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Background: Multiple clinical trials of modern antipsychotics have failed in pediatric samples. One possibility for these failures is the use of a primary outcome measure that was developed for adults. Surprisingly, the psychometric properties of primary outcome measures have never been reported for a pediatric sample using modern methods. The present study’s aim is to use a pediatric sample to evaluate the psychometrics of the most used primary outcome measure in pediatric schizophrenia trials, the Positive and Negative Syndrome Scale (PANSS). Methods: To evaluate the factor structure, item characteristics, and treatment sensitivity of the PANSS in a pediatric sample, secondary analyses of PANSS data at baseline and weekly throughout an 8-week randomized double-blind study of three antipsychotic agents (registered and previously published) were conducted. Subjects were 118 youths receiving outpatient psychiatric treatment for schizophrenia spectrum disorders (Mage=14.26(2.41) years). Outcomes: A 10-item short form, keeping two strongest items for each factor, had r=.89 with the full-length scale. Each of the 5 2-item subscales has alphas ranging from .66 to .84. Item Response Theory (IRT) found that the 10-item scale and 2-item subscores had high reliability across the severity range typical of clinical trials. Criterion validity was high, with equal sensitivity to treatment effects. Interpretation: The short version eliminates weaker items in the pediatric population without loss of sensitivity to treatment effects and thus may be more appropriate for subsequent pediatric trials. Funding: NIMH funded the original protocol; NDA archived the data; Signant paid for secondary statistical analyses. Declaration of Interest: Dr. Findling receives or has received research support, acted as a consultant and/or has received honoraria from Acadia, Adamas, Aevi, Afecta, Akili, Alkermes, Allergan, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo, Emelex, Gedeon Richter, Genentech, Idorsia, Intra-Cellular Therapies, Kempharm, Luminopia, Lundbeck, MedAvante-ProPhase, Merck, MJH Life Sciences,NIH, Neurim, Otsuka, PaxMedica, PCORI, Pfizer, Physicians Postgraduate Press, Q BioMed, Receptor Life Sciences, Roche, Sage, Signant Health, Sunovion, Supernus Pharmaceuticals, Syneos, Syneurx, Takeda, Teva, Tris, and Validus. Dr. Youngstrom has received royalties from the American Psychological Association and Guilford Press, consulted with Signant Health about psychological assessment, and received funding from NIMH. He is the founder and Executive Director of Helping Give Away Psychological Science (HGAPS.org). Dr. Sikich receives or has received research support from NIMH, NICHD, and Roche. She has received partial salary support from Tris. She has a patent submission through Duke University for a new formulation of intranasal oxytocin. Dr. Frazier receives or has received funding from NIMH, NICHD, Autism Speaks, Roche pharmaceuticals, and Fulcrum. Dr. McClellan receives or has received funding from NIMH. Dr. Daniel is an employee and equity holder in Signant Health. Dr. Busner is an employee and equity holder in Signant Health. Ethical Approval: The secondary analyses were reviewed and approved by the UNC Chapel Hill IRB.

Impairing emotional outbursts, defined by extreme anger or distress in response to relatively ordinary frustrations and disappointments, impact all mental health care systems, emergency departments, schools, and juvenile justice programs. However, the prevalence, outcome, and impact of outbursts are difficult to quantify because they are transdiagnostic and not explicitly defined by current diagnostic nosology. Research variably addresses outbursts under the rubrics of tantrums, anger, irritability, aggression, rage attacks, or emotional and behavioral dysregulation. Consistent methods for identifying and assessing impairing emotional outbursts across development or systems of care are lacking.The American Academy of Child and Adolescent Psychiatry Presidential Task Force (2019-2021) conducted a narrative review addressing impairing emotional outbursts within the limitations of the existing literature and independent of diagnosis.Extrapolating from the existing literature, best estimates suggest that outbursts occur in 4%-10% of community children (preschoolers through adolescents). Impairing emotional outbursts may respond to successful treatment of the primary disorder, especially for some children with attention-deficit/hyperactivity disorder whose medications have been optimized. However, outbursts are generally multi-determined and often represent maladaptive or deficient coping strategies and responses.Evidence-based strategies are necessary to address factors that trigger, reinforce, or excuse the behaviors and to enhance problem-solving skills. Currently available interventions yield only modest effect sizes for treatment effect. More specific definitions and measures are needed to track and quantify outbursts and to design and assess the effectiveness of interventions. Better treatments are clearly needed.

Background Despite the well-documented negative impact of untreated bipolar illness, approaches to early intervention in childhood-onset bipolar and related disorders are not well delineated. Methods We reviewed the extant treatment literature on children at high risk for bipolar disorder, with definitions based on family history, childhood adversity, and prodromal symptoms. Results A panoply of approaches have been described, but most interventions are based on an inadequate database to support their routine implementation. We classify early stage interventions as a function of their safety and tolerability with the hope that these might generate more rigorous study and a stronger database. Limitations Critics may rightly argue that identifying viable treatment methods is premature given our lack of ability to reliably predict illness trajectory in very young children. However, many of the psychosocial and pharmacological interventions we present could have nonspecific positive effects across a variety of symptoms, syndromes, and diagnoses, further enhancing the rationale for more rigorous study. Conclusions Early stage interventions have the potential to improve functioning in prodromal illness and exert long-term positive effects on the course of illness. Many of the safest interventions deserve consideration for implementation and dissemination studies.

An increasing number of antipsychotic medications have demonstrated efficacy in randomized placebo-controlled trials in the treatment of children and adolescents with schizophrenia. This review summarizes and synthesizes relevant antipsychotic medication studies, with particular emphasis on second-generation agents, and discusses other clinical considerations that may influence medication selection. With the exception of clozapine demonstrating superior efficacy in the improvement of psychotic symptoms in treatment-resistant patients, many antipsychotic agents have been shown to be similarly efficacious, including first-generation medications. Consideration of the side-effect profile, which can differ substantially from medication to medication, is essential when choosing treatment options.

To evaluate the efficacy and safety of vortioxetine in adolescents with major depressive disorder (MDD).After 4 weeks of single-blind lead-in treatment with a Brief Psychosocial Intervention (BPI) plus placebo, patients (aged 12-17 years) with MDD (DSM-5) who did not meet response criteria (Children's Depression Rating Scale-Revised [CDRS-R]; total score ≥40 plus 40% reduction and a Parent Global Assessment score2) were randomized 1:1:1:1 to 8 weeks of BPI plus double-blind treatment with vortioxetine 10 mg, vortioxetine 20 mg, fluoxetine 20 mg, or placebo. The primary endpoint was change from randomization in CDRS-R total score at week 8; the primary comparison was the average effect of 2 vortioxetine doses vs placebo.Of 784 patients enrolled in the lead-in, 616 were randomized. At week 8, the mean change in CDRS-R total score averaged for vortioxetine doses was -18.01 (SE = 0.98) and the mean difference vs placebo was 0.21 (P = .878; not significant). For fluoxetine, the mean change in CDRS-R total score was -21.95 and the mean difference vs placebo was -3.73 (P = .015). Treatment-emergent adverse events occurring in ≥5% of patients in either vortioxetine arm and at least twice more frequently than placebo were nausea, headache, vomiting, and dizziness.Patients in all groups showed reduction in CDRS-R scores by the end of the study, with no difference between combined doses of vortioxetine and placebo. The primary endpoint was not met, thereby rendering the study negative. The overall favorable safety profile of vortioxetine in an adolescent patient population was consistent with that seen in adults.Active Reference (Fluoxetine) Fixed-Dose Study of Vortioxetine in Paediatric Patients Aged 12 to 17 Years With Major Depressive Disorder (MDD); http://clinicaltrials.gov; NCT02709746.

Bipolar disorder is a debilitating illness that often leads to functional impairment when untreated. Monotherapy with mood stabilizers is preferable, although combination therapy may be necessary in refractory cases. Most studies focus on the use of lithium, anticonvulsants, and second-generation antipsychotics in the treatment of acute manic or depressive phases, as well as maintaining adequate response after the episode. More research is needed in the area of psychopharmacology of pediatric bipolar disorder to bridge the gap between clinical needs and the available data.

Objectives: The objective of this presentation is to test the efficacy and safety of 2 doses of suramin vs placebo in children aged 4 to 17 years with autism spectrum disorder (ASD). The hypotheses are that at least 1 of 2 suramin doses would show improvement in the Aberrant Behavior Checklist (ABC) Core score and that treatment would be safe and tolerable. Methods: Fifty-two boys were enrolled in 3 treatment arms: 10 mg/kg and 20 mg/kg, and placebo dosed at baseline, at weeks 4 and 8. Subjects were diagnosed by DSM-5 criteria and severity measured by the Autism Diagnostic Observation Schedule. The main efficacy analyses were ABC Core (subscales 2, 3, and 5) and Clinical Global Impression–Improvement (CGI-I) scale. Question 1 was assessed using intent-to-treat sample change scores from baseline to endpoint using ANOVA. Although the study was not designed for formal statistical comparison, ABC Core and CGI-I were tested at a family-wise Type I level of 0.05 using Dunnett’s p value for multiple comparisons. The study was approved by the South Africa Health Products Regulatory Authority and each site’s IRB. Results: The study was conducted at 6 sites in South Africa. The sample was multiracial with a mean age of approximately 8 years and a range of 4 to 15 years. There was a wide variability in the severity of ASD symptoms at baseline. Forty-four subjects completed the study, and there were 8 early withdrawals (COVID-19: 5;serious adverse event [SAE]: 1;other reason: 2). The 10 mg arm showed a sustained benefit across time points. The ABC Core modeling mean ± standard error (SE) of 10 mg showed a greater numeric improvement (–12.5 ± 3.18) vs placebo (–8.9 ± 2.86) (nonsignificant) at Week 14. The 20 mg arm did not show improvement vs placebo at Week 14. In exploratory analyses, the 10 mg arm showed greater differences from placebo in ABC Core in younger and less severe subjects. CGI-I modeled mean ± SE changes from baseline were 2.8 ± 0.30 (p = 0.016) in the 10 mg arm and 2.0 ± 0.28 (p = 0.65) in the 20 mg arm vs 1.7 ± 0.27 in the placebo. Suramin was generally safe and well tolerated over 14 weeks. There was 1 SAE, status epilepticus, in a subject (20-mg arm) with multiple risk factors for seizure;it resolved without sequelae. Conclusions: This dose-ranging proof-of-concept study showed some positive results from a treatment with a novel mechanism of action. Limitations include the small sample size and exploratory analyses that require confirmation in a larger study. Suramin was safe and tolerable over 14 weeks.

Background Changes in neural circuitry function may be associated with longitudinal changes in psychiatric symptom severity. Identification of these relationships may aid in elucidating the neural basis of psychiatric symptom evolution over time. We aimed to distinguish these relationships using data from the Longitudinal Assessment of Manic Symptoms cohort. Methods Forty-one youth completed two study visits (interscan mean = 21.3 months). Elastic net regression (multiple-response Gaussian family) identified emotional regulation neural circuitry that changed in association with changes in depression, mania, anxiety, affect lability, and positive mood and energy dysregulation, accounting for clinical and demographic variables. Results Nonzero coefficients between change in the previously mentioned symptom measures and change in activity over the interscan interval were identified in right amygdala and left ventrolateral prefrontal cortex. Differing patterns of neural activity change were associated with changes in each of the previously mentioned symptoms over time. Specifically, from scan 1 to scan 2, worsening affective lability and depression severity were associated with increased right amygdala and left ventrolateral prefrontal cortical activity. Worsening anxiety and positive mood and energy dysregulation were associated with decreased right amygdala and increased left ventrolateral prefrontal cortical activity. Worsening mania was associated with increased right amygdala and decreased left ventrolateral prefrontal cortical activity. These changes in neural activity between scans accounted for 13.6% of the variance; that is, 25% of the total explained variance (39.6%) in these measures. Conclusions Distinct neural mechanisms underlie changes in different mood and anxiety symptoms over time.

Mood disorders and behavioral are broad psychiatric diagnostic categories that have different symptoms and neurobiological mechanisms, but share some neurocognitive similarities, one of which is an elevated risk for reading deficit. Our aim was to determine the influence of mood versus behavioral dysregulation on reading ability and neural correlates supporting these skills in youth, using diffusion tensor imaging in 11- to 17-year-old children and youths with mood disorders or behavioral disorders and age-matched healthy controls. The three groups differed only in phonological processing and passage comprehension. Youth with mood disorders scored higher on the phonological test but had lower comprehension scores than children with behavioral disorders and controls; control participants scored the highest. Correlations between fractional anisotropy and phonological processing in the left Arcuate Fasciculus showed a significant difference between groups and were strongest in behavioral disorders, intermediate in mood disorders, and lowest in controls. Correlations between these measures in the left Inferior Longitudinal Fasciculus were significantly greater than in controls for mood but not for behavioral disorders. Youth with mood disorders share a deficit in the executive-limbic pathway (Arcuate Fasciculus) with behavioral-disordered youth, suggesting reduced capacity for engaging frontal regions for phonological processing or passage comprehension tasks and increased reliance on the ventral tract (e.g., the Inferior Longitudinal Fasciculus). The low passage comprehension scores in mood disorder may result from engaging the left hemisphere. Neural pathways for reading differ mainly in executive-limbic circuitry. This new insight may aid clinicians in providing appropriate intervention for each disorder., Highlights • Mood disorders scored higher on phonological test but lower on comprehension tests • Correlations between FA and phonological processing in the left Arcuate Fasciculus was strongest in behavioral disorders • Reduced capacity for engaging frontal regions for phonological processing in youth with mood disorders • The low passage-comprehension scores in mood disorder may result from engaging the left vs the right hemisphere.

Objective: A recent 3-month double-blind, placebo-controlled study demonstrated efficacy and safety of pediatric prolonged-release melatonin (PedPRM) for insomnia in children with autism spectrum disorder. This study examined the long-term effects of PedPRM treatment on sleep, growth, body mass index, and pubertal development. Method: Eighty children and adolescents (2–17.5 years of age; 96% with autism spectrum disorder) who completed the double-blind, placebo-controlled trial were given 2 mg, 5 mg, or 10 mg PedPRM nightly up to 104 weeks, followed by a 2-week placebo period to assess withdrawal effects. Results: Improvements in child sleep disturbance and caregiver satisfaction with child sleep patterns, quality of sleep, and quality of life were maintained throughout the 104-week treatment period (p < .001 versus baseline for all). During the 2-week withdrawal placebo period, measures declined compared with the treatment period but were still improved compared with baseline. PedPRM was generally safe; the most frequent treatment-related adverse events were fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%). Changes in mean weight, height, body mass index, and pubertal status (Tanner staging done by a physician) were within normal ranges for age with no evidence of delay in body mass index or pubertal development. Conclusion: Nightly PedPRM at optimal dose (2, 5, or 10 mg nightly) is safe and effective for long-term treatment in children and adolescents with autism spectrum disorder and insomnia. There were no observed detrimental effects on children’s growth and pubertal development and no withdrawal or safety issues related to the use or discontinuation of the drug. Clinical trial registration information: Efficacy and Safety of Circadin in the Treatment of Sleep Disturbances in Children With Neuro-development Disabilities; https://clinicaltrials.gov/; NCT01906866.

ObjectiveTo evaluate asenapine versus placebo in 403 patients aged 10 to 17 years with bipolar I disorder currently in manic or mixed episodes.MethodIn this double-blind, placebo-controlled, international trial, patients were randomized 1:1:1:1 to placebo, asenapine 2.5, 5, or 10 mg b.i.d. (twice daily). Primary efficacy measure was change from baseline in Young-Mania Rating Scale (YMRS) total score at day 21. Analyses of patients with/without attention-deficit/hyperactivity disorder (ADHD) and with/without stimulant use were performed.ResultsThe mean difference in asenapine versus placebo in YMRS was –3.2 (p = .0008), –5.3 (p < .001), and –6.2 (p

PurposeThe aim of this study was to evaluate the pharmacokinetic (PK) profile and tolerability of lurasidone in children and adolescents with a range of psychiatric disorders.MethodsThis multicenter, open-label, single and multiple ascending-dose study of the PK profile of lurasidone (20, 40, 80, 120, and 160 mg/d) enrolled outpatients aged 6 to 17 years with a diagnosis of attention deficit/hyperactivity disorder, bipolar spectrum disorder, or other psychiatric disorder. Serial blood samples were collected for analysis of PK parameters, including Cmax, Tmax, and AUC0–24.FindingsExposure (Cmax and AUC0–24) to lurasidone and its active metabolites showed linear increases across the entire dose range. Slope estimates (95% CI) across the dose range studied was 0.90 ng · h/mL (0.74–1.06) for AUC0–24 and 0.70 ng/mL (0.52–0.87) for Cmax on day 10 or 12. Lurasidone exposure, after multiple-dose administration in this child and adolescent population, was similar to exposure observed at steady state in adults. The effects of dose on exposure to the 3 active metabolites of lurasidone were linear and similar after the administration of single and multiple doses. Adverse events were qualitatively similar to those reported in adults. Discontinuations due to adverse events were dose related, with doses

Introduction : Children in the US have a high incidence of psychiatric disorders, but the symptoms of these illnesses are often poorly recognized and treated. We thus created a Child Network for parents of children aged 2-12 to rate their child on a weekly basis on a secure website so that longitudinal ratings could be easily visualized. Methods : After giving informed consent, parents filled out: a one-time questionnaire and a 97 item Child Checklist; and then rated the severity of depression, anxiety, ADHD, oppositional behavior, and mania each week. The new Checklist ratings were correlated with the 23 previous validated in adults (the M-3), and symptom burden was compared with diagnoses received in the community. Results : The 23 item M-3 ratings were highly correlated with the more extensive Child Checklist. Symptom severity also corresponded to diagnoses received in the community. An example of the longitudinal weekly ratings of a child with a dysphoric mania is also presented. Conclusions : The convergence of scores on the adult and child portions of the Child Checklist and the ease of visualization of symptoms and response to treatment suggest the utility of the ratings in the Child Network.

Objectif Une etude randomisee et controlee (ERC) recente a demontre l’efficacite a 3 mois d’une nouvelle forme pediatrique de melatonine a liberation prolongee (PedPRM ; 2/5 mg) vs. Placebo chez l’enfant et adolescent avec troubles du spectre de l’autisme (TSA) atteint d’insomnie chronique. L’objectif de notre etude etait d’evaluer l’efficacite et la securite de PedPRM a long terme (sur 1 an) chez ces patients, ainsi que l’impact du traitement sur leur famille. Methodes Au total, 95 patients âges de 2–17,5 ans [M 9 ans + 4,24, 74,7 % garcons] ayant complete les 3 mois d’ERC (51 du bras PedPRM et 44 du bras placebo) ont poursuivi la partie ouverte de l’etude. Les mesures de sommeil incluaient, pour les enfants, un agenda de sommeil en ligne et le CSDI, et pour la famille, le PSQI, l’ESS et la qualite de vie (index WHO-5). Resultats A la fin des 52 semaines, les enfants traites avec PedPRM dormaient en moyenne 62 ? 08 minutes de plus (p = 0,007) et s’endormaient −48 ?6 minutes plus vite (p 50 % (p = 0,001). En parallele, on notait une qualite du sommeil des parents amelioree (PSQI, p Conclusion La forme pediatrique de la melatonine a liberation prolongee est une option therapeutique efficace et sure a long terme (52 semaines) pour l’insomnie chronique de l’enfant et adolescent avec TSA., avec un impact positif egalement sur la qualite du sommeil et de vie des familles.

Objective To evaluate the efficacy, safety, and tolerability of the selective serotonin norepinephrine inhibitor duloxetine in children and adolescents with generalized anxiety disorder (GAD). Method Youth aged 7 through 17 years with a primary diagnosis of GAD were treated with flexibly dosed duloxetine (30–120 mg daily, n = 135) or placebo (n = 137) for 10 weeks, followed by open-label duloxetine (30–120mg daily) for 18 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS), Clinical Global Impression–Severity (CGI-Severity) scale, and Children’s Global Assessment Scale (CGAS). Safety measures included the Columbia–Suicide Severity Rating Scale (C-SSRS) as well as vital signs and electrocardiographic and laboratory monitoring. Results On the primary efficacy measure (PARS severity for GAD), mean improvement from baseline to 10 weeks was statistically significantly greater for duloxetine (–9.7) compared with placebo (–7.1, p ≤ .001, Cohen’s d: 0.5). Symptomatic response (50% improvement on the PARS severity for GAD), remission (PARS severity for GAD ≤8), and functional remission (CGAS >70) rates for the duloxetine group (59%, 50%, 37%, respectively) were statistically significantly greater than for the placebo group (42%, 34%, 24%, respectively, p ≤ .05) during acute treatment. Changes in systolic and diastolic blood pressure and discontinuation because of adverse events did not statistically differ between the duloxetine and placebo groups, although gastrointestinal-related adverse events, oropharyngeal pain, dizziness, cough, and palpitations were reported with a statistically significantly greater incidence for the duloxetine group compared with the placebo group. Mean changes in pulse and weight for the duloxetine group (+6.5 beats/min, –0.1 kg, respectively) were statistically different from the placebo group (+2.0 beats/min, +1.1 kg, respectively, p ≤ .01). Conclusion In this study, duloxetine was superior to placebo on the primary efficacy analysis of mean change from baseline to week 10 on the PARS severity for GAD score, and safety results were consistent with the known safety profile of duloxetine in pediatric and adult patients. Clinical trial registration information—A Study in Pediatric Participants With Generalized Anxiety Disorder; http://clinicaltrials.gov ; NCT01226511 .

Objectives: The purpose of this study was to evaluate the validity and reliability of a Korean version of the Parent General Behavior Inventory-10-item Mania Scale (P-GBI-10M) and the Adolescent General Behavior Inventory (A-GBI) for bipolar and depressive disorder in youths. Methods: Ninety-two subjects with mood disorder and their parents were recruited from September 2011 to June 2013 through the Department of Psychiatry at the Asan Medical Center, Seoul, Korea. In addition, 125 community participants were recruited through two middle schools and one high school in Seoul. The parents of subjects completed the Parent-version Mood Disorder Questionnaire (P-MDQ), P-GBI-10M and Attention-deficit/hyperactivity disorder Rating Scale (ARS). Adolescents complete the 76-item A-GBI, Beck Depression Inventory (BDI), and Adolescent version of the Mood Disorder Questionnaire (A-MDQ). Results: Different profiles were evident between the clinic-referred group and the community control, including different P-GBI-10M (t = 3.07, p = 0.003), A-GBI Depressive (t = 4.99, p

Summary: Astrocytic differentiation is developmentally impaired in patients with childhood-onset schizophrenia (SCZ). To determine why, we used genetic gain- and loss-of-function studies to establish the contributions of differentially expressed transcriptional regulators to the defective differentiation of glial progenitor cells (GPCs) produced from SCZ patient-derived induced pluripotent cells (iPSCs). Negative regulators of the bone morphogenetic protein (BMP) pathway were upregulated in SCZ GPCs, including BAMBI, FST, and GREM1, whose overexpression retained SCZ GPCs at the progenitor stage. SMAD4 knockdown (KD) suppressed the production of these BMP inhibitors by SCZ GPCs and rescued normal astrocytic differentiation. In addition, the BMP-regulated transcriptional repressor REST was upregulated in SCZ GPCs, and its KD similarly restored normal glial differentiation. REST KD also rescued potassium-transport-associated gene expression and K+ uptake, which were otherwise deficient in SCZ glia. These data suggest that the glial differentiation defect in childhood-onset SCZ, and its attendant disruption in K+ homeostasis, may be rescued by targeting BMP/SMAD4- and REST-dependent transcription. : Astrocytic differentiation is impaired in childhood-onset schizophrenia (SCZ). Liu et al. report that SMAD4-dependent BMP signaling and REST are upregulated in hiPSC-derived SCZ glia and that SMAD4 and REST knockdown rescue both astroglial differentiation and K+ transport. SCZ astrocytic maturation may thus be rescued by targeting SMAD4- and REST-dependent transcription. Keywords: schizophrenia, stem cells, iPSC, astrocytes, glial progenitor cells, epigenetics, REST, potassium channel, BMP inhibitors, BAMBI

Background Few studies have evaluated the value of a parent- and subject-rated scale in detecting symptom change in response to pharmacologic treatment. Methods This was a post-hoc analysis of data from a 4-week, randomized, double-blind, placebo-controlled study to evaluate which informants detect response to treatment with aripiprazole in pediatric subjects experiencing a mixed or manic episode associated with bipolar I disorder. Efficacy assessments included clinician-rated scales and the parent- and subject-rated 10-item General Behavior Inventory Mania (GBI-M10) and Depression (GBI-D10) scales. Cohen's d quantified effect sizes for total scale scores and individual line items. Results Parent-GBI-M10 total, clinician-rated Young Mania Rating Scale (YMRS) total, and Clinical Global Impression–Bipolar Disorder (CGI-BP) Mania scores produced similar effect sizes, suggesting that the parent-GBI-M10 is sensitive to treatment-related improvements in manic symptoms. Aripiprazole improved a broad spectrum of parent-rated mania symptoms; six parent-GBI-M10 line item effect sizes were moderate (>0.5) in at least one of the two aripiprazole treatment arms (10 or 30 mg/day). Subject-completed GBI-M10 line item effect sizes were consistently smaller, indicating that the subjects' experience of treatment effects were less pronounced. Limitations Study inclusion/exclusion criteria may limit generalizability of these findings. Conclusions Parent ratings of mania severity were in agreement with clinician ratings, indicating that parent-rated assessments can be valuable in detecting symptom change over the course of treatment. These data support the use of the parent-GBI-M10 as an outcome measure in research and clinical settings.

Our recent 8-week, randomized, placebo-controlled trial of fluoxetine in adolescents (ages 12–17 years) with comorbid depression and substance use disorder (SUD) did not detect a significant antidepressant treatment effect. The purpose of this secondary analysis was to explore moderators of the effect of fluoxetine in this sample. Static moderators measured at baseline were depression chronicity and hopelessness severity; time-varying moderators measured at baseline and weekly during the 8-week trial period were alcohol and marijuana use severity. Treatment effects on depression outcomes were examined among moderating subgroups in random effects regression models. Subjects assigned to fluoxetine treatment with chronic depression at baseline (p = .04) or no more than moderate alcohol use during the trial (p = .04) showed significantly greater decline in depression symptoms in comparison to placebo-assigned subgroups. The current analysis suggests that youth with chronic depression and no more than moderate alcohol consumption are likely to respond better to treatment with fluoxetine compared with placebo than youth with transient depression and heavy alcohol use.

Cyclothymic disorder is a subtype of bipolar disorder included in the Diagnostic and Statistical Manual of Mental Disorders since 1980, but largely neglected in research. Additionally, it is rarely diagnosed clinically, in spite of evidence that it may be the most prevalent form of bipolar disorder. Neglect has contributed to confusion about the diagnosis and clinical presentation of cyclothymic disorder. Its status as a mood disorder is also ambiguous due to overlap in terminology and symptoms with temperament and personality disorders. Subthreshold bipolar disorder appears more prevalent among young people than previously thought, and follows a range of trajectories from remission to escalation—raising questions about risk factors and traits associated with the varied course. Cyclothymic disorder may be an important diathesis for major mood disorders. Constructs such as cyclothymic disorder link major mood disorder and peri-clinical fluctuations of mood, thus warranting a prominent role in dimensional models of mood and psychopathology. Current evidence indicates that cyclothymic disorder is a prevalent and highly impairing disorder on the bipolar spectrum, with the potential to make unique contributions to our understanding of the risk factors and outcomes associated with bipolar disorder. The inclusion of cyclothymic disorder in future research studies is essential to accurate diagnosis and effective treatment for the full spectrum of bipolar disorder, as well as understanding the developmental trajectory of bipolar spectrum disorders.

This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder.In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15 mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference35 in. in women and40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months.Pioglitazone decreased depression symptom severity from a total IDS score of 40.3±1.8 to 19.2±1.8 at Week 12 (p.001). Among partial responders (≥25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration=24 weeks) according to IDS total scores (p.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (-0.8±0.75; p.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (-0.87±0.72; p.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects.These data are limited by a small sample size and an open-label study design with no placebo control.Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.

Four subtypes of bipolar disorder (BP) - bipolar I, bipolar II, cyclothymia and bipolar not otherwise specified (NOS) - are defined in DSM-IV-TR. Though the diagnostic criteria for each subtype are intended for both adults and children, research investigators and clinicians often stray from the DSM when diagnosing pediatric bipolar disorder (PBD) (Youngstrom, 2009), resulting in a lack of agreement and understanding regarding the PBD subtypes.The present study uses the diagnostic validation method first proposed by Robins and Guze (1970) to systematically evaluate cyclothymic disorder as a distinct diagnostic subtype of BP. Using a youth (ages 5-17) outpatient clinical sample (n=827), participants with cyclothymic disorder (n=52) were compared to participants with other BP spectrum disorders and to participants with non-bipolar disorders.Results indicate that cyclothymic disorder shares many characteristics with other bipolar subtypes, supporting its inclusion on the bipolar spectrum. Additionally, cyclothymia could be reliably differentiated from non-mood disorders based on irritability, sleep disturbance, age of symptom onset, comorbid diagnoses, and family history.There is little supporting research on cyclothymia in young people; these analyses may be considered exploratory. Gaps in this and other studies are highlighted as areas in need of additional research.Cyclothymic disorder has serious implications for those affected. Though it is rarely diagnosed currently, it can be reliably differentiated from other disorders in young people. Failing to accurately diagnose cyclothymia, and other subthreshold forms of bipolar disorder, contributes to a significant delay in appropriate treatment and may have serious prognostic implications.