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We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

Several studies suggest that a two-factor model positing internalizing and externalizing factors explains the interrelationships among psychiatric disorders. However, it is unclear whether the covariation between internalizing and externalizing disorders is due to common genetic or environmental influences. We examined whether a model positing two latent factors, internalizing and externalizing, explained the interrelationships among six psychiatric disorders (major depressive disorder, generalized anxiety disorder, separation anxiety disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder) in adolescents, and whether there are common genetic and environmental influences on internalizing and externalizing latent factors. Multivariate behavior genetic analyses of data from 1162 twin pairs and 426 siblings ascertained from the general population via the Colorado Center for Antisocial Drug Dependence (CADD) were conducted. We found support for a model positing two latent factors (internalizing and externalizing). These factors were moderately heritable and influenced by significant common genetic and nonshared environmental influences. These findings suggest that co-occurrence of internalizing and externalizing psychopathology in adolescents results from both genetic and environmental influences.

There is significant covariation between internalizing and externalizing behavior, although there is also evidence that internalizing behavior is a protective factor against externalizing behavior. Several researchers have posited that the examination of the relationship between temperament or personality and behavior problems may help explain these seemingly contradictory results. Specifically, negative emotionality or neuroticism has been cited as a temperament characteristic that internalizing and externalizing behavior share in common, whereas behavioral inhibition may be related only to internalizing behavior. We examined the degree to which the covariation between internalizing and externalizing behavior assessed from age 4 to 12 years can be explained by temperament characteristics assessed from age 14 to 36 months. Additionally, we assessed the extent to which this relationship is due to genetic or environmental factors, analyzing data from 225 monozygotic and 185 dizygotic twin pairs assessed by the Colorado Longitudinal Twin Study. In males, a portion of the covariation between internalizing and externalizing behavior was explained by shared environmental influences in common with emotionality and shared environmental influences in common with shyness. In females, most of the covariation between internalizing and externalizing behavior was explained by shared environmental influences in common with emotionality. A possible limitation of this study is that the covariation between temperament and behavior problems may be due to shared measurement variance, as parent ratings were used to assess both temperament and behavior problems. [ABSTRACT FROM AUTHOR]

The article offers information on medical technology-based interventions for treatment of young people with bipolar disorder. It is evident that digital psychosocial interventions combining psychoeducation with instructional modules focused on basic cognitive and behavioral skills, obstacles to the successful design and implementation of digital interventions for adolescents and potential impact of technology to relieve the suffering of adolescents with mood disorders.