Ignite Creation Date:
2024-05-06 @ 8:27 PM
Last Modification Date:
2024-10-26 @ 3:28 PM
Study NCT ID:
NCT06396312
Status:
RECRUITING
Last Update Posted:
2024-05-02
First Post:
2024-04-12
Brief Title:
Deep Phenotyping for Clinical Inferring Response in Treatment Resistant Depression
Sponsor:
Max-Planck-Institute of Psychiatry
Organization:
Max-Planck-Institute of Psychiatry
Study Overview
Official Title:
DECIDE- Deep Phenotyping for Clinical Inferring Response in Treatment Resistant Depression -Study
Status:
RECRUITING
Status Verified Date:
2024-04
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:
DECIDE
Brief Summary:
DECIDE- Deep phenotyping for clinical inferring response in treatment resistant depression -Study
Building upon the Biobanking initiative at the Max Planck Institute of Psychiatry the present project aims to identify clinically relevant subtypes of treatment-resistant depression TRD through Clinical Deep Phenotyping CDP According to clinical trials 30-40 of the patients suffering from TRD benefit from lithium treatment By collecting multimodal biological and clinical-diagnostic markers such as structural and functional brain imaging via magnetic resonance imaging MRI brain signals from electroencephalography comprehensive blood tests assessment of perception and cognition through neuropsychological testing as well as the evaluation of specific depression symptoms and psychological and other comorbidities using standardized questionnaires a bio-clinical signature will be identified using multivariate machine learning algorithms as an integration method This signature aims to predict the response to lithium therapy in TRD Prospectively such an algorithm could later personalize the treatment decision of lithium administration in TRD This concept is in line with the Research Domain Criteria RDoC of the National Institute of Mental Health NIH and aims to offer lithium therapy as a personalized treatment strategy for TRD Specifically this means that the likelihood of treatment response can be estimated before administration based on the results of the present study thus enabling lithium to be offered specifically to those patients who are likely to benefit from it The study design is non-interventional meaning the decision for lithium treatment is made for patients according to clinical routine in accordance with the recommendation of the German National Treatment Guideline NVL independent of study enrollment Study participation does not influence treatment decisions for the patients
Building upon the Biobanking initiative at the Max Planck Institute of Psychiatry the present project aims to identify clinically relevant subtypes of treatment-resistant depression TRD through Clinical Deep Phenotyping CDP According to clinical trials 30-40 of the patients suffering from TRD benefit from lithium treatment By collecting multimodal biological and clinical-diagnostic markers such as structural and functional brain imaging via magnetic resonance imaging MRI brain signals from electroencephalography comprehensive blood tests assessment of perception and cognition through neuropsychological testing as well as the evaluation of specific depression symptoms and psychological and other comorbidities using standardized questionnaires a bio-clinical signature will be identified using multivariate machine learning algorithms as an integration method This signature aims to predict the response to lithium therapy in TRD Prospectively such an algorithm could later personalize the treatment decision of lithium administration in TRD This concept is in line with the Research Domain Criteria RDoC of the National Institute of Mental Health NIH and aims to offer lithium therapy as a personalized treatment strategy for TRD Specifically this means that the likelihood of treatment response can be estimated before administration based on the results of the present study thus enabling lithium to be offered specifically to those patients who are likely to benefit from it The study design is non-interventional meaning the decision for lithium treatment is made for patients according to clinical routine in accordance with the recommendation of the German National Treatment Guideline NVL independent of study enrollment Study participation does not influence treatment decisions for the patients
Detailed Description:
DECIDE- Deep phenotyping for clinical inferring response in treatment resistant depression -Study
Background
TRD is a form of major depressive disorder MDD typically characterized by an inadequate response partial or no response to first-line antidepressants AD therapy of adequate dose and duration This variant of depression common in psychiatry affects approximately 30-50 of all patients with depression and is the focus of the present DECIDE-study In treating TRD augmenting existing antidepressant pharmacotherapy with lithium proves to be an effective option recommended in the German national care guideline The precise definition of TRD within this study encompasses the following criteria and is based on Bauer et al 2013
1 Confirmation of MDD diagnosis according to DSM-V verified through the Mini Neuropsychiatric Interview MINI-Interview
2 Inadequate response to treatment after 4 weeks of antidepressant AD therapy Inadequate response is defined as not achieving remission from depressive symptoms following 28 days of AD usage prior to the study This determination includes the exclusion of pseudo-resistance through measurement of medication plasma levels
3 Stage I TRD is characterized by the failure of 1 adequate trial using one major class of AD Major classes are selective serotonin reuptake inhibitors SSRIs serotonin and norepinephrine reuptake inhibitors SNRIs tricyclic and tetracyclic antidepressants TCAs Monoamine oxidase inhibitors MAOIs and atypical antidepressants
4 Stage II TRD is characterized by the failure of two distinct classes of major AD A Montgomery-Åsberg Depression Rating Scale MADRS total score of 25 serves as an additional qualifying criterion
Importantly while only around 30 patients experience benefits after 4 to 6 weeks of lithium treatment those who do respond often experience significant relief In the NVL it is recommended to assess the effectiveness of lithium therapy after 2-4 weeks If the patient does not benefit lithium should be discontinued However despite substantial benefits by the recommended lithium application in clinical use the augmentation strategy of lithium in TRD faces limitations in clinical practice due to concerns by physicians about lithiums potential side effects Therefore there is a risk that the use of lithium treatment in TRD remains under-exploited despite evidence for its significant potential to aid patients with TRD Having a predictive tool indicating lithium efficacy in specific TRD patients before therapy initiation could aid psychiatrists in deciding to pursue lithium treatment
DECIDE - the here described prospective diagnostic study aims to explore whether in-depth clinical and biological phenotyping of TRD before lithium treatment could provide the basis to classify TRD into responders and non-responders to lithium This concept aligns with the RDoC the research criteria established by the NIH
Various studies have investigated predictors of lithium response in bipolar disorder BP Given the clinically observed heritability of lithium responsiveness initial approaches involved analyzing genetic markers As the field of lithium prediction evolved subsequent investigations delved into epigenetic markers and genome-wide methylation data associated with lithium response
Genome-wide association studies GWAS identified genetic loci that were associated with lithium non-response but yielded inconclusive predictions in pooled datasets Still there was supporting evidence linking polygenic risk scores for schizophrenia and major depression to poor lithium response Behind genetics a recent study that focused on serotonergic receptors and transporters explored differences between responders and non-responders using nuclear medical imaging techniques Only a limited number of studies have focused on analyzing noncoding RNA levels in cells from patients and their impact on the response to lithium Valuable insights might arise from investigations focusing on the microRNA miRNA levels found in peripherally derived exosomes Exosomes secreted by diverse neuronal cell types facilitate intercellular communication and signaling Their capacity to traverse the blood-brain barrier allows for analysis through blood sampling Initial results regarding the application of miRNAs from extracellular vesicles as BD biomarkers are promising however the investigation of exosomes as a source of biomarkers in lithium response remains largely unexplored
While there have been studies on biomarker signatures of lithium responses in MDD these studies have not established an algorithm for personalized treatment decisions so far However the precise molecular mechanisms behind lithium augmentation in TRD are still undergoing intensive investigation
Most previous studies have focused on individual clinical or biological markers likely explaining only a fraction of mental illness diversity Integrating clinical and multimodal response markers could enable the development of a composite prediction algorithm and the testing of it in subsequent projects applicable to new populations
The differentiation between nonspecific and clinically relevant molecular mechanisms of lithium response remains too intertwined to be approached solely through clinical studies Therefore in addition this study aims to stratify a subgroup of the deeply clinical classified TRD patients generate patient-derived induced pluripotent stem cells iPSCs and forward these to iPSC-based technology In vitro studies utilizing neurobiological test systems derived from iPSC obtained from patients could make a substantial contribution to advance our understanding of psychiatry diseases in general and the mechanism of lithium response in particular Interestingly the cellular response to lithium mirrored the clinical response indicating significant neurobiological mechanisms in bipolar disorder The goal here is to examine whether lithium response is also reflected on a cellular level in TRD and to analyze the specific pathways active in different types of TRD Moreover the iPSC-based part of DECIDE aims to translate clinical and iPSC-based phenotypes in order to deliver neuroscience-based methods to improve the prediction of treatment response and non-response in TRD
Statistical analysis concept
The statistical analysis is conducted at both the individual and multi-marker levels using linear and logistic regression models Machine learning techniques such as clustering methods are utilized to create the biosignature The analyses are not intended solely at the end of data collection interim analyses are also planned
Study protocol
After positive evaluation of study inclusion at baseline the following examinations are to be conducted subsequently After the initiation of lithium therapy routine serum level monitoring occurs with Follow-up 1 defined as the timepoint when an effective lithium level is achieved target range of 06-08 mmolL Two weeks later at Follow-up 2 MADRS assessments are conducted to capture therapy response If during weeks 3-6 Follow-up 3 Follow-up 4 Follow-up 5 Follow-up 6 the endpoint MADRS response 50 reduction in baseline MADRS total score is achieved optional additional examinations will be conducted If not the optional additional examinations will take place in week 6 Follow-up 6 If the treating psychiatrist decides to discontinue lithium earlier due to non-response or other reasons the optional additional examinations will be conducted at that timepoint If the clinical treatment team decides to change the antidepressant medication the patient must be withdrawn from the study Follow up 7 will take place after 52 weeks for all included patients independent of initial classification of responsenon-response
Clinical characterization
The clinical characterization includes the MINI Interview according to DSM-V to confirm the diagnosis of MDD The MINI Interview stands as the globally most recognized and extensively employed psychiatric structured diagnostic interview Information regarding patients psychiatric history and medication history will be evaluated using a designed questionnaire sociodemographic information and family history will be assessed additionally
Biosamples
Biosamples will be collected from all participants and used for the generation of a biosinature namely for RNA isolation Proteomics Metabolomics Exosomes Genotyping Methylation drug levels and PBMC isolation
Multimodal MRI mMRI
The mMRI includes anatomical techniques functional MRI measurements and single voxel proton MR spectroscopy at different locations
Electroencephalography EEG
All subjects recruited into the study will undergo digitized EEG recordings of about 20 minutes using a standardized set-up with scalp electrodes exactly as it is recommended in clinical routine during Lithium therapy
Neurocognitive assessment Cognition
The standardized Brief Assessment of cognitive function in schizophrenia BACS battery will be administered to all patients The BACS includes six tasks evaluating four cognitive domains deemed crucial for clinical trials by the MATRICS Neurocognition Committee For the sake of comparability with other studies that focuses on Treatment resistance involving schizophrenic patients this DECIDE Study will also use the BACS These domains are processing speed verbal fluency in category instances such as supermarket items and letter fluency using F and S words Token Motor Task Symbol Coding reasoning and problem-solving Tower of London test verbal memory list learning and working memory digit sequencing Additionally we enhance the assessment with the widely used Montreal Cognitive Assessment MoCA for a quick and comprehensive neurocognitive evaluation
Background
TRD is a form of major depressive disorder MDD typically characterized by an inadequate response partial or no response to first-line antidepressants AD therapy of adequate dose and duration This variant of depression common in psychiatry affects approximately 30-50 of all patients with depression and is the focus of the present DECIDE-study In treating TRD augmenting existing antidepressant pharmacotherapy with lithium proves to be an effective option recommended in the German national care guideline The precise definition of TRD within this study encompasses the following criteria and is based on Bauer et al 2013
1 Confirmation of MDD diagnosis according to DSM-V verified through the Mini Neuropsychiatric Interview MINI-Interview
2 Inadequate response to treatment after 4 weeks of antidepressant AD therapy Inadequate response is defined as not achieving remission from depressive symptoms following 28 days of AD usage prior to the study This determination includes the exclusion of pseudo-resistance through measurement of medication plasma levels
3 Stage I TRD is characterized by the failure of 1 adequate trial using one major class of AD Major classes are selective serotonin reuptake inhibitors SSRIs serotonin and norepinephrine reuptake inhibitors SNRIs tricyclic and tetracyclic antidepressants TCAs Monoamine oxidase inhibitors MAOIs and atypical antidepressants
4 Stage II TRD is characterized by the failure of two distinct classes of major AD A Montgomery-Åsberg Depression Rating Scale MADRS total score of 25 serves as an additional qualifying criterion
Importantly while only around 30 patients experience benefits after 4 to 6 weeks of lithium treatment those who do respond often experience significant relief In the NVL it is recommended to assess the effectiveness of lithium therapy after 2-4 weeks If the patient does not benefit lithium should be discontinued However despite substantial benefits by the recommended lithium application in clinical use the augmentation strategy of lithium in TRD faces limitations in clinical practice due to concerns by physicians about lithiums potential side effects Therefore there is a risk that the use of lithium treatment in TRD remains under-exploited despite evidence for its significant potential to aid patients with TRD Having a predictive tool indicating lithium efficacy in specific TRD patients before therapy initiation could aid psychiatrists in deciding to pursue lithium treatment
DECIDE - the here described prospective diagnostic study aims to explore whether in-depth clinical and biological phenotyping of TRD before lithium treatment could provide the basis to classify TRD into responders and non-responders to lithium This concept aligns with the RDoC the research criteria established by the NIH
Various studies have investigated predictors of lithium response in bipolar disorder BP Given the clinically observed heritability of lithium responsiveness initial approaches involved analyzing genetic markers As the field of lithium prediction evolved subsequent investigations delved into epigenetic markers and genome-wide methylation data associated with lithium response
Genome-wide association studies GWAS identified genetic loci that were associated with lithium non-response but yielded inconclusive predictions in pooled datasets Still there was supporting evidence linking polygenic risk scores for schizophrenia and major depression to poor lithium response Behind genetics a recent study that focused on serotonergic receptors and transporters explored differences between responders and non-responders using nuclear medical imaging techniques Only a limited number of studies have focused on analyzing noncoding RNA levels in cells from patients and their impact on the response to lithium Valuable insights might arise from investigations focusing on the microRNA miRNA levels found in peripherally derived exosomes Exosomes secreted by diverse neuronal cell types facilitate intercellular communication and signaling Their capacity to traverse the blood-brain barrier allows for analysis through blood sampling Initial results regarding the application of miRNAs from extracellular vesicles as BD biomarkers are promising however the investigation of exosomes as a source of biomarkers in lithium response remains largely unexplored
While there have been studies on biomarker signatures of lithium responses in MDD these studies have not established an algorithm for personalized treatment decisions so far However the precise molecular mechanisms behind lithium augmentation in TRD are still undergoing intensive investigation
Most previous studies have focused on individual clinical or biological markers likely explaining only a fraction of mental illness diversity Integrating clinical and multimodal response markers could enable the development of a composite prediction algorithm and the testing of it in subsequent projects applicable to new populations
The differentiation between nonspecific and clinically relevant molecular mechanisms of lithium response remains too intertwined to be approached solely through clinical studies Therefore in addition this study aims to stratify a subgroup of the deeply clinical classified TRD patients generate patient-derived induced pluripotent stem cells iPSCs and forward these to iPSC-based technology In vitro studies utilizing neurobiological test systems derived from iPSC obtained from patients could make a substantial contribution to advance our understanding of psychiatry diseases in general and the mechanism of lithium response in particular Interestingly the cellular response to lithium mirrored the clinical response indicating significant neurobiological mechanisms in bipolar disorder The goal here is to examine whether lithium response is also reflected on a cellular level in TRD and to analyze the specific pathways active in different types of TRD Moreover the iPSC-based part of DECIDE aims to translate clinical and iPSC-based phenotypes in order to deliver neuroscience-based methods to improve the prediction of treatment response and non-response in TRD
Statistical analysis concept
The statistical analysis is conducted at both the individual and multi-marker levels using linear and logistic regression models Machine learning techniques such as clustering methods are utilized to create the biosignature The analyses are not intended solely at the end of data collection interim analyses are also planned
Study protocol
After positive evaluation of study inclusion at baseline the following examinations are to be conducted subsequently After the initiation of lithium therapy routine serum level monitoring occurs with Follow-up 1 defined as the timepoint when an effective lithium level is achieved target range of 06-08 mmolL Two weeks later at Follow-up 2 MADRS assessments are conducted to capture therapy response If during weeks 3-6 Follow-up 3 Follow-up 4 Follow-up 5 Follow-up 6 the endpoint MADRS response 50 reduction in baseline MADRS total score is achieved optional additional examinations will be conducted If not the optional additional examinations will take place in week 6 Follow-up 6 If the treating psychiatrist decides to discontinue lithium earlier due to non-response or other reasons the optional additional examinations will be conducted at that timepoint If the clinical treatment team decides to change the antidepressant medication the patient must be withdrawn from the study Follow up 7 will take place after 52 weeks for all included patients independent of initial classification of responsenon-response
Clinical characterization
The clinical characterization includes the MINI Interview according to DSM-V to confirm the diagnosis of MDD The MINI Interview stands as the globally most recognized and extensively employed psychiatric structured diagnostic interview Information regarding patients psychiatric history and medication history will be evaluated using a designed questionnaire sociodemographic information and family history will be assessed additionally
Biosamples
Biosamples will be collected from all participants and used for the generation of a biosinature namely for RNA isolation Proteomics Metabolomics Exosomes Genotyping Methylation drug levels and PBMC isolation
Multimodal MRI mMRI
The mMRI includes anatomical techniques functional MRI measurements and single voxel proton MR spectroscopy at different locations
Electroencephalography EEG
All subjects recruited into the study will undergo digitized EEG recordings of about 20 minutes using a standardized set-up with scalp electrodes exactly as it is recommended in clinical routine during Lithium therapy
Neurocognitive assessment Cognition
The standardized Brief Assessment of cognitive function in schizophrenia BACS battery will be administered to all patients The BACS includes six tasks evaluating four cognitive domains deemed crucial for clinical trials by the MATRICS Neurocognition Committee For the sake of comparability with other studies that focuses on Treatment resistance involving schizophrenic patients this DECIDE Study will also use the BACS These domains are processing speed verbal fluency in category instances such as supermarket items and letter fluency using F and S words Token Motor Task Symbol Coding reasoning and problem-solving Tower of London test verbal memory list learning and working memory digit sequencing Additionally we enhance the assessment with the widely used Montreal Cognitive Assessment MoCA for a quick and comprehensive neurocognitive evaluation
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