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Journal of Anxiety Disorders 28 (2014) 530–536

Contents lists available at ScienceDirect

Journal of Anxiety Disorders

sychotropic drug utilization in children with concurrentttention-deficit/hyperactivity disorder and anxiety

inyue Liua, Paul Kubilisa, Dandan Xua, Regina Bussingb, Almut G. Wintersteina,c,∗

Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, 1225 Center Drive, HPNP 3334, Gainesville, FL 32611, United StatesPsychiatry, College of Medicine, University of Florida, Box 100234 UFHSC, Gainesville, FL 32610-0234, United StatesEpidemiology, Colleges of Medicine and Public Health & Health Professions, University of Florida, 2004 Mowry Road, PO Box 100231, Gainesville, FL2610, United States

r t i c l e i n f o

rticle history:eceived 1 March 2014eceived in revised form 5 June 2014ccepted 6 June 2014vailable online 16 June 2014

. Introduction

Attention-deficit/hyperactivity disorder (ADHD) is one of theost prevalent neurobehavioral disorders in childhood. Based on

he National Health Interview Survey 2010, five million (8%) chil-ren aged 3–17 years were reportedly diagnosed with ADHD in thenited States (Bloom, Cohen, & Freeman, 2011).

Children with ADHD are subject to a variety of psychiatrico-morbidities, including anxiety among the most common co-orbidities. According to 2007 National Survey of Children’s Health

NSCH) which included 61,779 children, 18% of children aged 6–17ith ADHD (n = 5028) had co-occurring anxiety disorders, com-ared to about 2% in children without ADHD (Larson, Russ, Kahn,

Halfon, 2011). The prevalence of anxiety in children with ADHDrom clinical samples is even higher, e.g. about 30% in the well-nown Multimodal Treatment Study of ADHD (MTA) (MTA, 1999).oexistent anxiety does not only complicate the treatment ofDHD, but also increases the likelihood of combination pharma-otherapy. Importantly, conflicting evidence about the impact ofnxiety on response to stimulant therapy for ADHD and the poten-ial of stimulants to exacerbate anxiety disorders make treatment

ecisions difficult (Spencer, 2009).

The use of stimulants to treat ADHD in children has been sup-orted by numerous studies and is unanimously recommended

∗ Corresponding author at: University of Florida, College of Pharmacy, PO Box00496, Gainesville, FL 32610-0496, United States. Tel.: +1 352 273 6258;ax: +1 352 273 6270.

E-mail addresses: almut@cop.ufl.edu, liuxinyue99999@ufl.eduA.G. Winterstein).

ttp://dx.doi.org/10.1016/j.janxdis.2014.06.005887-6185/© 2014 Elsevier Ltd. All rights reserved.

in all recent national and international ADHD guidelines (Seixas,Weiss, & Muller, 2012). All other medications, such as atomox-etine (Garnock-Jones & Keating, 2009), �-agonists or bupropion,are second-line or adjunct therapies (Connor, Fletcher, & Swanson,1999; Sallee, Connor, & Newcorn, 2013).

The American Academy of Child and Adolescent Psychiatry(AACAP) practice parameters include the most updated guidelinesfor obsessive compulsive disorder (OCD) (AACAP, 2012) and post-traumatic stress disorder (PSD) (Cohen et al., 2010), and a historicalguideline for anxiety disorders (Connolly & Bernstein, 2007) forchildren and adolescents. In contrast to ADHD, cognitive behav-ioral therapy (CBT) is the first-line therapy for childhood anxietydisorders. The short-term efficacy of SSRIs in the treatment of selec-tive mutism with OCD, social phobia, generalized anxiety disorder(GAD), social phobia, and separation anxiety disorder (SAD) hasbeen tested in clinical trials. However, the FDA has only approvedfour drugs (sertraline for children age 6–18 years, in 2002; fluoxe-tine, 7–18 years, in 2002; fluvoxamine, 8–18 years, in 1997; andclomipramine, 10–18 years, in 1992) for children with OCD. Nodrugs have been approved for other types of anxiety in childrenand adolescents.

Interpretation of evidence concerning the treatment of ADHDwith comorbid disorders is complicated. The 2001 AmericanAcademy of Pediatrics (AAP) guidelines state that the literatureprovides minimal information about how to treat these coexistingconditions in conjunction with ADHD, including anxiety (AAP,2001). The National Institute of Mental Health (NIMH) Multimodal

Treatment Study of ADHD (MTA) and several other studies showedthat anxiety disorders do not have adverse effect on medicationresponse for core ADHD symptoms (Garcia et al., 2009; March et al.,2000; van der Oord, Prins, Oosterlaan, & Emmelkamp, 2008), but

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X. Liu et al. / Journal of Anxi

thers report that response to methylphenidate is inversely cor-elated with the reported anxiety level (Moshe, Karni, & Tirosh,012; Ter-Stepanian, Grizenko, Zappitelli, & Joober, 2010). In con-rast, stimulants neither improve nor exacerbate anxiety symptomsAbikoff et al., 2005; MTA, 1999). The combination of stimulantsnd SSRIs is a common pharmacotherapeutic option for ADHD andnxiety, but clinical trials evaluating this practice are very limitedAbikoff et al., 2005). The suicidal risk of SSRIs in children and ado-escents is also a safety concern (Sparks & Duncan, 2013). Finally,tomoxetine was efficacious in reducing ADHD as well as anxietyymptoms (Geller et al., 2007; Kratochvil et al., 2005), however, themprovement of both ADHD and anxiety symptoms is difficult tonterpret as effects on both disorders may be directly attributed torug effects, or alternatively, reflect the effect of improvement innly one disorder, which then positively affected the other (without

direct drug effect).In light of the above facts it is surprising that there has been no

rug utilization study describing the pharmacological treatmentattern of ADHD with anxiety in children and adolescents. There-ore, this study aims to describe concurrent ADHD and anxietyreatment in clinical practice. We also explore potential reasons forariations in treatment, such as socio-demographic and geographicharacteristics.

. Methods

.1. Study design and data sources

We used a retrospective cross-sectional design to describe psy-hotropic drug use in children and adolescents aged 4–18 withoncurrent ADHD and anxiety in the US. The study includes theediatric population eligible for Medicaid fee-for-service programs

n 26 states, totaling 24 million children and adolescents duringn 8-year study period from 1999 to 2006. The study dataset wasstablished from the Medicaid Analytic eXtract Files (MAX), whichncludes monthly information on Medicaid eligibility and billingetails for in- and outpatient services and prescription dispensing

nformation. The Institutional Review Board and Privacy Office athe University of Florida and the Centers for Medicare and Medicaidervices (CMS) approved this study.

.2. Study population

Children who had at least two outpatient diagnoses for ADHDICD9-CM codes: 314, 314.0, 314.00, 314.01 and 314.9) and two out-atient diagnoses for anxiety (300.0–300.09, 300.2–300.29, 300.3,09.21, 309.81, 313.0, 313.2x, 308.0, 308.2x–308.9x) between 1anuary 1999 and 31 December 2006 were included in the study.

e had two study samples with different exclusion criteria. Inhe first sample children with any of the following psychiatricisorders at any time during the study period were excludedrom the analysis: autism (299.0x, 299.8x, 299.9x), ODD/CD312–312.29, 312.4x–312.9x, 312.30, 312.34, 312.35, 313, 313.8,13.81 and 313.9x), bipolar disorder (296.0–296.19, 296.4–296.81,96.83–296.99, and 301.13), depression (296.2x, 296.3x, 296.82,00.4, 311), schizophrenia and other psychotic disorders (295.xx,98.xx, and 297.xx), and tics disorder/Tourette syndrome (307.2xnd 307.3x). In the second sample we excluded the same psy-hiatric co-morbidities except ODD/CD and depression. ODD/CD

nd depression are the most common psychiatric comorbidi-ies in children with ADHD and their presence may affect therobability and/or selection of psychotropic treatment of anxietyr ADHD.

sorders 28 (2014) 530–536 531

2.3. Identification of study time

We established a framework to identify time periods when chil-dren had concurrent ADHD and anxiety. We assigned the durationof ADHD as the day of the first outpatient diagnosis of ADHD untilthe day of the last outpatient diagnosis of ADHD. The duration ofanxiety was set as the day of each (new or recurrent) outpatientdiagnosis to 90 days thereafter (main study cohort). Periods of over-lapping ADHD and anxiety diagnoses of at least 1 day were includedin the analysis.

As the designation of the disorders’ duration was arbitrary, weran sensitivity analyses to examine the impact of different disorderduration definitions on the drug utilization results. We defined theduration of both ADHD and anxiety as the day of each (new or recur-rent) outpatient diagnosis until 90, 183 or 365 days thereafter inthree separate sensitivity analyses. Because the main results of thetwo study populations differed only marginally, sensitivity analy-ses are only shown for the first study sample, which was restrictedto patients with only ADHD and anxiety.

2.4. Definition of drug exposure

We used pharmacy billing data to determine psychotropic drugexposure during the periods of concurrent ADHD and anxiety. Theprescription fill date was set as the start day of treatment. The phar-macy recorded days’ supply plus a 10-day grace period definedthe duration of each filled prescription to compensate for smallbut irrelevant treatment breaks due to late refills. We also reportsensitivity analyses in which no grace period was used for studysample 1 in the appendix. Eighty-eight active ingredients includedin the study were grouped into eight drug classes, includingcentral nervous stimulants, atomoxetine, antidepressants, antipsy-chotics, anticonvulsants, anxiolytics, lithium and �-agonists.Concomitant therapy was defined as overlap of specific activeingredients.

A systematic review focusing on antipsychotic polyphar-macy summarized the methodology in 15 studies. Antipsychoticpolypharmacy was defined as ≥1 day, ≥30 days, ≥60 days and≥90 days in 10, 1, 3 and 1 study, respectively (Toteja et al., 2014).However, using short overlap (e.g. ≥1 day) to define polypharmacymay misclassify switch therapy to concomitant therapy, resultingin overestimation of the prevalence. Since switching of antipsy-chotics in clinical practice is usually accomplished within 5 weeks(DMHMRSAS, 2005), we categorized all exposure period overlapsof more than 40 days as concomitant use, and overlaps of less than40 days as “undetermined”.

2.5. Data analysis

We estimated treatment prevalence defined as the proportionof time patients were treated with single-, dual- or triple therapywhile they met all inclusion criteria. Thus, analyses are based onperson-time and one patient may contribute different amounts ofperson time to several categories.

We used chi-square test to compare the proportions of “notherapy” in the periods when the patients were below and above6-years. We used a logistic regression model to evaluate the impactof state, gender, race, age, foster care, disability (supplementalsecurity income, SSI) and poverty (temporary assistance for needy

families, TANF) on the treatment of combination versus no com-bination therapy after controlling for the total length of periodswith ADHD and anxiety. All analyses were completed with SAS 9.2(Cary, NC).

532 X. Liu et al. / Journal of Anxiety Disorders 28 (2014) 530–536

Table 1Study population in the two study samples.

Demographics Study sample 1 (comprehensiveexclusion criteria)

Study sample 2 (ODD/CD anddepression not excluded)

No. patients 20,461 62,064Male: n (%) 12,810 (62.6) 39,308 (63.3)White: n (%) 13,508 (66.0) 39,972 (64.4)Black: n (%) 4049 (19.8) 13,333 (21.5)Hispanic: n (%) 2014 (9.8) 5998 (9.7)Foster care: n (%) 3997 (19.5) 15,957 (25.7)Disability: n (%) 482 (2.4) 1374 (2.2)Poverty: n (%) 1986 (9.7) 6558 (10.6)Total duration of concomitant ADHD/anxiety (patient-years) 13,192 44,843Number of concomitant ADHD/anxiety periods, average per patient 1.4 1.5Length of concomitant ADHD/anxiety periods (days)

Mean(±SD), median 235 (±282), 139 264 (±308), 161Age at the first period of ADHD/anxiety

Mean (±SD), median 9.6 (±3.3), 9.2 10.3 (±3.4), 10.0<6: n (%) 2564 (12.5%) 6329 (10.2%)6–9: n (%) 7101 (34.7%) 17,959 (28.9%)

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. Results

We identified 2,096,714 patients who had at least one outpa-ient physician visit with the diagnosis of ADHD from January 1,999 to December 31, 2006. Based on the main definition of con-omitant ADHD and anxiety and after restriction to time periodshere patients were between 4 and 18 years and eligible for Med-

caid fee-for-service coverage the study included 20,461 and 62,064atients in the two study samples respectively (Table 1). Thus, per-itting presence of ODD or depression tripled the sample size.

atients in study sample 1 were slightly older and had slightlyonger follow-up time than those in study sample 2.

Examining period of concomitant use of specific active ingredi-nts, we observed that the majority of time (48.0% and 44.5%, forhe two study samples, respectively) was allocated to monotherapynd 28.9% and 25.8% of time was allocated to no drug therapy forhe two study samples, respectively. Combination therapy occurreduring 11.0% and 13.2% (dual therapy) and 2.2% and 3.2% (multi-le therapies) of time, while 10.0% and 13.3% was “undetermined”ecause the periods of drug overlap were less than 40 days for thewo study samples, respectively. The prevalence of psychotropicreatment and psychotropic polypharmacy in children with ADHDnd anxiety permitting presence of ODD/CD or depression waslightly higher than in children with ADHD and anxiety only. Theroportions of dual therapy, triple therapy and multiple therapies

n the analyses with no grace period were considerably lower thanhat with a 10-day grace period (appendix, Table 2). This is becauseven one day of late refills is counted as discontinuation of drugherapy and thus affects the availability of uninterrupted periodsf overlapping drug therapy of at least 40-days as used to defineombination therapy. Sensitivity analyses assuming longer dura-ion of the disorders increased the proportion of no therapy andecreased the proportion of pharmacotherapy slightly (appendix,able 2).

For time periods when patients were 6 years or younger (over-ll 746 and 2187 patient-years) we observed a greater proportionith no psychotropic therapy (37.3% and 34.9%), compared to timeeriods at greater age (27.8% and 25.3%, 10,060 and 42,656 patient-ears) in the two study samples (P < 0.001 for both comparisons).

Table 2 shows the distribution of psychotropic drug classesithin the above-described monotherapy, dual therapy and

riple therapy combinations in the two study samples. Stimulantonotherapy (33.8% and 27.5%) was the most common treat-ent choice, followed by antidepressant monotherapy (5.4% and

.6%) and atomoxetine (3.7% in study sample 1) or antipsychotic

4 (41.1%) 27,174 (43.8%)2 (11.6%) 10,602 (17.1%)

monotherapy (3.6% in study sample 2). The combination of stim-ulants and antidepressants (4.1% and 5.0%) and the combinationof stimulants and �-agonists (2.3% in study sample 1) or antipsy-chotics (2.4% in study sample 2) were the most common treatmentchoices for dual therapy. Sensitivity analyses showed similar resultsfor monotherapy and decreased prevalence for combination ther-apy when the grace period of ten days between refills was removed(appendix, Table 3).

Table 3 shows the top active ingredients or active ingredientcombinations for monotherapy (top 10) and dual therapy (top10) based on concomitant therapy defined as ≥40 day overlap.We do not display triple or more combination therapy as propor-tions were small. Mono- or combination pharmacotherapy withmethylphenidate, amphetamine, atomoxetine, clonidine, risperi-done and sertraline were the most commonly treatment choices.

After excluding patients with missing information about fostercare, disability, poverty or state designation (<2.5%), we identified20,060 and 60, 618 patients for the analysis of associations betweencombination therapy and geographic and sociodemographic factorsin the two study samples, respectively. Among these patients, 21.9%and 29.6% (with 10-day grace period) had at least one period ofmore than 40 days of psychotropic combination pharmacotherapyfor the two study samples, respectively. This proportion droppedsubstantially if no grace period was applied (e.g. 9.4% in study sam-ple 1).

After controlling for the length of concurrent diagnoses ofADHD and anxiety, we found females, Blacks, Hispanics, chil-dren with cash assistance (TANF) showed lower, while those infoster care showed higher probabilities of being treated with com-bination pharmacotherapy. Disability did not have a significantimpact on combination pharmacotherapy (Table 4). The Hosmerand Lemeshow Goodness-of-Fit Test of the logistic regressionshows p = 0.2175 and 0.0217 for the two study samples respec-tively, indicating moderate goodness-of-fit. The main study cohortand sensitivity analyses showed similar results (appendix, Table 5).

The likelihood of being treated with multiple psychotropic drugsin the 26 states varied greatly with highest propensity for treatmentin IA, LA, TX and MA. After we grouped the states to regions accord-ing to the census bureau, we found that compared to the South, thepropensity for combination treatment was slightly higher in theMiddle West (OR = 1.2 (1.1–1.3) and 1.2 (1.2–1.3) for study sam-

ple 1 and 2, respectively) and slightly lower in the West in studysample 2 (OR = 0.7 (0.6–0.9)), while not significantly different in theWest in study sample 1 (OR = 0.9 (0.7–1.2)), and North East (OR = 1.1(0.9–1.2) and 1.0 (0.9–1.0) for study sample 1 and 2, respectively).

X. Liu et al. / Journal of Anxiety Disorders 28 (2014) 530–536 533

Table 2Top drug classes used in children with ADHD/anxiety in the two study samples.

Pharmacotherapy therapeutic class Study sample 1 (comprehensiveexclusion criteria) % (95%CI)

Study sample 2 (ODD/CD anddepression not excluded) % (95%CI)

MonotherapySTI 33.84 (33.78–33.90) 27.49 (27.46–27.52)ADP 5.36 (5.33–5.39) 7.55 (7.54–7.57)ATO 3.69 (3.66–3.71) 2.72 (2.70–2.73)APC 2.28 (2.26–2.30) 3.57 (3.56–3.58)AGN 1.75 (1.74–1.77) 1.96 (1.95–1.97)AXL 0.64 (0.63–0.65) 0.64 (0.63–0.64)ACV 0.61 (0.60–0.62) 0.89 (0.89–0.90)LIT 0.01 (0.01–0.01) 0.03 (0.02–0.03)

Dual therapy (Top 5)STI + ADP 4.08 (4.05–4.10) 4.97 (4.96–4.99)STI + AGN 2.31 (2.29–2.33) 2.28 (2.27–2.29)STI + APC 1.70 (1.68–1.71) 2.37 (2.36–2.38)STI + ACV 0.46 (0.45–0.47) 0.61 (0.60–0.61)ADP + ATO 0.41 (0.40–0.42) /ADP + APC / 0.55 (0.55–0.56)

Triple therapy (Top 5)STI + ADP + AGN 0.42 (0.41–0.43) 0.49 (0.48–0.49)STI + ADP + APC 0.34 (0.33–0.34) 0.64 (0.63–0.64)STI + AGN + APC 0.24 (0.23–0.24) 0.30 (0.29–0.30)STI + ADP + ACV 0.15 (0.14–0.15) 0.20 (0.19–0.20)STI + APC + ACV 0.11 (0.10–0.11) 0.16 (0.16–0.16)

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or monotherapy, all the drug classes are displayed; for dual and triple therapy, onot ranked as top 5 in the specific study sample.bbreviations: STI, stimulant; ADP, antidepressant; APC, antipsychotics; ATO, atom

. Discussion

Our study has several key findings. First, we noted distinct vari-tion in treatment of children with ADHD and anxiety and no other

sychiatric diagnoses. The time when the patient had the two dis-rders was almost equally distributed between no treatment (30%nd 25%), monotherapy (40% and 45%) and combination pharma-otherapy (30% and 30%) in the two study samples, which might

able 3op 10 active ingredients or active ingredient combinations used in children with ADHD/

Pharmacotherapy therapeutic class Study sample 1 (compreexclusion criteria) % (95

Monotherapy (Top 10)MPH 18.57 (18.52–18.62)

AMP 13.54 (13.50–13.59)

ATO 3.69 (3.66–3.71)

RIS 1.50 (1.48–1.51)

CLN 1.32 (1.31–1.34)

SER 1.09 (1.08–1.10)

dMPH 0.83 (0.82–0.85)

dAMP 0.79 (0.78–0.80)

BUP /

FLU /

PAR 0.66 (0.65–0.67)

IMP 0.59 (0.58–0.60)

Dual therapy (Top 10)MPH + CLN 0.95 (0.94–0.96)

AMP + CLN 0.88 (0.87–0.89)

MPH + RIS 0.52 (0.51–0.53)

AMP + RIS 0.50 (0.49–0.51)

MPH + SER 0.42 (0.41–0.43)

AMP + SER 0.34 (0.34–0.35)

AMP + MIR 0.31 (0.30–0.31)

MPH + MIR 0.27 (0.26–0.27)

MPH + FLU 0.23 (0.23–0.24)

AMP + BUP /

AMP + PAR 0.21 (0.20–0.22)

MPH + ATO 0.23 (0.23–0.24)

bbreviations: AMP-amphetamine; ATO-atomoxetine; BUP-bupropion; CLN-clonidine;

acine; IMP-imipramine; MIR- mirtazapine; MPH-methylphenidate; PAR-paroxetine; Rombination was not ranked as top 10 in the specific study sample.

top 5 combinations are displayed; “/” means the corresponding combination was

e; AGN, �-agonist; ACV, anticonvulsant; AXL, anxiolytics; LIT, lithium.

include some switching between monotherapy approaches. Sec-ond, the emphasis on treatment of ADHD outweighs the treatmentof anxiety. Despite the limited evidence about the effectivenessof stimulants in children with co-existing ADHD and anxiety,

and despite concerns that stimulants may exacerbate the symp-toms of anxiety, stimulants and combination regimens containingstimulants consistently ranked as the most common treatmentapproaches, followed by SSRIs, antipsychotics, atomoxetine and

anxiety in the two study samples.

hensive%CI)

Study sample 2 (ODD/CD anddepression not excluded) % (95%CI)

14.51 (14.48–14.53)11.56 (11.54–11.59)2.72 (2.70–2.73)2.37 (2.36–2.38)1.43 (1.43–1.44)1.48 (1.47–1.49)/0.79 (0.79–0.80)1.05 (1.05–1.06)0.87 (0.86–0.88)0.85 (0.85–0.86)/

0.97 (0.96–0.98)0.82 (0.82–0.83)0.77 (0.76–0.77)0.65 (0.64–0.66)0.51 (0.51–0.52)0.41 (0.40–0.41)0.32 (0.32–0.33)0.32 (0.32–0.32)0.27 (0.27–0.27)0.23 (0.23–0.23)//

dAMP-d-amphetamine; dMPH-dexmethylphenidate; FLU-fluoxetine; GFC: Guan-IS-risperidone; SER-sertraline; “/” means the corresponding active ingredient or

534 X. Liu et al. / Journal of Anxiety Disorders 28 (2014) 530–536

Table 4Association between combination pharmacotherapy for ADHD/anxiety vs. no combination pharmacotherapy and geographic and sociodemographic factors in the two studysamples.

Geographic/sociodemographic factors Study sample 1 (comprehensiveexclusion criteria) OR (95%CI)

Study sample 2 (ODD/CD anddepression not excluded) OR (95%CI)

Gender Female vs. male 0.93 (0.86, 1.00) 0.88 (0.84, 0.91)

Race/ethnicity Black vs. White 0.51 (0.46, 0.57) 0.51 (0.48, 0.54)Hispanic vs. White 0.50 (0.43, 0.59) 0.49 (0.45, 0.54)Other vs. White 0.86 (0.72. 1.04) 0.86 (0.78. 0.95)

Age (years) 6–9 Reference Reference<6 0.99 (0.86. 1.13) 0.88 (0.81.0.96)10–14 1.02 (0.94, 1.10) 1.06 (1.01, 1.11)≥14 0.95 (0.83, 1.09) 0.95 (0.83, 1.09)

Length of follow up 3–6 months Reference Reference<3 months 0.18 (0.15, 0.21) 0.17 (0.16, 0.19)6 months–1 year 2.11 (1.92, 2.32) 2.28 (2.17, 2.40)1 year–2 years 4.41 (3.96, 4.91) 4.73 (4.46, 5.01)>2 years 9.67 (8.39, 11.14) 10.9 (10.0, 11.7)

Foster care Yes vs No 1.09 (0.99, 1.20) 1.44 (1.37, 1.51)

Disability Yes vs No 1.00 (0.77, 1.30) 1.03 (0.89, 1.19)

Cash assistance Yes vs No 0.76 (0.67, 0.87) 0.80 (0.75, 0.86)

State FL Reference ReferenceAR 1.01 (0.78, 1.30) 1.11 (0.96, 1.27)GA 0.89 (0.73, 1.08) 0.97 (0.86, 1.09)IA 2.38 (1.72, 3.31) 2.37 (1.97, 2.85)ID 0.98 (0.70, 1.36) 0.86 (0.73, 1.02)IL 1.22 (0.95, 1.57) 1.30 (1.14, 1.48)IN 1.09 (0.87, 1.36) 1.33 (1.18, 1.49)KS 1.57 (1.14, 2.17) 1.48 (1.23, 1.77)LA 1.75 (1.37, 2.24) 1.61 (1.39, 1.87)MA 1.75 (1.22, 2.51) 1.76 (1.39, 2.22)MN 1.34 (1.00, 1.78) 1.47 (1.28, 1.68)MO 1.00 (0.78, 1.29) 1.14 (1.00, 1.30)MS 0.99 (0.72, 1.35) 1.09 (0.91, 1.30)NC 1.10 (0.91, 1.33) 1.27 (1.14, 1.42)NE 1.72 (1.23, 2.41) 1.60 (1.34, 1.91)NH 1.36 (0.98, 1.88) 1.32 (1.09, 1.59)NY 1.08 (0.86, 1.36) 0.95 (0.84, 1.08)OH 1.39 (1.13, 1.70) 1.59 (1.42, 1.78)PA 0.93 (0.71, 1.22) 1.15 (1.01, 1.32)SC 0.70 (0.57, 0.85) 0.85 (0.76, 0.95)TN 1.17 (0.92, 1.48) 1.06 (0.92, 1.23)TX 1.68 (1.40, 2.01) 1.83 (1.65, 2.04)VA 0.99 (0.70, 1.40) 1.33 (1.10, 1.23)VT 1.52 (1.09, 2.12) 1.41 (1.18, 1.69)

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-agonists. Besides stimulants and atomoxetine, sertraline was theost commonly used SSRI, while risperidone was the most com-only used antipsychotic in this population. Third, both clinical and

on-clinical factors have impact on combination pharmacotherapy.ales, Whites and children in foster care are more likely, while

hildren with TANF are less likely, to be treated with concomitantultiple psychotropic drugs for comorbid ADHD and anxiety dis-

rders. Furthermore, significant treatment differences exist amongtates after gender, race, age, foster care, disability, poverty andength of the two concomitant disorders are controlled, with a pat-ern consistent to that described for ADHD treatment.

We found that an average of 30% and 25% of time with con-omitant ADHD and anxiety was not treated for either of theisorders in the two study samples. This is consistent with pre-ious reports on ADHD treatment prevalence. For example, theSCH reported that only 66.3% of children with ADHD were tak-

ng medication for the disorder (CDC, 2010). Likewise, based on

single-center study, only 31% of children with anxiety disor-er had received counseling or pharmacotherapy (Chavira, Stein,ailey, & Stein, 2004).The untreated periods may be explained byeveral factors. First, patients might implement drug holidays of

1.83) 1.28 (1.11, 1.47)1.11) 0.90 (0.75, 1.10)

ADHD treatment. For example, 10-week summer school breakswould represent 19.2% of the year where therapy might have beenomitted. However there is no theoretical base or practice guidelinefor implementing drug holidays for children with anxiety. Second,psychological interventions, which are typically implemented asfirst line treatment of anxiety might be effective resulting in noneed for drug therapy. Other explanations include the decision toforgo medication treatment due to adverse drug events or lackof efficacy. Of note, consistent with current treatment guidelines,which emphasize behavioral therapy in preschoolers, younger chil-dren (<6 years of age) exhibited larger proportions of untreatedtime. This notwithstanding, since untreated ADHD or anxiety canresult in poor self-esteem, school performance and social functionproblems, or develop into adult mental health problems (Harpin,Mazzone, Raynaud, Kahle, & Hodgkins, 2013; Moreno, Furtner, &Rivara, 2010), future research should further evaluate the appro-priateness of the untreated periods in patients with ADHD and

anxiety.

Noteworthy is the focus on sertraline among SSRIs used either asmonotherapy or in combination with stimulants. Sertraline was thesecond SSRI approved by the FDA in 1991. Compared to other SSRIs,

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ertraline has a lower drug interaction potential and more safetyata for pediatric patients, which may partially explain physicianreference (Gentile, 2011). On the other hand, paroxetine, which

s the only SSRI whose label includes all five anxiety disorderategories in adults, was used much less than sertraline in chil-ren. Two facts may explain this phenomenon: first, paroxetineas not approved by the FDA in children and adolescents; second,

he concern for suicidal thinking and behavior prevents the use ofaroxetine in children and adolescents.

In October 2004 and September 2005, the FDA issued a publicealth advisory on the increased risk of suicidal thinking and behav-

or in children and adolescents treated with antidepressants andtomoxetine, respectively. Utilization studies report concordantly aramatic decline in atomoxetine use and a lesser but visible decline

n SSRI use following the public health advisory. Thus, it is conceiv-ble that treatment pattern after 2004 have changed, particularlyith lower use of atomoxetine.

Another interesting finding is the prevalent use of risperidoneespite exclusion of all labeled and reported off-label indications

ncluding autism, bipolar disorder, mania, schizophrenia, agita-ion, and Tourette’s syndrome (Maher & Theodore, 2012). Typicallyisperidone is not indicated for anxiety disorders, and one of theeported adverse events of risperidone is anxiety. Furthermore,ven though antipsychotics are viewed as an augmentation ther-py for severe, treatment-resistant anxiety disorders (Farach et al.,012), the use of risperidone in patients with anxiety and ADHDeserves further investigation in the absence of RCT and consider-

ng the significant side effect profile of atypical antipsychotics. Anlternative explanation for the use of risperidone may be off-labelse for the treatment of ADHD. As risperidone can be used to treatggression, we observed higher prevalence of using antipsychoticsnd risperidone in study sample 2 where patients were allowed toave ODD/CD as the third psychiatric comorbidity.

In this analysis, we found both clinical and non-clinical factors,uch as gender, race, foster care, poverty and states, have profoundmpact on treatment decisions regarding combination therapy.revious studies have explored determinants of combination phar-acotherapy in specific settings, such as patients with mild

ntellectual disabilities or borderline intellectual functioning andsychiatric or behavioral disorders in hospitals (Stolker, Heerdink,eufkens, Clerkx, & Nolen, 2001), patients with schizophrenia inutpatient clinics (Xiang, Weng, Leung, Tang, & Ungvari, 2007),he use of multiple antipsychotics in hospital (Biancosino, Barbui,

armai, Dona, & Grassi, 2005) or in outpatient clinics (Xiang et al.,007). Different from these studies which exclusively focused onlinical factors, our study showed non-clinical factors play anmportant role in the use of combination therapy in children withDHD and anxiety covered by Medicaid programs, which has noteen reported before.

Geographic variation in the treatment of ADHD ranged from aow of 1.2% in Nevada to a high of 9.4% in North Carolina basedn the NSCH survey (National Survey of Children’s Health) in 2007onducted by CDC (Visser, Blumberg, Danielson, Bitsko, & Kogan,013). In children with ADHD and anxiety, we find similar geo-raphic variation. This variation could be indicative of differencesn the understanding and belief of the role of pharmacotherapymong clinicians, the availability of local expertise, or reimburse-ent policies and formulary management strategies. Geographic

ariation in prescribing pattern for almost identical patient popu-ations has been reported outside of the US also (Xiang et al., 2007).t points to the needs for better evidence to guide practice towardhe safest and most effective treatment options.

Our study has three unique strengths. First, our study samplerawn from children in 26 states represents 85% of all chil-ren in Medicaid fee-for-service programs in the US. Thus, whileinorities and families with lower socio-economic status are

sorders 28 (2014) 530–536 535

overrepresented, the generalizability of this study within thesecaveats is noteworthy. Second, we used a novel method to linkthe disorders and treatments through the assignment of diagno-sis duration based on outpatient visits, which is particularly usefulin the determination of simultaneous or sequential disorders anddrug use. Through this method we were able to identify periodswith concomitant ADHD and anxiety. We also ran sensitivity anal-yses with various definitions for the length of the disorders anddrug claims to examine the consistency of our findings. Third,we defined two study samples to describe psychotropic phar-macotherapy in children with ADHD and anxiety. Study sample1 with comprehensive exclusion criteria represents a small buthomogeneous study population confined to physician-billed diag-noses of ADHD and anxiety. Study sample 2 allows patients tohave ODD/CD and/or depression, which are common psychiatriccomorbidities with ADHD or anxiety. Not excluding ODD/CD and/ordepression enlarged sample size and improved generalizability.However, because prescriptions and pharmacy data do not indi-cate the targeted indication of the prescribed drug, study sample2 allows lesser inferences about treatment choices for anxiety asODD/CD or depression may have been alternative indications.

In correspondence with its strengths, our study has severallimitations. First, our study only focused on pharmacological treat-ment, and the psychological or behavioral interventions were notcaptured. Therefore, the period of “no treatment” does not inferabsence of any non-pharmacological treatments. Second, becauseour study period ended in 2006, results may not be generalizableto the most current practice pattern. Third, diagnoses of men-tal disorders were ascertained from physician-assigned diagnosticcodes in Medicaid claims without additional validity assessmentand pharmacy dispensing claims allow no direct linkage to physi-cian diagnoses. Thus, psychotropic drugs may have been intendedfor other indications that were not captured by diagnostic codesin claims data or not excluded. Finally, because mental disorderswere identified based on ICD9-CM codes, we were not able to fur-ther differentiate between subtypes of ADHD as well as anxietydisorders.

5. Conclusion

Pharmacotherapeutic regimens containing ADHD medicationsare the most common regimen for children with ADHD andanxiety. Antidepressants and atypical antipsychotics, and specif-ically sertraline and risperidone, are utilized as the most commonnon-ADHD therapies in this pediatric Medicaid population. Sig-nificant treatment differences of combination pharmacotherapyexist across gender, age, race, foster care, disability and poverty-based subgroups and among study states. The understanding ofthe origins of the treatment differences and how they relate tobest practices warrants further investigation. Comparative safetyand effectiveness studies of psychotropic drug combinations forthe treatment of ADHD with anxiety, and evaluation of long-termbenefits and risks of combination pharmacotherapy are neededto promote evidence-based practice for this common comorbiditypairing.

Appendix A. Supplementary data

Supplementary data associated with this article can befound, in the online version, at http://dx.doi.org/10.1016/j.janxdis.2014.06.005.

References

AACAP. (2012). Practice parameter for the assessment and treatment ofchildren and adolescents with obsessive-compulsive disorder. Journal of

5 ety Di

A

A

B

B

C

C

C

C

C

DF

G

G

G

G

H

K10, E09. http://dx.doi.org/10.5888/pcd9.120073

36 X. Liu et al. / Journal of Anxi

the American Academy of Child and Adolescent Psychiatry, 51(1), 98–113.http://dx.doi.org/10.1016/j.jaac.2011.09.019

AP. (2001). Clinical practice guideline: treatment of the school-aged child withattention-deficit/hyperactivity disorder. Pediatrics, 108(4), 1033–1044.

bikoff, H., McGough, J., Vitiello, B., McCracken, J., Davies, M., Walkup, J., et al.(2005). Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders. Journal of the American Academy ofChild and Adolescent Psychiatry, 44(5), 418–427.

iancosino, B., Barbui, C., Marmai, L., Dona, S., & Grassi, L. (2005). Determinantsof antipsychotic polypharmacy in psychiatric inpatients: a prospective study.International Clinical Psychopharmacology, 20(6), 305–309.

loom, B., Cohen, R. A., & Freeman, G. (2011). Summary health statistics for U.S. chil-dren: National Health Interview Survey, 2010. Vital and Health Statistics, 10(250),1–80.

DC. (2010). Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children – United States, 2003 and2007. MMWR. Morbidity and Mortality Weekly Report, 59(44), 1439–1443.

havira, D. A., Stein, M. B., Bailey, K., & Stein, M. T. (2004). Child anxiety in pri-mary care: prevalent but untreated. Depression and Anxiety, 20(4), 155–164.http://dx.doi.org/10.1002/da.20039

ohen, J. A., Bukstein, O., Walter, H., Benson, S. R., Chrisman, A., Farchione, T. R., et al.(2010). Practice parameter for the assessment and treatment of children andadolescents with posttraumatic stress disorder. Journal of the American Academyof Child and Adolescent Psychiatry, 49(4), 414–430.

onnolly, S. D., & Bernstein, G. A. (2007). Practice parameter for the assessmentand treatment of children and adolescents with anxiety disorders. Journalof the American Academy of Child and Adolescent Psychiatry, 46(2), 267–283.http://dx.doi.org/10.1097/01.chi.0000246070.23695.06

onnor, D. F., Fletcher, K. E., & Swanson, J. M. (1999). A meta-analysis of cloni-dine for symptoms of attention-deficit hyperactivity disorder. Journal of theAmerican Academy of Child and Adolescent Psychiatry, 38(12), 1551–1559.http://dx.doi.org/10.1097/00004583-199912000-00017

MHMRSAS, V. (2005). ACP formulary and pocket guide to psychopharmacology.arach, F. J., Pruitt, L. D., Jun, J. J., Jerud, A. B., Zoellner, L. A., & Roy-Byrne, P. P. (2012).

Pharmacological treatment of anxiety disorders: current treatments and futuredirections. Journal of Anxiety Disorders, 26(8), 833–843. http://dx.doi.org/10.1016/j.janxdis.2012.07.009

arcia, S. P., Guimaraes, J., Zampieri, J. F., Martinez, A. L., Polanczyk, G., & Rohde, L. A.(2009). Response to methylphenidate in children and adolescents with ADHD:does comorbid anxiety disorders matters? Journal of Neural Transmission, 116(5),631–636. http://dx.doi.org/10.1007/s00702-009-0211-3

arnock-Jones, K. P., & Keating, G. M. (2009). Atomoxetine: a review of its use inattention-deficit hyperactivity disorder in children and adolescents. PaediatricDrugs, 11(3), 203–226. http://dx.doi.org/10.2165/00148581-200911030-00005

eller, D., Donnelly, C., Lopez, F., Rubin, R., Newcorn, J., Sutton, V., et al. (2007). Ato-moxetine treatment for pediatric patients with attention-deficit/hyperactivitydisorder with comorbid anxiety disorder. Journal of the American Academyof Child and Adolescent Psychiatry, 46(9), 1119–1127. http://dx.doi.org/10.1097/chi.0b013e3180ca8385

entile, S. (2011). Efficacy of antidepressant medications in children andadolescents with obsessive-compulsive disorder: a systematic appraisal.Journal of Clinical Psychopharmacology, 31(5), 625–632. http://dx.doi.org/10.1097/JCP.0b013e31822bb1ff

arpin, V., Mazzone, L., Raynaud, J. P., Kahle, J., & Hodgkins, P. (2013). Long-term out-comes of ADHD: a systematic review of self-esteem and social function. Journalof Attention Disorders, http://dx.doi.org/10.1177/1087054713486516

ratochvil, C. J., Newcorn, J. H., Arnold, L. E., Duesenberg, D., Emslie, G. J., Quin-tana, H., et al. (2005). Atomoxetine alone or combined with fluoxetine fortreating ADHD with comorbid depressive or anxiety symptoms. Journal ofthe American Academy of Child and Adolescent Psychiatry, 44(9), 915–924.http://dx.doi.org/10.1097/01.chi.0000169012.81536.38

sorders 28 (2014) 530–536

Larson, K., Russ, S. A., Kahn, R. S., & Halfon, N. (2011). Patterns of comorbidity, func-tioning, and service use for US children with ADHD, 2007. Pediatrics, 127(3),462–470. http://dx.doi.org/10.1542/peds.2010-0165

Maher, A. R., & Theodore, G. (2012). Summary of the comparative effectivenessreview on off-label use of atypical antipsychotics. Journal of Managed Care Phar-macy, 18(5 Suppl. B), S1–S20.

March, J. S., Swanson, J. M., Arnold, L. E., Hoza, B., Conners, C. K., Hinshaw, S. P., et al.(2000). Anxiety as a predictor and outcome variable in the multimodal treatmentstudy of children with ADHD (MTA). Journal of Abnormal Child Psychology, 28(6),527–541.

Moreno, M. A., Furtner, F., & Rivara, F. P. (2010). Anxiety disorders in childrenand adolescents. Archives of Pediatrics & Adolescent Medicine, 164(10), 984.http://dx.doi.org/10.1001/archpediatrics.2010.179

Moshe, K., Karni, A., & Tirosh, E. (2012). Anxiety and methylphenidate inattention deficit hyperactivity disorder: a double-blind placebo-drug trial. Atten-tion Deficit and Hyperactivity Disorders, 4(3), 153–158. http://dx.doi.org/10.1007/s12402-012-0078-2

MTA. (1999). A 14-month randomized clinical trial of treatment strategies forattention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multi-modal Treatment Study of Children with ADHD. Archives of General Psychiatry,56(12), 1073–1086.

Sallee, F., Connor, D. F., & Newcorn, J. H. (2013). A review of the rationale and clinicalutilization of alpha2-adrenoceptor agonists for the treatment of attention-deficit/hyperactivity and related disorders. Journal of Child and AdolescentPsychopharmacology, 23(5), 308–319. http://dx.doi.org/10.1089/cap.2013.0028

Seixas, M., Weiss, M., & Muller, U. (2012). Systematic review of nationaland international guidelines on attention-deficit hyperactivity disorder.Journal of Psychopharmacology, 26(6), 753–765. http://dx.doi.org/10.1177/0269881111412095

Sparks, J. A., & Duncan, B. L. (2013). Outside the black box: re-assessing pediatricantidepressant prescription. Journal of the Canadian Academy of Child and Ado-lescent Psychiatry, 22(3), 240–246.

Spencer, T. J. (2009). Issues in the management of patients with complexattention-deficit hyperactivity disorder symptoms. CNS Drugs, 23(Suppl. 1),9–20. http://dx.doi.org/10.2165/00023210-200923000-00003

Stolker, J. J., Heerdink, E. R., Leufkens, H. G., Clerkx, M. G., & Nolen, W. A. (2001). Deter-minants of multiple psychotropic drug use in patients with mild intellectualdisabilities or borderline intellectual functioning and psychiatric or behavioraldisorders. General Hospital Psychiatry, 23(6), 345–349.

Ter-Stepanian, M., Grizenko, N., Zappitelli, M., & Joober, R. (2010). Clinical responseto methylphenidate in children diagnosed with attention-deficit hyperactiv-ity disorder and comorbid psychiatric disorders. Canadian Journal of Psychiatry,55(5), 305–312.

Toteja, N., Gallego, J. A., Saito, E., Gerhard, T., Winterstein, A., Olfson, M., et al.(2014). Prevalence and correlates of antipsychotic polypharmacy in chil-dren and adolescents receiving antipsychotic treatment. The InternationalJournal of Neuropsychopharmacology, 17(7), 1095–1105. http://dx.doi.org/10.1017/S1461145712001320

van der Oord, S., Prins, P. J., Oosterlaan, J., & Emmelkamp, P. M. (2008). Treat-ment of attention deficit hyperactivity disorder in children. Predictors oftreatment outcome. European Child & Adolescent Psychiatry, 17(2), 73–81.http://dx.doi.org/10.1007/s00787-007-0638-8

Visser, S. N., Blumberg, S. J., Danielson, M. L., Bitsko, R. H., & Kogan, M. D. (2013).State-based and demographic variation in parent-reported medication rates forattention-deficit/hyperactivity disorder, 2007–2008. Preventing Chronic Disease,

Xiang, Y. T., Weng, Y. Z., Leung, C. M., Tang, W. K., & Ungvari, G. S. (2007). Clinicaland social determinants of antipsychotic polypharmacy for Chinese patientswith schizophrenia. Pharmacopsychiatry, 40(2), 47–52. http://dx.doi.org/10.1055/s-2007-970062