Ignite Creation Date:
2024-05-06 @ 7:48 PM
Last Modification Date:
2024-10-26 @ 3:13 PM
Study NCT ID:
NCT06130371
Status:
RECRUITING
Last Update Posted:
2024-02-22
First Post:
2023-09-05
Brief Title:
Stress Inflammation and Neuroimaging in Major Depressive Disorder as Compared to Premenstrual Dysphoric Disorder
Sponsor:
University Hospital Tuebingen
Organization:
University Hospital Tuebingen
Study Overview
Official Title:
Stress Inflammation and Neuroimaging in Major Depressive Disorder as Compared to Premenstrual Dysphoric Disorder
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Premenstrual dysphoric disorder PMDD is a sex-specific depressive disorder where depressive symptom severity drastically changes in relation to menstrual cycle phase It is characterized by late luteal phase symptoms of affective lability irritability depressed mood and anxiety A lot remains unclear and further studies are needed in order to improve the understanding of PMDD and to differentiate it from major depressive disorder MDD To date and in contrast to MDD the neural correlates of PMDD have been sparsely and poorly investigated The aim of this study is therefore to investigate the neural correlates of PMDD as compared to MDD and to relate them to stress reactivity Therefore three groups of naturally cycling women will be investigated and compared namely 1 women with MDD 2 women with PMDD and 3 healthy control women
Stress and HPA axis activity are assumed to play a crucial role in the development of many mental disorders including MDD How stress reactivity and HPA axis activity are connected to PMDD still needs to be investigated Furthermore the HPA axis can affect or suppress the activity of the hypothalamic-pituitary-gonadal HPG axis which is involved mainly in the reproductive but also the immune system making it an important candidate for the investigation of sex-specific differences in stress reactivity
There are sex-specific differences in stress reactivity but also in the prevalence of stress-related diseases Women are twice as likely to suffer from depression than men and the first onset of MDD usually peaks during the reproductive years As to why these differences exist a recent theory suggests that ovarian hormone fluctuations function as modulators of womens susceptibility to stress and that altered reactivity to stressors during different cycle phases plays a role in the etiology of depressive disorders This hypothesis extends the Social Signal Transduction Theory of Depression which first and foremost relates depression to inflammation They postulate a critical role of cytokines for understanding the pathogenesis of depression Therefore ovarian hormone fluctuations but also inflammation in regard to MDD and PMDD and stress reactivity will be investigated in this study
Stress and HPA axis activity are assumed to play a crucial role in the development of many mental disorders including MDD How stress reactivity and HPA axis activity are connected to PMDD still needs to be investigated Furthermore the HPA axis can affect or suppress the activity of the hypothalamic-pituitary-gonadal HPG axis which is involved mainly in the reproductive but also the immune system making it an important candidate for the investigation of sex-specific differences in stress reactivity
There are sex-specific differences in stress reactivity but also in the prevalence of stress-related diseases Women are twice as likely to suffer from depression than men and the first onset of MDD usually peaks during the reproductive years As to why these differences exist a recent theory suggests that ovarian hormone fluctuations function as modulators of womens susceptibility to stress and that altered reactivity to stressors during different cycle phases plays a role in the etiology of depressive disorders This hypothesis extends the Social Signal Transduction Theory of Depression which first and foremost relates depression to inflammation They postulate a critical role of cytokines for understanding the pathogenesis of depression Therefore ovarian hormone fluctuations but also inflammation in regard to MDD and PMDD and stress reactivity will be investigated in this study
Detailed Description:
In the proposed study the investigators aim to investigate in more detail how women with MDD and women with PMDD differ in their stress response from healthy women The investigators are directly comparing three groups of 1 women with MDD 2 women with PMDD and 3 healthy women All women will be measured in two different cycle phases to disentangle the effects of the menstrual cycle on stress reactivity Furthermore including inflammatory markers will help to shed light on the connection between stress depressive disorders and the immune system
The overall aim of this study is to elucidate the influence of stress on inflammation as well as on brain function in women with MDD in contrast to PMDD Therefore the behavioral neural immunological and endocrine profiles of women with MDD as well as women with PMDD will be compared to the ones of naturally cycling women The goal is to delineate the psychobiological characteristics of reproductive states and mental disorders The results will provide the basis to develop more targeted treatments in the framework of precision medicine
Open questions
1 How do women with MDD women with PMDD and healthy women differ in their stress reactivity on a neural level as measured by fMRI activity
2 How do women with MDD women with PMDD and healthy women differ in their stress reactivity in their HPA axis response as measured via cortisol levels
3 How do women with MDD women with PMDD and healthy women differ in their stress reactivity on an immunological level as measured by inflammation markers
The investigators hypothesize that after an acute psychosocial stressor
1 women with MDD show hypoactivation in the CCN especially so in the left DLPFC when compared to healthy controls For women with PMDD this effect might be pronounced only when tested in the symptomatic meaning the late luteal menstrual cycle phase
2 women with MDD have higher cortisol levels than healthy controls but show a blunted stress response As there are no studies on cortisol reactivity in women with PMDD it is unclear how they will react to stress compared to healthy and MDD women
3 women with MDD have higher inflammatory markers such as IL-6 and TNF-alpha when compared to healthy controls For women with PMDD the investigators also expect higher inflammatory markers than in healthy controls
This combined neuroimaging and stress study will investigate naturally cycling women with MDD n 25 PMDD n 25 and matched healthy control women n 25 All participants will be exposed to the Montreal Imaging Stress Task MIST a stress induction task during neuroimaging using fMRI In order to disentangle the influence of the menstrual cycle within a randomized design one session will take place during the mid-follicular phase and one during the late-luteal phase of the menstrual cycle Besides assessing heart rate variability as a measure of stress the investigators will obtain cortisol from saliva and hair samples as well as steroids eg progesterone estrogen and ALLO and inflammation markers from blood samples eg adipokines IL-1 IL-6 and TNF-alpha
The investigators plan to assess 75 women to compare women with MDD to women with PMDD and healthy women In total the following samples will be recruited
Group 1 25 women with MDD
Group 2 25 women with PMDD
Group 3 25 healthy women
If subjects qualify for the current study the investigators will invite them to the laboratory T0 where they will give written informed consent Subsequently the investigators will perform a standardized clinical interview to screen for mental disorders SCID-5-CV Participants will also be informed about the study process and the data analysis After the interview they will receive a password-protected link provided by email to assess among others depressive symptoms personality traits gender identity and norms sexual health state and trait anxiety and verbal intelligence using questionnaires Participants will also be asked to report their average cycle length Participants then will be divided into two groups where Group A has their first MRI session in the mid-follicular phase before ovulation and the second MRI session in the late-luteal phase after ovulation and Group B has the first MRI session in the late-luteal phase and the second MRI session in the mid-follicular phase MRI sessions will be scheduled according to self-reported beginning of menses and self-reported average cycle length
For the PMDD group PMDD diagnosis has to be confirmed by daily prospective ratings of premenstrual symptom severity during two consecutive cycles as this is an official criterion for the disorder in the DSM-5 For this the smartphone app m-path will be used They will be asked daily about their premenstrual symptoms with the Daily Record of Severity of Problems Questionnaire DRSP that takes about 3 minutes per day
At the beginning and the end of the MRI sessions T1 and T2 a blood draw of 30 ml will be performed by medically trained personnel After ensuring that all requirements to take part in an MRI study are met the participants will be put into the MRI and the MIST will be applied Throughout the session saliva samples will be taken six times for the measurement of salivary cortisol once at arrival once before the MIST 40 minutes after the MIST 60 minutes after the MIST and 120 minutes after the MIST Additionally at both MRI sessions hair samples are collected to record the cumulative cortisol secretion of the past three months 3cm hair At the end of the last measurement day T2 participants will be informed about the exact goals of the study and will have to sign a final consent form that their data can be used after full disclosure of the goals
Montreal Imaging Stress Task In the Montreal Imaging Stress Task MIST a frequently used performance-based stress paradigm arithmetic tasks are presented to generate increased cognitive workload and thus performance demands The arithmetic tasks must be solved either without time pressure and social evaluation control condition or with time pressure and social evaluation stress condition Before entering the fMRI scanner arithmetic tasks are practiced on a computer in an approximately 3-minute training session in which task difficulty is determined for the fMRI measurement In total the MIST lasts about 20 minutes
MRI measurements will be performed at the 3T PRISMA scanner located at the Department of Psychiatry and Psychotherapy University Hospital Tübingen On each measurement day all participants will undergo the MIST a resting-state scan an anatomical scan and a diffusion tensor imaging DTI scan For the resting-state scan approx 8 min a low-TR multi-band echo-planar-imaging EPI sequence will be applied Participants will be instructed to keep their eyes open while they are watching the Inscape movie that was specifically designed to improve imaging at rest The anatomical scan approx 8 min will be acquired using an MPRAGE 3-D Magnetization Prepared Rapid Gradient Echo sequence consisting of 160 sagittal slices Lastly the DTI scan approx 8 min will be performed All MR parameters will be established with experts from the radiology department
Determination of stress markers in saliva and hair Biological stress markers are regarded as so-called objective stress measures which in addition to subjective stress parameters represent further facets of the multidimensionality of stress While saliva samples can represent physiological acute stress reactions or characteristic circadian rhythms hair samples represent the retrospective recording of cumulative cortisol secretion over a period of several months In the course of the laboratory measurement the investigators will repeatedly collect saliva samples in order to trace the stress reaction ie increase in cortisol Due to the circadian rhythm the laboratory measurement takes place between 1500 and 2000 in the afternoon only on workdays Additionally one hair sample per MRI measurement is collected by cutting a small strand of hair as close to the scalp as possible as a marker for chronic stress
Blood samples for hormones and epigenetics For measuring among others estradiol progesterone allopregnanolone and testosterone as well as inflammation markers such as adipokines interleukines and TNF-alpha ethylenediaminetetraacetic acid EDTA blood samples will be taken after the MRI sessions In addition to the phenotypic characterization all participants will provide EDTA-blood samples for epigenetic analyses which will be sent to the Department of Psychiatry and Psychotherapy Research Group Molecular Psychiatry Head Prof Dr Vanessa Nieratschker for storage and analysis Methylation changes will be studied in peripheral blood due to the accessibility of the study material in living humans The investigation of brain material of living human participants for epigenetic processes is unrealistic As a similar differential methylation in peripheral blood as in the brain has been demonstrated for the candidate genes under investigation in this study the investigators consider blood as an adequate surrogate material reflecting the situation in the brain Furthermore epigenetic factors influence the psychophysiological stress response and can thus explain interindividual differences found within the current study
The overall aim of this study is to elucidate the influence of stress on inflammation as well as on brain function in women with MDD in contrast to PMDD Therefore the behavioral neural immunological and endocrine profiles of women with MDD as well as women with PMDD will be compared to the ones of naturally cycling women The goal is to delineate the psychobiological characteristics of reproductive states and mental disorders The results will provide the basis to develop more targeted treatments in the framework of precision medicine
Open questions
1 How do women with MDD women with PMDD and healthy women differ in their stress reactivity on a neural level as measured by fMRI activity
2 How do women with MDD women with PMDD and healthy women differ in their stress reactivity in their HPA axis response as measured via cortisol levels
3 How do women with MDD women with PMDD and healthy women differ in their stress reactivity on an immunological level as measured by inflammation markers
The investigators hypothesize that after an acute psychosocial stressor
1 women with MDD show hypoactivation in the CCN especially so in the left DLPFC when compared to healthy controls For women with PMDD this effect might be pronounced only when tested in the symptomatic meaning the late luteal menstrual cycle phase
2 women with MDD have higher cortisol levels than healthy controls but show a blunted stress response As there are no studies on cortisol reactivity in women with PMDD it is unclear how they will react to stress compared to healthy and MDD women
3 women with MDD have higher inflammatory markers such as IL-6 and TNF-alpha when compared to healthy controls For women with PMDD the investigators also expect higher inflammatory markers than in healthy controls
This combined neuroimaging and stress study will investigate naturally cycling women with MDD n 25 PMDD n 25 and matched healthy control women n 25 All participants will be exposed to the Montreal Imaging Stress Task MIST a stress induction task during neuroimaging using fMRI In order to disentangle the influence of the menstrual cycle within a randomized design one session will take place during the mid-follicular phase and one during the late-luteal phase of the menstrual cycle Besides assessing heart rate variability as a measure of stress the investigators will obtain cortisol from saliva and hair samples as well as steroids eg progesterone estrogen and ALLO and inflammation markers from blood samples eg adipokines IL-1 IL-6 and TNF-alpha
The investigators plan to assess 75 women to compare women with MDD to women with PMDD and healthy women In total the following samples will be recruited
Group 1 25 women with MDD
Group 2 25 women with PMDD
Group 3 25 healthy women
If subjects qualify for the current study the investigators will invite them to the laboratory T0 where they will give written informed consent Subsequently the investigators will perform a standardized clinical interview to screen for mental disorders SCID-5-CV Participants will also be informed about the study process and the data analysis After the interview they will receive a password-protected link provided by email to assess among others depressive symptoms personality traits gender identity and norms sexual health state and trait anxiety and verbal intelligence using questionnaires Participants will also be asked to report their average cycle length Participants then will be divided into two groups where Group A has their first MRI session in the mid-follicular phase before ovulation and the second MRI session in the late-luteal phase after ovulation and Group B has the first MRI session in the late-luteal phase and the second MRI session in the mid-follicular phase MRI sessions will be scheduled according to self-reported beginning of menses and self-reported average cycle length
For the PMDD group PMDD diagnosis has to be confirmed by daily prospective ratings of premenstrual symptom severity during two consecutive cycles as this is an official criterion for the disorder in the DSM-5 For this the smartphone app m-path will be used They will be asked daily about their premenstrual symptoms with the Daily Record of Severity of Problems Questionnaire DRSP that takes about 3 minutes per day
At the beginning and the end of the MRI sessions T1 and T2 a blood draw of 30 ml will be performed by medically trained personnel After ensuring that all requirements to take part in an MRI study are met the participants will be put into the MRI and the MIST will be applied Throughout the session saliva samples will be taken six times for the measurement of salivary cortisol once at arrival once before the MIST 40 minutes after the MIST 60 minutes after the MIST and 120 minutes after the MIST Additionally at both MRI sessions hair samples are collected to record the cumulative cortisol secretion of the past three months 3cm hair At the end of the last measurement day T2 participants will be informed about the exact goals of the study and will have to sign a final consent form that their data can be used after full disclosure of the goals
Montreal Imaging Stress Task In the Montreal Imaging Stress Task MIST a frequently used performance-based stress paradigm arithmetic tasks are presented to generate increased cognitive workload and thus performance demands The arithmetic tasks must be solved either without time pressure and social evaluation control condition or with time pressure and social evaluation stress condition Before entering the fMRI scanner arithmetic tasks are practiced on a computer in an approximately 3-minute training session in which task difficulty is determined for the fMRI measurement In total the MIST lasts about 20 minutes
MRI measurements will be performed at the 3T PRISMA scanner located at the Department of Psychiatry and Psychotherapy University Hospital Tübingen On each measurement day all participants will undergo the MIST a resting-state scan an anatomical scan and a diffusion tensor imaging DTI scan For the resting-state scan approx 8 min a low-TR multi-band echo-planar-imaging EPI sequence will be applied Participants will be instructed to keep their eyes open while they are watching the Inscape movie that was specifically designed to improve imaging at rest The anatomical scan approx 8 min will be acquired using an MPRAGE 3-D Magnetization Prepared Rapid Gradient Echo sequence consisting of 160 sagittal slices Lastly the DTI scan approx 8 min will be performed All MR parameters will be established with experts from the radiology department
Determination of stress markers in saliva and hair Biological stress markers are regarded as so-called objective stress measures which in addition to subjective stress parameters represent further facets of the multidimensionality of stress While saliva samples can represent physiological acute stress reactions or characteristic circadian rhythms hair samples represent the retrospective recording of cumulative cortisol secretion over a period of several months In the course of the laboratory measurement the investigators will repeatedly collect saliva samples in order to trace the stress reaction ie increase in cortisol Due to the circadian rhythm the laboratory measurement takes place between 1500 and 2000 in the afternoon only on workdays Additionally one hair sample per MRI measurement is collected by cutting a small strand of hair as close to the scalp as possible as a marker for chronic stress
Blood samples for hormones and epigenetics For measuring among others estradiol progesterone allopregnanolone and testosterone as well as inflammation markers such as adipokines interleukines and TNF-alpha ethylenediaminetetraacetic acid EDTA blood samples will be taken after the MRI sessions In addition to the phenotypic characterization all participants will provide EDTA-blood samples for epigenetic analyses which will be sent to the Department of Psychiatry and Psychotherapy Research Group Molecular Psychiatry Head Prof Dr Vanessa Nieratschker for storage and analysis Methylation changes will be studied in peripheral blood due to the accessibility of the study material in living humans The investigation of brain material of living human participants for epigenetic processes is unrealistic As a similar differential methylation in peripheral blood as in the brain has been demonstrated for the candidate genes under investigation in this study the investigators consider blood as an adequate surrogate material reflecting the situation in the brain Furthermore epigenetic factors influence the psychophysiological stress response and can thus explain interindividual differences found within the current study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None