Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test's norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Depression risk factors and affect dynamics: An experience sampling study.

Affect dynamics reflect individual differences in how emotional information is processed, and may provide insights into how depressive episodes develop. To extend prior studies that examined affect dynamics in currently depressed individuals, the present study tested in 68 non-depressed young adults whether three well-established risk factors for major depressive disorder (MDD) - (a) past episodes of MDD, (b) family history of MDD, and (c) reduced neurophysiological responses to reward - predicted mean levels, instability, or inertia (i.e., inflexibility) of positive affect (PA) and/or negative affect (NA). Momentary PA and NA were assessed up to 6 times per day for 14 days (mean number of surveys completed = 45.89). MDD history and family history of MDD were assessed via semi-structured interview, and neurophysiological responses to reward were indexed using the Reward Positivity, an event-related potential related to depression. After adjusting for current depressive symptoms, results indicated that (a) past episodes of MDD predicted higher mean levels of NA, (b) family history of MDD predicted greater PA inertia, and (c) blunted reactivity to reward predicted greater NA inertia. Collectively, these results suggest that elevated mean levels of NA and inflexibility of PA and NA may be potential mechanisms that confer risk for depression.

Unique longitudinal relationships between symptoms of psychopathology in youth: A cross-lagged panel network analysis in the ABCD study.

BACKGROUND: The network theory suggests that psychopathology may reflect causal relationships between individual symptoms. Several studies have examined cross-sectional relationships between individual symptoms in youth. However, these studies cannot address the directionality of the temporal relationships hypothesized by the network theory. Therefore, we estimated the longitudinal relationships between individual internalizing, externalizing, and attention symptoms in youth. METHODS: Data from 4,093 youth participants in the Adolescent Brain Cognitive Development (ABCD) study were used. Symptoms were assessed using the Brief Problem Monitor, which was administered at three time points spaced six months apart. Unique longitudinal relationships between symptoms at T1 and T2 were estimated using cross-lagged panel network modeling. Network replicability was assessed by comparing this network to an identically estimated replication network of symptoms at T2 predicting symptoms at T3. RESULTS: After controlling for all other symptoms and demographic covariates, depressed mood, inattention, and worry at T1 were most predictive of other symptoms at T2. In contrast, threats of violence and destructiveness at T2 were most prospectively predicted by other symptoms at T1. The reciprocal associations between depressed mood and worthlessness were among the strongest bivariate relationships in the network. Comparisons between the original network and the replication network (correlation between edge lists = .61; individual edge replicability = 64%-84%) suggested moderate replicability. CONCLUSIONS: Although causal inferences are precluded by the observational design and methodological considerations, these findings demonstrate the directionality of relationships between individual symptoms in youth and highlight depressed mood, inattention, and worry as potential influencers of other symptoms.

Test-retest & familial concordance of MDD symptoms.

Psychopathology research has increasingly sought to study the etiology and treatment of individual symptoms, rather than categorical diagnoses. However, it is unclear whether commonly used measures have adequate psychometric properties for assessing individual symptoms. This study examined the test-retest reliability and familial concordance (an indicator of validity) of the symptoms of Major Depressive Disorder (MDD), a disorder consisting of nine core symptoms, most of which are aggregated (e.g., symptom 7 of the DSM criteria for MDD is worthlessness or guilt). Lifetime MDD symptoms were measured in 504 young adults (237 sibling pairs) using the Structured Clinical Interview for DSM-5 (SCID). Fifty-one people completed a second SCID within three weeks of their first SCID. Results indicated that aggregated and unaggregated symptoms demonstrated moderate to substantial test-retest reliability and generally significant, but slight to fair familial concordance (with the highest familial concordance being for markedly diminished interest or pleasure and its unaggregated components - decreased interest and decreased pleasure). Given the increasing focus on the differential validity of individual MDD symptoms, the present study suggests that interview-based assessments of depression can assess most individual symptoms with adequate levels of reliability and validity.

A Double-Blind Randomized Placebo-Controlled Trial of Citalopram Adjunctive to Stimulant Medication in Youth With Chronic Severe Irritability.

OBJECTIVE: Despite the clinical importance of chronic and severe irritability, there is a paucity of controlled trials for its pharmacological treatment. Here, we examine the effects of adding citalopram (CTP) to methylphenidate (MPH) in the treatment of chronic severe irritability in youth using a double-blind randomized placebo-controlled design. METHOD: After a lead-in phase of open treatment with stimulant, 53 youth meeting criteria for severe mood dysregulation (SMD) were randomly assigned to receive CTP or placebo (PBO) for 8 weeks. A total of 49 participants, 48 of them (98%) meeting disruptive mood dysregulation disorder (DMDD) criteria, were included in the intent-to-treat analysis. The primary outcome measure was the proportion of response based on improvements of irritability at the week 8 of the trial. RESULTS: At the end of the trial, a significantly higher proportion of response was seen in those participants randomly assigned to CTP+MPH compared to PBO+MPH (35% CTP+MPH versus 6% PBO+MPH; odds ratio = 11.70, 95% CI = 2.00-68.16, p = 0.006). However, there were no differences in functional impairment between groups at the end of the trial. No differences were found in any adverse effect between treatment groups, and no trial participant exhibited hypomanic or manic symptoms. CONCLUSION: Adjunctive CTP might be efficacious in the treatment of chronic severe irritability in youth resistant to stimulant treatment alone. CLINICAL TRIAL REGISTRATION INFORMATION: A Controlled Trial of Serotonin Reuptake Inhibitors Added to Stimulant Medication in Youth With Severe Mood Dysregulation; https://clinicaltrials.gov; NCT00794040.

Deficits in emotion recognition are associated with depressive symptoms in youth with disruptive mood dysregulation disorder.

BACKGROUND: Although severe irritability is a predictor of future depression according to recent meta-analytic evidence, other mechanisms for this developmental transition remain unclear. In this study, we test whether deficits in emotion recognition may partially explain this specific association in youth with severe irritability, defined as disruptive mood dysregulation disorder (DMDD). METHODS: Participants aged 8-20 years (M = 13.3, SD = 2.8) included youth with DMDD, split by low depressive (DMDD/LD; n = 52) and high depressive (DMDD/HD; n = 25) symptoms, and healthy controls (HC; n = 39). A standardized computer task assessed emotion recognition of faces and voices of adults and children expressing happiness, fear, sadness, and anger. A Group (3) × Emotion (4) × Actor (2) × Modality (2) repeated measures analysis of covariance examined the number of errors and misidentification of emotions. Linear regression was then used to assess whether deficits in emotion recognition were predictive of depressive symptoms at a 1 year follow-up. RESULTS: DMDD/HD youth were more likely to interpret happy stimuli as angry and fearful compared to DMDD/LD (happy as angry: p = 0.018; happy as fearful: p = 0.008) and HC (happy as angry: p = 0.014; happy as fearful: p = 0.024). In youth with DMDD, the misidentification of happy stimuli as fearful was associated with higher depressive symptoms at follow-up (ß = 0.43, p = 0.017), independent of baseline depressive and irritability symptoms. CONCLUSIONS: Deficits in emotion recognition are associated, cross-sectionally and longitudinally, with depressive symptoms in youth with severe irritability. Future studies should examine the neural correlates that contribute to these associations.

Reward Processing in Depression: A Conceptual and Meta-Analytic Review Across fMRI and EEG Studies.

OBJECTIVE: A role for aberrant reward processing in the pathogenesis of depression has long been proposed. However, no review has yet examined its role in depression by integrating conceptual and quantitative findings across functional MRI (fMRI) and EEG methodologies. The authors quantified these effects, with an emphasis on development. METHOD: A total of 38 fMRI and 12 EEG studies were entered into fMRI and EEG meta-analyses. fMRI studies primarily examined reward anticipation and reward feedback. These were analyzed using the activation likelihood estimation method. EEG studies involved mainly the feedback-related negativity (FRN) event-related potential, and these studies were analyzed using random-effects meta-analysis of the association between FRN and depression. RESULTS: Analysis of fMRI studies revealed significantly reduced striatal activation in depressed compared with healthy individuals during reward feedback. When region-of-interest analyses were included, reduced activation was also observed in reward anticipation, an effect that was stronger in individuals under age 18. FRN was also significantly reduced in depression, with pronounced effects in individuals under age 18. In longitudinal studies, reduced striatal activation in fMRI and blunted FRN in EEG were found to precede the onset of depression in adolescents. CONCLUSIONS: Taken together, the findings show consistent neural aberrations during reward processing in depression, namely, reduced striatal signal during feedback and blunted FRN. These aberrations may underlie the pathogenesis of depression and have important implications for development of new treatments.