Objectives: In this 6-month open-label extension (OLE) of NCT01491035 (a 14-day, open-label, pharmacokinetic/safety lead-in study), the long-term safety and tolerability of vortioxetine (5-20mg/day) were investigated in children and adolescents with a DSM-IV-TR diagnosis of depressive or anxiety disorder in the United States or Germany. The study also was designed to provide data to inform dose selection and titration in future pediatric studies with vortioxetine. Methods: Safety evaluations included spontaneously reported adverse events (AEs), the Columbia Suicide Severity Rating Scale (C-SSRS), and the Pediatric Adverse Events Rating Scale (PAERS; clinician administered). Clinical effectiveness was determined by Clinical Global Impressions. Comorbid attention-deficit/hyperactivity disorder was permitted, including concomitant use of stimulant medication (US sites only). Results: Of the 47 patients who completed the lead-in period, 41 continued into the OLE. Most patients (n=39 [95%]) continued their previous dose regimen. Twenty-one patients (51%) withdrew during the OLE; the most common primary reasons were administrative [n=8], AEs [n=4], and lack of efficacy [n=3]. Thirty-five patients (85%) had 1 AE, 86% of which were mild or moderate in severity. Five patients (12%) reported a severe AE, none of which was considered related to study medication. The most common AEs (10%) were headache (27%), nausea (20%), dysmenorrhea (females; 19%), and vomiting (15%), with no relationship between AE intensity and age or dose. Five patients reported instances of suicidal ideation during the OLE, one of whom also reported this during the lead-in period. Two patients had nonsuicidal self-injurious behavior; one had a nonfatal suicide attempt. Throughout the study, there was a decrease over time in the incidence and intensity of AEs collected using the PAERS. Effectiveness assessment indicated a trend toward improvement based on numeric results. Conclusion: This OLE confirms the findings from the lead-in study, which concluded that a dosing strategy of 5-20mg/day is safe, well tolerated, and suitable for future clinical studies of vortioxetine in pediatric patients.

Objective: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. Methods: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20mg q.d. for 14 days. The total treatment period lasted 14-20 days with patients in the higher dose cohorts uptitrated over 2-6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. Results: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration-time curve from time 0 to 24 hours, was 30%-40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. Conclusion: The results suggest that the dosages of vortioxetine evaluated (5-20mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking. METHODS: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7–17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis. RESULTS: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression–Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 ± 3.1 mIU/L) compared with placebo (–0.1 ± 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain. CONCLUSIONS: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder.

OBJECTIVE:The objective of this study was to determine the efficacy and safety of valproic acid versus risperidone in children, 3-7 years of age, with bipolar I disorder (BPD), during a mixed or manic episode.METHODS:Forty-six children with Diagnostic and Statistical Manual of Mental Disorders. 4th ed., Text Revision (DSM-IV-TR) diagnosis of bipolar disorder, manic, hypomanic, or mixed episode, were recruited over a 6 year period from two academic outpatient programs for a double-blinded, placebo-controlled trial in which subjects were randomized in a 2:2:1 ratio to risperidone solution, valproic acid, or placebo.RESULTS:After 6 weeks of treatment, the least-mean Young Mania Rating Scale (YMRS) total scores change, adjusted for baseline YMRS scores, from baseline by treatment group was: Valproic acid 10.0±2.46 (p=0.50); risperidone 18.82±1.55 (p=0.008); and placebo 4.29±3.56 (F=3.93, p=0.02). The mixed models for repeated measure (MMRM) analysis found a significant difference for risperidone-treated subjects versus placebo treated subjects (p=0.008) but not for valproic acid-treated subjects versus placebo-treated subjects (p=0.50). Treatment with risperidone over 6 weeks led to increased prolactin levels, liver functions, metabolic measures, and weight/body mass index (BMI). Treatment with valproic acid led to increases in weight/BMI and decreases in total red blood cells (RBC), hemoglobin, and hematocrit.CONCLUSIONS:In this small sample of preschool children with BPD, risperidone demonstrated clear efficacy versus placebo, whereas valproic acid did not. The laboratory and weight findings suggest that younger children with BPD are more sensitive to the effects of both of these psychotropics, and that, therefore, frequent laboratory and weight monitoring are warranted.

OBJECTIVE:To implement a treatment algorithm to operationalize treatment-resistance and improve patient outcomes in youth with pediatric bipolar disorder (PBD). The term "treatment resistance" was operationally defined as significant persistent symptoms following the application of a treatment algorithm. METHOD:Youth (6-17 years of age, n=120) with treatment-refractory bipolar I or II disorder, currently in a manic or mixed episode, were treated in accordance with the following 3 step algorithm: (1) removal of destabilizing agents (antidepressants, gamma aminobutyric acid [GABA]-agonists, and stimulants), (2) optimization of antimanic agents, and (3) use of a limited number (E 2) of mood stabilizers. The primary efficacy measure was change in scores on the Young Mania Rating Scale (YMRS) over the 6-month treatment course. Response was defined as repeated YMRS scores E 12. RESULTS:The sample was dichotomized into responders and non-responders. Both responders and non-responders improved significantly, with responders improving by a greater margin (d=3.2). At the end of 6 months, 75.8% of subjects demonstrated a significant and stable decrease in manic symptoms consistent with symptomatic remission (YMRS E 12). None of the subjects withdrew from the clinical process due to adverse events. CONCLUSION:The application of this proposed treatment algorithm allows for more accurate identification of true treatment resistance and can significantly reduce manic symptoms in patients previously described as having treatment-refractory bipolar disorder.

OBJECTIVE:The aim of this study was to evaluate the tolerability and efficacy of rapid quetiapine loading in youth diagnosed with pediatric bipolar disorder (PBD).METHOD:Quetiapine was started at 100 mg/day, and increased to 400 mg/day by day 5 in 75 bipolar children (6-16 years), presenting in an acute manic or hypomanic episode. Subsequent dose adjustments were predicated on the clinical picture. Response was defined as a ≥ 50% reduction in baseline scores on the Young Mania Rating Scale (YMRS). Clinical Global Impression-Improvement Scale (CGI-I) scores of "2 much improved" or "1 very much improved" were used as secondary measures of response. Remission was defined as a YMRS score of ≤ 12. Adverse events, blood pressure, weight change, somnolence, extrapyramidal syndrome (EPS), and akathisia were monitored to determine tolerability.RESULTS:At 8 weeks, 94% of the sample had a CGI-I score ≤ 2, and 70% were in remission at 6 months. Sedation was reported by 50% of subjects during the first week; this rate dropped to 5.6% at 6 months.CONCLUSION:The findings indicate that rapid dose administration of quetiapine in children and adolescents with PBD is generally well tolerated and efficacious.

Attention-deficit/hyperactivity disorder (ADHD) frequently is present concurrently with bipolar disorder (BPD) in youth. This concurrence appears to be more common in younger children. It appears to become less common with increasing age, at least until adulthood. Psychiatric and behavioral symptoms associated with ADHD and BPD have significant overlap. However, the core symptoms of BPD are relatively independent from those of ADHD and can be used to distinguish between the two conditions. The core symptoms of each disorder also respond to different pharmacologic and behavioral strategies. This implies different underlying pathophysiology even when the conditions coexist. Although much symptomatic overlap exists between ADHD and BPD, these conditions can be reliably differentiated from each other and require independent treatments that frequently need to be sequenced.

Attention-deficit/hyperactivity disorder (ADHD) frequently is present concurrently with bipolar disorder (BPD) in youth. This concurrence appears to be more common in younger children. The degree to which ADHD is present in adults with BPD has not been well studied. The psychiatric and behavioral symptoms associated with ADHD and BPD have significant overlap. The core symptoms of BPD are relatively independent and respond to different pharmacologic and behavioral strategies. Although much symptomatic overlap exists between ADHD and BPD, these conditions can be reliably differentiated from each other and require independent treatments that frequently need to be sequenced.

PURPOSE OF REVIEW:Pediatric bipolar disorder is a serious mental illness with significant morbidity and mortality. A variety of medical and psychiatric conditions occur concurrently with bipolar disorder. These conditions have been more frequently reported in adults. There prevalence in pediatric bipolar disorder is less known. This report is particularly relevant and timely due to the chronic nature of bipolar disorder and the profound impact on health that its treatments can bring. This evolving area needs to be understood to maximize clinical outcomes. RECENT FINDINGS:While little has been published about pediatric bipolar disorder and its concurrent medical conditions specifically, many reports that focused on adults included pediatric subjects. Concurrent medical conditions fall into a small number of groupings. (1) Those that are related to bipolar disorder or its treatment. (2) Medical conditions that mimic mania. (3) Conditions that occur more commonly in patients with bipolar disorder, but do not appear to be related to its treatment. (4) Those that may be related to risk behaviors associated with bipolar disorder. SUMMARY:Many medical conditions that occur concurrently with bipolar disorder in adults are also present in youth. The premature (iatrogenic) initiation of some conditions related to its treatment may pose specific ethical dilemmas for those treating psychiatric conditions.

There is an increasing prescription of psychotropic medications to youth. This use is accompanied by a developing, but lagging, evidence base for this use. These agents predominantly interact with regulatory neurotransmitters, which have known functions in the developing embryo. This article reviews major diagnostic categories in regards to the biological basis of the mainstays of pharmacology for each condition. Adverse events also are discussed in regards to these common psychopharmacological agents. There is growing evidence that the consequences of not treating serious psychiatric illnesses outweigh known risks of the medications. Prescription practices should endeavor to limit adverse consequences whenever possible.

Back to table of contents Previous article Next article Letter to the EditorFull AccessDr. Scheffer and Colleagues ReplyRUSSELL E. SCHEFFER, M.D., , ROBERT A. KOWATCH, M.D., , THOMAS CARMODY, Ph.D., and A. JOHN RUSH, M.D., RUSSELL E. SCHEFFER, M.D., Milwaukee, Wis., ROBERT A. KOWATCH, M.D., Cincinnati, Ohio, THOMAS CARMODY, Ph.D., and A. JOHN RUSH, M.D., Dallas, Tex.Published Online:1 Nov 2005https://doi.org/10.1176/appi.ajp.162.11.2197-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: In reply to Drs. Kruszewski and Paczynski's comments, let us consider each point.•1. The doses of mixed amphetamine salts were not ineffective. In fact, the study revealed efficacy for mixed amphetamine salts for the doses used compared to placebo. It is true that higher doses might have been even more effective.•2. We agree that higher doses of divalproex might have led to even greater benefits, although the doses and serum levels used were associated with a substantial rate of response of 80%.•3 and 4. We agree that the small group size and a study conducted at only one site, by definition, limited generalizability and also recommend replication studies. However, we demonstrated strong statistical significance with the group we used.•5. We agree that longer-term studies are needed to best evaluate long-term safety and outcome.That 20% of the patients with bipolar disorder could not be stabilized while taking open-label divalproex is not particularly surprising. The response rate of 80% with open-label divalproex was substantial, however, and similar to what has been found in other open-label studies (1). The 14-day treatment with mixed amphetamine salts and placebo was long enough to establish clinical statistical significance. Most patients (23 of 29) did elect open treatment with mixed amphetamine salts for 6 additional weeks. We made no claims of efficacy for open divalproex treatment, only that it was associated with a benefit in this group. The elicited and spontaneously reported side effects in the entire trial were very low, perhaps because we did not aggressively "load" the divalproex and we used relatively low doses of mixed amphetamine salts in the crossover study. In the open extension (when the dosing of mixed amphetamine salts was not limited), the average dose remained low, at 14.5 mg/day, suggesting that this relatively low dose was clinically useful.The use of the last observation carried forward is considered the most rigorous way to look at data from clinical trials. The divalproex responders were, in fact, all study completers. The only patient with a response who did not complete this phase of the study was one who improved so much during the first arm of the mixed amphetamine salts/placebo crossover study that the child's mother did not want to risk a change in treatment. This patient was treated with mixed amphetamine salts outside the study and did very well.As to adverse events, one other patient developed mania: this was clearly stated in the article and the abstract. There were no serious adverse reactions: this was clearly stated in the article. Three patients were hospitalized very early in the course of the open-label divalproex treatment, likely before these patients had adequate opportunity to respond to divalproex.We do believe that this small, well-controlled study provides a basis for considering larger, more definitive and generalizable trials. Given the clear lack of efficacy of divalproex for ADHD symptoms and the positive effects of mixed amphetamine salts (versus placebo) in a randomized blinded comparison, we believe that such a combination approach (divalproex followed by mixed amphetamine salts) seems promising, and at least with the group and follow-up data that were available, reasonable tolerability and safety can be expected (at the doses used). We certainly believe that this first study should be followed by larger, more definitive controlled trials to better assess generalizability and tolerability in a larger group.Reference1. Wagner KD, Weller EB, Carlson GA, Sachs G, Biederman J, Frazier JA, Wozniak P, Tracy K, Weller RA, Bowden C: An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2002; 41:1224–1230Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 162Issue 11 November 2005Pages 2197-a-2198 Metrics PDF download History Published online 1 November 2005 Published in print 1 November 2005

Background: Diagnosis of bipolar disorder (BPD) in preschool children is controversial, although preliminary data suggest that children with BPD may present with classic manic symptoms in a more chronic, rapid cycling presentation. While children with BPD are extremely dysfunctional, presenting symptoms and symptom expression remains to be further defined. Clarification of the presentation of BPD in children could result in better treatment.Methods: Thirty-one patients, ages 2-5 years, were identified by chart review of all children treated at our pediatric bipolar clinic. All available historical, symptom, and treatment information was collected and summarized.Results: Patients were similar to2:1 male: female, predominantly Caucasian, with an average age of symptom onset of 3 years. Most frequent presenting symptoms (100%) included irritability, increased energy, and aggression. Prominent symptoms (>80%) included euphoria, grandiosity, decreased need for steep, pressured speech, and distractibility. Eighty percent of patients had concurrent Attention-Deficit Hyperactivity Disorder (ADHD). Twenty-one of the 31 patients reported prior treatment attempts with either a stimulant or antidepressant without the protective benefit of a mood stabilizer, and of these, 13 (62%) reported a worsening of mood symptoms during that treatment period. Twenty-six of 31 were initially treated in our clinic openly with a mood stabilizer, primarily valproic acid, with a significant decrease in manic symptoms (p=0.03) following initial treatment. Long-term treatment demonstrated continued improvements from baseline (p=0.01).Limitations: The retrospective design of this study limits the conclusions that can be drawn. Due to the lack of a formal protocol, treatment was open and based on clinical judgment on an individual case basis.Conclusions: The symptom expression in these patients allowed for diagnosis according to DSM-IV criteria. Treatment with mood stabilizers was clinically effective, with corresponding significant developmental benefits. (C) 2004 Elsevier B.V. All rights reserved.