clot formation.
- Major infections.
- Any current or past psychiatric disorder
- Use of medication likely to interfere with the study (e.g., benzodiazepines, St John's Wort).
- Pregnancy or breastfeeding.
- History of regular (more than once per month during three or more months) use of hard drugs (including XTC) or any use during past month.
- Alcohol use of more than 14 units per week or more than 4 units on any day during the week prior to the study or during the study period.
- Regular smoker during past year or use of nicotine product during past week
- Participants will be tested outside their menstrual period (two days before until five days after start of period).
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Leiden University - Institute of Psychology
Leiden, South Holland, 2333 AK
About this study
Official title: The Effects of Fludrocortisone on Information Processing in Healthy Female Volunteers
Stimulating the mineralocorticoid receptor (MR) may restore a disturbed balance as seen in depression. In this double-blind, randomized, placebo-controlled trial the investigators will test the effects of a single dose (500mg) fludrocortisone, an MR-agonist, on the information processing in healthy female volunteers (N = 2x20).
The investigators want to investigate whether the acute administration of fludrocortisone (FC) in healthy females enhances the appraisal of emotional information related to depression, hypothesizing that:
Read more
- FC relative to placebo selectively improves the recognition of happy and fearful faces: resulting in more correct responses and faster RTs.
- FC induces a bias towards more positive self-description and an improved memory for positive information.
Female participants were selected because the haplotype MRI180V is related to depression vulnerability in women, not in men. If the effects of fludrocortisone are comparable to the effects of antidepressants on the same tests and the same population, it might be a first indication that fludrocortisone may function as an antidepressant.
Read the detailed description
We found in depressed individuals, compared with non-depressed controls, that MRs had a decreased (approximately -30%) expression in hippocampus, inferior frontal gyrus and cingulate gyrus. It is proposed that decreased expression of MRs is part of the underlying pathological process in depression.
Recent studies have revealed considerable interpersonal differences with regard to the functioning of the MRs. Firstly, common MR gene polymorphisms influence the cortisol awakening response (CAR). Secondly, clinical populations differ in observed depressive symptoms as a function of MRI180V genotype. This MR I180V gene variant showed less activity in vitro, which suggests that functionality in vivo is decreased. Finally, MR haplotype 2, which is prevalent in 35% of the Caucasian population, enhances the transcription, translation and transactivation of the MR. This haplotype is associated with higher dispositional optimism, fewer thoughts of hopelessness and lower risk of major depression. These effects are restricted to pre-menopausal women. This suggests that female sex steroids may interact with the MR gene, thereby modulating resilience. Indeed, it has been shown that progesterone and oestrogen modulate MR-expression in rats. Taken together, mineralocorticoid receptors in the brain are considered to be a new target for the treatment of stress related disorders like depression.
Fludrocortisone (9α fluoro-hydrocortisone) (FC) is a specific MR-agonist currently used to treat diseases of the adrenal cortex, septic shock (Russel, 2008) and occasionally orthostatic hypotension. It is shown that FC significantly inhibits nocturnal HPA axis activity without first depleting MR receptors with an MR-antagonist. This suggests FC have interesting implications in disorders of HPA axis excess, such as depression. Consistent with the idea that the stimulation of the MR might be useful in the treatment of depression, fludrocortisone accelerated the antidepressant effects of the SSRI escitalopram, at least in those patients who responded to escitalopram. This is in line with a previous observation that spironolactone, a MR antagonist, decreased the efficacy of the antidepressant amitriptyline in depressed patients. These studies show that stimulation of the MR might be a useful addition to the treatment of depression. Though, the explanatory mechanism behind these observations remains unclear.
This project is a first step in investigating the potential antidepressant effects of MR stimulation by fludrocortisone. We will test the effects of FC on indices of emotional information processing in healthy volunteers, which is a recently validated model of antidepressant drug action. It has been demonstrated repeatedly that a single dose of an antidepressant changes the processing of emotionally relevant information in healthy volunteers, within a few hours after administration. For instance, one dose of citalopram improved the recognition of facial expressions of fear and happiness relative to placebo in healthy female volunteers. This finding has been replicated with different antidepressants and different populations.
- Conditions
- Depression
- Being tested
- Fludrocortisone, Placebo
- Keywords
- Mineralocorticoid receptor, Fludrocortisone, Information Processing, Cognition, Depression
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FludrocortisoneDrug
Also called Florinef
single dose 500 mg, capsule
PlaceboDrug
Also called Placebo comparator
| Study group | Role | What they receive |
|---|---|---|
| Fludrocortisone | Experimental | Fludrocortisone 500 mg in capsule Receives: Drug: Fludrocortisone |
| Placebo | Placebo comparator | Placebo capsule, single dose, main ingredient lactose Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Accuracy to recognize emotions in facial expressions
This primary outcome is measured by performing the Facial Expression Recognition Task (FERT).
Measured: 2 hrs after intake fludrocortisone or placebo
Explicit memory for positive and negative information
This primary outcome is measured by the Emotional categorization and Memory(EMT)task. This task consists of two parts, the encoding and recall.
Measured: 2 hrs after intake of fludrocortisone or placebo
Secondary outcomes (1)
Subjective mood states
This is measured by administration of the 'Positive Affect Negative Affect Schedule'(PANAS). It measures positive and negative mood states (tension, vigor, anxiety, fatigue, boredom, alertness...) (20 items adding to two subscales, positive and negative affect).
Measured: 2 hrs after intake fludrocortisone or placebo
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jul 2012 (estimated)
- Study startMay 2012
- Primary completionJun 2013
- Study completionDec 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Willem Van der Does, Leiden University Medical Center
- Investigators
- Willem van der Does, Professor, Principal investigator, Leiden University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01648998
- Sponsor's protocol ID
- P12-12
- Status last verified
- Feb 2014
- First submitted
- 23 May 2012
- Last updated
- 25 Feb 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
Otte C, Hinkelmann K, Moritz S, Yassouridis A, Jahn H, Wiedemann K, Kellner M. Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res. 2010 Apr;44(6):339-46. doi: 10.1016/j.jpsychires.2009.10.006. Epub 2009 Nov 11.
PubMed 19909979Klok MD, Vreeburg SA, Penninx BW, Zitman FG, de Kloet ER, DeRijk RH. Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response: Interaction with SSRIs. Psychoneuroendocrinology. 2011 May;36(4):484-94. doi: 10.1016/j.psyneuen.2010.07.024. Epub 2010 Sep 29.
PubMed 20884124Harmer CJ, Goodwin GM, Cowen PJ. Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Br J Psychiatry. 2009 Aug;195(2):102-8. doi: 10.1192/bjp.bp.108.051193.
PubMed 19648538Buckley TM, Mullen BC, Schatzberg AF. The acute effects of a mineralocorticoid receptor (MR) agonist on nocturnal hypothalamic-adrenal-pituitary (HPA) axis activity in healthy controls. Psychoneuroendocrinology. 2007 Sep-Nov;32(8-10):859-64. doi: 10.1016/j.psyneuen.2007.05.016. Epub 2007 Jul 30.
PubMed 17666187Klok MD, Alt SR, Irurzun Lafitte AJ, Turner JD, Lakke EA, Huitinga I, Muller CP, Zitman FG, de Kloet ER, Derijk RH. Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder. J Psychiatr Res. 2011 Jul;45(7):871-8. doi: 10.1016/j.jpsychires.2010.12.002. Epub 2010 Dec 30.
PubMed 21195417
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Fludrocortisone on Information Processing in Healthy Female Volunteers
- ClinicalTrials.gov ID
- NCT01648998
- Acronym / sponsor ID
- P12-12
- Conditions
- Depression
- Keywords
- Mineralocorticoid receptor, Fludrocortisone, Information Processing, Cognition, Depression
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Study start
- May 2012
- Primary completion
- Jun 2013 (actual)
- Study completion
- Dec 2013 (actual)
- First posted
- 25 Jul 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Stimulating the mineralocorticoid receptor (MR) may restore a disturbed balance as seen in depression. In this double-blind, randomized, placebo-controlled trial the investigators will test the effects of a single dose (500mg) fludrocortisone, an MR-agonist, on the information processing in healthy female volunteers (N = 2x20).
The investigators want to investigate whether the acute administration of fludrocortisone (FC) in healthy females enhances the appraisal of emotional information related to depression, hypothesizing that:
- FC relative to placebo selectively improves the recognition of happy and fearful faces: resulting in more correct responses and faster RTs.
- FC induces a bias towards more positive self-description and an improved memory for positive information.
Female participants were selected because the haplotype MRI180V is related to depression vulnerability in women, not in men. If the effects of fludrocortisone are comparable to the effects of antidepressants on the same tests and the same population, it might be a first indication that fludrocortisone may function as an antidepressant.
Detailed description
We found in depressed individuals, compared with non-depressed controls, that MRs had a decreased (approximately -30%) expression in hippocampus, inferior frontal gyrus and cingulate gyrus. It is proposed that decreased expression of MRs is part of the underlying pathological process in depression.
Recent studies have revealed considerable interpersonal differences with regard to the functioning of the MRs. Firstly, common MR gene polymorphisms influence the cortisol awakening response (CAR). Secondly, clinical populations differ in observed depressive symptoms as a function of MRI180V genotype. This MR I180V gene variant showed less activity in vitro, which suggests that functionality in vivo is decreased. Finally, MR haplotype 2, which is prevalent in 35% of the Caucasian population, enhances the transcription, translation and transactivation of the MR. This haplotype is associated with higher dispositional optimism, fewer thoughts of hopelessness and lower risk of major depression. These effects are restricted to pre-menopausal women. This suggests that female sex steroids may interact with the MR gene, thereby modulating resilience. Indeed, it has been shown that progesterone and oestrogen modulate MR-expression in rats. Taken together, mineralocorticoid receptors in the brain are considered to be a new target for the treatment of stress related disorders like depression.
Fludrocortisone (9α fluoro-hydrocortisone) (FC) is a specific MR-agonist currently used to treat diseases of the adrenal cortex, septic shock (Russel, 2008) and occasionally orthostatic hypotension. It is shown that FC significantly inhibits nocturnal HPA axis activity without first depleting MR receptors with an MR-antagonist. This suggests FC have interesting implications in disorders of HPA axis excess, such as depression. Consistent with the idea that the stimulation of the MR might be useful in the treatment of depression, fludrocortisone accelerated the antidepressant effects of the SSRI escitalopram, at least in those patients who responded to escitalopram. This is in line with a previous observation that spironolactone, a MR antagonist, decreased the efficacy of the antidepressant amitriptyline in depressed patients. These studies show that stimulation of the MR might be a useful addition to the treatment of depression. Though, the explanatory mechanism behind these observations remains unclear.
This project is a first step in investigating the potential antidepressant effects of MR stimulation by fludrocortisone. We will test the effects of FC on indices of emotional information processing in healthy volunteers, which is a recently validated model of antidepressant drug action. It has been demonstrated repeatedly that a single dose of an antidepressant changes the processing of emotionally relevant information in healthy volunteers, within a few hours after administration. For instance, one dose of citalopram improved the recognition of facial expressions of fear and happiness relative to placebo in healthy female volunteers. This finding has been replicated with different antidepressants and different populations.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Fludrocortisone | Experimental | Drug: FludrocortisoneFludrocortisone 500 mg in capsule |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo capsule, single dose, main ingredient lactose |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Fluent in Dutch
- Age 18-35 yrs
- BMI 18 to 30 kg/m2
- Northwestern European ancestry
Key exclusion criteria (16 listed)
- Known contra-indications for fludrocortisone use:
- Major physical illness, such as diabetes, thyroid disease, epilepsy, multiple sclerosis, pituitary disease, or any other serious medical condition.
- Hypertension or history of stroke. Increased blood clot formation.
- Major infections.
- Any current or past psychiatric disorder
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FludrocortisoneAlso: Florinefsingle dose 500 mg, capsule | Drug | Fludrocortisone |
| PlaceboAlso: Placebo comparator | Drug | Placebo |
Primary outcome
Accuracy to recognize emotions in facial expressions
Time frame: 2 hrs after intake fludrocortisone or placebo
This primary outcome is measured by performing the Facial Expression Recognition Task (FERT).
Explicit memory for positive and negative information
Time frame: 2 hrs after intake of fludrocortisone or placebo
This primary outcome is measured by the Emotional categorization and Memory(EMT)task. This task consists of two parts, the encoding and recall.
1 secondary outcome
Subjective mood states
Time frame: 2 hrs after intake fludrocortisone or placebo
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2014.
- Background: PubMed 19909979Otte C, Hinkelmann K, Moritz S, Yassouridis A, Jahn H, Wiedemann K, Kellner M. Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res. 2010 Apr;44(6):339-46. doi: 10.1016/j.jpsychires.2009.10.006. Epub 2009 Nov 11.
- Background: PubMed 20884124Klok MD, Vreeburg SA, Penninx BW, Zitman FG, de Kloet ER, DeRijk RH. Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response: Interaction with SSRIs. Psychoneuroendocrinology. 2011 May;36(4):484-94. doi: 10.1016/j.psyneuen.2010.07.024. Epub 2010 Sep 29.
- Background: PubMed 19648538Harmer CJ, Goodwin GM, Cowen PJ. Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Br J Psychiatry. 2009 Aug;195(2):102-8. doi: 10.1192/bjp.bp.108.051193.
- Background: PubMed 17666187Buckley TM, Mullen BC, Schatzberg AF. The acute effects of a mineralocorticoid receptor (MR) agonist on nocturnal hypothalamic-adrenal-pituitary (HPA) axis activity in healthy controls. Psychoneuroendocrinology. 2007 Sep-Nov;32(8-10):859-64. doi: 10.1016/j.psyneuen.2007.05.016. Epub 2007 Jul 30.
- Background: PubMed 21195417Klok MD, Alt SR, Irurzun Lafitte AJ, Turner JD, Lakke EA, Huitinga I, Muller CP, Zitman FG, de Kloet ER, Derijk RH. Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder. J Psychiatr Res. 2011 Jul;45(7):871-8. doi: 10.1016/j.jpsychires.2010.12.002. Epub 2010 Dec 30.
Related trials for Depression
Not yet recruiting
Examining the Effectiveness of a Brief Therapeutic Intervention for Reducing Self-Harm Among Adolescents
Self Injurious Behavior, Self Injurious Behavior Without Suicidal Intent
RecruitingPhase 3
A Study of Brenipatide (LY3537031) in Adult Participants With Major Depressive Disorder
Depressive Disorder, Major
Recruiting
EEG-Guided Transcranial Magnetic Stimulation for Adults With Depression
Major Depressive Disorder (MDD), Treatment Resistant Depression
Recruiting
Aquatic Exercise in Patients With Knee Osteoarthritis
Central Sensitization, Knee Osteoarthristis
Recruiting
Defining Neurobiological Links Between Substance Use and Mental Illness
Major Depressive Disorder, Substance Use Disorder
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Willem van der Does, Professor principal investigator
Leiden University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Fludrocortisone in people with Depression, run by Leiden University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Accuracy to recognize emotions in facial expressions (time frame: 2 hrs after intake fludrocortisone or placebo). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01648998, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2014.