Psychopharmacological Treatment Algorithms of Manic/Mixed and Depressed Episodes in Pediatric Bipolar Disorder.

Introduction: Pediatric bipolar disorder (PBD) is a severe psychiatric illness diagnosed before the age of 18, which is associated with extreme shifts in mood characterized by manic and depressive episodes. In 2005, AACAP published algorithms to guide pharmacological treatment of manic/mixed episodes associated with PBD. At that time, lithium was the only Food and Drug Administration (FDA)-approved treatment for pediatric bipolar manic/mixed episodes. The goal of this article is to review evidence that has emerged since the AACAP algorithm in 2005. Methods: Literature searches were conducted through PubMed and limited to studies published between 2005 and 2021, using keywords that focused on randomized controlled trials (RCTs) for available psychopharmacological medications. In addition, the authors conducted in-depth searches for articles providing evidence for agents included in the 2005 AACAP algorithm. Results: Since the publication of the AACAP algorithm in 2005, multiple RCTs have been conducted in PBD, leading to FDA approval of five medications (aripiprazole, asenapine, olanzapine, quetiapine, and risperidone) for the treatment of manic/mixed episodes and two medications (lurasidone and olanzapine-fluoxetine combination) for the treatment of depressed episodes. Divalproex sodium and oxcarbazepine were studied in pediatric RCTs and failed to separate from placebo. Conclusions: We offer an update to the 2005 AACAP algorithms for the treatment of pediatric bipolar mixed/manic episodes and added an evidence-based algorithm for the treatment of depression in PBD. In addition to treatment algorithms, we review current evidence for efficacy of agents proposed in the AACAP algorithm and provide tables summarizing medication side effects and efficacy.

Altered striatal intrinsic functional connectivity in pediatric anxiety.

Anxiety disorders are among the most common psychiatric disorders of adolescence. Behavioral and task-based imaging studies implicate altered reward system function, including striatal dysfunction, in adolescent anxiety. However, no study has yet examined alterations of the striatal intrinsic functional connectivity in adolescent anxiety disorders. The current study examines striatal intrinsic functional connectivity (iFC), using six bilateral striatal seeds, among 35 adolescents with anxiety disorders and 36 healthy comparisons. Anxiety is associated with abnormally low iFC within the striatum (e.g., between nucleus accumbens and caudate nucleus), and between the striatum and prefrontal regions, including subgenual anterior cingulate cortex, posterior insula and supplementary motor area. The current findings extend prior behavioral and task-based imaging research, and provide novel data implicating decreased striatal iFC in adolescent anxiety. Alterations of striatal neurocircuitry identified in this study may contribute to the perturbations in the processing of motivational, emotional, interoceptive, and motor information seen in pediatric anxiety disorders. This pattern of the striatal iFC perturbations can guide future research on specific mechanisms underlying anxiety.

Anxiety and Gender Influence Reward-Related Processes in Children and Adolescents.

OBJECTIVE: This study examined the effects of pediatric anxiety and its interaction with gender on reward processes. Based on the purported greater sensitivity to risk in females than males and the propensity for risk aversion in anxiety, clinical anxiety and female gender were hypothesized to act synergistically in reducing reward sensitivity and increasing risk aversion in a pediatric population. METHODS: This hypothesis was tested in two separate experiments using two independent samples. Both experiments compared clinically anxious with typically developing (TD) youth, 8-18 years. Experiment 1 used a decision-making task, the Wheel of Fortune task (WOF), to examine risk taking as a function of varying levels of risk and reward in 36 anxious and 61 TD youths. Experiment 2 used an incentive delay task, the Piñata task, to examine sensitivity to reward and motivation to work for a reward in 38 anxious and 30 TD youth. Percent bet, reaction time, and accuracy were analyzed as a function of gender and diagnostic group. RESULTS: As hypothesized, anxiety was associated with reduced risk taking and sensitivity to reward. However, contrary to prediction, this effect was seen in males and not in females. These findings are consistent across both experiments. In experiment 1 (WOF), betting rate (i.e., risk taking) was significantly lower in anxious than in TD males (F[1;53] = 7.07, p = 0.01), whereas anxious females did not differ from TD females (F[1,42] = 1.2, p = 0.28). In experiment 2 (Piñata), anxiety impaired performance accuracy in males (F[1;36] = 8.39; p < 0.01) but not females (F[1;28] = 0.6; p = 0.445). CONCLUSIONS: Anxiety affected reward function differently in males and females. Contrary to hypothesis, anxious females behaved similarly to TD females on both tasks. However, anxious males were significantly more risk averse and less accurate than TD males. These findings suggest that therapeutic interventions for anxiety, which use manipulations of reward processes, should consider gender for optimal outcome.

STRADalpha regulates LKB1 localization by blocking access to importin-alpha, and by association with Crm1 and exportin-7.

LKB1, a serine/threonine kinase, regulates cell polarity, metabolism, and cell growth. The activity and cellular distribution of LKB1 are determined by cofactors, STRADalpha and MO25. STRADalpha induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRADalpha/LKB1 interaction. We investigated the mechanism of nucleocytoplasmic transport of LKB1 in response to its cofactors. Although LKB1 is imported into the nucleus by importin-alpha/beta, STRADalpha and MO25 passively diffuse between the nucleus and the cytoplasm. STRADalpha induces nucleocytoplasmic shuttling of LKB1. STRADalpha facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRADalpha inhibits import of LKB1 by competing with importin-alpha for binding to LKB1. MO25 stabilizes the LKB1-STRADalpha complex but it does not facilitate its nucleocytoplasmic shuttling. Strikingly, the STRADbeta, isoform which differs from STRADalpha in the N- and C-terminal domains that are responsible for interaction with export receptors, does not efficiently relocalize LKB1 from the nucleus to the cytoplasm. These results identify a multifactored mechanism to control LKB1 localization, and they suggest that the STRADbeta-LKB1 complex might possess unique functions in the nucleus.

Protons enhance the gating kinetics of the alpha3/beta4 neuronal nicotinic acetylcholine receptor by increasing its apparent affinity to agonists.

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the nervous system. Although there is a vast literature on the molecular, structural and pharmacological properties of neuronal nAChR, little is known of their pH regulation. Here we report that rapid acidification (pH 6.0) enhances the current through the alpha3/beta4 recombinant nAChRs expressed stably in human embryonic kidney 293 cells and accelerates its activation kinetics without altering selectivity. Acidification also strongly accelerates the decay kinetics ("desensitization") of cytisine- and nicotine-evoked currents (pK(a) approximately 6.1), but the effect is somewhat smaller with acetylcholine and carbachol (undetermined pK(a) values), suggesting that protonation of the agonist contributes to the relaxation of the current. Transient increases of [H(+)](o) from pH 7.4 to 6.0, during the time course of decay of the current, enhances the current and accelerates its decay kinetics in a manner similar to reactivation of current by higher concentrations of agonists. We suggest that protons interact with multiple extracellular sites on alpha3/beta4 nAChRs, decreasing the effective EC(50) values of the agonist and accelerating gating kinetics, in part by promoting agonist-induced block. We speculate that corelease of protons with ACh from the secretory vesicles may induce rapid and reversible conformational changes in the slowly "desensitizing" alpha3/beta4 nAChRs, leading to accelerated signaling.