Cost-Effectiveness of Treatment Options for ADHD: A Systematic Literature Review

  

    
Study
    
Studied treatment
    
Approach
    
Relevant year
    
Costs
    
Adjusted costs
    
Findings
  
  

    
Chan et al. 2002
    
Stimulants vs.
      
no stimulants
    
Health care expenditures derived from panel data

      (inpatient costs, outpatient costs,
      
drug costs and out of-pocket payments)
    
1996
    
Children with ADHD treated with stimulants: 1,113    €

      Children with ADHD with no stimulants: 412 €

      (First converted from $ to DM for the    year 1996 and then to € by the first exchange rate of 1€ =1,95583 DM, because    introduction of the euro was first on January, 1999)
    
Not for this comparison
    
ADHD patients with no stimulant treatment show    lower health care expenditures

      and significant lower resource use regarding outpatient visits and    prescriptions
  
  

    
Vanoverbeke et al. 2003
    
Methylphenidate and Behavioral treatment
    
Incidence based
      
medical decision tree model
    
2001
    
Starting with MPH-OROS and switch to:
      
behavioral treatment: 2,662 €total costs
      
combination treatment: 4,122 € total costs
      
other drug: 2,209 € total costs
    
No adjustment for patient’s characteristics
    
A switch to behavioral treatment should be    avoided.
  
  

    
Donnelly et al. 2004
    
Dexamphetamine
      
(DEX) and Methylphenidate (MPH) interventions
      
compared to current practice
    
Meta-analysis of
      
randomized controlled trials and
      
Incremental Cost Effectiveness
      
Ratio (ICER)
    
2000
    
The ICER for DEX is 2,579 €/DALY saved) and for
      
MPH is 9,437 €/DALY saved
    
Uncertainty parameter included
    
MPH and DEX are cost-effective interventions for    childhood ADHD. DEX is
      
more cost-effective than MPH, although if MPH    were listed at a lower price on the
      
Pharmaceutical Benefits Scheme it would become    more cost-effective. DEX is more costly than MPH for
      
the government, but much less costly for the    patient.
  
  

    
Narayan et al. 2004
    
Treatment with amphetamine/dextroamphetamine    compared to no treatment
    
Decision-tree analysis with ICER per QALY
    
2003
    
AMP/DEX versus no treatment (as MPH IR is    dominated):
      
19,433 €
    
No adjustment for patient’s characteristics
    
Treatment with amphetamine/dextroamphetamine or    methylphenidate is cost effective versus no treatment.
      
Methylphenidate is dominated by    amphetamine/dextroamphetamine therypy in the base case.
  
  

    
Jensen et al. 2005
    
Major forms of ADHD treatments

      (Medical Management, Intensive Behavioral Treatment, Combined Medical

      Management, Behavioral Treatment, Routine Community Care)
    
The societal perspective was used to determine    the costs for this study derived by the NIMH’s Multimodal Treatment

      Study of Children with ADHD (MTA Study)
    
2002
    
Cost per child per treatment arm  for children with ADHD during 14 months of    treatment :

      - Medical Management: 1,280 € 

      - Intensive Behavioral

      Treatment: 7,577 €

      - Combined Medical

      Management and

      Behavioral Treatment: 8,487 €

      - Routine Community Care: 1,161 €
    
No adjustment for patient’s characteristics
    
Medical management treatment,

      although not as effective as combined

      medical management and behavioral

      treatment, is likely to be more cost-effective

      in routine treatment for children

      with ADHD, particularly those without comorbid

      disorders. For some children with

      comorbid disorders, it may be cost-effective

      to provide combination treatment
  
  

    
Stevens et al. 2005
    
Short-acting stimulants vs. longer-acting stimulants
    
Adjusted healthcare expenditures (inpatient,    outpatient, drug costs and out-of-pocket payments ) derived from panel data
    
2000-2001
    
mean total expenditures:

      short-acting-stimulants user: 1,746 €

      longer-acting-stimulants user: 2,271 €
    
Adjusted for patient’s characteristics (income,    health status and ethnicity)
    
Longer-acting stimulants user show higher total    healthcare expenditures
  
  

    
Wu et al. 2007
    
Extended-release methylphenidate

      (osmotic release oral system-MPH), mixed amphetamine salts extended

      release (MAS-XR), or atomoxetine
    
Generalized linear models (GLMs) to compare costs    of adults receiving alternative therapies (medical costs and drug costs (6    month time period) derived from claims database of 5 million beneficiaries.
    
2004
    
Risk-adjusted mean medical costs, excluding drug    costs, for adults

      treated with OROS-MPH were 114 € less (10.4%, 982 € vs. 1,096 €) compared

      with MAS-XR (P = 0.022) and 106 € less (9.8%, 982 € vs. 1,088 €) compared

      with atomoxetine (P = 0.033); risk-adjusted mean medical costs were not

      significantly different between MAS-XR and atomoxetine.
    
Adjusted for
      
demographic characteristics, substance abuse,    depression, and the Charlson
      
Comorbidity Index
    
Adults treated with

      OROS-MPH had, on average, slightly lower medical and total medical and

      drug costs than those treated with MAS-XR or atomoxetine over the 6-month

      period after drug therapy initiation.
  
  

    
Cotrell et al. 2008
      
Prasad et al. 2009
    
Atomoxetine vs. Methylphenidate

      (immediate-release; extended release)
    
Incremental cost per QALY using Monte Carlo

      simulation and Markov model
    
2004
    
atomoxetine algorithm compared with

      stimulant exposed population:

      - immediate-release Methylphenidate (MPH):
      
22,924 €

        - with extended release MPH: 19,938 €
      
- atomoxetine compared to defaximine (i.e. failed    on either IR-MPH or XR-MPH): 22,025 €
      
- atomoxetine compared to no treatment: 16,982 €    to 18,230 €
    
-
    
Atomoxetine is an effective alternative across a    range of ADHD patients

      and offers value-for-money
  
  

    
Faber et al. 2008
    
Long-acting

      methylphenidate osmotic release oral system for youths

      with ADHD for whom treatment with immediate-release (IR) methylphenidate is    suboptimal
    
Markov model to obtain ICER per QALY
    
2005
    
The ICER of methylphenidate-OROS treatment in    youths with ADHD

      for whom treatment with IR methylphenidate is suboptimal was 2,004 € per

      QALY. Total costs after 10 years were 15,739 € for the IR methylphenidate

      pathway and 16,015 € for the methylphenidate-OROS pathway.
    
-
    
Methylphenidate-OROS is a cost-effective    treatment for youths with

      ADHD for whom treatment with IR methylphenidate is suboptimal. Higher

      medication costs of methylphenidate-OROS were compensated by savings on

      resource use, yielding similar 10-year costs compared with treatment with IR

      methylphenidate.
  
  

    
Hong et al. 2009
    
Atomoxetine vs. Methylphenidate (immediate-release; extended release),

      no medication
    
Incremental cost per QALY using Monte Carlo

      simulation and Markov model
    
2004
    
incremental cost per QALY gained for the atomoxetine    algorithm (here only stimulant-naive patients are provided) compared with:

      - immediate-release Methylphenidate (MPH): 34,308 €

      - with extended release MPH: 24,310 €

      atomoxetine compared to no treatment: 23,323 € to 23,820 €
    
-
    
Atomoxetine is an effective alternative across a    range of ADHD patients

      and offers value-for-money
  
  

    
Myrén et al. 2010
    
Atomoxetine
    
Resource utilization was derived by questionnaire
      
Published unit costs/prices were used to    calculate costs
    
2004
    
On treatment with atomoxetine (no medication    costs):

      828 € at baseline, 495 € at 10 weeks, 266 € at 25 weeks and 224 € at 49 weeks
    
No adjustment for patient’s characteristics
    
Atomoxetine together with parental    psychoeducation reduces nonmedication costs associated with ADHD
  
  

    
Sikirica et al. 2012 (a)
    
Atypical Antipsychotics (AAP) vs. Non-Antipsychotics
    
Annual resource utilization was compared using McNamara’s    test and Poisson regression
    
2010
    
The AAP group 

      incurred higher all-cause mean medical, prescription drug, and total health

      care costs compared with the non-antipsychotic group (2,332 € vs. 1,689 €;

      2,901 € vs. 1,893 €; 5,233 vs. 3,538, respectively; all P <    0.001)
    
No adjustment for patient’s characteristics
    
Stimulant-treated children with ADHD who switched    to or

      augmented with AAPs versus non-antipsychotics had significantly greater

      rates of subsequent augmentation and health care resource utilization as

      well as higher total health care costs
  
  

    
Sikirica et al. 2012 (b)
    
Guanfacine Extended

      Release as an Adjunctive Therapy to a

      Stimulant Compared with Stimulant

      Monotherapy
    
ICER per QALY within a 1-year Markov model
    
2010
    
Adding

      GXR to existing stimulant monotherapy was associated with an incremental

      drug cost of 767 € but a lower medical cost of 94 €, resulting in a total

      incremental cost of 673 € at 1 year
    
-
    
The adjunctive therapy of GXR with

      stimulants is a cost-effective treatment based on a willingness-to-pay    threshold

      of 37,732 €/QALY. This may address an unmet need among patients

      with suboptimal response to stimulant monotherapy
  
  

    
Sikirica et al. 2013
    
Guanfacine Immediate Release (GIR) versus

      Guanfacine Extended Release (GXR)
    
Claims data analyses (medical service and    prescription

      drug costs)
    
2010
    
GIR users

      incurred significantly lower all-cause pharmacy costs (P <.001)

      but significantly higher medical costs (P = .009), resulting in no

      significant difference in total all-cause healthcare costs (P = .068)

      between the 2 groups (GIR 3,180 € vs GRX 2,969 €)
    
Unadjusted results shown here
    
Total all-cause healthcare costs were comparable

      between the 2 groups
  
  

    
Braun et al. 2013
    
Drug treatment–persistent, drug treatment–

      no persistent, and nondrug treatment
    
The differences

      in costs and resource utilization are reported in a descriptive manner, with    paired and unpaired

      2-sample Wilcoxon tests used. Claims data analyses were conducted.
    
2007
    
Significant average savings of 187 €/year in    overall

      costs (P = 0.05) were noted for the drug treatment–persistent group compared    with the drug treatment–no persistent group. These mean savings were

      €739/year and €552/year (drug treatment–persistent group and drug treatment–no    persistent group, respectively)

      compared with nondrug-treated patients.
    
No adjustment for patient’s characteristics
    
There are potential cost-savings benefits

      when patients are treatment persistent
  
  

    
Sikirica et al. 2014
    
patients who switched to or augmented with    atypical antipsychotics compared to those who switched to or augmented with no    antipsychotic medication
    
Retrospective cohort study
    
2010
    
The AAP cohort incurred significantly higher mean    annual medical (2,733 € vs 2,499 €),    drug (3,256 € vs 2,176 € and total    healthcare (5,990 € vs 4,676 €)    costs.
    
Propensity-Score-Matching
    
Stimulant-treated adolescents with ADHD who    switched to or augmented with AAPs had significantly costs compared with the    non-antipsychotic cohort
  

Table 2:  Costs for studied treatment option.

The focus of most of the studies was on the cost-effectiveness of different medications or mean costs. The cost-effectiveness of different agents were compared among each other or versus no treatment as well as among different formulations in the same class (i.e., whether the agent was short- or long-acting (Table 2)).

Medication

One study concluded that the total annual treatment costs associated with pharma co-stimulant users are higher than the costs associated with patients not using stimulant medication. The found difference was significant and took value of 701 €. The information on costs was retrieved from the Medical Expenditure Panel Survey (MEPS) which contains representative data on costs for the US population including out-of-pocket payments [28]. There is significant higher resource use by patients with stimulant treatment. Therefore, a higher severity of disease can be assumed.

Comparision of atomoxetine, methylphenidate and dexampthetamine

Furthermore, within the United Kingdom, atomoxetine is a costeffective treatment option compared to methylphenidate, although atomoxetine is less effective in first-line patients. Atomoxetine is a treatment option with a greater time of therapeutic response. Markov models were used for estimation of the costs and benefits of atomoxetine including 18 different health states [29,30]. These results were confirmed by Spanish data using the same methods [31]. However, atomoxetine treatment is associated with higher treatment costs as well Claims data analyses (5 million beneficiaries from 31 large self-insured employers) from the USA show that for the year 2004, adults treated with extended-release methylphenidate had lower risk-adjusted total costs in a 6-month period (i.e. 982 € vs. 1,088 € for patients treated with atomoxetine). Even when compared to patients treated with mixed amphetamine salts, the costs associated with patients treated with extended-release methylphenidate were 114 € less. [32]. More over cost-effectiveness is higher for dexamphetamine than for methylphenidate. The Incremental Cost-Effectiveness Ratio (ICER) for dexamphetamine is 2,579 €/DALY saved, and 9,437 €/ DALY saved for methylphenidate. The study by Donnelly et al., (2004) used a meta-analysis of randomized controlled trials to derive utility values [33]. In addition, Narayan et al., (2004) found that the costeffectiveness of amphetamine /dextroamphetamine treatment versus none is 19,433 €/DALY within a social perspective. The methods include a decision-tree analysis and the assumption that treatment decision was finalized for each patient within six months [34].

Swedish data provides a trend of costs over time for atomoxetine. At baseline, non-medication costs for the atomoxetine group (combined with parental psycho education) were 828 €, which decreased to 224 € 49 weeks after baseline. Similar results were found for patients from the placebo group who switched to atomoxetine. The cost reduction was due to lower direct and indirect costs. Therefore, the non medication costs (eg. fewer visits to health care providers) can be reduced by atomoxetine treatment [35].

Methylphenidate as a main treatment option can be differentiated into long-acting and short-acting formulations. A study from the Netherlands showed that the total cost associated with methylphenidate treatment after 10 years was 15,739 € for the immediate-release version of the drug, and 16,015 € for the longacting Osmotic Release Oral System (OROS) version. It was stated that long-acting medications are a cost-effective treatment for patients with suboptimal treatment success using immediate-release medication [36]. In addition, general studies, which differentiate between short-acting and long-acting medications, but not by drug, report lower healthcare expenditures for short-acting stimulant users (1,746 €) compared to long-acting stimulant users (2,271 €).Therefore, depot agents seem to be associated with higher total treatment costs; however, the reported annual stimulant expenses were lower than those given in other published studies [37].

Off-Label-Use of antipsychotics for ADHD patients

Atypical and typical antipsychotics are known as off-label treatment options for ADHD. For example, risperidone isan atypical antipsychotic used for ADHD patients. Studies have shown that risperidone can reduce ADHD symptoms, especially if specific comorbidities are diagnosed. Data from the USA indicate that ADHD patients, who switched to or extended their existing therapy with atypical antipsychotics, have higher rates of switching and augmentation, greater resource use, and higher total health care costs (5,233 €) compared to ADHD patients who switched to or augmented to non-antipsychotics (3,538 €) like atomoxetine [38]. A more recent study of Sikirica et al., (2014) confirmed these results [39].

Complementary treatment with guanfacine

Adding guanfacine (extended-release) to another stimulant is a complementary treatment strategy. According to an exemplary study conducted in 2010, total costs for stimulant users are 1,581 € compared to 2,254 € for patients on monotherapy. Higher drug costs can partly be compensated for by lower extraneous medical costs. With an ICER of 23,892 €/QALY, guanfacine in addition to stimulants could be considered cost-effective [40]. Further studies using claims data from the USA differentiate Guanfacine Immediate- Release (GIR) from Guanfacine Extended-Release (GRX) in children and adolescents with ADHD. Total healthcare costs were similar for both agents (GIR 3,180 € vs. GRX 2,969 €) during a 6-month study period. However, GXR users show lower rates of therapy adjustment and fewer inpatient and emergency room visits [41].

Potential of persistence for cost reduction

Another dimension of potential reduction of treatment costs is to investigate drug treatment persistence. Persistence in a detailed exemplary study was defined as at least 1 prescription every 3 months during the year after the first methylphenidate prescription. Savings in total costs of 187 € per year could be identified for persistent patients compared to the non-persistent group. Thus, it can be concluded that treatment costs can potentially be reduced if ADHD patients are persistent. The study consisted of German claims data [42].

Behavioral and multimodal treatment

In addition to drug treatment, the costs and efficiency of multimodal treatment of children was evaluated by Jensen et al., (2005). Several treatment options were considered for medication management, as well as behavioral treatment and a combination of both in this study. The main result was that medical management treatment is likely to be more cost-effective in treatment for children with ADHD, particularly in those with lower severity. Cost per treatment arm within 14 months of treatment was 1,280 €, while for intensive behavioral treatment (defined predominantly by a high proportion of parent, school, and child components), mean costs were 7,577 €. Combined treatment with medical management and behavioral treatment was more costly than routine community care (i.e., 8,487 € versus 1,161 €). Medical management is more costly but also more effective than community care. It has been estimated that 390 € has to be invested to treat a child and provide a nearly normal life. An ICER of 32,356 € suggests that it is most cost-effective to use combined treatment for children with comorbid disorders (i.e., internalizing disorders, such as anxiety or depression, and externalizing disorders, such as conduct or oppositional defiant disorder). Costs per additional child treated by combined treatment are higher (ICER of 80,889 €) than the costs of the same treatment for children with ADHD plus both types of comorbid disorder (32,356 €) in comparison to medical management alone. The analyses by Jensen et al., (2005) were derived from the Multimodal Treatment Study of Children with ADHD (MTA) [43]. If a medication strategy fails, a switch to behavioral treatment (2,662 €total costs) should be avoided compared to a switch to another drug (2,209 € total costs) [44].

Because the aim of this review was not only to consolidate existing evidence, but to provide future research ideas, a speculative view on the evidence without specific monetary values for cost reduction is part of the following discussion.

Discussion

Summary of findings

To summarize, the existing evidence shows that medication is a cost-effective treatment strategy compared to no treatment. Additionally, atomoxetine is a cost-effective alternative to methylphenidate [29–31]. The effects of long-acting and short-acting formulations have an influence on cost-effectiveness regarding the patients’ characteristics (e.g., persistent/non-persistent patients) [42]. Furthermore, guanfacine used as a complementary strategy is costeffective and with respect to multimodal treatment, more evidence is necessary to determine the cost-effectiveness. In some cases, costeffectiveness can be assumed [40,43].

Influences on treatment cost-effectiveness

Treatment costs for ADHD could be high if hospitalization is necessary [19]. While only a small number of patients are hospitalized because of ADHD, these cases can be monitored and personal care provided because they are high-cost cases. Secnik et al., (2005) found no significant inpatient cost difference in employees diagnosed with ADHD and their control group in the USA. This is explained by the fact that only a small number of patients are hospitalized due to ADHD [45]. Additionally, Braun et al., (2013) reported that the proportion of costs due to inpatient care was 20%, but that the larger share of the total costs was due to therapeutic devices and remedies (43.8%). Therefore, costs for therapeutic devices and remedies should be recognized for potential treatment cost reduction [46].

In addition, treatment costs for ADHD increase with the number of comorbidities [47,48], such as asthma, anxiety, bipolar disorder, depression, drug or alcohol abuse, and oppositional disorder. The cost associated with patients with this level of comorbidity is significantly higher compared to control groups without ADHD. Consequently, direct and indirect costs associated with ADHD treatment have the potential for cost reduction [45]. It has to be recognized that in the second year after diagnosis, the adjusted excess costs for children with ADHD compared with the costs for children without ADHD are lower than in the first year after diagnosis, but not for patients with comorbidities. A study with data from a nonprofit integrated health care delivery system in California shows a decrease in adjusted health care system costs of 151 € from the first year after index diagnosis, compared to the second year after index diagnosis for patients without comorbidity. However, the findings in the unadjusted data are different in the cohort of ADHD children with coexisting mental health conditions. The influence of comorbidities is evident by the cost increase from the first to the second year of diagnosis (i.e., 280 €) [14]. Therefore, there is an important influence of comorbidities on the cost of illness and their treatment options. For example, diagnostic measures, such as EEG screening before initiating stimulant medication for ADHD, is a cost-effective method for preventing sudden cardiac death [49].

Indirect factors of the most cost-effective medication strategy

In line with other reviews, drug therapy seems to be superior to no medication treatment strategy [23,50]. For example, Catala Lopez et al., (2013) stated that methylphenidate and atomoxetine are cost-effective alternatives compared to placebo or no treatment, but direct comparison methylphenidate and atomoxetine treatment show contradictory results [25]. In ADHD cases with normal course and no comorbidities, pharmacotherapy is superior compared to behavioral treatment only [24]. Furthermore, there is evidence that extendedrelease methylphenidate has a higher compliance rate and less injuries versus more costly 3-times-daily immediate-release methylphenidate. Higher compliance could decrease costs associated with the need for re-evaluation for dose adjustment, to switch medications, and to expand therapy [51]. Other outcome parameters used to estimate cost-effectiveness include emergency room rates, medication switch probability, and periods of persistence (adherence) [52].

Medication side effects, such as abuse liability, cause direct and indirect costs; these, however, have been reduced by the availability of longer-acting agents. A large-scale community survey in the USA has shown that abuse is more common with short-acting preparations [53]. Therefore, long-acting ADHD drugs have nearly replaced shortacting stimulant use for children with ADHD [54].

Pharmacotherapy has shown significant benefits in patients’ outcomes as well as direct and indirect savings, however, drugs are increasingly costly due to their expanding use. Therefore, management of ADHD and promoting adherence are likely to improve cost-effectiveness [55].

Additionally, switching drugs may lead to higher treatment costs due to medication adjustment. Among patients using longacting methylphenidate, the rate of drug switching was the lowest [56]. Furthermore, patient’s out-of-pocket payments can be used to reduce treatment costs because these raise awareness for costs and the need for treatment. Out-of-pocket payments are lower for generic prescriptions than for brand name prescriptions [57]. Thus, price conscious out-of-pocket-payments could reduce treatment costs. However, it may also lead to a lack of health care in population groups with low income.

Guidelines define first choice medication. Methylphenidate is the most common first-line drug but atomoxetine is more effective if certain comorbidities are diagnosed [58]. The discussion about medication or non-pharmaceutical therapy alone is not useful. Optimal treatment should be multimodal. Intensive medication management may be cost-effective for uncomplicated cases, but the resources saved by higher cost-effectiveness should be used for other types of treatment for patients of higher complexity or severity [59].

Innovative treatment options

Other non-pharmaceutical treatment options have implications for cost reduction. These options mainly consist of behavioral training, but also include sport and nutritional medicine. The evidence for alternative treatment compared to pharmaceutical treatment is sparse and, to the best of our knowledge, Jensen et al., (2005) is the only publication that reports the cost-effectiveness of non-medication treatments for ADHD [60]. Even if costs are not the focus of the investigation, an overview of the effectiveness could provide information about best-practice treatment strategies and potential for cost reduction. These studies with no explicit costeffectiveness are presented in the following section. The evidence for effectiveness is higher for parental behavior training than for child training [61]. Psychiatric treatment is often considered effective treatment for ADHD and cost-effective [62]. Similar results are found in the area of behavioral therapy; however, group cognitive behavioral therapy is assumed cost-effective [63]. Another treatment strategy for ADHD is neuro feedback. One study showed that neuro feedback could achieve a high cost-benefit ratio. In contrast to drug treatment, the causes for ADHD, not the symptoms, are addressed. The use of neuro feedback is supposed to reduce medication use and the learned behavior is presumed to endure over 10 years. Furthermore, neuro feedback is not associated with side effects [64,65]. More, controlled studies are necessary to provide these messages as true. In addition, the cost-effectiveness of neuro feedback needs to be further explored. Research on the impact of neuropsychological assessment on the psychological, social, academic, and functional wellbeing of ADHD patients is needed [66].

Complementary and alternative treatment options for ADHD could have the potential to reduce treatment costs. However, there is no clear evidence for the cost-effectiveness of these treatments. For example, Sinha et al., (2005) stated that modified diet, vitamins and/ or minerals, dietary supplements, aromatherapy, and chiropractic are forms of treatment used in Australia [67]. A notice has to be made that dietary is a possible complementary treatment option only for a small number of patients. Furthermore, sports can serve as a concomitant treatment within a multimodal treatment strategy. However, to the best of our knowledge, there are no studies on the cost-effectiveness of these treatment strategies. If effectiveness of these treatment options could be shown in a broader way, e.g. dietary and sports could be implemented with relatively low cost. But without a health economic evaluation this cannot be stated as a generalization [68].

Some influences on costs could be identified within the discussion. Hospitalization, therapeutic devices as well as existing comorbidities can influence costs. But it can also be supposed that compliant patients can provide lower costs over a longer period.

Limitations of included studies and implications for future research

There are some limitations with this review. There may be a risk of bias across the studies as German terms were used, perhaps resulting in a skewed perspective on the topic. However, because all relevant studies published in English were included, the addition of German studies supports the comprehensiveness of our review. Because the majority of the articles report results from USA populations [28,32,34,37,38,40,41,43], the cost information may have been affected since there are substantial differences in global health care systems. This is another reason to include German studies as well as those from other countries. In general, there are limitations in systematic literature reviews. For example, not all of the relevant studies may be included, or heterogeneous studies may be inappropriately combined. Therefore, we implemented a manual literature review and screening of existing reviews. However, there are also limitations regarding the included studies. Markov-models differ in their assumptions as well as other study types as shown within the results section. Within the study of Sikirica et al., (2012) e.g. for the used Markov model some costs for health care status had to be estimated by other studies, but sensitivity analysis showed that the results were not sensitive for the assumptions applied [40]. Chan et al., (2002) reveals a possibility of under identification of ADHD patients by the method (telephone survey). Parents often don’t want to stigmatize their children as ADHD patients. But the authors conducted a validation by medication data and found only a small number of patients with a stimulant medication who were not reported as ADHD patients. This fact suggests that there is no comprehensive limitation by underreporting within the telephone survey [28].

There might be some restriction to estimate the utilities by expert opinion or placebo controlled clinical trial data. Utilities were not collected in a head-to-head clinical trial and not estimated from the patient perspective in two studies [29,30]. The study by Donnelly et al., (2004) used a meta-analysis of randomized controlled trials to derive utility values and raised the awareness that the results might be not representative. They stated that most trials excluded patients with chronic medical or neurological diseases [33]. For the quality of the studies and for comparison with the results of other authors small samples (N=99) [35] regarding the number of patients or included experts (N=5) [36] can be an issue to derive costs. Furthermore, for comparison with other studies it has to mentioned that ICD-9-CM code 314.00 (attention deficit disorder without hyperactivity) was included by Wu et al., (2007), which is not restricted specifically to the ADHD disease [32]. Within German claims data clinical parameters, like severity, were not available and, therefore, no adjustment was provided in this study [42]. A closer examination on the study of Jensen et al., (2005) has to be done as this study is the only one observing cost-effectiveness of behavioral and multimodal treatment. The behavioral interventions utilized in the MTA, which was used as data base for the study, are supposed to be more intensive and lengthy than in community practice. For instance, only children with ADHD combined type (no inattentive patients) were included in this study [43]. Costs associated with behavioral interventions can be higher than what is typically seen in community practice and that affects the comparison to medication treatment. Although, it might bring limitations regarding the transferability to practice, it is the only study which includes cost-effectiveness of behavioral treatment. There is a need to evaluate behavioral treatment more precisely to provide stronger evidence for the treatment strategy.

The differing methodology including the different identification algorithm of ADHD patients can bias comparison of the results. However, the inclusion of different study types broadens the view on the topic and provides a range for cost-effectiveness, which can be interpreted as a more sensitive analysis of the results. Inclusion or exclusion of indirect costs has an influence on total costs as well. Therefore, this perspective is included in (Tables 1 and 2) in order to classify the study. Additionally, the studies included in our review are from a limited time range (2002 to 2013; Tables 1 and 2). Medical practice, legal regulation, and pricing could have changed during this time, which affects cost estimates. Furthermore, all but one article [32] dealt with the cost-effectiveness of ADHD medications in children alone, despite the fact that ADHD is a chronic disorder that in most cases persists into adulthood. In adulthood, rates of comorbidity increase, which affects total cost and the choice of optimal treatment options. Therefore, the age of the included patients should be compared in future studies and reviews. It could be concluded that overall treatment costs are a function of these different components.

Conclusion

This review has shown evidence that medications are cost-effective. Analysis of treatment shows that particular ADHD age groups are supplied only with methylphenidate by approximately one-quarter to one-third [2]. This illustrates that although methylphenidate is a costeffective treatment and predominantly defined as first-line treatment, it is not the main treatment option. However, a lack of information remains regarding behavioral treatment and other complementary measures that could help to reduce treatment costs. Furthermore, research should analyze the cost-effectiveness associated with every stage of ADHD treatment.

It is necessary to evaluate behavioral and pharmacological treatment options in the short-and long-term. In contrast to drug therapy, behavioral treatment efficacy is often found only in the middle-to-long-term period. This must be considered in the assessment of behavioral therapies versus drug therapies. Contrarily, there could be consecutive long-term medication-based symptoms that influence cost-effectiveness [69]. With more evidence limited resources could be better allocated to more cost effective-treatment options.

Acknowledgement

The authors have no relevant affiliations or financial involvement with any organization, which would affect this article. No assistance was utilized during the writing process of this manuscript.

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