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European Journal of Drug Metabolism and... Mar 2024BACKGROUND AND OBJECTIVE: Attention deficit hyperactivity disorder is one of the most common neuropsychiatric conditions in children, and methylphenidate (MPH) is one...
UNLABELLED
BACKGROUND AND OBJECTIVE: Attention deficit hyperactivity disorder is one of the most common neuropsychiatric conditions in children, and methylphenidate (MPH) is one of the first-line therapies. MPH is available in a variety of extended-release (ER) formulations worldwide, and most formulations are not considered bioequivalent due to differences in pharmacokinetics. It is hypothesized that the current bioequivalence guidelines from the different regulatory bodies may generate inconsistent findings or recommendations when assessing the bioequivalence of ER MPH formulations. This manuscript aims to conduct a comprehensive and narrative critical literature review to analyze pharmacokinetic data pertaining to ER formulations of MPH in order to assess bioequivalence, differences in regulatory guidelines, and additional pharmacokinetic-pharmacodynamic parameters that may help define interchangeability.
METHODS
A literature search was conducted in EMBASE, Medline, and Cochrane Library with no time limits. Study characteristics, non-compartmental pharmacokinetic parameters, and bioequivalence data were extracted for analysis.
RESULTS
Thirty-three studies were identified with primary pharmacokinetic data after the administration of ER MPH, of which 10 were direct comparative studies (i.e., at least 2 formulations tested within a single setting) and 23 were indirect comparisons (i.e., different experimental settings). Two formulations were consistently reported as bioequivalent across the regulatory bodies using criteria from their guidance documents, although inconsistencies have been observed. However, when additional kinetic criteria (discussed in this manuscript) were imposed, only one study met the more stringent definition of bioequivalence. Various clinical factors also had inconsistent effects on the pharmacokinetics and interchangeability of the different formulations, which were associated with a lack of standardization for assessing covariates across the regulatory agencies.
CONCLUSION
Additional pharmacokinetic parameters and consistency in guidelines across the regulatory bodies may improve bioequivalence assessments. Based on our findings, more research is also required to understand whether bioequivalence is an appropriate measure for determining MPH interchangeability. This critical review is suitable for formulation scientists, clinical pharmacologists, and clinicians.
Topics: Child; Humans; Methylphenidate; Central Nervous System Stimulants; Therapeutic Equivalency; Attention Deficit Disorder with Hyperactivity; Delayed-Action Preparations; Cross-Over Studies
PubMed: 38127227
DOI: 10.1007/s13318-023-00873-1 -
Critical Reviews in Oncology/hematology Oct 2021Evidence regarding the pharmacological interventions to manage cancer-related fatigue (CRF) is currently synthesized in several systematic reviews, portraying a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Evidence regarding the pharmacological interventions to manage cancer-related fatigue (CRF) is currently synthesized in several systematic reviews, portraying a fragmented literature synthesis. Thus, we aimed to critically appraise the available systematic reviews on pharmacological intervention for improving CRF in adult cancer patients.
METHODS
Three databases were systematically searched from January 2010 to July 2020. The pooled meta-analyses' effect sizes (standardized mean difference, SMD) were quantitatively pooled using a random-effects model. Chi-squared (Q) and I-square statistics (I²) tested the heterogeneity.
RESULTS
The SMD of the effect of psychostimulants on CRF was -0.20 (95 % CI: -0.32, 0.08; p < 0.0001), along with significant higher improvement of fatigue (SMD=-0.69; 95 % CI=-1.29, -0,09, p < 0.0001) after methylphenidate administration. No statistical differences were found in the occurrences of adverse events between methylphenidate and placebo.
CONCLUSIONS
This study corroborated that psychostimulant therapy may be moderately effective in reducing CRF. Scarce evidence on the short- and long-term adverse events.
PROSPERO
CRD42020181879 (registration date: 26/07/2020).
Topics: Adult; Fatigue; Humans; Methylphenidate; Neoplasms; Systematic Reviews as Topic
PubMed: 34051301
DOI: 10.1016/j.critrevonc.2021.103373 -
Addiction (Abingdon, England) Feb 2024There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo-controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD.
METHODS
Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random-effect meta-analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random-effect meta-analysis of continuous variables.
RESULTS
Ten RCTs (n = 561 participants) were included in the meta-analysis. Trials studied methylphenidate (n = 7), with daily doses of 54-180 mg, and dextroamphetamine (n = 3), with daily doses of 60-110 mg, for 2-24 weeks. PPs significantly decreased end-point craving [SMD -0.29; 95% confidence interval (CI) = -0.55, -0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85-1.01). No effect was observed for self-reported ATS use, retention in treatment, dropout following adverse events, early-stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79-0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention.
CONCLUSIONS
Among individuals with amphetamine-type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications.
Topics: Humans; Central Nervous System Stimulants; Methylphenidate; Substance-Related Disorders; Amphetamines; Prescriptions; Randomized Controlled Trials as Topic
PubMed: 37880829
DOI: 10.1111/add.16347 -
CNS Spectrums Oct 2019Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia. (Meta-Analysis)
Meta-Analysis
Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder.
OBJECTIVE
Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia.
METHODS
We undertook a systematic review, searching PubMed/Scopus/Clinicaltrials.gov for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented.
RESULTS
We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6). Six studies of these two groups plus one additional study investigated biological effects of psychostimulants or atomoxetine. No effect resulted from interventional studies on weight loss (k=1), smoking cessation (k=1), and positive symptoms (k=12), and no improvement was reported with atomoxetine (k=3) for negative symptoms, with equivocal findings for negative (k=6) and mood symptoms (k=2) with amphetamines. Attention, processing speed, working memory, problem solving, and executive functions, among others, showed from no to some improvement with atomoxetine (k=3) or amphetamines (k=6). Meta-analysis did not confirm any effect of stimulants in any symptom domain, including negative symptoms, apart from atomoxetine improving problem solving (k=2, standardized mean difference (SMD)=0.73, 95% CI=0.10-1.36, p=0.02, I2=0%), and trending toward significant improvement in executive functions with amphetamines (k=2, SMD=0.80, 95% CI=-1.68 to +0.08, p=0.08, I2=66%). In challenge studies, amphetamines (k=1) did not worsen symptoms, and methylphenidate (k=5) consistently worsened or predicted relapse. Biological effects of atomoxetine (k=1) and amphetamines (k=1) were cortical activation, without change in β-endorphin (k=1), improved response to antipsychotics after amphetamine challenge (k=2), and an increase of growth hormone-mediated psychosis with methylphenidate (k=2). No major side effects were reported (k=6).
CONCLUSIONS
No efficacy for stimulants or atomoxetine on negative symptoms is proven. Atomoxetine or amphetamines may improve cognitive symptoms, while methylphenidate should be avoided in patients with schizophrenia. Insufficient evidence is available to draw firm conclusions.
Topics: Amphetamines; Antipsychotic Agents; Atomoxetine Hydrochloride; Attention; Executive Function; Humans; Memory, Short-Term; Methylphenidate; Problem Solving; Psychotic Disorders; Schizophrenia
PubMed: 30460884
DOI: 10.1017/S1092852918001050 -
Current Neuropharmacology 2020To systematically review the literature on the therapeutic use of amphetamine, lisdexamfetamine and methylphenidate in elderly population with and without dementia.
OBJECTIVE
To systematically review the literature on the therapeutic use of amphetamine, lisdexamfetamine and methylphenidate in elderly population with and without dementia.
METHODS
We conducted two researches on the PubMed, Scopus and Embase using the keywords ("elderly") AND ("amphetamine" OR "methylphenidate" OR "lisdexamfetamine") and then ("Alzheimer" OR "dementia") AND ("amphetamine" OR "methylphenidate" OR "lisdexamfetamine").
RESULTS
Twenty-nine papers met all the eligibility criteria. The results are encouraging as 81.5% of the studies showed clinical improvement of the investigated condition.
CONCLUSION
Amphetamines and methylphenidate are probably effective strategies for different conditions in the elderly population. However, further studies are needed to provide more robust evidence on efficacy, dosage and safety for this population.
Topics: Aged; Amphetamine; Dementia; Depressive Disorder, Major; Humans; Lisdexamfetamine Dimesylate; Methylphenidate
PubMed: 31660835
DOI: 10.2174/1570159X17666191010093021 -
Journal of the American Academy of... May 2024We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to...
OBJECTIVE
We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect differs between stimulants and non-stimulants.
METHOD
From the dataset of a published network meta-analysis (Cortese et al., 2018), updated on 27 February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multi-level meta-analytic models were conducted with R 4.3.1.
RESULTS
We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedges g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults.
CONCLUSION
In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and non-stimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and non-pharmacological interventions is likely to further improve QoL in people with ADHD.
STUDY PREREGISTRATION INFORMATION
Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/;qvgps.
PubMed: 38823477
DOI: 10.1016/j.jaac.2024.05.023 -
Supportive Care in Cancer : Official... Oct 2019Cognitive impairment is recognized as a common symptom experienced by cancer survivors which impacts on quality of life (QoL) and day-to-day activities. One of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cognitive impairment is recognized as a common symptom experienced by cancer survivors which impacts on quality of life (QoL) and day-to-day activities. One of the treatment options is the use of psychostimulants but the evidence supporting its use remains unclear.
OBJECTIVES
To identify the level of evidence of psychostimulants' effect on the management of cognitive impairment in adult cancer survivors.
METHODS
Electronic databases (MEDLINE, EMBASE, CENTRAL, CINAHL) and reference lists of relevant reviews were searched from inception to December 2017, with no language restrictions applied. Randomized controlled trials (RCTs), evaluating the effect of psychostimulants on cognitive impairment among cancer patients with no primary or secondary brain tumor or brain radiation, were included. The primary outcome was cognitive function changes, whereas secondary outcomes were adverse events (AEs) and QoL.
RESULTS
Six RCTs were included: three studies investigating methylphenidate and three modafinil, with a total of 244 and 146 patients, respectively. Due to important differences in methodologies between studies, a meta-analysis was assumed inappropriate for the primary outcome. A narrative synthesis was performed. One study using methylphenidate and two using modafinil demonstrated improvements in some cognitive functions as measured by objective cognitive assessment tests. Psychostimulants did not improve QoL and were not associated with more AEs.
CONCLUSION
To date, limited evidence is available to estimate the usefulness (or lack) of psychostimulants on cognitive function in this population.
Topics: Adult; Cancer Survivors; Central Nervous System Stimulants; Cognition; Cognitive Dysfunction; Humans; Methylphenidate; Modafinil; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 31250183
DOI: 10.1007/s00520-019-04907-w -
The Cochrane Database of Systematic... Jul 2022Attention Deficit Hyperactivity Disorder (ADHD) can co-occur in up to 40% of people with epilepsy. There is debate about the efficacy and tolerability of stimulant and... (Review)
Review
BACKGROUND
Attention Deficit Hyperactivity Disorder (ADHD) can co-occur in up to 40% of people with epilepsy. There is debate about the efficacy and tolerability of stimulant and non-stimulant drugs used to treat people with ADHD and co-occurring epilepsy.
OBJECTIVES
To assess the effect of stimulant and non-stimulant drugs on children and adults with ADHD and co-occurring epilepsy in terms of seizure frequency and drug withdrawal rates (primary objectives), as well as seizure severity, ADHD symptoms, cognitive state, general behaviour, quality of life, and adverse effects profile (secondary objectives).
SEARCH METHODS
We searched the following databases on 12 October 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 9 October 2020), CINAHL Plus (EBSCOhost, 1937 onwards). There were no language restrictions. CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy. SELECTION CRITERIA: We included randomised controlled trials of stimulant and non-stimulant drugs for people of any age, gender or ethnicity with ADHD and co-occurring epilepsy.
DATA COLLECTION AND ANALYSIS
We selected articles and extracted data according to predefined criteria. We conducted primary analysis on an intention-to-treat basis. We presented outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), except for individual adverse effects where we quoted 99% CIs. We conducted best- and worst-case sensitivity analyses to deal with missing data. We carried out a risk of bias assessment for each included study using the Cochrane risk of bias tool and assessed the overall certainty of evidence using the GRADE approach.
MAIN RESULTS
We identified two studies that matched our inclusion criteria: a USA study compared different doses of the stimulant drug osmotic-release oral system methylphenidate (OROS-MPH) with a placebo in 33 children (mean age 10.5 ± 3.0 years), and an Iranian study compared the non-stimulant drug omega-3 taken in conjunction with risperidone and usual anti-seizure medication (ASM) with risperidone and ASM only in 61 children (mean age 9.24 ± 0.15 years). All children were diagnosed with epilepsy and ADHD according to International League Against Epilepsy and Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria, respectively. We assessed both studies to be at low risk of detection and reporting biases, but assessments varied from low to high risk of bias for all other domains. OROS-MPH No participant taking OROS-MPH experienced significant worsening of epilepsy, defined as: 1. a doubling of the highest 14-day or highest two-day seizure rate observed during the 12 months before the trial; 2. a generalised tonic-clonic seizure if none had been experienced in the previous two years; or 3. a clinically meaningful intensification in seizure duration or severity (33 participants, 1 study; low-certainty evidence). However, higher doses of OROS-MPH predicted an increased daily risk of a seizure (P < 0.001; 33 participants, 1 study; low-certainty evidence). OROS-MPH had a larger proportion of participants receiving 'much improved' or 'very much improved' scores for ADHD symptoms on the Clinical Global Impressions for ADHD-Improvement tool (33 participants, 1 study; low-certainty evidence). OROS-MPH also had a larger proportion of people withdrawing from treatment (RR 2.80; 95% CI 1.14 to 6.89; 33 participants, 1 study; moderate-certainty evidence). Omega-3 Omega-3 with risperidone and ASM were associated with a reduction in mean seizure frequency by 6.6 seizures per month (95% CI 4.24 to 8.96; 56 participants, 1 study; low-certainty evidence) and an increase in the proportion of people achieving 50% or greater reduction in monthly seizure frequency (RR 2.79, 95% CI 0.84 to 9.24; 56 participants, 1 study; low-certainty evidence) compared to people on risperidone and ASM alone. Omega-3 with risperidone and ASM also had a smaller proportion of people withdrawing from treatment (RR 0.65, 95% CI 0.12 to 3.59; 61 participants, 1 study; low-certainty evidence) but a larger proportion of people experiencing adverse drug events (RR 1.40, 95% CI 0.44 to 4.42; 56 participants, 1 study; low-certainty evidence) compared to people on risperidone and ASM alone.
AUTHORS' CONCLUSIONS
In children with a dual-diagnosis of epilepsy and ADHD, there is some evidence that use of the stimulant drug OROS-MPH is not associated with significant worsening of epilepsy, but higher doses of it may be associated with increased daily risk of seizures; the evidence is of low-certainty. OROS-MPH is also associated with improvement in ADHD symptoms. However, this treatment was also associated with a large proportion of treatment withdrawal compared to placebo. In relation to the non-stimulant drug omega-3, there is some evidence for reduction in seizure frequency in children who are also on risperidone and ASM, compared to children who are on risperidone and ASM alone. Evidence is inconclusive whether omega-3 increases or decreases the risk of adverse drug events. We identified only two studies - one each for OROS-MPH and omega-3 - with low to high risk of bias. We assessed the overall certainty of evidence for the outcomes of both OROS-MPH and omega-3 as low to moderate. More studies are needed. Future studies should include: 1. adult participants; 2. a wider variety of stimulant and non-stimulant drugs, such as amphetamines and atomoxetine, respectively; and 3. additional important outcomes, such as seizure-related hospitalisations and quality of life. Clusters of studies which assess the same drug - and those that build upon the evidence base presented in this review on OROS-MPH and omega-3 - are needed to allow for meta-analysis of outcomes.
Topics: Adolescent; Adult; Anticonvulsants; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Drug Resistant Epilepsy; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Humans; Iran; Quality of Life; Risperidone
PubMed: 35844168
DOI: 10.1002/14651858.CD013136.pub2 -
Pharmacopsychiatry Apr 2020Several reports of the effectiveness of the use of psychostimulants for the treatment of Alzheimer's disease (AD) are available. (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Several reports of the effectiveness of the use of psychostimulants for the treatment of Alzheimer's disease (AD) are available.
METHODS
A systematic review and meta-analysis was conducted including double-blind, randomized, placebo-controlled trials. Outcomes were the improvement of apathy scales score (primary), mini-mental state examination (MMSE) score, activities of daily living scale score, Zarit burden interview score, all-cause discontinuation, discontinuation due to adverse events, and incidence of at least 1 adverse event.
RESULTS
Three methylphenidate studies and 1 modafinil study were identified (n=156). Results from combined psychostimulants were superior to placebo in the improvement of apathy scales score (standardized mean differences [SMD]=-0.63 (-1.22, -0.04), p=0.04, all studies) and the MMSE score (SMD=-0.58 (-1.14, -0.02), p=0.04, 3 methylphenidate studies). The modafinil study was excluded from the meta-analysis for the improvement of apathy scales score; therefore, the effect size increased (SMD=-0.82 (-1.43, -0.20), p=0.009). However, no significant differences were observed in terms of other outcomes, including safety outcomes between the treatment groups.
DISCUSSION
Methylphenidate would be effective in treating apathy and cognitive impairment in AD patients.
Topics: Aged; Alzheimer Disease; Apathy; Central Nervous System Stimulants; Cognitive Dysfunction; Double-Blind Method; Humans; Methylphenidate; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 32000270
DOI: 10.1055/a-1076-8228 -
Addiction (Abingdon, England) Dec 2019Addiction to methamphetamine/amphetamine (MA/A) is a major public health problem. Currently there are no pharmacotherapies for MA/A use disorder that have been approved... (Meta-Analysis)
Meta-Analysis
AIMS
Addiction to methamphetamine/amphetamine (MA/A) is a major public health problem. Currently there are no pharmacotherapies for MA/A use disorder that have been approved for use by the US Food and Drug Administration or the European Medicines Agency. We reviewed the effectiveness of pharmacotherapy for MA/A use disorder to assess the quality, publication bias and overall strength of the evidence.
METHODS
Systematic review and meta-analysis. We searched multiple data sources (MEDLINE, PsycINFO and Cochrane Library) to April 2019 for systematic reviews (SRs) and randomized controlled trials (RCTs). Included studies recruited adults who had MA/A use disorder; sample sizes ranged from 19 to 229 participants. Outcomes of interest were abstinence, defined as 3 or more consecutive weeks with negative urine drug screens (UDS); overall use, analyzed as the proportion of MA/A negative UDS specimens; and treatment retention. One SR of pharmacotherapies for MA/A use disorder and 17 additional RCTs met our inclusion criteria encompassing 17 different drugs (antidepressants, antipsychotics, psychostimulants, anticonvulsants and opioid antagonists). We combined the findings of trials with comparable interventions and outcome measures in random-effects meta-analyses. We assessed quality, publication bias and the strength of evidence for each outcome using standardized criteria.
RESULTS
There was low-strength evidence from two RCTs that methylphenidate may reduce MA/A use: 6.5 versus 2.8% MA/A-negative UDS in one study (n = 34, P = 0.008) and 23 versus 16% in another study (n = 54, P = 0.047). Antidepressants as a class had no statistically significant effect on abstinence or retention on the basis of moderate strength evidence. Studies of anticonvulsants, antipsychotics (aripiprazole), opioid antagonists (naltrexone), varenicline and atomoxetine provided either low-strength or insufficient evidence of no effect on the outcomes of interest. Many of the studies had high or unclear risk of bias.
CONCLUSIONS
On the basis of low- to moderate-strength evidence, most medications evaluated for methamphetamine/amphetamine use disorder have not shown a statistically significant benefit. However, there is low-strength evidence that methylphenidate may reduce use.
Topics: Amphetamine-Related Disorders; Anticonvulsants; Antidepressive Agents; Antipyretics; Drug Therapy; Humans; Methylphenidate; Naltrexone; Outcome Assessment, Health Care; Varenicline
PubMed: 31328345
DOI: 10.1111/add.14755