In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population
IntroductionAttention-deficit/hyperactivity disorder (ADHD) is an impairing psychiatric condition with the stimulants, lisdexamfetamine (LDX), and methylphenidate (MPH), as the first lines pharmacological treatment.MethodsHerein, we applied a novel in silico method to evaluate virtual LDX (vLDX) and...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-06-01
|
| Series: | Frontiers in Psychiatry |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.939650/full |
| _version_ | 1797813458046025728 |
|---|---|
| author | José Ramón Gutiérrez-Casares Javier Quintero Cristina Segú-Vergés Cristina Segú-Vergés Pilar Rodríguez Monterde Tamara Pozo-Rubio Mireia Coma Carmen Montoto |
| author_facet | José Ramón Gutiérrez-Casares Javier Quintero Cristina Segú-Vergés Cristina Segú-Vergés Pilar Rodríguez Monterde Tamara Pozo-Rubio Mireia Coma Carmen Montoto |
| author_sort | José Ramón Gutiérrez-Casares |
| collection | DOAJ |
| description | IntroductionAttention-deficit/hyperactivity disorder (ADHD) is an impairing psychiatric condition with the stimulants, lisdexamfetamine (LDX), and methylphenidate (MPH), as the first lines pharmacological treatment.MethodsHerein, we applied a novel in silico method to evaluate virtual LDX (vLDX) and vMPH as treatments for ADHD applying quantitative systems pharmacology (QSP) models. The objectives were to evaluate the model’s output, considering the model characteristics and the information used to build them, to compare both virtual drugs’ efficacy mechanisms, and to assess how demographic (age, body mass index, and sex) and clinical characteristics may affect vLDX’s and vMPH’s relative efficacies.Results and DiscussionWe molecularly characterized the drugs and pathologies based on a bibliographic search, and generated virtual populations of adults and children-adolescents totaling 2,600 individuals. For each virtual patient and virtual drug, we created physiologically based pharmacokinetic and QSP models applying the systems biology-based Therapeutic Performance Mapping System technology. The resulting models’ predicted protein activity indicated that both virtual drugs modulated ADHD through similar mechanisms, albeit with some differences. vMPH induced several general synaptic, neurotransmitter, and nerve impulse-related processes, whereas vLDX seemed to modulate neural processes more specific to ADHD, such as GABAergic inhibitory synapses and regulation of the reward system. While both drugs’ models were linked to an effect over neuroinflammation and altered neural viability, vLDX had a significant impact on neurotransmitter imbalance and vMPH on circadian system deregulation. Among demographic characteristics, age and body mass index affected the efficacy of both virtual treatments, although the effect was more marked for vLDX. Regarding comorbidities, only depression negatively impacted both virtual drugs’ efficacy mechanisms and, while that of vLDX were more affected by the co-treatment of tic disorders, the efficacy mechanisms of vMPH were disturbed by wide-spectrum psychiatric drugs. Our in silico results suggested that both drugs could have similar efficacy mechanisms as ADHD treatment in adult and pediatric populations and allowed raising hypotheses for their differential impact in specific patient groups, although these results require prospective validation for clinical translatability. |
| first_indexed | 2024-03-13T07:52:12Z |
| format | Article |
| id | doaj.art-90d39d2315d54c8ea4a5e1f187f0cd23 |
| institution | Directory Open Access Journal |
| issn | 1664-0640 |
| language | English |
| last_indexed | 2024-03-13T07:52:12Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Psychiatry |
| spelling | doaj.art-90d39d2315d54c8ea4a5e1f187f0cd232023-06-02T11:35:27ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402023-06-011410.3389/fpsyt.2023.939650939650In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ populationJosé Ramón Gutiérrez-Casares0Javier Quintero1Cristina Segú-Vergés2Cristina Segú-Vergés3Pilar Rodríguez Monterde4Tamara Pozo-Rubio5Mireia Coma6Carmen Montoto7Unidad Ambulatoria de Psiquiatría y Salud Mental de la Infancia, Niñez y Adolescencia, Hospital Perpetuo Socorro, Badajoz, SpainServicio de Psiquiatría, Hospital Universitario Infanta Leonor, Universidad Complutense, Madrid, SpainAnaxomics Biotech, Barcelona, SpainStructural Bioinformatics Group, Research Programme on Biomedical Informatics, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, SpainMedical Department, Takeda Farmacéutica España, Madrid, SpainMedical Department, Takeda Farmacéutica España, Madrid, SpainAnaxomics Biotech, Barcelona, SpainMedical Department, Takeda Farmacéutica España, Madrid, SpainIntroductionAttention-deficit/hyperactivity disorder (ADHD) is an impairing psychiatric condition with the stimulants, lisdexamfetamine (LDX), and methylphenidate (MPH), as the first lines pharmacological treatment.MethodsHerein, we applied a novel in silico method to evaluate virtual LDX (vLDX) and vMPH as treatments for ADHD applying quantitative systems pharmacology (QSP) models. The objectives were to evaluate the model’s output, considering the model characteristics and the information used to build them, to compare both virtual drugs’ efficacy mechanisms, and to assess how demographic (age, body mass index, and sex) and clinical characteristics may affect vLDX’s and vMPH’s relative efficacies.Results and DiscussionWe molecularly characterized the drugs and pathologies based on a bibliographic search, and generated virtual populations of adults and children-adolescents totaling 2,600 individuals. For each virtual patient and virtual drug, we created physiologically based pharmacokinetic and QSP models applying the systems biology-based Therapeutic Performance Mapping System technology. The resulting models’ predicted protein activity indicated that both virtual drugs modulated ADHD through similar mechanisms, albeit with some differences. vMPH induced several general synaptic, neurotransmitter, and nerve impulse-related processes, whereas vLDX seemed to modulate neural processes more specific to ADHD, such as GABAergic inhibitory synapses and regulation of the reward system. While both drugs’ models were linked to an effect over neuroinflammation and altered neural viability, vLDX had a significant impact on neurotransmitter imbalance and vMPH on circadian system deregulation. Among demographic characteristics, age and body mass index affected the efficacy of both virtual treatments, although the effect was more marked for vLDX. Regarding comorbidities, only depression negatively impacted both virtual drugs’ efficacy mechanisms and, while that of vLDX were more affected by the co-treatment of tic disorders, the efficacy mechanisms of vMPH were disturbed by wide-spectrum psychiatric drugs. Our in silico results suggested that both drugs could have similar efficacy mechanisms as ADHD treatment in adult and pediatric populations and allowed raising hypotheses for their differential impact in specific patient groups, although these results require prospective validation for clinical translatability.https://www.frontiersin.org/articles/10.3389/fpsyt.2023.939650/fullattention-deficit/hyperactivity disorderlisdexamfetaminemethylphenidatemathematical modelingin silico clinical trial |
| spellingShingle | José Ramón Gutiérrez-Casares Javier Quintero Cristina Segú-Vergés Cristina Segú-Vergés Pilar Rodríguez Monterde Tamara Pozo-Rubio Mireia Coma Carmen Montoto In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population Frontiers in Psychiatry attention-deficit/hyperactivity disorder lisdexamfetamine methylphenidate mathematical modeling in silico clinical trial |
| title | In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population |
| title_full | In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population |
| title_fullStr | In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population |
| title_full_unstemmed | In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population |
| title_short | In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population |
| title_sort | in silico clinical trial evaluating lisdexamfetamine s and methylphenidate s mechanism of action computational models in an attention deficit hyperactivity disorder virtual patients population |
| topic | attention-deficit/hyperactivity disorder lisdexamfetamine methylphenidate mathematical modeling in silico clinical trial |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.939650/full |
| work_keys_str_mv | AT joseramongutierrezcasares insilicoclinicaltrialevaluatinglisdexamfetaminesandmethylphenidatesmechanismofactioncomputationalmodelsinanattentiondeficithyperactivitydisordervirtualpatientspopulation AT javierquintero insilicoclinicaltrialevaluatinglisdexamfetaminesandmethylphenidatesmechanismofactioncomputationalmodelsinanattentiondeficithyperactivitydisordervirtualpatientspopulation AT cristinaseguverges insilicoclinicaltrialevaluatinglisdexamfetaminesandmethylphenidatesmechanismofactioncomputationalmodelsinanattentiondeficithyperactivitydisordervirtualpatientspopulation AT cristinaseguverges insilicoclinicaltrialevaluatinglisdexamfetaminesandmethylphenidatesmechanismofactioncomputationalmodelsinanattentiondeficithyperactivitydisordervirtualpatientspopulation AT pilarrodriguezmonterde insilicoclinicaltrialevaluatinglisdexamfetaminesandmethylphenidatesmechanismofactioncomputationalmodelsinanattentiondeficithyperactivitydisordervirtualpatientspopulation AT tamarapozorubio insilicoclinicaltrialevaluatinglisdexamfetaminesandmethylphenidatesmechanismofactioncomputationalmodelsinanattentiondeficithyperactivitydisordervirtualpatientspopulation AT mireiacoma insilicoclinicaltrialevaluatinglisdexamfetaminesandmethylphenidatesmechanismofactioncomputationalmodelsinanattentiondeficithyperactivitydisordervirtualpatientspopulation AT carmenmontoto insilicoclinicaltrialevaluatinglisdexamfetaminesandmethylphenidatesmechanismofactioncomputationalmodelsinanattentiondeficithyperactivitydisordervirtualpatientspopulation |