Adherence to Psychotropic Medication Before and During COVID-19: A Population-Wide Retrospective Observational Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and associated public health measures have shifted the way people access health care. We aimed to study the effects of the COVID-19 pandemic on psychotropic medication adherence. METHODS: A retrospective cohort study using administrative data from the Manitoba Centre for Health Policy Manitoba Population Research Data Repository was conducted. Outpatients who received at least 1 prescription for an antidepressant, antipsychotic, anxiolytic/sedative-hypnotic, cannabinoid, lithium, or stimulants from 2015 to 2020 in Manitoba, Canada, were included. Adherence was measured using the proportion of individuals with a mean possession ratio of ≥0.8 over each quarter. Each quarter of 2020 after COVID-19-related health measures were implemented was compared with the expected trend using autoregression models for time series data plus indicator variables. Odds ratio of drug discontinuation among those previously adherent in 2020 was compared with each respective quarter of 2019. RESULTS: There were 1,394,885 individuals in the study population in the first quarter of 2020 (mean [SD] age, 38.9 [23.4] years; 50.3% female), with 36.1% having a psychiatric diagnosis in the preceding 5 years. Compared with the expected trend, increases in the proportions of individuals adherent to antidepressants and stimulants were observed in the fourth quarter (October-December) of 2020 (both P < 0.001). Increases in the proportions of individuals with anxiolytic and cannabinoid adherence were observed in the third quarter (July-September) of 2020 (both P < 0.05), whereas a decrease was seen with stimulants in the same quarter ( P < 0.0001). No significant changes were observed for antipsychotics. All drug classes except lithium had decreases in drug discontinuation in previously adherent patients during the pandemic compared with 2019. CONCLUSIONS: Improved adherence to most psychotropic medications in the 9 months after public health restrictions were enacted was observed. Patients who were already adherent to their psychotropic medications were less likely to discontinue them during the pandemic.

The impact of educational attainment, intelligence and intellectual disability on schizophrenia: a Swedish population-based register and genetic study.

Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence. To examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two Swedish samples: a national cohort (14,230 SCZ cases and 3,816,264 controls) and a subsample with comprehensive genetic data (4992 cases and 6009 controls). Population-based analyses confirmed worse cognition as a risk factor for SCZ, and the pedigree and SNP-based genetic correlations were comparable. In the genotyped cases, those with high EDU and premorbid cognitive ability tended to have higher polygenetic risk scores (PRS) of EDU and intelligence and fewer rare exonic variants. Finally, by applying an empirical clustering method, we dissected SCZ cases into four replicable subgroups characterized by EDU and ID. In particular, the subgroup with higher EDU in the national cohort had fewer adverse outcomes including long hospitalization and death. In the genotyped subsample, this subgroup had higher PRS of EDU and no excess of rare genetic burdens than controls. In conclusion, we found extensive evidence of a robust relation between cognitive traits and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.

Genetic heterogeneity and subtypes of major depression.

Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment, and postpartum depression; N ~ 3000-47000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders/traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (-0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.

Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study.

A high proportion of those with schizophrenia experience treatment non-response, placing them at higher risk for mortality and suicide attempts, compared to treatment responders. The clinical, social, and economic burden of treatment-resistant schizophrenia (TRS) are substantial. Previous genomic and epidemiological studies of TRS were often limited by sample size or lack of comprehensive genomic data. We aimed to systematically understand the clinical, demographic, and genomic correlates of TRS using epidemiological and genetic epidemiological modelling in a Swedish national population sample (n = 24,706) and then in a subgroup with common variant genetic risk scores, rare copy-number variant burden, and rare exonic burden (n = 4936). Population-based analyses identified increasing schizophrenia family history to be significantly associated with TRS (highest quartile of familial burden vs. lowest: adjusted odds ratio (aOR): 1.31, P = 4.8 × 10-8). In males, a decrease of premorbid IQ of one standard deviation was significantly associated with greater risk of TRS (minimal aOR: 0.94, P = 0.002). In a subset of cases with extensive genomic data, we found no significant association between the genetic risk scores of four psychiatric disorders and two cognitive traits with TRS (schizophrenia genetic risk score: aOR = 1.07, P = 0.067). The association between copy number variant and rare variant burden measures and TRS did not reach the pre-defined statistical significance threshold (all P ≥ 0.005). In conclusion, direct measures of genomic risk were not associated with TRS; however, premorbid IQ in males and schizophrenia family history were significantly correlated with TRS and points to new insights into the architecture of TRS.

Genetic architecture of schizophrenia: a review of major advancements.

Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.

BACKGROUND: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. OBJECTIVE: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). METHODS: We selected genetic instruments associated with risk of MDD (n = 660,937 cases; 1,453,489 controls) and MS (n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. RESULTS: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90-1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99-1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09-1.65) and MDD (OR = 1.08, 95% CI = 1.01-1.15). CONCLUSION: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

Investigating the Prevalence of Comorbidity in Multiple Sclerosis Clinical Trial Populations.

BACKGROUND AND OBJECTIVES: Comorbidity is common in multiple sclerosis (MS) with the most prevalent conditions being depression, anxiety, hypertension, and hyperlipidemia. Limited information regarding the representation of comorbidity status is available from phase III clinical trials in MS leading to concern about the potential underrepresentation of individuals with comorbidity in clinical trials. The objective was to estimate the prevalence of comorbidities in MS clinical trial populations. METHODS: Individual-level data from multiple sponsors were requested for a 2-stage meta-analysis of phase III clinical trials of MS disease-modifying therapies. To ensure consistency of our approach across trials, we followed the Maelstrom retrospective harmonization guidelines. Chronic comorbidities at clinical trial enrollment recommended by the International Advisory Committee on Clinical Trials in MS were considered (depression, anxiety, hypertension, hyperlipidemia, migraine, diabetes, chronic lung disease). Additional comorbidities were also classified. Classification was based on medical history data. Individual comorbidities were summed and categorized as 0, 1, 2, or ≥3. We report the pooled prevalence (95% confidence interval [95% CI]) of comorbidity. The pooled prevalence and prevalence ratios across age, sex, race, disability level, and treatment were also reported. Heterogeneity was assessed using the I2 statistic. RESULTS: Seventeen trials involving 17,926 participants were included. Fourteen trials enrolled participants with relapsing MS (RMS) while 3 enrolled participants with progressive MS (PMS). The distributions of sex, age, and disability level were generally consistent within RMS and PMS trials. When pooled, almost half of trial participants (46.5%) had ≥1 comorbidity (1: 25.0%, 95% CI 23.0-27.0, I2 = 89.9; 2: 11.4% [9.3-14.0], I2 = 96.3; ≥3: 6.0% [4.2-8.4], I2 = 97.7). Depression (16.45% [12.96-20.88], I2 = 98.3) was the most prevalent comorbidity reported, followed by hypertension (10.16% [8.61-11.98], I2 = 93.2). Heterogeneity was high across trials. Older age and female participants were associated with increased number of comorbidities. Older individuals and male participants had a higher prevalence of hyperlipidemia, while older individuals and female participants had a higher prevalence of depression and anxiety. DISCUSSION: Individuals with comorbidities are included in clinical trials, although they may still be underrepresented compared with the general MS population. Given the comorbidity prevalence in the trial populations and studies suggesting an association of comorbidities with disease activity, comorbidity may influence outcomes in clinical trials.

Knowledge, perceptions, and attitudes toward pharmacogenomics among pharmacists and pharmacy students: A systematic review.

Background and Aims: Pharmacists have been recognized as one of the most qualified healthcare professionals in the clinical implementation of pharmacogenomics, yet its widespread implementation in clinical pharmacy practice has remained limited. The review aims to systematically investigate knowledge, perceptions, and attitudes toward pharmacogenomics among pharmacists and pharmacy students to inform the future delivery of pharmacogenomics education programs. Methods: PubMed, MEDLINE, Embase, Scopus, and the International Pharmaceutical Abstracts were searched up to May 17, 2022. Studies were selected if they included data on pharmacists' or pharmacy students' knowledge, perception, or attitude about pharmacogenomics and were published in a peer-reviewed, English-language journal with full-text availability. Any published study not deemed original research was excluded. All included studies were critically appraised using the Center for Evidence-Based Management's critical appraisal tools. The data were descriptively analyzed and presented based on pharmacists' and pharmacy students' knowledge/awareness, perception/attitudes toward pharmacogenomic (PGx), confidence in using or interpreting PGx testing results, and their desire to get further PGx education or their most preferred method of further education. Results: A combined total of 12,430 pharmacists and pharmacy students from 26 countries are represented in the 52 included studies. Despite overwhelmingly positive attitudes and perceptions toward pharmacogenomics among pharmacists and pharmacy students, an overall lack of adequate knowledge and confidence was found. The review also found a strong desire for further pharmacogenomics education among pharmacists and pharmacy students. Conclusion: Pharmacists and pharmacy students have positive perceptions and attitudes toward pharmacogenomics, which is hindered by a lack of knowledge and confidence. However, inadequate control for confounders, limited representativeness of the studied population or region, and small sample sizes diminish the generalizability of the review results. Knowledge and confidence could be improved through enhanced delivery of pharmacogenomic courses within the pharmacy curriculum and continuing education programs.

The state of mental health among Ebola virus disease survivors through a cross-sectional study in Sierra Leone.

BACKGROUND: The West African Ebola virus disease (EVD) epidemic resulted in >28 000 disease cases and >11 000 fatalities. The unprecedented number of survivors from this epidemic has raised questions about the long-term mental health impacts of EVD survivorship and the capacity to meet these needs. OBJECTIVES: Assess the frequency and factors associated with mental health consequences of EVD survivorship in Sierra Leone. METHODS: A cross-sectional study of 595 EVD survivors and 403 close contacts (n=998) from Sierra Leone assessed via in-person survey between November 2021 and March 2022. The assessment included validated mental health screening tools (Patient Health Questionnaire-9, PTSD Checklist-5, Alcohol Use Disorders Identification Test, Drug Abuse Screening Test-20) to indicate the presence/absence of disorder. The frequency of each disorder and factors associated with each disorder were assessed. FINDINGS: EVD-associated post-traumatic stress disorder (PTSD) was reported by 45.7% (n=257) of EVD survivors. Moreover, 3.9% (n=22) and 12.0% (n=67) of EVD survivors reported major depression (MD) and substance use, respectively; all mental health outcomes were higher than baseline rates in the region (PTSD: 6%-16%, MD: 1.1%, substance use: 2.2%). PTSD among EVD survivors was associated with acute EVD duration of ≥21 days (adjusted OR, AOR 2.24, 95% CI 1.16 to 4.43), 35-44 years of age (AOR 3.31, 95% CI 1.33 to 8.24; AOR 2.99, 95% CI 1.09 to 8.24) and residential mobility (AOR 4.16, 95% CI 2.35 to 7.35). CONCLUSIONS: Concerningly, the levels of mental health disorders among EVD survivors in Sierra Leone remained elevated 6-8 years after recovery. CLINICAL IMPLICATIONS: Results can be used to inform policy efforts and target resources to address mental health in EVD survivors.

Knowledge and perceptions of pharmacogenomics among pharmacists in Manitoba, Canada.

Objective: This work was designed to describe the knowledge and perceptions of pharmacogenomics (PGx) among pharmacists in the Canadian province of Manitoba. Methods: A 40-item, web-based survey was distributed to pharmacists in Manitoba. Results: Of 74 participants, one third had some education or training in PGx, and 12.2% had used PGx test results in their practice. Participants' self-rated knowledge of PGx testing and common PGx resources (e.g., Pharmacogenomics Knowledge Base, Clinical Pharmacogenetics Implementation Consortium) was low. Most pharmacists surveyed believe that PGx can improve medication efficacy (82.4%) or prevent adverse drug reactions (81.1%). Most (91%) desired more education on PGx. Conclusion: Manitoba pharmacists reported positive perceptions toward PGx. However, they are currently underprepared to implement PGx into practice.

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis.

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. RESULTS: A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. INTERPRETATION: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Genetic Contribution to the Heterogeneity of Major Depressive Disorder: Evidence From a Sibling-Based Design Using Swedish National Registers.

OBJECTIVE: Major depressive disorder (MDD) is highly heterogeneous. Standard typology partly captures the disorder's symptomatic heterogeneity, although whether it adequately captures etiological heterogeneity remains elusive. The aim of this study was to investigate the genetic characterization of MDD heterogeneity. METHODS: Using Swedish patient register data on 1.5 million individuals, the authors identified 46,255 individuals with specialist-diagnosed MDD. Eighteen subgroups were identified based on nine comparison groups defined by clinical and psychosocial features, including severity, recurrence, comorbidities, suicidality, impairment, disability, care unit, and age at diagnosis. A sibling-based design and classic quantitative genetic models were applied to estimate heritability of MDD subgroups and genetic correlations between subgroups. RESULTS: Estimates of heritability ranged from 30.5% to 58.3% across subgroups. The disabled and youth-onset subgroups showed significantly higher heritability (55.1%-58.3%) than the overall MDD sample (45.3%, 95% CI=43.0-47.5), and the subgroups with single-episode MDD and without psychiatric comorbidity showed significantly lower estimates (30.5%-34.4%). Estimates of genetic correlations between the subgroups within comparison groups ranged from 0.33 to 0.90. Seven of nine genetic correlations were significantly smaller than 1, suggesting differences in underlying genetic architecture. These results were largely consistent with previous work using genomic data. CONCLUSIONS: The findings of differential heritability and partially distinct genetic components in subgroups provide important insights into the genetic heterogeneity of MDD and a deeper etiological understanding of MDD clinical subgroups.

Sex differences among users of NSAIDs and opioids during COVID-19 Pandemic.

BACKGROUND: Sex-based inequalities in healthcare have been exposed and amplified during the COVID-19 pandemic. However, few studies have reported sex differences in medication utilization and no studies have examined sex differences in prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and opioids utilization. AIM: To compare the utilization patterns of prescribed NSAIDs and opioids between males and females in Manitoba, Canada during the COVID-19 pandemic. METHOD: A cohort of incident and prevalent users of prescribed NSAIDs and opioids was created. Interrupted times series analysis using autoregressive models were used to evaluate the quarterly change in the prevalent and incident users before and after COVID-19 restrictions were applied (first quarter of 2020). RESULTS: COVID-19 restrictions were associated with a significant decrease in the utilization of prescribed NSAIDs and opioids in all users, followed by a revert to the pre-pandemic trends. Among female prevalent and incident NSAIDs users, there was a significant change in trend after COVID-19 restrictions were introduced (ß3 = 0.087 and 0.078, P = 0.023 and 0.028, respectively). However, there was non-significant change in trend among male prevalent and incident NSAIDs and opioids users during the pandemic. CONCLUSION: In this study, a significant sharp decline in the use of prescribed NSAIDs and opioids was shown in both sexes at the onset of the pandemic. However, a significant upward trend is observed in female NSAIDs users as restrictions began to be lifted.

Etiology, effects and management of comorbidities in multiple sclerosis: recent advances.

Comorbid conditions commonly affect people with multiple sclerosis (MS). Population-based studies indicate that people with MS have an increased incidence of ischemic heart disease, cerebrovascular disease, peripheral vascular disease, and psychiatric disorders as compared to people without MS. People with MS from underrepresented minority and immigrant groups have higher comorbidity burdens. Comorbidities exert effects throughout the disease course, from symptom onset through diagnosis to the end of life. At the individual level, comorbidity is associated with higher relapse rates, greater physical and cognitive impairments, lower health-related quality of life, and increased mortality. At the level of the health system and society, comorbidity is associated with increased health care utilization, costs and work impairment. A nascent literature suggests that MS affects outcomes from comorbidities. Comorbidity management needs to be integrated into MS care, and this would be facilitated by determining optimal models of care.

Sex differences evident in elevated anxiety symptoms in multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis.

Introduction: Immune-mediated inflammatory diseases (IMID), such as multiple sclerosis (MS), inflammatory bowel disease (IBD) or rheumatoid arthritis (RA) have high rates of elevated anxiety symptoms. This can may worsen functioning and increase IMID disease burden. The rate of and factors associated with elevated anxiety symptoms may differ between males and females, which, in turn can affect diagnosis and disease management. We evaluated whether the frequency and factors associated with comorbid elevated anxiety symptoms in those with an IMID differed by sex. Methods: Participants with an IMID (MS, IBD or RA) completed two anxiety measures (HADS, GAD-7). We used logistic regression to investigate whether sex differences exist in the presence of comorbid elevated anxiety symptoms or in the endorsement of individual anxiety items in those with an IMID. Results: Of 656 participants, females with an IMID were more likely to have elevated anxiety symptoms compared to males (adjusted odds ratio [aOR] 2.05; 95%CI: 1.2, 3.6). Younger age, higher depressive symptoms and income were also associated with elevated anxiety symptoms in IMID. Lower income in males with an IMID, but not females, was associated with elevated anxiety symptoms (aOR: 4.8; 95%CI: 1.5, 15.6). No other factors demonstrated a sex difference. Males had nearly twice the odds of endorsing restlessness on the GAD-7 (OR = 1.8, 95%CI: 1.07, 3.15) compared to females. Discussion: We found evidence for sex differences in the factors associated with experiencing elevated anxiety symptoms in those with an IMID. These findings could be helpful to sensitize clinicians to monitor for comorbid anxiety symptoms in males with an IMID.

Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS: We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS: Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION: Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Preterm birth and stillbirth rates associated with socioeconomic disparities during COVID-19 pandemic: a population-based cross-sectional study.

BACKGROUND: Conflicting evidence exists on the impact of the COVID-19 pandemic restrictions on preterm birth (PTB) and stillbirth rates. We aimed to evaluate changes in PTB and stillbirth rates before and during the pandemic period and assess the potential effect modification of socioeconomic status (SES). METHODS: Using the linked administrative health databases from Manitoba, Canada, we conducted a cross-sectional study among all pregnant women, comparing 3.5 years pre-pandemic (1 October 2016 to 29 February 2020) to the first year of the pandemic (1 March 2020 to 31 March 2021). We used generalised linear models to assess the quarterly rates of PTB (<37 weeks) and stillbirths. We calculated the predicted trends based on pre-pandemic period data. Finally, we evaluated the PTB and stillbirth rates among lower and higher SES pregnant women (average annual household income) using subgroup analysis and interaction models. RESULTS: We examined 70 931 pregnancies in Manitoba during the study period. The risk of PTB increased by 7.7% (95%CI 1.01 to 1.13) and stillbirths by 33% (95% CI 1.08 to 1.64) during the pandemic period. Following COVID-19 restrictions implemented in March 2020, there were increases in the quarterly rates of both PTB (immediate increase (ß2)=1.37; p=0.0247) and stillbirths (immediate increase (ß2)=0.12; p=0.4434). Among the lower income groups, the pandemic restrictions resulted in an immediate relative increase in PTB and stillbirth rates by 20.12% (immediate increase (ß2)=3.17; p=0.0057) and 27.19% (immediate increase (ß2)=0.48; p=0.0852). However, over the pandemic, the overall PTB rate significantly decreased as a rebound effect by 0.85% per quarter (p=0.0004), whereas the overall stillbirth rate did not decrease significantly (slope decrease (ß3) =-0.01; p=0.8296) compared with the pre-pandemic period. The quarterly rates during the pandemic among the higher income group decreased by 0.39% (p=0.1296) for PTB and increased by 0.07% (p=0.1565) for stillbirth. We observed an effect modification by SES for PTB rates (p=0.047). CONCLUSION: While the onset of COVID-19 pandemic restrictions was not associated with significant effects on stillbirth rates, we observed an immediate and rebound effect on PTB rates. The impact of COVID-19 on preterm birth was dependent on SES, with higher influence on families with lower SES. Further studies are needed to detect future trend changes during pandemic waves after 2021 and assess potential underlying mechanisms.

Investigating genetic overlap between antidepressant and lithium response and treatment resistance in major depressive disorder.

Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) within ~ 4 500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores of antidepressant and lithium response for individuals with MDD, and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1 778 ECT-treated MDD cases, nearly all (94%) used antidepressants before first ECT, and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We found that TRD cases tend to have lower genetic load of antidepressant response than non-TRD, although the difference was not significant; furthermore, TRD cases had significantly higher genetic load of lithium response (OR = 1.10-1.12 under different definitions). The results support evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.

Assessment of differential item functioning of the PHQ-9, HADS-D and PROMIS-depression scales in persons with and without multiple sclerosis.

OBJECTIVE: We tested for the presence of differential item functioning (DIF) in commonly used measures of depressive symptoms, in people with multiple sclerosis (MS) versus people with a psychiatric disorder without MS. METHODS: Participants included individuals with MS, or with a lifetime history of a depressive or anxiety disorder (Dep/Anx) but no immune-mediated inflammatory disease. Participants completed the Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), and the Patient Reported Outcome Measurement Information System (PROMIS)-Depression. We assessed unidimensionality of the measures using factor analysis. We evaluated DIF using logistic regression, with and without adjustment for age, gender and body mass index (BMI). RESULTS: We included 555 participants (MS: 252, Dep/Anx: 303). Factor analysis showed that each depression symptom measure had acceptable evidence of unidimensionality. In unadjusted analyses comparing the MS versus Dep/Anx groups we identified multiple items with evidence of DIF, but few items showed DIF effects that were large enough to be clinically meaningful. We observed non-uniform DIF for one PHQ-9 item, and three HADS-D items. We also observed DIF with respect to gender (one HADS-D item), and BMI (one PHQ-9 item). For the MS versus Dep/Anx groups, we no longer observed DIF post-adjustment for age, gender and BMI. On unadjusted and adjusted analyses, we did not observe DIF for any PROMIS-D item. CONCLUSION: Our findings suggest that DIF exists for the PHQ-9 and HADS-D with respect to gender and BMI in clinical samples that include people with MS whereas DIF was not observed for the PROMIS-Depression scale.

Polygenic risk scores of lithium response and treatment resistance in major depressive disorder.

Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate the genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) and non-TRD within ~4500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores (PRS) of antidepressants and lithium response for individuals with MDD and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1778 ECT-treated MDD cases, nearly all (94%) used antidepressants before their first ECT and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We did not observe a significant difference in the mean PRS of antidepressant response between TRD and non-TRD; however, we found that TRD cases had a significantly higher PRS of lithium response compared to non-TRD cases (OR = 1.10-1.12 under various definitions). The results support the evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.