Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aß-positive and Aß-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Long-term environmental enrichment is associated with better fornix microstructure in older adults.

Background: Sustained environmental enrichment (EE) through a variety of leisure activities may decrease the risk of developing Alzheimer's disease. This cross-sectional cohort study investigated the association between long-term EE in young adulthood through middle life and microstructure of fiber tracts associated with the memory system in older adults. Methods: N = 201 cognitively unimpaired participants (≥ 60 years of age) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) baseline cohort were included. Two groups of participants with higher (n = 104) or lower (n = 97) long-term EE were identified, using the self-reported frequency of diverse physical, intellectual, and social leisure activities between the ages 13 to 65. White matter (WM) microstructure was measured by fractional anisotropy (FA) and mean diffusivity (MD) in the fornix, uncinate fasciculus, and parahippocampal cingulum using diffusion tensor imaging. Long-term EE groups (lower/higher) were compared with adjustment for potential confounders, such as education, crystallized intelligence, and socio-economic status. Results: Reported participation in higher long-term EE was associated with greater fornix microstructure, as indicated by higher FA (standardized ß = 0.117, p = 0.033) and lower MD (ß = -0.147, p = 0.015). Greater fornix microstructure was indirectly associated (FA: unstandardized B = 0.619, p = 0.038; MD: B = -0.035, p = 0.026) with better memory function through higher long-term EE. No significant effects were found for the other WM tracts. Conclusion: Our findings suggest that sustained participation in a greater variety of leisure activities relates to preserved WM microstructure in the memory system in older adults. This could be facilitated by the multimodal stimulation associated with the engagement in a physically, intellectually, and socially enriched lifestyle. Longitudinal studies will be needed to support this assumption.

Brain reserve contributes to distinguishing preclinical Alzheimer's stages 1 and 2.

BACKGROUND: In preclinical Alzheimer's disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions. METHODS: We tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol. RESULTS: In asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs. CONCLUSIONS: These data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline.

Linking early-life bilingualism and cognitive advantage in older adulthood.

Previous studies have identified bilingualism as a protective factor against dementia. Here we aimed to test whether being bilingual at different life stages impacts cognition and brain structure in older adulthood. We included 746 participants from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Assessment of bilingualism at 3 life stages (early: 13-30, middle: 30-65 and late: over 65 years old) was determined with the Lifetime of Experiences Questionnaire. Individuals reporting bilingualism (i.e., daily use of L2) in the early life stage outperformed monolinguals on learning & memory, working-memory, executive functions and language. Bilingualism in middle life stage showed a significant advantage on learning & memory, while no effect of bilingualism in old life stage was identified. Brain gray matter volume was not associated with L2 use and did not differ between groups. However, stronger correlations between brain gray matter volume in selected brain regions and cognitive performance were found in bilingual participants in the early and middle life stages. Our results indicate that bilingualism in early life might provide a long-lasting protective effect on cognition and shape the brain to sustain cognitive performance in older adulthood.

Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve.

Introduction: Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them. Methods: We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE). Results: Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aß42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM. Discussion: Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.

Musical Activity During Life Is Associated With Multi-Domain Cognitive and Brain Benefits in Older Adults.

Regular musical activity as a complex multimodal lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer's disease. This cross-sectional study investigated the association and interplay between musical instrument playing during life, multi-domain cognitive abilities and brain morphology in older adults (OA) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Participants reporting having played a musical instrument across three life periods (n = 70) were compared to controls without a history of musical instrument playing (n = 70), well-matched for reserve proxies of education, intelligence, socioeconomic status and physical activity. Participants with musical activity outperformed controls in global cognition, working memory, executive functions, language, and visuospatial abilities, with no effects seen for learning and memory. The musically active group had greater gray matter volume in the somatosensory area, but did not differ from controls in higher-order frontal, temporal, or hippocampal volumes. However, the association between gray matter volume in distributed frontal-to-temporal regions and cognitive abilities was enhanced in participants with musical activity compared to controls. We show that playing a musical instrument during life relates to better late-life cognitive abilities and greater brain capacities in OA. Musical activity may serve as a multimodal enrichment strategy that could help preserve cognitive and brain health in late life. Longitudinal and interventional studies are needed to support this notion.

Novelty-Related fMRI Responses of Precuneus and Medial Temporal Regions in Individuals at Risk for Alzheimer Disease.

BACKGROUND AND OBJECTIVES: We assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy. METHODS: We studied 499 participants aged 60-88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of ß-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus, and precuneus as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, sex, study site, and education. RESULTS: In the precuneus, we observed an inverted U-shaped pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared with HC, but not in patients with AD who showed relatively lower activity than MCI. This nonlinear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to the precuneus, hippocampal activity was reduced in AD dementia compared with all other groups and related to AD biomarkers. DISCUSSION: Novelty-related activity in the precuneus follows a nonlinear pattern across the clinical spectrum of increased AD risk. Although the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the nonlinearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity.

Presenilin 1 Gene Mutation (M139V) in a German Family with Early-Onset Alzheimer's Disease: A Case Report.

OBJECTIVE: This study describes a 44-year-old German male with early-onset Alzheimer's disease as a result of a M139V presenilin 1 mutation. The patient has at least seven affected family members, spanning at least four generations. METHOD: We performed a complete demographic, genetic, neuropsychological, neuropsychiatric, neuroradiological, and neuropathological characterizations of this patient. The findings were compared with previous reports of patients with the same mutation. Demographic, neuropsychological, neuropsychiatric, neuroradiological, and neuropathological data from several affected members of the patient's family were also addressed. RESULTS: We describe similarities shared with other cases, including age at onset, rapid disease progression, severe deficits in arithmetic and visuo-constructive abilities with relative preservation of naming skills, and the presence of predominant frontal behavioral symptoms. Differences with respect to previously described cases, including the absence of positive neurological or radiological findings, psychotic symptoms, or a depressive disorder, are also identified and discussed. CONCLUSIONS: Heterogeneity in symptoms between affected patients from the same or from different families suggests that individual, genetic, or epigenetic factors most likely modulate the phenotype of patients carrying the M139V mutation.

Overcoming barriers to the adoption of locating technologies in dementia care: a multi-stakeholder focus group study.

BACKGROUND: Locating technologies are a subtype of assistive technology that aim to support persons with dementia by helping manage spatial orientation impairments and provide aid to care partners by intervening when necessary. Although a variety of locating devices are commercially available, their adoption has remained low in the past years. Several studies have explored barriers to the adoption of assistive technologies from the perspective of professional stakeholders, but in-depth explorations for locating technologies are sparse. Additionally, the inputs of business professionals are lacking. The aim of this study was to expand knowledge on barriers to the adoption of locating technologies from a multi-stakeholder professional perspective, and to explore strategies to optimize adoption. METHODS: In total, 22 professionals working in business (n = 7), healthcare (n = 6) and research (n = 9) fields related to gerontology and gerontechnology participated in our focus group study. Perceptions on the value of using locating technologies for dementia care, barriers to their adoption, as well as salient services and information dissemination strategies were explored. After verbatim transcription, transcripts were analysed following an inductive data-driven content analysis approach in MAXQDA. RESULTS: Six key adoption barriers centering on: (1) awareness-, (2) technological-, (3) product characteristic- and (4) capital investment-based limitations, (5) unclear benefits, as well as (6) ethical concerns emerged. The interplay between barriers was high. Five core themes on services and information dissemination strategies centering on: (1) digital autonomy support, (2) emergency support, (3) information dissemination actors, (4) product acquisition, and (5) product advertising were extracted. CONCLUSIONS: Our study with interdisciplinary stakeholders expands knowledge on barriers to the adoption of locating technologies for dementia care, and reinforces recommendations that an interdisciplinary strategy is needed to optimize adoption. Also, our findings show that focusing on services to increase digital autonomy and on information dissemination strategies has been largely overlooked and may be particularly effective.

Mediterranean Diet, Alzheimer Disease Biomarkers and Brain Atrophy in Old Age.

OBJECTIVE: To determine if following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer's disease (AD), we analyzed cross-sectional data from the German Longitudinal Cognitive Impairment and Dementia Study METHOD: The sample (n=512, mean age: 69.5±5.9 years) included 169 cognitively normal participants and subjects at higher AD risk (53 AD relatives, 209 SCD and 81 MCI). We defined MeDi adherence based on the Food Frequency Questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI and cognitive performance with an extensive neuropsychological battery. AD-related biomarkers (Aß42/40 ratio, pTau181) in cerebrospinal fluid were assessed in n=226 individuals. We analyzed the associations between MeDi and the outcomes with linear regression models controlling for several covariates. Additionally, we applied hypothesis-driven mediation and moderation analysis. RESULTS: Higher MeDi adherence related to larger mediotemporal gray matter volume (p<0.05 FWE corrected), better memory (ß±SE = 0.03 ± 0.02; p=0.038), and less amyloid (Aß42/40 ratio, ß±SE = 0.003 ± 0.001; p=0.008) and pTau181 pathology (ß±SE = -1.96±0.68; p=0.004). Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations between Aß42/40 ratio, pTau181 and mediotemporal atrophy. Results were consistent correcting for ApoE-ε4 status. CONCLUSION: Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. Importantly, they suggest that these associations might be explained by a decrease of amyloidosis and tau-pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications.

Value of Neuropsychological Tests to Identify Patients with Depressive Symptoms on the Alzheimer's Disease Continuum.

BACKGROUND: Depressive symptoms often co-occur with Alzheimer's disease (AD) and can impact neuropsychological test results. In early stages of AD, disentangling cognitive impairments due to depression from those due to neurodegeneration often poses a challenge. OBJECTIVE: We aimed to identify neuropsychological tests able to detect AD-typical pathology while taking into account varying degrees of depressive symptoms. METHODS: A battery of neuropsychological tests (CERAD-NP) and the Geriatric Depression Scale (GDS) were assessed, and cerebrospinal fluid (CSF) biomarkers were obtained. After stratifying patients into CSF positive or negative and into low, moderate, or high GDS score groups, sensitivity and specificity and area under the curve (AUC) were calculated for each subtest. RESULTS: 497 participants were included in the analyses. In patients with low GDS scores (≤10), the highest AUC (0.72) was achieved by Mini-Mental State Examination, followed by Constructional Praxis Recall and Wordlist Total Recall (AUC = 0.714, both). In patients with moderate (11-20) and high (≥21) GDS scores, Trail Making Test-B (TMT-B) revealed the highest AUCs with 0.77 and 0.82, respectively. CONCLUSION: Neuropsychological tests showing AD-typical pathology in participants with low GDS scores are in-line with previous results. In patients with higher GDS scores, TMT-B showed the best discrimination. This indicates the need to focus on executive function rather than on memory task results in depressed patients to explore a risk for AD.

Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers-results from the DELCODE study.

BACKGROUND: Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries. METHODS: We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries. RESULTS: The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996-1.000, p < .05). CONCLUSION: These findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated with underlying AD pathology in cognitively unimpaired participants who worry about cognitive decline. TRIAL REGISTRATION: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.

The hippocampal-to-ventricle ratio (HVR): Presentation of a manual segmentation protocol and preliminary evidence.

Disentangling age-related changes from developmental variations in hippocampal volume has proven challenging. This article presents a manual segmentation protocol for the hippocampal-to-ventricle ratio (HVR), a measure combining the assessment of hippocampal volume with surrounding ventricular volume. By providing in a single measure both a standard volumetric assessment of the hippocampus and an approximation of volume loss, based on ventricular enlargement, we believe the HVR provides a superior cross-sectional estimation of hippocampal structural integrity. In a first attempt to validate this measure, we contrasted the HVR and standard hippocampal volume in their associations with age and memory performance in two independent cohorts of healthy aging individuals. The first cohort consisted in 50 cognitively normal subjects (mean age: 66.8 years, SD: 4.96, range: 60-75 years), while the second cohort included 88 cognitively normal subjects (mean age: 65.06 years, SD: 6.42, range: 55-80 years). We showed that the manual segmentation protocol for the HVR can be implemented with high reliability. In both cohorts, the HVR showed stronger negative associations with age than standard hippocampal volume. Correlations with memory performance were also numerically superior with the HVR than standard hippocampal volume, across the two cohorts. These findings support an added benefit of using the HVR over standard hippocampal volume when examining relationships with age or memory function in aging individuals. Although further validation is required, we propose that the computation of the HVR is a promising method to improve the evaluation of hippocampal integrity from cross-sectional MR images.

User experience and clinical effectiveness with two wearable global positioning system devices in home dementia care.

INTRODUCTION: The user experience and clinical effectiveness with wearable global positioning system (GPS) devices for persons with dementia (PwDs) and caregivers (CGs) remain unclear although many are available. METHODS: Using a crossover design, 20 dyads tested two similar commercial GPS watches (products A and B) at home for 4 weeks each. Usability, product functions, design features and product satisfaction at home and the clinic were investigated. Caregiver burden and quality of life assessed clinical effectiveness. RESULTS: The final 17 dyads rated the usability, telephone function, overall design features, font, buttons, and battery life of B significantly better than A. PwDs rated the overall design features and buttons of A significantly better than CGs. Product satisfaction with both products was significantly lower at home. Clinical effectiveness was not found. DISCUSSION: User experience can be improved by optimizing specific product details. This might translate to clinical effectiveness. Social desirability bias may explain different product satisfaction ratings.

Technology for home dementia care: A prototype locating system put to the test.

INTRODUCTION: The user experience of persons with dementia and their primary caregivers with locating systems is not firmly established. METHODS: Eighteen dyads used a prototype locating system during 4 weeks. Primary outcome measures were ratings of usability, and product functions and features. Secondary outcome measures were caregiver burden, perceived self-efficacy, frequency of use, and willingness to purchase the prototype. Changes in scores between baseline (T1) and end of testing period (T2) were compared by performing independent and dependent samples correlations and descriptive statistics. RESULTS: Seventeen dyads made up the final sample. Ratings of usability and product functions and features were fair, but usability ratings were significantly reduced after 4 weeks. Although the prototype was used infrequently by majority of the participants, most caregivers would be willing to purchase the prototype, with men more willing than women. No significant change in technological willingness, caregiver burden, or perceived self-efficacy was found between T1 and T2. Perceived self-efficacy significantly negatively correlated with willingness to purchase the prototype after 4 weeks. DISCUSSION: Results highlight the importance of including end users in the research and development phase of locating systems to improve the user experience in home dementia care. Necessary indications for further research are carrying out randomized controlled trials with larger, more representative samples and developing innovative software and hardware solutions.

A systematic review of agomelatine-induced liver injury.

Agomelatine is an antidepressant with a unique mechanism of action. Since its marketing in 2009, concerns have been raised regarding its potential to induce liver injury. The authors therefore address the need to comprehensively evaluate the potential risk posed by agomelatine of inducing liver injury by reviewing data from published and unpublished clinical trials in both the pre- and postmarketing settings, as well as data from non-interventional studies, pharmacovigilance database reviews and one case report. Recommendations for clinicians are also provided. In this review, agomelatine was found to be associated with higher rates of liver injury than both placebo and the four active comparator antidepressants used in the clinical trials for agomelatine, with rates as high as 4.6% for agomelatine compared to 2.1% for placebo, 1.4% for escitalopram, 0.6% for paroxetine, 0.4% for fluoxetine, and 0% for sertraline. The review also provides evidence for the existence of a positive relationship between agomelatine dose and liver injury. Furthermore, rates of liver injury were found to be lower in non-interventional studies. Findings from pharmacovigilance database reviews and one case report also highlight the risk of agomelatine-induced liver injury. As agomelatine does pose a risk of liver injury, clinicians must carefully monitor liver function throughout treatment. However, agomelatine's unique mechanism of action and favourable safety profile render it a valuable treatment option. A quantitative analysis of agomelatine-induced liver injury is lacking in the literature and would be welcomed.