Bupropion for attention deficit hyperactivity disorder (ADHD) in adults

Wim Verbeeck; Geertruida E Bekkering; Wim Van den Noortgate; Cornelis Kramers

doi:10.1002/14651858.CD009504.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Figure 3

Forest plot of comparison: 1 Bupropion versus placebo, outcome: 1.1 Severity of ADHD (at study completion).

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Figure 4

Forest plot of comparison: 1 Bupropion vs placebo, outcome: 1.1 Achievement of significant clinical improvement (% participants).

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Figure 5

Forest plot of comparison: 1 Bupropion vs placebo, outcome: 1.3 Clinical Global Impression (CGI) ‐ improvement scale (% participants achieving at least 1 or 2 on CGI).

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Figure 6

Forest plot of comparison: 1 Bupropion versus placebo, outcome: 1.4 Number of participants withdrawn due to adverse events.

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Analysis 1.1

Comparison 1 Bupropion versus placebo, Outcome 1 Severity of ADHD (at study completion).

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Analysis 1.2

Comparison 1 Bupropion versus placebo, Outcome 2 Achievement of significant clinical improvement (% participants).

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Analysis 1.3

Comparison 1 Bupropion versus placebo, Outcome 3 Clinical Global Impression (CGI) ‐ Improvement scale (% participants achieving at least one or two on CGI).

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Analysis 1.4

Comparison 1 Bupropion versus placebo, Outcome 4 Number of participants withdrawn due to adverse events.

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Analysis 1.5

Comparison 1 Bupropion versus placebo, Outcome 5 Depressive symptoms (change from baseline to study completion).

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Analysis 1.6

Comparison 1 Bupropion versus placebo, Outcome 6 Anxiety symptoms (change from baseline to study completion).

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Analysis 1.7

Comparison 1 Bupropion versus placebo, Outcome 7 Retention rate (number of patients completing study).

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Analysis 1.8

Comparison 1 Bupropion versus placebo, Outcome 8 Number of participants that lowered their dose due to adverse events.

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Analysis 1.9

Comparison 1 Bupropion versus placebo, Outcome 9 Number of participants with at least one adverse event.

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Analysis 2.1

Comparison 2 Bupropion versus placebo (sensitivity analyses), Outcome 1 Severity of ADHD (at study completion) ‐ clinician rated.

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Analysis 2.2

Comparison 2 Bupropion versus placebo (sensitivity analyses), Outcome 2 Severity if ADHD (at study completion) ‐ studies that exclude psychiatric comorbidity.

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Analysis 2.3

Comparison 2 Bupropion versus placebo (sensitivity analyses), Outcome 3 Achievement of significant clinical improvement (% participants) ‐ studies that exclude psychiatric comorbidity.

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Analysis 2.4

Comparison 2 Bupropion versus placebo (sensitivity analyses), Outcome 4 CGI ‐ Improvement (% participants achieving at least one or two on CGI) ‐ studies that exclude psychiatric comorbidity.

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Analysis 2.5

Comparison 2 Bupropion versus placebo (sensitivity analyses), Outcome 5 Number of participants withdrawn due to adverse events ‐ studies that exclude psychiatric comorbidity.

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Bupropion compared with placebo for adult ADHD
Participant or population: Adults with ADHD Settings: Ambulant care Intervention: Bupropion Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Bupropion
Severity of ADHD (at study completion) WRAADDS scale (0 to 28), ADHD‐RS scale (0 to 54) or CAARS scale (0 to 48). On all scales, a higher score equates to more symptoms (at 6 weeks)	The mean score for severity of ADHD ranged across control groups from 14.70 (WRAADDS) to 23.80 (ADHD‐RS) and 34.43 (CAARS)	The standardised mean score for severity of ADHD in the intervention groups was on average 0.50 lower (0.86 lower to 0.15 lower)	‐	129 (3 studies)	⊕⊕⊝⊝ Low^{1, 2}
Achievement of significant clinical improvement (% participants) (at 6 to 10 weeks)	212 per 1000	318 per 1000 (from 240 to 422)	RR 1.50 (1.13 to 1.99)	315 (4 studies)	⊕⊕⊝⊝ Low^{1, 2}
CGI ‐ Improvement scale (% participants achieving at least 1 or 2 on CGI) (at 6 to 10 weeks)	222 per 1000	395 per 1000 (from 282 to 555)	RR 1.78 (1.27 to 2.50)	337 (5 studies)	⊕⊕⊝⊝ Low^{1, 2}
Number of participants withdrawn due to adverse events (at 6 to 10 weeks)	61 per 1000	73 per 1000 (from 21 to 250)	RR 1.20 (0.35 to 4.10)	253 (3 studies)	⊕⊕⊝⊝ Low^{1, 2}
The basis for the assumed risk* was the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ADHD: attention deficit hyperactivity disorder; ADHD‐RS: ADHD symptoms rating scale; CAARS: Conners' Adult ADHD Rating Scales; CGI: Clinical Global Impression scale;CI: Confidence interval; RR: Risk Ratio; WRAADDS: Wender‐Reimherr Adult Attention Deficit Disorder Scale
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded by one level due to limitations in study design. Most quality items were poorly reported. ²Downagraded by one level due to imprecision. Optimal information size (OIS) not met.

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Table 1. Methods archived for future updates of this review

Topic	Method
Unit of analysis issues	Cross‐over trials We will include cross‐over trials. Given the risk of carry‐over effects, we will use data from the first period (before cross‐over) only, and treat these as parallel‐group trials.
Assessment of reporting biases	We will produce funnel plots (estimated treatment effects against their standard error). We will test funnel plot asymmetry when there are at least 10 studies included in the meta‐analysis. Asymmetry could be due to publication bias, but could also be due to a relationship between trial size and effect size. In the event that we find a relationship, we will examine the clinical diversity of the studies, selection biases and poor methodological quality as alternative explanations to publication bias.
Subgroup analysis and investigation of heterogeneity	We will perform two subgroup analyses: Type of drug release formulation: immediate release, sustained release and extended release. Dose: above versus below median dose. When there are more than 10 studies included in the analyses, we will investigate statistical heterogeneity using meta‐regression (Deeks 2011).
Multiple time points	We will classify outcomes of all studies based on time of measurement from randomisation: acute (less than 24 hours), short‐term (less than six weeks), medium‐term (six weeks to six months), and long‐term (more than six months). Within each time period, we will include the latest outcome in the meta‐analysis.
Sensitivity analysis	We will conduct sensitivity analyses to determine whether findings are sensitive to restricting the analyses to studies judged to be at low risk of bias. In these analyses, we will restrict the analysis to the following: Studies with low risk of selection bias (associated with sequence generation and allocation concealment). Studies without financial support from the pharmaceutical industry. Studies that used standardised instrument(s) to measure efficacy. Studies without imputed data (see also 'Dealing with missing data').

Table 1. Methods archived for future updates of this review

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Table 2. Results of individual studies

Study ID	Outcome/scale	Results for bupropion	Results for placebo (P value for difference between groups)
Kuperman 2001	Self‐rated ADHD symptoms	‐13.7 (SD 6.9)	‐12.4 (SD 10.6) (P = 0.69)
Reimherr 2005	Global level of functioning	Mean final value at study completion 57.5 (SD 8.1)	Mean final value at study completion 56.2 (SD 3.6) (P > 0.05)
Wilens 2005	ADHD Symptom Checklist (DuPaul 1990)	Mean difference from baseline ‐12.7	Mean difference ‐6.9 (P < 0.001)
Wilens 2005	Global level of functioning	Mean change from baseline 7.3 (SD 10.4)	4.0 (SD 8.0) (P = 0.035)
ADHD: attention deficit hyperactivity disorder ID: identifier SD: standard deviation.

Table 2. Results of individual studies

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Table 3. Results sensitivity analysis

Outcome	Fixed‐effect model	Studies excluding psychiatric comorbidity (fixed‐effect model)	Random‐effects model	Studies using clinician‐rated scales (fixed‐effect model)
Severity of ADHD symptoms	SMD ‐0.50 (95% CI ‐0.86 to ‐0.15), 129 participants	SMD ‐0.55 (95% CI ‐0.98 to ‐0.12), 89 participants	SMD ‐0.50 (95% CI ‐0.86 to ‐0.15), 129 participants	SMD ‐0.36 (95% CI ‐0.79 to 0.07), 87 participants
Proportion with significant clinical improvement	RR 1.50 (95% CI 1.13 to 1.99), 315 participants	RR 1.58 (95% CI 1.06 to 2.35), 209 participants	RR 1.48 (95% CI 1.05 to 2.11), 315 participants	N/A
Proportion with at least 1 or 2 on CGI	RR 1.78 (95% CI 1.27 to 2.50), 337 participants	RR 2.06 (95% CI 1.34 to 3.16), 231 participants	RR 1.79 (95% CI 1.02 to 3.14), 337 participants	N/A
Adverse events: number of patients withdrawn	RR 1.20 (95% CI 0.35 to 4.10), 253 participants	RR 2.42 (95% CI 0.49 to 12.01), 187 participants	RR 0.85 (95% CI 0.07 to 9.77), 253 participants	N/A
ADHD: attention deficit hyperactivity disorder CGI: Clinical Global Impression scale CI: confidence interval N/A: not applicable RR: risk ratio SMD: standardised mean difference

Table 3. Results sensitivity analysis

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Comparison 1. Bupropion versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severity of ADHD (at study completion) Show forest plot	3	129	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐0.86, ‐0.15]

2 Achievement of significant clinical improvement (% participants) Show forest plot	4	315	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [1.13, 1.99]

3 Clinical Global Impression (CGI) ‐ Improvement scale (% participants achieving at least one or two on CGI) Show forest plot	5	337	Risk Ratio (M‐H, Fixed, 95% CI)	1.78 [1.27, 2.50]

4 Number of participants withdrawn due to adverse events Show forest plot	3	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.35, 4.10]

5 Depressive symptoms (change from baseline to study completion) Show forest plot	2	184	Mean Difference (IV, Fixed, 95% CI)	0.52 [‐0.46, 1.51]

6 Anxiety symptoms (change from baseline to study completion) Show forest plot	2	184	Mean Difference (IV, Fixed, 95% CI)	0.36 [‐0.72, 1.43]

7 Retention rate (number of patients completing study) Show forest plot	5	352	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.87, 1.06]

8 Number of participants that lowered their dose due to adverse events Show forest plot	2	104	Risk Ratio (M‐H, Fixed, 95% CI)	1.86 [0.57, 6.10]

9 Number of participants with at least one adverse event Show forest plot	3	227	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.95, 1.37]

Comparison 1. Bupropion versus placebo

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Comparison 2. Bupropion versus placebo (sensitivity analyses)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severity of ADHD (at study completion) ‐ clinician rated Show forest plot	2	87	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.36 [‐0.79, 0.07]

2 Severity if ADHD (at study completion) ‐ studies that exclude psychiatric comorbidity Show forest plot	2	89	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.55 [‐0.98, ‐0.12]

3 Achievement of significant clinical improvement (% participants) ‐ studies that exclude psychiatric comorbidity Show forest plot	2	209	Risk Ratio (M‐H, Fixed, 95% CI)	1.58 [1.06, 2.35]

4 CGI ‐ Improvement (% participants achieving at least one or two on CGI) ‐ studies that exclude psychiatric comorbidity Show forest plot	3	231	Risk Ratio (M‐H, Fixed, 95% CI)	2.06 [1.34, 3.16]

5 Number of participants withdrawn due to adverse events ‐ studies that exclude psychiatric comorbidity Show forest plot	2	187	Risk Ratio (M‐H, Fixed, 95% CI)	2.42 [0.49, 12.01]

Comparison 2. Bupropion versus placebo (sensitivity analyses)

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