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Meta-Analysis
, 8 (8), CD007813

Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in Adults

Affiliations
Meta-Analysis

Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in Adults

Xavier Castells et al. Cochrane Database Syst Rev.

Abstract

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company, Shire, and we searched the reference lists of retrieved studies and reviews for other published, unpublished, or ongoing studies.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.

Conflict of interest statement

Xavier Castells received a research grant for 'Improving the scientific productivity' (MPCUdG2016/ref50) from the Universitat de Girona, Spain. Ruth Cunill ‐ none known. Lídia Blanco‐Silvente has a pre‐doctoral research contract (IFUdG2015/17) with the Universitat de Girona, Spain.

Figures

Figure 1
Figure 1
Flow diagram.
Figure 2
Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Note: scores for blinding of participants, personnel, and outcome assessors refer to amphetamines vs placebo only comparisons; scores on all remaining domains refer to amphetamines vs placebo, guanfacine, modafinil, or paroxetine.
Figure 3
Figure 3
Forest plot of comparison: 1 Amphetamines vs placebo for ADHD in adults, outcome: 1.1 Severity of ADHD symptoms: clinician rated.
Figure 4
Figure 4
Funnel plot of comparison: 1 Amphetamines vs placebo for ADHD in adults, outcome: 1.1 Severity of ADHD symptoms: clinician rated.
Figure 5
Figure 5
Forest plot of comparison: 1 Amphetamines vs placebo for ADHD in adults, outcome: 1.11 Retention in treatment.
Figure 6
Figure 6
Forest plot of comparison: 1 Amphetamines vs placebo for ADHD in adults, outcome: 1.13 Proportion of participants withdrawn owing to any adverse event.
Analysis 1.1
Analysis 1.1
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 1 ADHD symptom severity: clinician‐rated.
Analysis 1.2
Analysis 1.2
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 2 ADHD symptom severity: patient‐rated.
Analysis 1.3
Analysis 1.3
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 3 Clinical impression of severity at study end.
Analysis 1.4
Analysis 1.4
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 4 Clinical impression of improvement at study end.
Analysis 1.5
Analysis 1.5
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 5 Proportion of participants achieving a reduction ≥ 30% in severity of ADHD symptoms.
Analysis 1.6
Analysis 1.6
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 6 Proportion of participants achieving a CGI‐Improvement score of 1 or 2.
Analysis 1.7
Analysis 1.7
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 7 Proportion of participants achieving a reduction ≥ 30% in severity of ADHD symptoms and a CGI‐Improvement score of 1 or 2.
Analysis 1.8
Analysis 1.8
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 8 Global functioning.
Analysis 1.9
Analysis 1.9
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 9 Depressive symptoms.
Analysis 1.10
Analysis 1.10
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 10 Anxiety symptoms.
Analysis 1.11
Analysis 1.11
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 11 Retention in treatment.
Analysis 1.12
Analysis 1.12
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 12 Proportion of participants withdrawn owing to any cardiovascular adverse event.
Analysis 1.13
Analysis 1.13
Comparison 1 Amphetamines vs placebo for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 13 Proportion of participants withdrawn owing to any adverse event.
Analysis 2.1
Analysis 2.1
Comparison 2 Subgroup analysis 1: comorbidity, Outcome 1 ADHD symptom severity: clinician‐rated.
Analysis 2.2
Analysis 2.2
Comparison 2 Subgroup analysis 1: comorbidity, Outcome 2 ADHD symptom severity: patient‐rated.
Analysis 2.3
Analysis 2.3
Comparison 2 Subgroup analysis 1: comorbidity, Outcome 3 Retention in treatment.
Analysis 2.4
Analysis 2.4
Comparison 2 Subgroup analysis 1: comorbidity, Outcome 4 Proportion of patients withdrawn owing to any adverse event.
Analysis 3.1
Analysis 3.1
Comparison 3 Subgroup analysis 2: type of amphetamine, Outcome 1 ADHD symptom severity: clinician‐rated.
Analysis 3.2
Analysis 3.2
Comparison 3 Subgroup analysis 2: type of amphetamine, Outcome 2 ADHD symptom severity: patient‐rated.
Analysis 3.3
Analysis 3.3
Comparison 3 Subgroup analysis 2: type of amphetamine, Outcome 3 Retention in treatment.
Analysis 3.4
Analysis 3.4
Comparison 3 Subgroup analysis 2: type of amphetamine, Outcome 4 Proportion of participants withdrawn owing to any adverse event.
Analysis 4.1
Analysis 4.1
Comparison 4 Subgroup analysis 3: dose of dexamphetamine, Outcome 1 ADHD symptom severity: patient rated.
Analysis 5.1
Analysis 5.1
Comparison 5 Subgroup analysis 3: dose of lisdexamfetamine, Outcome 1 ADHD symptom severity: clinician rated.
Analysis 5.2
Analysis 5.2
Comparison 5 Subgroup analysis 3: dose of lisdexamfetamine, Outcome 2 ADHD symptom severity: patient rated.
Analysis 5.3
Analysis 5.3
Comparison 5 Subgroup analysis 3: dose of lisdexamfetamine, Outcome 3 Retention in treatment.
Analysis 5.4
Analysis 5.4
Comparison 5 Subgroup analysis 3: dose of lisdexamfetamine, Outcome 4 Proportion of participants withdrawn owing to any adverse event.
Analysis 6.1
Analysis 6.1
Comparison 6 Subgroup analysis 3: dose of mixed amphetamine salts, Outcome 1 ADHD symptom severity: clinician rated.
Analysis 6.2
Analysis 6.2
Comparison 6 Subgroup analysis 3: dose of mixed amphetamine salts, Outcome 2 Retention in treatment.
Analysis 6.3
Analysis 6.3
Comparison 6 Subgroup analysis 3: dose of mixed amphetamine salts, Outcome 3 Proportion of participants withdrawn owing to any adverse event.
Analysis 7.1
Analysis 7.1
Comparison 7 Subgroup analysis 4: type of drug‐release formulation, Outcome 1 ADHD symptom severity: clinician rated.
Analysis 7.2
Analysis 7.2
Comparison 7 Subgroup analysis 4: type of drug‐release formulation, Outcome 2 ADHD symptom severity: patient rated.
Analysis 7.3
Analysis 7.3
Comparison 7 Subgroup analysis 4: type of drug‐release formulation, Outcome 3 Retention in treatment.
Analysis 8.1
Analysis 8.1
Comparison 8 Sensitivity analysis: incomplete subjective outcome data, Outcome 1 ADHD symptom severity: clinician rated.
Analysis 8.2
Analysis 8.2
Comparison 8 Sensitivity analysis: incomplete subjective outcome data, Outcome 2 ADHD symptom severity: patient rated.
Analysis 9.1
Analysis 9.1
Comparison 9 Sensitivity analysis: other potential sources of bias, Outcome 1 ADHD symptom severity: clinician rated.
Analysis 9.2
Analysis 9.2
Comparison 9 Sensitivity analysis: other potential sources of bias, Outcome 2 ADHD symptom severity: patient rated.
Analysis 9.3
Analysis 9.3
Comparison 9 Sensitivity analysis: other potential sources of bias, Outcome 3 Retention in treatment.
Analysis 10.1
Analysis 10.1
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 1 ADHD symptom severity: clinician‐rated.
Analysis 10.2
Analysis 10.2
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 2 ADHD symptom severity: patient‐rated.
Analysis 10.3
Analysis 10.3
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 3 Clinical impression of severity at study end.
Analysis 10.4
Analysis 10.4
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 4 Clinical impression of improvement at study end.
Analysis 10.5
Analysis 10.5
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 5 Proportion of participants achieving a reduction ≥ 30% in severity of ADHD symptoms.
Analysis 10.6
Analysis 10.6
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 6 Proportion of participants achieving a CGI‐Improvement score of 1 or 2.
Analysis 10.7
Analysis 10.7
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 7 Proportion of participants achieving a reduction ≥ 30% in severity of ADHD symptoms and a CGI‐Improvement score of 1 or 2.
Analysis 10.8
Analysis 10.8
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 8 Global functioning.
Analysis 10.9
Analysis 10.9
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 9 Depressive symptoms.
Analysis 10.10
Analysis 10.10
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 10 Anxiety symptoms.
Analysis 10.11
Analysis 10.11
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 11 Retention in treatment.
Analysis 10.12
Analysis 10.12
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 12 Proportion of participants withdrawn owing to any cardiovascular adverse event.
Analysis 10.13
Analysis 10.13
Comparison 10 Sensitivity analysis: fixed‐effect model, Outcome 13 Proportion of participants withdrawn owing to any adverse event.
Analysis 11.1
Analysis 11.1
Comparison 11 Post hoc sensitivity analysis 1: calculation of effect sizes using correlation coefficient from Taylor 2000, Outcome 1 ADHD symptom severity: clinician rated.
Analysis 11.2
Analysis 11.2
Comparison 11 Post hoc sensitivity analysis 1: calculation of effect sizes using correlation coefficient from Taylor 2000, Outcome 2 ADHD symptom severity: patient rated.
Analysis 12.1
Analysis 12.1
Comparison 12 Post hoc sensitivity analysis 2: pooled risk difference for proportion of participants withdrawn owing to cardiovascular adverse events and any adverse event, Outcome 1 Proportion of participants withdrawn owing to any cardiovascular adverse event.
Analysis 12.2
Analysis 12.2
Comparison 12 Post hoc sensitivity analysis 2: pooled risk difference for proportion of participants withdrawn owing to cardiovascular adverse events and any adverse event, Outcome 2 Proportion of participants withdrawn owing to any adverse event.
Analysis 13.1
Analysis 13.1
Comparison 13 Post hoc sensitivity analysis 3: exclusion of cross‐over study, Outcome 1 ADHD symptom severity: clinician rated.
Analysis 14.1
Analysis 14.1
Comparison 14 Amphetamines vs guanfacine for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 1 ADHD symptom severity: patient rated.
Analysis 15.1
Analysis 15.1
Comparison 15 Amphetamines vs modafinil for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 1 ADHD symptom severity: patient rated.
Analysis 16.1
Analysis 16.1
Comparison 16 Amphetamines vs paroxetine for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 1 ADHD symptom severity: clinician rated.
Analysis 16.2
Analysis 16.2
Comparison 16 Amphetamines vs paroxetine for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 2 Proportion of participants achieving a CGI‐Improvement score of 1 or 2.
Analysis 16.3
Analysis 16.3
Comparison 16 Amphetamines vs paroxetine for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 3 Global functioning.
Analysis 16.4
Analysis 16.4
Comparison 16 Amphetamines vs paroxetine for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 4 Depressive symptoms.
Analysis 16.5
Analysis 16.5
Comparison 16 Amphetamines vs paroxetine for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 5 Anxiety symptoms.
Analysis 16.6
Analysis 16.6
Comparison 16 Amphetamines vs paroxetine for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 6 Retention in treatment.
Analysis 16.7
Analysis 16.7
Comparison 16 Amphetamines vs paroxetine for adult attention deficit hyperactivity disorder (ADHD) in adults, Outcome 7 Proportion of participants withdrawn owing to any adverse event.

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