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The Cochrane Database of Systematic... Aug 2018Attention deficit hyperactivity disorder (ADHD) is a childhood-onset disorder characterised by inattention, hyperactivity, and impulsivity. ADHD can persist into... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) is a childhood-onset disorder characterised by inattention, hyperactivity, and impulsivity. ADHD can persist into adulthood and can affects individuals' social and occupational functioning, as well as their quality of life and health. ADHD is frequently associated with other mental disorders such as substance use disorders and anxiety and affective disorders. Amphetamines are used to treat adults with ADHD, but uncertainties about their efficacy and safety remain.
OBJECTIVES
To examine the efficacy and safety of amphetamines for adults with ADHD.
SEARCH METHODS
In August 2017, we searched CENTRAL, MEDLINE, Embase, PsycINFO, 10 other databases, and two trials registers, and we ran citation searches for included studies. We also contacted the corresponding authors of all included studies, other experts in the field, and the pharmaceutical company, Shire, and we searched the reference lists of retrieved studies and reviews for other published, unpublished, or ongoing studies. For each included study, we performed a citation search in Web of Science to identify any later studies that may have cited it.
SELECTION CRITERIA
We searched for randomised controlled trials comparing the efficacy of amphetamines (at any dose) for ADHD in adults aged 18 years and over against placebo or an active intervention.
DATA COLLECTION AND ANALYSIS
Two review authors extracted data from each included study. We used the standardised mean difference (SMD) and the risk ratio (RR) to assess continuous and dichotomous outcomes, respectively. We conducted a stratified analysis to determine the influence of moderating variables. We assessed trials for risk of bias and drew a funnel plot to investigate the possibility of publication bias. We rated the quality of the evidence using the GRADE approach, which yielded high, moderate, low, or very low quality ratings based on evaluation of within-trial risk of bias, directness of evidence, heterogeneity of data; precision of effect estimates, and risk of publication bias.
MAIN RESULTS
We included 19 studies that investigated three types of amphetamines: dexamphetamine (10.2 mg/d to 21.8 mg/d), lisdexamfetamine (30 mg/d to 70 mg/d), and mixed amphetamine salts (MAS; 12.5 mg/d to 80 mg/d). These studies enrolled 2521 participants; most were middle-aged (35.3 years), Caucasian males (57.2%), with a combined type of ADHD (78.8%). Eighteen studies were conducted in the USA, and one study was conducted in both Canada and the USA. Ten were multi-site studies. All studies were placebo-controlled, and three also included an active comparator: guanfacine, modafinil, or paroxetine. Most studies had short-term follow-up and a mean study length of 5.3 weeks.We found no studies that had low risk of bias in all domains of the Cochrane 'Risk of bias' tool, mainly because amphetamines have powerful subjective effects that may reveal the assigned treatment, but also because we noted attrition bias, and because we could not rule out the possibility of a carry-over effect in studies that used a cross-over design.Sixteen studies were funded by the pharmaceutical industry, one study was publicly funded, and two studies did not report their funding sources.Amphetamines versus placeboSeverity of ADHD symptoms: we found low- to very low-quality evidence suggesting that amphetamines reduced the severity of ADHD symptoms as rated by clinicians (SMD -0.90, 95% confidence interval (CI) -1.04 to -0.75; 13 studies, 2028 participants) and patients (SMD -0.51, 95% CI -0.75 to -0.28; six studies, 120 participants).Retention: overall, we found low-quality evidence suggesting that amphetamines did not improve retention in treatment (risk ratio (RR) 1.06, 95% CI 0.99 to 1.13; 17 studies, 2323 participants).Adverse events: we found that amphetamines were associated with an increased proportion of patients who withdrew because of adverse events (RR 2.69, 95% CI 1.63 to 4.45; 17 studies, 2409 participants).Type of amphetamine: we found differences between amphetamines for the severity of ADHD symptoms as rated by clinicians. Both lisdexamfetamine (SMD -1.06, 95% CI -1.26 to -0.85; seven studies, 896 participants; low-quality evidence) and MAS (SMD -0.80, 95% CI -0.93 to -0.66; five studies, 1083 participants; low-quality evidence) reduced the severity of ADHD symptoms. In contrast, we found no evidence to suggest that dexamphetamine reduced the severity of ADHD symptoms (SMD -0.24, 95% CI -0.80 to 0.32; one study, 49 participants; very low-quality evidence). In addition, all amphetamines were efficacious in reducing the severity of ADHD symptoms as rated by patients (dexamphetamine: SMD -0.77, 95% CI -1.14 to -0.40; two studies, 35 participants; low-quality evidence; lisdexamfetamine: SMD -0.33, 95% CI -0.65 to -0.01; three studies, 67 participants; low-quality evidence; MAS: SMD -0.45, 95% CI -1.02 to 0.12; one study, 18 participants; very low-quality evidence).Dose at study completion: different doses of amphetamines did not appear to be associated with differences in efficacy.Type of drug-release formulation: we investigated immediate- and sustained-release formulations but found no differences between them for any outcome.Amphetamines versus other drugsWe found no evidence that amphetamines improved ADHD symptom severity compared to other drug interventions.
AUTHORS' CONCLUSIONS
Amphetamines improved the severity of ADHD symptoms, as assessed by clinicians or patients, in the short term but did not improve retention to treatment. Amphetamines were associated with higher attrition due to adverse events. The short duration of studies coupled with their restrictive inclusion criteria limits the external validity of these findings. Furthermore, none of the included studies had an overall low risk of bias. Overall, the evidence generated by this review is of low or very low quality.
Topics: Adult; Amphetamines; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Dextroamphetamine; Humans; Lisdexamfetamine Dimesylate; Randomized Controlled Trials as Topic
PubMed: 30091808
DOI: 10.1002/14651858.CD007813.pub3 -
Pharmacology, Biochemistry, and Behavior Dec 2020Delay discounting, in which an animal chooses between a small, immediate or large, delayed reinforcer, is an experimental model of impulsivity. In previous studies,...
RATIONALE
Delay discounting, in which an animal chooses between a small, immediate or large, delayed reinforcer, is an experimental model of impulsivity. In previous studies, d-amphetamine has both increased and decreased preference for larger-delayed reinforcers depending on experimental conditions.
OBJECTIVE
Identify genotype X environment interactions responsible for these disparate findings in a single study and assess the hypothesis that baseline-dependence unifies d-amphetamine's effects.
METHODS
Delay discounting by BALB/c and C57Bl/6 mice was evaluated using a choice procedure in which six delays to a larger reinforcer were presented in a single session. Components were presented both with and without stimuli that uniquely signaled reinforcer delays. d-Amphetamine's (0.1-1.7 mg/kg) effects on delay and magnitude sensitivity were assessed when specific stimuli did or did not uniquely signal the delay to a larger reinforcer. d-Amphetamine's effects were determined using a model-comparison approach.
RESULTS
During baseline, magnitude and delay sensitivity were identical across signal conditions for BALB/c mice and generally greater than the C57Bl/6 mice. For C57Bl/6 mice, magnitude and delay sensitivity were higher during the signaled than the unsignaled component. Amphetamine decreased delay sensitivity during both components for BALB/c mice, but this effect was attenuated by delay-specific stimuli. For C57Bl/6 mice, amphetamine decreased their high magnitude and delay sensitivity when delays were signaled and, conversely, increased the low magnitude and delay sensitivity when delays were unsignaled.
CONCLUSIONS
BALB/c mice showed high delay and magnitude sensitivity regardless of signal conditions. C57Bl/6's magnitude and delay sensitivity depended on signaling. d-Amphetamine usually decreased high baseline delay- and magnitude sensitivity and increased low sensitivities, a baseline-dependence that occurred regardless of whether delay sensitivity was driven by biological (genotype) or environmental (signaling) variables. The C57Bl/6 mouse may be a good model of environmentally-induced impulsivity while BALB/c mice could model impulsivity with a strong genetic contribution.
Topics: Animals; Delay Discounting; Dextroamphetamine; Genotype; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Reinforcement Schedule
PubMed: 33144205
DOI: 10.1016/j.pbb.2020.173070 -
Clinical Therapeutics Jan 2009Lisdexamfetamine dimesylate (LDX) is a once-daily medication approved by the US Food and Drug Administration for the management of attention-deficit/hyperactivity... (Review)
Review
The efficacy and safety profile of lisdexamfetamine dimesylate, a prodrug of d-amphetamine, for the treatment of attention-deficit/hyperactivity disorder in children and adults.
BACKGROUND
Lisdexamfetamine dimesylate (LDX) is a once-daily medication approved by the US Food and Drug Administration for the management of attention-deficit/hyperactivity disorder (ADHD) in children (aged 6-12 years) and adults.
OBJECTIVE
This article reviews the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of LDX.
METHODS
Studies, abstracts, reviews, and consensus statements published in English were identified through computerized searches of MEDLINE (1966-August 2008) and International Pharmaceutical Abstracts (1977-August 2008) using search headings lisdexamfetamine dimesylate, attention-deficit/hyperactivity disorder, NRP 104, NRP104-201, NRP104-301, NRP104-302, NRP104-303, and stimulant. Selected information provided by the manufacturer of LDX was included, as were all pertinent clinical trials. The reference lists of identified articles were also searched for pertinent information. Relevant abstracts presented at annual professional meetings were included as well.
RESULTS
Several studies have evaluated the pharmacokinetics of LDX in pediatric patients (6-12 years of age) and healthy adults with ADHD. LDX, a prodrug that is therapeutically inactive until metabolized in the body to dextroamphetamine (d-amphetamine), follows linear pharmacokinetics at therapeutic doses (30-70 mg). The efficacy of LDX in the treatment of ADHD was established on the basis of 1 long-term and 2 short-term controlled clinical trials in children who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for ADHD (either the combined or the hyperactive-impulsive subtype) and in 1 clinical trial with adults with ADHD. The efficacy trials in children found significant improvements in scores on the Swanson, Kotkin, Agler, M-Flynn, and Pelham deportment sub-scales, the Permanent Product Measure of Performance (Attempted and Correct), and the ADHD Rating Scale Version IV (ADHD-RS-IV) compared with placebo (all, P < 0.001). In the clinical studies designed to measure duration of effect, LDX, compared with placebo, provided efficacy for a full treatment day, up through and including 6 PM, based on parent ratings (Conners' Parent Rating Scale-Revised Short Form) in the morning, afternoon, and early evening (all, P < 0.001). Data from a long-term, open-label extension study that assessed the safety, tolerability, and efficacy of LDX for up to 12 months found LDX treatment resulted in significant improvement (>60%) from baseline in the ADHD-RS-IV at end point (P < 0.001), with good tolerability. The trial in adults found significant improvements in ADHD-RS scores at end point in patients receiving LDX (30,50, and 70 mg) (P < 0.001 for all active doses); significant improvements in ADHD-RS (using adult prompts) scores were observed at each postbaseline weekly assessment, with improvements noted within the first week in all active treatment arms. Results from human abuse liability studies noted that LDX had lower abuse-related drug-liking scores compared with immediate-release d-amphetamine at equivalent doses. The most common adverse events reported with LDX were typical of amphetamine products and included decreased appetite, insomnia, upper abdominal pain, headache, irritability, weight loss, and nausea.
CONCLUSIONS
Current evidence supports the efficacy and tolerability of LDX as a treatment option for the management of children (aged 6-12 years) and adults with ADHD. As such, LDX may be an integral part of a total treatment program for ADHD that can include other measures such as psychological, educational, and social interventions.
Topics: Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Clinical Trials as Topic; Dextroamphetamine; Dose-Response Relationship, Drug; Humans; Lisdexamfetamine Dimesylate; Prodrugs; Substance-Related Disorders
PubMed: 19243715
DOI: 10.1016/j.clinthera.2009.01.015 -
Pharmacology, Biochemistry, and Behavior Mar 1984Whether diminished or augmented behavioral effects are observed after repeated amphetamine administration may reflect the relative balance between tolerance and drug...
Whether diminished or augmented behavioral effects are observed after repeated amphetamine administration may reflect the relative balance between tolerance and drug cumulation. To investigate this, we measured the distribution of d-amphetamine in various tissues and its effects on performance of a conditioned behavior after acute or chronic treatment. Rats trained to lever press under a fixed ratio 5 schedule for food-reinforcement were tested daily for 4 min epochs in each of 6 consecutive hours. After responding was stable, animals were injected for 16 days with saline or 1.0, 2.5 or 5.0 mg 3H-d-amphetamine sulfate/kg IP 15 min before the second daily behavioral epoch. On the 17th day, animals which had been receiving 3H-d-amphetamine were given their usual dose and those which had been receiving saline were given one of the doses of 3H-d-amphetamine; all animals were decapitated approximately 2 1/4 hours after this final injection, immediately after the 4th behavioral epoch. Brain, heart, muscle, epididymal fat, and kidney were removed for subsequent analysis of unchanged 3H-d-amphetamine. The experiment was carried out in two phases, 3 1/2 months apart, which inadvertently resulted in shipment of rats from different buildings on the supplier's campus. Acute treatment produced dose-related effects on operant responding, the lowest dose increasing responding and the highest dose suppressing it. Chronic injection of the highest dose of d-amphetamine resulted in significant attenuation of its acute suppressant effect. Additionally, chronic treatment suppressed responding of rats 23 1/4 hours after injection (i.e., before the subsequent daily injection). Tissue levels of d-amphetamine were dose related and d-amphetamine cumulated after chronic treatment with the highest dose. When d-amphetamine was administered acutely, the behavioural effect immediately before decapitation was highly correlated with the concentration of d-amphetamine in brain and in heart. This was not the case after chronic treatment, since rats given the higher doses showed less behavioural effect than would have been predicted from the concentrations of d-amphetamine in their tissues. Besides evidence of tolerance and cumulation of drug in one or more tissues, a significant phase or colony difference emerged, which could have been due to seasonal or other factors. Additional, different experiments, performed concurrently on a new shipment of rats from each colony, allowed us to conclude that the original observations of phase differences were not due to seasonal differences or chance.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Behavior, Animal; Brain; Dextroamphetamine; Drug Tolerance; Male; Myocardium; Rats; Rats, Inbred Strains; Reinforcement Schedule; Time Factors; Tissue Distribution
PubMed: 6709676
DOI: 10.1016/0091-3057(84)90280-6 -
Psychopharmacology Jul 1978Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and...
Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil. The dopaminergic agonists appear to suppress amphetamine intake in the same way as do 'free' amphetamine injections, by extending drug satiation in a given interresponse period. Clonidine, an alpha noradrenergic agonist, did not have similar effects. Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism. Rats responding for amphetamine continued to respond for apomorphine or peribedil when the latter drugs were substituted for the former. Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil. The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine. These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties.
Topics: Amphetamine; Animals; Butaclamol; Clonidine; Dextroamphetamine; Dopamine; Male; Piribedil; Rats; Reinforcement, Psychology; Self Administration; Time Factors
PubMed: 98800
DOI: 10.1007/BF00427393 -
Experimental and Clinical... Apr 2022Recent advances in diagnostic research identified that individuals with higher impulsivity and sensation-seeking scores tend to report more positive subjective responses...
Recent advances in diagnostic research identified that individuals with higher impulsivity and sensation-seeking scores tend to report more positive subjective responses to stimulant drugs such as amphetamine. The current exploratory study hypothesized that differences in underlying mesocorticolimbic circuitry may mediate the relationship between personality and responses to stimulants due to its previously established implication in reward processes as well as the overlap between its dopaminergic projections and the pharmacodynamics of many stimulants. Forty participants (20 female) were recruited with relatively high- and low-impulsivity and sensation-seeking scores as defined by the Zuckerman-Kuhlman Personality Questionnaire (Form IIIR; Zuckerman, Kuhlman, Joireman, Teta, & Kraft, 1993) for a double-blind, placebo-controlled, intranasal amphetamine administration study conducted within an MRI scanner. Active state seed-to-voxel connectivity analyses assessed the effects of amphetamine, personality, subjective responses to amphetamine, and their interactions with mesocorticolimbic seeds on data collected during monetary incentive delay and go/no-go task performance. Results indicated that amphetamine administration largely disrupted brain activity as evidenced by connectivity values shifting toward no correlation among brain stem, striatal, and frontal cortex regions. Additionally, associations of impulsivity and connectivity between ventral tegmental and medial orbitofrontal as well as lateral orbitofrontal and putamen regions were inverted from negative to positive during the placebo and amphetamine conditions, respectively. Personality was unrelated to subjective responses to amphetamine. Results are interpreted as providing evidence of underlying differences in mesocorticolimbic circuitry being a potential target for requisite diagnostic and treatment strategies implicated with stimulant use disorders, but further research is needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Topics: Amphetamine; Dextroamphetamine; Double-Blind Method; Exploratory Behavior; Female; Humans; Impulsive Behavior; Male; Sensation
PubMed: 33764102
DOI: 10.1037/pha0000406 -
Pharmacology, Biochemistry, and Behavior Dec 1990There are three possible ring-substituted methyl amphetamines (or tolylaminopropanes; TAPs): oTAP, mTAP and pTAP. These agents are positional isomers of methamphetamine....
There are three possible ring-substituted methyl amphetamines (or tolylaminopropanes; TAPs): oTAP, mTAP and pTAP. These agents are positional isomers of methamphetamine. Although all three isomers have been previously reported to possess amphetamine-like character, few studies have examined all three agents in comparison with (+)amphetamine. Using rats trained to discriminate 1 mg/kg of (+)amphetamine from saline under a variable-interval 15-sec schedule of reinforcement, tests of stimulus generalization were conducted with the three positional isomers. Only oTAP (ED50 dose = 4.1 mg/kg) completely substituted for (+)amphetamine. mTAP and pTAP resulted only in partial (ca. 50% amphetamine-appropriate responding) generalization. It is concluded that oTAP is capable of producing amphetamine-like stimulus effects and that it is approximately one-tenth as potent as (+)amphetamine; however, because the partial generalization produced by mTAP and pTAP was followed by disruption of behavior at slightly higher doses, it cannot be reliably stated that these latter two isomers lack amphetamine-like character.
Topics: Amphetamines; Animals; Dextroamphetamine; Discrimination, Psychological; Generalization, Stimulus; Isomerism; Male; Methamphetamine; Rats; Rats, Inbred Strains; Structure-Activity Relationship
PubMed: 2093186
DOI: 10.1016/0091-3057(90)90571-x -
Journal of Neurology, Neurosurgery, and... Dec 1973The narcoleptic syndrome is a life-long and sometimes familial disorder in which there is a disturbance of the rapid eye movement phase of sleep. Patients with periodic... (Clinical Trial)
Clinical Trial
The narcoleptic syndrome is a life-long and sometimes familial disorder in which there is a disturbance of the rapid eye movement phase of sleep. Patients with periodic sleep in the daytime but no other symptoms seldom develop the narcoleptic syndrome and have a separate unrelated disorder. Twelve patients with the narcoleptic syndrome were treated separately with l(-) amphetamine and d(+) amphetamine. Both drugs abolished narcolepsy, d(+) amphetamine being slightly more potent than l(-) amphetamine. In equipotent doses, unwanted effects of nervousness and insomnia were equal in frequency. No tolerance to either preparation developed during a six month period. Cataplexy was not affected by amphetamine treatment, but was abolished in two patients when clomipramine was given together with either amphetamine.
Topics: Adult; Amphetamine; Antidepressive Agents; Cataplexy; Dextroamphetamine; Electroencephalography; Evaluation Studies as Topic; Female; Hallucinations; Humans; Isomerism; Male; Middle Aged; Narcolepsy; Placebos; Sleep Initiation and Maintenance Disorders; Sleep Stages; Sleep Wake Disorders; Sleep, REM; Sweating; Tremor
PubMed: 4359162
DOI: 10.1136/jnnp.36.6.1076 -
The British Journal of Psychiatry : the... Mar 1970
Topics: Adolescent; Amphetamine; Dextroamphetamine; England; Humans; Juvenile Delinquency; Male; Substance-Related Disorders
PubMed: 5434244
DOI: 10.1192/bjp.116.532.349-a -
Psychopharmacology 1986In the present experiments, the effects of a wide range of doses of d-amphetamine and apomorphine were studied on investigatory behavior in an automated eight-hole box....
In the present experiments, the effects of a wide range of doses of d-amphetamine and apomorphine were studied on investigatory behavior in an automated eight-hole box. Amphetamine (0.125, 0.25, 0.5, 1.0, 3.0, 5.0 mg/kg) increased frequency and total duration of responses, and decreased mean duration in a dose-dependent manner. The strategy and organization of responses, as measured by the order of hole-visits and hole-switching, were unchanged at lower doses of amphetamine but were altered at higher doses. Perseverative hole-poking was observed at the highest dose (5.0) as indicated by increased number of hole-pokes per hole-visit. Apomorphine (0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 mg/kg) decreased mean duration of responses, but in contrast to amphetamine markedly diminished frequency. Locomotor activity was also measured at all doses of both drugs. Our observations indicate that these two stimulant drugs both of which increase motor activity, have markedly different effects on investigatory responses. It is likely that amphetamine increases prepotent response tendencies (i.e., hole-poking), although this does not necessarily reflect enhanced exploration. Further, the results obtained with amphetamine support predictions made by the Lyon-Robbins behavioral theory of amphetamine effects.
Topics: Amphetamine; Animals; Apomorphine; Dextroamphetamine; Exploratory Behavior; Male; Motor Activity; Rats; Rats, Inbred Strains; Time Factors
PubMed: 3080777
DOI: 10.1007/BF00310515