Pediatric Major Depressive Disorder Research Articles

Distinct functional patterns in child and adolescent bipolar and unipolar depression during emotional processing.

Accumulating evidence from functional magnetic resonance imaging studies supported brain dysfunction during emotional processing in bipolar disorder (BD) and major depressive disorder (MDD). However, child and adolescent BD and MDD could display different activation patterns, which have not been fully understood. This study aimed to investigate common and distinct activation patterns of pediatric BD (PBD) and MDD (p-MDD) during emotion processing using meta-analytic approaches. Literature search identified 25 studies, contrasting 252 PBD patients, and 253 healthy controls (HCs) as well as 311 p-MDD patients and 263 HCs. A total of nine meta-analyses were conducted pulling PBD and p-MDD experiments together and separately. The results revealed that PBD and p-MDD showed distinct patterns during negative processing. PBD patients exhibited activity changes in bilateral precuneus, left inferior parietal gyrus, left angular gyrus, and right posterior cingulate cortex while p-MDD patients showed functional disruptions in the left rectus, left triangular part of the inferior frontal gyrus, left orbital frontal cortex, left insula, and left putamen. In conclusion, the activity changes in PBD patients were mainly in regions correlated with emotion perception while the dysfunction among p-MDD patients was in the fronto-limbic circuit and reward-related regions in charge of emotion appraisal and regulation.

Executive functions and borderline personality features in adolescents with major depressive disorder.

Executive functions (EF) consolidate during adolescence and are impaired in various emerging psychiatric disorders, such as pediatric Major Depressive Disorder (pMDD) and Borderline Personality Disorder. Previous studies point to a marked heterogeneity of deficits in EF in pMDD. We examined the hypothesis that deficits in EF in adolescents with pMDD might be related to comorbid Borderline Personality features (BPF). We examined a sample of 144 adolescents (15.86 ± 1.32) diagnosed with pMDD. Parents rated their child's EF in everyday life with the Behavior Rating Inventory of Executive Function (BRIEF) and BPF with the Impulsivity and Emotion Dysregulation Scale (IED-27). The adolescents completed equivalent self-rating measures. Self- and parent-ratings of the BRIEF scores were compared with paired t-Tests. Correlation and parallel mediation analyses, ICC, and multiple regression analyses were used to assess symptom overlap, parent-child agreement, and the influence of depression severity. Over the whole sample, none of the self- or parent-rated BRIEF scales reached a mean score above T > 65, which would indicate clinically impaired functioning. Adolescents tended to report higher impairment in EF than their parents. Depression severity was the strongest predictor for BPF scores, with Emotional Control predicting parent-rated BPF and Inhibit predicting self-rated BPF. Furthermore, the Behavioral Regulation Index, which includes EF closely related to behavioral control, significantly mediated the relationship between depression severity and IED-27 factors emotional dysregulation and relationship difficulties but not non-suicidal self-injuries. On average, adolescents with depression show only subtle deficits in executive functioning. However, increased EF deficits are associated with the occurrence of comorbid borderline personality features, contributing to a more severe overall psychopathology. Therefore, training of executive functioning might have a positive effect on psychosocial functioning in severely depressed adolescents, as it might also improve comorbid BPF. www.ClinicalTrials.gov, identifier NCT03167307.

Error-related brain activity in pediatric major depressive disorder: An ERP and time-frequency investigation

BackgroundThe error-related negativity (ERN) reflects individual differences in error monitoring. However, findings on the ERN in adult and adolescent depression have been inconsistent. Analyzing electroencephalographic (EEG) data in both the time- and time-frequency domain can be useful to better quantify neural response to errors. The present study aimed at examining electrocortical measures of error monitoring in early adolescents with and without depression. MethodEEG activity was collected during an arrowhead version of the flanker task in 29 (25 females) early adolescents with depression and 34 without MDD (29 females). ResultsThe depression group showed reduced ERN amplitude, reduced error-related theta power and increased error-related beta power compared to the control group. When all variables that related to MDD diagnosis were considered simultaneously, both theta and beta power, but not the ERN, were independently related to an increased likelihood of being diagnosed with depression. ConclusionsBy examining both time-domain and separate time-frequency measures, the present study provided novel evidence on error monitoring alterations in youth depression, suggesting that depression during adolescence may be characterized by reduced error monitoring (i.e., reduced ERN and error-related theta) and post-error inhibition (i.e., greater error-related beta power). These results support that time-frequency measures might be better suited for examining error-related neural activity in MDD relative to time-domain measures.

Childhood depression and oxidative stress

BackgroundOxidative stress is a contributing factor in the etiopathogenesis of major depressive disorder (MDD). Pediatric studies regarding MDD-oxidative stress relationship are insufficient. In this study, we aimed to compare oxidative stress parameters of pediatric MDD patients with those of the control group and to examine factors affecting these parameters.ResultsTotal oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), malondialdehyde (MDA) and superoxide dismutase (SOD) activities of 42 patients with MDD and 38 healthy controls were evaluated. Children depression inventory (CDI) was applied to all participants. In the MDD group, serum levels of TOS, OSI and MDA were higher, while TAS and SOD levels were lower (p < 0.001). When all participants were examined, oxidative stress increased as the CDI score increased, but in the MDD group, SOD increased as the CDI score increased. Increase in body mass index (BMI) percentile increased the oxidative stress in the MDD group. When factors affecting the presence of MDD were analyzed by binary logistic regression analysis, a one-unit increase in SOD decreased depression by 0.190 times.ConclusionsThis study showed that oxidative stress increases in children and adolescents with MDD, and the increase in the severity of depression further increases oxidative stress, but when the depression becomes very severe, level of SOD increases compensatorily. It has been observed that high BMI in MDD patients creates an additional burden on oxidative stress. The role of oxidative stress in the etiopathogenesis of MDD in children and adolescents should be evaluated more comprehensively.

Association between frontal cortico-limbic white-matter microstructure and risk for pediatric depression

This study aimed to identify white-matter microstructural characteristics associated with risk for pediatric major depressive disorder (MDD) measured by the Child Behavior Checklist (CBCL) Anxiety/Depression scores. Children (N = 32) of both sexes, aged 6–12, underwent T1-weighted whole-head anatomical and diffusion-weighted imaging. Each participant's mean diffusion measure image was generated and thinned to create an alignment-invariant tract representation. Voxel-wise analysis on the resulting map was carried out in Track Based Spatial Statistics (TBSS) using general linear models by regressing the CBCL-Anxiety/Depression score against measures of diffusion tensor imaging (DTI). We also compared these results with prior DTI findings from the same children associated with CBCL-Emotion Dysregulation profile, an indicator for bipolar disorder. TBSS voxel-wise analysis showed a significant negative correlation between fractional anisotropy (FA) and CBCL-Anxiety/Depression scores localized in the right anterior cingulum and connected corpus callosal region. The negative FA correlations in these regions were greater in CBCL-Anxiety/ Depression scores compared to CBCL-Emotional Dysregulation scores. Reduced white-matter connectivity in the anterior cingulum and connected corpus callosal region may represent a biomarker of risk for pediatric MDD. These results may help identify brain differences associated with the development of MDD, and assist with earlier clinical identification of pediatric MDD.

Systematic Review of Affective Functional Magnetic Resonance Imaging in Pediatric Major Depressive Disorder

Pediatric major depressive disorder (MDD) is a debilitating disorder with long-term negative health risks. Understanding the affective neurobiological mechanisms of pediatric MDD may be crucial for refining assessment and identifying intervention targets. To systematically review the literature on affective brain function in pediatric MDD, PubMed and PsycInfo databases were searched to identify task-based affective functional magnetic resonance imaging (fMRI) studies statistically comparing children and adolescents currently diagnosed with MDD to healthy controls. Twenty-six studies met inclusion criteria and assessed neural constructs related to positive valence, negative valence, affective cognitive control, and self-related affective processing. The most consistent group differences among depressed compared to healthy youth observed were higher levels of amygdala blood oxygen–level dependent (BOLD) response to negatively valenced stimuli and lower levels of striatal BOLD response to positively valenced stimuli, respectively suggesting heightened negative affective reactivity and blunted reward processing. Findings also implicated extended medial prefrontal and salience network regions, including aberrant function in medial prefrontal cortex (mPFC), lateral PFC, insula, and anterior cingulate cortex (ACC); however, the directions of effects were mixed and may be context specific. In all, studies reviewed here underscore affective dysfunction in pediatric MDD and highlight the need to systematically consider neural responsivity in pediatric MDD across contexts.

Omega-3 Fatty Acids as a Treatment for Pediatric Depression. A Phase III, 36 Weeks, Multi-Center, Double-Blind, Placebo-Controlled Randomized Superiority Study.

Background: Depressive disorders in childhood and adolescence are a major health problem and often follow a chronic course with severe consequences in later life. Depressive disorders cause the highest burden of disease in this age group across all medical conditions. Treatment adherence is usually very poor, and the use of antidepressant drugs is heavily debated, as suicidal ideations may increase, in particular in the early phase of treatment. Omega-3 fatty acids rich in eicosapentaenoic acid have shown some promising results in over a dozen small scale randomized controlled trials (RCTs) in adult major depressive disorders, with only very few published RCTs in children and adolescents. High-quality phase III RCTs are missing. Methods and Design: The omega-3-pMDD trial is a carefully designed phase III RCT to assess the efficacy and safety of omega-3 fatty acids in the early course of pediatric major depressive disorder (MDD). The study is designed as a multi-center, double-blinded, placebo-controlled, randomized clinical trial enrolling 220 patients aged 8 to 17 years meeting DSM-IV criteria for major depressive disorder of at least moderate symptom severity. After a single-blinded placebo-lead-in phase (7 to 10 days) patients are randomly assigned to omega-3 fatty acids or placebo over 36 weeks. Primary outcomes are changes in depression severity, as well as remission and recovery rates. Secondary outcome measures include the omega-3 index and inflammatory parameters as predictors of response. Data analysis will be performed in the intention-to-treat sample using a (generalized) linear random intercept regression model. Through sampling of blood, hair, saliva, and urine, further putative biological markers for depression and omega-3 fatty response will be investigated. Discussion: This trial addresses if omega-3 fatty acids play a role in the pathogenesis of pediatric MDDs and have antidepressant properties, in particular in clinically depressed children and adolescents with a pre-existing omega-3 fatty acid deficiency, increased markers of oxidative stress, and/or markers of (low grade) inflammation. Ethics and Dissemination: The study was approved by the local ethics committees. The results will be published in peer-reviewed journals irrespective of specific outcomes. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03167307.

Anxious depression as a clinically relevant subtype of pediatric major depressive disorder.

In adults, anxious depression has been identified as a more severe form of major depressive disorder (MDD), associated with higher depression severity, more suicidal ideation and worse treatment outcome. Research in pediatric depression, however, has been sparse. 126 children and adolescents aged 8-18years with a primary diagnosis of MDD were categorized into a MDD-only group and an anxious depression group based on clinically elevated scores on the Beck Anxiety Inventory. One-third of the sample was classified as having anxious depression with females being overrepresented in the anxious depressed compared to the MDD-only group. 42.2% of the anxious depressed youth met diagnostic criteria for a comorbid anxiety disorder. Anxious depressed youth were more likely to suffer recurrent depressive episodes, showed higher depression severity and a unique pattern of depressive symptoms characterized by more severe sleep problems, more somatic complaints, more severely depressed mood and more frequent suicidal ideations. Scores on a suicidal ideation scale were increased even when controlling for overall depression severity. However, when comparing depressed patients with and without comorbid anxiety disorders, no differences in depression severity, symptom patterns or suicidal ideations were observed. The results indicate that high anxiety levels in depressed youth are clinically relevant, and given the increase in suicidal ideation, anxiety symptoms during depressive episodes should routinely be screened in clinical practice even in the absence of a fully formed comorbid anxiety disorder.

FDA Updates Guidance for Developing Antidepressant Medications

Back to table of contents Previous article Professional NewsFull AccessFDA Updates Guidance for Developing Antidepressant MedicationsNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:31 Jul 2018https://doi.org/10.1176/appi.pn.2018.8a9AbstractRecommendations in the FDA’s first antidepressant guidance update in over 40 years include specifics on conducting clinical trials with rapid-acting antidepressants such as ketamine.For the first time in over 40 years, the Food and Drug Administration (FDA) is proposing updates and revisions to its guidance on how industries should develop and clinically test drugs intended to treat major depressive disorder (MDD). This new guidance finally reflects the many antidepressant advances made since 1977, such as finding new rapid mechanisms of action and gaining a better understanding of depression relapse.Perhaps the most noticeable updates are the new recommendations for clinical trials involving fast-acting antidepressants such as ketamine. Whereas short-term efficacy studies of traditional antidepressants typically need six to eight weeks to demonstrate an effect, the new guidance states that efficacy of rapid-acting drugs should be demonstrated within one week. However, clinical trials of rapid-acting drugs should be continued after this period so that the durability of rapid-acting antidepressants can be determined. The FDA also highlighted that rapid-acting drugs have their own specific set of safety concerns. NMDA receptor-targeting drugs like ketamine, for example, can cause Olney lesions—fluid-filled vesicles in the brain that sometimes precede permanent neuronal injury or death. Therefore, for all NMDA receptor drugs, investigators should complete preclinical studies testing for acute neurotoxic effects before conducting any human studies, according to the FDA.These are among other notable recommendations in the new guidance:Given the high placebo response increasingly seen in clinical antidepressant studies, noninferiority trials that compare two active drugs are not practical, and thus all trials of new antidepressant agents should include a placebo group.Studies for maintenance treatment should last at least six months; long-term safety and tolerability measurements should also be incorporated into the design of all maintenance trials. The FDA also noted that it was interested in maintenance studies that explored the effects of lower drug doses; the results of these studies could be included in drug labeling.Even for antidepressants already approved for adult MDD, at least two adequately sized and well-controlled efficacy trials should be conducted in relevant pediatric patients (along with pharmacology and safety studies) before an approved drug can be given a pediatric indication. For pediatric MDD, children aged 7 through 12 and adolescents aged 13 through 17 are considered unique populations with their own needs.Clinical trial sponsors are encouraged to enroll demographically broad populations in studies whenever possible. This includes special populations such as elderly patients or individuals with medical problems such as renal insufficiency, cardiac disease, HIV, or hepatitis C. In addition, patients with a history of substance abuse and/or a history of suicidal ideation should not be automatically excluded from trials.Related to the above, the FDA made no comments on enrollment restrictions typically applied to pregnant women. However, the guidance did suggest that drug sponsors should collect and register safety data from women who become pregnant during a trial and become inadvertently exposed to an antidepressant or pregnant women who use approved antidepressants in a postmarketing study.As with the existing industry guidance, the FDA noted these updates reflect the agency’s current thinking on MDD and represent recommendations and not requirements. The draft guidance is intended to stimulate continued discussions among the Division of Psychiatry Products, pharmaceutical companies, the academic community, and the public.The FDA will accept public comments and suggestions on the new draft guidance until August 20, at which point it will finalize the document. ■The draft document, “Major Depressive Disorder: Developing Drugs for Treatment. Guidance for Industry,” can be accessed here. Comments may be submitted here. ISSUES NewArchived

Treatment of Major Depressive Disorder in Pediatric Populations.

Major depressive disorder (MDD) is a severe illness that afflicts about 16.6% of people over their lifetime. MDD is highly correlated with suicidality, and often first presents in adolescence. Unfortunately, many pediatric patients suffering from MDD go undiagnosed, and current evidence-based treatment options in the U.S. are limited to psychotherapy and two selective serotonin reuptake inhibitors approved by the United States Food and Drug Administration. Molecular mechanisms have been shown to play a role in MDD pathogenesis, progression, and response to medication, yet few studies have explored the role of these pathways in pediatric MDD. In this review, we outline the gravity and importance of MDD in pediatric patients, some challenges in diagnosis and treatment, current treatments available for pediatric patients, and research to investigate differences between pediatric and adult MDD. We hope that this review will provide an outline of the current understanding and treatment of MDD in pediatric patients, and provide thoughtful insights for future work that could advance our understanding of MDD in pediatric populations, and also identify new therapeutic strategies.

12.1 Risk Factors That Differentiate Bipolar Depression From Unipolar Depression and Predict Manic Switches in Youth

Differentiating between pediatric unipolar major depressive disorder (unipolar MDD) and bipolar major depression (bipolar MDD) poses a unique challenge for clinicians; this is particularly true given the high rate of switching from unipolar MDD to bipolar MDD (manic switches) among children. We examined the scientific literature to synthesize knowledge on the clinical features and correlates that differentiate the two types of major depression and predict bipolar switches.

White matter microstructure in boys with persistent depressive disorder

BackgroundPersistent depressive symptoms in children and adolescents are considered a risk factor for the development of major depressive disorder (MDD) later in life. Previous research has shown alterations in white matter microstructure in pediatric MDD but discrepancies exist as to the specific tracts affected. The current study aimed to improve upon previous methodology and address the question whether previous findings of lower fractional anisotropy (FA) replicate in a sample of children with persistent depressive disorder characterized by mild but more chronic symptoms of depression. MethodsWhite matter microstructure was examined in 25 boys with persistent depressive disorder and 25 typically developing children. Tract specific analysis implemented with the Diffusion Tensor Imaging - ToolKit (DTI-TK) was used to probe fractional anisotropy (FA) in eleven major white matter tracts. ResultsClusters within the left uncinate, inferior fronto-occipital and cerebrospinal tracts showed lower FA in the clinical group. FA in the left uncinate showed a negative association with self-reported symptoms of depression. ConclusionsThe results demonstrate lower FA in several white matter tracts in children with persistent depressive disorder. These findings support the contention that early onset depression is associated with altered white matter microstructure, which may contribute to the maintenance and recurrence of symptoms.

Can subsyndromal manifestations of major depression be identified in children at risk?

Children of parents with major depression are at significantly increased risk for developing major depression themselves; however, not all children at genetic risk will develop major depressive disorder (MDD). We investigated the utility of subsyndromal scores on the Child Behavior Checklist (CBCL) Anxiety/Depression scale in identifying children at the highest risk for pediatric MDD from among the pool of children of parents with MDD or bipolar disorder. The sample was derived from two previously conducted longitudinal case-control family studies of psychiatrically and pediatrically referred youth and their families. For this study, probands were stratified based on the presence or absence of a parental mood disorder. Subsyndromal scores on the CBCL Anxiety/Depression scale significantly separated the children at high risk for pediatric MDD from those at low risk in a variety of functional areas, including social and academic functioning. Additionally, children at genetic risk without elevated CBCL Anxiety/Depression scale scores were largely indistinguishable from controls. These results suggest that the CBCL Anxiety/Depression scale can help identify children at highest risk for pediatric MDD. If implemented clinically, this scale would cost-effectively screen children and identify those most in need of early intervention resources to impede the progression of depression.

PMH60 - Disparities In The Process And The Outcomes Of Depression Management Between Pediatric Major Depressive Disorder Cases Identified By Primary Care Providers Versus Psychiatrists

PMH60 - Disparities In The Process And The Outcomes Of Depression Management Between Pediatric Major Depressive Disorder Cases Identified By Primary Care Providers Versus Psychiatrists

SSRIs have a smaller benefit in paediatric when compared to adult major depressive disorder

ABSTRACT FROM: Varigonda AL, Jakubovski E, Taylor MJ, et al . Systematic review and meta-analysis: early treatment responses of selective serotonin reuptake inhibitors in pediatric major depressive disorder. J Am...

Continued Effectiveness of Relapse Prevention Cognitive-Behavioral Therapy Following Fluoxetine Treatment in Youth With Major Depressive Disorder

To evaluate the continued effect of a sequential treatment strategy (fluoxetine followed by continued medication plus relapse prevention cognitive-behavioral therapy [RP-CBT]) on relapse prevention beyond the treatment phase. Youth (aged 8-17 years) with major depressive disorder (MDD) were treated with fluoxetine for 6 weeks. Responders (≥50% reduction on the Children's Depression Rating Scale-Revised [CDRS-R]) were randomized to continued medication management alone (MM) or continued medication management plus RP-CBT (MM+CBT) for an additional 6 months. Long-term follow-up assessments were conducted at weeks 52 and78. Of 144 youth randomized to MM (n= 69) or MM+CBT (n= 75), 67% had at least 1 follow-up assessment, with equal rates in the 2 groups. Remission rates were high, although most had remitted during the 30-week treatment period. Only 6 additional participants remitted during long-term follow-up, and there were no differences on time to remission between MM+CBT and MM. The MM+CBT group had a significantly lower risk of relapse than the MM group throughout the 78-week follow-up period (hazard ratio= 0.467, 95% CI= 0.264 to 0.823; χ(2)= 6.852, p= .009). The estimated probability of relapse during the 78-week period was lower with MM+CBT than MM only (36% versus 62%). Mean time to relapse was also significantly longer with MM+CBT compared to MM alone by approximately 3 months (p= .007). The addition of RP-CBT after acute response to medication management had a continued effect on reducing risk of relapse even after the end of treatment. Clinical trial registration information-Sequential Treatment of Pediatric MDD to Increase Remission and Prevent Relapse; http://clinicaltrials.gov/; NCT00612313.

Systematic Review and Meta-Analysis: Early Treatment Responses of Selective Serotonin Reuptake Inhibitors in Pediatric Major Depressive Disorder

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for pediatric major depressive disorder (MDD). We conducted a meta-analysis to examine the following: the time-course of response to SSRIs in pediatric depression; whether higher doses of SSRIs are associated with an improved response in pediatric depression; differences in efficacy between SSRI agents; and whether the time-course and magnitude of response to SSRIs is different in pediatric and adult patients with MDD. We searched PubMed and CENTRAL for randomized controlled trials comparing SSRIs to placebo for the treatment of pediatric MDD. We extracted weekly symptom data from trials to characterize the trajectory of pharmacological response to SSRIs. Pooled estimates of treatment effect were calculated based on standardized mean differences between treatment and placebo groups. The meta-analysis included 13 pediatric MDD trials with a total of 3,004 patients. A logarithmic model indicating that the greatest benefits of SSRIs occurred early in treatment best fit the longitudinal data (log[week]= 0.10, 95% CI= 0.06-0.15, p< .0001). There were no significant differences based on maximum SSRI dose or between particular SSRI agents. SSRIs were demonstrated to have a smaller benefit in pediatric compared to adult MDD. Treatment gains in pediatric MDD are greatest early in treatment and are, on average, minimal after 4 weeks of SSRI pharmacotherapy in pediatric MDD. Further research is needed using individual patient data to examine the power of early SSRI response (e.g., 2-4 weeks) to predict outcomes in short-term pharmacological trials.

The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression.

Acute antidepressant exposure elevates the frequency of impulsive behavior and suicidal thoughts in children and adolescents with major depressive disorder (MDD). Long-term antidepressant treatment, however, is beneficial for pediatric MDD, so it is necessary to explore novel treatments that prevent the potentially dangerous consequences of acute antidepressant initiation. In the present study, a treatment strategy designed to reverse the acute negative behavioral effects of antidepressants was tested in rodents. Co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, a serotonin reuptake inhibitor, but not reboxetine, a norepinephrine reuptake inhibitor, supporting the involvement of 5-HT1AR in mediating the negative consequences of acute selective serotonin reuptake inhibitor (SSRI) treatment. No 5-HT1AR antagonists are currently approved for use in pediatric populations, so alternative strategies should be explored. One such strategy was suggested based on the hypothesis that the rate of 5-HT1AR activation and the subsequent inhibition of serotonergic neuron activity caused by acute SSRI administration is proportional to the loading rate of an antidepressant. Existing pharmacological data were examined, and significant correlations were observed between the half-life of antidepressants and the rate of suicide-related events (SREs). Specifically, antidepressants with longer half-lives have lower rates of SREs. On the basis of these data, novel dosing strategies were developed for five antidepressants to mimic the pharmacological profile of the antidepressant with the longest half-life, fluoxetine. These dosing strategies could be used to decrease the rate of SREs associated with acute antidepressant treatment in pediatric MDD until an improved pharmacological treatment is developed.

Genetic Characteristics of Pediatric Major Depressive Disorder

Ya z›fl ma Ad re si/Ad dress for Cor res pon den ce Dr. Rezzan Aydin, Ege Universitesi Tip Fakultesi, Cocuk ve Ergen Ruh Sagligi ve Hastaliklari Anabilim Dali, Izmir, Turkiye Tel.: +90 232 390 14 07 E-posta: aydinrezzan@hotmail.com Ge lis ta ri hi/Re cei ved: 12.01.2014 Ka bul ta ri hi/ Ac cep ted: 22.04.2014 Ege Universitesi Tip Fakultesi, Cocuk ve Ergen Ruh Sagligi ve Hastaliklari Anabilim Dali, Izmir, Turkiye Rezzan Aydin, Muharrem Burak Baytunca, Serpil Erermis

Pharmacokinetics of orally administered duloxetine in children and adolescents with major depressive disorder.

Duloxetine, a selective serotonin (5-hydroxytryptamine) and norepinephrine reuptake inhibitor, has been approved since 2004 for the treatment of adults with major depressive disorder (MDD). It is currently not approved for use in pediatric patients (aged <18 years) with MDD. The clinical development program for duloxetine in the pediatric MDD population, which consisted of three clinical studies, provided extensive data on the safety, tolerability, and pharmacokinetics of duloxetine across a wide dose range in pediatric patients of differing ages, sex, body weights, and sexual maturation. The objectives were to characterize the pharmacokinetics of duloxetine based on population modeling following daily oral administration in children and adolescents aged 7-17 years diagnosed with MDD; to estimate the magnitude of between- and within-patient variability; to identify potential patient factors affecting duloxetine pharmacokinetics, and to compare duloxetine pharmacokinetics in the pediatric population with those characterized in adults. The analyses meta-dataset was created from pharmacokinetic and demographic data available from one phase II (open-label) and two phase III (randomized, double-blind) clinical trials of duloxetine in children and adolescents. Patients received 20-120 mg of oral duloxetine once daily. Duloxetine concentrations (a total of 1,581 concentrations) were obtained from 428 patients: 34% were children (aged 7-11 years) and 66% were adolescents (aged 12-18 years). Population modeling analyses were performed using nonlinear mixed-effects modeling and the first-order conditional estimation method with interaction. Patient factors were assessed for their potential influence on duloxetine apparent clearance (CL/F) and apparent volume of distribution (V d/F). Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the pediatric population were compared with those in adults. Duloxetine pharmacokinetics in pediatric patients was described by a one-compartmental model. Typical values of CL/F, V d/F, and half-life (t 1/2) at 60 mg/day of duloxetine were 79.7 L/h, 1,200 L, and 10.4 h, respectively. The between-patient variability in CL/F and V d/F was 68 and 87%, respectively, while within-patient variability was 57% (proportional error) and 2.04 ng/mL (additive error). Body surface area (BSA), dose, and race had a statistically significant effect on duloxetine pharmacokinetics. With a 2.2-fold increase in BSA, the CL/F increased about twofold. A sixfold increase in dose (20 to 120 mg) decreased CL/F by 32%. In American Indian patients, V d/F was 131% higher than the other races combined. Age, sex, body mass index, serum creatinine, cytochrome P450 2D6 predicted phenotype, and menarche status did not have a statistically significant effect. Estimates of CL/F and V d/F were higher in the pediatric population than in adults; subsequently, the average steady-state duloxetine concentration was approximately 30% lower in the pediatric population than in adults. Duloxetine pharmacokinetics was similar in children and adolescents with MDD. The statistically significant effects of dose, BSA, and race on duloxetine pharmacokinetics in pediatric patients did not appear to be clinically meaningful. At a given dose, the typical steady-state duloxetine concentrations in the pediatric population were lower than in adults, and the distribution of steady-state duloxetine concentrations in pediatric patients were typically in the lower range of concentrations in adults.