Treatment Patterns, Resource Use, and Economic Outcomes Associated With Atypical Antipsychotic Prescriptions in Children and Adolescents With Attention-Deficit Hyperactivity Disorder in Quebec

Abstract

Objective:

To assess treatment patterns, health care resource utilization (HRU), and costs among previously stimulant-treated children and adolescents with attention-deficit hyperactivity disorder (ADHD) receiving atypical antipsychotic (AAP) prescriptions in Quebec.

Methods:

Health care claims data extracted from Quebec’s provincial health plan database between March 2007 and February 2012 were analyzed. Children and adolescents (6 to 17 years) with ADHD who were taking a stimulant and either switched to, or augmented with, an AAP (with the first AAP defined as the index AAP) without a documented diagnosis for which AAPs are Health Canada–approved were included. Discontinuation, augmentation, and switching of the index AAP during the 12-month, follow-up period were estimated using Kaplan–Meier survival analysis. HRU and costs for the 6 months before (baseline period) and after initiation of the index AAP were compared.

Results:

A total of 453 children and adolescents with ADHD, mostly male (74.6%) and aged 6 to 12 years (73.7%), met the inclusion criteria. The 12-month discontinuation, augmentation, and switching rates were 45.5%, 68.2%, and 80.7%, respectively. Patients had, on average, more all-cause prescription fills (22.2, compared with 13.3) and incurred more all-cause pharmacy ($889, compared with $710), total medical ($1096, compared with $644), and total health care ($1985, compared with $1354) costs during the 6-month study period than during the 6-month baseline period (all P < 0.05). Similarly, ADHD-related total health care costs were higher during the study period ($1269, compared with $835; P < 0.05); all-cause and ADHD-related total health care costs increased by 46.6% and 52.0%, respectively.

Conclusion:

Use of an AAP among stimulant-treated children and adolescents with ADHD in Quebec was associated with high rates of therapy changes and increased HRU and costs.

Attention-deficit hyperactivity disorder is a common psychiatric disorder in children, affecting 2.6% of children in Canada.¹ Children and adolescents with ADHD are often diagnosed with psychiatric comorbidities, such as conduct disorders (30% to 50%), mood disorders (15% to 75%), and anxiety disorders (about 25%).^2,3

Treatment for ADHD is often multi-modal, including both behavioural and pharmacologic options. Stimulants, such as amphetamines and methylphenidate, are recommended by the CADDRA guidelines and other guidelines as first-line pharmacotherapy with or without behavioural interventions for children (aged 6 years and older), adolescents, and adults.^4,5 The estimated number needed to treat (that is, number of patients that need to be treated to achieve the desired outcome for 1 patient) has been reported as about 2 for lisdexamfetamine dimesylate and 3 for methylphenidate.^6,7 Patients who are unresponsive or intolerant to their initial stimulant monotherapy may require an adjunctive or alternative drug therapy.⁸ Two nonstimulants are currently approved by Health Canada for the treatment of ADHD: ATX (Strattera, Eli Lilly, Indianapolis, IN), a selective norepinephrine reuptake inhibitor approved for monotherapy for children (aged 6 to 12 years), adolescents (aged 13 to 17 years), and adults, and guanfacine extended release (Intuniv, Shire, Wayne, PA), a selective alpha-2A adrenergic receptor agonist approved for monotherapy for children and as adjunctive therapy to stimulants for the subgroup of children with a suboptimal response to stimulants. In addition, certain psychotropic and nonpsychotropic medications are often prescribed off label for the treatment of ADHD, including clonidine immediate release and AAPs.

Clinical Implications

• In clinical practice, the HRU or cost consequences of treatment decisions are often poorly understood.

• High rates of therapy changes, increased HRU, and costs were observed in stimulant-treated children and adolescents with ADHD using AAPs in Quebec.

• This indicates a need for informed decision making and further research on alternative treatment options when stimulant monotherapy is insufficient.

Limitations

• Common limitations inherent to retrospective claims analysis may apply (for example, lack of clinical information on patients and treatments).

• Limitations specific to use of the RAMQ database also apply to our study, as described within the article.

Among off-label drugs, AAPs have received special attention. ADHD is among the top diagnoses associated with AAP prescriptions, which increased 5-fold from 1999 to 2008.⁹ Risperidone is one of the most frequently prescribed AAPs in this population.^10–12 In 2004, an international expert panel for child and adolescent psychiatry recommended augmenting stimulants with risperidone as a second-line treatment for children and adolescents who had persistent and marked aggression or impulsivity and were diagnosed with ADHD and disruptive behaviour disorders.¹² However, published evidence supporting the efficacy and safety of AAPs for treating ADHD is currently limited.^13,14 Clinical trials of AAPs have been conducted on specific ADHD subpopulations, including patients with comorbidities, such as bipolar disorder or mental retardation,^11,15 or on specific symptoms, such as treatment-resistant aggression.¹⁰ The effectiveness of AAPs in controlling core ADHD symptoms was variable in these trials. Serious side effects associated with AAP use, such as extrapyramidal symptoms, tardive dyskinesia, metabolic syndrome including hyperprolactinemia, type-2 diabetes, and weight gain, are of concern.^14,16–22

A recent study in the province of Quebec found that the 1-year period prevalence of combination therapy and switching among 9431 children and adolescents with ADHD treated with stimulants was 19.8% and 18.7%, respectively. The most frequent combination categories were AAPs (10.8%), atomoxetine (5.5%), and clonidine (5.3%). The most frequent switched-to categories were other stimulants (7.9%), AAPs (5.5%), and ATX (4.7%).²³ However, to our knowledge, costs associated with AAP use among children and adolescents with ADHD in Canada have not been assessed. Given the high prevalence of AAP use in this population, it is important to understand the treatment patterns, HRU, and economic impact associated with AAP use. Such information can help clarify the economic impact of initiating AAPs in children and adolescents with ADHD. In our retrospective observational study, we evaluated the treatment patterns, HRU, and health care costs after initiation of AAPs among children and adolescents with ADHD in Quebec who received AAPs either as an augmenting drug or as an alternative therapy to stimulants.

Methods

Data and Patient Selection

A retrospective analysis of health care claims data from Quebec’s provincial health plan database, the RAMQ, was conducted. The RAMQ database contains information on medical services for the entire Quebec population (more than 7.5 million people covered annually) and prescription drug claims from the RAMQ prescription drug plan (about 3.3 million people). Enrollees in the drug plan include recipients of last-resort financial assistance, people who are not eligible for a private insurance plan and their dependents, and people who are 65 years or older.

For the purpose of our study, medical and prescription drug claims data for children and adolescents with ADHD who had at least 1 prescription for a stimulant between March 1, 2007, and February 29, 2012, were extracted. Patients were required to have their first prescription fill of their first AAP (see list of AAPs in online eAppendix A), defined as the index AAP, after a stimulant fill, and had to have augmented with or switched (as defined below) to the index AAP from a stimulant (defined as the index stimulant). The date on which the index AAP prescription was filled was defined as the index date, with the 6 months preceding the index date and the 12 months following the index date, defined as the baseline period and the follow-up period, respectively. Patients were also required to have at least 1 documented ADHD diagnosis (ICD-9 codes: 314.0 to 314.9) during the baseline or follow-up periods, continuous enrolment in both medical and prescription drug plans throughout these 2 periods, and at least 30 days’ supply of a stimulant before the index date. To protect patient confidentiality, patients’ ages were reported in groups of 2- to 3-year intervals. Based on these age groups, patients were required to be between 6 and 17 years of age as of January 1st of the year of the index date. Finally, patients who had a documented psychiatric diagnosis for which AAPs are indicated (according to the approved product labels by Health Canada summarized in online eAppendix B) during the baseline or follow-up periods were excluded from this study.

Study Measures

The following outcomes were measured in our study: treatment patterns after AAP initiation, including discontinuation, augmentation, and switching; HRU; and health care costs.

Discontinuation of the index AAP was defined as a gap of at least 30 consecutive days between the end of the supply of a prescription fill, and either the beginning of the following fill for the index AAP or the end of the study period, whichever occurred earliest. The discontinuation date was defined as the last day of supply of the index AAP before the gap. Augmentation of the index AAP was defined as the event in which a new psychotropic (see list in online eAppendix A) was initiated after the index AAP and was used concomitantly with the index AAP for at least 30 consecutive days during the study period.²⁴ Switching was defined as a prescription fill of a new psychotropic that could be used for the treatment of ADHD that had an overlap in supply of less than 30 days with the index AAP or a gap of less than 30 days between the end of supply of the index AAP and the initiation of the new treatment. Stimulants, ATX, clonidine, or other AAPs (online eAppendix A) were considered psychotropics that could be used for augmentation or switching.

Assessment of HRU included medical services and prescription drugs. Medical services included inpatient admissions, inpatient days, ED visits, outpatient visits (all outpatient and office visits, excluding psychiatric department visits), psychiatric department visits, and other medical services (for example, visits to local community service centres, chronic pain centres, foster care establishments, or laboratories). Because the number of inpatient admissions and lengths of stay were not directly available in the data, the number of inpatient admissions and inpatient days were estimated from the RAMQ medical claims using a published algorithm developed and validated to replicate hospitalization episodes, which first identifies all claims for services delivered in hospitals (from variables describing the date and the location of the billed service) and then identifies hospitalizations from the temporal sequence of the inpatient claims.²⁵

The medical services and prescription claims were further categorized into all-cause, ADHD-related (services associated with an ADHD diagnosis or pharmacy claims for medications that could be used for ADHD, listed in online eAppendix A) and mental health-related HRU (services associated with a diagnosis of mental health disorder or pharmacy claims for mental health-related medications within the therapeutic classes listed in online eAppendix C). ADHD and mental HRU were not mutually exclusive. ADHD diagnoses (ICD-9 codes: 314.0 to 314.9) were a subgroup of mental health-related diagnoses (ICD-9: 290 to 319), and ADHD medications were a subgroup of mental health-related medications.

Medical service costs included costs charged by physicians to the RAMQ for inpatient, ED, outpatient, psychiatric, and other medical services. In addition, as the RAMQ database Services médicaux rémunérés à l’acte only includes information on physician costs, hospitalization costs for inpatient admissions and ED visits were imputed based on average costs charged for an inpatient day and an ED day using data provided by the Ministère de la Santé et des Services Sociaux of Quebec (that is, Quebec’s Ministry of Health and Social Services). Prescription drug costs reported were amounts charged by pharmacists to the RAMQ. Total health care costs were defined as the sum of medical service costs and prescription drug costs. Each type of health care cost was further categorized into all-cause, ADHD-related, and mental health-related costs. Similar to resource use, ADHD-related costs were a component of mental health-related costs.

Costs were calculated from the Quebec public payer’s perspective. All costs were inflated to 2012 Canadian dollars using the Quebec consumer price index for health and personal care, published by Statistics Canada.

Statistical Analysis

Mean, median, and SD were reported for continuous variables. Frequency and percentage were reported for categorical variables. Patients’ demographics (for example, age, sex, index year, and enrolment type), treatment (for example, class of index stimulant and number of stimulants used during baseline), comorbidities, and other baseline characteristics (for example, physician specialty) were summarized using descriptive statistics. Time from the index date to AAP treatment discontinuation, augmentation, or switching during the 12-month follow-up period were estimated using KM survival analyses. Patients were censored at discontinuation of the index AAP when analyzing treatment switching, and at discontinuation or switching when evaluating treatment augmentation.

A pre–post design was used to evaluate the HRU and health care costs associated with initiation of the index AAP. To ensure comparable duration of time between the pre and post periods, the proportion of patients with at least 1 visit or at least 1 drug prescription was compared between the 6-month baseline period and the 6-month study period (defined as the first 6 months of the 12-month follow-up period) using McNemar’s tests. HRU and health care costs were summarized for the 6-month baseline period, the 6-month study period, and the entire 12-month follow-up period. The mean HRU and costs were compared between the 6-month baseline period and the 6-month study period using Wilcoxon signed-rank tests. For comparison purposes, statistical significance was evaluated at the 0.05 significance level (2-sided).

Sensitivity Analysis

Several sensitivity analyses were undertaken to evaluate the robustness of the study findings. An alternative definition for treatment discontinuation, which required a gap of at least 60 consecutive days between the end of a prescription supply and the beginning of the next fill of the index AAP, was used. Additionally, switching was alternatively defined as an overlap in days of supply of the index AAP and the new drug of less than 30 consecutive days, or a gap of less than 60 days.

Results

Baseline Characteristics

A total of 13 850 children and adolescents with ADHD who received stimulant prescriptions during the 5-year period from March 2007 to February 2012 were identified in the RAMQ database. Among these 13 850 patients, 1894 (13.7%) filled an AAP prescription. After applying additional inclusion criteria, 453 children and adolescents with ADHD aged 6 to 17 years were identified as having initiated their first AAP, either as an augmenting drug or as alternative therapy to a stimulant. Among these patients, 206 (45.5%) augmented a stimulant with an AAP and 247 (54.5%) switched from a stimulant to an AAP. The sample selection flow chart is shown in Figure 1.

Figure 1.

Flow chart of patient selection

As shown in Table 1, the mean age of patients was 10.4 (SD 2.5) years, with the majority (73.7%) of them being children (that is, aged 6 to 12 years) and male (74.6%). The index stimulants used by these patients were LA methylphenidate (50.3%), LA amphetamines (25.4%), SA methylphenidate (22.3%), and SA amphetamines (2.0%) (online eTable 2). The index AAPs were predominantly risperidone (81.7%), followed by quetiapine (16.3%) (online eTable 3).

Table 1.

Patient demographics and baseline characteristics

Baseline characteristics	Patients, n = 453 n (%)
Demographics
Age, years, mean (SD) [median]	10.42 (2.5) [10.0]
Children (≤12 years)	334 (73.7)
Adolescents (>12 years)	119 (26.3)
Female	115 (25.4)
Enrolment type
Employment assistance recipient	173 (38.22)
Subscriber	280 (61.78)
Class and formulation of index stimulant
Amphetamines, short acting	9 (2.0)
Amphetamines, long acting	115 (25.4)
Methylphenidate, short acting	101 (22.3)
Methylphenidate, long acting	228 (50.3)
Number of distinct stimulants, mean (SD) [median]	1.39 (0.5) [1.0]
Comorbidity profile
Mental comorbidities
Adjustment reaction	32 (7.1)
Anxiety disorder	23 (5.1)
Learning disability	20 (4.4)
Physical comorbidities
Accidents and injuries	43 (9.5)
Asthma	11 (2.4)
Number of comorbidities
Patients with 1 comorbidity	117 (25.8)
Patients with 2 comorbidities	26 (5.7)
Patients with ≥3 comorbidities	9 (2.0)
Physician specialtya
Physician prescribing the index AAP
Psychiatry	186 (41.1)
Pediatrics	162 (35.8)
Neurology	30 (6.6)
Missing	74 (16.3)
Physician prescribing ≥1 stimulant
Pediatrics	236 (52.1)
Psychiatry	128 (28.3)
Neurology	28 (6.2)
Missing	143 (31.6)
Physician providing ≥1 ADHD diagnosisb
Pediatrics	144 (31.8)
Psychiatry	125 (27.6)
Neurology	21 (4.6)
Missing	63 (13.9)

^aOnly the most common physician specialties are reported.

^bNumbers are not mutually exclusive as patients could have been seen by >1 specialist during the baseline period.

AAP = atypical antipsychotic; ADHD = attention-deficit hyperactivity disorder

About 33.5% of patients had at least 1 documented comorbidity during the 6-month baseline period. The most frequently documented psychiatric or neurologic comorbidities were adjustment reaction (7.1%), anxiety disorder (5.1%), and learning disability (4.4%). Index AAPs were most commonly prescribed by psychiatrists (41.1%) (Table 1).

Treatment Patterns

Pharmacologic therapy regimen changes occurred in 92.1% of patients during the 12-month, follow-up period. The KM survival curves of treatment discontinuation, augmentation, switching (not mutually exclusive), or any one of these

Health Care Resource Utilization

A significantly higher proportion of patients had at least 1 all-cause outpatient visit in the 6-month study period after initiating the index AAP, compared with baseline (92.3%, compared with 87.4%, P = 0.01) (Table 4). There were no significant differences (P > 0.05) in the proportion of patients with at least 1 psychiatric department visit, the proportion of patients with at least 1 inpatient admission, and the proportion of patients with at least 1 ED visit between the baseline and study periods.

Table 4.

Health care resource utilization in patients with at least 1 service: comparison between the 6-month period before and after atypical antipsychotic initiation, n = 453

Health care resource utilization	6-month period
	Before index date	After index date	Pa	12-month follow-up period
Patients with ≥1 all-cause service, n (%)
Inpatient admission	38 (8.4)	37 (8.2)	0.89	49 (10.8)
Emergency department visit	112 (24.7)	101 (22.3)	0.32	139 (30.7)
Outpatient visit	396 (87.4)	418 (92.3)	0.01b	442 (97.6)
Psychiatric department visit	11 (2.4)	13 (2.9)	0.56	16 (3.5)
Other medical servicec	28 (6.2)	33 (7.3)	0.44	56 (12.4)
Prescription drugs	453 (100.0)	453 (100.0)	—	453 (100.0)
Patients with ≥1 ADHD-related service, n (%)
Inpatient admission	13 (2.9)	10 (2.2)	0.37	12 (2.6)
Emergency department visit	9 (2.0)	7 (1.5)	0.62	7 (1.5)
Outpatient visit	302 (66.7)	301 (66.4)	0.94	369 (81.5)
Psychiatric department visit	5 (1.1)	4 (0.9)	0.71	4 (0.9)
Other medical servicec	3 (0.7)	4 (0.9)	0.71	5 (1.1)
Prescription drugs	453 (100.0)	453 (100.0)	—	453 (100.0)
Patients with ≥1 mental health-related service, n (%)
Inpatient admission	24 (5.3)	13 (2.9)	0.02b	17 (3.8)
Emergency department visit	35 (7.7)	27 (6.0)	0.27	35 (7.7)
Outpatient visit	365 (80.6)	388 (85.7)	0.04b	420 (92.7)
Psychiatric department visit	10 (2.2)	11 (2.4)	0.76	13 (2.9)
Other medical servicec	5 (1.1)	10 (2.2)	0.10	13 (2.9)
Prescription drugs	453 (100.0)	453 (100.0)	—	453 (100.0)
All-cause utilization, mean (SD), number per patient [median]
Inpatient admission	0.12 (0.42) [0.00]	0.13 (0.51) [0.00]	0.92	0.17 (0.60) [0.00]
Inpatient days	0.27 (1.90) [0.00]	0.64 (5.40) [0.00]	0.80	1.06 (8.78) [0.00]
Emergency department visits	0.38 (0.87) [0.00]	0.37 (1.12) [0.00]	0.61	0.60 (1.55) [0.00]
Outpatient visits	3.22 (3.12) [2.00]	4.63 (6.24) [3.00]	<0.001b	8.19 (10.59) [6.00]
Psychiatric department visits	0.18 (1.54) [0.00]	0.20 (1.60) [0.00]	0.89	0.36 (2.58) [0.00]
Other medical servicesc	0.09 (0.53) [0.00]	0.10 (0.43) [0.00]	0.46	0.18 (0.58) [0.00]
All medical services	3.98 (4.13) [3.00]	5.42 (6.86) [4.00]	<0.001b	9.49 (11.46) [7.00]
Prescription drugs	13.34 (14.01) [10.00]	22.16 (21.38) [16.00]	<0.001b	45.49 (45.26) [31.00]
ADHD related utilization, mean (SD), number per patient [median]
Inpatient admission	0.03 (0.19) [0.00]	0.04 (0.26) [0.00]	0.82	0.04 (0.29) [0.00]
Inpatient days	0.09 (0.94) [0.00]	0.31 (4.13) [0.00]	0.92	0.59 (6.77) [0.00]
Emergency department visits	0.02 (0.18) [0.00]	0.02 (0.12) [0.00]	0.40	0.02 (0.12) [0.00]
Outpatient visits	1.59 (2.39) [1.00]	2.27 (5.69) [1.00]	<0.001b	3.97 (9.03) [2.00]
Psychiatric department visits	0.05 (0.54) [0.00]	0.04 (0.46) [0.00]	0.93	0.06 (0.70) [0.00]
Other medical servicesc	0.02 (0.39) [0.00]	0.01 (0.16) [0.00]	—	0.02 (0.17) [0.00]
All medical services	1.71 (2.47) [1.00]	2.37 (5.71) [1.00]	0.001b	4.11 (9.06) [2.00]
Prescription drugs	10.46 (10.14) [8.00]	18.90 (17.21) [14.00]	<0.001b	38.43 (36.45) [27.00]
Mental health related use, mean (SD), number per patient [median]
Inpatient admission	0.06 (0.28) [0.00]	0.05 (0.30) [0.00]	0.31	0.06 (0.36) [0.00]
Inpatient days	0.14 (1.01) [0.00]	0.33 (4.14) [0.00]	0.21	0.70 (7.95) [0.00]
Emergency department visits	0.11 (0.42) [0.00]	0.08 (0.39) [0.00]	0.18	0.10 (0.44) [0.00]
Outpatient visits	2.43 (2.78) [2.00]	3.52 (5.93) [2.00]	<0.001b	6.06 (10.02) [4.00]
Psychiatric department visits	0.17 (1.53) [0.00]	0.19 (1.59) [0.00]	0.84	0.27 (2.02) [0.00]
Other medical servicesc	0.03 (0.43) [0.00]	0.03 (0.25) [0.00]	0.50	0.04 (0.28) [0.00]
All medical services	2.80 (3.46) [2.00]	3.87 (6.24) [3.00]	<0.001b	6.54 (10.33) [4.00]
Prescription drugs	11.58 (11.96) [9.00]	20.22 (19.53) [14.00]	<0.001b	41.43 (41.47) [28.00]

^aThe medical service use during the 6-month baseline period (before index date) was compared with the use of the 6-month study period (after index date). McNemar’s tests were used to compare binary variables and Wilcoxon signed-rank tests were used for the comparison of continuous variables.

^bSignificant at the 5% level.

^cOther medical services include services dispensed from a local community service centre, a chronic pain centre, a foster care establishment, or a laboratory.

ADHD = attention-deficit hyperactivity disorder; — = not calculable

Consistent with all-cause outpatient visits, a higher proportion of patients with at least 1 mental health-related changes in the index AAP treatment are presented in Figure 2. The 12-month KM rates of treatment discontinuation, treatment augmentation, and treatment switching were 45.5%, 68.2%, and 80.7%, respectively. For most patients with pharmacologic therapy regimen changes, the changes occurred in the first 6 months after the index AAP was initiated (6-month KM rate of 87.6%).

Figure 2.

Kaplan–Meier analyses of treatment patterns after atypical antipsychotic use: a) treatment discontinuation^a; b) treatment augmentation^b

Kaplan–Meier analyses of treatment patterns after atypical antipsychotic use: c) treatment switching^c; d) any therapy regimen change

AAP = atypical antipsychotic; ADHD = attention-deficit hyperactivity disorder

^a Discontinuation of the index AAP was defined as a gap of at least 30 consecutive days between the end of the supply of a prescription fill and either the beginning of the following fill for the index AAP or the end of the study period, whichever occurred earliest.

^b Augmentation of the index AAP was defined as the event in which a new psychotropic (see list in online eAppendix A) was initiated after the index AAP and was used concomitantly with the index AAP for at least 30 consecutive days during the study period.

^c Switching was defined as a prescription fill of a new psychotropic that could be used for the treatment of ADHD that had an overlap in supply <30 days with the index AAP, or a gap of <30 days between the end of supply of the index AAP and the initiation of the new treatment.

Results of the sensitivity analyses that used alternative definitions of discontinuation and switching were similar, with the 12-month KM rates of treatment discontinuation, augmentation, and switching estimated at 35.1%, 67.0%, and 78.0%, respectively (online eFigure 3).

outpatient visit was observed in the study period, compared with at baseline (85.7%, compared with 80.6%, P = 0.04). However, the proportion of patients who had at least 1 mental health-related inpatient admission was smaller during the study period than during the baseline period (2.9% compared with 5.3%, P = 0.02). No significant difference was seen in the proportions of patients with at least 1 ADHD-related health care service between the baseline and study periods.

When comparing all-cause medical services and prescription drug use, patients with ADHD incurred significantly more outpatient visits (4.6, compared with 3.2) and number of prescriptions filled (22.2, compared with 13.3) after they initiated treatment with AAPs (both P < 0.001) (Table 4). There were no significant differences (P > 0.05) between the average number of inpatient admissions, inpatient days, and psychiatric department visits between the baseline and study periods. For both ADHD- and mental health–related services, the average numbers of outpatient visits (ADHD-related: 2.3 compared with 1.6; mental health–related: 3.5, compared with 2.4) and prescriptions (ADHD-related: 18.9, compared with 10.5; mental health–related: 20.2, compared with 11.6) per patient increased significantly during the study period (all P < 0.001).

Health Care Costs

Congruent with HRU patterns, the average all-cause outpatient costs ($303, compared with $207), prescription drug costs ($889, compared with $710), medical costs ($1096, compared with $644), and total health care costs ($1985, compared with $1354) were significantly higher during the study period than the baseline period (all P ≤ 0.001) (Table 5). The ADHD-related outpatient ($136, compared with $96, P = 0.02), prescription drug ($812, compared with $635, P < 0.001), and total health care ($1269, compared with $835, P < 0.001) costs were all significantly higher in the study period than in the baseline period. The mental health–related outpatient ($227, compared with $157, P < 0.001), prescription drug ($831, compared with $653, P < 0.001), medical ($605, compared with $355, P = 0.01), and total health care ($1435, compared with $1008, P < 0.001) costs were also significantly higher in the study period. During the study period, all-cause, ADHD-related, and mental health–related total health care costs increased by 46.6%, 52.0%, and 29.8%, respectively, from the baseline period.

Table 5.

Health care costs: comparison between the 6-month period before and after atypical antipsychotic initiation n = 453

Health care cost a	6-month period Mean (SD) cost per patient [median]
				12-month follow-up period Mean (SD) cost per patient [median]
	Before index date	After index date	Pb
All-cause
Inpatient costc	285 (1904) [0]	647 (5343) [0]	0.69	1056 (8528) [0]
Emergency department costd	133 (318) [0]	128 (381) [0]	0.50	206 (529) [0]
Outpatient cost	207 (196) [159]	303 (383) [211]	<0.001e	543 (682) [376]
Psychiatric department visit cost	15 (135) [0]	15 (119) [0]	0.87	24 (168) [0]
Other medical costf	4 (36) [0]	3 (14) [0]	0.71	6 (20) [0]
All medical cost	644 (2047) [253]	1096 (5401) [295]	0.001e	1834 (8610) [527]
Prescription drug cost	710 (510) [634]	889 (522) [808]	<0.001e	1803 (1041) [1654]
Total health care cost	1354 (2096) [969]	1985 (5419) [1190]	<0.001e	3637 (8642) [2403]
ADHD-related
Inpatient cost	88 (933) [0]	310 (4065) [0]	0.73	573 (6550) [0]
Emergency department cost	10 (74) [0]	8 (67) [0]	0.71	8 (67) [0]
Outpatient cost	96 (127) [47]	136 (315) [68]	0.02e	245 (519) [131]
Psychiatric department visit cost	4 (44) [0]	2 (28) [0]	0.38	4 (50) [0]
Other medical costf	2 (35) [0]	1 (7) [0]	0.94	1 (8) [0]
All medical cost	200 (935) [70]	457 (4072) [70]	0.26	830 (6555) [140]
Prescription drug cost	635 (475) [582]	812 (480) [763]	<0.001e	1640 (949) [1526]
Total health care cost	835 (1022) [712]	1269 (4087) [891]	<0.001e	2470 (6580) [1795]
Mental health-related
Inpatient cost	140 (1009) [0]	330 (4077) [0]	0.13	680 (7671) [0]
Emergency department cost	41 (167) [0]	32 (155) [0]	0.31	42 (176) [0]
Outpatient cost	157 (167) [112]	227 (347) [149]	<0.001e	402 (609) [254]
Psychiatric department visit cost	15 (132) [0]	14 (116) [0]	0.94	19 (145) [0]
Other medical costf	2 (35) [0]	1 (10) [0]	0.30	1 (10) [0]
All medical cost	355 (1115) [133]	605 (4096) [168]	0.01e	1145 (7705) [299]
Prescription drug cost	653 (480) [591]	831 (489) [767]	<0.001e	1681 (966) [1549]
Total health care cost	1008 (1199) [796]	1435 (4118) [999]	<0.001e	2825 (7729) [1956]

^aAll costs were estimated from the Quebec public payer perspective, adjusted for inflation, and expressed in 2012 Canadian dollars.

^bWilcoxon signed-rank tests were used for the comparison of continuous variables.

^cInpatient cost was estimated based on the average 2010–2011 inpatient daily cost ($948.90) provided by the Quebec’s Ministry of Health and Social Services.

^dEmergency department cost was estimated based on the average 2010–2011 emergency department visit cost ($271.44) provided by the Quebec’s Ministry of Health and Social Services.

^eSignificant at the 5% level.

^fOther medical costs include services dispensed from a local community service centre, a chronic pain centre, a foster care establishment, or a laboratory.

ADHD = attention-deficit hyperactivity disorder

Discussion

Our study observed that more than 90% of children and adolescents with ADHD augmenting their stimulants with, or switching to, AAPs experienced a pharmacologic therapy regimen change in the form of augmentation, switching, or discontinuation within 12 months after initiating the AAPs. Moreover, for most patients, these changes occurred within the first 6 months of initiating the AAPs. The reasons for these therapeutic changes soon after AAP initiation could not be determined based on this data source. Suboptimal response to AAPs, physicians’ preference to use AAPs for short-term treatment only, tolerability and (or) the complexity of this patient population’s symptoms and pathology are possible explanations. Further research is needed to better understand the clinical basis and appropriateness for such treatment changes.

In addition to the high rate of pharmacologic therapy regimen changes, we also observed that children and adolescents with ADHD had significantly more outpatient visits and prescriptions, most of which were ADHD- and mental health–related, after than before initiation of the index AAP. Cost outcomes followed the same pattern as HRU. It should be noted that our study used health care claims data, which do not contain enough clinical details to determine the reasons for the increased HRU, which may be related to periodic monitoring recommended by AAP treatment guidelines,^14,22 treatment of the metabolic side effects associated with AAPs,^19,20 potential worsening of ADHD symptoms, or development of new conditions for which AAPs are used off label. Nevertheless, a recent US study²⁶ on stimulant-treated children with ADHD found that patients subsequently treated with AAPs had higher HRU and costs, compared with those subsequently treated with non-AAPs, after controlling for observed confounding factors.

In recent years, AAPs have been increasingly prescribed for various behavioural symptoms in the pediatric population.^27,28 Although no AAPs are approved by Health Canada for the treatment of ADHD, the findings of our study showed that about 70% of children and adolescents with ADHD who used an AAP have initiated the AAP without a documented diagnosis for any conditions for which AAPs are approved by Health Canada in the 6 months before and 12 months after the AAP initiation. This may indicate a high proportion of off-label AAP use for ADHD, consistent with recent studies indicating ADHD to be one of the leading diagnoses associated with AAP prescriptions.^9,28 Our findings are comparable with a retrospective analysis²⁶ of US health care claims, which found that stimulant-treated children with ADHD had greater rates of subsequent pharmacologic therapy regimen changes and higher HRU and costs after they initiated treatment with AAPs. The findings in this study highlight the need for additional research on the clinical benefits and risks of using AAPs among patients with ADHD when stimulants do not adequately control symptoms, compared with other treatment options, and associated public health implications.

Limitations

Our study is subject to the common limitations inherent to retrospective studies that rely on claims data; mainly lack of clinical information to represent patient severity or ADHD symptoms and subtypes (for example, hyperactivity and impulsivity, compared with inattention), exact reasons for treatment discontinuation, augmentation, or switching, reasons for initiation of AAPs (for example, treatment of comorbidities, controlling specific ADHD symptoms, such as emotional dysregulation or impulsivity), and other factors, such as nonmedical interventions, that might have affected patients’ treatment outcomes. Because of the lack of clinical details in the claims database, the reasons for increased HRU and costs after AAP initiation could not be determined, which could be associated with increasing severity and complexity of ADHD over time or AAP treatment in some patients. Future studies could use clinically rich data to further investigate the sources of the costs. In addition, treatment patterns were analyzed based on documented claims for filled prescriptions, which do not guarantee the actual consumption of a medication by a patient. A retrospective analysis of a claims database is also subject to coding errors or data omissions, but such errors are not expected to depend on specific patient characteristics and are unlikely to alter the conclusions.

Common limitations specific to use of the RAMQ database also apply to this study.^29–31 A potential limitation is that the listing of multiple diagnoses besides the primary diagnosis is not mandatory, which may result in the omission of some comorbidities, such as those for which the AAPs had approved indications. As RAMQ is not responsible for hospital administration, no information is available regarding the costs of a hospitalization stay or visit, such as costs related to nurses’ or other employees’ remuneration, drugs provided during an episode, or equipment used. In addition, medical services paid by a fixed income package (instead of fee) are not reported in the database. Finally, the study sample containing RAMQ enrollees may not be fully representative of the entire population of Quebec and Canada. Despite such limitations, our study provides a first attempt at quantifying treatment patterns, HRU, and economic outcomes of AAP use in a real-world setting in Quebec.

Conclusions

In this retrospective analysis, children and adolescents with ADHD who received an AAP experienced a high rate of pharmacologic therapy regimen changes and incurred higher HRU and costs after initiation of the AAP treatment. Additional research is needed to better assess the clinical benefit and tolerability issues associated with AAP use among children and adolescents with ADHD.

Abbreviations

AAP

atypical antipsychotic

ADHD

attention-deficit hyperactivity disorder

ATX

atomoxetine HCl

CADDRA

Canadian ADHD Resource Alliance

ED

emergency department

HRU

health care resource utilization

ICD

International Classification of Diseases

KM

Kaplan–Meier

LA

long acting

RAMQ

Régie de l’assurance maladie du Québec

SA

short acting

SD

standard deviation