Anhedonia characterizes major depressive episodes in bipolar depression and is associated with more severe illness/poor prognosis. These post hoc analyses assess effect of cariprazine 1.5 and 3 mg/d on anhedonia symptoms in patients with bipolar I depression.

Data were pooled from 3 randomized, double-blind, placebo-controlled bipolar I depression trials in cariprazine. Cariprazine 1.5 and 3 mg/d versus placebo were evaluated in patient subgroups stratified by median baseline MADRS anhedonia score (higher anhedonia=score ≥19; lower anhedonia=score <19). Outcomes included mean change from baseline to week 6 in MADRS total and anhedonia factor score (sum of apparent sadness, reported sadness, concentration, lassitude, and inability to feel items). The proportion of patients with week 6 anhedonia factor response (≥50% improvement from baseline) was also determined. Changes from baseline were analyzed using a mixed-effect model for repeated measures.

There were 760 patients in the higher anhedonia subgroup (placebo=249, cariprazine: 1.5 mg/d=261; 3 mg/d=250) and 623 patients in the lower anhedonia subgroup (placebo=211, cariprazine: 1.5 mg/d=200; 3 mg/d=212). Mean baseline MADRS total score was higher in the higher anhedonia subgroup (total=33.6) than in the lower anhedonia subgroup (total=27.6). Change from baseline to week 6 in MADRS total score was greater for both cariprazine doses versus placebo in the higher anhedonia subgroup (least squares mean difference [LSMD] and 95% confidence interval [CI]: 1.5 mg/d=-3.01 [-4.84, -1.19], P=.0012; 3 mg/d: -3.26 [-5.12, -1.40], P=.0006); in the lower anhedonia subgroup, cariprazine 1.5 mg/d was statistically significant versus placebo (-2.61 [-4.28, -0.93], P=.0024). In the higher anhedonia subgroup at week 6, change from baseline in anhedonia factor score was significant versus placebo for both cariprazine doses (1.5 mg/d=-1.97 [-3.13, -0.81], P=.0009; 3 mg/d=-2.07 [-3.26, -0.89], P=.0006); in the lower subgroup, the difference was significant versus placebo for cariprazine 1.5 mg/d (-1.70 [-2.77, -0.62], P=.0021). After adjusting for changes in other depressive symptoms, LSMDs versus placebo in the anhedonia factor score remained significant for cariprazine 1.5 mg/d (-1.21 [-2.05, -0.36], P=.0052) and 3 mg/d (-1.00 [-1.86, -0.14], P=.0233) in the higher anhedonia subgroup, and for 1.5 mg/d (-1.06 [-1.92, -0.19], P=.0164) in the lower subgroup. In the higher anhedonia subgroup, rates of anhedonia factor response were greater versus placebo (31.7%) for cariprazine 1.5 mg/d (44.8%, P=.0028) and 3 mg/d (45.6%, P=.0019); in the lower subgroup, response rates were 39.3% for placebo, 48.0% for 1.5 mg/d, and 46.7% for 3 mg/d. Adverse events in ≥5% cariprazine and twice placebo were nausea, akathisia, restlessness, and EPS.

Those with bipolar depression and anhedonia cariprazine demonstrated a potent antidepressant and antianhedonic effect in higher/lower anhedonia subgroups.

AbbVie

This data was previously presented at the European College of Neuropsychopharmacology (ECNP) Congress; Barcelona, Spain; October 7 – 10, 2023.

Anhedonia, a multidimensional domain including the reduced ability to experience pleasure, is a core diagnostic symptom of major depressive disorder (MDD) and a common residual symptom. In patients with MDD, anhedonia has been associated with poor treatment outcomes, suicide and reduced functioning and quality of life. This post-hoc analysis of data from a phase 3 trial (NCT03738215) evaluated the efficacy of adjunctive cariprazine (CAR) treatment on anhedonia symptoms in patients with MDD.

Patients with MDD and inadequate response to ongoing antidepressant therapy (ADT) were randomized to CAR 1.5 mg/d + ADT, CAR 3 mg/d + ADT, or placebo + ADT for 6 weeks of double-blind treatment. Post hoc analyses evaluated the change from baseline to Week 6 in Montgomery–Åsberg Depression Rating Scale (MADRS) total score, MADRS anhedonia subscale score (items: 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]), and MADRS anhedonia item 8 in the overall modified intent-to-treat (mITT) population and in subgroups of patients with baseline MADRS anhedonia item 8 score of ≥4 or baseline anhedonia subscale score of ≥18. Least square (LS) mean change from baseline to Week 6 was analyzed using a mixed-effects model for repeated measures.

There were 751 patients in the mITT population (CAR + ADT: 1.5 mg/d=250, 3 mg/d=252; placebo + ADT=249). At baseline, 508 (67.6%) patients had MADRS anhedonia item 8 scores ≥4, and 584 (77.8%) had MADRS anhedonia subscale scores ≥18. In the overall mITT population, LS mean change from baseline to Week 6 in anhedonia subscale score was significantly greater for CAR 1.5 mg/d + ADT (-8.4) and CAR 3 mg/d + ADT (-7.9) than for placebo + ADT (-6.8; both P<.05). The LS mean change from baseline in MADRS individual item 8 was also significantly greater for CAR 1.5 mg/d + ADT (-1.7) vs placebo + ADT (-1.3; P=.0085). In both subgroups of patients with baseline anhedonia, CAR 1.5 mg/d + ADT was associated with significantly greater reduction in MADRS total score, MADRS anhedonia subscale score, and MADRS item 8 score compared with placebo + ADT (all P<.05). In the CAR 3 mg/d + ADT group, significantly greater reductions vs placebo + ADT were observed for MADRS total score and MADRS anhedonia subscale score in the subgroup of patients with baseline anhedonia subscale scores ≥18 (both P<.05).

Adjunctive treatment with CAR was associated with a reduction in symptoms of anhedonia relative to adjunctive placebo in patients with MDD and inadequate response to ADT alone. In subgroups of patients with moderate-to-severe anhedonia at baseline, CAR + ADT demonstrated greater improvements than placebo + ADT in overall depressive symptoms and symptoms of anhedonia. These results suggest that adjunctive CAR treatment may be effective for improving symptoms of anhedonia in patients with MDD who have symptoms of anhedonia.

AbbVie

Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk.

Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11–36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones.

Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20).

Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Therapeutics targeting frontotemporal dementia (FTD) are entering clinical trials. There are challenges to conducting these studies, including the relative rarity of the disease. Remote assessment tools could increase access to clinical research and pave the way for decentralized clinical trials. We developed the ALLFTD Mobile App, a smartphone application that includes assessments of cognition, speech/language, and motor functioning. The objectives were to determine the feasibility and acceptability of collecting remote smartphone data in a multicenter FTD research study and evaluate the reliability and validity of the smartphone cognitive and motor measures.

A diagnostically mixed sample of 207 participants with FTD or from familial FTD kindreds (CDR®+NACC-FTLD=0 [n=91]; CDR®+NACC-FTLD=0.5 [n=39]; CDR®+NACC-FTLD>1 [n=39]; unknown [n=38]) were asked to remotely complete a battery of tests on their smartphones three times over two weeks. Measures included five executive functioning (EF) tests, an adaptive memory test, and participant experience surveys. A subset completed smartphone tests of balance at home (n=31) and a finger tapping test (FTT) in the clinic (n=11). We analyzed adherence (percentage of available measures that were completed) and user experience. We evaluated Spearman-Brown split-half reliability (100 iterations) using the first available assessment for each participant. We assessed test-retest reliability across all available assessments by estimating intraclass correlation coefficients (ICC). To investigate construct validity, we fit regression models testing the association of the smartphone measures with gold-standard neuropsychological outcomes (UDS3-EF composite [Staffaroni et al., 2021], CVLT3-Brief Form [CVLT3-BF] Immediate Recall, mechanical FTT), measures of disease severity (CDR®+NACC-FTLD Box Score & Progressive Supranuclear Palsy Rating Scale [PSPRS]), and regional gray matter volumes (cognitive tests only).

Participants completed 70% of tasks. Most reported that the instructions were understandable (93%), considered the time commitment acceptable (97%), and were willing to complete additional assessments (98%). Split-half reliability was excellent for the executive functioning (r’s=0.93-0.99) and good for the memory test (r=0.78). Test-retest reliabilities ranged from acceptable to excellent for cognitive tasks (ICC: 0.70-0.96) and were excellent for the balance (ICC=0.97) and good for FTT (ICC=0.89). Smartphone EF measures were strongly associated with the UDS3-EF composite (ß's=0.6-0.8, all p<.001), and the memory test was strongly correlated with total immediate recall on the CVLT3-BF (ß=0.7, p<.001). Smartphone FTT was associated with mechanical FTT (ß=0.9, p=.02), and greater acceleration on the balance test was associated with more motor features (ß=0.6, p=0.02). Worse performance on all cognitive tests was associated with greater disease severity (ß's=0.5-0.7, all p<.001). Poorer performance on the smartphone EF tasks was associated with smaller frontoparietal/subcortical volume (ß's=0.4-0.6, all p<.015) and worse memory scores with smaller hippocampal volume (ß=0.5, p<.001).

These results suggest remote digital data collection of cognitive and motor functioning in FTD research is feasible and acceptable. These findings also support the reliability and validity of unsupervised ALLFTD Mobile App cognitive tests and provide preliminary support for the motor measures, although further study in larger samples is required.

There is increasing interest in examining a general psychopathology factor (p factor) in children and adolescents. In previous work, the relationship between the p factor and cognition in youth has largely focused on general intelligence (IQ) and executive functions (EF). Another cognitive construct, processing speed (PS), is dissociable from these cognitive constructs, but has received less research attention despite being related to many different mental health symptoms. This study aimed to examine the association between a latent processing speed factor and the p factor in youth.

The present sample included 795 youth, ages 11-16 from the Colorado Learning Disability Research Center (CLDRC) sample. Confirmatory factor analyses tested multiple p factor models, with the primary model being a novel second-order, multireporter p factor where caregivers reported on externalizing symptoms (oppositional defiant disorder and conduct disorder modules from the Diagnostic Interview for Children and Adolescents [DICA]; aggression, delinquency, and attention problems subscales from the Child Behavior Checklist; and inattentive and hyperactive/impulsive subscales from the Disruptive Behavior Rating Scale) and youth self-reported on internalizing symptoms (Child Depression Inventory, generalized anxiety module from the DICA, and withdrawn, anxious/depression, and somatic subscales from the Youth Self Report). We then tested the correlation between the p factor and a latent PS factor. The latent PS factor was composed of WISC Symbol Search, WISC Coding, Colorado Perceptual Speed Test, and Identical Pictures Test. Three secondary p factor models were examined for comparison to previous literature, including (1) a bifactor, multi-reporter model, (2) a second-order model with just caregiver-report, and (3) a bifactor model with just caregiver-report.

There was a significant, negative correlation between the p factor and PS (r=-0.42, p<.001), indicating that slower processing speed is associated with higher general mental health symptoms. This finding was robust across models that used different raters (youth and caregiver-report vs. caregiver-report only) and modeling approaches (second-order vs. bifactor). This association is stronger than previously reported associations with IQ or EF in the p factor literature. Further, in this sample, we found that the association between PS and the p factor was robust to covariation for general cognition, whereas the correlation between general cognition and the p factor was fully accounted for by PS.

Our findings indicate that PS is related to general psychopathology symptoms, expanding the existing literature relating PS to specific, distinct disorders by showing that PS is related to what is shared across psychopathology. As cognition and psychopathology both undergo significant development across childhood and adolescence, elucidating neurodevelopmental mechanisms that relate to risk for a broad range of symptoms may be critical to informing early intervention and prevention approaches. This research points to processing speed as an important transdiagnostic construct that warrants further attention and exploration across development.

There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer’s dementia.

We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates.

Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: β = −0.33, p = .002; Cohort 2: β = −0.36, p = .03) and parietal ROIs (Cohort 1: β = −0.31, p = .01; Cohort 2: β = −0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: β = −0.38, p = .01; Cohort 2: β = −0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP.

Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

Clinically normal older adults (52–92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178–207, mean ages = 74–76) at annual study visits occurring approximately 15–18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics.

Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044).

Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories. (JINS, 2020, xx, xx-xx)

Former studies show low treatment rates of outpatients with a diagnosis of depression. The aims of this study are to examine

1. (1) the rate of diagnosed depression in outpatient care,

2. (2) rates of treatment of depression according to individual and regional characteristics and

3. (3) effects of individual and regional characteristics on getting depression-specific treatment in the federal state of Bavaria.

Prevalence of depression and outpatient treatment for depression as well as individual and regional characteristics of outpatients diagnosed with depression were analysed based on secondary data from the Association of Statutory Health Insurance Physicians Bavaria in 2006 (N=780,226). Descriptive analyses were followed by logistic regression analysis (STATA, PASW) to examine predictive effects of individual and regional characteristics on getting depression-specific treatment.

Prevalence of diagnosed depression is 9.2% for persons who are statutory health insured and older than 17 years. 55% of diagnosed depressed patients do not get a depression-specific treatment within one year. Rates of a depression-specific treatment are higher for persons who are female, of middle age, with a moderate or severe depression, with a psychiatric comorbidity, without somatic comorbidity, who live in more rural areas.

The access to depression-specific treatment after a diagnosis of depression must be facilitated. Training for physicians, psychoeducation for patients and anti-stigma campaigns are necessary measures to reach this goal. The knowledge about influence of individual characteristics on getting a depression-specific treatment is important to reach the groups who get least depression-specific treatment.

To obtain information on ECT practice in Asia.

From September 1, 2001 to August 31, 2003, a 29-item questionnaire was sent to 977 institutions in 45 countries in Asia.

334 institutions (34%) in 29 countries replied, of which 257 institutions in 23 countries had ECT. 39,875 patients (men: women = 1.56: 1) received 240,314 ECTs from 1,919 psychiatrists during the survey period. Brief-pulse device was used in 103 institutions, 60 did not know the type of their ECT devices. Thymatron or MECTA devices were used in 58 institutions, 115 respondents did not know the brand of their ECT devices. EEG monitoring was used routinely in 59 institutions. Bilateral ECT was always used in 202 institutions. Patients commonly received ECT were schizophrenia (41.8%), major depressive disorder (32.4%), mania (14%), catatonia (6.9%), drug abuse (1.8%), and dysthymia (1.6%). 26,167 ECTs (73%) were given to patients age group 18-44 years, 2,138 ECTs (5.4%) to children and adolescent, and 1,581 ECTs (4%) to age group 65 and above. 22,194 patients (55.7%) received unmodified ECT totally of 129,906 treatments (54%) at 141 institutions in 14 countries. Continuation ECT was done in 115 institutions in 17 countries and maintenance ECT was done in 63 institutions in 14 countries.

ECT is commonly practiced in Asia. Unmodified ECT accounted for 54% of treatments. There was no formal training in any institution.

Former studies show low treatment rates of outpatients with a diagnosis of depression. Various characteristics influence these treatment rates.

To examine the effects of individual and regional characteristics on getting depression-specific treatment in the federal state of Bavaria.

Outpatient treatment for depression as well as individual and regional characteristics of outpatients diagnosed with depression were analyzed based on secondary data from the Association of Statutory Health Insurance Physicians Bavaria in 2006 (N = 780,226). Depression-specific treatment was classified in “Threshold” and “Subthreshold” treatment according to its intensity. Descriptive analyses were followed by logistic regression analysis (STATA, PASW).

More than half of the patients diagnosed with depression did not use any depression-specific treatment within one year. Individual factors which heighten the rates of a depression-specific treatment were female gender, middle age, a moderate or severe depression, a psychiatric comorbidity and no somatic comorbidity. Interestingly, living in a more rural area increased the chance of using “Threshold” treatment.

The knowledge about the influence of individual characteristics on getting a depression-specific treatment is important to reach the risk groups. A possible reason for higher rates of “Threshold” treatment in rural areas is the higher rate of pharmacotherapy in rural areas, which was more often classified as “Threshold” treatment than psychotherapy according to our classification.

In the brain, estrogen plays an important role in neural plasticity and its decline during menopause might result in cognitive impairment and predispose to the development of dementia. Two estrogen receptors – α and ß – mediate estrogen actions either as ligand-activated dimeric transcription factors or as membrane-embedded ER monomers.

To analyze ERß-variants and ApoE-genotype in the population-based SALIA cohort of 834 non-demented, elderly women.

We aimed to explore, whether ERß variants may impact on cognitive performance in interaction with air pollution and APOE.

DNA was isolated from lymphocytes. ApoE-epsilon-variants and ERß SNPs rs944045, rs1256062, rs10144225 and rs2274705 were determined by LCG /KBioscience (Hoddesdon, UK). All participants were assessed for cognitive impairment by the CERAD-Plus test battery. Subtests were merged to a total z-score, that corrected for gender, age and time of education. Long-term exposure to air pollution was backextrapolated from data collected by monitoring stations using a geographic information system.

SNP analysis revealed that 3 ERß variants (rs1256062, rs10144225 and rs2274705) were significantly correlated with lower CERAD z total scores and especially with decline in episodic memory. These effects were strengthened in APOE-epsilon-E4 carriers. Air pollution (NO2, PM2,5) did not worsen the CERAD z total score of the women, but interacting with the ERß variants PM2,5 affected their visuoconstructive practice and NO2 their semantic memory.

In this population-based, prospective study a gene-gene interaction effect of ApoE and ERß on cognitive performance appeared. Moreover, significant gene-environment interactions on cognition were found for air pollution.

Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.

We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.

In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).

AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.

Poor clinical trial (CT) recruitment is a significant barrier to translating basic science discoveries into medical practice. Improving support for primary care provider (PCP) referral of patients to CTs may be an important part of the solution. However, implementing CT referral support in primary care is not only technically challenging, but also presents challenges at the person and organization levels.

The objectives of this study were (1) to characterize provider and clinical supervisor attitudes and perceptions regarding CT research, recruitment, and referrals in primary care and (2) to identify perceived workflow strategies and facilitators relevant to designing a technology-supported primary care CT referral program. Focus groups were conducted with PCPs, directors, and supervisors.

Analysis indicated widespread support for the intrinsic scientific value of CTs, while at the same time deep concerns regarding protecting patient well-being, perceived loss of control when patients participate in trials, concern about the impact of point-of-care referrals on clinic workflow, the need for standard processes, and the need for CT information that enables referring providers to quickly confirm that the burdens are justified by the benefits at both patient and provider levels. PCP suggestions pertinent to implementing a CT referral decision support system are reported.

The results from this work contribute to developing an implementation approach to support increased referral of patients to CTs.