Sex Differences in Longitudinal Trajectories of Cognitive Aging in Zaragoza, Spain.

OBJECTIVES: The objective of this study was to document the longitudinal trajectories of cognitive aging in a sample of cognitively healthy subjects of 55 years or older. The following differences between men and women were hypothesized: 1) in the cognitive loss through aging, 2) in the distinct trajectories identified; and 3) in the predictors associated with the identified trajectories. DESIGN AND SETTING: A 4-wave, population-based study in Zaragoza, Spain (1994-2006). PARTICIPANTS: A total of 2,403 individuals aged 55+ years, cognitively healthy at baseline. MEASUREMENTS: All participants had at least three measurements with the Mini-Mental State Examination (MMSE). Validated Spanish versions of international instruments were used for assessment. Random effects linear panel regression model for analyzing differences by sex in MMSE scores through aging were performed, and growth mixture models (GMM) applied independently for each sex for modeling the longitudinal cognitive trajectories. RESULTS: Women showed lower mean MMSE scores in all phases and significantly higher loss in the MMSE from phases 2 to 3 and 3 to 4. The best fitting age-adjusted model of the cognitive trajectories was a 4-class GMM in men and a 3-class in women. Education was a predictor of cognitive trajectories in both men and women. Dependence on iADLs and alcohol status were predictors only for men, and depression and diabetes only for women. CONCLUSIONS: The identified differences by sex in cognitive trajectories and their associated factors suggest that men and women may require a different strategy when addressing cognitive aging.

Prevalence of depression among medical students during the COVID-19 pandemic. A systematic review and meta-analysis.

BACKGROUND: Medical students frequently have depressive symptoms. Thus, the psychological impact of COVID-19 on them should be high. AIM: To conduct a systematic review and meta-analysis on the prevalence of depression in medical students during the COVID-19 pandemic. MATERIAL AND METHODS: MEDLINE via PubMed, Embase and Web of Science were searched for studies reporting the prevalence of depression in medical students, published from December 1, 2019 to December 27, 2020. RESULTS: Eleven studies were included, most of them from Asia. The estimated overall prevalence of depression in medical students was 31% (95% CI: 23%-40%), with lower prevalence rates reported in studies from Asia in general, and China in particular. CONCLUSIONS: Our findings indicate that the proportion of medical students with depression during the pandemic was high, and comparable with that reported in other university students.

Pathways to care for people with dementia: An international multicentre study.

OBJECTIVE: The aim of the present study was to characterize the clinical pathways that people with dementia (PwD) in different countries follow to reach specialized dementia care. METHODS: We recruited 548 consecutive clinical attendees with a standardized diagnosis of dementia, in 19 specialized public centres for dementia care in 15 countries. The WHO "encounter form," a standardized schedule that enables data concerning basic socio-demographic, clinical, and pathways data to be gathered, was completed for each participant. RESULTS: The median time from the appearance of the first symptoms to the first contact with specialist dementia care was 56 weeks. The primary point of access to care was the general practitioners (55.8%). Psychiatrists, geriatricians, and neurologists represented the most important second point of access. In about a third of cases, PwD were prescribed psychotropic drugs (mostly antidepressants and tranquillizers). Psychosocial interventions (such as psychological counselling, psychotherapy, and practical advice) were delivered in less than 3% of situations. The analyses of the "pathways diagram" revealed that the path of PwD to receiving care is complex and diverse across countries and that there are important barriers to clinical care. CONCLUSIONS: The study of pathways followed by PwD to reach specialized care has implications for the subsequent course and the outcome of dementia. Insights into local differences in the clinical presentations and the implementation of currently available dementia care are essential to develop more tailored strategies for these patients, locally, nationally, and internationally.

Does depression increase the risk of dementia? Updated meta-analysis of prospective studies.

BACKGROUND: Our primary aim was to conduct an update meta-analysis of prospective studies investigating the association between depression and dementia risk. METHODS: We searched Pubmed database to identify all relevant papers published from January 2014 to March 2019. Prospective studies with a minimum follow-up period of 1 year, baseline depression assessment, absence of dementia or mild cognitive impairment at baseline were selected. We calculated pooled relative risks (RR), with a random effect model, as well as compute population attributable fraction (PAF) of dementia due to depression. RESULTS: Eight cohorts were included. A statistically significant association between depression and dementia risk, with a pooled RR of 1.63 (95% CI: 1.30-2.04), and a PAF of 9.0% (95% CI: 4.5%-14.1%), were found. CONCLUSIONS: Depression is associated with an increased risk of dementia in this meta-analysis.

Mortality in Mild Cognitive Impairment Diagnosed with DSM-5 Criteria and with Petersen's Criteria: A 17-Year Follow-Up in a Community Study.

OBJECTIVE: To explore the possibility that the mortality risk of mild cognitive impairment (MCI) as diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria (DSM-5-MCI) will be higher than using Petersen's criteria (P-MCI) and to report the population-attributable fraction (PAF) of mortality due to MCI. METHODS: A representative community sample of 4,803 individuals aged 55 or more years was interviewed and then followed for 17 years. Standardized instruments were used in the assessment, including the Geriatric Mental State-AGECAT, and research psychiatrists diagnosed P-MCI and DSM-5-MCI cases following operationalized criteria. Mortality information was obtained from the official population registry. Kaplan-Meier age-adjusted survival curves were built for the MCI diagnostic groups, and Cox proportional hazards regression models were used to calculate the hazard ratio of death in participants with MCI relative to those without. We also estimated the PAF of mortality due to specific MCI diagnostic groups. RESULTS: Compared with noncases, the mortality rate ratio was approximately double in DSM-5-MCI individuals (2.3) than in P-MCI individuals (1.2). In the multivariate statistical analysis, a significant association between each diagnostic category and mortality was observed but was only maintained in the final model in DSM-5-MCI cases (hazard ratio: 1.24). The PAF of mortality due to MCI was approximately 1% in both MCI categories. CONCLUSION: The mortality risk in comparison with noncases was higher in DSM-5-MCI than in P-MCI. The PAF of mortality in DSM-5-MCI individuals was ~ 1% over a 17-year period.

Depression and incident Alzheimer disease: the impact of disease severity.

OBJECTIVES: To test the hypothesis that clinically significant depression (particularly severe depression) increases the risk of Alzheimer's disease (AD). METHODS: A longitudinal, three-wave epidemiologic study was implemented in a sample of individuals aged 55 years and older (n = 4,803) followed up at 2.5 years and 4.5 years. This was a population-based cohort drawn from the Zaragoza Dementia and Depression (ZARADEMP) Project, in Zaragoza, Spain. Participants included individuals cognitively intact at baseline (n = 3,864). The main outcome measures were depression as assessed by using the diagnostic interview Geriatric Mental State- Automated Geriatric Examination for Computer Assisted Taxonomy package; and AD diagnosed by a panel of research psychiatrists according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. The Fine and Gray multivariate regression model was used in the analysis, accounting for mortality. RESULTS: At baseline, clinically significant depression was diagnosed in 452 participants (11.7%); of these, 16.4% had severe depression. Seventy incident cases of AD were found at follow-up. Compared with nondepressed individuals, the incidence rate of AD was significantly higher in the severely depressed subjects (incidence rate ratio: 3.59 [95% confidence interval: 1.30-9.94]). A consistent, significant association was observed between severe depression at baseline and incident AD in the multivariate model (hazard ratio: 4.30 [95% CI: 1.39-13.33]). Untreated depression was associated with incident AD in the unadjusted model; however, in the final model, this association was attenuated and nonsignificant. CONCLUSIONS: Severe depression increases the risk of AD, even after controlling for the competing risk of death.

Longitudinal trajectories of cognitive aging.

PURPOSE OF REVIEW: This review summarizes recent evidence related to the cognitive trajectories of aging, the factors associated with the different trajectories, and the effect of sex on cognitive decline. RECENT FINDINGS: Trajectories of cognitive aging identified in different studies vary in number, in the proportion of individuals falling into each of the classes and in the predictors of class membership. Trajectories observed include types with 'rapid decline', those with 'gradual decline' and those with 'maintenance of high level' of cognitive performance. Predictors of decline and predictors of maintenance of cognitive performance may be different. While factors such as education were in general associated with high performance, and reversely with low performance, other factors, such as depression were predictors only for some groups, particularly the declining ones. Sex differences in cognitive trajectories and the associated predictive factors have also been identified. SUMMARY: The findings on education may be particularly important in populations with low educational level, especially among women and the findings on depression have special interest in preventing cognitive decline in women. Further work is required to explain intriguing inconsistencies observed in the literature.

Clinically significant anxiety as a risk factor for Alzheimer's disease: Results from a 10-year follow-up community study.

OBJECTIVE: There is growing evidence for an association between anxiety and an increased risk of dementia, but it is not clear whether anxiety is a risk factor or a prodromic symptom. In this study, we investigated if clinically significant anxiety increases the risk of developing Alzheimer's disease (AD) up to 10 years later. METHODS: We used data from the longitudinal Zaragoza Dementia and Depression (ZARADEMP) Project. Excluding subjects with dementia at baseline left us with 3044 individuals aged >65 years. The Geriatric Mental State-Automated Geriatric Examination for Computer Assisted Taxonomy (GMS-AGECAT) package was used to identify cases and subcases of anxiety. AD was diagnosed by a panel of research psychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. Multivariate survival analysis with a competing risk regression model was performed. RESULTS: We observed a significant association between clinically significant anxiety at baseline and AD risk within a 10-year follow-up (SHR 2.82 [95% CI 1.21-6.58]), after controlling for confounders including depression. In contrast, isolated symptoms of anxiety were not significantly associated with an increased incidence of AD. CONCLUSION: Our results support the hypothesis that clinically significant anxiety is an independent risk factor for AD and not just a prodromic symptom. Future studies should clarify if treating anxiety reduces the incidence of AD.

Elevated plasma ceramides in depression.

The authors did a preliminary examination asking whether plasma ceramides were elevated in depression, and whether the elevation was more pronounced in Alzheimer's disease patients than in control subjects. Results suggest that plasma ceramides are elevated in persons with a diagnosis of major depression, regardless of dementia status.

Apathy and neurocognitive correlates: review from the perspective of 'precision psychiatry'.

PURPOSE OF REVIEW: From the perspective of motivated behaviour and the so-called 'precision psychiatry', we try to identify recent advances in the neurocognitive and biological correlates of apathy. RECENT FINDINGS: New evidence supports the notion that apathy is a common transdiagnostic and heterogeneous clinical syndrome, now conceptualized as a reduction in 'goal-directed' activity. Similarly, abundant evidence has been found related to neurocognitive correlates of apathy and the associations between clinical apathy and the processes primarily responsible for mediating motivational drive and effort-based decision making.Notwithstanding that the neurobiological basis is still poorly understood, there is some agreement in recent articles about a common system-level mechanism underlying apathy, pointing at specific medial frontal cortex and subcortical structures, including anterior cingulate cortex, medial orbitofrontal cortex and ventral striatum and related circuitry. SUMMARY: Although difficulties in interpreting the results of these studies are apparent, because of different concepts of apathy used and methodological shortcomings identified, we have found consistent advances in the neurocognitive and biological correlates of apathy, relevant for the deep phenotyping proposed by the 'precision psychiatry' approach. This framework may eventually facilitate the identification of predictive-risk models and new specific therapeutic targets in psychiatry.

Differences in Trajectories and Predictive Factors of Cognition over Time in a Sample of Cognitively Healthy Adults, in Zaragoza, Spain.

Great inter-individual variability has been reported in the maintenance of cognitive function in aging. We examined this heterogeneity by modeling cognitive trajectories in a population-based longitudinal study of adults aged 55+ years. We hypothesized that (1) distinct classes of cognitive trajectories would be found, and (2) between-class differences in associated factors would be observed. The sample comprised 2403 cognitively healthy individuals from the Zaragoza Dementia and Depression (ZARADEMP) project, who had at least three measurements of the Mini-Mental State Examination (MMSE) in a 12-year follow-up. Longitudinal changes in cognitive functioning were modeled using growth mixture models (GMM) in the data. The best-fitting age-adjusted model showed 3 distinct trajectories, with 1-high-to-moderate (21.2% of participants), 2-moderate-stable (67.5%) and, 3-low-and-declining (9.9%) cognitive function over time, respectively. Compared with the reference 2-trajectory, the association of education and depression was significantly different in trajectories 1 and 3. Instrumental activities of daily living (iADLs) were only associated with the declining trajectory. This suggests that intervention strategies should be tailored specifically to individuals with different trajectories of cognitive aging, and intervention strategies designed to maintain cognitive function might be different from those to prevent decline. A stable cognitive performance ('successful cognitive aging') rather than a mild decline, might be more 'normal' than generally expected.

Prevalence of depression during the COVID-19 outbreak: A meta-analysis of community-based studies.

Introduction: COVID-19 pandemic, declared on March 11, 2020, constitute an extraordinary health, social and economic global challenge. The impact on people's mental health is expected to be high. This paper sought to systematically review community-based studies on depression conducted during the COVID-19 and estimate the pooled prevalence of depression. Method: We searched for cross-sectional, community-based studies listed on PubMed or Web of Science from January 1, 2020 to May 8, 2020 that reported prevalence of depression. A random effect model was used to estimate the pooled proportion of depression. Results: A total of 12 studies were included in the meta-analysis, with prevalence rates of depression ranging from 7.45% to 48.30%. The pooled prevalence of depression was 25% (95% CI: 18% - 33%), with significant heterogeneity between studies (I 2  = 99.60%, p < .001). Conclusions: Compared with a global estimated prevalence of depression of 3.44% in 2017, our pooled prevalence of 25% appears to be 7 times higher, thus suggesting an important impact of the COVID-19 outbreak on people's mental health. Addressing mental health during and after this global health crisis should be placed into the international and national public health agenda to improve citizens' wellbeing.

Introducción: La pandemia de COVID-19, declarada el 11 de marzo de 2020, representa un reto global extraordinario a nivel sanitario, social y económico. Se espera un impacto alto en la salud mental de las personas. Este artículo tiene como objetivo realizar una revisión sistemática de estudios transversales basados en muestras comunitarias que proporcionaban la prevalencia de depresión durante la crisis del COVID-19. Método: Se realizó una búsqueda de estudios comunitarios publicados en Pubmed y Web of Science desde el 1 de enero del 2020 al 8 de mayo del 2020 y que informaron sobre la prevalencia de depresión. Se usó un modelo de efectos aleatorios para estimar la proporción agrupada de depresión. Resultados: Un total de 12 estudios fueron incluidos en el meta-análisis, con prevalencias de depresión que oscilaban entre 7,45% y 48,30%. La prevalencia agrupada de depresión fue de 25% (95% CI: 18%-33%), con heterogeneidad significativa entre estudios (I 2  = 99,60%, p < 0,001). Conclusiones: En comparación con una estimación global de depresión en 2017 del 3,44%, nuestra prevalencia agrupada del 25% es 7 veces mayor, sugiriendo un impacto importante del brote de COVID-19 en la salud mental de las personas. El abordaje de la salud mental durante y después de esta crisis global sanitaria debe ser parte de las agendas de salud pública nacionales e internacionales para mejorar el bienestar de los ciudadanos.

Prevalence of Depression among Healthcare Workers during the COVID-19 Outbreak: A Systematic Review and Meta-Analysis.

BACKGROUND: There is evidence of a high psychological toll from the COVID-19 pandemic in healthcare workers. This paper was aimed at conducting a systematic review and meta-analysis of studies reporting levels of depression among healthcare workers during the COVID-19 and estimating the pooled prevalence of depression. METHODS: We searched for cross-sectional studies listed on PubMed from 1 December 2019 to 15 September 2020 that reported prevalence of depression in healthcare workers, nurses, medical doctors, and COVID-19 frontline professionals. The pooled proportions of depression were calculated with random effects models. RESULTS: We identified 57 studies from seventeen countries. The pooled prevalence of depression in healthcare workers was 24% (95% CI: 20-28%), 25% for nurses (95% CI: 18-33%), 24% for medical doctors (95% CI: 16-31%), and 43% for frontline professionals (95% CI: 28-59%). CONCLUSIONS: The proportion of depression in nurses and medical doctors during the COVID-19 pandemic was similar to that found in the general population as previously reported in other meta-analyses conducted with smaller numbers of studies. Importantly, almost half of the frontline healthcare workers showed increased levels of depression. There is need for a comprehensive, international response to prevent and treat common mental health problems in healthcare workers.

Prevalence of anxiety in health care professionals during the COVID-19 pandemic: A rapid systematic review (on published articles in Medline) with meta-analysis.

During the COVID-19, healthcare workers are exposed to a higher risk of mental health problems, especially anxiety symptoms. The current work aims at contributing to an update of anxiety prevalence in this population by conducting a rapid systematic review and meta-analysis. Medline and Pubmed were searched for studies on the prevalence of anxiety in health care workers published from December 1, 2019 to September 15, 2020. In total, 71 studies were included in this study. The pooled prevalence of anxiety in healthcare workers was 25% (95% CI: 21%-29%), 27% in nurses (95% CI: 20%-34%), 17% in medical doctors (95% CI: 12%-22%) and 43% in frontline healthcare workers (95% CI: 25%-62%). Our results suggest that healthcare workers are experiencing significant levels of anxiety during the COVID-19 pandemic, especially those on the frontline and nurses. However, international longitudinal studies are needed to fully understand the impact of the pandemic on healthcare workers' mental health, especially those working at the frontline.

Anhedonia as a Potential Risk Factor of Alzheimer's Disease in a Community-Dwelling Elderly Sample: Results from the ZARADEMP Project.

(1) Introduction: Dementia is a major public health problem, and Alzheimer's disease (AD) is the most frequent subtype. Clarifying the potential risk factors is necessary in order to improve dementia-prevention strategies and quality of life. Here, our purpose was to investigate the role of the absence of hedonic tone; anhedonia, understood as the reduction on previous enjoyable daily activities, which occasionally is underdetected and underdiagnosed; and the risk of developing AD in a cognitively unimpaired and non-depressed population sample. (2) Method: We used data from the Zaragoza Dementia and Depression (ZARADEMP) project, a longitudinal epidemiological study on dementia and depression. After excluding subjects with dementia, a sample of 2830 dwellers aged ≥65 years was followed for 4.5 years. The geriatric mental state examination was used to identify cases of anhedonia. AD was diagnosed by a panel of research psychiatrists according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. A multivariate survival analysis and Cox proportional hazards regression model were performed, and the analysis was controlled by an analysis for the presence of clinically significant depression. (3) Results: We found a significant association between anhedonia cases and AD risk in the univariate analysis (hazard ratio (HR): 2.37; 95% CI: 1.04-5.40). This association persisted more strongly in the fully adjusted model. (4) Conclusions: Identifying cognitively intact individuals with anhedonia is a priority to implement preventive strategies that could delay the progression of cognitive and functional impairment in subjects at risk of AD.

Cognition and daily activities in a general population sample aged +55.

Objective: We tested the association of individual cognitive domains measured with the Mini-Mental State Examination (MMSE) and disability. Method: Cross-sectional study in a population-based cohort aged ≥55 years (n = 4,803). Sample was divided into two groups: individuals with cognition within the normal range (CNR) (n = 4,057) and those with cognitive impairment (CI) (n = 746). Main outcome measures: The MMSE, the Katz Index (Basic Activities of Daily Living, bADL), the Lawton and Brody Scale (Instrumental Activities of Daily Living, iADL), and the Geriatric Mental State (GMS-AGECAT). Results: MMSE-orientation was associated with disability in bADL, iADL and a decrease in social participation, regardless of cognitive status. MMSE-attention was associated with disability in iADL, but only in CNR. MMSE-language was associated with disability in bADL, iADL and with reduced social participation, but only in CI. Conclusions: The associations observed between disability and orientation may have clinical and public health implications.

Depression as a Risk Factor for Alzheimer's Disease: A Systematic Review of Longitudinal Meta-Analyses.

Alzheimer's disease (AD) is the most frequent cause of dementia, linked to morbidity and mortality among elderly patients. Recently, several clinical studies suggested that depression is a potential risk factor for cognitive decline and AD. A review of meta-analyses was performed, calculating pooled odds ratios to estimate the risk of AD in people with a prior diagnosis (or clinically significant symptoms) of depression. A total of six meta-analyses which represented 28 individual studies were analyzed. A significant association between depression and AD was found (OR = 1.54, 95% CI [1.02-2.31]; p = 0.038). The results showed that heterogeneity across studies was substantial. We found a significant positive effect size for clinical measures of depression, but not for symptomatic rating scales, in the association of depression with risk of AD. The type of rating scale used to assess depression and the cut-off criteria selected also moderated the relationship between depression and AD risk. We found that studies that used clinically significant criteria for diagnosis of depression had more consistent and significant results than studies that used symptomatic scales.

A Novel Score for Predicting Alzheimer's Disease Risk from Late Life Psychopathological and Health Risk Factors.

With the increasing size of the aging population, dementia risk reduction has become a main public health concern. Dementia risk models or indices may help to identify individuals in the community at high risk to develop dementia. We have aimed to develop a novel dementia risk index focused on the late-life (65 years or more) population, that addresses risk factors for Alzheimer's disease (AD) easily identifiable at primary care settings. These risk factors include some shown to be associated with the risk of AD but not featured in existing indices, such as hearing loss and anxiety. Our index is also the first to account for the competing risk of death. The Zaragoza Dementia and Depression Project (ZARADEMP) Alzheimer Dementia Risk Score predicts an individual´s risk of developing AD within 5 years. The probability of late onset AD significantly increases in those with risk scores between 21 and 28 and, furthermore, is almost 4-fold higher for those with risk scores of 29 or higher. Our index may provide a practical instrument to identify subjects at high risk of AD and to design preventive strategies targeting the contributing risk factors.

Prevalence of anxiety in the COVID-19 pandemic: An updated meta-analysis of community-based studies.

BACKGROUND: The unprecedented worldwide crisis caused by the rapid spread of COVID-19 and the restrictive public health measures enforced by some countries to slow down its transmission have severely threatened the physical and mental wellbeing of communities globally. METHODS: We conducted a systematic review and meta-analysis to determine the prevalence of anxiety in the general population during the COVID-19 pandemic. Two researchers independently searched for cross-sectional community-based studies published between December 1, 2019 and August 23, 2020, using PubMed, WoS, Embase, and other sources (e.g., grey literature, manual search). RESULTS: Of 3049 records retrieved, 43 studies were included. These studies yielded an estimated overall prevalence of anxiety of 25%, which varied significantly across the different tools used to measure anxiety. Consistently reported risk factors for the development of anxiety included initial or peak phase of the outbreak, female sex, younger age, marriage, social isolation, unemployment and student status, financial hardship, low educational level, insufficient knowledge of COVID-19, epidemiological or clinical risk of disease and some lifestyle and personality variables. CONCLUSIONS: As the overall global prevalence of anxiety disorders is estimated to be 7.3% normally, our results suggest that rates of anxiety in the general population could be more than 3 times higher during the COVID-19 pandemic. These findings suggest a substantial impact on mental health that should be targeted by individual and population-level strategies.

Gut microbiota, innate immune pathways, and inflammatory control mechanisms in patients with major depressive disorder.

Although alterations in the gut microbiota have been linked to the pathophysiology of major depressive disorder (MDD), including through effects on the immune response, our understanding is deficient about the straight connection patterns among microbiota and MDD in patients. Male and female MDD patients were recruited: 46 patients with a current active MDD (a-MDD) and 22 in remission or with only mild symptoms (r-MDD). Forty-five healthy controls (HC) were also recruited. Psychopathological states were assessed, and fecal and blood samples were collected. Results indicated that the inducible nitric oxide synthase expression was higher in MDD patients compared with HC and the oxidative stress levels were greater in the a-MDD group. Furthermore, the lipopolysaccharide (an indirect marker of bacterial translocation) was higher in a-MDD patients compared with the other groups. Fecal samples did not cluster according to the presence or the absence of MDD. There were bacterial genera whose relative abundance was altered in MDD: Bilophila (2-fold) and Alistipes (1.5-fold) were higher, while Anaerostipes (1.5-fold) and Dialister (15-fold) were lower in MDD patients compared with HC. Patients with a-MDD presented higher relative abundance of Alistipes and Anaerostipes (1.5-fold) and a complete depletion of Dialister compared with HC. Patients with r-MDD presented higher abundance of Bilophila (2.5-fold) compared with HC. Thus, the abundance of bacterial genera and some immune pathways, both with potential implications in the pathophysiology of depression, appear to be altered in MDD, with the most noticeable changes occurring in patients with the worse clinical condition, the a-MDD group.