Vortioxetine Treatment for Depression in Alzheimer's Disease: A Randomized, Double-blind, Placebo-controlled Study.

Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. Traditionally thought of as an untreatable degenerative condition, recent advances in drug therapy have challenged this view. The disease is characterised by an insidious decline in cognitive and non-cognitive function. Classically, short and long-term memory is impaired while language skills, concentration and attention are often affected. This results in impaired ability to learn and retain new skills as well as the loss of existing ones. Non-cognitive function is the global term used to describe problems such as depression, agitation, personality changes, delusions and hallucinations. These factors have a significant impact on patient behaviour and a very real impact on the quality of life for both patients and caregivers. Diagnosis of AD is clinically based, and using the NINCDS-ADRDA criteria (Table 1) [1], a diagnosis of probable or possible AD can be made. Definitive diagnosis relies on pathological confirmation, which in the majority of cases is rarely completed. With the development of AD specific treatments, definition of AD from other types of dementia is very important. Table 1 NINCDS-ADRDA Criteria for clinical diagnosis of Alzheimer’s disease. Pathogenesis The pathogenesis of AD has not yet been elucidated. It is widely accepted that a combination of genetic susceptibility factors and environmental triggers are responsible for late onset sporadic AD, the most common form of the disease. An understanding of the disease mechanism remains elusive, and is the key to developing a disease modifying agent. Currently, it is proposed that beta amyloid protein, abnormal tau protein or possibly both play key factors in the development of disease. It has been widely postulated that oxidative damage and a slow inflammatory process are two possible mechanisms involved. As yet, no product with proven disease modifying properties is available, and current treatments offer symptomatic benefit only. The development of acetylcholinesterase (AChe) inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD [2] and the resultant cholinergic deficit contributes to the cognitive impairment of these patients [3]. Although many believe this ‘cholinergic hypothesis’ to be important, others feel it represents a less significant component of the disease process [4]. Many other neurotransmitters are affected in AD, and the relative importance of each in relation to clinical findings has not been fully elucidated. Initial work focused on the use of acetylcholine precursors, using a similar rationale to dopamine therapy in Parkinson’s disease. A series of small trials using precursors such as choline and phosphatidylcholine showed no reliable improvement in cognitive function, with only 10 out of 43 trials reporting any positive effect [5]. There has been renewed interest in muscarinic agonists drugs, which when first introduced, had major problems with adverse cholinergic effects. Better understanding of the molecular pathology of muscarinic receptors and their subtypes has led to the development of more specific agonists. Drugs such as xanomeline, milameline, and civimeline have reached clinical trials, and the improvements seen in cognitive function are reviewed by Avery et al. [6]. There are also claims that these drugs have disease modifying properties, with effects on APP processing and tau phosphorylation. Muscarinic agonists remain in trial, but have yet to fulfil their potential in AD treatment. The only group of drugs currently licensed for AD treatment is the AChe inhibitors, which act through inhibition of the enzyme acetylcholinesterase (AChe), responsible for the breakdown of ACh in the neural synapse. A meta-analysis of the early AChe inhibitor treatments was encouraging [7] and these proceeded to larger placebo controlled double-blind trials.

Mild cognitive impairment and subjective cognitive impairment

Purpose: Depression, which affects about 52% of Alzheimer's disease (AD) patients, can worsen cognitive impairment and increase mortality and suicide rates. We hope to provide clinical evidence for the prevention and treatment of depression in AD patients by investigating related risk factors of depression in AD patients.Methods: 158 AD inpatients of the Department of Neurology, Daping Hospital from September 2017 to March 2019 were enrolled. General information, laboratory tests, cognitive and emotional function assessments of the inpatients were collected. Logistic regression was used to analyze the risk factors of depression in AD patients, and the relationship between 17 Hamilton depression scale scores and HbA1c levels in AD patients was further analyzed.Results: The prevalence of age, gender, hypertension, hyperlipidemia, Type 2 diabetes mellitus (T2DM), and white matter lesions (WML) in the AD with depression group was significantly different from without depression group. Hypertension, T2DM, and WML are independent risk factors for depression in AD patients. The depression scores of AD patients with HbA1c>6.5% were significantly higher than AD patients with HbA1c ≤ 6.5%, and there were significant difference in depression scale scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is >6.5%, while no difference in depression scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is ≤6.5%.Conclusion: T2DM is an independent risk factor for AD patients with depression. Increased HbA1c levels aggravate depression in AD patients, and controlling HbA1c levels and anti-diabetes drugs can reduce the severity of depression in AD patients.

BackgroundDelusions in neurocognitive disorder due to Alzheimer’s disease (AD) worsen patients’ cognitive functions and activities of daily living (ADL), increasing caregiver burden and the risk of mortality. AD patients with delusions tend to experience a more rapid decline in cognition and have demonstrated poorer performance on various cognitive function tests. Considering the prognosis of delusion in AD patients, it tends to be more favorable with appropriate treatment. However, there is a lack of neuropsychological research, specifically examining the impact of delusions in AD, characterized by progressive deterioration of cognitive function. This study investigates the impact of delusions on cognitive function and ADL under conditions controlling for disease severity.MethodsWe compared cognitive function and ADL in AD patients aged 65 years or older according to the presence of delusions. To assess longitudinal change, we analyzed data from patients monitored for an average of 15 to 16 months. We assessed cognitive function and ADL using the Seoul Neuropsychological Screening Battery-Second Edition (SNSB–II) and delusions using the Neuropsychiatric Inventory (NPI). We used IBM SPSS Statistics version 25.0 for all statistical analyses. The analysis was not adjusted for multiple comparisons. We investigated how delusions impact cognitive function and ADL, controlling for age, educational level, and disease severity.ResultsThe delusions group exhibited poorer immediate recall of verbal memory than the non-delusions group. In the follow-up evaluation, patients who developed delusions had lower baseline cognitive function than those who did not, and their language fluency declined over time. In addition, we found the presence of delusions associated with worse functional impairment in ADL as the disease progressed.ConclusionWhile controlling for the severity of AD, we found no significant negative impacts of delusions on most cognitive functions. Nevertheless, it is noteworthy that the immediate recall of verbal memory and the Controlled Oral Word Association Test (COWAT)_animal sensitively detected the negative impact of delusions. Furthermore, since delusions are associated with worsening ADL, we understand that delusion treatment is important for improving the quality of life for patients and caregivers.

Editorial: New drugs for Alzheimer's disease in Japan

P4-203: The effect of cognitive function and depressive mood on the activity of daily living and quality of life in Chinese elderly patients with Alzheimer’s disease

Background/Aims: Depression occurs in 20–50% of the Alzheimer disease (AD) patients. It is not known whether depression in AD shares its pathophysiology with depressive disorder. Previously we found a fourfold increase of corticotropin-releasing hormone (CRH)-immunoreactive (IR) neurons in the hypothalamic paraventricular nucleus in depression. The objective of the present study was to find out whether in depression in AD the same phenomenon of an increased number of CRH-IR neurons could be observed. Methods: Post-mortem brain tissue was obtained from a cohort of 23 AD patients prospectively studied using the Cornell Scale for Depression in Dementia to measure depressive symptoms. The number of CRH-IR neurons was determined using immunocytochemistry and the Image Pro Plus analysis program. Results: A significant positive correlation was found between the Cornell scores and the number of CRH-IR neurons (p = 0.039) in AD patients. Conclusion: These results suggest that depressive disorder and depression in AD share, at least partly, their pathophysiology.

Sertraline for the Treatment of Depression in Alzheimer Disease

(Reprinted with permission from American Psychiatric Association, http://psychiatryonline.org/guidelines).

The foundation for using intravenous immunoglobulin (IVIg) to treat Alzheimer's disease (AD) can be traced back to the discovery, in the early 1990s, of naturally occurring anti-amyloid antibodies in human blood. A decade later, a number of independent investigators reported reduced levels of naturally occurring anti-amyloid antibodies in the spinal fluid and blood of AD patients relative to age-matched controls 1–3. Dodel subsequently reported that IVIg contained elevated levels of antibodies against amyloid-β (Aβ) monomers and proposed its use as a potential treatment for AD 4.

Cognitive decline in dementia often leads to impaired activities of daily living (ADL), which worsens as the condition progresses. Although a complex rehabilitation program that includes exercise, cognitive tasks, and family guidance improves physical ability in people with dementia and mild cognitive impairment (MCI), the effects on cognitive function and ADL remain unclear. We conducted this study to clarify this point. This retrospective observational study was conducted at the outpatient rehabilitation department of the National Center for Geriatrics and Gerontology, Japan. It analyzed 50 MCI and Alzheimer disease (AD) patients who participated in a holistic physico-cognitive rehabilitation (HPCR) program. The control group consisted of 50 patients matched by age, gender, disease, and Barthel Index (BI) from 963 MCI and AD patients who did not undergo HPCR. Cognitive function was assessed using the Mini-Mental State Examination, and ADL was evaluated with the BI. Both groups showed a significant decline in MMSE scores after 1 year. However, the intervention group maintained its ADL function, while the control group experienced a significant reduction in BI scores. HPCR, combining exercise therapy and cognitive training, may help maintain ADL in patients with MCI and AD despite cognitive decline. This study suggests that rehabilitation plays a crucial role in sustaining daily functioning in dementia care.

Declines in activities of daily living (ADL) and instrumental activities of daily living (IADL) performances due to cognitive impairments hinder mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients' independent and safe daily lives. In order to prevent and treat this, several cognitive interventions have been implemented, but their ecological validity was not ensured due to that their contents are far from real life. Virtual reality (VR) can resemble real life with immersive stimuli, but there have been few studies confirming its ecological effects on ADL and IADL. Therefore, this study conducted a meta-analysis of VR-based cognitive training to investigate its ecological effects on ADL and IADL in MCI and AD patients. From February 2012 to February 2022, a search was conducted for articles published in PubMed, Cochrane, Science Direct, and Web of Science. Quality assessment was assessed by the PEDro scale, and the Cochrane Collaboration tool was used to assess risk of bias. Publication bias was assessed by Egger's regression. Five studies that met inclusion criteria were included in this study. The VR-based cognitive training showed significant effects on ADL and IADL in both MCI and AD patients. When comparing effects in each group, both MCI and AD patients showed significant effects on ADL and IADL, but MCI patients showed lower effects on ADL and IADL than AD patients. The results indicated that VR-based cognitive training would be beneficial to improve ADL and IADL in MCI and AD patients, suggesting that VR-based cognitive training is ecologically valid.

Neuropsychiatric symptoms and cognitive impairment are independent contributors of functional impairment in activities of daily living (ADL) in Alzheimer's disease (AD) patients. ADL could be divided according to its complexity in three subdomains: basic (BADL), instrumental (IADL), and advanced (a-ADL). Studying the cognitive and neuropsychiatric determinants of BADL, IADL, and a-ADL in normal cognitive elders and AD patients. 144 subjects were graduated using the clinical dementia rating (CDR) in CDR = 0, n = 52 (control group) and 92 AD patients CDR = 0.5, n = 34 and CDR = 1&2, n = 58. They were assessed with measures of cognitive performance and neuropsychiatric symptoms that were included in regression models to measure the best predictors for each ADL subdomain at every CDR status. AD patients were significantly older, and had significantly more severe functional impairment, neuropsychiatric symptoms, and cognitive decline than controls. The best predictors of functional impairment in controls and CDR = 0.5 AD patients were neuropsychiatric symptoms; in the CDR 0.5 patients, apathy severity was the most important determinant of IADL and a-ADL impairment. While in the CDR 1&2 AD patients, cognitive impairment was the principal determinant of functional impairment, being memory the best determinant of IADL and a-ADL impairment, while global cognition was of BADL impairment. The contribution of cognitive impairment and neuropsychiatric symptoms varied according to the subdomain of ADL, and the CDR. In very mild AD and controls the neuropsychiatric symptoms are the best predictors of more complex ADL impairment, while cognitive impairment is more important at mild to moderate states of AD.

To examine the efficacy of fluoxetine in the treatment of depression in patients with probable Alzheimer's disease (AD). This double-blind, parallel-design study included a consecutive series of 41 AD subjects meeting DSM-IV criteria for major or minor depression who were randomized to receive fluoxetine (up to 40 mg/day) or identical-appearing placebo. All patients received biweekly evaluations consisting of the Hamilton Depression Scale (HAM-D) and the Clinical Global Impression as primary efficacy measures, and the Mini-Mental State Exam, Hamilton Rating Scale for Anxiety, and the Functional Independence Measure as secondary efficacy measures. Complete remission of depression was found in 47% of subjects treated with fluoxetine and in 33% of subjects treated with placebo. Both the fluoxetine and the placebo groups showed a significant decline in HAM-D scores over time, but the magnitude of mood improvement was similar for both groups. Fluoxetine was well tolerated, and most side effects were mild. Fluoxetine treatment for depression in AD did not differ significantly from treatment with placebo. Our study also confirms the presence of a placebo effect in the treatment of depression in AD.

Intrinsic Connectivity Identifies the Hippocampus as a Main Crossroad between Alzheimer’s and Semantic Dementia-Targeted Networks