Inhibition Predicts the Course of Depression and Anxiety Symptoms Among Adolescents: The Moderating Role of Familial Risk.

ABSTRACT: Numerous theoretical models suggest that inhibition difficulties-the inability to moderate automatic responses-contribute to the onset and/or maintenance of internalizing symptoms. Inhibition deficits and internalizing disorders run in families and share overlapping genetic risk factors, suggesting that inhibition deficits may be particularly prognostic of internalizing symptoms in those with high familial risk. This study tested this hypothesis in a longitudinal sample during the transition from adolescence to early adulthood. As hypothesized, prospective associations between inhibition and anxiety and depressive symptoms 8 years later were moderated by familial risk for depression. Specifically, poorer inhibition prospectively predicted greater anxiety and depressive symptoms in those at high (but not low) familial risk for major depressive disorder. These findings provide preliminary support for impaired inhibition as an indicator of risk for later internalizing symptoms in those at high familial risk.

Proof of Concept of the Contribution of the Interaction between Trait-like and State-like Effects in Identifying Individual-Specific Mechanisms of Action in Biological Psychiatry.

Background: Identifying individual-specific mechanisms of action may facilitate progress toward precision medicine. Most studies seeking to identify mechanisms of action collapse together two distinct components: pre-treatment trait-like characteristics differentiating between individuals and state-like characteristics changing within each individual over the course of treatment. We suggest a conceptual framework highlighting the importance of studying interactions between trait-like and state-like components in the development of moderated mediation models that can guide personalized targeted interventions. Methods: To facilitate implementation of this framework, two empirical demonstrations are presented from a recent clinical trial and neuroimaging study. The first examines limbic reactivity during an emotional face task; the second concerns striatal activation in a monetary reward task. Results: In both tasks, considering the interaction between trait-like and state-like components predicted treatment outcome more robustly than did the trait-like or state-like components examined individually. Conclusions: These findings suggest that the extent to which state-like modulation of neural activations can serve as a potential treatment target depends on the pre-treatment, trait-like levels of activation in these regions. Thus, the interaction between trait-like and state-like components can serve as a promising path to the development of personalized interventions within a precision medicine framework in which mechanisms of action are individual-specific.

Enduring problems in the offspring of depressed parents followed up to 38 years.

BACKGROUND: while the increased risk of major depressive disorder (MDD) in offspring of depressed parents is one of the best-replicated findings in psychiatry, their long-term outcomes are less well known. The clinical outcomes of biological offspring of depressed (high-risk) and not depressed (low-risk) parents who have been directly interviewed over the years are presented. METHODS: a longitudinal retrospective cohort study began in 1982, and 276 biological offspring of moderately-to-severely depressed or non-depressed parents from the same community were followed up to 38 years. Rates of psychiatric disorders for offspring were collected by clinically trained interviewers. Final diagnoses were made by M.D. or Ph.D. clinicians. Mortality and cause of death were obtained from relatives and registries. FINDINGS: high- compared to low-risk offspring continue to have about a three-fold increased risk of MDD, increased rates of anxiety disorder, substance dependence, and poorer functioning over the life course. Adolescence and early adulthood remain prime age of first onsets. Within high-risk group only, the death rate due to unnatural causes, suicides and overdose was 4·97/100 in the offspring and 5·36/100 in their parents. This subsample of White, lower-educated, often unemployed persons, who died by unnatural causes are similar demographically to those described as having a recent increase in 'deaths of despair'. INTERPRETATION: family history of MDD continues to be a powerful predictor of clinical course and mortality and should be probed in clinical visits, especially in youth when depression usually first appears.

Association of Multigenerational Family History of Depression With Lifetime Depressive and Other Psychiatric Disorders in Children: Results from the Adolescent Brain Cognitive Development (ABCD) Study.

Importance: Three-generation family studies of depression have established added risk of psychopathology for offspring with 2 previous generations affected with depression compared with 1 or none. Because of their rigorous methodology, there are few of these studies, and existing studies are limited by sample sizes. Consequently, the 3-generation family risk paradigm established in family studies can be a critical neuropsychiatric tool if similar transmission patterns are reliably demonstrated with the family history method. Objective: To examine the association of multigenerational family history of depression with lifetime depressive disorders and other psychopathology in children. Design, Setting, and Participants: In this analysis of the Adolescent Brain Cognitive Development (ABCD) study data, retrospective, cross-sectional reports on psychiatric functioning among 11 200 children (generation 3 [G3]) and parent reports on parents' (G2) and grandparents' (G1) depression histories were analyzed. The ABCD study sampling weights were used for generalized estimating equation models and descriptive analyses. Data were collected from September 2016 to November 2018, and data were analyzed from July to November 2020. Main Outcomes and Measures: Four risk categories were created, reflecting how many prior generations had history of depression: (1) neither G1 nor G2 (G1-/G2-), (2) only G1 (G1+/G2-), (3) only G2 (G1-/G2+), and (4) both G1 and G2 (G1+/G2+). Child lifetime prevalence and relative risks of psychiatric disorders were based on child and caregiver reports and grouped according to familial risk category derived from G1 and G2 depression history. Results: Among 11 200 included children, 5355 (47.8%) were female, and the mean (SD) age was 9.9 (0.6) years. By parent reports, the weighted prevalence of depressive disorder among children was 3.8% (95% CI, 3.2-4.3) for G1-/G2- children, 5.5% (95% CI, 4.3-7.1) for G1+/G2- children, 10.4% (95% CI, 8.6-12.6) for G1-/G2+ children, and 13.3% (95% CI, 11.6-15.2) for G1+/G2+ children (Cochran-Armitage trend = 243.77; P < .001). The weighted suicidal behavior prevalence among children was 5.0% (95% CI, 4.5-5.6) for G1-/G2- children, 7.2% (95% CI, 5.8-8.9) for G1+/G2- children, 12.1% (95% CI, 10.1-14.4) for G1-/G2+ children, and 15.0% (95% CI, 13.2-17.0) for G1+/G2+ children (Cochran-Armitage trend = 188.66; P < .001). By child reports, the weighted prevalence of depressive disorder was 4.8% (95% CI, 4.3-5.5) for G1-/G2- children, 4.3% (95% CI, 3.2-5.7) for G1+/G2- children, 6.3% (95% CI, 4.9-8.1) for G1-/G2+ children, and 7.0% (95% CI, 5.8-8.5) for G1+/G2+ children (Cochran-Armitage trend = 9.01; P = .002), and the weighted prevalence of suicidal behaviors was 7.4% (95% CI, 6.7-8.2) for G1-/G2- children, 7.0% (95% CI, 5.6-8.6) for G1+/G2- children, 9.8% (95% CI, 8.1-12.0) for G1-/G2+ children, and 13.8% (95% CI, 12.1-15.8) for G1+/G2+ children (Cochran-Armitage trend = 46.69; P < .001). Similar patterns were observed for other disorders for both parent and child reports and across sex, socioeconomic status, and race/ethnicity. Conclusions and Relevance: In this study, having multiple prior affected generations was associated with increased risk of childhood psychopathology. Furthermore, these findings were detectable even at prepubertal ages and existed in diverse racial/ethnic and socioeconomic groups. Clinically, they underscore the need for screening for family history in pediatric settings and highlight implications for biological research with homogenous subgroups using magnetic resonance imaging or genetic analyses.

Dissociating disorders of depression, anxiety, and their comorbidity with measures of emotional processing: A joint analysis of visual brain potentials and auditory perceptual asymmetries.

In a multigenerational study of families at risk for depression, individuals with a lifetime history of depression had: 1) abnormal perceptual asymmetry (PA; smaller left ear/right hemisphere [RH] advantage) in a dichotic emotion recognition task, and 2) reduced RH late positive potential (P3RH) during an emotional hemifield task. We used standardized difference scores for processing auditory (PA sad-neutral) and visual (P3RH negative-neutral) stimuli for 112 participants (52 men) in a logistic regression to predict history of depression, anxiety or comorbidity of both. Whereas comorbidity was separately predicted by reduced PA (OR = 0.527, p = .042) or P3RH (OR = 0.457, p = .013) alone, an interaction between PA and P3RH (OR = 2.499, p = .011) predicted depressive disorder. Follow-up analyses revealed increased probability of depression at low (lack of emotional differentiation) and high (heightened reactivity to negative stimuli) levels of both predictors. Findings suggest that reduced or heightened right-lateralized emotional responsivity to negative stimuli may be uniquely associated with depression.

ADHD Symptoms in a Non-Referred Low Birthweight/Preterm Cohort: Longitudinal Profiles, Outcomes, and Associated Features.

OBJECTIVE: This study's objective is to differentiate possible ADHD syndromes on the basis of symptom trajectories, prognosis, and associated clinical features in a high-risk cohort. METHOD: Latent class analysis of inattentive (IA) and hyperactive-impulsive (HI) symptoms in 387 non-disabled members of a regional low birthweight/preterm birth cohort who were evaluated for ADHD at 6, 9, and 16 years. Adolescent functional outcomes and other clinical features were examined across the classes. RESULTS: Three latent classes were identified: unaffected (modest IA and HI symptom prevalences at six, remitting by nine), school age limited (relatively high IA and HI symptom prevalences at six and nine, declining by 16), and persistent inattentive (high IA and HI prevalences at six and nine, with high IA levels persisting to 16). The persistent inattentive class was distinctively associated with poor functioning, motor problems, other psychiatric disorders, and social difficulties as indexed by a positive screen for autism spectrum disorder at 16. CONCLUSION: These findings differentiate a potential persistent inattentive syndrome relevant to ADHD evaluation and treatment.