The impact of chronic pain and opioid use on cognitive decline and mild cognitive impairment (MCI) is unclear. We investigated these associations in early older adulthood, considering different definitions of chronic pain.

Men in the Vietnam Era Twin Study of Aging (VETSA; n = 1,042) underwent cognitive testing and medical history interviews at average ages 56, 62, and 68. Chronic pain was defined using pain intensity and interference ratings from the SF-36 over 2 or 3 waves (categorized as mild versus moderate-to-severe). Opioid use was determined by self-reported medication use. Amnestic and non-amnestic MCI were assessed using the Jak-Bondi approach. Mixed models and Cox proportional hazards models were used to assess associations of pain and opioid use with cognitive decline and risk for MCI.

Moderate-to-severe, but not mild, chronic pain intensity (β = −.10) and interference (β = −.23) were associated with greater declines in executive function. Moderate-to-severe chronic pain intensity (HR = 1.75) and interference (HR = 3.31) were associated with a higher risk of non-amnestic MCI. Opioid use was associated with a faster decline in verbal fluency (β = −.18) and a higher risk of amnestic MCI (HR = 1.99). There were no significant interactions between chronic pain and opioid use on cognitive decline or MCI risk (all p-values > .05).

Moderate-to-severe chronic pain intensity and interference related to executive function decline and greater risk of non-amnestic MCI; while opioid use related to verbal fluency decline and greater risk of amnestic MCI. Lowering chronic pain severity while reducing opioid exposure may help clinicians mitigate later cognitive decline and dementia risk.

US forces used Agent Orange (AO) during the Vietnam War and continued to store/test it at other locations after the war. AO is a powerful herbicide including dioxin, a highly toxic ingredient classified as a human carcinogen. The National Academies of Sciences, Engineering, and Medicine periodically review the literature on the health effects of AO exposure (AOE) and concluded in 2018 that there is sufficient evidence linking AO with a wide range of adverse health outcomes, including neurologic disorders (e.g., Parkinson’s disease). The VA has a list of medical disorders considered presumptive conditions related to AOE. More recently, AOE has been linked to a nearly double risk compared to those without AOE for receiving a dementia diagnosis. To our knowledge, no one has investigated the association of AOE to mild cognitive impairment (MCI), a condition thought to precede dementia.

We examined men in three waves of the Vietnam Era Twin Study of Aging (VETSA). In wave 3, participants self-reported yes/no to the question of whether they ever had prolonged or serious AOE. MCI was diagnosed by the Jak-Bondi approach. Impairment was defined as 2+ tests within a cognitive domain that were more than 1.5 standard deviations below normative means after adjusting for premorbid cognitive ability. In mixed effects models, we tested the effect of AOE on MCI status. Models were adjusted for age, ethnicity, and non-independence within twin pairs.

In wave 3, 12.6% (230) of 1167 participants reported AOE. Those with AOE data had mean ages of 51.1 (wave 1), 56.0 (wave 2), and 61.4 (wave 3). Those with data on both AOE and MCI numbered 861 (wave 1), 900 (wave 2), 1121 (wave 3), and 766 had AOE and MCI at all waves. AOE was significantly related to wave 2 MCI (p < .001), but not to waves 1 and 3 MCI. AOE was significantly associated with the number of time points at which someone met criteria for MCI (p = .011). Analyses were conducted on six cognitive domains used to diagnose MCI, using available participants per wave. At all 3 waves, AOE was significantly associated with lower scores in processing speed (p = .003, p = .004, p = .005, respectively), working memory (p < .001, p = .002, p = .008) and nearly significant at all waves for executive dysfunction (p < .001, p < .001, p = .050). There were two other significant associations [wave 2 memory (p = .038), wave 3 fluency (p = .024)]. The semantic fluency cognitive domain was unrelated to AOE in all waves.

AOE was consistently associated with lower processing speed, working memory, and executive dysfunction in males ages 51-61. It was also associated with the number of time points at which one met criteria for MCI in that age range, and with MCI in the mid-fifties. Findings support the idea of a risk for greater cognitive decline in those exposed to AO earlier in their lives, and with a risk for developing MCI.

Currently approved treatments for schizophrenia (antipsychotics) have demonstrated effectiveness for treating positive symptoms; however, these agents are largely ineffective in treating other domains. Negative symptoms, including avolition, alogia, blunted affect, and asociality, are difficult to treat, and often persist despite adequate control of positive symptoms. Additionally, some patients experience “predominant” (moderate-to-severe negative symptoms that have greater relative severity than co-occurring positive symptoms) or “prominent” (severity of negative symptoms [moderate-to-severe] without any reference to positive symptoms) negative symptoms. These symptoms are known to have great impact on patient social functioning and quality of life, and are associated with poorer clinical course and outcomes for patients. Here, we examined inpatient healthcare resource utilization in patients with schizophrenia experiencing predominantly negative symptoms (PNS).

De-identified data were extracted from electronic health records in the NeuroBlu Database across 25 US mental healthcare providers. Positive and negative symptom data were derived from free-text records using natural language processing. PNS was defined as the presence of three or more negative symptoms and three or fewer positive symptoms at first clinical contact following schizophrenia diagnosis. Groups were balanced for baseline demographic and clinical characteristics by minimizing the generalized Mahalanobis distance and compared using chi-square and t-tests. Treatment patterns were visualized using Sankey diagrams.

A total of 4444 patients with schizophrenia were identified and 8% were classified as PNS. A balanced cohort of 720 patients (50% PNS) was generated. Patients with PNS were more likely to be hospitalized in the 12 months following diagnosis (PNS: 76%, non-PNS: 60%, χ2: 22.5, p < 0.001) and were switched to a second-line antipsychotic after a shorter first-line treatment duration. The most frequently prescribed antipsychotics differed between groups (PNS: risperidone, aripiprazole, haloperidol; non-PNS: risperidone, olanzapine, other atypical).

This study demonstrates that negative symptoms in schizophrenia may be associated with worse illness course and higher healthcare resource utilization. There remains a need for new treatment options for patients with persistent, prominent, or predominant negative symptoms which specifically improve this historically hard-to-treat and assess symptom domain.

Sunovion Pharmaceuticals, Inc.

Abnormal tau, a hallmark Alzheimer’s disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here, we aimed to explore these potential associations.

We examined 381 community-dwelling men (mean age = 67.58; SD = 2.62) in the Vietnam Era Twin Study of Aging who underwent LC-sensitive magnetic resonance imaging and completed the Everyday Cognition scale to measure subjective cognitive decline along with their selected informants. Mixed models examined the associations between rostral-middle and caudal LC integrity and subjective cognitive decline after adjusting for depressive symptoms, physical morbidities, and family. Models also adjusted for current objective cognitive performance and objective cognitive decline to explore attenuation.

For participant ratings, lower rostral-middle LC contrast to noise ratio (LCCNR) was associated with significantly greater subjective decline in memory, executive function, and visuospatial abilities. For informant ratings, lower rostral-middle LCCNR was associated with significantly greater subjective decline in memory only. Associations remained after adjusting for current objective cognition and objective cognitive decline in respective domains.

Lower rostral-middle LC integrity is associated with greater subjective cognitive decline. Although not explained by objective cognitive performance, such a relationship may explain increased AD risk in people with subjective cognitive decline as the LC is an important neural substrate important for higher order cognitive processing, attention, and arousal and one of the first sites of AD pathology.

To investigate the association between cognitive impairment and hospitalizations, quality of life and satisfaction with life among patients with schizophrenia.

A point-in-time survey was conducted between July and October 2019 via the Adelphi Schizophrenia Disease Specific Programme across the USA. Patients were stratified as mild or severe based on the level of cognitive impairment reported by their psychiatrist (normal, mild = mild; moderate, severe, very severe = severe). Multiple regression analysis was used to model the association between cognitive impairment and outcomes, adjusting for baseline characteristics.

Data were provided by 124 psychiatrists for 651 mildly and 484 severely impaired patients with schizophrenia; PSCs were completed by 349 mildly and 206 severely impaired patients. Severe cognitive impairment was associated with increased odds of hospitalization due to schizophrenia relapse since diagnosis (2.10 odds ratio [OR], P = .004) and within 12 months (1.95 OR, P < .001) compared to mild impairment. Moreover, patients with severe cognitive impairment had poorer quality of life according to the EuroQoL 5-dimension (EQ-5D) Health Index (−0.085 coefficient, P < .001) and EQ-5D Visual Analogue Scale (−6.24 coefficient, P = .041) compared to patients with mild cognitive impairment. Severe cognitive impairment was also associated with lower overall life satisfaction according to the Quality-of-Life Enjoyment and Satisfaction Questionnaire (−8.13 coefficient, P = .006) compared to mild cognitive impairment.

Schizophrenia patients with severe cognitive impairment had more hospitalizations due to relapse than patients with mild cognitive impairment. Additionally, patients with severe cognitive impairment had significantly lower quality of life and overall satisfaction with life compared to patients with mild cognitive impairment.

Sunovion Pharmaceuticals

Schizophrenia-related, health, social, and fiscal consequences are substantial, affecting patients, caregivers, and society. The incidence of health, social, and fiscal outcomes are frequently reported for the overall schizophrenia population, not stratified by remission or relapse status.

This study aimed to assess healthcare resource use, employment status, and housing circumstances for patients with schizophrenia in remission or relapse, compared to the overall schizophrenia population.

The Adelphi Schizophrenia Disease Specific Programme was a point-in-time survey conducted across the USA between July and October 2019. Remission was defined using Clinical Global Impression-Severity (CGI-S) score of 1-3 (stable), with relapse defined as a CGI-S score of 4-7 (unstable). Outcome-specific rate ratios were calculated by dividing the cumulative incidence for those in remission or relapse by the cumulative incidence of the overall schizophrenia population. Ratios greater than 1 indicate a higher probability of the event.

Psychiatrists (n = 124) provided data for 409 patients in remission and 609 patients in relapse. Patients with schizophrenia in remission were more likely to be employed (1.66, 95% confidence interval [1.46-1.90]) and to live with a partner or family (1.08 [1.01-1.17]) compared to the overall schizophrenia population, whereas patients in relapse were more likely to experience hospitalizations in the previous 12 months (1.34 [1.19-1.15]), disability-related unemployment (1.38 [1.25-1.51]), sick leave absences (1.23 [0.66-2.31]), need to support housing (1.39 [1.08-1.79]), and homelessness (1.47 [0.95-2.27]).

Schizophrenia patients in relapse were more likely to experience hospitalizations, unemployment, and have unfavorable housing circumstances compared to the overall schizophrenia population. Identifying patients at risk of relapse may aid physicians in targeting interventional support, thereby reducing the burden of schizophrenia.

Sunovion Pharmaceuticals

Schizophrenia is associated with health, social, and financial burdens for patients, caregivers, and society. Major systemic changes, reforms, and technological advances have happened in the USA since the prior estimate of the societal cost of schizophrenia, $155.7B in 2013. This study analyzes the most recent data and literature to update this estimate.

Direct and indirect costs associated with schizophrenia in the US in 2019 were estimated using a prevalence-based approach (ICD-10 codes: F20, F25). Direct healthcare costs were assessed retrospectively using a matched cohort design in the IBM Watson Health MarketScan Commercial, Medicare, and Medicaid databases from October 1, 2015, through December 31, 2019. Patients were matched to controls on demographics, insurance type, and index year. Direct nonhealthcare costs were estimated using published literature and government data. Indirect costs were estimated using a human capital approach and the value of quality-adjusted life years lost. Cost offsets were applied to account for basic living costs avoided. Excess costs, comparing costs for individuals with and without schizophrenia, were reported in 2019 USD.

The estimated excess economic burden of schizophrenia in the US in 2019 was $330.6B, including $62.3B in direct healthcare costs (19%), $19.7B in direct nonhealthcare costs (5%), and $251.9B in excess indirect costs (76%). The largest drivers of indirect costs were caregiving ($112.3B), premature mortality ($77.9B), and unemployment ($54.2B).

The estimated societal burden of schizophrenia in the USA in 2019 was $330.6B, which represented a 93.5% increase from 2013 to 2019, after accounting for inflation. This study underscores the increasing and apparent burden of schizophrenia not only on the patient, but also on caregivers and society.

Sunovion Pharmaceuticals

To investigate the association between cognitive impairment and hospitalizations, quality of life and satisfaction with life among patients with schizophrenia.

A point-in-time survey was conducted between July and October 2019 via the Adelphi Schizophrenia Disease Specific Programme across the United States of America. Patients were stratified as mild or severe based on the level of cognitive impairment reported by their psychiatrist (normal, mild = mild; moderate, severe, very severe = severe). Multiple regression analysis was used to model the association between cognitive impairment and outcomes, adjusting for baseline characteristics.

Data were provided by 124 psychiatrists for 651 mildly and 484 severely impaired patients with schizophrenia; PSCs were completed by 349 mildly and 206 severely impaired patients. Severe cognitive impairment was associated with increased odds of hospitalization due to schizophrenia relapse since diagnosis (2.10 odds ratio [OR], P = .004) and within 12 months (1.95 OR, P < .001) compared to mild impairment. Moreover, patients with severe cognitive impairment had poorer quality of life according to the EuroQoL 5-dimension (EQ-5D) Health Index (−0.085 coefficient, P < .001) and EQ-5D Visual Analogue Scale (−6.24 coefficient, P = .041) compared to patients with mild cognitive impairment. Severe cognitive impairment was also associated with lower overall life satisfaction according to the Quality-of-Life Enjoyment and Satisfaction Questionnaire (−8.13 coefficient, P = .006) compared to mild cognitive impairment.

Schizophrenia patients with severe cognitive impairment had more hospitalizations due to relapse than patients with mild cognitive impairment. Additionally, patients with severe cognitive impairment had significantly lower quality of life and overall satisfaction with life compared to patients with mild cognitive impairment.

Sunovion Pharmaceuticals

Extrapyramidal symptoms (EPS) affect 15% to 30% of patients with schizophrenia treated with antipsychotics and have been associated with poor patient outcomes.

To examine the incidence and economic burden of EPS in patients with schizophrenia initiating treatment with atypical antipsychotics (AAPs).

Patients with schizophrenia newly initiating AAPs with no prior EPS were identified in the MarketScan Commercial and Medicare Supplemental database from January 1, 2012 to December 31, 2018. Incidence of EPS (new diagnosis or medication) was assessed in the year following AAP initiation. Patients were classified as developing (EPS cohort) or not developing (non-EPS cohort) EPS. All-cause and schizophrenia-related healthcare resource use and costs were compared between cohorts over the year following the first EPS claim (EPS) or randomly assigned index date (non-EPS). Multivariate models were developed for total healthcare costs and inpatient admissions.

A total of 3558 patients qualified for the study; 22.1% developed EPS in the year following AAP initiation (incidence: 26.9 cases/100-person-years). Multivariate analyses demonstrated that EPS patients had a 34% higher odds of all-cause (OR:1.3361, 95% CI:1.0770-1.6575, P < .01) and 84% increased odds of schizophrenia-related (OR:1.8436, 95% CI:1.0434-2.4219, P < .0001) inpatient admissions, as well as significantly higher all-cause (EPS: $26,632 vs non-EPS: $21,273, P < .001) and schizophrenia-related (EPS: $9018 vs non-EPS: $4475, P < .0001) total costs compared to the non-EPS cohort.

Approximately 20% of patients developed EPS in the year following AAP initiation. The significant increases in healthcare resource utilization and costs in the EPS cohorts highlight the need for treatments that effectively target schizophrenia symptoms while reducing the risk of EPS.

Sunovion Pharmaceuticals

To determine associations of alcohol use with cognitive aging among middle-aged men.

1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003–2007 to 2016–2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1–4 drinks in past 14 days), light (5–14 drinks), moderate (15–28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors.

Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by –0.21 SD (95% CI –0.35, –0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, –0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association.

Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.

Alzheimer’s disease (AD) is highly heritable, and AD polygenic risk scores (AD-PRSs) have been derived from genome-wide association studies. However, the nature of genetic influences very early in the disease process is still not well known. Here we tested the hypothesis that an AD-PRSs would be associated with changes in episodic memory and executive function across late midlife in men who were cognitively unimpaired at their baseline midlife assessment..

We examined 1168 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively normal (CN) at their first of up to three assessments across 12 years (mean ages 56, 62, and 68). Latent growth models of episodic memory and executive function were based on 6–7 tests/subtests. AD-PRSs were based on Kunkle et al. (Nature Genetics, 51, 414–430, 2019), p < 5×10−8 threshold.

AD-PRSs were correlated with linear slopes of change for both cognitive abilities. Men with higher AD-PRSs had steeper declines in both memory (r = −.19, 95% CI [−.35, −.03]) and executive functioning (r = −.27, 95% CI [−.49, −.05]). Associations appeared driven by a combination of APOE and non-APOE genetic influences.

Memory is most characteristically impaired in AD, but executive functions are one of the first cognitive abilities to decline in midlife in normal aging. This study is among the first to demonstrate that this early decline also relates to AD genetic influences, even in men CN at baseline.