Methylphenidate Research Articles

SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with putative pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting.

Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without psychostimulant-like side effect liability. We compared AMPH, MPH, and SK609 within dose ranges that display their cognitive enhancing properties in a probabilistic discounting task (PDT) of risk/reward decision making behavior to assess their potential to increase risky choice preference. Rats chose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with descending probabilities across a session (100 - 6.25%) following administration of AMPH (0.25-1mg/kg), MPH (2-8mg/kg), and SK609 (4mg/kg). AMPH and MPH increased risky choice behavior at doses previously reported to enhance cognition, whereas SK609 did not. AMPH and MPH also reduced sensitivity to non-rewarded risky choices. These data highlight the combination of NE transporter blockade and selective D3 activation in pro-cognitive action without psychostimulant-like side effect liability. The absence of DA transporter blockade and non-selective dopaminergic activation are beneficial properties of SK609 that differentiates it from the traditional pro-cognitive psychostimulants.

Long-term Administration of High-Dose Methylphenidate Impairs Spatial Memory and Induces Neurodegeneration in the Hippocampus

Background: Methylphenidate hydrochloride (MPH) is used as a first-line treatment for attention-deficit/hyperactivity disorder. Nonetheless, there are a few studies regarding the relationship between memory and hippocampal neuron changes following long-term MPH treatment. Objectives: This study aimed to investigate the effects of pathological changes on memory following long-term MPH treatment. Methods: Forty rats were randomly and equally divided into four groups based on dosages. Animals underwent 0.6, 2.5 (low doses), or 10 (high dose) mg/kg MPH or saline (control) per day for 28 days. The Morris water maze (MWM) test was conducted at two time points: Two hours and four weeks after initiating MPH administration. The two-hour test evaluated single dose effects of MPH on memory, while the four-week test assessed long-term administration of MPH effects on memory performance. Finally, the brains were removed and pathological alterations in the cornu ammonis (CA1) and dentate gyrus (DG) regions of the hippocampus were investigated. Results: Single-dose administration of 10 mg/kg MPH decreased the latency time in the MWM test, while long-term administration of MPH increased the latency time. Furthermore, histopathology results showed that MPH at doses of 2.5 mg/kg and 10 mg/kg significantly increased the percentage of neurodegeneration in both the CA1 and DG regions compared to controls. Conclusions: Our findings show that a high single dose of MPH improves memory in rats. However, long-term administration of high dose of MPH impaired memory; such impairment may be associated with the neurodegeneration in the pyramidal layer cell of the CA1 and the granular layer cell of the DG.

Drug Holidays May Attenuate Beneficial Effects of Treatment on Emotion Regulation and Recognition Among Children with ADHD: A Single-Center, Prospective Study.

In this study, we aimed to evaluate the effects of drug holidays during summer vacations on children with attention deficit/hyperactivity disorder (ADHD) treated with methylphenidate in terms of ADHD symptoms and emotion regulation (ER). This single-center, naturalistic, prospective cohort study included pre-, post-, and post-drug holiday evaluations. All patients diagnosed with ADHD and included in our study were administered the Clinical Global Impression Scale, Affective Reactivity Index-parent and child, reading the mind in the eyes test (RMET), Faces test and Cognitive Emotion Regulation Questionnaire for Children 3 times. Fifty-six patients met the inclusion criteria and ten were lost to follow-up. Thirty-nine participants had complete evaluations at all time points. Both parent and self-report ratings of child irritability were significantly reduced after methylphenidate (MPH) treatment (P=.003 and .002, respectively), although they returned to baseline after drug holidays (P=.618 and .974, respectively). The use of self-blame as a cognitive emotion regulation strategy increased significantly after treatment and remained significantly elevated even after drug holidays (P=.024 and .022, respectively). Children used planning as a cognitive strategy significantly more frequently during MPH treatment (P=.034), although this elevation was temporary and returned to baseline levels after the drug holidays (P=.890). Reading the mind in the eyes test performance was significantly improved after MPH treatment and did not change after drug holidays (P=.009 and .006, respectively), while there was a tendency for facial emotion recognition abilities to improve at the last visit (P=.051). Our results suggest that MPH treatment improves child- and parent-reported irritability, clinician-rated disorder severity, RMET performance, and the use of planning as a cognitive ER strategy, although only improvement in RMET performance continued after drug holidays. Our results may support the importance of continuing treatment over the holidays for most children with ADHD unless necessitated by adverse events, growth problems, or development of tolerance.

Prediction of methylphenidate treatment response for ADHD using conventional and radiomics T1 and DTI features: Secondary analysis of a randomized clinical trial

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) is commonly treated with methylphenidate (MPH). Although highly effective, MPH treatment still has a relatively high non-response rate of around 30%, highlighting the need for a better understanding of treatment response. Radiomics of T1-weighted images and Diffusion Tensor Imaging (DTI) combined with machine learning approaches could offer a novel method for assessing MPH treatment response. PurposeTo evaluate the accuracy of both conventional and radiomics approaches in predicting treatment response based on baseline T1 and DTI data in stimulant-naive ADHD participants. MethodsWe performed a secondary analysis of a randomized clinical trial (ePOD-MPH), involving 47 stimulant-naive ADHD participants (23 boys aged 11.4 ± 0.4 years, 24 men aged 28.1 ± 4.3 years) who underwent 16 weeks of treatment with MPH. Baseline T1-weighted and DTI MRI scans were acquired. Treatment response was assessed at 8 weeks (during treatment) and one week after cessation of 16-week treatment (post-treatment) using the Clinical Global Impressions − Improvement scale as our primary outcome. We compared prediction accuracy using a conventional model and a radiomics model. The conventional approach included the volume of bilateral caudate, putamen, pallidum, accumbens, and hippocampus, and for DTI the mean fractional anisotropy (FA) of the entire brain white matter, bilateral Anterior Thalamic Radiation (ATR), and the splenium of the corpus callosum, totaling 14 regional features. For the radiomics approach, 380 features (shape-based and first-order statistics) were extracted from these 14 regions. XGBoost models with nested cross-validation were used and constructed for the total cohort (n = 47), as well as children (n = 23) and adults (n = 24) separately. Exact binomial tests were employed to compare model performance. ResultsFor the conventional model, balanced accuracy (bAcc) in predicting treatment response during treatment was 63 % for the total cohort, 32 % for children, and 36 % for adults (Area Under the Receiver Operating Characteristic Curve (AUC-ROC): 0.69, 0.33, 0.41 respectively). Radiomics models demonstrated bAcc’s of 68 %, 64 %, and 64 % during treatment (AUC-ROCs of 0.73, 0.62, 0.69 respectively). These predictions were better than chance for both conventional and radiomics models in the total cohort (p = 0.04, p = 0.003 respectively). The radiomics models outperformed the conventional models during treatment in children only (p = 0.02). At post-treatment, performance was markedly reduced. ConclusionWhile conventional and radiomics models performed equally well in predicting clinical improvement across children and adults during treatment, radiomics features offered enhanced structural information beyond conventional region-based volume and FA averages in children. Prediction of symptom improvement one week after treatment cessation was poor, potentially due to the transient effects of stimulant treatment on symptom improvement.

Predictors of Methylphenidate response in children and adolescents with ADHD: the role of sleep disturbances.

Sleep Disturbances (SD) have been linked to children and adolescents with ADHD, impacting its progression and outcomes. Methylphenidate (MPH), a commonly used stimulant medication for ADHD treatment, has been observed to potentially influence SD as a side effect, while SD can in turn potentially affect the response to MPH. This study aimed to explore the potential role of SD on MPH response in children and adolescents with ADHD. At this aim, 43 children and adolescents with ADHD received a single dose of MPH and were assessed for attention before and after medication administration. As expected, the administration of MPH resulted in improved attention levels. Our data indicate that patients with higher SD experienced greater benefits from the medication, stabilizing Reaction Times Variability (VRTs). This suggests that SD might influence the response to MPH, with individuals exhibiting higher SD deriving more advantages from the treatment. In addition, we found that other factors, such as externalizing problems and IQ, interact with each other and with SD, influencing the response to stimulant medication. Early detection of SD, along with the study of cognitive and emotional-behavioral characteristics, could assist clinicians in predicting the effectiveness of MPH therapy in children and adolescents with ADHD. However, further research is necessary to gain a deeper understanding of the role of SD and other factors in the long-term effects of MPH.

Safety and effectiveness of methylphenidate ER multi-unit pellet system in ADHD patients: An open label study.

Attention deficit hyperactive disorder (ADHD) is a neurodevelopmental disorder occurring in children and adults. Pharmacotherapy remains the cornerstone of ADHD treatment. Stimulants such as methylphenidate are effective and have been one of the best studied and most frequently used treatment for ADHD. However, different delivery mechanisms and devices may potentially impact patient experience and real-life outcomes. This study evaluated the effectiveness of Multiple-Unit Pellet System Delivered Extended-Release Methylphenidate (Contramyl XR) on symptom control and reported outcomes in ADHD patients, in a real-world setting. A phase IV, open label, flexible dose, prospective, observational study conducted at six sites covering five provinces of South Africa. About 119 participants with ADHD (both newly diagnosed [treatment-naïve] and methylphenidate-treated [switch-over] patients) were enrolled and initiated either on Contramyl XR or switched over from methylphenidate to Contramyl XR. Primary efficacy was assessed by Weiss Functional Impairment Rating Scale (WFIRS) over 12 weeks. In all, 117 participants completed the study (treatment-naïve patients: 46% [n = 55] and switch-over patients: 54% [n = 64]). Mean change from baseline in total WFIRS (95% confidence interval) was -17.7 (-21.1, -14.3; p < 0.001) at week 4 and -29.3 (-33.5, -25.2; p < 0.001) at week 12. At week 12, there was significant improvement in WFIRS scores, with treatment satisfaction reported by treatment-naïve patients. Switch-over patients also demonstrated comparable effectiveness. Contramyl XR was found to be clinically effective either as de novo or as switch therapy. It was well tolerated, and all patients chose to continue with the treatment option. Despite distinct and different delivery mechanism of Contramyl XR, this study provides evidence for using it as an alternate treatment option versus reference methylphenidate, in both treatment-naïve and switch-over ADHD patients. Study participants willingness to continue Contramyl XR therapy post study, further strengthens the confidence on the effectiveness of Contramyl XR in managing ADHD patients.

Behavioral and neurophysiological signatures of cognitive control in humans and rats.

Deficits in cognitive control are implicated in numerous neuropsychiatric disorders. However, relevant pharmacological treatments are limited, likely due to weak translational validity of applicable preclinical models used. Neural indices derived from electroencephalography may prove useful in comparing and translating the effects of cognition-enhancing drugs between species. In the current study, we aimed to extend our previous cross-species results by examining if methylphenidate (MPH) modulates behavioral and neural indices of cognitive control in independent cohorts of humans and rats. We measured continuous electroencephalography data from healthy adults (n = 25; 14 female) and Long Evans rats (n = 22; 8 female) and compared both stimulus- and response-locked event-related potentials and spectral power measures across species, and their MPH-related moderation following treatment with vehicle (placebo) or 1 of 2 doses of MPH. Across both species, linear mixed effects modeling confirmed the expected Flanker interference effect on behavior (eg, accuracy) and response-related event-related potentials. Unexpectedly, in contrast to past work, we did not observe any task-related effects on the spectral power of rodents. Moreover, MPH generally did not modulate cognitive control of either species, although some species-specific patterns offer insight for future research. Collectively, these findings in independent human and rodent subjects replicate some of our previously reported behavioral and neurophysiological patterns partly consistent with the notion that similar neural mechanisms may regulate cognitive control in both species. Nonetheless, these results showcase an approach to accelerate translation using a coordinated between-species platform to evaluate pro-cognitive treatments.

ADHD and Risk of Precocious Puberty: Considering the Impact of MPH.

The complex association between attention-deficit/hyperactivity disorder (ADHD) and methylphenidate (MPH) with precocious puberty (PP) is still unclear. This study aims to investigate the association between ADHD, MPH, and PP. This is a nationwide cohort study including a total of 3,342,077 individuals, 186,681 with ADHD and 3,155,396 without. First, we compared the risk of PP between ADHD cases and non-ADHD cases. Second, we compared the risk of PP between MPH users and non-MPH users in patients with ADHD. Patients with ADHD were at a greater risk of PP (adjusted hazard ratio [aHR], 2.01 [95% CI, 1.91-2.11]). In our moderation analyses, the female gender was a positive additive effect modifier of the association between ADHD and PP, whereas tics and intellectual disability were negative effect modifiers. In patients with ADHD, MPH users had a significantly lower risk of PP (aHR, 0.63 [95% CI 0.57-0.70]), and females had a negative effect modification on the association between MPH and PP. Our study found that children with ADHD were at a greater risk of PP. Girls with ADHD were a group particularly vulnerable to PP. Comorbid tics or intellectual disability was associated with a lower risk of PP. Among patients with ADHD, MPH was protective against PP, especially in girls. However, these preliminary results need further validation due to the nature of them being from an electronic database study. Unmeasured confounding factors might affect the association between MPH and PP.

Association Between Single-Dose and Longer Term Clinical Response to Stimulants in Attention-Deficit/Hyperactivity Disorder: A Systematic Review of Randomized Controlled Trials.

Objectives: Stimulants, such as methylphenidate (MPH) and amphetamines, represent the first-line pharmacological option for attention-deficit/hyperactivity disorder (ADHD). Randomized controlled trials (RCTs) have demonstrated beneficial effects at a group level but could not identify characteristics consistently associated with varying individual response. Thus, more individualized approaches are needed. Experimental studies have suggested that the neurobiological response to a single dose is indicative of longer term response. It is unclear whether this also applies to clinical measures. Methods: We carried out a systematic review of RCTs testing the association between the clinical response to a single dose of stimulants and longer term improvement. Potentially suitable single-dose RCTs were identified from the MED-ADHD data set, the European ADHD Guidelines Group RCT Data set (https://med-adhd.org/), as updated on February 1, 2024. Quality assessment was carried out using the Cochrane Risk of Bias (RoB) 2.0 tool. Results: A total of 63 single-dose RCTs (94% testing MPH, 85% in children) were identified. Among these, only a secondary analysis of an RCT tested the association between acute and longer term clinical response. This showed that the clinical improvement after a single dose of MPH was significantly associated with symptom improvement after a 4-week MPH treatment in 46 children (89% males) with ADHD. The risk of bias was rated as moderate. A further RCT used near-infrared spectroscopy, thus did not meet the inclusion criteria, and reported an association between brain changes under a single-dose and longer term clinical response in 22 children (82% males) with ADHD. The remaining RCTs only reported single-dose effects on neuropsychological, neuroimaging, or neurophysiological measures. Conclusion: This systematic review highlighted an important gap in the current knowledge. Investigating how acute and long-term response may be related can foster our understanding of stimulant mechanism of action and help develop stratification approaches for more tailored treatment strategies. Future studies need to investigate potential age- and sex-related differences.

Scheduling of methylphenidate: Preventing misuse or impeding ADHD treatment adherence?

Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, with a chronic, and potentially debilitating course if untreated. Medication adherence is poor - negatively affecting emotional, social, educational and employment outcomes. The current Schedule 6 status of methylphenidate (MPH) drives healthcare resource utilisation and costs - a potential barrier to care. This study explored stakeholders' understanding and perceptions of the potential impact of a regulatory shift in the scheduling of MPH on treatment accessibility and adherence for ADHD. Participants from multiple stakeholder groups, involved in ADHD management in South Africa, were recruited via professional networks. A qualitative analysis of semi-structured interviews with 23 stakeholders was conducted to explore their views on the utility, benefits and risks associated with rescheduling MPH. Six key themes emerged from the interviews: 'adherence', 'accessibility', 'affordability', 'stigma', 'rescheduling of MPH' and 'risk mitigation'. Core to these themes is the role of the scheduling of MPH - which can have a protective societal role, but also acts as a barrier to care for individuals with ADHD. The current Schedule 6 status of MPH is not an effective strategy to prevent misuse and diversion but negatively impacts on treatment adherence. The positive outlook from stakeholders on rescheduling MPH holds significant implications for the ADHD landscape in South Africa. It is crucial to address stigma, facilitate fundamental change in service delivery and remove structural and practical barriers to care to improve outcomes for individuals with ADHD. A framework for ADHD treatment adherence is provided.

Bioinformatics and experimental validation were combined to explore lactylation-related biomarkers in HBV-associated acute liver failure.

Currently, hepatitis B virus-related acute liver failure (HBV-ALF) has limited treatment options. Studies have shown that histone lactylation plays a role in the progression of liver-related diseases. Therefore, it is essential to explore lactylation-related gene (LRGs) biomarkers in HBV-ALF to provide new information for the treatment of HBV-ALF. Two HBV-ALF-related datasets (GSE38941 and GSE14668) and 65 LRGs were used. First, the differentially expressed genes (DEGs) were derived from differential expression analysis, the key module genes from weighted gene co-expression network analysis; and LRGs were used to intersect to obtain the candidate genes. Subsequently, the feature genes obtained from least absolute shrinkage and selection operator regression analysis and support vector machine analysis were intersected to obtain the candidate key genes. Among them, genes with consistent and significant expression trends in both GSE38941 and GSE14668 were used as biomarkers. Subsequently, biomarkers were analyzed for functional enrichment, immune infiltration, and sensitive drug prediction. In this study, five candidate genes (PIGM, PIGA, EGR1, PIGK, and PIGL) were identified by intersecting 6461 DEGs and 2496 key module genes with 65 LRGs. We then screened four candidate key genes from the machine learning algorithm, among which PIGM and PIGA were considered biomarkers in HBV-ALF. Moreover, the results of enrichment analysis showed that the significant enrichment signaling pathways for biomarkers included allograft rejection and valine, leucine, and isoleucine degradation. Thereafter, 11 immune cells differed significantly between groups, with resting memory CD4+ T cells having the strongest positive correlation with biomarkers. Methylphenidate hydrochloride is a potential therapeutic drug for PIGM. Two genes, PIGM and PIGA, were identified as biomarkers related to LRGs in HBV-ALF, providing a basis for understanding HBV-ALF pathogenesis.

Association between methylphenidate use and long-term cardiovascular risk in paediatric patients with attention deficit and hyperactivity disorder

BackgroundThere have been concerns about the potential cardiovascular (CV) adverse effects associated with methylphenidate (MTH) use. However, only limited evidence exists on the long-term safety of MTH.ObjectiveTo evaluate whether MTH...

Intranasal transfersomal based in situ gel for augmenting methylphenidate bioavailability and brain delivery: In vitro and in vivo evaluation

Methylphenidate, a CNS stimulant drug, has poor oral bioavailability due to extensive first-pass effect. In this study, Methylphenidate loaded transfersomes based in situ gel (MPH-TFs Gel) was prepared for brain targeting through intranasal (IN) drug delivery. Methylphenidate transfersomes (MPH-TFs) were prepared using the thin film hydration method. Box-Behnken Design expert software was utilized for the optimization by assessing the effect of independent variables phospholipon 90-G, Tween-80, and Methylphenidate (MPH) on particle size (PS), zeta potential (ZP), Polydispersity index (PDI), and Entrapment Efficiency (EE). The observed mean particle size of the optimized MPH-TFs was found to be 139.7 ± 3.75 nm, mono dispersion with PDI (0.208 ± 0.002), negatively charged (−27.9 ± 0.287 mV) and had an excellent entrapment efficiency (86 ± 3 %). Fourier-Transform Infrared (FTIR) spectra have depicted the compatibility of the components. X-r Diffraction analysis showed the conversion of crystalline structure methylphenidate to amorphous. The optimized MPH-TFs were then subsequently incorporated into an already optimized MPH-TFs Gel. MPH-TFs Gel was then characterized for its physicochemical properties, in vitro and in vivo studies. In vitro release and ex vivo permeation analysis showed sustained release and improved permeation of the MPH-TFs Gel, respectively. Additionally, histopathological studies of nasal membrane affirmed the safety of MPH-TFs Gel after intranasal application. In vivo pharmacokinetic study demonstrated improved brain bioavailability of MPH-TFs Gel compared to orally administered Methylphenidate solution (MPH-Sol).

Generation of induced pluripotent stem cells from ADHD patients who do or do not respond to Methylphenidate treatment

As a neurodevelopmental multifactorial disorder whose prevalence has been increasing worldwide, attention-deficit hyperactivity disorder (ADHD) is considered a public health concern. Methylphenidate (MPH) is the drug of choice for ADHD; however, not all patients respond fully to this treatment. Therefore, exploring the underlying molecular mechanisms involved in ADHD and potential novel therapeutic targets is crucial. Here, we generated induced pluripotent stem cells (iPSCs) from Peripheral Blood Mononuclear Cells (PBMCs) retrieved from four ADHD patients (two MPH responders and two non-responders) using Sendai virus. These lines might be helpful for the in vitro investigation of ADHD pathophysiology in a patient-specific manner.

Methylphenidate Exposing During Neurodevelopment Alters Amino Acid Profile, Astrocyte Marker and Glutamatergic Excitotoxicity in the Rat Striatum.

There is a public health concern about the use of methylphenidate (MPH) since the higher prescription for young individuals and non-clinical purposes is addressed to the limited understanding of its neurochemical and psychiatric consequences. This study aimed to evaluate the impact of early and chronic MPH treatment on the striatum focusing on amino acid profile, glutamatergic excitotoxicity, redox status, neuroinflammation and glial cell responses. Male Wistar rats were treated with MPH (2.0mg/kg) or saline solution from the 15th to the 44th postnatal day. Biochemical and histological analyses were conducted after the last administration. MPH altered the amino acid profile in the striatum, increasing glutamate and ornithine levels, while decreasing the levels of serine, phenylalanine, and branched-chain amino acids (leucine, valine, and isoleucine). Glutamate uptake and Na+,K+-ATPase activity were decreased in the striatum of MPH-treated rats as well as increased ATP levels, as indicator of glutamatergic excitotoxicity. Moreover, MPH caused lipid peroxidation and nitrative stress, increased TNF alpha expression, and induced high levels of astrocytes, and led to a decrease in BDNF levels. In summary, our results suggest that chronic early-age treatment with MPH induces parallel activation of damage-associated pathways in the striatum and increases its vulnerability during the juvenile period. In addition, data presented here contribute to shedding light on the mechanisms underlying MPH-induced striatal damage and its potential implications for neurodevelopmental disorders.

Enhancing pediatric attention-deficit hyperactivity disorder treatment: exploring the gut microbiota effects of French maritime pine bark extract and methylphenidate intervention.

The pathogenesis of Attention-Deficit Hyperactivity Disorder (ADHD) is thought to be multifactorial, with a potential role for the bidirectional communication between the gut microbiome and brain development and function. Since the "golden-standard" medication therapy with methylphenidate (MPH) is linked to multiple adverse effects, there is a need for alternative treatment options such as dietary polyphenols. These secondary plant metabolites exert antioxidant and anti-inflammatory effects, but much less is known about their impact on the gut microbiota. Since polyphenols are believed to modulate gut microbial composition, interventions might be advantageous in ADHD therapy. Therefore, intervention studies with polyphenols in ADHD therapy investigating the gut microbial composition are highly relevant. Besides the primary research questions addressed previously, this study explored a potential prebiotic effect of the polyphenol-rich French Maritime Pine Bark Extract (PBE) compared to MPH and a placebo in pediatric ADHD patients by studying their impact on the gut microbiota via amplicon sequencing of the full length 16S rRNA gene ribosomal subunit (V1-V9). One interesting finding was the high relative abundance of Bifidobacteria among all patients in our study cohort. Moreover, our study has identified that treatment (placebo, MPH and PBE) explains 3.94% of the variation in distribution of microbial taxa (adjusted p-value of 0.011). Our small sample size (placebo: n = 10; PBE: n = 13 and MPH: n = 14) did not allow to observe clear prebiotic effects in the patients treated with PBE. Notwithstanding this limitation, subtle changes were noticeable and some limited compositional changes could be observed. doi: 10.1186/S13063-017-1879-6.

The Effects of Chronic Psychostimulant Administration on Bone Health: A Review.

(1) Background: Methylphenidate (MP) and amphetamine (AMP) are psychostimulants that are widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. In recent years, 6.1 million children received an ADHD diagnosis, and nearly 2/3 of these children were prescribed psychostimulants for treatment. The purpose of this review is to summarize the current literature on psychostimulant use and the resulting effects on bone homeostasis, biomechanical properties, and functional integrity. (2) Methods: Literature searches were conducted from Medline/PubMed electronic databases utilizing the search terms "methylphenidate" OR "amphetamine" OR "methylphenidate" AND "bone health" AND "bone remodeling" AND "osteoclast" AND "osteoblast" AND "dopamine" from 01/1985 to 04/2023. (3) Results: Of the 550 publications found, 44 met the inclusion criteria. Data from identified studies demonstrate that the use of MP and AMP results in decreases in specific bone properties and biomechanical integrity via downstream effects on osteoblasts and osteoclast-related genes. (4) Conclusions: The chronic use of psychostimulants negatively affects bone integrity and strength as a result of increased osteoclast activity. These data support the need to take this into consideration when planning the treatment type and duration for bone fractures.

The effect of a single dose of methylphenidate on attention in children and adolescents with ADHD and comorbid Oppositional Defiant Disorder.

The co-occurrence Oppositional Defiant Disorder (ODD) in children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD) has been associated to difficulties in regulating adverse states, elevated functional impairment, deficits in Executive Functions and high risk for psychopathology. Recent studies have shown that ODD is a negative predictor of a positive response to methylphenidate (MPH) treatment for ADHD symptoms in children and adolescents and that patients with a diagnosis of comorbid ADHD and ODD are less likely to respond favorably to pharmacological treatment with MPH. We conducted a naturalistic study to understand the clinical characteristics of drug-naïve children and adolescents with ADHD that influence the response to MPH by measuring the effect on attention. Specifically, we investigated whether a single dose of MPH differently affects the performance of 53 children and adolescents with ADHD with or without ODD comorbidity. In addition, participant characteristics such as symptom severity, functional impairment, and associated behavioral and emotional symptoms at baseline were examined to better understand what aspects affect the response to MPH. We found that a single dose of MPH improved the attention of children and adolescents with ADHD without ODD more than those with comorbid ADHD and ODD, resulting in reduced reaction times. Our findings indicated that children and adolescents with comorbid ADHD and ODD and those with ADHD alone did not exhibit differences in measures of attention prior to taking MPH, nor in demographic variables (age, intelligence quotient, gender), clinical characteristics related to symptom severity, and adaptive behaviors. However, we observed differences between the two groups in certain behavioral aspects, including the Dysregulation Profile and disruptive behaviors. Assessing symptoms in combination with the presence of ADHD can be beneficial in determining which individuals would derive the greatest benefits from treatment.

A matching-adjusted indirect comparison of centanafadine versus lisdexamfetamine, methylphenidate and atomoxetine in adults with attention-deficit/hyperactivity disorder: long-term safety and efficacy.

Aim: To compare long-term safety and efficacy outcomes of centanafadine versus lisdexamfetamine dimesylate (lisdexamfetamine), methylphenidate hydrochloride (methylphenidate) and atomoxetine hydrochloride (atomoxetine), respectively, in adults with attention-deficit/hyperactivity disorder (ADHD) using matching-adjusted indirect comparisons (MAICs). Patients & methods: Patient-level data from a centanafadine trial (NCT03605849) and published aggregate data from a lisdexamfetamine trial (NCT00337285), a methylphenidate trial (NCT00326300) and an atomoxetine trial (NCT00190736) were used. Patient characteristics were matched in each comparison using propensity score weighting. Study outcomes were assessed up to 52weeks and included safety (rates of adverse events [AEs]) and efficacy (mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale [AISRS] or ADHD Rating Scale [ADHD-RS] score). Results: In all comparisons of matched populations, risks of AEs were statistically significantly lower with centanafadine or non-different between centanafadine and comparator; the largest differences in AE rates included upper respiratory tract infection (risk difference in percentage points: 18.75), insomnia (12.47) and dry mouth (12.33) versus lisdexamfetamine; decreased appetite (20.25), headache (18.53) and insomnia (12.65) versus methylphenidate; and nausea (26.18), dry mouth (25.07) and fatigue (13.95) versus atomoxetine (all p<0.05). Centanafadine had a smaller reduction in the AISRS/ADHD-RS score versus lisdexamfetamine (6.15-point difference; p<0.05) and no statistically significant difference in the change in AISRS score versus methylphenidate (1.75-point difference; p=0.13) and versus atomoxetine (1.60-point difference; p=0.21). Conclusion: At up to 52weeks, centanafadine showed significantly lower incidence of several AEs than lisdexamfetamine, methylphenidate and atomoxetine; efficacy was lower than lisdexamfetamine and non-different from methylphenidate and atomoxetine.

Differences in the Interleukin Profiles in Inattentive ADHD Prepubertal Children Are Probably Related to Conduct Disorder Comorbidity.

Inflammatory cytokines are involved in attention deficit hyperactivity disorder (ADHD), a highly prevalent neurodevelopmental disorder. To quantify the baseline levels of pro- and anti-inflammatory cytokines and their changes after methylphenidate (MPH), a total of 31 prepubertal children with ADHD were recruited and subclassified into only two ADHD presentations-ADHD attention deficit (n = 13) or ADHD combined (n = 18). The children were also screened for oppositional defiant conduct disorder (ODCD) and anxiety disorder. Blood samples were drawn at 09:00 and after 4.63 ± 1.87 months of treatment. Four pro-inflammatory cytokines (interleukin-1beta (IL-1β), IL-5, IL-6, tumor necrosis factor-alpha (TNF-α)) and three anti-inflammatory cytokines (IL-4, IL-10, IL-13) were measured using a Luminex® assay. For statistics, a factorial analysis was performed in Stata 15.1. Overall, there were no statistically significant differences in the interleukin (IL) values induced by treatment. When grouped by presentation, the differences were present almost exclusively in ADHD-AD, usually with a profile opposite to that observed in ADHD-C, and with interactions between comorbid factors, with IL-1β (p = 0.01) and IL-13 (p = 0.006) being the ones reaching the greatest statistical significance. These differences are probably related to the ODCD factor, and they disappear after treatment. In conclusion, the changes observed in cytokine levels in prepubertal children only in the ADHD-AD presentation are probably related to comorbidities (specifically ODCD) and are mitigated after treatment.