Faculty Bibliography

Numerous risk factors for mental disorders have been identified. However, we do not know how many disorders we could prevent and to what extent by modifying these risk factors. This study quantifies the Population Attributable Fraction (PAF) of potentially modifiable risk factors for mental disorders. We conducted a PRISMA 2020-compliant (Protocol: https://osf.io/hk2ag ) meta-umbrella systematic review (Web of Science/PubMed/Cochrane Central Register of Reviews/Ovid/PsycINFO, until 05/12/2021) of umbrella reviews reporting associations between potentially modifiable risk factors and ICD/DSM mental disorders, restricted to highly convincing (class I) and convincing (class II) evidence from prospective cohorts. The primary outcome was the global meta-analytical PAF, complemented by sensitivity analyses across different settings, the meta-analytical Generalised Impact Fraction (GIF), and study quality assessment (AMSTAR). Seven umbrella reviews (including 295 meta-analyses and 547 associations) identified 28 class I-II risk associations (23 risk factors; AMSTAR: 45.0% high-, 35.0% medium-, 20.0% low quality). The largest global PAFs not confounded by indication were 37.84% (95% CI = 26.77-48.40%) for childhood adversities and schizophrenia spectrum disorders, 24.76% (95% CI = 13.98-36.49%) for tobacco smoking and opioid use disorders, 17.88% (95% CI = not available) for job strain and depression, 14.60% (95% CI = 9.46-20.52%) for insufficient physical activity and Alzheimer's disease, 13.40% (95% CI = 7.75-20.15%) for childhood sexual abuse and depressive disorders, 12.37% (95% CI = 5.37-25.34%) for clinical high-risk state for psychosis and any non-organic psychotic disorders, 10.00% (95% CI = 5.62-15.95%) for three metabolic factors and depression, 9.73% (95% CI = 4.50-17.30%) for cannabis use and schizophrenia spectrum disorders, and 9.30% (95% CI = 7.36-11.38%) for maternal pre-pregnancy obesity and ADHD. The GIFs confirmed the preventive capacity for these factors. Addressing several potentially modifiable risk factors, particularly childhood adversities, can reduce the global population-level incidence of mental disorders.

OBJECTIVE:This systematic review and meta-analysis aimed to determine the accuracies of a broad range of screening tools for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents, and to compare the diagnostic accuracy of tools between population-based and clinical/high-risk samples, and across reporters. METHOD:MEDLINE, PsycINFO, EMBASE, and PubMed were searched up until February 20, 2020, with no language restrictions. Studies reporting diagnostic accuracy of a screening tool against a diagnosis of ADHD in children and adolescents <18 years of age were eligible for inclusion. Meta-analyses were undertaken to provide pooled estimates of the area under the curve (AUC), and sensitivity and specificity of groups of measures. RESULTS:A total of 75 studies published between 1985 and 2021 reporting on 41 screening tools that were grouped into 4 categories (Achenbach System of Empirically Based Assessment [ASEBA], DSM-IV symptom scales, SDQ, and Other Scales) were retained. The pooled AUC for studies using a combined ADHD symptoms score was 0.82 (95% CI = 0.78-0.86), although this varied considerably across reporters (0.67-0.92) and populations (CI = 0.60-0.95). None of the measures met minimal standards for acceptable sensitivity (0.8) and specificity (0.8). CONCLUSION:Most tools have excellent overall diagnostic accuracy as indicated by the AUC. However, a single measure completed by a single reporter is unlikely to have sufficient sensitivity and specificity for clinical use or population screening.

OBJECTIVE:Previous research has demonstrated that the amygdala is enlarged in children with autism spectrum disorder (ASD). However, the precise onset of this enlargement during infancy, how it relates to later diagnostic behaviors, whether the timing of enlargement in infancy is specific to the amygdala, and whether it is specific to ASD (or present in other neurodevelopmental disorders, such as fragile X syndrome) are all unknown. METHODS:Longitudinal MRIs were acquired at 6-24 months of age in 29 infants with fragile X syndrome, 58 infants at high likelihood for ASD who were later diagnosed with ASD, 212 high-likelihood infants not diagnosed with ASD, and 109 control infants (1,099 total scans). RESULTS:Infants who developed ASD had typically sized amygdala volumes at 6 months, but exhibited significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen's d=0.56) compared with all other groups. Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the infants were diagnosed with ASD. Infants with fragile X syndrome had a persistent and significantly enlarged caudate volume at all ages between 6 and 24 months (d=2.12), compared with all other groups, which was significantly associated with greater repetitive behaviors. CONCLUSIONS:This is the first MRI study comparing fragile X syndrome and ASD in infancy, demonstrating strikingly different patterns of brain and behavior development. Fragile X syndrome-related changes were present from 6 months of age, whereas ASD-related changes unfolded over the first 2 years of life, starting with no detectable group differences at 6 months. Increased amygdala growth rate between 6 and 12 months occurs prior to social deficits and well before diagnosis. This gradual onset of brain and behavior changes in ASD, but not fragile X syndrome, suggests an age- and disorder-specific pattern of cascading brain changes preceding autism diagnosis.

BACKGROUND:Antipsychotic-induced weight gain (AIWG) is a clinically relevant and concerning adverse effect of contemporary antipsychotic medications. Lumateperone is a novel antipsychotic, which became commercially available in 2020 and received Food and Drug Administration approval for schizophrenia and bipolar disorder in 2019 and 2021, respectively. To date, no comprehensive review exists on its AIWG profile. This systematic review aims to assess the association between lumateperone and AIWG. METHODS:Data Sources: A comprehensive search of published studies on "lumateperone" OR "ITI-007" OR "Caplyta" was conducted on PubMed, CINAHL Complete, APA PsychInfo, Cochrane Library, and Embase databases until January 2022.Study Selection: A total of 149 articles in English were collected. After removing duplicates, all human trials on lumateperone were screened for the inclusion criteria.Data Extraction: Two reviewers conducted an independent screening followed by full-text analysis of extracted studies adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Third reviewer resolved the conflicts as tiebreaker. RESULTS:Primary search generated 77 articles, excluding 72 duplicates, of which 51 were deemed appropriate for exclusion. Full-text analysis of the remaining 26 articles concluded with 5 studies for finalized review per inclusion criteria. Excluded studies were manually reviewed for relevant citation of studies per inclusion criteria. Three randomized, double-blinded, placebo-controlled clinical trials and 2 open-label trials were derived from this systematic review. Lumateperone showed a favorable weight profile compared with placebo and alternate antipsychotics. CONCLUSIONS:Lumateperone displays minimal to no weight gain among participants in the studies reviewed.

PURPOSE/BACKGROUND/OBJECTIVE:Centanafadine is an inhibitor of norepinephrine, dopamine, and serotonin reuptake transporters under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS/PROCEDURES/METHODS:Two phase 3 randomized, double-blind, placebo-controlled, parallel-group studies of 200 mg/d or 400 mg/d centanafadine sustained-release tablets versus placebo included adults (18-55 years of age) with a diagnosis of ADHD. The primary and key secondary efficacy endpoints were the change from baseline at day 42 in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score and the Clinical Global Impression-Severity of Illness Scale, respectively. FINDINGS/RESULTS/RESULTS:Subjects randomized in study 1 (centanafadine 200 mg/d, n = 149; centanafadine 400 mg/d, n = 149; placebo, n = 148) and study 2 (centanafadine 200 mg/d, n = 145; centanafadine 400 mg/d, n = 143; placebo, n = 142) had moderate to severe ADHD (mean AISRS total score, 38.7 [SD, 6.8] across both studies). At day 42, statistically significant least-squares mean differences in AISRS total score were observed in favor of centanafadine versus placebo in study 1 (200 mg/d: -3.16, P = 0.019; 400 mg/d: -2.74, P = 0.039) and study 2 (200 mg/d: -4.01, P = 0.002; 400 mg/d: -4.47, P = 0.001). Effect sizes versus placebo were -0.28 for 200 mg/d and -0.24 for 400 mg/d in study 1 and -0.37 for 200 mg/d and -0.40 for 400 mg/d in study 2. The overall rate of treatment-emergent adverse events (TEAEs) was low, but there was a small increase in TEAE occurrence with increasing dose. Incidences of serious TEAEs and abuse potential-related AEs were low. IMPLICATIONS/CONCLUSIONS/CONCLUSIONS:These are the first large-scale studies to demonstrate the efficacy and safety profiles of 200 mg/d and 400 mg/d centanafadine in adults with ADHD.

Although intimate partner violence (IPV) is often conceptualized as occurring unilaterally, reciprocal or bidirectional violence is actually the most prevalent form of IPV. The current study assessed physical IPV experiences in couples and evaluated risk and protective factors that may be differentially associated with reciprocal and nonreciprocal IPV concurrently and over time. As part of a multi-wave longitudinal study, women and men reported on the frequency of their IPV perpetration and victimization three times across the transition to parenthood. Participants also reported on risk factors related to personal adjustment, psychosocial resources, attitudes toward gender role egalitarianism, and sociodemographic characteristics at each wave. Participants were classified into one of four IPV groups (reciprocal violence, male perpetrators only, female perpetrators only, and no violence) based on their self-report and based on a combined report, which incorporated both partners' reports of IPV for a maximum estimate of violence. Women and men were analyzed separately, as both can be perpetrators and/or victims of IPV. Cross-sectional analyses using self-reported IPV data indicated that IPV groups were most consistently distinguished by their levels of couple satisfaction, across gender; psychological distress also appeared to differentiate IPV groups, although somewhat less consistently. When combined reports of IPV were used, sociodemographic risk markers (i.e., age, income, and education) in addition to couple functioning were among the most robust factors differentiating IPV groups concurrently, across gender. In longitudinal analyses, sociodemographic vulnerabilities were again among the most consistent factors differentiating subsequent IPV groups over time. Several gender differences were also found, suggesting that different risk factors (e.g., women's social support and men's emotion regulation abilities) may need to be targeted in interventions to identify, prevent, and treat IPV among women and men.

OBJECTIVE:To determine whether the self-report frequency of inter-agency collaboration about children's mental health issues is associated with the self-report frequency of using research evidence in children's mental health policy and program decision making in mental health agencies (MHAs). DATA SOURCES/METHODS:Primary data were collected through web-based surveys of state (N = 221) and county (N = 117) MHA officials. DESIGN/METHODS:The primary independent variable was a composite score quantifying the frequency of collaboration about children's mental health issues between officials in MHAs and six other state agencies. The dependent variables were composite scores quantifying the frequency of research use in children's mental health policy and program decision making in general and for specific purposes (i.e., conceptual, instrumental, tactical, imposed). Covariates were composite scores quantifying well-established determinants of research use (e.g., agency leadership, research use skills) in agency policy and program decision making. DATA METHODS/UNASSIGNED:Separate multiple linear regression models estimated associations between frequency of inter-agency collaboration and research use scores, adjusting for other determinants of research use, respondent state, and other covariates. Data from state and county officials were analyzed separately. PRINCIPAL FINDINGS/RESULTS:The frequency of inter-agency collaboration was positively and independently associated with the frequency of research use in children's mental health policy making among state (β = 0.22, p = 0.004) and county (β = 0.39, p < 0.0001) MHA officials. Inter-agency collaboration was also the only variable significantly associated with the frequency of research use for all four specific purposes among state MHA officials, and similar findings we observed among county MHA officials. The magnitudes of associations between inter-agency collaboration and frequency of research use were generally stronger than for more well-established determinants of research use in policy making. CONCLUSIONS:Strategies that promote collaboration between MHA officials and external agencies could increase the use of research evidence in children's mental health policy and program decision making in MHAs.

BACKGROUND:The degree of efficacy, safety, quality, and certainty of meta-analytic evidence of biological non-pharmacological treatments in mental disorders is unclear. METHODS:We conducted an umbrella review (PubMed/Cochrane Library/PsycINFO-04-Jul-2021, PROSPERO/CRD42020158827) for meta-analyses of randomized controlled trials (RCTs) on deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), electro-convulsive therapy (ECT), and others. Co-primary outcomes were standardized mean differences (SMD) of disease-specific symptoms, and acceptability (for all-cause discontinuation). Evidence was assessed with AMSTAR/AMSTAR-Content/GRADE. RESULTS:We selected 102 meta-analyses. Effective interventions compared to sham were in depressive disorders: ECT (SMD=0.91/GRADE=moderate), TMS (SMD=0.51/GRADE=moderate), tDCS (SMD=0.46/GRADE=low), DBS (SMD=0.42/GRADE=very low), light therapy (SMD=0.41/GRADE=low); schizophrenia: ECT (SMD=0.88/GRADE=moderate), tDCS (SMD=0.45/GRADE=very low), TMS (prefrontal theta-burst, SMD=0.58/GRADE=low; left-temporoparietal, SMD=0.42/GRADE=low); substance use disorder: TMS (high frequency-dorsolateral-prefrontal-deep (SMD=1.16/GRADE=moderate), high frequency-left dorsolateral-prefrontal (SMD=0.77/GRADE=very low); OCD: DBS (SMD=0.89/GRADE=moderate), TMS (SMD=0.64/GRADE=very low); PTSD: TMS (SMD=0.46/GRADE=moderate); generalized anxiety disorder: TMS (SMD=0.68/GRADE=low); ADHD: tDCS (SMD=0.23/GRADE=moderate); autism: tDCS (SMD=0.97/GRADE=very low). No significant differences for acceptability emerged. Median AMSTAR/AMSTAR-Content was 8/2 (suggesting high-quality meta-analyses/low-quality RCTs), GRADE low. DISCUSSION/CONCLUSIONS:Despite limited certainty, biological non-pharmacological interventions are effective and safe for numerous mental conditions. Results inform future research, and guidelines. FUNDING/BACKGROUND:None.

Local protein synthesis at synapses can provide a rapid supply of proteins to support synaptic changes during consolidation of new memories, but its role in the maintenance or updating of established memories is unknown. Consolidation requires new protein synthesis in the period immediately following learning, whereas established memories are resistant to protein synthesis inhibitors. We have previously reported that polyribosomes are up-regulated in the lateral amygdala (LA) during consolidation of aversive-cued Pavlovian conditioning. In this study, we used serial section electron microscopy reconstructions to determine whether the distribution of dendritic polyribosomes returns to baseline during the long-term memory phase. Relative to control groups, long-term memory was associated with up-regulation of polyribosomes throughout dendrites, including in dendritic spines of all sizes. Retrieval of a consolidated memory by presentation of a small number of cues induces a new, transient requirement for protein synthesis to maintain the memory, while presentation of a large number of cues results in extinction learning, forming a new memory. One hour after retrieval or extinction training, the distribution of dendritic polyribosomes was similar except in the smallest spines, which had more polyribosomes in the extinction group. Our results demonstrate that the effects of learning on dendritic polyribosomes are not restricted to the transient translation-dependent phase of memory formation. Cued Pavlovian conditioning induces persistent synapse strengthening in the LA that is not reversed by retrieval or extinction, and dendritic polyribosomes may therefore correlate generally with synapse strength as opposed to recent activity or transient translational processes.

The year 2020 brought unprecedented challenges and renewed focus on racial disparities and inequities in the United States. For racial and ethnic minority groups, and in particular African Americans, racial disparities have been a constant presence and threat from the time of slavery through the present day. These racial disparities, sanctioned and maintained by institutional racism, manifest in all aspects of life for African Americans-segregated and unequal education and housing systems, health and mental health care disparities, disproportionally elevated incarceration rates, and, as painfully highlighted this past year, continued vulnerability to acts of violence at the hands of law enforcement. In addition, most recently, there has been a renewed focus on the increased suicide rate for Black youth and its relationship to these racial disparities.¹ In a large urban environment, our academic Child Psychiatry Department recognized that progress toward addressing racial disparities would be impeded without raising awareness and taking individual and collective action to identify implicit bias, power, and privilege differentials, and systemic racism inherent within academic medicine and our own lived experiences. This letter describes the development of such examination through facilitated dialogues on race and antiracism in our department.