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Personalizing transcranial direct current stimulation for treating major depressive disorder. reevaluation of clinical trials in the context of precision psychiatry
Personalizing transcranial direct current stimulation for treating major depressive disorder. reevaluation of clinical trials in the context of precision psychiatry
Transcranial direct current stimulation (tDCS) is a safe and efficient intervention for treating major depressive disorder (MDD). However, research has suggested heterogeneity of response between patients. The emerging field of precision psychiatry aims to use statistical modeling of multi-modal data to tailor treatment to the single patient. To this end, more in-depth analysis of randomized controlled trials (RCTs) will be relevant (1) due to limited availability of other large datasets with high phenotypic detail and (2) to develop tools for personalization within counterfactually controlled environments (i.e. experimental designs with sham intervention and/or active treatment comparison) to distinguish specific vs. non-specific patterns in treatment data. Previous research has aimed at identifying patient-related factors associated with better response. However, most analyses have operated on the group-level, ignoring natural clusters within the patients' constituting factors, their individual trajectories of symptom improvement, and their presented symptoms. Furthermore, group-based modeling strategies were limited to explanatory approaches using in-sample hypothesis-testing, that are ill-suited to prognosticate outcomes of single patients. This dissertation provides a methodological framework for reevaluation of existing clinical trial data (1) to provide future investigations with more differentiated units of analysis and (2) to complement explanatory approaches with predictive modeling strategies enabling prediction of single-patient outcomes. Using data from a landmark 3-arm clinical trial paradigmatic for a rigorously controlled experimental design (10-week treatment of tDCS vs. escitalopram vs. placebo) the dissertation provides three blueprint studies for modeling heterogeneity of tDCS response: Study 1 characterized response to tDCS by considering patient-individual dynamics of symptom change over the course of treatment. Distinct trajectories of tDCS response could be identified (rapid-, slow-, and no/minimal improvement), representing patient subgroups with varying strength and speed of improvement. These results suggest development of individualized treatment protocols and exploration of prolonged treatment courses. Study 2 reevaluated the efficacy of tDCS, in distinct, naturally occurring clusters of depressive symptoms. Using unsupervised machine learning (ML), a global depression measure (HAM-D) was parsed into 4 distinct symptom clusters. Analysis of cluster-scores showed superiority of tDCS and escitalopram over placebo in core depressive symptoms, but only tDCS was superior in improving sleep and only escitalopram was superior in improving guilt/anxiety symptoms, suggesting treatment selection based on patients' symptom profiles. In Study 3 supervised ML algorithms were employed to predict response to tDCS. In this proof-of-concept approach, response could be predicted above chance on the single-patient level, but overall accuracy was modest. Features employed for model training were explored using interpretable ML methods. Trained algorithms were provided to the field for expansion as well as tests of generalizability and incremental utility. The presented studies illustrate how in-depth secondary analyses of clinical trial data can aid personalization of treatment. The provided methodological framework can be expanded (options are discussed) and generalized to other contexts and interventions that show heterogeneity of treatment effects. Yet, the empirical studies also epitomize challenges precision psychiatry is faced with, including low data availability, low outcome granularity, and limited external validation opportunities. The dissertation concludes with a discussion of challenges and future directions resulting from infrastructural demands in data acquisition, data management, data sharing, and interdisciplinary collaboration.
tDCS, neuromodulation, major depression, precision psychiatry, personalized treatments
Goerigk, Stephan
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Goerigk, Stephan (2021): Personalizing transcranial direct current stimulation for treating major depressive disorder: reevaluation of clinical trials in the context of precision psychiatry. Dissertation, LMU München: Faculty of Psychology and Educational Sciences
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Abstract

Transcranial direct current stimulation (tDCS) is a safe and efficient intervention for treating major depressive disorder (MDD). However, research has suggested heterogeneity of response between patients. The emerging field of precision psychiatry aims to use statistical modeling of multi-modal data to tailor treatment to the single patient. To this end, more in-depth analysis of randomized controlled trials (RCTs) will be relevant (1) due to limited availability of other large datasets with high phenotypic detail and (2) to develop tools for personalization within counterfactually controlled environments (i.e. experimental designs with sham intervention and/or active treatment comparison) to distinguish specific vs. non-specific patterns in treatment data. Previous research has aimed at identifying patient-related factors associated with better response. However, most analyses have operated on the group-level, ignoring natural clusters within the patients' constituting factors, their individual trajectories of symptom improvement, and their presented symptoms. Furthermore, group-based modeling strategies were limited to explanatory approaches using in-sample hypothesis-testing, that are ill-suited to prognosticate outcomes of single patients. This dissertation provides a methodological framework for reevaluation of existing clinical trial data (1) to provide future investigations with more differentiated units of analysis and (2) to complement explanatory approaches with predictive modeling strategies enabling prediction of single-patient outcomes. Using data from a landmark 3-arm clinical trial paradigmatic for a rigorously controlled experimental design (10-week treatment of tDCS vs. escitalopram vs. placebo) the dissertation provides three blueprint studies for modeling heterogeneity of tDCS response: Study 1 characterized response to tDCS by considering patient-individual dynamics of symptom change over the course of treatment. Distinct trajectories of tDCS response could be identified (rapid-, slow-, and no/minimal improvement), representing patient subgroups with varying strength and speed of improvement. These results suggest development of individualized treatment protocols and exploration of prolonged treatment courses. Study 2 reevaluated the efficacy of tDCS, in distinct, naturally occurring clusters of depressive symptoms. Using unsupervised machine learning (ML), a global depression measure (HAM-D) was parsed into 4 distinct symptom clusters. Analysis of cluster-scores showed superiority of tDCS and escitalopram over placebo in core depressive symptoms, but only tDCS was superior in improving sleep and only escitalopram was superior in improving guilt/anxiety symptoms, suggesting treatment selection based on patients' symptom profiles. In Study 3 supervised ML algorithms were employed to predict response to tDCS. In this proof-of-concept approach, response could be predicted above chance on the single-patient level, but overall accuracy was modest. Features employed for model training were explored using interpretable ML methods. Trained algorithms were provided to the field for expansion as well as tests of generalizability and incremental utility. The presented studies illustrate how in-depth secondary analyses of clinical trial data can aid personalization of treatment. The provided methodological framework can be expanded (options are discussed) and generalized to other contexts and interventions that show heterogeneity of treatment effects. Yet, the empirical studies also epitomize challenges precision psychiatry is faced with, including low data availability, low outcome granularity, and limited external validation opportunities. The dissertation concludes with a discussion of challenges and future directions resulting from infrastructural demands in data acquisition, data management, data sharing, and interdisciplinary collaboration.