Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons.

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.

Anxiety symptom trajectories from treatment to 5- to 12-year follow-up across childhood and adolescence.

OBJECTIVE: The current study examined trajectories of anxiety during (a) acute treatment and (b) extended follow-up to better characterize the long-term symptom trajectories of youth who received evidence-based intervention for anxiety disorders using a person-centered approach. METHOD: Participants were 319 youth (age 7-17 years at enrollment), who participated in a multicenter randomized controlled trial for the treatment of pediatric anxiety disorders, Child/Adolescent Anxiety Multimodal Study, and a 4-year naturalistic follow-up, Child/Adolescent Anxiety Multimodal Extended Long-term Study, an average of 6.5 years later. Using growth mixture modeling, the study identified distinct trajectories of anxiety across acute treatment (Weeks 0-12), posttreatment (Weeks 12-36), and the 4-year-long follow-up, and identified baseline predictors of these trajectories. RESULTS: Three nonlinear anxiety trajectories emerged: "short-term responders" who showed rapid treatment response but had higher levels of anxiety during the extended follow-up; "durable responders" who sustained treatment gains; and "delayed remitters" who did not show an initial response to treatment, but showed low levels of anxiety during the maintenance and extended follow-up periods. Worse anxiety severity and better family functioning at baseline predicted membership in the delayed remitters group. Caregiver strain differentiated short-term responders from durable responders. CONCLUSIONS: Findings suggest that initial response to treatment does not guarantee sustained treatment gains over time for some youth. Future follow-up studies that track treated youth across key developmental transitions and in the context of changing social environments are needed to inform best practices for the long-term management of anxiety.

Caregiver behaviors and childhood maladaptive grief: Initial validation of the Grief Facilitation Inventory.

The Grief Facilitation Inventory (GFI) is a newly-developed measure of caregiver behaviors theorized to facilitate or hinder children's adaptive grief reactions. We examine its factor structure, reliability, and validity. An exploratory factor analysis identified four factors: Ongoing Connection, Existential Continuity/Support, Caregiver Grief Expression, and Grief Inhibition/Avoidance. Both child- and caregiver-report versions had adequate-to-good internal consistency. The child-report GFI showed evidence of criterion-referenced validity via significant correlations with measures of child maladaptive grief and other psychological symptoms. Results provide preliminary evidence of the reliability, validity, and clinical utility of the GFI as a measure of caregiver grief-facilitation behaviors.

The Appetite Suppressant D-norpseudoephedrine (Cathine) Acts via D1/D2-Like Dopamine Receptors in the Nucleus Accumbens Shell.

D-norpseudoephedrine (NPE), also known as cathine, is found naturally in the shrub Catha edulis "Khat." NPE has been widely used as an appetite suppressant for the treatment of obesity. Although it is known that NPE acts on α1-adrenergic receptors, there is little information about the role of dopamine receptors on NPE's induced anorectic and weight loss effects. Equally untouched is the question of how NPE modulates neuronal activity in the nucleus accumbens shell (NAcSh), a brain reward center, and a pharmacological target for many appetite suppressants. To do this, in rats, we characterized the pharmacological effects induced by NPE on weight loss, food intake, and locomotion. We also determined the involvement of dopamine D1- and D2-like receptors using systemic and intra-NAcSh antagonists, and finally, we recorded single-unit activity in the NAcSh in freely moving rats. We found that NPE decreased 24-h food intake, induced weight loss, and as side effects increased locomotor activity and wakefulness. Also, intraperitoneal and intra-NAcSh administration of D1 and D2 dopamine antagonists partially reversed NPE's induced weight loss and food intake suppression. Furthermore, the D1 antagonist, SCH-23390, eliminated NPE-induced locomotion, whereas the D2 antagonist, raclopride, only delayed its onset. We also found that NPE evoked a net activation imbalance in NAcSh that propelled the population activity trajectories into a dynamic pharmacological brain state, which correlated with the onset of NPE-induced wakefulness. Together, our data demonstrate that NPE modulates NAcSh spiking activity and that both dopamine D1 and D2 receptors are necessary for NPE's induced food intake suppression and weight loss.

Validation of the UCLA PTSD Reaction Index for DSM-5: A Developmentally Informed Assessment Tool for Youth.

OBJECTIVE: To describe the test construction procedure and evaluate the internal consistency, criterion-referenced validity, and diagnostic accuracy of the Child/Adolescent Self-Report Version of the UCLA PTSD Reaction Index for DSM-5 (RI-5) across 2 independent samples. METHOD: Study 1 examined the clarity, developmental appropriateness, acceptability of individual RI-5 items, and internal consistency and criterion-referenced validity of the full test. The study 1 sample included 486 youth recruited from 2 major US cities who completed the RI-5 and a measure of depression. Study 2 evaluated the reliability and diagnostic accuracy of the RI-5 in 41 treatment-seeking youth who completed the RI-5 and a "gold standard" structured diagnostic interview, the Clinician-Administered PTSD Scale for DSM-5-Child/Adolescent Version. RESULTS: RI-5 total scale scores showed excellent internal consistency in the 2 samples. Study 1 provided evidence of criterion-referenced validity, in that total scale scores correlated positively with depressive symptoms. Study 2 provided evidence of diagnostic accuracy (including discriminant-groups validity). RI-5 total scores discriminated youth with from youth without PTSD as benchmarked against the structured diagnostic interview. Further, receiver operating characteristic analyses using a total score of 35 provided excellent diagnostic classification accuracy (area under the curve 0.94). CONCLUSION: The developmental appropriateness and diagnostic accuracy of the RI-5 support its utility for clinical assessment, case conceptualization, and treatment planning in different child-serving systems, including schools, juvenile justice, child welfare, and mental health.

The UCLA PTSD Reaction Index for DSM-5 Brief Form: A Screening Tool for Trauma-Exposed Youths.

OBJECTIVE: Children and adolescents who experience potentially traumatic events are at risk for developing posttraumatic stress disorder (PTSD). Although psychometrically sound measures are now available to assess these youths, brief tools are currently needed for screening purposes. Two studies were conducted to develop and validate the UCLA PTSD Reaction Index for DSM-5-Brief Form (RI-5-BF). METHOD: Study 1 used item response theory models to derive the RI-5-BF from the UCLA PTSD Reaction Index for DSM-5 and assess its internal consistency using a sample of 486 trauma-exposed youths (mean age = 13.32 years, SD = 2.90) recruited through a practice research network. Study 2 used receiver operating characteristic analyses and diagnostic efficiency statistics to assess the discriminant-groups validity and clinical utility of the RI-5-BF in identifying children at different levels of PTSD risk using a sample of 41 treatment-seeking youths (mean age = 12.44 years, SD = 2.99). RESULTS: In study 1, item response theory models identified the 11 most informative items across their respective subscales. The RI-5-BF exhibited excellent internal consistency in both studies (α > .93). In study 2, receiver operating characteristic analyses indicated that an RI-5-BF score of 21 maximized sensitivity and specificity. Moreover, diagnostic likelihood ratios across multiple levels of scores provided support for the measure's clinical utility in identifying different levels of PTSD risk. CONCLUSION: These findings provide support for both the psychometric properties of the RI-5-BF as a brief screening measure for PTSD in children and adolescents and its utility for identifying youths meriting further assessment and consideration for treatment.

Neuropsychological Predictors of ODD Symptom Dimensions in Young Children.

Oppositional defiant disorder (ODD) is a commonly diagnosed childhood behavior disorder, yet knowledge of relations between ODD and early neuropsychological functions, particularly independent of attention deficit/hyperactivity disorder (ADHD), is still limited. In addition, studies have not examined neuropsy chological functioning as it relates to the different ODD symptom dimensions. Structural equation modeling was used to investigate how preschool neuropsychological functioning predicted negative affect, oppositional behavior, and antagonistic behavior symptom dimensions of ODD in 224 six-year-old children, oversampled for early behavior problems. Working memory, inhibition, and sustained attention predicted negative affect symptoms of ODD, controlling for ADHD, whereas delay aversion uniquely predicted oppositional behavior, controlling for ADHD. Delay aversion also marginally predicted antagonistic behavior, controlling for ADHD. Results demonstrate that different ODD symptom dimensions may be differentially predicted by different neuropsychological functions. The findings further underscore the importance of future research on ODD to take into account the possible heterogeneity of both symptoms and underlying neuropsychological functioning.

Reciprocal Relations Between Parenting Behaviors and Conduct Disorder Symptoms in Preschool Children.

Reciprocal relations between children's conduct disorder (CD) symptoms and parenting behaviors were examined across the preschool years. Participants were 199 children (M = 44.26 months, SD = 3.37; 92 girls) and their 199 mothers and 158 fathers. CD symptoms were assessed via structured interviews; parenting was assessed via observational and self-report measures. Fixed effects models were used to assess within-individual changes and traditional cross-lagged models were used to assess between-individual changes; comparisons by sex were also carried out. Increases in maternal overreactivity predicted increases in CD symptoms. During the later preschool years, decreases in maternal warmth predicted increases in CD symptoms and increases in CD symptoms predicted increases in paternal overreactivity. Reciprocal effects were found between girls' CD symptoms and paternal negative affect. Findings suggest maternal and paternal influence on the development of CD symptoms and suggest that CD symptoms influence fathers' parenting during the preschool years.

A Longitudinal Study of Fathers' and Young Children's Depressive Symptoms.

Considerable research has examined the effects of maternal depression on children, but few studies have focused on the relation between paternal and child depressive symptoms, particularly during early childhood. Even fewer studies have been longitudinal, leaving open questions about how paternal and child depression covary over time. The present study sought to address this gap by examining the relation between fathers' and children's depressive symptoms over a 3-year period. Participants were 153 preschool children with behavior problems and their parents. Three longitudinal analytic approaches were used to examine how father and child depression change together and predict one another over time. Additional analyses examined whether externalizing problems or maternal depression might account for the associations between fathers' and children's depressive symptoms. Changes in paternal depression significantly predicted changes in father-reported and mother-reported child depressive symptoms. These effects were evident both in year-to-year fluctuations and in linear trajectories across the 3-year period. Cross-lagged analyses suggested that these relations may have been driven by father-effects; paternal depression at one time point predicted child depression at the next time point, but child depression did not significantly predict later paternal depression. We found little evidence that externalizing problems or maternal depression accounted for the relations between fathers' and children's depressive symptoms. Results provide convergent evidence that fathers' depression may play an important role in the development of depressive symptoms in young children and underscore the importance of including fathers in studies of depression in families.

Assessing Attention and Disruptive Behavior Symptoms in Preschool-Age Children: The Utility of the Diagnostic Interview Schedule for Children.

Data are presented from two samples of preschool children to evaluate the reliability, concurrent validity, and predictive validity of the ADHD, ODD, and CD sections of the Diagnostic Interview Schedule for Children, Fourth Edition (DISC-IV). Information was obtained from a community sample of 128 children (Mage = 53.16 months; 63 girls) and from a sample of 72 externalizing children (Mage = 45.23 months; 31 girls) plus 25 control children (Mage = 44.51 months; 8 girls). In both studies, the DISC-IV was administered to parents along with parent and teacher behavior rating scales, and teacher rating scales were obtained again later to evaluate the predictive validity of the DISC-IV (after approximately 6 months in Study 1, and 3 years in Study 2). The ADHD and ODD sections exhibited acceptable internal consistency in both studies, and showed concurrent validity with parent behavior rating scales. In both studies, the ADHD section was also concurrent with teacher reports. In Study 2, the ADHD, ODD, and CD sections distinguished externalizing children from controls. In both studies, the ADHD section predicted future teacher ratings beyond initial teacher ratings, and beyond initial parent rating scales; the ODD section similarly predicted later teacher ratings in Study 1. Findings provide strong support for the utility of the ADHD section for preschool children and moderate support for the ODD and CD sections.

The predictive utility of conduct disorder symptoms in preschool children: a 3-year follow-up study.

Conduct disorder (CD) symptoms often emerge during the preschool years, but it is not clear whether they predict later symptoms. The present study examined whether age 3 CD symptoms predict age 6 CD symptoms beyond oppositional defiant disorder (ODD) and attention-deficit/hyperactivity disorder-hyperactive/impulsive (ADHD-HI) symptoms. Participants were 216 preschool children (M Age  = 44.19 months), including an externalizing sample (n = 161) and a comparison group (n = 55). Parents were administered a diagnostic interview when children were 3 years old and again 3 years later. The externalizing sample exhibited more CD symptoms than the comparison sample. In the externalizing sample, initial CD symptoms predicted later CD symptoms above and beyond ODD and ADHD HI symptoms; this relation was stronger for boys than for girls. Stealing, property destruction, and fighting independently predicted later CD symptoms. CD symptoms also predicted subsequent ADHD HI symptoms and predicted ODD symptoms at a level that approached significance. Results support the predictive validity of CD symptoms in preschool.