Effect of non-invasive spinal cord stimulation in unmedicated adults with major depressive disorder: a pilot randomized controlled trial and induced current flow pattern.

Converging theoretical frameworks suggest a role and a therapeutic potential for spinal interoceptive pathways in major depressive disorder (MDD). Here, we aimed to evaluate the antidepressant effects and tolerability of transcutaneous spinal direct current stimulation (tsDCS) in MDD. This was a double-blind, randomized, sham-controlled, parallel group, pilot clinical trial in unmedicated adults with moderate MDD. Twenty participants were randomly allocated (1:1 ratio) to receive "active" 2.5 mA or "sham" anodal tsDCS sessions with a thoracic (anode; T10)/right shoulder (cathode) electrode montage 3 times/week for 8 weeks. Change in depression severity (MADRS) scores (prespecified primary outcome) and secondary clinical outcomes were analyzed with ANOVA models. An E-Field model was generated using the active tsDCS parameters. Compared to sham (n = 9), the active tsDCS group (n = 10) showed a greater baseline to endpoint decrease in MADRS score with a large effect size (-14.6 ± 2.5 vs. -21.7 ± 2.3, p = 0.040, d = 0.86). Additionally, compared to sham, active tsDCS induced a greater decrease in MADRS "reported sadness" item (-1.8 ± 0.4 vs. -3.2 ± 0.4, p = 0.012), and a greater cumulative decrease in pre/post tsDCS session diastolic blood pressure change from baseline to endpoint (group difference: 7.9 ± 3.7 mmHg, p = 0.039). Statistical trends in the same direction were observed for MADRS "pessimistic thoughts" item and week-8 CGI-I scores. No group differences were observed in adverse events (AEs) and no serious AEs occurred. The current flow simulation showed electric field at strength within the neuromodulation range (max. ~0.45 V/m) reaching the thoracic spinal gray matter. The results from this pilot study suggest that tsDCS is feasible, well-tolerated, and shows therapeutic potential in MDD. This work also provides the initial framework for the cautious exploration of non-invasive spinal cord neuromodulation in the context of mental health research and therapeutics. The underlying mechanisms warrant further investigation. Clinicaltrials.gov registration: NCT03433339 URL: https://clinicaltrials.gov/ct2/show/NCT03433339 .

Liraglutide in Obese or Overweight Individuals With Stable Bipolar Disorder.

BACKGROUND: Obesity is common among persons with bipolar disorder (BD). Liraglutide 3.0 mg/d subcutaneous injection is indicated for chronic weight management and associated with minimal adverse neuropsychiatric effects. This study evaluated whether liraglutide 3 mg/d reduced body weight, improved metabolic factors and eating psychopathology, and was safe and well tolerated in persons with stable BD who were obese (body mass index [BMI] >30 kg/m 2 ) or overweight (BMI ≥27 kg/m 2 ) with at least one weight-related comorbidity. METHODS: This was a 40-week, randomized (1:1 ratio), placebo-controlled, double-blind, parallel-group, 2-arm clinical trial of liraglutide targeted to 3.0 mg/d (in combination with a reduced-calorie diet and increased physical activity) in 60 participants with stable BD who were obese or overweight. Primary outcome was percent change in body weight from baseline to study end. Secondary outcomes included percentage of patients who lost ≥5% of baseline body weight, and changes in metabolic variables and measures of eating psychopathology. RESULTS: There were no significant baseline differences between the 29 liraglutide recipients and the 31 placebo recipients, except that liraglutide recipients had higher levels of binge eating and lower levels of high-density lipoprotein cholesterol. Compared with placebo, liraglutide was associated with significantly greater reductions in percent change in body weight, percentage of participants who lost at least 5% of body weight, and reductions in weight, BMI, hemoglobin A 1c levels, binge eating, and hunger. Liraglutide was well tolerated. CONCLUSIONS: Liraglutide 3 mg/d may be efficacious and safe for weight loss in individuals with stable BD and obesity or overweight. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03158805).

Aberrant brain network topology in youth with a familial risk for bipolar disorder: a task-based fMRI connectome study.

BACKGROUND: Youth with a family history of bipolar disorder (BD) may be at increased risk for mood disorders and for developing side effects after antidepressant exposure. The neurobiological basis of these risks remains poorly understood. We aimed to identify biomarkers underlying risk by characterizing abnormalities in the brain connectome of symptomatic youth at familial risk for BD. METHODS: Depressed and/or anxious youth (n = 119, age = 14.9 ± 1.6 years) with a family history of BD but no prior antidepressant exposure and typically developing controls (n = 57, age = 14.8 ± 1.7 years) received functional magnetic resonance imaging (fMRI) during an emotional continuous performance task. A generalized psychophysiological interaction (gPPI) analysis was performed to compare their brain connectome patterns, followed by machine learning of topological metrics. RESULTS: High-risk youth showed weaker connectivity patterns that were mainly located in the default mode network (DMN) (network weight = 50.1%) relative to controls, and connectivity patterns derived from the visual network (VN) constituted the largest proportion of aberrant stronger pairs (network weight = 54.9%). Global local efficiency (Elocal , p = .022) and clustering coefficient (Cp , p = .029) and nodal metrics of the right superior frontal gyrus (SFG) (Elocal : p < .001; Cp : p = .001) in the high-risk group were significantly higher than those in healthy subjects, and similar patterns were also found in the left insula (degree: p = .004; betweenness: p = .005; age-by-group interaction, p = .038) and right hippocampus (degree: p = .003; betweenness: p = .003). The case-control classifier achieved a cross-validation accuracy of 78.4%. CONCLUSIONS: Our findings of abnormal connectome organization in the DMN and VN may advance mechanistic understanding of risk for BD. Neuroimaging biomarkers of increased network segregation in the SFG and altered topological centrality in the insula and hippocampus in broader limbic systems may be used to target interventions tailored to mitigate the underlying risk of brain abnormalities in these at-risk youth.

Network-level functional topological changes after mindfulness-based cognitive therapy in mood dysregulated adolescents at familial risk for bipolar disorder: a pilot study.

BACKGROUND: Given that psychopharmacological approaches routinely used to treat mood-related problems may result in adverse outcomes in mood dysregulated adolescents at familial risk for bipolar disorder (BD), Mindfulness-Based Cognitive Therapy for Children (MBCT-C) provides an alternative effective and safe option. However, little is known about the brain mechanisms of beneficial outcomes from this intervention. Herein, we aimed to investigate the network-level neurofunctional effects of MBCT-C in mood dysregulated adolescents. METHODS: Ten mood dysregulated adolescents at familial risk for BD underwent a 12-week MBCT-C intervention. Resting-state functional magnetic resonance imaging (fMRI) was performed prior to and following MBCT-C. Topological metrics of three intrinsic functional networks (default mode network (DMN), fronto-parietal network (FPN) and cingulo-opercular network (CON)) were investigated respectively using graph theory analysis. RESULTS: Following MBCT-C, mood dysregulated adolescents showed increased global efficiency and decreased characteristic path length within both CON and FPN. Enhanced functional connectivity strength of frontal and limbic areas were identified within the DMN and CON. Moreover, change in characteristic path length within the CON was suggested to be significantly related to change in the Emotion Regulation Checklist score. CONCLUSIONS: 12-week MBCT-C treatment in mood dysregulated adolescents at familial risk for BD yield network-level neurofunctional effects within the FPN and CON, suggesting enhanced functional integration of the dual-network. Decreased characteristic path length of the CON may be associated with the improvement of emotion regulation following mindfulness training. However, current findings derived from small sample size should be interpreted with caution. Future randomized controlled trials including larger samples are critical to validate our findings.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode.

OBJECTIVES: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. METHODS: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. RESULTS: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. CONCLUSIONS: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.

Neurophysiological effects of multiple mood episodes in bipolar disorder.

OBJECTIVES: Bipolar disorder is marked by progressive symptomatic changes, which have been linked with episode-related structural findings-particularly in the prefrontal cortex. However, few studies have examined neurofunctional and neurochemical effects of disease burden. In this study, we compared first- and multi-episode bipolar individuals. We hypothesized that the latter would demonstrate evidence of neurophysiological differences consistent with a model of progressive functional degradation of these networks. METHODS: First- and multi-episode manic bipolar subjects participated in functional magnetic resonance imaging (fMRI) including a continuous performance task with emotional distractors, and in single-voxel (1 H) magnetic resonance spectroscopy (MRS). A priori fMRI regions-of-interest (ROI) included structures comprising prefrontal-striatal-amygdala networks; (1 H)MRS voxels were placed within bilateral ventrolateral prefrontal (VLPFC) and anterior cingulate cortex (ACC). Both ROI and voxel-based brain activation in response to emotional stimuli, and neurochemical concentrations derived from (1 H)MRS were compared across bipolar groups. RESULTS: Multi-episode bipolar subjects showed relatively lower regional activation across prefrontal-striatal-amygdala networks, including bilateral VLPFC, orbitofrontal cortex, ACC, putamen, caudate, and amygdala. Exploratory whole-brain, voxel-based analysis suggested additional areas of lower activation extending into Brodmann area 22, posterior parietal regions, and right thalamus. Glutamate and N-acetylaspartate (NAA) concentrations were also relatively lower in the ACC of multi-episode subjects. CONCLUSIONS: Disease burden, exemplified by multiple affective episodes is associated with evidence of widespread decrements in affective network activity. Lower ACC NAA concentration is similarly consistent with a model of progressive functional deficits. These findings support the functional significance of previously observed progressive structural changes throughout these regions.

Placebo response and cessation in binge eating disorder: A pooled analysis of two randomized parallel-group clinical trials.

OBJECTIVE: This study aims to explore predictors and clinical correlates of placebo response and cessation in binge eating disorder (BED). METHOD: Data from two identically designed, randomized, placebo-controlled, parallel-group, and multicenter pharmacotherapy studies for adults with moderate to severe BED were pooled. RESULTS: Of 360 placebo recipients, 134 (37%) were responders and 53 (15%) achieved 4-week binge eating cessation. Placebo response and cessation were each associated with higher baseline disability scores but not with measures of BED symptomatology severity. Compared with placebo noncessation, placebo cessation was further associated with increased blood pressure at baseline and greater improvement in pulse and triglyceride levels at endpoint. DISCUSSION: Future clinical trial design for BED pharmacotherapy trials might consider disability level among participants to enhance signal detection. Cessation of binge eating with placebo might be associated with improvement in cardiovascular and metabolic variables, at least over the short term.

Cardiometabolic risks and omega-3 index in recent-onset bipolar I disorder.

OBJECTIVES: The aims of the present study were to characterize cardiometabolic risk factors in a cohort of bipolar disorder patients with limited exposure to psychotropic medications, and to evaluate their associations with mood symptoms and omega-3 polyunsaturated fatty acid (PUFA) blood levels. METHODS: Cardiometabolic risk assessments were compared in individuals with bipolar I disorder experiencing a first manic or mixed episode or an early depressive episode (n=117) and healthy subjects (n=56). Patients were medication free at assessment and had no or limited exposure to mood-stabilizer or antipsychotic medications prior to the current admission. Associations among cardiometabolic parameters and Clinical Global Impression-Severity scale (CGI-S), manic (Young Mania Rating Scale [YMRS]), and depressive (Hamilton Depression Rating Scale [HDRS]) symptom ratings were evaluated within the bipolar group. RESULTS: Following adjustment for demographic variables (i.e., age, gender, and parental education), significantly higher fasting triglyceride levels were observed in the bipolar group compared to the healthy group (121.7 mg/dL vs 87.0 mg/dL; P<.01). There were no clear trends for other metabolic indicators, including blood pressure, body mass index, and fasting glucose. Nineteen percent of the bipolar group and 6% of the healthy group met the criteria for metabolic syndrome (P=.23). The omega-3 index was lower in the bipolar group (3.4% vs 3.9%; P<.01). Within the bipolar group, no associations were found between the cardiometabolic parameters and CGI-S, YMRS, and HDRS symptom ratings. CONCLUSIONS: Recent-onset medication-free bipolar disorder is associated with higher triglyceride levels. These findings are suggestive of early metabolic dysregulation prior to long-term psychotropic medication exposure. Lower omega-3 PUFA levels in individuals with bipolar I disorder represent a potential therapeutic target for additional investigation.

Prediction of lithium response in first-episode mania using the LITHium Intelligent Agent (LITHIA): Pilot data and proof-of-concept.

OBJECTIVES: Individualized treatment for bipolar disorder based on neuroimaging treatment targets remains elusive. To address this shortcoming, we developed a linguistic machine learning system based on a cascading genetic fuzzy tree (GFT) design called the LITHium Intelligent Agent (LITHIA). Using multiple objectively defined functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1 H-MRS) inputs, we tested whether LITHIA could accurately predict the lithium response in participants with first-episode bipolar mania. METHODS: We identified 20 subjects with first-episode bipolar mania who received an adequate trial of lithium over 8 weeks and both fMRI and 1 H-MRS scans at baseline pre-treatment. We trained LITHIA using 18 1 H-MRS and 90 fMRI inputs over four training runs to classify treatment response and predict symptom reductions. Each training run contained a randomly selected 80% of the total sample and was followed by a 20% validation run. Over a different randomly selected distribution of the sample, we then compared LITHIA to eight common classification methods. RESULTS: LITHIA demonstrated nearly perfect classification accuracy and was able to predict post-treatment symptom reductions at 8 weeks with at least 88% accuracy in training and 80% accuracy in validation. Moreover, LITHIA exceeded the predictive capacity of the eight comparator methods and showed little tendency towards overfitting. CONCLUSIONS: The results provided proof-of-concept that a novel GFT is capable of providing control to a multidimensional bioinformatics problem-namely, prediction of the lithium response-in a pilot data set. Future work on this, and similar machine learning systems, could help assign psychiatric treatments more efficiently, thereby optimizing outcomes and limiting unnecessary treatment.

Suicidality in psychiatrically hospitalized children and adolescents: Demographics, treatment, and outcome.

BACKGROUND: Despite the high prevalence of suicidality in psychiatrically hospitalized youth, its risk factors and impact on inpatient psychopharmacologic treatment are unknown. We identified characteristics associated with suicidality in psychiatrically hospitalized youth and determined the association of suicidality with subsequent psychopharmacologic interventions. METHODS: Medical records from consecutive psychiatric admissions to a large, acute care, urban, pediatric hospital were analyzed retrospectively (N = 1,309). Demographic, clinical, and treatment-related features of suicidal and nonsuicidal youth were characterized. Logistic regression identified predictors of suicidality, and multiple comparison analyses evaluated the association between suicidality and changes to antidepressant prescribing during inpatient course. RESULTS: Compared with nonsuicidal patients, inpatients who were suicidal were more likely to have a mood disorder or posttraumatic stress disorder, as well as Cannabis and alcohol use, were more commonly girls, and at least 13 years of age (all P ≤ .05). Hospitalization was shorter for suicidal patients, was more likely to be associated with antidepressant treatment (P ≤ .001), and among suicidal patients prescribed antidepressants at the time of admission, was associated with a greater likelihood of changing antidepressant treatment compared with nonsuicidal inpatients (P ≤ .05). CONCLUSIONS: These findings reveal differences between suicidal and nonsuicidal psychiatrically hospitalized youth and suggest that suicidality is associated with specific pharmacologic treatment approaches within this population.

fMRI brain activation changes following treatment of a first bipolar manic episode.

OBJECTIVES: We tested the hypothesis that, with treatment, functional magnetic resonance imaging (fMRI) regional brain activation in first-episode mania would normalize - i.e., that differences from healthy subjects would diminish over time, and would be associated with clinical remission status, potentially identifying neuroanatomic treatment response markers. METHODS: Forty-two participants with bipolar I disorder were recruited during their first manic episode, pseudo-randomized to open-label lithium or quetiapine, and followed for 8 weeks. fMRI scans were obtained at baseline and then after 1 and 8 weeks of treatment, while participants performed a continuous performance task with emotional distracters. Healthy participants received fMRI scans at these same intervals. Specific region-of-interest (ROI) activations within prefrontal emotional networks were assessed as potential measures of treatment response. RESULTS: ROI data were reduced using exploratory factor analysis, which identified five factors that were organizationally consistent with functional anatomic models of human emotion modulation. Half of the participants with bipolar disorder achieved remission by Week 8 and were contrasted with the other half that did not. Analyses demonstrated that, in the bipolar disorder group in general, treatment led to decreases in activation across brain regions toward healthy subject values. However, differences in activation changes were observed between subjects with bipolar disorder who did or did not achieve remission in subcortical and amygdala factors. CONCLUSIONS: These findings provide evidence for potential neuroanatomic treatment response markers in first-episode bipolar disorder.

Lisdexamfetamine dimesylate in binge eating disorder: a placebo controlled trial.

OBJECTIVE: To evaluate lisdexamfetamine dimesylate (LDX) in the treatment of binge eating disorder (BED). METHOD: Fifty participants with BED received LDX (20-70 mg/day) (n = 25) or placebo (n = 25) for up to 12 weeks in a single-center, randomized, double-blind, and flexible-dose trial. The primary outcome measure was binge eating (BE) days/week. RESULTS: In the primary longitudinal analysis, compared with placebo, LDX was not associated with a significantly greater rate of reduction in BE days/week, as well as BE episodes/week, and scores on the Clinical Global Impression-Severity or Yale-Brown Obsessive-Compulsive Scale modified for binge eating scales. It was, however, associated with significantly decreased weight, body mass index, and fasting triglyceride level. In the secondary last observation carried forward analyses, LDX was associated with statistically significant reductions in BE days/week, BE episodes/week, weight, and BMI, as well as a statistically significant greater level of categorical response and global improvement. The mean (standard deviation) LDX daily dose at endpoint evaluation was 59.6 (14.9) mg. One participant discontinued LDX for a serious adverse cardiovascular event, which resolved fully. CONCLUSION: Lisdexamfetamine dimesylate may have clinical utility for BED but further studies of its efficacy, tolerability, and safety in this population are needed. Copyright © 2016 John Wiley & Sons, Ltd.

Neurofunctional effects of quetiapine in patients with bipolar mania.

OBJECTIVES: Several lines of evidence suggest that abnormalities within portions of the extended limbic network involved in affective regulation and expression contribute to the neuropathophysiology of bipolar disorder. In particular, portions of the prefrontal cortex have been implicated in the appearance of manic symptomatology. The effect of atypical antipsychotics on activation of these regions, however, remains poorly understood. METHODS: Twenty-two patients diagnosed with bipolar mania and 26 healthy subjects participated in a baseline functional magnetic resonance imaging scan during which they performed a continuous performance task with neutral and emotional distractors. Nineteen patients with bipolar disorder were treated for eight weeks with quetiapine monotherapy and then rescanned. Regional activity in response to emotional stimuli was compared between healthy and manic subjects at baseline; and in the subjects with bipolar disorder between baseline and eight-week scans. RESULTS: At baseline, functional activity did not differ between subjects with bipolar disorder and healthy subjects in any region examined. After eight weeks of treatment, subjects with bipolar disorder showed a significant decrease in ratings on the Young Mania Rating Scale (YMRS) (p < 0.001), and increased activation in the right orbitofrontal cortex (OFC) (p = 0.002); there was a significant association between increased right OFC activity and YMRS improvement (p = 0.003). CONCLUSIONS: These findings are consistent with suggestions that mania involves a loss of emotional modulatory activity in the prefrontal cortex--restoration of the relatively greater elevation in prefrontal activity widely observed in euthymic patients is associated with clinical improvement. It is not clear, however, whether changes are related to quetiapine treatment or represent a non-specific marker of affective change.

A randomized, placebo-controlled, double-blinded trial of duloxetine in the treatment of general fatigue in patients with chronic fatigue syndrome.

OBJECTIVE: To assess the efficacy and safety of duloxetine in patients with chronic fatigue syndrome. METHODS: A 12-week, randomized, double-blind study was designed to compare duloxetine 60-120 mg/d (n = 30) with placebo (n = 30) for efficacy and safety in the treatment of patients with chronic fatigue syndrome. The primary outcome measure was the Multidimensional Fatigue Inventory general fatigue subscale (range: 4-20, with higher scores indicating greater fatigue). Secondary measures were the remaining Multidimensional Fatigue Inventory subscales, Brief Pain Inventory, Medical Outcomes Study Short Form-36, Hospital Anxiety and Depression Scale, Centers for Disease Control and Prevention Symptom Inventory, Patient Global Impression of Improvement, and Clinical Global Impression of Severity. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the measure of effect. RESULTS: The improvement in the Multidimensional Fatigue Inventory general fatigue scores for the duloxetine group was not significantly greater than for the placebo group (P = 0.23; estimated difference between groups at week 12 = -1.0 [95% CI: -2.8, 0.7]). The duloxetine group was significantly superior to the placebo group on the Multidimensional Fatigue Inventory mental fatigue score, Brief Pain Inventory average pain severity and interference scores, Short Form-36 bodily pain domain, and Clinical Global Impression of Severity score. Duloxetine was generally well tolerated. CONCLUSION: The primary efficacy measure of general fatigue did not significantly improve with duloxetine when compared with placebo. Significant improvement in secondary measures of mental fatigue, pain, and global measure of severity suggests that duloxetine may be efficacious for some chronic fatigue syndrome symptom domains, but larger controlled trials are needed to confirm these results.

Placebo cessation in binge eating disorder: effect on anthropometric, cardiovascular, and metabolic variables.

OBJECTIVE: The aim of this study was to evaluate the effects of cessation of binge eating in response to placebo treatment in binge eating disorder (BED) on anthropometric, cardiovascular, and metabolic variables. METHOD: We pooled participant-level data from 10 randomized, double-blind, placebo-controlled trials of medication for BED. We then compared patients who stopped binge eating with those who did not on changes in weight, body mass index (BMI), systolic and diastolic blood pressure, pulse, and fasting lipids and glucose. RESULT: Of 234 participants receiving placebo, 60 (26%) attained cessation from binge eating. Patients attaining cessation showed modestly decreased diastolic blood pressure compared with patients who continued to binge eat. Weight and BMI remained stable in patients who stopped binge eating, but increased somewhat in those who continued to binge eat. DISCUSSION: Patients who stopped binge eating with placebo had greater reductions in diastolic blood pressure and gained less weight than patients who continued to binge eat. Self-report of eating pathology in BED may predict physiologic variables. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.

Placebo response in binge eating disorder: a pooled analysis of 10 clinical trials from one research group.

OBJECTIVE: The aim of this study was to gain further understanding of placebo response in binge eating disorder. METHOD: We pooled participant-level data from 10 double-blind, placebo-controlled, randomized trials of medications for binge eating disorder. The primary outcomes were response (75% reduction in binge eating episodes), cessation of binge eating episodes, change in mean weekly binge eating episodes and binge eating episodes per week. RESULTS: Of 234 participants receiving placebo, 89 (38%) were responders and 59 (26%) attained cessation. Placebo-treated participants significantly reduced their binge eating. The mean (SD) binge eating episodes per week at baseline was 5.2 (3.2) and at endpoint was 2.2 (2.6). Lower baseline binge eating episode frequency and longer study participation were significantly associated with response and cessation. DISCUSSION: Less severe eating pathology at baseline was associated with higher placebo response and cessation rates. Future clinical trials may want to stipulate that participants exceed a threshold of illness severity, which may lead to better placebo and drug separation.

Prevalence and Correlates of Eating Disorder Symptoms in Adolescents with Bipolar I Disorder.

Objective: To investigate the prevalence and correlates of eating disorder symptoms in adolescents with bipolar I disorder (BP I). Methods: We retrospectively collected a DSM-IV-TR-based diagnostic assessment of 179 adolescents with BP I and evaluated clinical variables in those with and without eating disorder symptoms. For comparison, we retrospectively evaluated eating disorder symptoms in adolescents with generalized anxiety disorder (GAD). Results: Thirty-six percent of adolescents with BP I experienced lifetime eating disorder symptoms; among comorbid adolescents, 74% reported eating disorder cognitions and 40% reported symptoms related to bingeing, 25% purging, and 17% restricting. BP I adolescents with (vs. without) eating disorder symptoms had higher Children's Depression Rating Scale-Revised scores (40.5 vs. 34.5; p < 0.001; effect size = 0.59) and were more likely to be female (75% vs. 45%; p < 0.001; odds ratio = 3.8). There were no differences in Young Mania Rating Scale scores (p = 0.70); lifetime presence of attention-deficit/hyperactivity disorder (p = 0.86) and alcohol (p = 0.59) or substance (p = 0.89) abuse/dependence symptoms; age of BP I onset (p = 0.14); inpatient hospitalization status at baseline (p = 0.53); presence of lifetime inpatient hospitalization (p = 0.64) or suicide attempt (p = 0.35); seriousness of suicidality (p = 0.86); body mass index (p = 0.48); and second-generation antipsychotic (SGA; p = 0.32) or non-SGA mood stabilizer (p = 0.09) use. Eating disorder cognitions (rather than behaviors) were higher in the GAD group (58%) compared with the BP I group (27%; p = 0.004). Limitations: A retrospective study is subject to recall bias and limits our understanding of the temporal relationship between eating disorder and mood symptoms. Conclusions: Eating disorder symptoms are frequently comorbid in adolescents with BP I. The comorbidity is associated with more severe depression but does not confer a more severe illness course.

Aberrant Neurofunctional Responses During Emotional and Attentional Processing Differentiate ADHD Youth With and Without a Family History of Bipolar I Disorder.

OBJECTIVE: To compare neurofunctional responses in emotional and attentional networks of psychostimulant-free ADHD youth with and without familial risk for bipolar I disorder (BD). METHODS: ADHD youth with (high-risk, HR, n = 48) and without (low-risk, LR, n = 50) a first-degree relative with BD and healthy controls (n = 46) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional distracters. Region-of-interest analyses were performed for bilateral amygdala (AMY), ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and anterior (ACC) and posterior cingulate cortex (PCC). RESULTS: Compared with HC, HR, but not LR, exhibited predominantly left-lateralized AMY, VLPFC, DLPFC, PCC, and rostral ACC hyperactivation to emotional distractors, whereas LR exhibited right VLPFC and bilateral dorsal ACC hypoactivation to attentional targets. Regional responses correlated with emotional and attention symptoms. CONCLUSION: Aberrant neurofunctional responses during emotional and attentional processing differentiate ADHD youth with and without a family history of BD and correlate with relevant symptoms ratings.

Adherence Rates and Barriers to Second-Generation Antipsychotic Medication Use in Youth with Bipolar Spectrum Disorders Who Have Overweight/Obesity.

Objective: Youth with bipolar spectrum disorders (BSD) are frequently prescribed second-generation antipsychotics (SGAs). Nonadherence to treatment often results in increased mood symptoms and diminished quality of life. We examined SGA adherence rates and adherence barriers among youth who have overweight/obesity and are diagnosed with BSD enrolled in a multisite pragmatic clinical trial. Methods: SGA adherence and adherence barriers at baseline via patient- and caregiver report was assessed. Adherence was defined as taking ≥70% of prescribed SGA doses in the past week. The weighted Kappa statistic was used to measure child-caregiver agreement about adherence rates, barriers, and caregiver assistance. Regression analyses were used to examine associations of caregiver assistance, age, sex, race, insurance status, dosing frequency, and number of concomitant medications with adherence. Barriers to adherence were analyzed separately for youth and their caregivers, using logistic regression to assess associations between informant-reported barriers and informant-reported adherence. Results: Participants included 1485 patients and/or caregivers. At baseline, 88.6% of patients self-reported as adherent; 92.0% of caregivers reported their child was adherent. Concordance between patients and caregivers was moderate (k = 0.42). Approximately, 50% of the sample reported no adherence barriers. Frequently endorsed barriers included forgetting, side effects, being embarrassed to take medications, and preferring to do something else. Concordance between informants regarding adherence barriers was weak (k = 0.05-0.36). Patients and caregivers who did not endorse adherence barriers reported higher adherence than those who endorsed barriers. Male sex and having once daily dosing of medications were associated with lower adherence. Discussion: One-week patient- and caregiver-reported adherence was high in this sample. Half of the sample reported adherence barriers. Most commonly endorsed barriers were forgetting, side effects, being embarrassed, and preferring to do something else. Caregivers and patients have unique perspectives regarding adherence barriers. Understanding and addressing treatment barriers in clinical practice may facilitate adherence.

Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes (CYP2C19 or CYP2D6), the serotonin transporter (SLC6A4), and the serotonin receptor 2A subtype (HTR2A). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC0-24; p = 0.025), trough concentrations (Ctrough; p = 0.013), and elimination half-lives (t1/2; p < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia (p = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores (p = 0.017). Escitalopram maximum concentration, AUC0-24, CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.