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出境医 / 临床实验 / Resting-state Functional Connectivity Throughout a Course of iTBS in Major Depression

Resting-state Functional Connectivity Throughout a Course of iTBS in Major Depression

Study Description
Brief Summary:
This study aims to investigate changes in functional connectivity over a four week treatment course with intermittent theta burst stimulation (iTBS) in patients with major depressive disorder (MDD). To this end, seven weekly resting-state fMRI (rs-fMRI) scans at 7 tesla (7T) will precede, accompany and follow the iTBS treatment course. By obtaining several samples of the modulatory effects of iTBS on functional connectivity networks and simultaneous measurements of the depressive symptoms it will be possible to assess the time course of changes in connectivity across different networks, and to assess the overall relationship between the network modulation and the antidepressant effects of the treatment over time.

Condition or disease Intervention/treatment
Depression Depressive Disorder Depressive Disorder, Major Depressive Episode Device: intermittent theta burst stimulation (iTBS)

Detailed Description:

The immense disease burden of major depressive disorder (MDD) and unsatisfactory response rates to pharmacological and psychological interventions highlight the need for further development of treatment alternatives. The development of these alternatives relies on an understanding of the pathophysiology of depression, which has, despite considerable efforts, remained largely elusive. Findings have converged on the proposition that depression cannot be attributed to a singular factor and is better understood as a dysfunctional interaction of multiple parameters. At the neural level, depression is described as a dysfunction of several cortical and sub-cortical networks associated with affective salience, cognitive control and self-reverential thoughts. Encouragingly, several studies have shown that pathological alterations in one of these networks, the Default Mode network, may normalize following several weeks of treatment using repetitive transcranial magnetic stimulation (rTMS), an accepted treatment for major depression.

The present study aims to elucidate the time course of this modulatory effect on the different networks showing pathological connectivity profiles. Specifically, our aim is to obtain several measurements of functional connectivity and concomitant measures of the symptoms of depression prior to, throughout, and following the 4 week treatment course of iTBS, a faster but equally effective non-invasive brain stimulation technique compared to rTMS. Due to the fact that weekly changes in network connectivity are expected to be relatively small, the stronger BOLD Signal at 7T and the fact that peak temporal correlation coefficients calculated between network nodes have been shown to be significantly higher at 7T than 3T (e.g.) in the Default Mode network should greatly aid in detecting these differences. At each of the 7 measurement time points, fluctuations of BOLD signal will be recorded during a rs-fMRI scan lasting about 15 minutes. Our approach will allow to characterize the temporal profiles of the antidepressant effects of iTBS, thereby furthering our understanding of the mechanism by which iTBS contributes to the normalization of pathological neural connectivity and the reduction of depression symptoms. This proposed longitudinal functional imaging of therapeutic changes is highly relevant to the field of clinical neuroscience and should further advance our understanding of the pathophysiology of depression.

Study Design
Layout table for study information
Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Resting-state Functional Connectivity Throughout a Course of iTBS in Major Depression
Actual Study Start Date : July 23, 2018
Estimated Primary Completion Date : February 1, 2020
Estimated Study Completion Date : June 1, 2020
Arms and Interventions
Group/Cohort Intervention/treatment
MDD patients Device: intermittent theta burst stimulation (iTBS)
20 sessions of iTBS
Healthy controls
Outcome Measures
Primary Outcome Measures :
  1. Change in functional connectivity coefficients based on rs-fMRI over 7 timepoints. [ Time Frame: Six weekly measurements starting 1 week before first iTBS treatment session, one follow-up measurement four weeks after last measurement. ]
    Seed-to-voxel functional connectivity analysis of rs-fMRI data.


Secondary Outcome Measures :
  1. Change in depression severity as measured by the Hamilton Depression Rating Scale (HDRS-17) over 7 timepoints. [ Time Frame: Six weekly measurements starting 1 week before first iTBS treatment session, one follow-up measurement four weeks after last measurement. ]
    Remission defined as HDRS-17 score (range: 0 to 52) of less than or equal to 8 after the iTBS course. Response defined as a reduction of at least 50% from baseline in HDRS-17 score after treatment.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Outpatients at the psychiatric hospital of the University Hospital Bonn. The patients diagnosis of major depressive disorder will be verified via the structured clinical interview for DSM-5. iTBS protocols in line with international standards administered by a trained professional.

Additionally, a healthy control sample is included in the study.

Criteria

Inclusion Criteria:

  • Participant is able to provide consent.
  • Diagnosis of Major Depressive Disorder according to DSM-V criteria.
  • The duration of the current episode is at least four weeks and no more than five years.
  • During the current episode, at least one antidepressant (adequate duration and dosage) was not effective OR at least two antidepressants were intolerable due to side effects.

Exclusion Criteria:

  • The participant does not fulfill requirements for iTBS treatment according to safety guidelines.
  • Cardiac or neurological surgery, active implants, metal parts within the body, claustrophobia.
  • Pregnancy or breast-feeding.
  • Psychiatric illness, e.g. substance abuse, psychosis, bipolar disorder, anorexia, obsessive compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, panic disorder, personality disorder.
  • Antipsychotic medication not approved for the treatment of depression.
  • Acute suicidality.
  • Conditions related to increased intracranial pressure.
  • Brain injury or stroke.
  • History of epilepsy in patient or in first-degree relative.
  • Cerebral aneurysm.
  • Neurological illness (e.g. dementia (score of less than 25 in Mini Mental State Exam), Parkinson's disease, chorea huntington, multiple sclerosis).
  • Course of electroconvulsive therapy (ECT) within the last three months
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Clemens Mielacher, Mag. +49 228 287 11519 clemens.mielacher@ukbonn.de
Contact: Maximilian Kiebs, M.Sc. +49 228 287 19710 m.kiebs@ukbonn.de

Locations
Layout table for location information
Germany
Klinik und Poliklinik für Psychiatrie und Psychotherapie Recruiting
Bonn, Germany
Contact: Clemens Mielacher, Mag.    +49 228 287 11519    clemens.mielacher@ukbonn.de   
Contact: Maximilian Kiebs, M.Sc.    +49 228 287 19710    m.kiebs@ukbonn.de   
Sponsors and Collaborators
University Hospital, Bonn
Clemens Mielacher, University Hospital, Bonn
Maximilian Kiebs, University Hospital, Bonn
Investigators
Layout table for investigator information
Principal Investigator: René Hurlemann, Prof. University Hospital, Bonn
Tracking Information
First Submitted Date May 7, 2019
First Posted Date May 9, 2019
Last Update Posted Date May 9, 2019
Actual Study Start Date July 23, 2018
Estimated Primary Completion Date February 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: May 8, 2019) 		Change in functional connectivity coefficients based on rs-fMRI over 7 timepoints. [ Time Frame: Six weekly measurements starting 1 week before first iTBS treatment session, one follow-up measurement four weeks after last measurement. ]
Seed-to-voxel functional connectivity analysis of rs-fMRI data.
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures
 (submitted: May 8, 2019) 		Change in depression severity as measured by the Hamilton Depression Rating Scale (HDRS-17) over 7 timepoints. [ Time Frame: Six weekly measurements starting 1 week before first iTBS treatment session, one follow-up measurement four weeks after last measurement. ]
Remission defined as HDRS-17 score (range: 0 to 52) of less than or equal to 8 after the iTBS course. Response defined as a reduction of at least 50% from baseline in HDRS-17 score after treatment.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Resting-state Functional Connectivity Throughout a Course of iTBS in Major Depression
Official Title Resting-state Functional Connectivity Throughout a Course of iTBS in Major Depression
Brief Summary This study aims to investigate changes in functional connectivity over a four week treatment course with intermittent theta burst stimulation (iTBS) in patients with major depressive disorder (MDD). To this end, seven weekly resting-state fMRI (rs-fMRI) scans at 7 tesla (7T) will precede, accompany and follow the iTBS treatment course. By obtaining several samples of the modulatory effects of iTBS on functional connectivity networks and simultaneous measurements of the depressive symptoms it will be possible to assess the time course of changes in connectivity across different networks, and to assess the overall relationship between the network modulation and the antidepressant effects of the treatment over time.
Detailed Description

The immense disease burden of major depressive disorder (MDD) and unsatisfactory response rates to pharmacological and psychological interventions highlight the need for further development of treatment alternatives. The development of these alternatives relies on an understanding of the pathophysiology of depression, which has, despite considerable efforts, remained largely elusive. Findings have converged on the proposition that depression cannot be attributed to a singular factor and is better understood as a dysfunctional interaction of multiple parameters. At the neural level, depression is described as a dysfunction of several cortical and sub-cortical networks associated with affective salience, cognitive control and self-reverential thoughts. Encouragingly, several studies have shown that pathological alterations in one of these networks, the Default Mode network, may normalize following several weeks of treatment using repetitive transcranial magnetic stimulation (rTMS), an accepted treatment for major depression.

The present study aims to elucidate the time course of this modulatory effect on the different networks showing pathological connectivity profiles. Specifically, our aim is to obtain several measurements of functional connectivity and concomitant measures of the symptoms of depression prior to, throughout, and following the 4 week treatment course of iTBS, a faster but equally effective non-invasive brain stimulation technique compared to rTMS. Due to the fact that weekly changes in network connectivity are expected to be relatively small, the stronger BOLD Signal at 7T and the fact that peak temporal correlation coefficients calculated between network nodes have been shown to be significantly higher at 7T than 3T (e.g.) in the Default Mode network should greatly aid in detecting these differences. At each of the 7 measurement time points, fluctuations of BOLD signal will be recorded during a rs-fMRI scan lasting about 15 minutes. Our approach will allow to characterize the temporal profiles of the antidepressant effects of iTBS, thereby furthering our understanding of the mechanism by which iTBS contributes to the normalization of pathological neural connectivity and the reduction of depression symptoms. This proposed longitudinal functional imaging of therapeutic changes is highly relevant to the field of clinical neuroscience and should further advance our understanding of the pathophysiology of depression.
Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population

Outpatients at the psychiatric hospital of the University Hospital Bonn. The patients diagnosis of major depressive disorder will be verified via the structured clinical interview for DSM-5. iTBS protocols in line with international standards administered by a trained professional.

Additionally, a healthy control sample is included in the study.
Condition
  • Depression
  • Depressive Disorder
  • Depressive Disorder, Major
  • Depressive Episode
Intervention Device: intermittent theta burst stimulation (iTBS)
20 sessions of iTBS
Study Groups/Cohorts
  • MDD patients
    Intervention: Device: intermittent theta burst stimulation (iTBS)
  • Healthy controls
Publications *
  • Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17.
  • Souery D, Papakostas GI, Trivedi MH. Treatment-resistant depression. J Clin Psychiatry. 2006;67 Suppl 6:16-22. Review.
  • Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry. 2010 Oct;9(3):155-61.
  • Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-Scale Network Dysfunction in Major Depressive Disorder: A Meta-analysis of Resting-State Functional Connectivity. JAMA Psychiatry. 2015 Jun;72(6):603-11. doi: 10.1001/jamapsychiatry.2015.0071.
  • Fischer AS, Keller CJ, Etkin A. The Clinical Applicability of Functional Connectivity in Depression: Pathways Toward More Targeted Intervention. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016 May;1(3):262-270. doi: 10.1016/j.bpsc.2016.02.004. Epub 2016 Mar 2. Review.
  • Liston C, Chen AC, Zebley BD, Drysdale AT, Gordon R, Leuchter B, Voss HU, Casey BJ, Etkin A, Dubin MJ. Default mode network mechanisms of transcranial magnetic stimulation in depression. Biol Psychiatry. 2014 Oct 1;76(7):517-26. doi: 10.1016/j.biopsych.2014.01.023. Epub 2014 Feb 5.
  • Philip NS, Barredo J, van 't Wout-Frank M, Tyrka AR, Price LH, Carpenter LL. Network Mechanisms of Clinical Response to Transcranial Magnetic Stimulation in Posttraumatic Stress Disorder and Major Depressive Disorder. Biol Psychiatry. 2018 Feb 1;83(3):263-272. doi: 10.1016/j.biopsych.2017.07.021. Epub 2017 Aug 8.
  • Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med. 2014 Jan;44(2):225-39. doi: 10.1017/S0033291713000512. Epub 2013 Mar 18. Review.
  • Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018 Apr 28;391(10131):1683-1692. doi: 10.1016/S0140-6736(18)30295-2. Epub 2018 Apr 26. Erratum in: Lancet. 2018 Jun 23;391(10139):e24.
  • Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipović SR, Hummel FC, Jääskeläinen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schönfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014 Nov;125(11):2150-2206. doi: 10.1016/j.clinph.2014.05.021. Epub 2014 Jun 5. Review.
  • Hale JR, Brookes MJ, Hall EL, Zumer JM, Stevenson CM, Francis ST, Morris PG. Comparison of functional connectivity in default mode and sensorimotor networks at 3 and 7T. MAGMA. 2010 Dec;23(5-6):339-49. doi: 10.1007/s10334-010-0220-0. Epub 2010 Jul 13.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Unknown status
Estimated Enrollment
 (submitted: May 8, 2019) 		60
Original Estimated Enrollment Same as current
Estimated Study Completion Date June 1, 2020
Estimated Primary Completion Date February 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Participant is able to provide consent.
  • Diagnosis of Major Depressive Disorder according to DSM-V criteria.
  • The duration of the current episode is at least four weeks and no more than five years.
  • During the current episode, at least one antidepressant (adequate duration and dosage) was not effective OR at least two antidepressants were intolerable due to side effects.

Exclusion Criteria:

  • The participant does not fulfill requirements for iTBS treatment according to safety guidelines.
  • Cardiac or neurological surgery, active implants, metal parts within the body, claustrophobia.
  • Pregnancy or breast-feeding.
  • Psychiatric illness, e.g. substance abuse, psychosis, bipolar disorder, anorexia, obsessive compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, panic disorder, personality disorder.
  • Antipsychotic medication not approved for the treatment of depression.
  • Acute suicidality.
  • Conditions related to increased intracranial pressure.
  • Brain injury or stroke.
  • History of epilepsy in patient or in first-degree relative.
  • Cerebral aneurysm.
  • Neurological illness (e.g. dementia (score of less than 25 in Mini Mental State Exam), Parkinson's disease, chorea huntington, multiple sclerosis).
  • Course of electroconvulsive therapy (ECT) within the last three months
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Germany
Removed Location Countries  
 
Administrative Information
NCT Number NCT03944213
Other Study ID Numbers DepRest
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Rene Hurlemann, University Hospital, Bonn
Study Sponsor University Hospital, Bonn
Collaborators
  • Clemens Mielacher, University Hospital, Bonn
  • Maximilian Kiebs, University Hospital, Bonn
Investigators
Principal Investigator: René Hurlemann, Prof. University Hospital, Bonn
PRS Account University Hospital, Bonn
Verification Date May 2019

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