an estimated 4.4% of adults in the united states are affected by attentiondeficit hyperactivity disorder ( adhd ) 1 , which is characterized by a persistent pattern of inattention , hyperactivity , and/or impulsivity at all ages 2 .
atomoxetine ( atx ) is a selective norepinephrine reuptake inhibitor indicated for the treatment of adhd , and is the only nonstimulant approved for the treatment of adhd in adults . for adults ,
atx is recommended to be initiated at a total daily dose of 40  mg / day and increased after a minimum of 3  days to a target total daily dose of approximately 80  mg / day administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon / early evening .
after 24 additional weeks , the dose may be increased to a maximum of 100  mg / day in patients who have not achieved an optimal response 3 .
results from clinical trials indicate that treatment using an adequate dose of atomoxetine for a sufficient duration of time is important for adhd symptom improvement and , conversely , that suboptimal dosing may lead to lower efficacy 4 .
however , despite the recommended 80  mg / day target dose , realworld data show that an approximately 60  mg / day average adult atx dose is utilized in clinical settings , at least partially driven by lack of knowledge rather than clinical need 4 . additionally , although slower dose titration can benefit some patients , it may add the risk of premature drug discontinuation due to impatience waiting for efficacious results , particularly for patients who are not stimulantnaive and who may be used to experiencing a quicker effect 4 .
the finding that lower atx doses could lead to lower persistency ( time from initial atomoxetine dose to discontinuation ) is supported by a post hoc analysis of data from a 12month prospective , observational study in pediatric and adolescent patients with adhd 5 .
medication persistence was assessed in 134 patients who were treated initially with low starting dose atx ( < 0.5  mg / kg / day ) or recommended starting dose atx ( 0.5  mg / kg / day ) .
initial treatment with lowdose atx was associated with statistically significantly shorter medication persistence throughout the study .
patients who initially received lowdose atomoxetine had higher discontinuation rates within the first 90  days ( 27.7% vs. 11.0% ) , after 180  days ( 45.8% vs. 15.3% ) , and after 365  days ( 51.8% vs. 21.1% ; all p  <  0.01 ) than patients who initially received standarddose atomoxetine .
it is also hypothesized that a large percentage of adult adhd patients treated with atx therapy in realworld clinical settings are not dosed to the recommended 80  mg / day target dose , and that not reaching the recommended dose leads to a shorter length of therapy ( lot ) than when the target dose is achieved . in a recent claims database study , kabul and
colleagues investigated dosing patterns over 1  year among 12,412 adults with claims for adhd and newly prescribed atx .
only 26.8% were treated consistently at the recommended dose range ( 80100  mg / day ) , whereas 36.6% were suboptimally dosed ( never reaching 80  mg / day ) and about a third had fluctuating dosing 6 .
they defined persistency as days until stopping the index atx , not allowing for breaks in prescriptions longer than 30  days .
average persistency was not notably different between the recommended dosing and suboptimal dosing cohorts . for defining the dosing cohorts , the 12month followup period started on day 31 instead of day 1 to allow for titration only during those 30  days .
patients prescribed atx were excluded from analysis if during followup they used atx in combination with other adhd medications or if their dosing fluctuated outside the ranges of the recommended dosing or suboptimal dosing definitions at any time during the followup .
reasons for poor adherence among patients with adhd include adverse effects , dosing inconvenience , social stigma , patient attitude , lack of adequate symptom control , and also adequate symptom control 7 , 8 . among adults ,
symptom relief combined with the general desire not to take medication chronically is a strong motivating factor 7 .
patients have a tendency to stop treatment once they feel their symptoms are under control and often take drug holidays when they feel better or when they perceive there is less need to control their adhd symptoms during that time  for example , during school breaks 7 , 9 . despite drug holidays not being in the best interest of patients ,
the use of drug holidays that is common in the treatment of children with adhd has generalized to the treatment of adults with adhd 10 .
thus , in contrast to the kabul study , the aim of the current study was to examine atx dosing and its effects on lot by expanding the patient sample to include more realworld practice patterns by using less specific and rigid definitions of recommended and suboptimal dosing , include patients whose dose fluctuated over time , include patients who reached 80  mg / day at any time during the followup period , and examine cumulative days of therapy during the followup regardless of treatment breaks . using this novel approach , among adhd adults with prescription claims that reached 80  mg / day ( atx    80 )
versus did not reach 80  mg / day ( atx  <  80 ) , the objectives were to compare : lot for atx monotherapy patients ( primary ) ; lot for atx combination therapy patients ; demographic , clinical characteristics , treatment patterns , and dosage patterns ; lot monotherapy versus combination therapy patients ; lot treatment naive versus not naive patients ; and factors associated with reaching 80  mg / day .
this retrospective analysis was conducted using administrative medical and pharmacy claims data from the truven health marketscan commercial claims and encounters database for the period july 2005 through september 2014 , including the preindex and followup period .
this database contains complete longitudinal records of inpatient and outpatient services , and prescription drug claims of more than 45 million employees and their dependents , covered under a variety of fee for service , fully capitated , and partially capitated health plans across all geographic regions of the united states .
all study data are deidentified and fully compliant with health insurance portability and accountability act of 1996 . because this study used only deidentified patient records and did not involve the collection , use , or transmittal of individually identifiable data , institutional review board approval to conduct this study was not necessary .
adult patients ( 18  years ) newly initiated on atx ( i.e. , no atx use in the prior 6  months ) with at least one pharmacy claim for atomoxetine between january 1 , 2006 and september 30 , 2013 were identified .
all patients were required to have at least one medical claim with an international classification of diseases , ninth revision , clinical modification diagnosis code ( icd9cm ) for adhd ( 314.0x ) and be continuously enrolled with medical and pharmacy benefits in the 6  months preindex and 12  months postindex . the study period spanned from july 1 , 2005 through september 30 , 2014 with a 6month preindex and 12month postindex ( followup ) period .
atomoxetine dosing was determined from pill strength based on the national drug code ( ndc ) and quantity dispensed and days supply information on pharmacy claims for atx .
patients were either categorized as having reached ( filled a prescription for ) 80  mg / day dose at least one time or did not reach 80  mg / day dose .
patients were categorized as monotherapy or combination therapy patients based on all atx prescriptions during followup including the index prescription .
each atx prescription was evaluated for the number of days overlap with another nonatx adhdindicated medication ( amphetamine , methylphenidate , or alpha2 adrenergic ) . if any atx prescription had > 30 continuous days of overlap with another adhd medication , the patient
patients were categorized as having been treatment naive or not during the 6  months prior to their index event ; that is , no prescriptions for adhdindicated medications in the 6month preindex period .
patients were characterized based on demographic information at the time of the index event including age and gender .
clinical characteristics based upon pre and followup period data included adhd subtype and selected comorbid psychiatric disorders based on the presence of 1 medical claim with relevant icd9cm diagnosis codes .
prescriber specialty and prior adhd medication use , based on pharmacy claims with relevant ndc codes , were also captured .
prescriber specialty was determined based on the clinician specialty for the preindex office visit that fell closest to the date of the index atx prescription .
lot was defined as all prescription claim fill days over the 365day followup period , including continuous and sporadic use such that lot was calculated as cumulative days of therapy rather than persistency .
all study variables were summarized descriptively and statistical tests of significance for differences between dosing cohorts ( atx    80 vs. atx  <  80 ) were performed with a pvalue 0.05 set as threshold for significance . based upon the data variable type , evidence of normality , and frequency size , the following tests were performed : independent ttest , wilcoxon ranksum test , chisquare test , or fisher 's exact test . for demographic and clinical characteristics
the following tests were performed : wilcoxon ranksum test ( age ) ; chisquare test ( proxied prescriber specialty ) ; and fisher 's exact test ( gender , predominate adhd subtype , preindex adhd medication use , preindex comorbidities ) .
dosing patterns and lot were assessed with the wilcoxon ranksum test . for demographic and clinical characteristic potential predictors ( p    0.20 from univariate analysis ) for reaching atomoxetine 80  mg / day dose , multivariate stepwise logistic regression was used to determine the pvalue , odds ratio , and odds ratio 95% confidence interval for each demographic and clinical characteristic showing a statistically significant ( p    0.05 for monotherapy ; p    0.10 for combination therapy ) relationship with those who did or did not reach 80  mg / day , with a cstatistic used to note multivariate model fit .
a sensitivity analysis was performed for dosing pattern variables and lot analyses , repeating the current monotherapy analyses using the index dates of 01 january 200631 december 2011 , which corresponds to the time period and truven patient population used in the kabul dosing and persistency study 6 discussed in this article .
mean dosing was analyzed at day 14 , 30 , 60 , 90 , and 210 .
time 80  mg / day reached was analyzed for days 17 , 815 , 1630 , 3160 , 6190 , 91210 , and 211 .
this retrospective analysis was conducted using administrative medical and pharmacy claims data from the truven health marketscan commercial claims and encounters database for the period july 2005 through september 2014 , including the preindex and followup period .
this database contains complete longitudinal records of inpatient and outpatient services , and prescription drug claims of more than 45 million employees and their dependents , covered under a variety of fee for service , fully capitated , and partially capitated health plans across all geographic regions of the united states .
all study data are deidentified and fully compliant with health insurance portability and accountability act of 1996 . because this study used only deidentified patient records and did not involve the collection , use , or transmittal of individually identifiable data , institutional review board approval to conduct this study was not necessary .
adult patients ( 18  years ) newly initiated on atx ( i.e. , no atx use in the prior 6  months ) with at least one pharmacy claim for atomoxetine between january 1 , 2006 and september 30 , 2013 were identified .
all patients were required to have at least one medical claim with an international classification of diseases , ninth revision , clinical modification diagnosis code ( icd9cm ) for adhd ( 314.0x ) and be continuously enrolled with medical and pharmacy benefits in the 6  months preindex and 12  months postindex . the study period spanned from july 1 , 2005 through september 30 , 2014 with a 6month preindex and 12month postindex ( followup ) period .
atomoxetine dosing was determined from pill strength based on the national drug code ( ndc ) and quantity dispensed and days supply information on pharmacy claims for atx .
patients were either categorized as having reached ( filled a prescription for ) 80  mg / day dose at least one time or did not reach 80  mg / day dose .
patients were categorized as monotherapy or combination therapy patients based on all atx prescriptions during followup including the index prescription .
each atx prescription was evaluated for the number of days overlap with another nonatx adhdindicated medication ( amphetamine , methylphenidate , or alpha2 adrenergic ) . if any atx prescription had > 30 continuous days of overlap with another adhd medication , the patient
patients were categorized as having been treatment naive or not during the 6  months prior to their index event ; that is , no prescriptions for adhdindicated medications in the 6month preindex period .
patients were characterized based on demographic information at the time of the index event including age and gender .
clinical characteristics based upon pre and followup period data included adhd subtype and selected comorbid psychiatric disorders based on the presence of 1 medical claim with relevant icd9cm diagnosis codes .
prescriber specialty and prior adhd medication use , based on pharmacy claims with relevant ndc codes , were also captured .
prescriber specialty was determined based on the clinician specialty for the preindex office visit that fell closest to the date of the index atx prescription .
lot was defined as all prescription claim fill days over the 365day followup period , including continuous and sporadic use such that lot was calculated as cumulative days of therapy rather than persistency .
all study variables were summarized descriptively and statistical tests of significance for differences between dosing cohorts ( atx    80 vs. atx  <  80 ) were performed with a pvalue 0.05 set as threshold for significance . based upon the data variable type , evidence of normality , and frequency size
, the following tests were performed : independent ttest , wilcoxon ranksum test , chisquare test , or fisher 's exact test . for demographic and clinical characteristics
the following tests were performed : wilcoxon ranksum test ( age ) ; chisquare test ( proxied prescriber specialty ) ; and fisher 's exact test ( gender , predominate adhd subtype , preindex adhd medication use , preindex comorbidities ) .
dosing patterns and lot were assessed with the wilcoxon ranksum test . for demographic and clinical characteristic potential predictors ( p    0.20 from univariate analysis ) for reaching atomoxetine 80  mg / day dose
, multivariate stepwise logistic regression was used to determine the pvalue , odds ratio , and odds ratio 95% confidence interval for each demographic and clinical characteristic showing a statistically significant ( p    0.05 for monotherapy ; p    0.10 for combination therapy ) relationship with those who did or did not reach 80  mg / day , with a cstatistic used to note multivariate model fit .
a sensitivity analysis was performed for dosing pattern variables and lot analyses , repeating the current monotherapy analyses using the index dates of 01 january 200631 december 2011 , which corresponds to the time period and truven patient population used in the kabul dosing and persistency study 6 discussed in this article .
mean dosing was analyzed at day 14 , 30 , 60 , 90 , and 210 .
time 80  mg / day reached was analyzed for days 17 , 815 , 1630 , 3160 , 6190 , 91210 , and 211 .
of the initial sample of 309,470 patients with at least one claim for atx in the commercial database between january 1 , 2006 and september 30 , 2013 , a total of 36,076 monotherapy ( 16,217 achieved 80  mg / day ) and 1548 combination therapy ( 1206 achieved 80  mg / day ) adult patients newly initiated on atx met  all of the study inclusion criteria ( figure  1 ) . of patients filling a claim for atx
, only 45.0% reached a dose of 80  mg / day or greater when used as monotherapy and 77.9% when used in combination therapy with other adhd medications over the course of 1  year ( table  1 ) .
demographic and clinical characteristics adhd , attentiondeficit / hyperactivity disorder ; sd , standard deviation . * wilcoxon ranksum test ( age ) ; chisquare test ( proxied prescriber specialty ) ; fishers exact test ( gender , predominate adhd subtype , preindex adhd medication use , preindex comorbidities ) .
inattentive defined as 1 claims with icd9 314.00 without any claims with icd9 314.01 ; hyperactiveimpulsive or combined defined as 1 claim with icd9 314.01 .
prescription claims do not list provider specialty ; proxies from provider specialty on the office visit on index or in the 6  months preindex that fell closest to index .
prescriber specialty was a missing variable for 657 and 673 monotherapy and 55 and 16 combination therapy patients in the reached 80  mg / day and did not reach 80  mg / day cohorts , respectively .
patients could have used more than one adhd medication class in the 6  months preindex .
some statistical differences in demographic and clinical characteristics were found between the atx    80 and atx  <  80 groups ( table  1 ) .
this was more apparent in the monotherapy rather than combination therapy group , perhaps in part due to the large number of patients in the monotherapy group .
however , patients reaching 80  mg / day versus those who did not were more likely to be older , male , and have more comorbid diagnostic claims overall , as well as for anxiety , bipolar / mania disorders , depression , diabetes , hypertension , personality disorders , pervasive development disorders , and sleep disorders .
patients in the atx    80 group were more likely to have had their atx prescribed by psychiatrists , whereas patients in the atx  <  80 group were more likely to have been prescribed their atx by a primary care physician ; although , the majority of prescriptions in both groups were provided by primary care physicians .
overall , within the combination therapy patients , patients who did and did not reach 80  mg / day were similar in regard to demographics and clinical characteristics .
differences did exist in baseline demographics and clinical characteristics between monotherapy and combination therapy patients . a larger percentage of combination therapy patients were of the hyperactiveimpulsive or combined type , had a larger percentage of patients prescribed atomoxetine by psychiatrists , had a larger percentage of patients with preindex adhd medication use , and had comorbid anxiety , depression , or sleep disorders .
while there were fewer comorbidities for the combination therapy group that showed a statistically significant difference between the atx    80 and atx  <  80 groups , this may be due to the smaller overall sample size , as trends were similar .
combination therapy patients achieving 80  mg / day had statistically significantly greater depression and sleep disorders . across all timepoints
examined , atx    80 patients had statistically significantly greater mean doses compared to atx  <  80 patients ( table  2 ) . in contrast to the atx    80 group , patients in the atx  <  80 group had similar mean lowest and highest doses and did not have their dose increase over time .
dosing patterns and length of therapy adhd , attentiondeficit / hyperactivity disorder ; lot , length of therapy ; sd , standard deviation . * wilcoxon ranksum test . only patients with a dose recorded at the examined time were included for that time .
mean lot days for all 36,076 monotherapy patients ( 107.7    101.4 ) was significantly less than for the 1548 combination patients ( 222.9    99.9 ; p  <  0.0001 ) ; the mean lot for monotherapy versus combination patients was significant less within both the patients reaching 80  mg / day as well as in the patients not reaching 80  mg / day ( p  <  0.0001 ) . of those monotherapy patients who reached 80  mg / day ,
71.7% did so by day 30 , while 20.4% did not get to 80  mg / day until after 60  days ( table  3 ) .
of those patients who achieved 80  mg / day , about 72% of monotherapy patients reached 80  mg / day between days 1630 while about 72% of combination therapy patients reached 80  mg / day between days 3160 .
time 80  mg / day reached lot , length of therapy ; na , not applicable .
patients in the atx    80 group had prescription claims covering a statistically significantly greater number of cumulative days annually than patients in the atx  <  80 group ( table  2 ) .
combination therapy patients had statistically significantly longer lot than monotherapy patients , regardless if they reached 80  mg / day or not ( table  2 ) .
patients with combination therapy who reached 80  mg / day had the longest lot .
the difference in lot between the atx    80 and atx  <  80 groups was greater for the monotherapy patients ( 93.8  days ) compared with the combination therapy patients ( 65.5  days ) . a greater number of patients were treatment nave than not nave during the 6  months prior to their index atx treatment in the monotherapy cohorts , whereas a greater number of patients were not treatment nave in the combination therapy cohort ( table  4 ) . when comparing lot between the atx    80 and atx  <  80 groups , the finding that atx    80 patients had longer lot than atx  <  80 patients held true within the nave and nonnave subgroups
however , the lot was statistically significantly longer for naive patients than it was for previously treated patients in the monotherapy cohort .
length of therapy of treatment naive versus not naive patients sd , standard deviation . * wilcoxon ranksum test .
adhd treatment naive is defined as not having adhd treatment in the 6month preindex period ; however , whether patients were treatment naive prior to this period is unknown .
the dosing pattern variable and lot sensitivity analyses provided similar and consistent results to those in table  2 , with a mean lot of 160.4 for atx    80 and 67.1 for atx  <  80 monotherapy patients ( p  <  0.0001 ) . the mean lowest and highest doses were 59.2 and 107.9 for atx    80 and 36.5 and 40.5 for atx  <  80 monotherapy patients ( p  <  0.0001 ) . within the monotherapy patient group ,
several factors were suggestive of increasing the likelihood a patient would fill an 80  mg / day prescription during their followup year ( table  5 ) . older patients ( 1.4% more likely per 1  year of age ) , males ( 22.6% ) , patients with a hyperactiveimpulsive or combined type diagnosis ( 6.7% ) , patients whose last provider type was a psychiatrist ( 25.4% ) or other ( 15.2% ) type versus the primary care / family practice reference group , and patients with a comorbidity diagnosis of bipolar ( 16.3% ) , depression ( 7.2% ) , hypertension ( 13.0% ) , or a pervasive development disorder ( 84.6% or almost twice as likely ) were more likely to achieve 80  mg / day .
demographic and clinical characteristic predictors of reaching atomoxetine 80  mg / day dose na , not applicable .
* multivariate stepwise logistic regression was used to determine the pvalue , odds ratio , and confidence interval for each demographic and clinical characteristic showing a statistically significant relationship with those who did or did not reach 80  mg / day , with a model fit cstatistic of 0.574 for monotherapy and 0.560 for combination therapy , which suggests a moderatetoweak fit .
patients whose last provider type was a neurologist versus the primary care / family practice reference group ( 29.9% ) , and patients who received intermediateacting ( 12.7% ) or shortacting stimulants ( 10.6% ) were less likely to achieve 80  mg / day .
within the combination therapy patient group , patients who received prodrug stimulants ( 33.9% ) , and patients with a comorbidity diagnosis of depression ( 31.9% ) or sleep disorder ( 36.8% ) were more likely to achieve 80  mg / day .
comorbidity diagnosis of depression or sleep disorder as statistically significant predictors could be questionable as their pvalue was between 0.05 and 0.10 .
of the initial sample of 309,470 patients with at least one claim for atx in the commercial database between january 1 , 2006 and september 30 , 2013 , a total of 36,076 monotherapy ( 16,217 achieved 80  mg / day ) and 1548 combination therapy ( 1206 achieved 80  mg / day ) adult patients newly initiated on atx met  all of the study inclusion criteria ( figure  1 ) . of patients filling a claim for atx
, only 45.0% reached a dose of 80  mg / day or greater when used as monotherapy and 77.9% when used in combination therapy with other adhd medications over the course of 1  year ( table  1 ) .
demographic and clinical characteristics adhd , attentiondeficit / hyperactivity disorder ; sd , standard deviation . * wilcoxon ranksum test ( age ) ; chisquare test ( proxied prescriber specialty ) ; fishers exact test ( gender , predominate adhd subtype , preindex adhd medication use , preindex comorbidities ) .
inattentive defined as 1 claims with icd9 314.00 without any claims with icd9 314.01 ; hyperactiveimpulsive or combined defined as 1 claim with icd9 314.01 .
prescription claims do not list provider specialty ; proxies from provider specialty on the office visit on index or in the 6  months preindex that fell closest to index .
prescriber specialty was a missing variable for 657 and 673 monotherapy and 55 and 16 combination therapy patients in the reached 80  mg / day and did not reach 80  mg / day cohorts , respectively .
patients could have used more than one adhd medication class in the 6  months preindex .
some statistical differences in demographic and clinical characteristics were found between the atx    80 and atx  <  80 groups ( table  1 ) .
this was more apparent in the monotherapy rather than combination therapy group , perhaps in part due to the large number of patients in the monotherapy group .
however , patients reaching 80  mg / day versus those who did not were more likely to be older , male , and have more comorbid diagnostic claims overall , as well as for anxiety , bipolar / mania disorders , depression , diabetes , hypertension , personality disorders , pervasive development disorders , and sleep disorders .
patients in the atx    80 group were more likely to have had their atx prescribed by psychiatrists , whereas patients in the atx  <  80 group were more likely to have been prescribed their atx by a primary care physician ; although , the majority of prescriptions in both groups were provided by primary care physicians .
overall , within the combination therapy patients , patients who did and did not reach 80  mg / day were similar in regard to demographics and clinical characteristics .
differences did exist in baseline demographics and clinical characteristics between monotherapy and combination therapy patients . a larger percentage of combination therapy patients were of the hyperactiveimpulsive or combined type , had a larger percentage of patients prescribed atomoxetine by psychiatrists , had a larger percentage of patients with preindex adhd medication use , and had comorbid anxiety , depression , or sleep disorders .
while there were fewer comorbidities for the combination therapy group that showed a statistically significant difference between the atx    80 and atx  <  80 groups , this may be due to the smaller overall sample size , as trends were similar .
combination therapy patients achieving 80  mg / day had statistically significantly greater depression and sleep disorders .
across all timepoints examined , atx    80 patients had statistically significantly greater mean doses compared to atx  <  80 patients ( table  2 ) . in contrast to the atx    80 group , patients in the atx  <  80 group had similar mean lowest and highest doses and did not have their dose increase over time .
dosing patterns and length of therapy adhd , attentiondeficit / hyperactivity disorder ; lot , length of therapy ; sd , standard deviation . * wilcoxon ranksum test . only patients with a dose recorded at the examined time were included for that time .
mean lot days for all 36,076 monotherapy patients ( 107.7    101.4 ) was significantly less than for the 1548 combination patients ( 222.9    99.9 ; p  <  0.0001 ) ; the mean lot for monotherapy versus combination patients was significant less within both the patients reaching 80  mg / day as well as in the patients not reaching 80  mg / day ( p  <  0.0001 ) . of those monotherapy patients who reached 80  mg / day , 71.7% did so by day 30 , while 20.4% did not get to 80  mg / day until after 60  days ( table  3 ) .
only 45.0% of all monotherapy patients ever reached 80  mg / day . of those patients who achieved 80  mg / day , about 72% of monotherapy patients reached 80  mg / day between days 1630 while about 72% of combination therapy patients reached 80  mg / day between days 3160 . for all combination patients ,
time 80  mg / day reached lot , length of therapy ; na , not applicable .
patients in the atx    80 group had prescription claims covering a statistically significantly greater number of cumulative days annually than patients in the atx  <  80 group ( table  2 ) .
combination therapy patients had statistically significantly longer lot than monotherapy patients , regardless if they reached 80  mg / day or not ( table  2 ) .
patients with combination therapy who reached 80  mg / day had the longest lot . the difference in lot between the atx    80 and atx  <  80 groups was greater for the monotherapy patients ( 93.8  days ) compared with the combination therapy patients ( 65.5  days )
. a greater number of patients were treatment nave than not nave during the 6  months prior to their index atx treatment in the monotherapy cohorts , whereas a greater number of patients were not treatment nave in the combination therapy cohort ( table  4 ) . when comparing lot between the atx    80 and atx  <  80 groups , the finding that atx    80 patients had longer lot than atx  <  80 patients held true within the nave and nonnave subgroups
however , the lot was statistically significantly longer for naive patients than it was for previously treated patients in the monotherapy cohort .
length of therapy of treatment naive versus not naive patients sd , standard deviation . * wilcoxon ranksum test .
adhd treatment naive is defined as not having adhd treatment in the 6month preindex period ; however , whether patients were treatment naive prior to this period is unknown .
the dosing pattern variable and lot sensitivity analyses provided similar and consistent results to those in table  2 , with a mean lot of 160.4 for atx    80 and 67.1 for atx  <  80 monotherapy patients ( p  <  0.0001 ) .
the mean lowest and highest doses were 59.2 and 107.9 for atx    80 and 36.5 and 40.5 for atx  <  80 monotherapy patients ( p  <  0.0001 ) .
within the monotherapy patient group , several factors were suggestive of increasing the likelihood a patient would fill an 80  mg / day prescription during their followup year ( table  5 ) .
older patients ( 1.4% more likely per 1  year of age ) , males ( 22.6% ) , patients with a hyperactiveimpulsive or combined type diagnosis ( 6.7% ) , patients whose last provider type was a psychiatrist ( 25.4% ) or other ( 15.2% ) type versus the primary care / family practice reference group , and patients with a comorbidity diagnosis of bipolar ( 16.3% ) , depression ( 7.2% ) , hypertension ( 13.0% ) , or a pervasive development disorder ( 84.6% or almost twice as likely ) were more likely to achieve 80  mg / day
. demographic and clinical characteristic predictors of reaching atomoxetine 80  mg / day dose na , not applicable .
* multivariate stepwise logistic regression was used to determine the pvalue , odds ratio , and confidence interval for each demographic and clinical characteristic showing a statistically significant relationship with those who did or did not reach 80  mg / day , with a model fit cstatistic of 0.574 for monotherapy and 0.560 for combination therapy , which suggests a moderatetoweak fit .
patients whose last provider type was a neurologist versus the primary care / family practice reference group ( 29.9% ) , and patients who received intermediateacting ( 12.7% ) or shortacting stimulants ( 10.6% ) were less likely to achieve 80  mg / day . within the combination therapy patient group , patients who received prodrug stimulants ( 33.9% ) , and patients with a comorbidity diagnosis of depression ( 31.9% ) or sleep disorder ( 36.8% ) were more likely to achieve 80  mg / day .
comorbidity diagnosis of depression or sleep disorder as statistically significant predictors could be questionable as their pvalue was between 0.05 and 0.10 .
in this retrospective observational claims database study of 37,624 adult adhd patients treated with atx , 55.0% of monotherapy and 22.1% of combination therapy patients were dosed lower than the recommended 80  mg / day during a year followup .
when patients filled at least one 80  mg / day prescription during the followup period , their cumulative days of therapy over the course of that year were significantly greater than if they did not . achieving 80  mg
/ day was associated with an increase of about 94 treatment days for monotherapy patients . for a patient group known for being poor with their medication adherence 7 , the increase in lot could be clinically meaningful for their chronic adhd symptom control 4 .
clinical trial data suggest that atx response occurs incrementally over time 11 . while atx can have an onset of action in adults within 12  weeks of treatment 11 , 12
incrementally increasing response occurs in adults up to 24  weeks or longer 13 , suggesting optimal response can take several months of treatment 14 .
wietecha and colleagues demonstrated that atx treatment in adults with adhd was associated with small effect sizes after 4  weeks , moderate effect sizes by 6  months of treatment , and increased response rates during longerterm treatment at the 80  mg / day adult target dose 15 . in this wietecha study , which assessed multiple dosing subgroups , increase in response rate over 126  weeks was most noticeable in the 80  mg / day group .
patients not staying on medication for an adequate duration may miss an opportunity for symptom improvement .
this is of particular relevance to current findings that suggest patient underdosing is associated with much shorter treatment duration compared with those patients who are treated per recommended dosing levels .
thus , the current research expands upon the wietecha findings regarding the importance for patients in reaching 80  mg / day dosing and staying on treatment longterm to maximize the chance for treatment response 
patients not being titrated to 80  mg / day during their ongoing treatment regimen are significantly less likely to stay on treatment .
the clinical impact of this finding is important , as the current study of 36,076 patients treated with atomoxetine monotherapy showed that only 45% of patients ever reached the recommended 80  mg / day dosing .
adhd is a chronic neurobiological disorder 16 and thus needs ongoing , longterm treatment to maintain symptom control 17 .
the current findings that most patients do not stay on medication through a year after the start of their prescription and that many patients have breaks in their treatment adherence over time is in line with evidence from other studies that have reported nonadherence and discontinuation as issues for patients with adhd 7 , 17 , 18 , 19 , 20 .
there is growing evidence of the inappropriateness of breaks in dosing regimens for patients with adhd 10 , and that longterm medication compliance is critical for longterm treatment outcome 19 .
intermittent dosing can negatively impact the efficacy of adhd treatment , lead to reemergence of significant life impairments , increase outcome risks such as car accidents , substance abuse , and relationship or work disturbances , and may actually increase the overall sideeffect burden as patients frequently need to redevelop medication tolerance 9 , 21 . a 12month prospective observational study examining propensitymatched patients
who either discontinued study drug early or maintained treatment showed that pharmacotherapy effectiveness for their adhd was significantly better in patients that did not discontinue 17 .
there is evidence that underdosing of atx can also lead to suboptimal efficacy 4 , 17 .
the current data suggest underdosing could contribute to suboptimal treatment because it leads to significantly reduced lot for a disorder known to be chronic .
the finding that underdosing leads to shorter lot is in contrast with previous data from the kabul study showing no difference in lot during a 12month followup comparing patients with recommended dosing versus those suboptimally dosed 6 .
the mean dose for patients in the recommended dosing cohort was 83.1  mg / day , while the mean dose for patients in the suboptimal dosing cohort was 42.9  mg / day .
the mean lot for patients in the recommended dosing cohort was 131  days compared with 129  days for those in the suboptimal dosing cohort .
other studies have reported poor persistence to adhd medications in general , with lot varying by medication class and definitions used to capture these variables 7 .
the contrast in the kabul study results versus the current study results appears to be due to how patient cohorts and length of therapy were defined , which has been previously shown to result in the reporting of different adherence rates across studies 9 . in the kabul study 6 , which utilized the same database and overlapped in study timing , patients ( 12,412 )
were grouped into 4 cohorts : ( 1 ) recommended dosing , 80100  mg / day throughout followup ( 26.8% of patients ) , ( 2 ) suboptimal dosing , < 80  mg / day throughout the followup ( 36.6% of patients ) , ( 3 ) above recommended dosing , > 100  mg / day through the followup ( 1.7% of patients ) , and ( 4 ) fluctuators , filled prescriptions that fluctuated across dosing groups throughout the followup ( 34.9% of patients ) .
lot was defined as days until stopping index treatment ( any gap of > 30  days ) .
thus , patients continually dosed at 80  mg / day were compared to those never reaching 80  mg / day in regard to persistency . above recommended and fluctuator patients were not included in analyses ( over a third of patients ) . additionally , patient 's data after a break in their dosing were not included and thus their full dosing patterns over the course of a year could not be fully evaluated .
in contrast , the current study looked at patients who reached 80  mg / day at least once versus those who never reached 80  mg / day in regard to cumulative treatment duration , allowing for fluctuation in dosing and gaps in treatment .
no patients were excluded , and drug holidays were allowed , thereby addressing the clinically relevant limitations in the kabul study 6 , such as not allowing for treatment gaps that are common in this patient population 7 , 9 , 10 .
the current , less rigid dosing group and lot definitions may better equate to realworld clinical practice and patient adherence regimens .
cumulative days of therapy over time rather than consecutive days of therapy may be more clinically relevant for patients with adhd who tend to start / stop medication over time .
the specific reasons for initial medication discontinuation that could affect lot could not be measured in the claims data from either the kabul or the current study .
however , speculation behind the similar persistency between dosing cohorts in the kabul study is possible .
it could be that patients in the suboptimal group continued therapy longer than expected due to placebo effect and few side effects or due to low and slow titration prescribed by their physician to meet individual patients needs .
patients on recommended dosing could have continued therapy for a shorter than expected duration because of symptom control or adverse effects .
this could have led to similar initial persistency , while not taking into account longterm compliance over time and thereby masking the dosing group differences in overall adherence seen in the present study .
sensitivity analyses provide support for this theory . when lot was reexamined in the kabul study patient population using the current dosing group and lot definitions ,
the lot results were aligned with the overall study results  those reaching 80  mg / day had a significantly longer lot . in this study ,
monotherapy patients reaching 80  mg / day had a mean dose of 64.8  mg / day at day 14 but had a mean dose of 80.6  mg / day at day 30 .
this is logical as atx is a titrated drug , although it does show that physicians are titrating patients at a much slower rate than the labelrecommended 40  mg / day for a minimum of 3  days followed by 80  mg / day thereafter . for patients that reach 80  mg /
day , the mean dose thereafter fell to a consistent mean dose of about 70  mg / day , perhaps suggesting a drop in dose to aid in tolerability for some patients .
the observations that monotherapy patients never reaching 80  mg / day had similar mean lowest ( 36.0  mg / day ) and highest ( 40.2  mg / day ) doses , had a mean dose of 37.0  mg / day on day 14 , and had a mean dose of 38.3  mg / day on day 30 suggests that physicians were not titrating their patients upward in dose after initial dosing .
healthcare providers appear to be more open to atx monotherapy for adult patients naive to other adhdindicated treatments in the prior 6  months .
the lot was statistically significantly less in previously treated patients compared to naive patients in the overall monotherapy cohort , suggesting naive patients have a longer lot .
this finding could be because patients used to the feeling of stimulant therapy are more likely to discontinue atx due to a perceived lack of efficacy , regardless of efficacy outcomes 22 . aligning with the atx prescribing information , physicians prescribe atx as a monotherapy a majority of the time .
factors that increased the likelihood of a patient receiving and filling an 80  mg / day monotherapy prescription during their followup year , included being older , male , hyperactiveimpulsive or combined type , psychiatrist prescriber , and having a bipolar , depression , hypertension , or pervasive development disorder as a comorbidity .
however , the increased likelihood was from about 7 to 25% except for pervasive development disorder comorbidity that was about 85% , all of which are less than a 1fold change . also , the multivariate model used to test statistical significance was found to only be of moderatetoweak fit .
study limitations to consider are that early dosing of 80  mg / day may be overestimated due to the dose algorithm used , such that some doses within the first 30  days of treatment could be added together but may actually be serial titration doses .
this is based upon how ndc codes for prescription claims are entered into the truven database .
data describing reasons for discontinuation and clinical outcome data are not available in an administrative claims database , so it was not possible to assess the true association between dosing cohorts and symptom control .
results were based upon medication prescribed and filled rather than actual patientlevel adherence , so it is not known whether or not the patients took their medication as intended .
the analysis was limited to only those individuals with commercial health insurance and thus may not be generalizable to adhd patients with other insurance types .
second , patients do not adhere to taking their medication longterm , also limiting the optimization of their treatment .
third , underdosing can exacerbate patient 's lack of treatment compliance over time , synergistically setting the patient up for treatment failure . to maximize potential atx efficacy ,
it is important for physicians to set appropriate expectations of atx treatment with their patients around labelbased recommended target dosing , length of time to maximized efficacy and how this is different than for stimulants , and the importance of longterm medication compliance . to our knowledge , this is the first study to show a datadriven rather than anecdotal linkage between atomoxetine underdosing , medication adherence , and the importance of assessing cumulative days of therapy over time in the adult adhd population .
a majority of adult adhd patients treated with atx were dosed lower than the recommended 80  mg / day .
when patients filled at least one 80  mg / day prescription , their cumulative days of therapy over the course of a year were significantly greater than if they did not .
ensuring adult adhd patients are treated with atx at a target dose of 80  mg / day is an important clinical consideration for maximizing patient days on therapy , which may be important for optimizing a patient 's chance for treatment response and maximal therapeutic benefit .
clemow , nyhuis , and robinson are employees and minor shareholders of eli lilly and company and/or one of its subsidiaries .
 summaryaimto compare atomoxetine ( atx ) length of therapy ( lot ) among adults with adhd who reached the recommended dose of 80  mg / day ( atx    80 ) versus those who did not ( atx  <  80 ) analyzed separately in patients prescribed atx as monotherapy ( mono ) and in combination with other adhd medications ( combo).methodsthis was a retrospective observational cohort study of the truven health marketscan commercial claims database from january 1 , 2006september 30 , 2013 , with a 6month preindex period free of atx ( 1st atx claim as index event ) and a 1year followup . lot during followup was calculated using prescription claim fill dates and included all days with medication on hand regardless of treatment gaps.resultsonly 45.0% of the 36,076 mono and 77.9% of the 1548 combo patients reached an atx dose of 80  mg / day in 1year followup . 
 when patients filled at least one 80  mg prescription , their total days of therapy over the course of a year were significantly greater than if they did not ( mono : 159.3 vs. 65.6  days ; combo : 237.4 vs. 172.0 ; p  <  0.0001 ) . across all timepoints examined ( day 14 , 30 , 60 , 90 , 210 ) for mono and combo , atx    80 versus atx  <  80 patients had greater mean doses ( p  <  0.0001 ) . 
 combo patients had longer atx lot than mono patients regardless if they reached 80  mg or not ( p  <  0.0001 ) , but mono patients lot was 93.8  days longer for atx    80 versus atx  <  80 patients compared to 65.5  days for combo patients . of patients reaching 80  mg / 
 day , 71.7% of mono and 62.8% of combo patients did so by day 30 . 
 for mono 
 atx    80 and atx  <  80 patients , lot was significantly ( p  <  0.0001 ) less in previously treated patients compared to naive patients.conclusionensuring adult adhd patients are treated with atx at a target dose of 80  mg / day is an important clinical consideration for maximizing patient days on therapy , which can be important for treatment optimization . 
Introduction
Materials and Methods
Data Source
Study Population
Statistical Analysis
Results
Demographic and Clinical Characteristics
Dosing Patterns
Length of Therapy
Predictors of Reaching Target Dose
Discussion
Conclusion
Conflict of Interest