Lithium for the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Discontinuation Study.

OBJECTIVE: This study examined the role of lithium in the maintenance treatment of pediatric patients with bipolar I disorder (BP-I). METHOD: Participants aged 7 to 17 years who presented with a manic or mixed episode received 24 weeks of lithium treatment in one of two multiphase studies, the Collaborative Lithium Trials (CoLT 1 and CoLT 2). Responders were randomized to continue lithium or to be cross-titrated to placebo for up to 28 weeks. The primary outcome measure was relative risk of study discontinuation for any reason. RESULTS: A Cox regression analysis found that those who continued treatment with lithium (n = 17) had a lower hazard ratio compared to those who received placebo (n = 14) (p = .015)]. The vast majority of discontinuations were due to mood symptom exacerbations, with most of these occurring in the placebo-treated group. Discontinuation for other reasons occurred at similarly low rates across both group. Most adverse events were mild to moderate in severity, and only one study participant was discontinued from the trial owing to a serious adverse event (aggression). There was no statistically significant difference with respect to weight gain in participants receiving lithium compared to those receiving placebo. CONCLUSION: This randomized, double-blind, placebo-controlled Discontinuation Trial builds support for the role of lithium as a maintenance treatment in pediatric patients with bipolar disorder and for the safety and tolerability of 28 weeks of maintenance lithium treatment. CLINICAL TRIAL REGISTRATION INFORMATION: Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT00442039 (CoLT 1). Safety and Efficacy Study of Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT01166425 (CoLT 2).

A 6-Month Open-Label Extension Study of Vortioxetine in Pediatric Patients with Depressive or Anxiety Disorders.

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 (5-20 mg/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 5-20 mg/day is safe, well tolerated, and suitable for future clinical studies of vortioxetine in pediatric patients.

Pharmacokinetics and Safety 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 20 mg 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 (5-20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study.

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.

Placebo-controlled trial of valproic Acid versus risperidone in children 3-7 years of age with bipolar I 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.

Guidelines for treatment-resistant mania in children with bipolar disorder.

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.

Rapid quetiapine loading in youths with 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.

Concurrent ADHD and bipolar disorder.

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.

Concurrent medical conditions with pediatric bipolar disorder.

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.

Psychopharmacology: clinical implications of brain neurochemistry.

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.

Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium.

OBJECTIVE: The purpose of this study was to determine whether adjunctive use of a psychostimulant (mixed amphetamine salts) was safe and efficacious for treatment of symptoms of attention deficit hyperactivity disorder (ADHD) in pediatric outpatients with bipolar I or bipolar II disorder and concurrent ADHD whose manic symptoms had been stabilized through treatment with divalproex sodium. METHOD: An 8-week open-label trial of divalproex sodium to control manic symptoms and to discern the effect of divalproex sodium on ADHD was followed by a 4-week randomized, double-blind, placebo-controlled crossover trial to determine if mixed amphetamine salts was safe and effective for treatment of ADHD symptoms. Patients in the crossover trial continued to receive divalproex sodium. Diagnoses, made by clinical interview, were confirmed with the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. The Young Mania Rating Scale (for manic symptoms) and the Clinical Global Impression of improvement (for ADHD symptoms) were the primary outcome measures. RESULTS: Forty subjects ages 6-17 years with bipolar I disorder (77.5%) or bipolar II disorder (22.5%) and a Young Mania Rating Scale score > or =14 entered open treatment with divalproex sodium. With divalproex sodium, 32 subjects achieved > or =50% reduction in Young Mania Rating Scale baseline scores, but only three participants had significant improvement in ADHD symptoms. For the 30 subjects who entered the placebo-controlled crossover trial, mixed amphetamine salts was significantly more effective than placebo for ADHD symptoms. No significant side effects or worsening of manic symptoms was observed. CONCLUSIONS: Pediatric patients with bipolar disorder and concurrent ADHD can be safely and effectively treated with mixed amphetamine salts after their manic symptoms are stabilized with divalproex sodium. Divalproex sodium alone (8-week trial) is not an effective treatment for ADHD in the context of bipolar disorder.

Abnormal neurological signs at the onset of psychosis.

INTRODUCTION: The objective of this investigation was to determine whether abnormal neurological signs (ANS) are present at the onset of psychosis, prior to the initiation of antipsychotic treatment, and to examine the effect of 6 weeks of antipsychotic treatment on these signs. METHODS: We examined 29 first-episode schizophrenic patients admitted at an Army Medical Center within 10 days of psychosis onset, using the Neurological Evaluation Scale and the 18-item Brief Psychiatric Rating Scale (BPRS) and compared them to controls. RESULTS: All of the subjects had neurological signs indicating problems in sensory integration, motor coordination, and sequencing of complex motor acts. No psychotic subject had fewer than two abnormal neurological signs. When compared to age and sex matched groups of normal controls and nonpsychotic psychiatric controls, the psychotic group had a significantly higher incidence of neurological signs. At baseline, the severity of neurological signs was associated with elevated BPRS total, positive, and negative symptom scores. The change in clinical symptoms was positively correlated with a change in neurological signs. DISCUSSION: These findings indicate that some neurological signs are present at the onset of psychosis, and that these signs may be altered by treatment. These abnormal neurological signs reflect an underlying brain function abnormality and may be useful in differential diagnosis, prognosis, and treatment selection.

Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics.

Abnormal membrane phospholipid essential polyunsaturated fatty acid (EPUFA) metabolism (i.e., reduced incorporation into phospholipids and increased breakdown) has been suggested to contribute to the etiopathophysiology of schizophrenia. However, most of the published studies have reported changes in the levels of membrane EPUFA in chronic medicated patients or in drug-naive patients long after onset of illness (1-2 years). Since the EPUFA metabolism can be altered by years of untreated illness or differentially altered by various antipsychotics, the significance of EPUFA membrane status to schizophrenia psychopathophysiology is unclear. We report the erythrocyte membrane EPUFA levels in drug-naive patients within +/- 4.5 days of onset of psychosis from an Army Medical Center, and in patients treated years with antipsychotics from a Veterans Affairs Medical Center. The levels of plasma lipid peroxides (TBARS, thiobarbituric acid reactive substances), products of damaged EPUFAs, were also determined. The levels of EPUFAs, particularly arachidonic acid (AA) and docosahexaenoic acid (DHA) were significantly lower (P < 0.001) in drug-naive patients at the onset of psychosis compared to matched normal controls. These lower EPUFA levels were associated with significantly higher levels of TBARS in patients (P < 0.001). The levels of AA and DHA were also lower (P < 0.001) and TBARS higher in chronic medicated patients than normal controls. However, the EPUFA levels were higher in chronic medicated patients than drug-naive first-episode patients. These data indicate that lower membrane AA and DHA most likely predate the illness and probably contribute to the onset of illness, and furthermore treatment with some antipsychotics may increase the levels of EPUFAs. The lipid peroxidation data suggest that possible increased oxidative stress, either as a part of the illness and/or its treatment with antipsychotics, may be one of the mechanisms of reduced membrane EPUFAs. These findings may have a significant impact on improving strategies for supplementation of EPUFAs and antioxidants to improve the outcome of schizophrenia.