Efficacy of Cognitive Behavioral Therapy and Methylphenidate in the Treatment of Attention Deficit Hyperactivity Disorder in Children and Adolescents: A Systematic Review

The treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents can be challenging and involve a combination of pharmacologic and non-pharmacological approaches. Using recent literature, we aim to identify the effectiveness of cognitive behavioral therapy (CBT) and methylphenidate (MPH) in reducing the symptoms and improving the quality of life. The investigators conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Investigators independently conducted a routine search on PubMed and Google Scholar for articles published within the last five years through July 30, 2022. Fourteen studies were identified as generally good quality but with some limitations. The final analysis included 2098 patients with an age range of three to eighteen. Nine studies reporting the efficacy of MPH in children, adolescents, or both had different formulations and doses. Six studies documenting the effectiveness of CBT had varying sessions, duration per therapy, modality of administration, and participants. The diagnostic assessment measures showed that the parent symptom rating was the highest and appeared in 11 studies, reflecting the burden on the family. In addition, a structured-self-rated questionnaire rating appeared in eight studies, and two diagnostic assessment measures, teacher symptom rating and investigators, appeared in six. The studies demonstrated significant reductions in the primary symptoms of ADHD at assessment, which led to improved behavioral and functional status with a reduced impact on family and society. Further trials are needed to understand the benefits of CBT and MPH when combined to reduce psychiatry co-morbidities and improve learning and overall quality of life in the long term.


Introduction And Background Introduction
Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition in childhood, affecting approximately 4-6% of children and adolescents [1]. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) includes ADHD under "Neurodevelopmental Disorders" [1]. ADHD is defined as six or more symptoms of persistent inattention, and/or hyperactivity, and impulsivity, present for six months in two or more settings that interfere with function and are inappropriate for developmental level [2]. Children and adolescents diagnosed with this disorder have difficulty focusing, controlling movements and impulses, and regulating behavior affecting their communication, daily living, and socialization [3].
Boys are two to four times more likely to be diagnosed than girls [4]. In addition, 65% of children diagnosed with ADHD are symptomatic in adulthood, which suggests that the disease is chronic [2]. The etiology of ADHD is multi-factorial and a combination of genetic predisposition and environmental factors, such as low birth weight, prematurity, pregnancy complications, prenatal maternal smoking, intrauterine alcohol exposure, and lead [5]. Family and twin studies have shown a high percentage of heritability with approximately 70% to 80% and substantial overlap between hyperactivity/impulsivity and inattention and with no sex differences in heritability [4]. Although family studies have shown a high heritability and Research has shown that pharmacological treatments, particularly stimulants and atomoxetine, psychosocial therapies, and their combination are well-established interventions for children and adolescents with ADHD [8]. Treatment options for ADHD in adolescents and children are limited and primarily require prescribing psychostimulant medication as a first-line treatment [3]. Improvements in behavior, attention, interpersonal interactions, cognition, and executive function reinforce stimulant medication's short-term efficacy. MPH and dextroamphetamine are the most prescribed [3]. Nevertheless, the limitations of these medicines (e.g., short-term effects, unknown long-term effects, and adverse effects such as insomnia and anorexia) have led parents and professionals to seek other treatments. Therefore, non-pharmacological interventions that decrease ADHD symptomatology, such as cognitive training, have been considered an excellent potential benefit [3].
The primary care provider roles include diagnosis, medication management, and referrals to other resources, both educational and behavioral [9]. The American Academy of Pediatrics (AAP) has recently updated its 2019 guidelines, providing the basis for managing ADHD. First-line treatment for the preschool age group four to five years is evidence-based parent training in behavior management (PTBM) and teacheradministered behavioral therapy. If there is no improvement, initiating MPH may be considered. For elementary school-aged children six to eleven years, approved medications by FDA, along with PTBM and classroom behavioral interventions, are preferred. For adolescents aged 12-18, FDA-approved medications are the treatment of choice. Evidence-based training interventions and behavioral interventions should also be encouraged [9].
CBT has been described as "a form of psychological therapy that uses cognitive and behavioral techniques to support individuals to change unhelpful behaviors and thought patterns that occur in situations of fear and to learn better ways of coping with them, thereby relieving their symptoms and becoming more effective in their lives" [9,10]. CBT is delivered in a series of structured sessions and is effective for depression, anxiety, eating disorders, and severe mental illness. Results of two studies of adolescents receiving CBT showed improved parental ratings of ADHD symptoms but found little evidence of benefit for functional impairment [9]. On the other hand, MPH, a dopamine and noradrenaline reuptake inhibitor, is the recommended firstline pharmacological treatment for ADHD in many countries, with treatment response rates between 70% and 90%. As stated previously, MPH is one of the most used psychostimulants and has been the most widely studied regarding its efficacy in treating ADHD worldwide [11]. Compliance with medication is a common problem in ADHD treatment. Lack of adherence may lead to reduced effectiveness, increased adverse events, and other consequential issues, hampering the course of pharmacological treatment. Clinicians should routinely assess medication compliance during treatment, and potential problems in adherence should be openly discussed [12]. In deciding whether to initiate pharmacological treatment in school children and adolescents, the severity of ADHD symptoms, as emphasized by clinical guidelines: cases with low and moderate severity "can" while severe cases "should" be offered pharmacological treatment. However, personal factors, for example, the level of suffering, the situation of the patient's family, comorbidities, and global psychosocial functioning, should also be considered [12].
This review aims to systematically evaluate the effectiveness of MPH and CBT, in treating children and adolescents with ADHD using available literature. The study also establishes the most efficacious treatment in the current period.

Guidelines
This systematic review of empirical literature was performed in agreement with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 [13].

Search Databases
Three investigators independently searched PubMed, PubMed Central, Medical Literature Analysis and Retrieval System Online (MEDLINE), and Google Scholar.

Search Strategy
A systematic literature search using boolean logic to perform a database search and boolean search operators "AND" and "OR" were used to connect the keywords.

Inclusion Criteria
The papers included in this study are within a range of five years, from 2017 to 2022. Only human studies published in English are part of this study. We included randomized control trials, observational studies, systematic reviews, or narrative reviews, including the age group of preschools to adolescents who received MPH and CBT for treating ADHD.

Exclusion Criteria
In our study, the authors excluded studies published before January 2017, studies that were not free full text on PubMed, studies not published in English, and finally, studies in individuals over 18 years of age. Furthermore, we excluded clinical guidelines and letters to the editor.

Study Selection and Quality Check
The studies we shortlisted were then imported into the EndNote software (Clarivate, London, UK) and transferred to the excel sheet, where we removed duplicates. In addition, we performed a manual check to remove any article to which the topic was non-related. Three reviewers independently reviewed papers based on title, keywords, and abstract. In addition, two reviewers thoroughly reviewed full-text articles that passed the initial screening to determine their suitability for inclusion in the systematic review. The quality of the paper included in the study was assessed by the primary author and two secondary authors using the Cochrane risk of bias tool for randomized controlled trials. We interpreted the result from the biases using the agency for healthcare research and quality (AHRQ) standards. Finally, the papers selected were of good quality. Finally, the investigators used the PRISMA diagram to check the quality of systematic reviews for inclusion.
Additionally, we used the scale for assessing narrative review articles (SANRA) checklist to determine if a narrative review was of good quality. Finally, in the event of disagreement, we reached a consensus after discussing it with a fourth author. The PRISMA flow diagram is below in Figure 1 [13].

FIGURE 1: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 flow diagram depicting the study selection process.
Reference [13] Results After a strategic search of various electronic databases, the total number of articles found was 10438 (PubMed -10432, Google Scholar -six). Records were removed before screening by PubMed filter inclusion criteria = 9722. We removed 52 duplicates with excel. The authors manually screened by title 664 studies and removed 619 articles with a non-related topic. We retrieved 45 records and excluded 21 studies after reviewing abstracts and full text using the eligibility criteria. The investigators identified 24 studies, and 10 did not meet the inclusion criteria after the quality assessment. Finally, we included 14 articles in our review. The PRISMA flow diagram is in the methods section ( Figure 1) above. Finally, we outlined the type and number of studies used in this review article ( Table 2).

Randomized Control Trial 11
Systematic Reviews 2 Narrative Reviews 1

General Study Characteristics
Study participants: The studies included were performed in seven countries; the United States, Taiwan, Norway, Australia, the Netherlands, Denmark, and France [6,7,11,[14][15][16][17][18][19][20][21][22][23][24]. The total number of participants recorded was 2,098. The age ranged from 3 to 18 years old, and the mean age observed from the review was 11. However, only one study in this review did not specify the sample size and age range [21]. Therefore, we will explore the essential characteristics of the studies included in this review (  Detailed information about studies we included in the review.
Note: access to the patient during the study determined the sample size#.
Outcome: improvement in the ADHD core symptoms: a = attention deficit, b = hyperactivity, c = impulsivity/aggressiveness, d = improvement in working memory (accuracy), e = reduction in medication, f = change in symptoms scores on the ADHA rating scale-IV, g = improvement of self-esteem, emotional regulation, and social integration, h = depression/anxiety. DR/ER = delay release/early release, N/A = not applicable, ND = not defined, NFT = neurofeedback is behavioral therapy No. = number, CBT = cognitive behavioral therapy, MPH = methylphenidate

Review of Diagnostic Assessment Measures
Two essential treatment modalities, CBT and MPH, were used to assess the primary efficacy outcome: reduced symptoms and improved function in patients with ADHD. The study outcomes were measured using diagnostic assessment measures, which were different in all studies and were undefined in two studies. The "parent symptom rating," the highest applied diagnostic assessment measure, was used in 11 studies. In contrast, eight studies showed that the "structured-self-rated questionnaire" is the second most used diagnostic assessment measure. The other diagnostic assessment measure, "teacher symptom rating" and "investigators," the third most utilized, appeared in six studies.

Type of Treatment Considered Dosage and Duration
The authors analyzed the treatment type, dose, duration of therapy, frequency of assessment, and patient response to demonstrate whether the administration of CBT and MPH is effective. One study assessed MPH and CBT in the included articles [18]. Six studies centered on CBT [15][16][17][18]23,24], while nine researchers centered on MPH administration [6,7,11,14,[18][19][20][21][22]. The dosage of MPH was different in each of the nine studies. In addition, the duration of the interventions ranged from five weeks to four years, while the frequency of assessment varied extensively.

Review Findings
Our findings showed an improvement in core ADHD symptoms. We observed that eight studies recorded a reduction in inattention, and seven reported a decrease in hyperactivity and impulsivity/aggressiveness. Two more studies also reported improvements in the change in symptom scores using the ADHD rating scale and improved working memory. Nonetheless, Sciberras et al. [17] randomized control trial study outcomes were undefined, and Ribeiro et al. [21] didn't find enough evidence regarding the benefits of MPH on treatment outcomes.

Discussion
A research review, including 11 random controlled trials, two systematic reviews, and one narrative review ( Table 2), was used to assess the effects of either CBT or MPH on core ADHD symptoms and function in children and adolescents. This review differs from previously published reviews, intending to focus on the effect of non-pharmacologic therapy (CBT) and stimulant therapy (MPH) as interventions for treating children and adolescents with diagnosed ADHD. In addition, the author's included the established rating scales used in assessing ADHD symptoms in children, as shown in (Table 4) for better understanding [19].  . Physicians must remain cautious in diagnosing ADHD in preschool children, monitoring very young children for the emergence of symptoms and impairments over time [19].

CBT Intervention
The CBT interventions in six studies included in this review had different measures of assessing the effectiveness of the ADHD treatment [15][16][17][18]23,24]. The study observed that CBT improved ADHD symptoms ( Table 3). However, CBT can be time-limited and resource-intensive. The variations in CBT treatments could be the mode and duration of CBT sessions. Most studies had weekly clinician-led sessions, and the number of sessions varied. The duration of each session also varied between studies lasting an hour long and beyond, and the sessions can be either with individual children/parents [17] or combined [24]. Finally, we will detail the CBT sessions reviewed in our study (

MPH Treatment
The nine studies included in this review have different formulations of MPH [6,7,11,14,[18][19][20][21][22]. Since the advent of MPH in the 1960s, MPH has been the drug of choice for ADHD worldwide and has proven to improve ADHD core symptoms. Pharmacological treatment optimization poses challenges, including careful dose adjustments and the risk of drug abuse during treatment [14]. The study reported marked improvement in ADHD core symptoms six months after treatment completion by parents, teachers, and participants, with significant improvement in inattention [14]. However, the study did not witness a significant improvement in hyperactivity or academic performance [14]. Furthermore, treatment with MPH ERCT (extended-release chewable tablet) showed a significant improvement in ADHD symptoms compared with placebo at two to eight hours post-dose, with a good safety and tolerability profile [7]. In the first multicenter, phase three study of the efficacy and safety of MPH ERCT formulations, the results showed a statistically significant improvement in behavior impairment in children aged six to twelve with ADHD [7].
Additionally, in the first randomized, placebo-controlled trial of an ER MPH formulation for preschool children aged four to six years, doses of up to 40 mg were effective and well tolerated [6]. It is like the known safety profile in older children [6]. Another study, a placebo-controlled crossover trial looking into the clinical efficacy and tolerability of ORADUR-MPH, reported that it significantly reduced symptoms of inattention, hyperactivity, and impulsivity within two weeks of treatment regardless of informants [11]. ORADUR-MPH is efficacious, safe, and well-tolerated for treating ADHD without serious side effects [11].

Limitations
This study has some critical limitations. The major one is the limited number of articles documenting the use of MPH and CBT alone to treat ADHD. Furthermore, a systematic, non-descriptive review of CBT sessions was included [15] and provided limited measures for the discussion. In addition, we included an unresolved research protocol, which can be controversial due to the lack of an evident result. Some studies lacked information on the study characteristics, and we did not contact the authors. This insufficiency in knowledge may have affected the quality of the outcome of the result. Also, our studies used different CBT session approaches and varying formulations and dosages for MPH; therefore, this needs to be considered for overt improvement.
Finally, our search strategy excluded studies published before the last five years and not freely available full text on PubMed. The inclusion of these might have provided more clarity.

Conclusions
The purpose of this review is to critically evaluate the efficacy of CBT and MPH in treating ADHD in children and adolescents to improve their core symptoms and functional capacity from published literature. The findings from the review of 2098 patients undergoing either or both treatment interventions showed significant reductions in the primary symptoms of ADHD at assessment, which led to improved behavior and functional status with an overall reduced impact on family and society. Additionally, accurate diagnosis by physicians using the rating scales is key to treatment choice. We observed how CBT helps with behavior management and the role of psychologists, parents, and teachers in ensuring effective therapy. Further trials are needed to understand the benefits of CBT and MPH when combined to reduce psychiatry comorbidities and improve learning and overall quality of life in the long term.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.