Effect of Continuing and Discontinuing Medications on Quality of Life After Symptomatic Remission in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis

ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate levels of inattention, hyperactivity, and/or impulsivity.1 The prevalence rate of this disorder in most cultures is 5%-8% in children and adolescents1-3 and 2%-5% in adults.4,5 It causes persistent functional impairments6 in areas such as interpersonal relationships, educational and occupational attainments,7 and risk awareness, which is closely associated with mortality risk.8 Patients with ADHD can present profound functional impairments that reduce their overall quality of life across the lifespan.9-14

Current clinical guidelines recommend pharmacologic interventions for patients with severe ADHD.7,15-18 Recommended medications for patients with ADHD include psychostimulants (eg, methylphenidate and amphetamines) and nonstimulants (eg, atomoxetine and α agonists). Current literature shows that these medications have short-term efficacy and limited safety for improving ADHD symptoms in pediatric, adolescent, and adult individuals.19-21 Over the past two decades, the prescription rates of ADHD medications have dramatically increased on a global scale.22-24

However, the long-term safety and efficacy of ADHD medications remain controversial.15,19-21,25 Some patients with ADHD receiving medications experience adverse medication effects that have a negative impact on their quality of life, especially children and adolescents with ADHD.14,26 Because of concerns regarding the long-term risks and benefits of ADHD medications, several clinical guidelines recommend at least an annual review of the treatment regimen7,17 or drug holidays (an agreed cessation of medication for a period of time)7,16,17 to ascertain the need for continuing these medications. Conversely, some studies27-29 have shown that discontinuing medications poses an obvious risk of the exacerbation of ADHD symptoms. These inconsistencies among findings raise questions regarding whether clinicians should terminate treatment for patients with ADHD who have responded to their medication treatments and, if so, when termination should be implemented.

Previous systematic reviews and meta-analyses7,30,31 on withdrawal trials for ADHD medications showed a clinically important exacerbation of ADHD symptoms with withdrawal. Previously published reviews, which included randomized controlled trials as well as open-label or single-blind trials,7,30 have focused on individual ADHD medications7 or evaluated the relapse of ADHD symptoms as defined by changes in the severity of those symptoms.7,30,31 The assessments of symptoms are dependent on responses to medication in the short term. However, once the medication has stabilized, other relevant domains for assessing treatment response are needed, especially for evaluating long-term outcomes.13,14 Recently, quality of life has been suggested as an important component in the comprehensive assessment for ADHD.9,14,32

Quality of life is defined as “the individuals’ perception of their position in life, in the context of culture and value systems in which they live, and in relation to their goals, expectations, standards and concerns.”33 Available evidence has emphasized that ADHD leads to a reduced quality of life in patients in terms of their subjective sense of well-being and their capacity for everyday functioning.12,14,34 The concept of quality of life can be applied in clinical practice as well as clinical trials,32 particularly for an outcome measure of pharmacologic interventions in patients with ADHD.12 Because improvement in symptoms has been found to correlate moderately, but not perfectly, with improvement in quality of life, quality of life is considered as a construct that relates to, but is distinct from, ADHD symptoms.14 Furthermore, a comprehensive assessment of the positive and negative effects of ADHD treatments is required when clinicians consider whether ADHD medication should be continued or discontinued.7 This comprehensive assessment includes a much broader range of outcome measures; ie, quality of life assessment should be incorporated into routine clinical practice rather than simply core ADHD symptoms.35 Recently, the National Institute for Health and Care Excellence committee7 has considered that quality of life is one of the critical outcomes for evaluating the potential effects of discontinuing pharmacologic treatment for ADHD. Thus, changes in quality of life could be an important outcome indicator in decisions regarding continuation or discontinuation of medications for individuals with ADHD, beyond changes in ADHD symptoms.

In this systematic review and meta-analysis focusing on randomized, double-blind, placebo-controlled withdrawal trials of ADHD medications, we investigated whether, compared with continuing ADHD medications, discontinuing them was more detrimental to quality of life among patients with ADHD who had responded to their medication treatments. In contrast to previous systematic reviews and meta-analyses, the present study evaluated quality of life and included only enrichment-design studies, wherein participants responded to ADHD medication before entering withdrawal trials. The present study aimed to identify the effect of discontinuing medications after symptomatic remission on quality of life of patients with ADHD. We intended to provide further information regarding whether to discontinue ADHD medications in these patients.

• Limited evidence regarding the long-term efficacy and safety of pharmacologic interventions in patients with attention-deficit/hyperactivity disorder (ADHD) raises questions regarding whether, compared with continuing ADHD medications, discontinuing them is more detrimental to quality of life among patients with the disorder.
• Discontinuing medications was found to be associated with a small but significant decrease in quality of life among children and adolescents with ADHD but not in adults with ADHD.
• In patients with ADHD who have responded to medication treatments, quality of life is an important factor for planning medication treatment for the disorder.

METHODS

We conducted this systematic review and meta-analysis in accordance with the reporting guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).36

Search Strategy and Eligibility Criteria

PubMed, Cochrane Library, and Embase databases were searched within the time frame beginning with the date of database inception to September 21, 2018, with no language restrictions. We used the following search terms: (1) participant terms, eg, ADHD; (2) ADHD medication terms, eg, methylphenidate; (3) intervention terms, eg, withdr*, discontinue*, stop*, and withhold*; (4) comparison terms, eg, continu* and maintenance*; and (5) study design terms, eg, randomized, double-blind, and placebo. A medical librarian was involved in formulating the search string (details shown in Supplementary Tables 1-3). Several additional eligible studies were identified by examining the reference lists for previously identified systematic reviews and guidelines.7,30,31 Pharmaceutical companies and experts in the field were also contacted to identify possible reviews for inclusion in the study.

We included only randomized, double-blind, placebo-controlled withdrawal trials of medications for patients with ADHD. We included double-blind, randomized controlled trials with a study duration of at least 1 week that enrolled children and adolescents (aged 5-17 years) or adults (aged ≥ 18 years) with a primary diagnosis of ADHD according to DSM-III, DSM III-R, DSM-IV-TR, DSM-5, ICD-9, or ICD-10. We included studies that examined the discontinuation of the following medications, which comprise drugs approved for ADHD in at least one country, as oral monotherapies: amphetamines (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, and methylphenidate (including dexmethylphenidate).

Studies in which all participants failed to respond to ADHD medications before random assignment to treatment groups (according to the definition provided in the study) were excluded from this meta-analysis.

Two independent authors screened the titles and abstracts of the retrieved references. The full texts of all potentially eligible studies were evaluated. Potentially eligible studies were then retrieved and independently verified for eligibility by the aforementioned authors. Disagreements regarding the eligibility of studies were resolved by discussion between the authors.

Outcomes

The primary outcome was a decrease in quality of life (negative change in the total quality of life score) expressed as standardized mean difference (SMD). If available, we used the intention-to-treat data and adopted the study authors’ methods to account for missing data (eg, last observation carried forward). Secondary outcomes included the relapse rate (the proportion of participants who experienced relapse according to study authors’ definition).

Data Extraction and Risk of Bias Assessment

Data extraction and study ratings were independently conducted by the authors using a standardized form (Excel, Microsoft; Redmond, Washington). Any discrepancy between the authors was resolved by reaching a consensus. The following variables were extracted from each study: first author, publication year, participant details (number of participants, mean age, age range, and sex distribution [% male]), type of ADHD medication, duration of initial phase, duration of trial, the quality of life scores (mean and SD), relapse rate, and study key findings.

We assessed the methodological quality of the trials using the risk of bias criteria from the Cochrane Handbook for Systematic Reviews of Interventions.37

Statistical Analysis

Owing to an anticipated heterogeneity, a random-effects meta-analysis model was applied using the Review Manager software (2014; Copenhagen, Denmark; RevMan. Review Manager Version 5.3). For continuous data, SMDs and 95% CIs were calculated as the effect sizes (ESs). ESs were presented as a mean ES obtained by combining ESs related to different quality of life measures mentioned in Table 1 (Adult Attention-Deficit/Hyperactivity Disorder Quality of Life [AAQoL], Child Health Questionnaire [CHQ], Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form [Q-LES-Q], and Weiss Functional Impairment Rating Scale-Parent report [WFIRS-P]). Because quality of life measures related to different quality of life domains (ie, global domain score for WFIRS-P, overall score for Q-LES-Q, psychosocial summary score for CHQ, and total score for AAQoL), mean ESs were calculated for each study as an overall quality of life outcome.

For binary data, risk ratio (RR) and 95% CIs and number needed to harm (NNH) were calculated. Definitions of relapse varied among the studies included in this study (Table 1); we calculated RRs, 95% CIs, and NNHs as the proportion of participants who experienced relapse according to study authors’ definition. The heterogeneity of effects was examined using the I2 statistic.37

To investigate the potential sources of heterogeneity and confounding effects, we conducted subgroup meta-analyses. Specifically, we classified the enrolled studies according to age distribution (children and adolescents aged 5-17 years or adults aged ≥ 18 years) and the type of ADHD medications (stimulants and nonstimulants).

Potential publication bias was examined using funnel plots for each outcome including more than 10 studies, which is the minimum number required to use the funnel plot.37 A P value of ≤ .05 was considered statistically significant.

RESULTS

The literature search yielded 4,571 articles; after eliminating duplicates, 3,672 articles were retrieved. Of them, 3,642 articles were excluded on the basis of title or abstract because they focused on constructs not related to the aims of the present study. Of the 30 articles that were inspected for their full texts, 9 met our predefined inclusion criteria on patients with ADHD38-46 (Figure 1): 5 studies measured quality of life,39,41,42,45,46 and all 9 studies measured relapse.38-46 Of the 9 studies, 5 focused on children and adolescents,38-42 whereas 4 focused on adults.43-46 Five studies included in this meta-analysis used stimulants (ie, dexmethylphenidate, lisdexamfetamine, and osmotic release oral system methylphenidate),38,40,43-45 whereas the other 4 studies used nonstimulants (atomoxetine and guanfacine).39,41,42,46 In total, 1,126 children and adolescents aged 6-17 years (boys, n = 937; girls, n = 189) and 708 adults aged 18-65 years (men, n = 374; women, n = 311; data were not available for 23 adults) were included (Table 1). The duration of initial phase ranged from 3 to 52 weeks, and the duration of randomized withdrawal phase ranged from 2 to 36 weeks. The results of the risk of bias assessment for each study are provided in Supplementary Figure 1.

Primary Outcome

Of the 9 studies that met our predefined inclusion criteria, 5 studies reporting on 1,463 patients with ADHD (boys/men, n = 1,077; girls/women, n = 386) measured quality of life and were included in our primary outcome meta-analysis.39,41,42,45,46 Of these 5 studies measuring quality of life, 2 used the CHQ,39,41 1 used the WFIRS-P,42 1 used the AAQoL,46 and 1 used the Q-LES-Q.45 Quality of life measures used in this meta-analysis were only observer-rated measures (CHQ and WFIRS-P) in children and adolescents with ADHD and only self-reported measures (AAQoL and Q-LES-Q) in adults with ADHD. Four studies reporting on 371 patients with ADHD (boys/men, n = 260; girls/women, n = 88; data were not available for 23 adults) did not measure quality of life and were not included in our primary outcome meta-analysis.38,40,43,44 Two of these 4 studies focused on children and adolescents,38,40 and 2 studies focused on adults.43,44 All of these 4 studies that did not measure quality of life used stimulants (ie, dexmethylphenidate, lisdexamfetamine, and osmotic release oral system methylphenidate).38,40,43,44

We divided these 5 studies, measuring quality of life, into the following subgroups: studies including children and adolescents (3 studies; N = 894; boys, n = 753 and girls, n = 141)39,41,42; studies including adults (2 studies; N = 569; men, n = 324 and women, n = 245)45,46; studies using stimulants (1 study; N = 45; men, n = 18 and women, n = 27)45; and studies using nonstimulants (4 studies; N = 1,418; boys/men, n = 1,059 and girls/women, n = 359).39,41,42,46 Two of the 3 studies in the children and adolescents subgroup used the CHQ,39,41 and the remaining study used the WFIRS-P.42 The 2 studies in the adults subgroup used the AAQoL46 and the Q-LES-Q.45 The one study in the stimulants subgroup used the Q-LES-Q45; of the 4 studies in the nonstimulants subgroup, 2 used the CHQ39,41 and 1 each used the WFIRS-P42 and AAQoL.46

Decreases in quality of life were higher among individuals discontinuing ADHD medications compared with those continuing ADHD medications (SMD = 0.19; 95% CI, 0.08 to 0.30) (Figure 2A).39,41,42,45,46 In the subgroup analysis restricted to children and adolescents with ADHD,39,41,42 decreases in quality of life were higher among patients discontinuing ADHD medications compared with those maintaining these medications (SMD = 0.21; 95% CI, 0.06 to 0.36) (Figure 2B). In the subgroup analysis restricted to adults with ADHD,45,46 no significant difference was observed (SMD = 0.02; 95% CI, −0.46 to 0.50) (Figure 2C).

In the subgroup analysis restricted to nonstimulants,39,41,42,46 decreases in quality of life were higher among patients discontinuing medications compared with those continuing them (SMD = 0.21; 95% CI, 0.10 to 0.32) (Figure 2D). A subgroup analysis restricted to stimulants was not conducted because only 1 study investigated changes in quality of life using stimulants.45

I2 values were low (0%) throughout the analyses, except for the analysis focusing on adults with ADHD (63%).

Secondary Outcome

Nine studies reported relapse rates (N = 1,834; boys/men, n = 1,311; girls/women, n = 500; data were not available for 23 adults).38-46 We divided these 9 studies into the following subgroups: studies including children and adolescents (5 studies, N = 1,126; boys, n = 937; girls, n = 189)38-42; studies including adults (4 studies, N = 708; men, n = 374; women, n = 311; data were not available for 23 adults)43-46; studies using stimulants (5 studies, N = 416; boys/men, n = 252; girls/women, n = 141; data were not available for 23 adults)38,40,43-45; and studies using nonstimulants (4 studies, N = 1,418; boys/men, n = 1,059; girls/women, n = 359).39,41,42,46

In our analyses of the secondary outcome relapse, a statistically significant RR of 2.85 was observed (95% CI, 1.78 to 4.56) among patients with ADHD (Figure 3A).38-46 NNH for the relapse of ADHD symptoms was 4 among all patients. I2 value was high at 82%.

A subgroup analysis confirmed the results of the secondary outcome analyses regarding relapse, with statistically significant RRs of 2.41 (95% CI, 1.44 to 4.04) for children and adolescents (5 studies, Figure 3B),38-42 3.70 (95% CI, 1.28 to 8.69) for adults (4 studies, Figure 3C),43-46 3.87 (95% CI, 2.26 to 6.62) for stimulants (5 studies, Figure 3D),38,40,43-45 and 1.77 (95% CI, 1.20 to 2.62) for nonstimulants (4 studies, Figure 3E).39,41,42,46

For these subgroup analyses, I2 values were consistently high at 51%-84%.

DISCUSSION

In this systematic review, we investigated and performed meta-analyses of randomized, double-blind, placebo-controlled withdrawal trials for ADHD medications. We also explored whether discontinuing any ADHD medication was associated with decreased quality of life compared with continuing this medication in patients with ADHD who had responded to medication treatments. Because previous systematic reviews and meta-analyses typically evaluated the relapse of ADHD symptoms, this meta-analysis is the first focusing on the effect of discontinuing medication on quality of life after symptomatic remission in patients with ADHD.

We reported that discontinuing any ADHD medication was associated with a small but statistically significant risk of reduced quality of life in patients with ADHD. Our main finding was partly supported by previous findings that showed little advantage of discontinuing medications in patients with ADHD.7,30,31 The results of subgroup analyses also favored our preliminary finding. Despite small ESs, our results are clinically significant for patients with ADHD who experience a considerable decrease in quality of life after discontinuing medications. After discontinuing medications, regularly assessing quality of life may support decisions regarding whether treatment should be resumed for patients with ADHD.

However, with small ESs, the impact of such discontinuation on quality of life may be not considered clinically relevant for most patients with ADHD. One possible explanation for changes in quality of life observed after discontinuing medications is that medications help patients with ADHD develop better coping abilities against stressful situations. Once their symptoms have stabilized, patients could partly maintain these coping skills even after discontinuing medications. These improved and maintained coping skills might impact the quality of life in some individuals with ADHD because coping helps in maintaining stability in quality of life.47 Our hypothesis is supported by a study48 that demonstrated continued effects of medication after its discontinuation on quality of life even when ADHD symptoms worsened. Banaschewski et al48 hypothesized that residual benefits associated with medications extend beyond the point of discontinuing treatment or that underlying deficits in quality of life attenuate over the course of treatment. Although quality of life is related to individuals’ appraisal of their situation, it can allow clinicians to better integrate the patients’ perspective into their clinical management, including adherence to pharmacologic treatments.32 Thus, quality of life can be considered in pharmacologic interventions to direct continuing and discontinuing medication.

In adults with ADHD, the effect of discontinuing medications on quality of life was nonsignificant. Differences in environmental demands or stress between children/adolescents and adults as well as better coping abilities in response to environmental demands among adults with ADHD7 may explain this result. Another explanation for the null effect found for adults is that adults are more likely to compensate for symptom return after discontinuing ADHD medications by increasing substance use (eg, cigarettes/nicotine, marijuana) to self-treat ADHD symptoms.49,50 Because no studies included in our meta-analysis investigated the occurrences of substance use after discontinuing ADHD medications, we cannot exclude this possibility. Further studies are needed to investigate the relationship between discontinuing medication and increased substance use. However, substantial statistical heterogeneity within our analysis restricted to adults with ADHD was considerable (I2 = 63%). This heterogeneity may be explained by the methodological differences across the studies included in our analysis. Further studies that control for confounding factors such as ADHD subtype or psychiatric comorbidities (eg, substance abuse) are needed to determine the association between discontinuing medication and quality of life in adults with ADHD.

Conversely, the duration of randomized withdrawal trials was relatively short in some studies, varying between 3 and 52 weeks for pre-randomization phase and between 2 and 36 weeks for randomized withdrawal phase. Although there is limited and inconsistent evidence regarding the long-term effects of medications on improving functional impairments or quality of life,30,51 it is possible that responses related to quality of life in patients with ADHD are affected by the duration of dose increase in pre-randomization phase or duration of randomized withdrawal phase. Furthermore, patients who clearly noticed a decrease in quality of life after discontinuing medications may have dropped out during study periods. These effects may have confounded our results. Of note, a number of patients with ADHD in the studies included in this meta-analysis continued to participate in the trials after discontinuing medications, while taking placebos (Table 1).

Finally, our analysis of the secondary outcome relapse showed a statistically significant RR of 2.85 in patients with ADHD. NNH for the relapse of ADHD symptoms was 4. All subgroup analyses supported the results of the secondary outcome analysis, with moderate RR ranging from 1.77 to 3.87. However, there were substantial heterogeneities among all the analyses. One possible explanation for these heterogeneities may be the numerous methodological differences in the definition of relapse among studies covered in this meta-analysis. Another possibility is that the assessments of symptoms are sensitive to medication responses in the short term rather than responses associated with discontinuing medications.13,14

Several limitations of our meta-analysis need to be considered. First, as data were meta-analyzed when outcomes were reported in at least 2 studies, we were unable to conduct a meta-analysis regarding quality of life among subgroups restricted to stimulants. Second, the present meta-analysis included only published studies while excluding unpublished studies or studies without adequate statistical information. If unpublished studies were more likely to contain null findings, their inclusion would have potentially reduced the effects seen here even further. In addition, we could not explore potential publication bias because our analysis included fewer than 10 studies, which is the minimum number required to use the funnel plot (funnel plots were shown in Supplementary Figure 2). This limitation warrants future research that includes unpublished data. Third, quality of life measures used in this meta-analysis were only observer-rated measures in children and adolescents with ADHD. This limits our findings for child-age samples because of the well-recognized positive illusory bias in children with ADHD, ie, they might have an overoptimistic view of their situation.12 Finally, the tools used to assess quality of life and symptom severity differed among the studies. This variation might relate to conflicting findings across studies included in this meta-analysis, especially with regard to our results on quality of life. Further research involving randomized withdrawal trials using ADHD-specific quality of life measures (eg, the AAQoL) or using measures of both quality of life and functional impairments are needed to further explore and confirm the utility of quality of life as an outcome of pharmacologic interventions for patients with ADHD. Moreover, research is needed to investigate the interactions and relationships among symptoms, functional impairments, and quality of life in patients with ADHD. If confirmed, these relationships and interactions may lead to an improved understanding of factors affecting quality of life in ADHD.

In summary, discontinuing ADHD medication was associated with a small but statistically significant risk of decreased quality of life in children and adolescents with ADHD. Although discontinuing ADHD medications may be dependent on patient responses,7 our results highlight the potential clinical utility of quality of life as a tool for determining this discontinuation compared with symptom rating scales. Regular assessments regarding the overall quality of life after discontinuing medication may assist in making decisions regarding continuing the withdrawal or resumption of medications for patients with ADHD. We believe that our results will help clinicians in considering the potential risks and benefits of discontinuing medications and optimizing individualized treatments for patients with ADHD.

Submitted: July 25, 2019; accepted December 18, 2019.

Published online: March 24, 2020.

Potential conflicts of interest: During the past 3 years, Dr Tsujii reports procuring personal fees from Janssen, Sumitomo Dainippon, Mitsubishi Tanabe, Yoshitomi, GlaxoSmithKline, Otsuka, Shionogi, and Takeda. Dr Okada reports procuring personal fees from Eli Lilly Japan, Teijin, Shionogi, Meiji Seika, Sawai, Janssen, Takeda, Yoshitomiyakuhin, Pfizer, Shire Japan, Mochida, Sumitomo Dainippon, and Astellas and also has received research grants from the Japan Society for the Promotion of Science; Japan Agency for Medical Research and Development; Japan Society for the Promotion of Science; Ministry of Health, Labour and Welfare; Ministry of Education, Culture, Sports, Science and Technology; and Otsuka. Dr Usami reports procuring personal fees from Janssen, Takeda, Shionogi, Otsuka, Takata, and Pfizer Japan not pertaining to the present study. Dr Kuwabara reports procuring personal fees from Meiji Seika and Otsuka. Dr Fujita reports procuring personal fees from Shionogi. Dr Negoro reports procuring personal fees from Janssen, Eli Lilly Japan, Shionogi, Shire, Otsuka, and Takeda. Dr Iida reports procuring personal fees from Janssen, Eli Lilly Japan, Shionogi, Shire Japan, Otsuka, Mochida, MSD KK, and Sumitomo Dainippon and has received grants from the Ministry of Education, Culture, Sports, Science and Technology; Ministry of Health, Labour and Welfare; and Agency for Medical Research and Development. Dr Saito reports procuring personal fees from Eli Lilly Japan, Janssen, Otsuka, Sumitomo Dainippon, Shionogi, and Takeda and has received grants from the Ministry of Health, Labour and Welfare; Japan Society for the Promotion of Science; and Health Economics and Policy. Ms Kawamura reports no conflicts of interest to declare.

Funding/support: This study was partly supported by research grants from the Ministry of Health, Labour and Welfare of Japan (H29-SEISHIN-ippan-001 and 19GC1012).

Role of the sponsor: The supporters had no role in the design, analysis, interpretation, or publication of this study.

Acknowledgments: The authors thank Mr Takanori Kikuchi, BACom, and Ms Yukari Kono, BA (Medical Sciences Group, Research Support Division, Hokkaido University Library), who assisted with the literature review. Mr Kikuchi and Ms Kono have no conflicts of interest to declare. We would like to thank Enago (https://www.enago.jp) for the English language review; the work done by Enago was not funded by an outside source.

Supplementary material: See accompanying pages.

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