congenital hypothyroidism ( ch ) is a condition of insufficient production of a thyroid hormone , which is due to thyroid dysgenesis or thyroid dyshormonogenesis . it results in irreversible damage of the central nervous system ( porterfield , 1994 ) , presenting serious mental and motor retardation ( simic et al . , 2009 ) . neonatal ch screening and early replacement therapy of thyroxine has been highly effective in preventing retardation ( maitusong et al . , 2012 ) . by raising the intelligent quotient ( iq ) to within normal range in subjects with ch , the individuals gain a higher quality of life and better cognitive functions . however , accumulating evidence suggests that , even though their performance is definitely improved by earlier initiation of thyroxine supplementation , children with ch still have some subtle cognitive and motor deficits ( fuggle et al . , 1991 ; bargagna et al . , 2000 ; rovet and ehrlich , 2000 ) , such as attention deficit and inhibitory control problems . rovet ( 1999 ) reported that adolescents with ch had poorer attention compared with matched controls . other studies found similar results in children , adolescents , and young adults ( kooistra et al . alvarez and colleagues ( 2010 ) also showed that inhibitory control was significantly lower in children with ch than in controls . all the results indicate that subjects with ch have a higher possibility of attention deficit hyperactivity disorder ( adhd ) symptoms . adhd is characterized by age - inappropriate inattention , hyperactivity - impulsivity , or both , which play an important role in the impairment of academic and social function for school - aged children . however , the multiplicity of the both conditions make the treatment challenging . to the best of our knowledge , there is no clinical trial to explore the treatment of children with both adhd and ch . atomoxetine is a selective norepinephrine reuptake inhibitor approved for the treatment of adhd . in the present pilot study , our aim was to evaluate the efficacy and tolerability of atomoxetine on adhd symptoms and cognitive functions in children with ch . in this pilot study , we evaluate the effects of 6-month atomoxetine treatment on adhd symptoms and cognitive functions in children with ch . the participants were recruited from an outpatient clinic . those children with ch who were suspected of having adhd symptoms were administered structured interviews in order to assess adhd symptomatology . children included in this study met adhd criteria according to the diagnostic and statistical manual of mental disorders , fourth edition , under the following three subtypes : adhd inattentive type , adhd hyperactive - impulsive type , and adhd combined type . all the patients were evaluated with the swanson , nolan and pelham teacher and parent rating scale , version iv ( snap - iv ) and clinical global impression - severity scale ( cgi - s ) , both scales of adhd symptoms , at baseline and at 6 weeks , 12 weeks , and/or 6 months after starting atomoxetine treatment . tests of cognitive functions , including the wechsler intelligence scale for chinese children ( wisc - r ) , , digit span , wisconsin card sorting test ( wcst ) , and stroop color - word test , were evaluated at baseline and endpoint . thirteen gender- and age - matched children ( 11 boys and 2 girls ) without adhd from a primary school voluntarily took part into the study as normal controls . exclusion criteria for the study were : ( a ) iq under 70 ; ( b ) a psychiatric diagnosis with significant symptoms ( psychosis , autism , depression , anxiety , mood disorder ) or taking psychoactive medications ; ( c ) a history of significant traumatic brain injury ; ( d ) sensorimotor handicaps ( paralysis , deafness , blindness ) ; or ( e ) serious somatic disorders , such as cardiovascular diseases , serious gastrointestinal stenosis , dysphagia , etc . the study procedures were explained to children and parents , and consents were obtained from the children and their families . the study protocol was approved by the institutional review board of the children s hospital , zhejiang university school of medicine . the children were assessed by a trained multidisciplinary adhd diagnostic team with a comprehensive assessment process , including physical examination , electroencephalogram and electrocardiograph ( ecg ) . adhd symptoms were assessed with the snap - iv ( 18 item ) and cgi - s ( wu , 1984 ) . the cgi - s is a 7-point scale ( 1 = not at all ill , 7 = maximal impairment ) . we employed the wisc - r , digit span , wcst , and stroop color - word test to evaluate the cognitive functions . the wisc - r is one of the most - used standardized tests of iq . the test consists of 12 subtests , and three iq scores can be yielded : full scale ( fiq ) , verbal ( viq ) , and performance ( piq ) . the chinese version of the wisc - r has good reliability and validity ( lin and zhang , 1986 ; zhang et al . , 2011 ) , which was employed to assess the cognitive abilities in the present study . the digit span is used to evaluate verbal working memory , immediate recall , and the ability to hold , retain , and manipulate new verbal information ( groth - marnat and baker , 2003 ) , which is a subtest of wisc - r ( lin and zhang , 1986 ) . participants are read a string of numbers and asked to repeat them in the same order and backward . the wcst ( tsuchiya et al . , 2005 ) measures the ability to form abstract concepts , to sustain attention , and to shift cognitive set flexibility in response to changing conceptual rules while inhibiting inappropriate responses . it is one of the most common tests for executive function in the school - aged population ( ozonoff , 1995 ; schmitz et al . , 2002 ) . children were requested to match those cards with additional cards under changing rules ( including matching the shapes , different colors , quantity , and designs ) . the number of right and wrong matches and the time children took to learn new rules , as well as the mistakes , were measured . the stroop color - word test ( stroop , 1935 ; ji and jiao , 1987 ; golden and golden , 2002 ) has been widely used to assess the executive functions of cognitive inhibition and selective attention . it includes four tasks : word reading , color reading , word reading of colored words , and color naming of colored words ( hong et al . , 2010 ) . the completion times and the number of errors made during each task / test were recorded . the patients received atomoxetine ( strattera , eli lilly and company ) at 0.5mg / kg / day for the first week , and then doses increased to 1.2mg / kg / day . atomoxetine was given orally once daily as 10 , 25 , and 40 mg capsules , with the doses adjusted to achieve the body - weight target dose . clinical safety was indicated by means of the child s and parents reports of adverse events , the ecg , and laboratory tests of thyroid and liver functions . data were entered into excel software and analyzed in the spss ( version 13.0 ) software package . analyses were conducted using one - way analyses of variance ( anovas ) with repeated measures to compare mean scores at baseline to scores at different time of post treatment . the t - test was used to compare the cognitive functions between the time of baseline and that of the endpoint ( month 6 ) . a p - value of less than 0.05 was regarded as statistically significant for all statistical tests . in this pilot study , we evaluate the effects of 6-month atomoxetine treatment on adhd symptoms and cognitive functions in children with ch . the participants were recruited from an outpatient clinic . those children with ch who were suspected of having adhd symptoms were administered structured interviews in order to assess adhd symptomatology . children included in this study met adhd criteria according to the diagnostic and statistical manual of mental disorders , fourth edition , under the following three subtypes : adhd inattentive type , adhd hyperactive - impulsive type , and adhd combined type . all the patients were evaluated with the swanson , nolan and pelham teacher and parent rating scale , version iv ( snap - iv ) and clinical global impression - severity scale ( cgi - s ) , both scales of adhd symptoms , at baseline and at 6 weeks , 12 weeks , and/or 6 months after starting atomoxetine treatment . tests of cognitive functions , including the wechsler intelligence scale for chinese children ( wisc - r ) , , digit span , wisconsin card sorting test ( wcst ) , and stroop color - word test , were evaluated at baseline and endpoint . thirteen gender- and age - matched children ( 11 boys and 2 girls ) without adhd from a primary school voluntarily took part into the study as normal controls . exclusion criteria for the study were : ( a ) iq under 70 ; ( b ) a psychiatric diagnosis with significant symptoms ( psychosis , autism , depression , anxiety , mood disorder ) or taking psychoactive medications ; ( c ) a history of significant traumatic brain injury ; ( d ) sensorimotor handicaps ( paralysis , deafness , blindness ) ; or ( e ) serious somatic disorders , such as cardiovascular diseases , serious gastrointestinal stenosis , dysphagia , etc . the study procedures were explained to children and parents , and consents were obtained from the children and their families . the study protocol was approved by the institutional review board of the children s hospital , zhejiang university school of medicine . the children were assessed by a trained multidisciplinary adhd diagnostic team with a comprehensive assessment process , including physical examination , electroencephalogram and electrocardiograph ( ecg ) . adhd symptoms were assessed with the snap - iv ( 18 item ) and cgi - s ( wu , 1984 ) . the cgi - s is a 7-point scale ( 1 = not at all ill , 7 = maximal impairment ) . we employed the wisc - r , digit span , wcst , and stroop color - word test to evaluate the cognitive functions . the wisc - r is one of the most - used standardized tests of iq . the test consists of 12 subtests , and three iq scores can be yielded : full scale ( fiq ) , verbal ( viq ) , and performance ( piq ) . the chinese version of the wisc - r has good reliability and validity ( lin and zhang , 1986 ; zhang et al . , 2011 ) , which was employed to assess the cognitive abilities in the present study . the digit span is used to evaluate verbal working memory , immediate recall , and the ability to hold , retain , and manipulate new verbal information ( groth - marnat and baker , 2003 ) , which is a subtest of wisc - r ( lin and zhang , 1986 ) . participants are read a string of numbers and asked to repeat them in the same order and backward . the wcst ( tsuchiya et al . , 2005 ) measures the ability to form abstract concepts , to sustain attention , and to shift cognitive set flexibility in response to changing conceptual rules while inhibiting inappropriate responses . it is one of the most common tests for executive function in the school - aged population ( ozonoff , 1995 ; schmitz et al . , children were requested to match those cards with additional cards under changing rules ( including matching the shapes , different colors , quantity , and designs ) . the number of right and wrong matches and the time children took to learn new rules , as well as the mistakes , were measured . the stroop color - word test ( stroop , 1935 ; ji and jiao , 1987 ; golden and golden , 2002 ) has been widely used to assess the executive functions of cognitive inhibition and selective attention . it includes four tasks : word reading , color reading , word reading of colored words , and color naming of colored words ( hong et al . , 2010 ) . the completion times and the number of errors made during each task / test were recorded . the patients received atomoxetine ( strattera , eli lilly and company ) at 0.5mg / kg / day for the first week , and then doses increased to 1.2mg / kg / day . atomoxetine was given orally once daily as 10 , 25 , and 40 mg capsules , with the doses adjusted to achieve the body - weight target dose . clinical safety was indicated by means of the child s and parents reports of adverse events , the ecg , and laboratory tests of thyroid and liver functions . data were entered into excel software and analyzed in the spss ( version 13.0 ) software package . analyses were conducted using one - way analyses of variance ( anovas ) with repeated measures to compare mean scores at baseline to scores at different time of post treatment . the t - test was used to compare the cognitive functions between the time of baseline and that of the endpoint ( month 6 ) . we used last observation carried forward in our analyses of missing data . a p - value of less than 0.05 was regarded as statistically significant for all statistical tests . of the 26 children initially assessed , 12 did not meet adhd criteria and 2 children and their parents refused to participate the study . of them , 10 were males ( 83.3% ) and 2 were females ( 16.7% ) . the mean age was 8.7 years old , with a standard deviation of 2.1 ( 6.511 years ) . among these children , 11 of them were diagnosed with ch by neonatal screening before they were 1 month old , and one was diagnosed with ch when he had developmental delay symptoms at 18 months of age . all were administered with levothyroxine ( euthyrox , merck kgaa ) replacement , presently with a dosage of 6.92.7 g / kg / day . ultrasound scanning suggested dysgenesis of thyroid tissue ( six cases ) , ectopic thyroid tissue ( two cases ) , and normal locations with generally normal sizes of thyroid glands ( four cases ) . this group of samples consisted of two children with an inattentive subtype , four children with a hyperactive - impulsive subtype , and six children with the combined subtype . thirteen children of normal controls were recruited from a local school with similar demographic characteristics to the ch group . all of them were in primary school with a mean age of 8.3 years ( standard deviation [ sd ] = 1.6 ) . there were no statistical differences found for mean age and gender proportion between these two groups ( t = 0.348 , p = 0.731 for mean age , and x = 0.008 , p = 0.93 for gender proportion ) . all the patients reached the target dose range with an average of 1.1mg / kg / day ( 0.81.3 ) of atomoxetine in 24 weeks . thyroid functions and liver function were detected along with the evaluation of snap - iv , and were all in normal ranges ( table 1 ) . scores of adhd symptoms and thyroid functions at baseline and different time points of post - treatment cgi - s , clinical global impression - severity scale ; snap - iv , swanson , nolan and pelham ( snap ) questionnaire . three patients reported adverse events ( 25% ) with the administration of atomoxetine , including a decrease in appetite ( n = 2 ) and abdominal pain ( n = 1 ) . the blood tests of thyroid functions and liver function were in normal range after atomoxetine treatment . the mean baseline score of the parents version of snap - iv was 33.8 ( sd = 4.9 ) . post - treatment scores at week 6 , week 12 , and month 6 reduced to 27.3 ( sd = 4.7 ) , 22.4 ( sd = 4.3 ) , and 17.5 ( sd = 3.7 ) , respectively ( table 1 ) . the mean baseline score of the teacher version of snap - iv was 34.3 ( sd = 5.5 ) . post - treatment scores at week 6 , week 12 , and month 6 reduced to 27.8 ( sd = 4.9 ) , 21.0 ( sd = 3.1 ) , and 17.2 ( sd = 3.1 ) , respectively ( table 1 ) . significant decreases of snap - iv scores were observed for both parent and teacher versions over baseline to month 6 . repeated measures anovas revealed these statistical differences : f = 131.5 , p < 0.01 for parent ratings , and f = 98.7 , p < 0.01 for teacher ratings . changes of cognitive functions after 6 months of atomoxetine treatment , children with ch and adhd showed significant improvement in fiq ( p = 0.002 ) and piq ( p = 0.011 ) , and a non - significant improvement trend in viq ( from 97.5 to 99.5 ; p = 0.239 ) . on the other hand , there were no significant changes found for wisc - r over 6 months in normal controls ( table 2 ) . cognitive functions between atx treatment group and controls at baseline and month 6 atx , atomoxetine ; piq , performance intelligent quotient ; viq , verbal intelligent quotient ; wcst , wisconsin card sorting test ; wisc - r , wechsler intelligence scale for chinese children - revised 
 p < 0.05 versus atx treated group at the baseline ; 
 p < 0.05 versus atx treated group at month 6 ( using t - test ) for the digit span , t - tests revealed that children treated with atomoxetine performed better at month 6 than at baseline . improvement in a subtest of a backward task was found , but was not significant ( p = 0.067 ) . compared with baseline , the improvement of wcst for children treated with atomoxetine at month 6 was significant in 12 of the 13 items . a decreasing trend for the parameter of failure to maintain set was found , but was not significant ( p = 0.305 ) . significant decreases in the completion time in word reading , color reading , word reading in the incongruent condition , and color reading in the incongruent condition were observed in the ch group at month 6 compared with baseline . furthermore , atomoxetine seemed to improve the cognitive functions of children with the inattentive subtype more than those with the other two subtypes according to the wisc - r and stroop tests . for the other tests , the results did not show any predominant trends in the three groups of subtypes . but because of the small sample size ( n = 2 , 4 , and 6 ) of the subtypes , it was difficult to do further statistical analyses , and we were unable to draw any definite conclusions . in addition , the medication also benefited the cognitive functions of girls more than those of boys for the wisc - r and stroop tests . similarly , because of the small sample size of girls ( n = 2 ) , further statistical analyses were not done . all the patients reached the target dose range with an average of 1.1mg / kg / day ( 0.81.3 ) of atomoxetine in 24 weeks . thyroid functions and liver function were detected along with the evaluation of snap - iv , and were all in normal ranges ( table 1 ) . scores of adhd symptoms and thyroid functions at baseline and different time points of post - treatment cgi - s , clinical global impression - severity scale ; snap - iv , swanson , nolan and pelham ( snap ) questionnaire . three patients reported adverse events ( 25% ) with the administration of atomoxetine , including a decrease in appetite ( n = 2 ) and abdominal pain ( n = 1 ) . the blood tests of thyroid functions and liver function were in normal range after atomoxetine treatment . the mean baseline score of the parents version of snap - iv was 33.8 ( sd = 4.9 ) . post - treatment scores at week 6 , week 12 , and month 6 reduced to 27.3 ( sd = 4.7 ) , 22.4 ( sd = 4.3 ) , and 17.5 ( sd = 3.7 ) , respectively ( table 1 ) . the mean baseline score of the teacher version of snap - iv was 34.3 ( sd = 5.5 ) . post - treatment scores at week 6 , week 12 , and month 6 reduced to 27.8 ( sd = 4.9 ) , 21.0 ( sd = 3.1 ) , and 17.2 ( sd = 3.1 ) , respectively ( table 1 ) . significant decreases of snap - iv scores were observed for both parent and teacher versions over baseline to month 6 . repeated measures anovas revealed these statistical differences : f = 131.5 , p < 0.01 for parent ratings , and f = 98.7 , p < 0.01 for teacher ratings . changes of cognitive functions after 6 months of atomoxetine treatment , children with ch and adhd showed significant improvement in fiq ( p = 0.002 ) and piq ( p = 0.011 ) , and a non - significant improvement trend in viq ( from 97.5 to 99.5 ; p = 0.239 ) . on the other hand , there were no significant changes found for wisc - r over 6 months in normal controls ( table 2 ) . cognitive functions between atx treatment group and controls at baseline and month 6 atx , atomoxetine ; piq , performance intelligent quotient ; viq , verbal intelligent quotient ; wcst , wisconsin card sorting test ; wisc - r , wechsler intelligence scale for chinese children - revised 
 p < 0.05 versus atx treated group at the baseline ; 
 p < 0.05 versus atx treated group at month 6 ( using t - test ) for the digit span , t - tests revealed that children treated with atomoxetine performed better at month 6 than at baseline . improvement in a subtest of a backward task was found , but was not significant ( p = 0.067 ) . compared with baseline , the improvement of wcst for children treated with atomoxetine at month 6 was significant in 12 of the 13 items . a decreasing trend for the parameter of failure to maintain set was found , but was not significant ( p = 0.305 ) . significant decreases in the completion time in word reading , color reading , word reading in the incongruent condition , and color reading in the incongruent condition were observed in the ch group at month 6 compared with baseline . furthermore , atomoxetine seemed to improve the cognitive functions of children with the inattentive subtype more than those with the other two subtypes according to the wisc - r and stroop tests . for the other tests , the results did not show any predominant trends in the three groups of subtypes . but because of the small sample size ( n = 2 , 4 , and 6 ) of the subtypes , it was difficult to do further statistical analyses , and we were unable to draw any definite conclusions . in addition , the medication also benefited the cognitive functions of girls more than those of boys for the wisc - r and stroop tests . similarly , because of the small sample size of girls ( n = 2 ) , further statistical analyses were not done . thyroxine deficiency results in damage to brain development , which may contribute to poor attention and self - inhibition . the extent of the damage may depend on the severity and duration of the hypothyroidism ( klein et al . , 1972 ) . it is not clear that the occurrence of adhd in these patients has either a coincidental or causative relationship to ch . definitely , there are more severe impairments of academic and social functions and quality of life in those with both conditions of ch and adhd . taking these impairments into consideration , children with both ch and adhd should be treated promptly and properly . however , when ch is combined with adhd the treatment is more challenging . safety should be the first consideration , ensuring that the treatment does not affect thyroid functions and has good tolerability . atomoxetine is a new compound that has been used in treatment for adhd on the basis of its pharmacologic property of blocking the presynaptic norepinephrine transporter . the efficacy and safety of atomoxetine have been indicated in multiple double - blind , placebo - controlled studies . to our knowledge , this is the first trial concerning the efficacy and tolerability of the medication on the cognitive functions in children with ch , diagnosed and treated early , and with adhd symptoms . the snap - iv and cgi - s scores decreased greatly , which meant the adhd core symptoms were improved . we also found that this medication was effective on cognitive functions during the 6-month follow - up . the results of cognitive functions , evaluated with the digit span , wcst , and stroop test , which were impaired before treatment , were also showing improvements after atomoxetine administration . these results were consistent with the treatment outcomes of atomoxetine on children with only adhd symptoms ( vaughan et al . , 2009 ) . we explored but found no significant improvement of cognitive functions and score changes of adhd symptoms . this was inconsistent with a previous report ( zhang et al . , 2011 ) . in addition , we found that atomoxetine seemed to improve the cognitive functions of children with the inattentive subtype based on the wisc - r and stroop tests . similar results revealed that the medication benefited the cognitive functions of girls more than boys for the wisc - r and stroop tests . in clinical trials of atomoxetine treatment for children with adhd , there were no findings showing these trends , but the small sample size in the present study did not allow us to do further statistical analyses and we could not draw definite conclusions . clinical safety was indicated by means of the child s and parents reports of adverse events , ecgs , and laboratory tests of thyroid functions , which we did before treatment and at week 6 , week 12 , and month 6 ( table 1 ) . three children reported mild adverse events , but none discontinued treatment because of side effects . interestingly , atomoxetine was also effective on one boy in the treatment group who was diagnosed with ch at 18 months . as is well known , thyroxine is crucial for the development of brain , even in utero . the 18-month age was too late for levothyroxine replacement and the damage had already occurred . fortunately , atomoxetine was effective for improvement of cognitive functions , including iq ( from 78 to 85 ) . in other words , atomoxetine benefited a child who was developmentally delayed , which was consistent with a previous study ( fernandez - jaen et al . this was a pilot trial to explore the treatment strategy for children with both diseases . but it was a pilot study , and further larger sample - sized trials should be designed to replicate the results . the scale scores rated by observers would be distorted to some extent in the open - labeled pattern . moreover , we did not include a control group of children who were affected with ch but without adhd . if there had been this group , the improvement of the atomoxetine - treated group could be examined for the effect of medication and we could exclude the effect of levothyroxine on cognition . thirdly , the follow - up of 6 months might be relatively short , and longer treatment times would provide more data . but it was a pilot study , and further larger sample - sized trials should be designed to replicate the results . the scale scores rated by observers would be distorted to some extent in the open - labeled pattern . moreover , we did not include a control group of children who were affected with ch but without adhd . if there had been this group , the improvement of the atomoxetine - treated group could be examined for the effect of medication and we could exclude the effect of levothyroxine on cognition . thirdly , the follow - up of 6 months might be relatively short , and longer treatment times would provide more data . those children with ch still have poor attention and self - inhibitory ( adhd symptoms ) even with early levothyroxine replacement . atomoxetine was effective and safe in cases with ch and adhd , and produced remarkable improvement on adhd symptoms as well as cognitive functions within 6 months of follow - up . long - term , randomized , placebo - controlled clinical trials with larger sample sizes are required .