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JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 16, Number 1/2, 2006Mary Ann Liebert, Inc.
Pp. 131–145 Robert L. Findling, M.D.,1,2 Nora K. McNamara, M.D.,1,2 Robert J. Stansbrey, M.D.,1 Norah C. Feeny, Ph.D.,1,3 Christopher M. Young, M.D.,1 Franco V. Peric, M.A.,1 and ABSTRACT
Introduction: Identifying evidence-based dosing strategies is a key part of new drug develop-
ment in pediatric populations. Pharmacokinetic (PK) studies can provide important information
regarding how best to dose medications in children and adolescents. Utilizing scientifically
supported dosing strategies provides the best chance for any given drug to demonstrate both
efficacy and acceptable tolerability in definitive, placebo-controlled studies.
Methods: Results of both PK studies and randomized, placebo-controlled efficacy trials
(RPCTs) in juvenile major depressive disorder (MDD) are reviewed. The degree to which the
medication dosing strategies that were employed in the efficacy studies were supported by
the extant PK data is considered. Medications that are reviewed include fluoxetine, sertra-
line, paroxetine, citalopram, escitalopram, venlafaxine, nefazodone, and mirtazapine.
Results: In many instances, the dosing paradigms that were used in the RPCTs differed,
sometimes substantially, from the dosing strategies that would have been supported based
on the results of PK studies.
Conclusions: Medication dosing regimens may have contributed to the failure of several
RPCTs to show drug efficacy in the treatment of pediatric MDD. In addition, the doses of
medication used in these RPCTs may also have contributed to the safety and tolerability con-
cerns that have been raised with these drugs. PK and dose-ranging studies should be per-
formed prior to the initiation of definitive efficacy trials so that empirically supported dosing
strategies can be incorporated into the design of RPCTs of antidepressants in children and
adolescents suffering from MDD.
INTRODUCTION
Interestingly, other agents have also been testedas potential treatments for juvenile depression AS OF MARCH 2005, only fluoxetine has re- in randomized, placebo-controlled trials (RPCTs).
Most of these studies did not demonstrate su- Drug Administration (FDA) as a pharmacologi- periority of active treatment when compared cal treatment for depressed youths (FDA 2003).
From the Departments of 1Psychiatry, 2Pediatrics, and 3Psychology, University Hospitals of Cleveland/Case West- ern Reserve University, Cleveland, Ohio.
FINDLING ET AL.
utilized a dose-ranging design, which allowed conducted studies have failed to show anti- for flexible dosing (within certain predetermined depressant efficacy have not been definitively parameters) at the treating physician’s discre- elucidated. Although some of these antidepres- tion. Such trials can provide information about sants may truly be of no benefit to young peo- the optimal dosing for a compound within clin- ple suffering from major depressive disorder ical settings. Furthermore, first- and multiple- (MDD), methodological issues also need to be dose PK studies were performed. This is an considered when examining why some of these important consideration, because differences in studies failed to show antidepressant efficacy.
PK parameter estimates may be observed at The field of child and adolescent psychophar- these two distinct time points. Finally, several macology appears to be in a state similar to that of the PK studies included patients with differ- point in time when studies of tricyclic antide- ent psychiatric diagnoses. Performing PK stud- pressants (TCAs) failed to demonstrate efficacy ies in patients with heterogeneous diagnoses in youths with MDD. Methodological consid- does not reduce methodological rigor because erations that were raised at that time included drug biodisposition does not appear to be adequate sample size, appropriate patient selec- tion, duration of treatment, and empirically sup- Agents that will be considered herein include: ported outcome measures (Jensen et al. 1992).
Fluoxetine, sertraline, paroxetine, citalopram, However, another key issue that needs to be escitalopram, venlafaxine, nefazodone, and considered when evaluating the safety and ef- mirtazapine. Although fluvoxamine has been ficacy of any agent, including an antidepressant, shown to have efficacy in the treatment of pe- is dosing (Atuah et al. 2004). Key parameters diatric obsessive-compulsive disorder (OCD) of dosing that should be empirically evaluated (Riddle et al. 2001) and several other pediatric may include identifying an appropriate total anxiety disorders (Research Unit on Pediatric daily dose and determining how frequently the medication needs to be administered each day.
2001) and bupropion has been shown to have If a medication is not dosed properly, clinical efficacy in the treatment of ADHD in children efficacy might go undetected. Similarly, if a (Conners et al. 1996), these compounds will medication is not dosed properly, adverse not be considered in this paper. This is because events might occur that might otherwise have there are no adequately powered RPCTs with been avoidable with a different dosing strat- egy. As development-based differences in phar-macokinetics may be seen with drugs (Kearnset al. 2003), one of the means by which empiri- cally based dosing strategies are derived in pe- Pharmacokinetic studies. Several PK parameter diatric patients is through pharmacokinetic estimates were reported for fluoxetine, and its primary metabolite norfluoxetine, based on the The aim of this paper is to consider what is results of a study in which 10 children and 11 known about the pharmacokinetics of the newer adolescents participated (Wilens et al. 2002).
generation of antidepressants and then to con- These youths were diagnosed with either MDD sider whether or not the dosing strategies that or OCD and treated with fluoxetine at a dose could be supported by these PK data were ac- of 20 mg per day for up to 60 days. Blood sam- tually employed in double-blind efficacy stud- ples for PK analyses were obtained at prede- termined time points between 8 and 12 hours Designs of the cited PK studies and the RPCTs are summarized in Tables 1 and 2. It should be The authors found that steady-state levels of noted that some of these trials incorporated a both fluoxetine and norfluoxetine were achieved forced titration design. In such studies, a pa- by 4 weeks after the initiation of drug therapy.
tient’s treatment is increased to a predetermined Although there was high intersubject variabil- target dose. In addition, several of the studies ity, the concentrations of both moieties were PHARMACOKINETIC STUDIES IN YOUTH DEPRESSION
TABLE 1. RECENT PHARMACOKINETIC STUDIES OF SELECTED ANTIDEPRESSANTS IN CHILDREN AND ADOLESCENTS
concentrations of fluoxetine andnorfluoxetine were approximatelytwo times higher in the childrenthan in adolescents. Population PKparameter estimates were similar towhat had previously been describedin adults.
exposure when compared to eitheradolescents or to what had beenpreviously reported in adults. At200 mg, t1⁄2 was similar for children,adolescents, and adults.
previously noted in Alderman et al.
(1998). Twice daily dosing foryouths receiving < 200 mg/daymight be optimal t1⁄2 shorter after single 10-mg dose than intra-subject variability in drug concentrations after multiple doses. Non-linear increases in systemicexposure with increased dose systemic paroxetine exposure andparoxetine dose observed parameters were similar inadolescents and adults FINDLING ET AL.
TABLE 1. RECENT PHARMACOKINETIC STUDIES OF SELECTED ANTIDEPRESSANTS IN
CHILDREN AND ADOLESCENTS (continued)
exposure to both venlafaxine and O-desmethylvenlafaxine was lowerthan reported in adults active metabolites whencomparedto adolescents = maximum concentration; t 1 = half-life.
TABLE 2. SELECTED PLACEBO-CONTROLLED TRIALS IN JUVENILE MAJOR DEPRESSIVE DISORDER
titrated up to 60 mg over the first 2 weeks 10 mg 1st week, then 20 mg. Could increase in 10-mg 25 mg ϫ 3 days, then 50 mg. Could be increased to a maximum of 200 mg. Once daily dosing.
25 mg ϫ 3 days, then 50 mg. Could be increased to a maximum of 200 mg. Once daily dosing.
20 mg with optional, subsequent increases in 10-mg 10 mg, with subsequent increases in 10-mg increments for a 20 mg, subsequent increases allowable up to a maximum 20 mg ϫ 4 weeks with a subsequent increase to 40 mg PHARMACOKINETIC STUDIES IN YOUTH DEPRESSION
10 mg with subsequent increases in 10 mg increments to a 10 mg ϫ 4 weeks, with subsequent increase to 20 mg Target dose 300–400 mg; maximum allowable dose 600 mg Children low dose arm: maximum of 100 or 150 mg/day; children high dose arm: maximum of 200–300 mg/day;adolescent low dose arm: maximum of 300 mg/day;adolescent high dose arm: maximum of 400–600 mg/day Initial dose 15 mg; could increase by 15 mg increments. Max Initial dose 15 mg; could increase by 15 mg increments. Max aStatistically significant difference between active drug and placebo on primary efficacy analysis.
bStatistical trend for difference between active drug and placebo on primary efficacy analysis.
cNo statistically significant difference between active drug and placebo on primary efficacy analysis.
approximately two times higher in the chil- cent MDD failed to show a difference between dren (ages 6–12) than in adolescents (ages 13– fluoxetine and placebo in a group of 40 adoles- 18). After weight normalization, drug and cents (ages 13–18 years) during a 7-week trial metabolite concentrations were found to be (Simeon et al. 1990). In this study, fluoxetine similar across the age groups. Population PK was titrated to a dose of 60 mg/day over the analysis of the collected samples yielded pa- first 2 weeks of treatment. It has been previ- rameter estimates for absorption rate constant, ously noted that methodological issues, such oral clearance, and volume of distribution.
as small sample size, high placebo response These parameter estimates were found to be rate, and the dosing strategy employed, may similar to what had previously been described have contributed to this trial’s failure to detect in adults. Based on these findings, the authors a difference between active treatment and suggested that 10 mg per day might be a ratio- nal initial dosing strategy for prepubertal Subsequently, Emslie et al. (1997) reported children, whereas 20 mg per day might be a that fluoxetine was superior to placebo in the reasonable starting dose for adolescents (Wilens treatment of MDD in a cohort of 96 youths 7–17 years of age who participated in an 8-week randomized, double-blind study RPCT.
Efficacy studies. The first published RPCT ex- In this trial, a fixed 20-mg dose of fluoxetine amining the efficacy of fluoxetine in adoles- was used in the active treatment arm.
FINDLING ET AL.
Fluoxetine was again found to be superior to placebo in another double-blind RPCT in which Pharmacokinetic studies. The first PK study to 122 children and 97 adolescents with MDD re- examine sertraline included 29 children (ages ceived treatment with either fluoxetine or 6–12 years) and 32 adolescent (ages 13–17 years) placebo. In this study, patients who were ran- suffering from either OCD or MDD (Alderman domized to active treatment initially received et al. 1998). After receiving a single 50-mg 10 mg of fluoxetine per day for the 1st week.
dose, patients had their sertraline gradually These subjects then received 20 mg of fluoxe- increased to a final dose of 200 mg/day in tine per day thereafter for up to 8 more weeks either 25- or 50-mg increments. Sampling for PK analyses was done after the single 50-mg In a follow-up trial to this study, patients dose and after multiple 200-mg doses.
who did not respond to 20 mg of fluoxetine mg/day), 40 mg/day or 60 mg/day of fluoxe- exposure to sertraline when compared to either tine (Hoog et al. 2001). Results suggest that doses of 40 or 60 mg per day of fluoxetine been previously reported in adults. The authors might be well tolerated, as well as superior to noted that differences in the PK parameters continued treatment with fluoxetine at 20 mg across the age groups were most likely the re- per day for those who do not adequately re- sult of body-weight differences. In this study, the half-life (t1⁄2 ) of sertraline exceeded 24 hours Finally, in a large multisite RPCT, 439 ado- across age groups after multiple 200-mg doses.
lescents (ages 12–17) with MDD were random- In another study, the multiple-dose PK para- ized to receive cognitive behavioral therapy, meters of sertraline, when given at doses less fluoxetine, active combination therapy, or than 200 mg to adolescents, were described placebo for up to 12 weeks (Treatment for (Axelson et al. 2002). After receiving multiple 50-mg doses, the authors noted that the t1⁄2 of Team 2004). Again, treatment with fluoxetine sertraline was 15.3 hours. After multiple 100- was found to be superior to placebo in depres- or 150-mg doses, it was noted that the t1⁄2 of sive symptom amelioration. In this study, flu- sertraline was 20.4 hours. As the t1⁄2 was shorter oxetine was initiated at a dose of 10 mg per than what had been previously noted in the day. Fluoxetine was then increased to a dose of study of Alderman et al. (1998) and was less 20 mg per day after 1 week of treatment. Flu- than 24 hours, the authors suggested that it oxetine could then be increased in 10-mg in- might be reasonable to dose sertraline initially crements to a maximum daily dose of 40 mg.
in divided daily doses, and to consider divideddaily dosing for those youths not responding Interpretation. In the three studies showing to once-daily dosing. The authors did note that, fluoxetine to be more beneficial than placebo for patients receiving 200 mg per day of sertra- (Emslie et al. 1997; Emslie et al. 2002; TADS line, once-daily dosing might be appropriate.
2004), the starting dose of fluoxetine was either10 or 20 mg per day. Notably, these were thedoses suggested by the authors of the one PK Efficacy studies. There are two RPCTs in which study of fluoxetine (Wilens et al. 2002). There the efficacy of sertraline was compared to are also data (Hoog et al. 2001) to support the placebo in the treatment of MDD in youths be- decision to allow for dose increases in fluoxe- tween the ages of 6 and 17 years. In these clinical tine above 20 mg per day, as was done in the trials, subjects received 10 weeks of double-blind TADS trial. However, it would have been in- treatment (Dubitsky 2004; Wagner et al. 2003). In teresting to see whether or not the RPCT re- one study, 97 patients received sertraline and 91 sults would have been affected if the younger received placebo. In the other trial, 92 youths re- children who participated in the RPCTs had ceived sertraline and 96 were administered received an initial 10-mg daily dose that did placebo. Sertraline treatment was initiated at a not have to be raised per study protocol.
dose of 25 mg per day for 3 days, with the dose PHARMACOKINETIC STUDIES IN YOUTH DEPRESSION
of sertraline subsequently increased to a dose of hours with wide intersubject variability. In ad- 50 mg per day until the end of the 2nd week.
dition, they noted that several PK parameters Thereafter, the dose of sertraline could be in- correlated with cytochrome P450 2D6 (2D6) creased in 50-mg-per-day increments to a maxi- phenotype. There was also a trend for cate- mum daily dose of 200 mg. Interestingly, divided chol-O-methyltransferase (COMT) activity to dosing was not allowed in these efficacy studies (Dubitsky 2004). The mean dose of active sertra- line given to patients across both trials was 131 were measured weekly during the course of mg/day. Although pooled analyses of both stud- the study. Drug concentrations for individual ies suggested superiority for sertraline over placebo (Wagner et al. 2003), each study, when paroxetine generally remained consistent dur- considered individually, failed to demonstrate a ing the course of the study. However, an almost statistically significant difference between active 7-fold increase in paroxetine concentration was noted in the subjects who had their paroxetinedose raised (n = 8) owing to insufficient clini- Interpretation. The dosing strategy used in the cal benefit. Similar to adults, this finding dem- sertraline efficacy studies diverged from the onstrated that paroxetine has nonlinear PKs in dosing strategies that could be best justified, based on the results of the PK studies. The ex- Overall, the study medication was well toler- tant data suggest that for subjects being treated ated and associated with salutary effects, with at doses of sertraline less than 200 mg per day, most subjects responding adequately to the 10- divided daily dosing might be more effective mg-per-day dose. There were only 2 early dis- than once-daily dosing. However, as already continuations from the trial. In both instances, noted, the efficacy studies did not permit split this was because of the development of hypo- daily dosing. These studies also did not force- mania. In addition, there were 2 poor metaboliz- titrate subjects to a 200-mg-per-day dose level ers with respect to 2D6 phenotype. Interestingly, (the level at which once-daily dosing is best the subject with the least amount of 2D6 activity supported). It is possible that if the dosing was the patient who discontinued earliest from schema in the two sertraline efficacy studies the study. Based on these observations, the au- were different, the distinctions between active thors raised the question of whether or not treatment and placebo that were noted only being a poor metabolizer with respect to 2D6 ac- though a pooled series of analyses (Wagner et al.
tivity conferred a vulnerability to paroxetine in- 2003) might have been more readily detectable.
tolerance in this patient population.
In addition, the authors noted that treatment with 10 mg of paroxetine was associated with substantial reductions in platelet-rich plasma Pharmacokinetic studies. There are two phar- serotonin concentrations. Similarly, paroxetine macokinetic studies of paroxetine in children also causes reductions in whole-blood seroto- and adolescents. The 1st-dose pharmacokinet- nin levels when it is administered to adults ics of paroxetine were described in a cohort of (Marsden et al. 1987). These data suggest that 30 children and adolescents with MDD (Find- paroxetine exerts pharmacodynamic effects on ling et al. 1999). Intensive blood sampling for serotonin in children that are similar to that PK analyses occurred after a single 10-mg dose.
seen in adults (Findling et al. 2002b).
Subsequently, subjects were treated with open- Based on these findings, the authors sug- label paroxetine for 8 weeks, with a starting gested that paroxetine at a dose of 10 mg per dose of 10 mg per day. After 4 weeks of open day appears to be an appropriate starting dose.
treatment, those patients with persistent de- For those who do not respond to this treatment, pressive symptomatology could have their dose a dose increase to 20 mg/day may be a reason- of paroxetine increased to 20 mg per day.
The investigators found that the average t1⁄ The other PK study was a 6-week, open-label of a single 10-mg dose of paroxetine was 11.1 trial in patients with either MDD or OCD.
FINDLING ET AL.
Twenty-seven (27) children between the ages only 5% of patients remained on the 10-mg of 7 and 11 years and 35 adolescents between paroxetine dose throughout the trial. In addi- the ages of 12 and 17 years were initially tion, approximately 60% of patients were treated treated with 10 mg of paroxetine per day for 2 with doses of paroxetine greater than 20 mg/ weeks. These patients then received 20 mg of paroxetine a day for 2 weeks, and were subse- In a 12-week study of 286 adolescents between quently treated with 30 mg of paroxetine per the ages of 13 and 18, paroxetine was again not day for 2 more weeks. Blood sampling for PK found to be superior to placebo (Laughren 2004; analyses was then performed at the end of the GlaxoSmithKline 2005d). In this study, paroxe- 2-week treatment period for each dose (Glaxo- tine was initiated at a dose of 20 mg per day. Sub- jects could be treated with a maximum dose of Results of this study confirmed the nonlin- 40 mg of paroxetine per day (Dubitsky 2004).
ear relationship between systemic paroxetine Fifty-six percent (56%) of subjects did not have exposure and paroxetine dose. In addition, the their dose of paroxetine raised from the 20- children in this study were noted to generally mg/day level (GlaxoSmithKline 2005d).
have higher systemic exposure to paroxetinethan the adolescents who participated. The data Interpretation. The doses of paroxetine em- from this trial suggest that children might be ployed in the RPCTs generally exceeded the able to be treated with a lower initial paroxe- mended, based on the results of the PK stud-ies. As the systemic exposure to paroxetine is Efficacy studies. In a study in which 275 youths not proportional to dose, the effects of this de- 12–18 years of age were randomized to receive cision could be substantial. Of particular inter- paroxetine, imipramine, or placebo in a dou- est is the finding that in a recent review by the ble-blind fashion, paroxetine was found not to FDA of antidepressant trials, paroxetine was be superior to placebo on the two primary out- found to have the highest risk of treatment- come measures (Keller et al. 2001). However, emergent agitation or hostility (Hammad 2004).
paroxetine was shown to be associated with It is interesting to speculate whether or not the greater symptom reduction than placebo on same rates of agitation or hostility, as well as several secondary outcome assessments. In this improved efficacy, would have been observed study, patients were initially treated with 20 if more conservative dosing strategies had been mg/day of paroxetine given as a single daily dose. Subjects could subsequently have theirdose of paroxetine increased in 10-mg incre-ments to a maximum total daily dose of 40 mg day, with doses of 30 or 40 mg/day given in Pharmacokinetic studies. The first PK study of divided doses, based on the treating physi- citalopram examined 11 adolescents (ages 12– cians’ discretion. Of the 93 youths treated with 17 years) and 7 adults (18–45 years) with MDD paroxetine, 42 remained on 20 mg/day, with (Gutierrez et al. 2000). These patients were the rest having their dose increased to 30 or 40 treated with citalopram at a dose of 20 mg/ day for 1 week, followed by 3 weeks of treat- ment with citalopram at a dose of 40 mg/day.
the ages of 7 and 17 years (Dubitsky 2004; After 4 weeks of treatment, subjects had blood GlaxoSmithKline 2005c), no statistically signif- sampling performed for subsequent pharma- icant difference between paroxetine and placebo cokinetic analyses. The authors found that the was found (Laughren 2004; GlaxoSmithKline PK parameters of citalopram were similar in 2005c). Of note, all patients were started on a the adolescents and adults. The t1⁄2 of citalo- dose of 10 mg per day for the 1st week of treat- pram in adolescents was 38.4 hours and the t1⁄2 ment. After 1 week of treatment, paroxetine of citalopram in adults was 44 hours.
could be increased at 10-mg increments to a maximum daily dose of 50 mg/day. Notably, ages of 9 and 17 years, Axelson et al. (2002) PHARMACOKINETIC STUDIES IN YOUTH DEPRESSION
treated patients with 20 mg of citalopram per superior to treatment with placebo (Laughren day (Perel et al. 2001; Findling et al. 2004). In- 2004). However, it should be noted that this tensive sampling for PK-parameter estimation study is different from the other multisite study was performed after both a single 20-mg dose of citalopram in methodology. This study per- (n = 9), as well as after multiple daily doses of mitted inpatients as subjects and allowed the citalopram. As part of this study, the authors use of concomitant psychoactive medications examined S-citalopram concentrations.
(Dubitsky 2004). It is possible that these two factors may have contributed to the discrepant States as escitalopram, is the S-enantiomer of results between these two citalopram trials.
racemic citalopram. It has been suggested thatthe S-enantiomer of the isomer is responsible Interpretation. The dose of citalopram exam- for the salutary effects of the compound and ined in both efficacy studies did not exceed the that the R-enantiomer is clinically inactive doses of citalopram that were examined in the PK studies. Based on the extant data, it ap- The authors found a substantial correlation pears that, for patients receiving 20 mg of between CYP 2C19 activity and S-citalopram citalopram per day, a twice-daily dosing strat- concentration after treatment with multiple egy might be reasonable. Whether or not evi- daily doses of citalopram. The authors also dence for improved efficacy for citalopram might have been found in the two RPCTs if a single 20-mg dose (16.9 hours), and the half twice-daily dosing schema had been employed life of S-citalopram after multiple 20 mg daily for patients receiving less than 40 mg per day doses (19.2 hours) were both shorter in the of citalopram remains an empiric question. In- adolescents they examined when compared to terestingly, one of the RPCTs (Wagner et al.
what had been previously observed in adults.
2004a) enrolled children and adolescents. How- Based on these data, the authors raised the ques- ever, based on the finding that the t1⁄2 of the ac- tion whether or not citalopram, when given at tive isomer of citalopram might be shorter in adolescents than adults (suggesting possible twice-daily in adolescents in order to obtain age-related effects on PK parameters), it is par- ticularly unfortunate that there is an absenceof available PK data for citalopram in children.
Efficacy studies. In an 8-week MDD study(Wagner et al. 2004a), 174 youths between 7 and 17 years were treated with an initial doseof 20 mg/day of citalopram. After 4 weeks of Pharmacokinetic studies. There is one PK study treatment, subjects could have this dose in- of escitalopram in youths. In this study, a sin- creased, based on the treating physician’s dis- gle 10-mg dose was given to 11 adolescents cretion, to a dose of 40 mg/day. Overall, at an (12–17 years) and 12 adults (ages 18–35 years) average dose of 24 mg/day, the medication (Periclou et al. 2003). The authors found that was found to be generally well tolerated, with the t1⁄2 of escitalopram was 19.0 hours in ado- those patients randomized to active treatment lescents and 28.9 hours in adults. It was also receiving superior benefit to those random- observed that the overall systemic exposure was approximately 15% greater in adults than In another multisite, placebo-controlled study, 244 youths between 13 and 18 years of agewith MDD were treated with citalopram at Efficacy studies. There is one RPCT of escitalo- doses ranging between 10 and 40 mg per day pram in juvenile MDD (Wagner et al. 2004b).
for up to 12 weeks. The starting dose of citalo- In this study, 264 youth between the ages of 6 pram was 10 mg/day. This could be increased and 17 years, were randomized to receive ei- in 10-mg increments, based on clinical response ther escitalopram or placebo for up to 8 weeks and tolerability (Dubitsky 2004). In this study, after a 1-week placebo lead-in. The starting dose treatment with citalopram was not found to be of escitalopram was 10 mg/day and could be FINDLING ET AL.
increased to 20 mg/day at the end of week 4 of week of the study to a target dose of 25 mg active treatment. Overall, no statistically sig- thrice-daily. Overall, the authors found that ben- nificant difference between the two treatment efit was equivalent across both treatment arms arms was found. However, post hoc analyses and that the study treatments were generally suggested that among adolescents (ages 12–17 well tolerated. This study lacked a placebo- years) who completed the study, those who re- only arm and randomized a small number of subjects. These methodological considerations amelioration than those who received placebo.
may have substantially contributed to the find-ing that active treatment was not superior to Interpretation. It is interesting to note that the results of Periclou et al. (2003) with escitalo- There are two larger-scale, double-blind, pram in adolescents are very similar to those placebo-controlled studies in which children of Axelson et al. (see above) with citalopram.
and adolescents between the ages of 7 and 17 As with citalopram, it is possible that im- years suffering from MDD were treated for up proved efficacy might have been seen if twice- to 8 weeks with either extended-release ven- daily dosing of escitalopram had occurred when lafaxine or placebo after either a 1- or 2-week doses less than 20 mg per day were admin- single-blind placebo run-in phase (Emslie et al.
istered in the RPCT. In addition, it appears 2004). In the first study, 165 youths were ran- that escitalopram might be more effective in domized to receive active treatment or placebo.
adolescents than children when the dosing In the second study, 196 youths were random- strategies employed in the RPCT are utilized.
ized (Dubitsky 2004). In each of these trials, Unfortunately, in the absence of PK data in chil- subjects had the opportunity of having their dren, the extent to which a development-based venlafaxine increased to a maximum dose of difference in escitalopram drug disposition 112.5–225 mg/day, depending on their body might have contributed to this observation re- weight. Some subjects could receive treatment that exceeded 4 mg/kg/day per protocol.
When considered separately, both studies failedto show overall efficacy of venlafaxine when compared to placebo (Laughren 2004). A post Pharmacokinetic studies. One PK study has been hoc analysis of the pooled data from the ado- conducted with venlafaxine. The multiple-dose lescents randomized (n = 161) across both PK of venlafaxine was examined in 6 children studies suggested that there was superior ben- and 6 adolescents who were administered a efit for active medication when compared to dose of approximately 2 mg per kg each day placebo in this subpopulation (Emslie et al.
(Derivan et al. 1995). The authors observed 2004). As far as tolerability is concerned, a rela- that the overall systemic exposure to both ven- tively high number of patients (10%) who were lafaxine and its active metabolite, O-desmethyl- randomized to receive active drug were dis- venlafaxine, was lower than that seen in adults continued from these studies because of ad- when a similar dosing strategy was used.
Efficacy studies. Three RPCTs have examined Interpretation. There seems to be very little the efficacy of venlafaxine. In the first (Man- empiric basis for the doses of medications used doki et al. 1997), 40 patients with MDD between in the placebo-controlled efficacy trials. In the the ages of 8 and 17 years were randomized to study of Mandoki et al., it appears that the receive either venlafaxine or placebo as an ad- subjects received lower doses of venlafaxine junct to psychotherapy for 6 weeks. Patients than might be recommended. However, in the between the ages of 8 and 12 years had their two larger-scale studies, it appears that some venlafaxine titrated to a dose of 12.5 mg thrice- of the study subjects could have received sub- daily over the course of the 1st week of the stantially higher doses of venlafaxine than what study. The older subjects had their dose of might be supported by the extant PK data. It is venlafaxine gradually increased during the 1st interesting to note that, based on the results of PHARMACOKINETIC STUDIES IN YOUTH DEPRESSION
the two larger, multisite venlafaxine trials, nefazodone’s active metabolites, meta-chlor- venlafaxine was found to be the antidepres- phenylpiperazine (mCPP) is metabolized by sant associated with the highest risk of suicidal cytochrome P450 2D6 (CYP 2D6) (Barbhaiya et behavior and suicidal ideation in MDD trials al. 1996). For that reason, the authors exam- (Hammad 2004). It is possible that improved ined whether or not being a poor metabolizer tolerability, reduced suicidality, and improved with respect to 2D6 was associated with re- efficacy might have been found if a different duced nefazodone tolerability. It is interesting dosing strategy had been employed in these to note that results suggested that being a poor metabolizer with respect to CYP 2D6 was notassociated with a reduced ability to toleratenefazodone therapy.
Pharmacokinetic studies. A PK study was con- Efficacy studies. In one study, 206 youths be- ducted in which 28 depressed children and tween the ages of 12 and 17 years with MDD adolescents (ages 7–17 years) were treated with were randomized to receive either nefazodone nefazodone (Findling et al. 2000). Blood sam- or placebo for 8 weeks (Emslie et al. 2002b; Du- pling for PK analysis was done at three sepa- bitsky 2004). Patients were initially treated with rate time points during the first 2 weeks of 50 mg of nefazodone twice-daily and could then treatment—after the first 50-mg dose, after 1 have their dose of medication increased to a week of treatment at 50 mg twice-daily, and target dose of 300–400 mg/day. If there was in- after 1 subsequent week of treatment at 100 sufficient clinical response, patients could re- ceive a maximum daily dose of 600 mg/day.
Results of this study suggested a trend for ne- were noted to generally have higher overall fazodone being superior to placebo in the treat- ment of adolescents with MDD (Emslie et al.
of nefazodone and its three active metabolites.
In another multicenter, placebo-controlled its metabolites appeared to be shorter in chil- efficacy study, treatment with nefazodone was dren and adolescents than what had been pre- not found to be superior to treatment with placebo (Laughren 2004). In this study, children After the 1st 2 weeks of the trial, patients (ages 7–11 years) and adolescents (age 12–17 were treated with open-label flexible doses of years) with MDD received either double-blind nefazodone for 6 more weeks. Children (7–12 treatment with nefazodone (n = 190) or placebo years old) could have their dose increased to a (n = 94) for 8 weeks (Dubitsky 2004). Subjects maximum dose of 300 mg/day in order to op- were randomized to receive placebo, “low- timize both clinical benefit and tolerability.
dose” nefazodone, or “high-dose” nefazodone Adolescents could have their dose increased to in approximately equal numbers. Children ran- domized to the “low dose” arm had their nefa- final doses for nefazodone were 233 mg/day for children and 342 mg/day for adolescents.
dose of 100 or 150 mg/day, and children ran- Overall, the authors noted that the nefazodone domized to the “high dose” arm had their ne- treatment was generally well tolerated and as- fazodone dose gradually increased to 200–300 sociated with substantial degrees of sympto- mg/day. Adolescents randomized to the “low matic response. It was also suggested that doses dose” group could receive up to 300 mg/day of medication that might be best for children of nefazodone, whereas adolescents in the may be lower than what may be optimal for “high dose” group received between 400 and It should also be mentioned that an attempt was made to identify whether or not there was Interpretation. In the study of adolescents in a subgroup of patients who might be at-risk which the dosing of nefazodone was based on for not tolerating nefazodone therapy. One of the PK data for the compound, a trend for drug FINDLING ET AL.
superiority to placebo was found. Interestingly, tion, there are cases in which there is inade- in the study of children and adolescents in quate evidence to either support or to refute which the dosing was not based on PK data, the dosing strategies employed in some of the no indication of therapeutic efficacy for nefa- placebo-controlled MDD studies. This is un- fortunate because identification of an evidence-based dosing strategy is generally consideredto be a pivotal aspect of pediatric drug devel- Pharmacokinetic studies. Findling et al. (2001) examined the pharmacokinetics of mirtazap- tributed to the failure to detect efficacy for some ine after a single 15-mg dose in a cohort of 16 antidepressant studies. Similarly, dosing may youths 7–17 years of age with MDD. The re- have contributed to the suboptimal tolerability sults of this study showed that there was a sig- nificant increase in t1⁄2 with increasing weight It should be remembered that there are lim- with the values of t1⁄2 for the individual pa- its to PK studies. Although PK data can pro- tients ranged between 17.8 and 48.4 hours. The vide vital information about how to dose a drug investigators also note that there was a de- in a given population, age-related differences in pharmacodynamics are important considera- tions that can also substantially influence drugefficacy and tolerability (Vitiello and Jensen Efficacy studies. There are two studies of mir- 1995). In addition, some of the PK studies that tazapine in juvenile MDD (Dubitsky 2004). Both were reviewed in this paper were not designed involved youths between the ages of 7 and 17 to determine effective dosing ranges for youths, years. In one study, 126 subjects were random- but to make comparisons with what was known ized. In the other study, 133 subjects were ran- about PK-parameter estimates in adults. Al- domized. Per protocol, the randomization ratio though such data can be used to provide ratio- of mirtazapine to placebo was 2:1. The double- nal dosing strategies for clinical trials, only blind treatment period was 8 weeks in length.
methodologically stringent treatment studies Subjects were treated at an initial dose of 15 can inform clinicians about the safety, tolera- mg/day. Subjects could subsequently have their bility, and efficacy of a given drug.
dose of mirtazapine increased in 15-mg incre- There is a need to develop evidence-based ments to a maximum daily dose of 45 mg. Both dosing strategies before studying any drug in studies failed to show that active treatment children. This may be particularly important was superior to placebo (Laughren 2004).
for antidepressants for several reasons. Firstly,other methodological factors, such as high Interpretation. As can be seen from previously placebo response rates, can make it difficult to discussed PK studies, differences may be ob- detect efficacy for an agent in the treatment of served when single- and multiple-dose PK pa- MDD. In addition, antidepressants can be as- rameters are examined for a given drug. As sociated with serious side effects when they are multiple doses of mirtazapine were used in the prescribed to children and adolescents. Thus, placebo-controlled efficacy trials, it is unfortu- in order for a drug to be studied in a way in nate that the one PK study of mirtazapine did which it has the best chance to adequately not examine the multiple-dose PKs of the drug.
evaluate both efficacy and optimal tolerability,empirically based dosing strategies are needed.
As children may respond to medications dif- DISCUSSION
ferently than adults, data derived from adultsmay not be applicable to youths (Wiznitzer and In many instances, the dosing strategies that Findling 2003). For this reason, it is important were employed in the placebo-controlled effi- that PK, PD, and RPCT studies be performed cacy studies in juvenile MDD are not supported in children and adolescents. The feasibility of by the data available from PK studies. In addi- successfully completing RPCTs in pediatric PHARMACOKINETIC STUDIES IN YOUTH DEPRESSION
MDD has been demonstrated. Because of the with obsessive-compulsive disorder or depres- challenges and the large sample sizes employed sion: Pharmacokinetics, tolerability, and efficacy.
in such efficacy trials, some might believe that J Am Acad Child Adolesc Psychiatry 37:386–394,1998.
open-label, dose-ranging, and PK studies may Aronson S, Delgado P: Escitalopram. Drugs Today not be important or as “rigorous” as placebo- controlled trials. However, the results of this Atuah KN, Hughes D, Pirmohamed M: Clinical review suggest that PK (first- and multiple- pharmacology: Special safety considerations in dose trials) and dose-ranging studies may be drug development and pharmacovigilance. Drug key steps that should be completed prior to the Axelson DA, Perel JM, Birmaher B, Rudolph GR, initiation of any definitive efficacy trial. Data Nuss S, Bridge J, Brent DA: Sertraline pharmaco- from these open-label trials can ultimately pro- kinetics and dynamics in adolescents. J Am Acad vide important information regarding both min- Child Adolesc Psychiatry 41:1037–1044, 2002.
imally effective and maximally-tolerated drug Barbhaiya R, Buch A, Greene D: Single- and multiple- dose pharmacokinetics of nefazodone in subjectsclassified as extensive and poor metabolizers ofdextromethorphan. Br J Clin Pharmacol 42:573–581, 1996.
CONCLUSIONS
Conners CK, Casat CD, Gualtieri CT, Weller E, Reader M, Reiss A, Weller RA, Khayrallah M, As- In short, in order to optimally study both the cher J: Bupropion hydrochloride in attention-deficit disorder with hyperactivity. J Am Acad safety and efficacy of a given drug, it is vital that Child Adolesc Psychiatry 35:1314–1321, 1996.
the drug is dosed properly. Methodologically Derivan A, Aguiar L, Upton GV, Martin P, D’Amico D, Troy S, Ferguson J, Preskorn S: A study of ven- should be incorporated into RPCT efficacy stud- lafaxine in children and adolescents with con- ies in pediatric MDD. By not employing scientif- duct disorder. New Orleans (Louisiana), AnnualMeeting of the American Academy of Child and ically based dosing strategies in efficacy trials of Adolescent Psychiatry, October 1995.
pediatric MDD, investigators risk the possibility Dubitsky GM: Review and evaluation of clinical of not being able to test whether or not these data: Placebo-controlled antidepressant studies in compounds are either safe or truly have efficacy.
pediatric patients. Online document at: www.fda.
gov/ohrms/dockets/ac/04/briefing/20044065b1-08-TAB06-Dubitsky-Review.pdf / Accessed onJanuary 24, 2005.
DISCLOSURES
Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, Rintelmann J: A double- Dr. Robert L. Findling receives or has received blind, randomized, placebo-controlled trial of research support, acted as a consultant or served fluoxetine in children and adolescents with de- on a speaker’s bureau for Abbott, AstraZeneca, pression. Arch Gen Psychiatry 54:1031–1037, 1997.
Emslie GJ, Findling RL, Rynn MA, Marcus RN, Fer- Bristol-Myers Squibb, Celltech-Medeva, For- nandes LA, D’Amico MF, Hardy SA: Efficacy and est, GlaxoSmithKline, Johnson & Johnson, Lilly, safety of nefazodone in the treatment of adoles- New River, Novartis, Otsuka, Pfizer, Sanofi- cents with major depressive disorder. J Child Synthelabo, Shire, Solvay, and Wyeth. Dr.
Adolesc Psychopharmacol 12:299, 2002b.
Norah C. Feeny has received research support Emslie G, Findling R, Yeung P, Kunz N, Durn B: from Pfizer. Dr. Nora K. McNamara, Dr. Robert Venlafaxine XR in the treatment of children andadolescents with major depressive disorder. Int J J. Stansbrey, Dr. Christopher M. Young, and Franco Peric have no financial ties to disclose.
Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Dr. Eric A. Youngstrom has received research Ernest DE, Brown E, Nilsson M, Jacobson JG: support from Abbott and AstraZeneca.
Fluoxetine for acute treatment of depression inchildren and adolescents: A placebo-controlled,randomized, clinical trial. J Am Acad Child Ado-lesc Psychiatry 41:1205–1215, 2002a.
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