In silico evaluation of the role of lisdexamfetamine on attention-deficit/hyperactivity disorder common psychiatric comorbidities: mechanistic insights on binge eating disorder and depression.

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric condition well recognized in the pediatric population that can persist into adulthood. The vast majority of patients with ADHD present psychiatric comorbidities that have been suggested to share, to some extent, the pathophysiological mechanism of ADHD. Lisdexamfetamine (LDX) is a stimulant prodrug approved for treating ADHD and, in the US, also for binge eating disorder (BED). Herein, we evaluated, through a systems biology-based in silico method, the efficacy of a virtual model of LDX (vLDX) as ADHD treatment to improve five common ADHD psychiatric comorbidities in adults and children, and we explored the molecular mechanisms behind LDX's predicted efficacy. After the molecular characterization of vLDX and the comorbidities (anxiety, BED, bipolar disorder, depression, and tics disorder), we created a protein-protein interaction human network to which we applied artificial neural networks (ANN) algorithms. We also generated virtual populations of adults and children-adolescents totaling 2,600 individuals and obtained the predicted protein activity from Therapeutic Performance Mapping System models. The latter showed that ADHD molecular description shared 53% of its protein effectors with at least one studied psychiatric comorbidity. According to the ANN analysis, proteins targeted by vLDX are predicted to have a high probability of being related to BED and depression. In BED, vLDX was modeled to act upon neurotransmission and neuroplasticity regulators, and, in depression, vLDX regulated the hypothalamic-pituitary-adrenal axis, neuroinflammation, oxidative stress, and glutamatergic excitotoxicity. In conclusion, our modeling results, despite their limitations and although requiring in vitro or in vivo validation, could supplement the design of preclinical and potentially clinical studies that investigate treatment for patients with ADHD with psychiatric comorbidities, especially from a molecular point of view.

In silico clinical trial evaluating lisdexamfetamine's and methylphenidate's mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients' population.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is an impairing psychiatric condition with the stimulants, lisdexamfetamine (LDX), and methylphenidate (MPH), as the first lines pharmacological treatment. Methods: Herein, 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 Discussion: We 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.

Influence of type of treatment on the well-being of Spanish patients with schizophrenia and their caregivers.

OBJECTIVE: This study aimed to investigate quality of life and burden on caregivers in Spanish outpatients with schizophrenia, treated with different antipsychotics. METHODS: Sociodemographic and clinical data were collected for 1865 patients diagnosed with schizophrenia. Patients answered the EuroQol-5D questionnaire and caregivers answered questionnaires assessing caregiver burden. Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression of Severity (CGI-S), and clinician's satisfaction were also recorded. The same data were also collected at months 3 and 6. RESULTS: According to EQ-5D results, usual activities (29.6%) and anxiety/depression (31.1%) were the most relevant reported problems. Good overall scores (5-7) on EQ-5D were reported by 47/118 (39.8%) of risperidone long-acting injectable (LAI) patients compared to 52/218 (23.9%) for oral conventional antipsychotics, 51/194 (26.2%) for injectable conventional antipsychotics, and 332/1110 (29.9%) for oral atypical antipsychotics. Significant benefits of risperidone LAI vs. other types of antipsychotic were also found in caregiver burden and clinician-derived outcome measures. At months 3 and 6, retention was > 85%, and score on the EQ5D improved for the overall sample. CONCLUSIONS: In Spanish patients with schizophrenia, activities of daily living and anxiety/depression were more relevant reported problems. Risperidone LAI was associated with better quality-of-life outcomes and lower caregiver burden compared to other types of antipsychotic.

Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate.

Regulatory agencies encourage computer modeling and simulation to reduce the time and cost of clinical trials. Although still not classified in formal guidelines, system biology-based models represent a powerful tool for generating hypotheses with great molecular detail. Herein, we have applied a mechanistic head-to-head in silico clinical trial (ISCT) between two treatments for attention-deficit/hyperactivity disorder, to wit lisdexamfetamine (LDX) and methylphenidate (MPH). The ISCT was generated through three phases comprising (i) the molecular characterization of drugs and pathologies, (ii) the generation of adult and children virtual populations (vPOPs) totaling 2,600 individuals and the creation of physiologically based pharmacokinetic (PBPK) and quantitative systems pharmacology (QSP) models, and (iii) data analysis with artificial intelligence methods. The characteristics of our vPOPs were in close agreement with real reference populations extracted from clinical trials, as did our PBPK models with in vivo parameters. The mechanisms of action of LDX and MPH were obtained from QSP models combining PBPK modeling of dosing schemes and systems biology-based modeling technology, i.e., therapeutic performance mapping system. The step-by-step process described here to undertake a head-to-head ISCT would allow obtaining mechanistic conclusions that could be extrapolated or used for predictions to a certain extent at the clinical level. Altogether, these computational techniques are proven an excellent tool for hypothesis-generation and would help reach a personalized medicine.

Adherence to treatment and therapeutic strategies in schizophrenic patients: the ADHERE study.

AIM: To assess the degree of compliance and adherence to treatment during the follow-up of schizophrenic outpatients after a new therapeutic strategy had been initiated. METHODS: A multicenter, retrospective, prospective, observational study of 1,848 outpatients with schizophrenia or schizoaffective disorders (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) was conducted. Patients were treated either with oral or injectable conventional or second generation antipsychotics, and were followed up for 3 months at mental health centers. Patient compliance with the pharmacological treatment was assessed by the use of questionnaires, scales, medication accountability, and the Medication Event Monitoring System. Patients were considered compliant if they reported a high compliance rate (> or = 80%). RESULTS: At baseline only 29% of patients on oral medication were compliant compared with 79% of patients on injectable medication (injection counting) (OR= 9.11; 95% CI 6.02-13.77; P<.0001). At the 3 month visit, 84% of patients had changed their treatment and in these, the compliance rate of those on injectable medication was 94% versus 87% of patients taking oral medication (OR= 2.47; 95% CI 1.21-5.05; P=.022). CONCLUSION: The use of long-acting injectable antipsychotics, which improves compliance rates and patient follow-up, should facilitate the management of Spanish patients with schizophrenia in mental health centers.