Peterson K, McDonagh MS, Fu R. Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis. Psychopharmacology (Berl) 197: 1-11
Recommended medication prescribing hierarchies for adult attention-deficit hyperactivity disorder (ADHD) vary between different guideline committees. Few trials directly compare competing ADHD medications in adults and provide little insight for clinicians making treatment choices.
The objective of this study was to assess comparative benefits and harms of competing medications for adult ADHD using indirect comparison meta-analysis.
Eligible studies were English-language publications of randomized controlled trials comparing ADHD drugs to placebo. Data sources were electronic bibliographic databases, Drugs@FDA, manufacturer data, and reference lists. Two reviewers independently abstracted data on design, internal validity, population, and results. Benefits and harms were compared between drug types using indirect comparison meta-regression (ratio of relative risks).
Twenty-two placebo-controlled trials were included (n = 2,203). Relative benefit of clinical response for shorter-acting stimulants, primarily immediate release methylphenidate, was 3.26 times greater than for patients taking longer-acting stimulants (95% CI 2.03, 5.22) and 2.24 times greater than for patients taking longer-acting forms of bupropion (95% CI 1.23, 4.08). Immediate release methylphenidate is also the only drug shown to reduce ADHD symptoms in adults with substance abuse disorders. Neither non-stimulants nor longer-acting stimulants reduced adverse effects compared to shorter-acting stimulants. Key gaps in evidence were academic, occupational, social functioning, cardiovascular toxicity, and longer-term outcomes, influences of ADHD subtype and/or comorbidities, and misuse/diversion of the drugs.
Current best evidence supports using immediate release methylphenidate as first-line treatment for most adults with ADHD.
"Compared with patients with ADHD without severe substance abuse, the ADHD/SUD group reported more ADHD symptoms during childhood and exhibited poorer general cognitive capacity (Bihlar Muld et al., 2013). Pharmacological treatments for ADHD effectively reduce ADHD symptoms (Castells et al., 2011; Koesters, Becker, Kilian, Fegert, & Weinmann, 2009; Peterson, McDonagh, & Fu, 2008) and improve the daily functioning and quality of life of ADHD patients (Buitelaar et al., 2012; Rosler et al., 2013). Long-term beneficial effects of these pharmacological treatments on both symptom reduction and life functioning have also been reported (Fredriksen, Halmoy, Faraone, & Haavik, 2012). "
[Show abstract][Hide abstract] ABSTRACT: The pharmacological treatment of individuals with attention deficit hyperactivity disorder (ADHD) and severe substance use disorder (SUD) is controversial, and few studies have examined the long-term psychosocial outcome of these treatments. Our aim was to investigate whether pharmacological treatment was associated with improved long-term psychosocial outcomes.Methods
The present naturalistic study consisted of a long-term follow-up of 60 male patients with ADHD and comorbid severe SUD; all participants had received compulsory inpatient treatment due to severe substance abuse. The average interval between inpatient discharge and follow-up was 18.4 months. Thirty patients had received pharmacological treatment for ADHD, and 30 patients were pharmacologically untreated. The groups were compared with respect to mortality and psychosocial outcomes operationalized as substance abuse status, ongoing voluntary rehabilitation, current housing situation and employment status.ResultsThe groups were comparable with regard to the demographic and background characteristics. Overall, mortality was high; 8.3% of the participants had deceased at follow-up (one in the pharmacologically treated group and four in the untreated group; the between-group difference was not significant). The group that received pharmacological treatment for ADHD exhibited fewer substance abuse relapses, received more frequently voluntary treatments in accordance with a rehabilitation plan, required less frequent compulsory care, were more frequently accommodated in supportive housing or a rehabilitation center, and displayed a higher employment rate than the non-treated group.Conclusions
The recommendations for the close clinical monitoring of high-risk populations and the prevention of misuse and drug diversion were fulfilled in the structured environment of compulsory care for the treated group. Pharmacological treatment of ADHD in individuals with severe SUD may decrease the risk of relapse and increase these patients’ ability to follow a non-pharmacological rehabilitation plan, thereby improving their long-term outcomes.
"In meta-analyses examining treatment efficacy in adults with ADHD, Peterson et al. found that short-acting stimulants were more effective than long-acting stimulants in the treatment of adults with ADHD . While an initial analysis by Faraone et al. supported this finding, no significant difference between the effect sizes for long- and short-acting stimulants in the treatment of adults with ADHD was detected after study confounders and publication bias were accounted for . "
[Show abstract][Hide abstract] ABSTRACT: The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed.The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection.
A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included.
Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study.
Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response.
"Most properly diagnosed individuals require treatment for ADHD starting from childhood through adulthood (Angold et al., 2000). However, few studies have examined the long term neurological effects of d-amphetamine or any other approved medications for ADHD over this time period (Peterson et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Adderall is widely prescribed for attention deficit hyperactivity disorder (ADHD) though long term neurological effects of the main ingredient d-amphetamine are not well understood. The purpose of this study was to examine effects of clinically prescribed doses of d-amphetamine and one abuse dose administered from childhood to adulthood on adult hippocampal neurogenesis and activation of the granule layer of the dentate gyrus. Beginning in early adolescence (age 28 days) to adulthood (age 71), male C57BL/6J mice were administered twice daily i.p. injections of vehicle, 0.25, 0.5 or 2 mg/kg d-amphetamine. Locomotor activity was measured in home cages by video tracking. At age 53–56, mice received bromodeoxyuridine (BrdU) injections to label dividing cells. Immunohistochemical detection of BrdU, neuronal nuclear protein (NeuN), doublecortin (DCX) and Ki67 was used to measure neurogenesis and cell proliferation at age 71. ΔFosB was measured as an indicator of repeated neuronal activation. An additional cohort of mice was treated similarly except euthanized at age 58 to measure activation of granule neurons from d-amphetamine (by detection of c-Fos) and cell proliferation (Ki67) at a time when the fate of BrdU cells would have been determined in the first cohort. d-Amphetamine dose-dependently increased survival and differentiation of BrdU cells into neurons and increased number of DCX cells without affecting the number of Ki67 cells. Low doses of d-amphetamine decreased c-Fos and ΔFosB in the granule layer. Only the high dose induced substantial locomotor stimulation and sensitization. Results suggest both therapeutic and abuse doses of d-amphetamine increase the number of new neurons in the hippocampus when administered from adolescence to adulthood by increasing survival and differentiation of cells into neurons not by increasing progenitor cell proliferation. Mechanisms for amphetamine-induced neurogenesis are unknown but appear activity independent. Results suggest part of the beneficial effects of therapeutic doses of d-amphetamine for ADHD could be via increased hippocampal neurogenesis.
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