Abstract
Background and Aim:
Pharmacotherapeutic options for attention-deficit hyperactivity disorder (ADHD) are limited due to adverse effects and inadequate efficacy of existing drugs. Clinical trials were conducted on dasotraline in search of a safer and more efficacious alternatives to stimulant agents. This meta-analysis was conducted to evaluate the efficacy and safety of dasotraline in ADHD compared to placebo.
Methods:
The reviewers extracted data from five relevant clinical trials after a literature search on Medline/PubMed, Embase, Scopus, Google Scholar, and Cochrane databases and Clinical Trial Registries. Quality assessment was done using the risk of bias assessment tool, and the random-effects model was used to estimate the effect size. Sub-group analysis, meta-regression, and sensitivity analysis were done as applicable. PRISMA guidelines were followed in the selection, analysis, and reporting of findings.
Results:
Dasotraline significantly reduced the ADHD total symptom score (SMD: -0.35; 95% CI: -0.55 to -0.15; P < 0.001), hyperactivity/impulsivity subscale score (SMD: -0.27; 95% CI: -0.44 to -0.11; P = 0.001), inattentiveness sub-scale score (SMD: -0.33; 95% CI: -0.53 to -0.14; P < 0.001), and CGI-S (SMD: -0.25; 95% CI: -0.42 to -0.08; P = 0.003). Sub-group analysis showed a significant reduction of ADHD symptoms in both pediatric and adult age groups. Meta-regression showed a significant association between SMD of ADHD symptom score reduction and the duration of dasotraline therapy. The incidence of decreased appetite showed dose dependence but not the incidence of insomnia.
Conclusions:
Dasotraline 4 mg (in children) and 6 mg (in adults) can improve the clinical outcome in patients with ADHD by improving symptoms and global functioning with acceptable tolerability.
PROSPERO Registration number: CRD42022321979
Keywords: Attention-deficit hyperactivity disorder, dasotraline, hyperactivity, inattentiveness
INTRODUCTION
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder marked by classic symptoms of inattention and/or hyperactivity–impulsivity that interferes with social, intellectual, and professional functioning or development.[1] ADHD is predominantly a childhood disorder affecting 5 to 7% of children but often continues into adulthood, with a prevalence of 4%.[2] The first-line pharmacological treatments for ADHD include stimulant drugs (methylphenidate and amphetamine) and non-stimulant drugs (atomoxetine, clonidine, and guanfacine).[3] The use of both classes of drugs is restricted due to their adverse effects, and it is reported that about 20% of patients are intolerant to current regimens or present with a lack of efficacy.[4,5] The non-stimulant agents are considered second-line options and recommended as an alternative to stimulants. The meta-analysis by Cortese et al.[6] found that the effect size of non-stimulant drugs in terms of reduction of core ADHD symptoms was of moderate magnitude. Hence, over the past years, different studies have been conducted to identify viable alternatives to the current treatment options for ADHD.
The prototypical symptoms of ADHD are hypothesized to be associated with specific defective functioning in cortico-striato-thalamo-cortical circuits. Several studies suggest that dysregulation in the dopaminergic and noradrenergic systems, with an ambiguous role of the serotonergic system, may curb the disruption of the normal function and control of neurons.[7] Hence, augmenting dopamine and/or noradrenaline in the prefrontal cortex and the basal ganglia can reduce ADHD symptoms. Inhibition of dopamine and, secondarily, noradrenaline reuptake are among the most valid mechanisms and basis of the current therapeutic practice.[8] Considering the involvement of dopamine, noradrenaline, and serotonin, triple reuptake inhibitors are emerging as a promising treatment option for ADHD.
Dasotraline is a triple reuptake inhibitor with a predominant affinity for dopamine and norepinephrine transporter and a weaker action on the serotonin transporter.[8,9] In previous pre-clinical studies, dasotraline significantly reduced impulsive and immediate reward choices, like methylphenidate.[8] In humans, dasotraline has been tested in a few randomized clinical trials and showed a significant reduction of ADHD symptoms.[10,11,12,13,14] Our literature search did not show any systematic review or meta-analysis for dasotraline in patients with ADHD. However, one systematic review by Nageye et al.[9] on 12 novel agents (including dasotraline) for ADHD concluded that it was unlikely that those novel agents would show better efficacy than stimulants. The systematic review described four trials on dasotraline qualitatively without conducting any meta-analysis or network meta-analysis. Hence, it is crucial to generate decisive evidence regarding the magnitude of the effect and safety of dasotraline for a successful translation into therapeutic practice. So, the present meta-analysis has been conducted to evaluate the efficacy and safety of dasotraline in both children and adults with ADHD in comparison to placebo.
METHODS
Development and registration of the protocol
We prepared the meta-analysis protocol following Preferred Reporting Items for Systematic Reviews and Meta-Analysis - Protocol (PRISMA-P) 2015 guidelines[15] and registered the protocol in the International Prospective Register of Ongoing Systematic Reviews (PROSPERO Registration number: CRD42022321979). The present meta-analysis has been conducted and reported in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.[16,17] As a standard methodological reference, the Cochrane Handbook for systematic reviews of interventions was used.[18]
Search strategy
Three review authors performed a systematic literature search independently by using MEDLINE/PubMed, EMBASE, Scopus, Google Scholar, Cochrane database, and WHO International Clinical Trials Registry Platform (ICTRP) for randomized clinical trials on dasotraline in ADHD published till September 2023. The search strategy was not restricted by language, publication date, and clinical variants of ADHD. The PICO scheme was followed to report inclusion criteria. The search terms for PubMed were [(attention deficit disorder with hyperactivity”[MeSH Terms] OR (“attention”[All Fields] AND “deficit”[All Fields] AND “disorder”[All Fields] AND “hyperactivity”[All Fields]) OR “attention deficit disorder with hyperactivity”[All Fields] OR “adhd”[All Fields])], AND [(“4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine”[Supplementary Concept] OR “4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine”[All Fields] OR “dasotraline”[All Fields])) AND (clinicaltrial[Filter]). The search terms for other databases were adapted accordingly.
Study selection criteria
Types of studies
Randomized clinical trials evaluated the effect of dasotraline for the treatment of ADHD to improve the score on the ADHD Rating Scale (Version IV) or Swanson, Kotkin, Agler, M-Flynn, and Pelham (SCAMP) rating scale and were included in this meta-analysis. Review articles, clinical studies in different indications, methodological research, letters to the editor, commentaries, opinions, case reports, case series, and studies with inadequate data were excluded from this meta-analysis.
Types of participants
Children (aged 6–12 years) and adults (aged 18–55 years) with a primary diagnosis of ADHD as per DSM 5 criteria with a total baseline score ≥26 on the ADHD Rating Scale Version IV (ADHD RS-IV) were included in the study. Patients with a diagnosis of major depressive disorders (MDD) or manic-depressive psychosis (MDP), obsessive-compulsive disorder (OCD), conduct disorder, psychosis, autism spectrum disorder, disruptive mood dysregulation disorder (DMDD), intellectual impairment, Tourette's syndrome, axis II personality disorder, or any genetic disorder with cognitive and/or behavioral disorders were excluded. Other exclusion criteria were patients who were being treated for ADHD with a stimulant or non-stimulant drug within 4 weeks of screening; any clinically significant medical morbidity or any significant abnormality on physical examination, laboratory test reports, or patients who received anticonvulsants, antipsychotics, antidepressants, lithium, MAO inhibitors, α2 adrenergic receptor agonists, modafinil, armodafinil, atomoxetine, pseudoephedrine, first-generation antihistaminics, herbal/complementary treatments, and substrate/inducers/inhibitors of CYP2B6.
Types of interventions
Experimental intervention: Patients received a fixed daily dose of dasotraline (2–8 mg) for 2–8 weeks.
Control intervention: A matching placebo was used as the control.
Outcome measures
Primary outcome: Change in the total/combined score on the ADHD Rating Scale Version IV (ADHD RS-IV)[19,20] or the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale[21] over the study period.
Secondary outcome: Change in the hyperactivity/impulsivity and inattentiveness subscale scores, Clinical Global Impression-Severity scale (CGI-S), and incidence of treatment-emergent adverse events.
Study selection and data collection
Selection of studies
In the first step, the titles, abstracts, and keywords of all published articles were screened independently by three review authors. Then, full texts of all selected studies were obtained and evaluated by the authors, and those studies which met the inclusion and exclusion criteria were included in the meta-analyses. The reasons for exclusion were recorded, and any disagreement among authors was resolved through discussion.
Data extraction and management
Three review authors collected data and assessed quality independently following the guidelines from the Cochrane Collaboration.[18] Any disagreement between the review authors was resolved by consensus or in consultation with the fourth review author. Extracted data included study sites, study design, participants, intervention, comparators, and outcome measures.
Data analysis
This meta-analysis was conducted using the Cochrane Program Review Manager Version 5.4.[22] Meta-regression and publication bias with trim-and-fill analysis were performed using Meta-Essentials (workbooks for meta-analysis).
Assessment of risk of bias in included studies
The internal validity of eligible studies, including the risk of bias, was assessed by three review authors independently using the Cochrane Collaboration's risk of bias 2 (RoB 2) tool.[18,23] We described the risk of bias and judged it as low, with some concerns, and high in different domains [arising from the randomization process, due to deviation from intended interventions (effect of adhering to intervention, due to missing outcome data, measurement of the outcome, selection of reported results, overall assessment of risk)].
Unit-of-analysis issue
In the present meta-analysis, the term “study” has been considered as a unit of design. In studies in which different doses of dasotraline were used, the different dose groups (study arms) were considered as separate units of analysis.
Measures of treatment effect
In this meta-analysis, the outcome measures of interest were changes in the total/combined score on ADHD RS-IV or SKAMP scales and hyperactivity/impulsivity, inattentiveness subscale scores, and CGI-S, which are continuous variables. For continuous variables, the standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated to estimate the effect size to assess the difference in outcome measures between dasotraline and placebo groups. For categorical variables like adverse drug events, the odds ratio (OR) was calculated. The random-effects model was used for overall between-group analyses, irrespective of heterogeneity between individual studies. We have also reported the prediction interval (PI) for the primary outcome measure.
Assessment of heterogeneity
Assessment of heterogeneity was done to assess the extent of the inconsistency or to quantify inconsistency across the included studies. The Chi-squared test was performed, and a low P value (or a large Chi-squared statistic relative to its degree of freedom) provided evidence of the heterogeneity of intervention effects (variation in effect estimates beyond chance). I2 statistics, which describe the percentage of the variability in effect, were used to quantify inconsistency. To investigate high heterogeneity (if any), sensitivity analysis was done by removing a particular study (one at a time) contributing to high heterogeneity.
Sensitivity analysis
In case of high heterogeneity, the forest plots were generated again after excluding individual studies, one at a time, and observing the effect of the exclusion of a particular study on individual parameters.
Meta-regression
As different study characteristics such as dose and duration of dasotraline can potentially modify the effect size of the intervention, we performed a meta-regression across the studies to estimate how the outcome variable (SMD in ADHD total symptom score) changes with the explanatory variable (dose of dasotraline or duration of therapy). The statistical significance of the regression coefficient served as a test of whether any linear relationship exists between the intervention effect and the explanatory variable.
Assessment of publication bias
The publication bias across studies has been assessed qualitatively by constructing the funnel plot and quantitatively by using the Begg and Mazumdar rank correlation test. The trim-and-fill method was used to adjust for funnel plot asymmetry using Meta-Essentials (workbooks for meta-analysis).[24]
Assessment of certainty of the evidence
Standard Cochrane methodology and the GRADE Working Group guidance were followed to create the ‘summary of findings’ table considering the risk of bias, consistency, imprecision, indirectness, publication bias, large effect size, plausible confounding, and dose–response gradient observed in the included studies, and the certainty of the evidence for each outcome was generated.[25]
RESULTS
Description of included studies
The literature search on databases identified 25 publications after the removal of duplicates that were screened by title abstract and keywords for eligibility, and 14 studies were excluded from the study as 10 were review articles, three were pre-clinical studies, one methodological research, one letter to editors, and three clinical studies conducted on different indications. The results of the search and screening process are shown in the PRISMA flow chart [Figure 1]. After screening, the full texts of seven publications were retrieved for detailed assessment. In the final stage of screening, five studies which met the selection criteria were included in the meta-analysis [Table 1], and the other two studies were excluded. Three studies[11,13,14] used different doses of dasotraline, which were considered separate units of analysis; hence, a total of eight units of analysis were dealt with in this meta-analysis. The overall assessment of the risk of bias is presented in Table S1, summarizing the judgment of the reviewers about each risk of bias domain across all included studies.
Figure 1.
PRISMA flow diagram for the study selection process
Table 1.
Characteristics of studies included in the meta-analysis and overall risk-of-bias (RoB2) of each study
| Trial and Location | Methods | Participants | Number of Participants | Interventions | Duration (Weeks) | Outcomes | Remarks | Overall risk-of-bias |
|---|---|---|---|---|---|---|---|---|
| Koblan et al. (2015)USA | Randomized Double-blind, Parallel group, Placebo-controlled, Fixed-dose proof of concept trial |
Primary diagnosis of ADHD (Aged 18-55 years) | Dasotraline (4 mg/d):114 Dasotraline (8 mg/d): 107 Placebo: 110 |
Dasotraline (4 mg/d) orally, Dasotraline (8 mg/d) orally, Placebo orally |
4 weeks | ADHD RS-IV (with adult prompts) total score CGI-S score Safety assessment |
Significant improvement in ADHD symptoms and behaviors and well tolerated. More insomnia was observed at 8 mg/d compared with 4 mg/d dose. | S |
| Findling et al. (2019) USA | Randomized Double-blind, Placebo-controlled, Fixed-dose multicentric trial |
Primary diagnosis of ADHD (Aged 6-12 years) | Dasotraline (2 mg/d):107 Dasotraline (4 mg/d): 113 Placebo: 116 |
Dasotraline (2 mg/d) orally, Dasotraline (4 mg/d) orally, Placebo orally |
6 weeks | ADHD RS-IV (Home Version) total score CGI-S score Safety assessment |
Significant improvement in ADHD symptoms and behaviors including attention and hyperactivity with dasortaline 4 mg/d dose. | L |
| Wigal et al. (2020) USA | Randomized Double-blind, Parallel group, Placebo-controlled, Fixed-dose multicentric laboratory classroom study |
Primary diagnosis of ADHD (Aged 6-12 years) | Dasotraline (4 mg/d): 56 Placebo: 56 |
Dasotraline (4 mg/d) orally, Placebo orally |
2 weeks | SKAMP-CS score Safety assessment |
Sustained 24-hour control of a broad range of attentional and behavioral symptoms of ADHD with dasortaline 4 mg/d dose. | L |
| Adler et al. (2021) USA | Randomized Double-blind, Placebo-controlled, Fixed-dose multicentric trial | Primary diagnosis of ADHD (Aged 18-55 years) |
Dasotraline (4 mg/d):207 Dasotraline (6 mg/d): 206 Placebo: 211 |
Dasotraline (4 mg/d) orally, Dasotraline (6 mg/d) orally, Placebo orally |
8 weeks | ADHD RS-IV (with adult prompts) total score CGI-S score |
Treatment with dasotraline 6 mg/day Significantly improved ADHD RS-IV total score and the CGI-S score. Treatment with 4 mg/day dose was not significant. |
S |
| Wigal et al. (2022) USA | Randomized Double-blind, Parallel group, Placebo-controlled, Fixed-dose multicentric laboratory classroom study |
Primary diagnosis of ADHD (Aged 6-12 years) | Dasotraline (2 mg/d): 47 Placebo: 48 |
Dasotraline (2 mg/d) orally, Placebo orally |
2 weeks | SKAMP-CS score Safety assessment |
Efficacious for short-term treatment of ADHD and well-tolerated. | L |
ADHD, Attention-Deficit Hyperactivity Disorder; ADHD RS-IV, ADHD Rating Scale Version IV; CGI-S, Clinical Global Impression-Severity scale; SKAMP-CS, Combined Score on the Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale. Risk-of-bias (L, Low risk of bias; S, Some concerns; H, High risk of bias)
Table S1.
Risk of bias table for included studies
| Included studies | Domain 1: Randomization process | Domain 2: Deviations from the intended interventions | Domain 3: Missing outcome data | Domain 4: Measurement of the outcome | Domain 5: Selection of the reported result | Overall risk-of-bias judgement |
|---|---|---|---|---|---|---|
| Koblan et al. 2015 | L | L | S | L | L | S |
| Findling et al. 2019 | L | L | L | L | L | L |
| Wigal et al. 2020 | L | L | L | L | L | L |
| Adler et al. 2021 | L | L | S | L | L | S |
| Wigal et al. 2022 | L | L | L | L | L | L |
L, Low risk of bias; S, Some concerns; H, High risk of bias.
Qualitative synthesis of the included studies
Koblan et al.[14] and Adler et al.[11] evaluated the efficacy of dasotraline in adults with ADHD. Koblan et al. reported a significant improvement in a dose of 8 mg/day, whereas Adler et al. concluded that a 6 mg dose showed significant improvement in the ADHD symptoms and clinical global impression compared to placebo. Both studies found the drug well tolerated and did not find significant improvement with a 4 mg dose. Findling et al.[13] and Wigal et al.[12] investigated the efficacy of dasotraline in children aged 6–12 years and concluded that dasotraline at 4 mg daily could be an effective treatment option for reducing ADHD symptoms in children compared to placebo, with a few adverse effects. However, the result regarding the efficacy of dasotraline 2 mg daily in children is conflicting as Findling et al.[13] did not find any significant benefit, but Wigal et al.[10] reported significant improvement. The present meta-analysis with sub-group analysis and meta-regression can address these issues and may help in determining the optimum dose for children and adults.
Effects of intervention on efficacy parameters
To assess the efficacy of dasotraline in ADHD, the effect sizes of different outcome measures from included studies were analyzed in Cochrane Program Review Manager (version 5.4)[22] using a random-effects model. All five studies reported outcomes of total ADHD symptom score, hyperactivity/impulsivity score, inattentiveness score, incidence of insomnia, and a decrease in appetite. The total sample size for efficacy assessment of these studies was 1498, and for safety assessment, it was 1523. A change in CGI-S score was reported in a total of 1291 patients by Findling et al.,[13] Koblan et al.,[14] and Adler et al.[11] All the RCs were conducted in USA.
Total/combined ADHD symptom score
Out of the five included studies, three studies[11,13,14] used ADHD RS-IV, and the other two studies[10,12] used SCAMP-CS for assessment of change in ADHD symptoms. The test for heterogeneity among the included studies was significant (Chi² =22.39; P = 0.002; I² =69%; n = 1498). Random effect model analysis of their results evaluated a pooled SMD of -0.35 (95% CI: -0.55 to -0.15; P < 0.001), favoring the dasotraline group. A sub-group analysis was done to evaluate the effect of dasotraline in children and adults individually. In children, the effect size was SMD of -0.53 (95% CI: -0.93 to -0.13; P = 0.009) with a significantly high heterogeneity (Chi² =14.60; P = 0.002; I² =79%; n = 543). In adults, the effect size was SMD of -0.19 (95% CI: -0.33 to -0.06; P = 0.005) with a non-significant heterogeneity (Chi² =1.7; P = 0.64; I² =0%; n = 955). [Figure 2a] To investigate high heterogeneity in the pediatric sub-group, sensitivity analysis was performed, and heterogeneity was found to reduce significantly (Chi² =0.41; P = 0.520; I2 = 0%; n = 207) by removing the study by Findling et al.,[13] without any significant change in the outcome result [Figure 2b]. The prediction interval (PI) was found to be -0.91 to 0.23.
Figure 2.
The forest plot for included studies pooled together using random effects model for assessing difference in ADHD total symptom score. Included studies are identified by first author and year. The boxes are proportional to the weight of each study in the analysis, and the lines represent their 95% CIs. The diamond represents the pooled effect size, and its width represents its 95% CI. The subgroup analysis has been done to show the changes in pediatric and adult age group (a). Sensitivity analysis has been done by removing the data of the study by Findling et al. (b)
Hyperactivity/impulsivity sub-scale score
The hyperactivity sub-scale score was evaluated for all studies as a secondary outcome measure. The test for heterogeneity among the included studies was significant (Chi² =15.57; P = 0.030; I² =55%; n = 1498). Random effect model analysis of their results evaluated a pooled SMD of -0.27 (95% CI: -0.44 to -0.11; P = 0.001), favoring the dasotraline group. A sub-group analysis was done to evaluate the effect of dasotraline in children and adults individually. In children, the effect size was SMD of -0.43 (95% CI: -0.71 to -0.14; P = 0.003) with a significant heterogeneity (Chi² =7.65; P = 0.050; I² =61%; n = 543). In adults, the effect size was SMD of -0.14 (95% CI: -0.27 to -0.00; P = 0.050) with a non-significant heterogeneity (Chi² =2.49; P = 0.48; I² =0%; n = 955) [Figure 3a]. To investigate high heterogeneity in the pediatric sub-group, sensitivity analysis was performed, and heterogeneity was found to reduce significantly (P = 0.980; I2 = 0%; n = 207) by removing the study by Findling et al.[13] without any significant change in the outcome result [Figure 3b].
Figure 3.
The forest plot for included studies pooled together using random effects model for assessing difference in hyperactivity/impulsivity subscale score. Included studies are identified by first author and year. The boxes are proportional to the weight of each study in the analysis, and the lines represent their 95% CIs. The diamond represents the pooled effect size, and its width represents its 95% CI. The subgroup analysis has been done to show the changes in pediatric and adult age group (a). Sensitivity analysis has been done by removing the data of the study by Findling et al. (b)
Inattentiveness sub-scale score
The inattentiveness subscale score was evaluated for all studies as a secondary outcome measure. The test for heterogeneity among the included studies was significant (Chi² =22.32; P = 0.002; I² =69%; n = 1498). Random effect model analysis of their results evaluated a pooled SMD of -0.33 (95% CI: -0.53 to -0.14; P < 0.001), favoring the dasotraline group. A sub-group analysis was done to evaluate the effect of dasotraline in children and adults individually. In children, the effect size was SMD of -0.49 (95% CI: -0.92 to -0.07; P < 0.001) with significantly high heterogeneity (Chi² =16.97; P < 0.001; I² =82%; n = 543). In adults, the effect size was SMD of -0.20 (95% CI: -0.33 to -0.07; P = 0.004) with a non-significant heterogeneity (Chi² =1.34; P = 0.72; I² =0%; n = 955) [Figure S1 (2.4MB, tif) [a]]. To investigate high heterogeneity in the pediatric sub-group, sensitivity analysis was performed, and heterogeneity became non-significant (P = 0.05; I2 = 74%; n = 207) by removing the study by Findling et al.[13] without any significant change in the outcome result. [Figure S1 (2.4MB, tif) [b]]
Clinical Global Impression-Severity scale (CGI-S)
Three[11,13,14] out of five included studies compared CGI-S between the treatment arms. The test for heterogeneity among the included studies was non-significant (Chi² =7.21; P = 0.21; I² =31%; n = 1291). Random effect model analysis of their results evaluated a pooled SMD of -0.25 (95% CI: -0.41 to -0.09; P = 0.002), favoring the dasotraline group. A sub-group analysis was done to evaluate the effect of dasotraline in children and adults individually. In children, the effect size was SMD of -0.15 (95% CI: -0.64 to 0.34; P = 0.550) with a significantly high heterogeneity (Chi² =4.17; P = 0.04; I² =76%; n = 336). In adults, the effect size was SMD of -0.30 (95% CI: -0.46 to -0.14; P < 0.001) with a non-significant heterogeneity (Chi² =2.00; P = 0.57; I² =0%; n = 955) [Figure S2 (1MB, tif) ].
Safety assessment
The treatment-emergent adverse events reported in the included studies are insomnia, decreased appetite, headache, dry mouth, tachycardia, nausea, irritability, decreased weight, anxiety, dizziness, and so on. In this meta-analysis, quantitative dose-dependent analysis has been done for the two most common adverse events, that is, insomnia and decreased appetite.
Incidence of insomnia
All included studies reported insomnia as a common adverse event, and the test for heterogeneity among the included studies was non-significant (Chi² =2.29; P = 0.940; I² =0%; n = 1523). Random effect model analysis of their results evaluated a pooled OR of 4.42 (95% CI: 3.17 to 6.16; P < 0.001), suggesting a higher incidence of insomnia in the dasotraline group compared to placebo. As different studies used different fixed-dose dasotraline, a sub-group analysis was done depending on the dose used. The OR in 2 mg, 4 mg, 6 mg, and 8 mg sub-groups were 3.55 (95% CI: 1.18 to 10.71), 4.95 (95% CI: 2.99 to 8.19), 4.13 (95% CI: 2.27 to 7.51), and 4.19 (95% CI: 1.87 to 9.38), respectively [Figure S3 (1.8MB, tif) ].
Incidence of decreased appetite
All included studies reported decreased appetite as a common adverse event, and the test for heterogeneity among the included studies was non-significant (Chi² =2.04; P = 0.96; I² =0%; n = 1523). Random effect model analysis of their results evaluated a pooled OR of 4.33 (95% CI: 2.74 to 6.86; P < 0.001), suggesting a higher incidence of decreased appetite in the dasotraline group compared to placebo. As different studies used different fixed-dose dasotraline, a sub-group analysis was done depending on the dose used. The OR in 2 mg, 4 mg, 6 mg, and 8 mg sub-groups were 2.94 (95% CI: 0.90 to 9.66), 3.92 (95% CI: 2.02 to 7.60), 5.23 (95% CI: 2.16 to 12.67), and 7.70 (95% CI: 1.75 to 33.85), respectively, suggesting dose dependence [Figure S4 (1.8MB, tif) ].
Optimal dose determination
The included studies were conducted on children who were prescribed doses of 2 mg and 4 mg of dasotraline. The effect of these two doses on ADHD symptoms in children was assessed, and it was found that the effect of 2 mg was not significant (SMD: -0.48; 95% CI: -1.39 to 0.43; P = 0.300), whereas 4 mg was significant (SMD: -0.58; 95% CI: -0.91 to -0.26; P < 0.001). Considering the fact that the 6 mg dose was discontinued in the study by Wigal et al.[12] due to adverse events, dasotraline 4 mg may be considered optimal for children aged 6–12 years. Similarly, in the studies on the adult population, the doses of 4 mg, 6 mg, and 8 mg were used, and it was found that the effect of 4 mg was not significant (SMD: -0.13; 95% CI: -0.32 to 0.05; P = 0.470), whereas 6 mg and 8 mg were significant. However, considering the higher incidence of adverse events with 8 mg, 6 mg dose of dasotraline may be considered optimal for adults [Figures S5 (1.1MB, tif) and S6 (1.1MB, tif) ].
Meta-regression
Meta-regression showed a statistically non-significant association between the SMD of ADHD symptom score reduction and the dose of dasotraline [slope coefficient (β) = -0.01; P = 0.97] [Figure S7 (1.6MB, tif) ]. However, the result showed a statistically significant association between SMD of ADHD symptom score reduction and the duration of dasotraline therapy [slope coefficient (β) = 0.73, P < 0.001] [Figure S8 (1.4MB, tif) ].
Publication bias in included studies
The funnel plot generated was found to be visually asymmetric. Hence, it was also analyzed quantitatively using the Begg and Mazumdar rank correlation test, which showed significant bias (Kendall's tau value of -0.75 with a 2-tailed P value of 0.005). Hence, to adjust funnel plot asymmetry, the trim-and-fill analysis, which simulated the present studies and filled in two more imputed data points, was performed. The adjusted effect size after correcting for asymmetry was -0.20 [95% CI: -0.30 to -0.11; PI: -0.88, 0.47] [Figure S9 (1.8MB, tif) ].
Certainty of evidence
The summary of the effect estimates and GRADE ratings is presented in Table 2. The certainty of the evidence was found to be moderate for the total ADHD symptom score, hyperactivity sub-scale score, and inattentiveness sub-scale score, suggesting that we are moderately confident in the effect estimate and the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. For CGI-S and treatment-emergent adverse events (insomnia and decreased appetite), the certainty of the evidence was found to be high, suggesting that we are very confident that the true effect lies close to that of the estimate of the effect.
Table 2.
Summary of findings
| Outcomes | No of participants (studies/unit) | Relative effect (95% CI) | Anticipated absolute effects | Certainty of the evidence (GRADE) | |
|---|---|---|---|---|---|
|
| |||||
| Risk with Placebo | Risk difference with Dasotraline | ||||
| ADHD total/combined symptom score | 1498 (5 RCTs/8 units) | SMD 0.35 lower (0.55 lower-0.15 lower) | ⨁⨁⨁○ Moderate | ||
| Hyperactivity/Impulsivity subscale score | 1498 (5 RCTs/8 units) | SMD 0.27 lower (0.44 lower-0.11 lower) | ⨁⨁⨁○ Moderate | ||
| Inattentiveness subscale score | 1498 (5 RCTs/8 units) | SMD 0.33 lower (0.53 lower-0.14 lower) | ⨁⨁⨁○ Moderate | ||
| CGI-S | 1291 (3 RCTs/6 units) | SMD 0.25 lower (0.42 lower-0.08 lower) | ⨁⨁⨁⨁ High | ||
| Incidence of insomnia (TEAE) | 1523 (5 RCTs/8 units) | OR 4.42 (3.17-6.16) | 89 per 1,000 | 213 more per 1,000 (148 more-287 more) | ⨁⨁⨁⨁ High |
| Incidence of decreased appetite (TEAE) | 1523 (5 RCTs/8 units) | OR 4.33 (2.74-6.86) | 40 per 1,000 | 113 more per 1,000 (62 more-182 more) | ⨁⨁⨁⨁ High |
CI: confidence interval; OR: odds ratio; SMD: standardized mean difference; ADHD, Attention-Deficit Hyperactivity Disorder; CGI-S, Clinical Global Impression-Severity scale; TEAE, Treatment Emergent Adverse Event. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect; Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
DISCUSSION
The present meta-analysis evaluated the efficacy and safety of dasotraline in the treatment of ADHD. The analysis revealed that dasotraline could reduce symptoms of ADHD significantly in children and adults. Not only was the total symptom score reduced but also significant improvement was found in the individual domains of hyperactivity/impulsivity and inattentiveness. Similarly, the clinical global impression (severity) scale showed significant change with the treatment with dasotraline. The treatment-emergent adverse events are a major concern of dasotraline, and previous studies reported insomnia, decreased appetite, headache, dry mouth, tachycardia, nausea, irritability, decreased weight, anxiety, and dizziness as common adverse effects. All included studies in this meta-analysis have reported an incidence of >10% for insomnia and decreased appetite. Three of the five studies included in this meta-analysis were at low overall risk of bias, whereas two had some concerns about missing outcome data. A selective publication of the results was evident from the significance of the publication bias measurement; however, it was taken care of using trim and fill analysis, with not much difference in the pooled estimate.
Among the presently approved medications, stimulant drugs exhibit larger effect sizes in comparison to non-stimulant agents; however, it is reported that one-third of patients treated with stimulants are found to be partial responders or non-compliant due to safety issues.[26,27] Based on the present viewpoint that ADHD is a life-long disorder, especially with high co-morbidity in adults, the development of a treatment with long-term effectiveness and safety profile is a priority.[8] In this context, clinical trials have been conducted in children[10,12,13] and adults[11,14] to explore the efficacy and safety of dasotraline. In a placebo-controlled trial, Findling et al.[13] found that dasotraline 4 mg/day significantly improved ADHD symptoms and behavior, whereas Wigal et al. conducted two trials with 2 mg/day[10] and 4 mg/day[12] dasotraline and reported its efficacy and tolerability. In the adult age group, the studies by Koblan et al.[14] and Adler et al.[11] found that the change in ADHD symptoms with 4 mg/day dasotraline was non-significant, but 6 mg/day and 8 mg/day were efficacious. The major concern with the use of 8 mg/day in the study by Koblan et al.[14] was the treatment-emergent adverse events that contributed to discontinuation of therapy in 28% of patients. This meta-analysis pooled the effects from all studies and also reported the result of sub-group analysis for children and adults.
Dasotraline, being a predominant inhibitor of presynaptic dopamine and norepinephrine transporters, does not trigger dopamine release like stimulants. The pharmacokinetic profile is similar in both children and adults, showing a slow absorption and long elimination half-life, leading to a stable plasma concentration over 24 hours with once-daily dosing. Hence, dasotraline does not exhibit marked peak and trough effects like stimulant drugs. The favorable pharmacodynamic and pharmacokinetic profiles make dasotraline a suitable and promising candidate for ADHD with lower abuse potential and 24-hour sustained coverage with once-daily dosing. Considering the efficacy and adverse effects, a daily dose of 4 mg and 6 mg may be optimal for children (6–12 years) and adults, respectively.
The major limitation of the present meta-analysis is the small number of available RCTs to analyze. Second, because of the fewer RCTs, we have kept our inclusion criteria broad and included studies on both children and adults. Moreover, the dose and duration of dasotraline used in the studies were different. These differences have led to higher heterogeneity among the included studies. To address this limitation, we have done sub-group analysis and meta-regression. Third, we could not find any clinical trial where dasotraline was compared with standard of care like methylphenidate. All the trials have been conducted with a placebo as a comparator. Fourth, while ADHD is a behavioral disorder that affects children globally, all the RCTs conducted on ADHD and included in the present meta-analysis are from USA. Hence, a global response pattern could not be obtained, and generalizability to other ethnicities cannot be made. Fifth, no form of gray literature and conference abstracts were included in the present meta-analysis. Finally, though the trim-and-fill method was used to correct the asymmetry of publication bias, heterogeneity between the studies may affect the results of the trim-and-fill analysis.
In conclusion, dasotraline can reduce the core symptoms of ADHD, that is, hyperactivity/impulsivity and inattentiveness, leading to an overall improvement of ADHD compared to placebo. Dasotraline can also improve clinician-determined patients’ global functioning compared to the placebo. The most common adverse drug reactions related to dasotraline were insomnia and decreased appetite. However, to fill the knowledge gap, multicentric randomized active-controlled clinical trials are warranted in this domain for a successful translation into clinical practice.
Ethics statement
The protocol of the meta-analysis was exempted from the full review and approved by the Institutional Ethics Committee, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, as per ICMR National ethical guidelines (2017) for biomedical and health research.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
[A] The forest plot for included studies pooled together using random effects model for assessing difference in Inattentiveness subscale score. The subgroup analysis has shown the changes in paediatric and adult age group. [B] Sensitivity analysis has been done by removing the data of the study by Findling et al.
The forest plot for included studies pooled together using random effects model for assessing difference in Clinical global impression – severity score. The subgroup analysis has shown the changes in paediatric and adult age group.
The forest plot for included studies pooled together using random effects model for assessing adverse effect of insomnia. The subgroup analysis shows the insomnia according to dose-groups.
The forest plot for included studies pooled together using random effects model for assessing adverse effect of decrease in appetite. The subgroup analysis shows the insomnia according to dose-groups.
The forest plot using random effects model for assessing the effect of Dasotraline 2 mg in paediatric and 4 mg in adult age group on the difference in ADHD total symptom score between the study groups.
The forest plot using random effects model for assessing the effect of Dasotraline 4 mg in paediatric and 6/8 mg in adult age group on the difference in ADHD total symptom score between the study groups.
Bubble plot. The effect of dose of Dasotraline on SMD in ADHD total symptom score. The studies are depicted by circles along the line of meta-regression. SMD, Standardized Mean Difference.
Bubble plot. The effect of duration of Dasotraline treatment on SMD in ADHD total symptom score. The studies are depicted by circles along the line of metaregression. SMD, Standardized Mean Difference.
Funnel plot (after trim and fill analysis) for the publication bias of the included studies. The effect size denotes difference in ADHD total symptom score. CES, Combined Effect Size.
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Associated Data
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Supplementary Materials
[A] The forest plot for included studies pooled together using random effects model for assessing difference in Inattentiveness subscale score. The subgroup analysis has shown the changes in paediatric and adult age group. [B] Sensitivity analysis has been done by removing the data of the study by Findling et al.
The forest plot for included studies pooled together using random effects model for assessing difference in Clinical global impression – severity score. The subgroup analysis has shown the changes in paediatric and adult age group.
The forest plot for included studies pooled together using random effects model for assessing adverse effect of insomnia. The subgroup analysis shows the insomnia according to dose-groups.
The forest plot for included studies pooled together using random effects model for assessing adverse effect of decrease in appetite. The subgroup analysis shows the insomnia according to dose-groups.
The forest plot using random effects model for assessing the effect of Dasotraline 2 mg in paediatric and 4 mg in adult age group on the difference in ADHD total symptom score between the study groups.
The forest plot using random effects model for assessing the effect of Dasotraline 4 mg in paediatric and 6/8 mg in adult age group on the difference in ADHD total symptom score between the study groups.
Bubble plot. The effect of dose of Dasotraline on SMD in ADHD total symptom score. The studies are depicted by circles along the line of meta-regression. SMD, Standardized Mean Difference.
Bubble plot. The effect of duration of Dasotraline treatment on SMD in ADHD total symptom score. The studies are depicted by circles along the line of metaregression. SMD, Standardized Mean Difference.
Funnel plot (after trim and fill analysis) for the publication bias of the included studies. The effect size denotes difference in ADHD total symptom score. CES, Combined Effect Size.