A Systematic Review of Neuropsychological and Psychiatric Sequalae of COVID-19

Implications for Treatment

William Michael Vanderlind; Beth B. Rabinovitz; Iris Yi Miao; Lauren E. Oberlin; Christina Bueno-Castellano; Chaya Fridman; Abhishek Jaywant; Dora Kanellopoulos

Disclosures

Curr Opin Psychiatry. 2021;34(4):420-433.

Abstract and Introduction

Abstract

Purpose of Review: COVID-19 impacts multiple organ systems and is associated with high rates of morbidity and mortality. Pathogenesis of viral infection, co-morbidities, medical treatments, and psychosocial factors may contribute to COVID-19 related neuropsychological and psychiatric sequelae. This systematic review aims to synthesize available literature on psychiatric and cognitive characteristics of community-dwelling survivors of COVID-19 infection.

Recent Findings: Thirty-three studies met inclusion/exclusion criteria for review. Emerging findings link COVID-19 to cognitive deficits, particularly attention, executive function, and memory. Psychiatric symptoms occur at high rates in COVID-19 survivors, including anxiety, depression, fatigue, sleep disruption, and to a lesser extent posttraumatic stress. Symptoms appear to endure, and severity of acute illness is not directly predictive of severity of cognitive or mental health issues. The course of cognitive and psychiatric sequelae is limited by lack of longitudinal data at this time. Although heterogeneity of study design and sociocultural differences limit definitive conclusions, emerging risk factors for psychiatric symptoms include female sex, perceived stigma related to COVID-19, infection of a family member, social isolation, and prior psychiatry history.

Summary: The extant literature elucidates treatment targets for cognitive and psychosocial interventions. Research using longitudinal, prospective study designs is needed to characterize cognitive and psychiatric functioning of COVID-19 survivors over the course of illness and across illness severity. Emphasis on delineating the unique contributions of premorbid functioning, viral infection, co-morbidities, treatments, and psychosocial factors to cognitive and psychiatric sequelae of COVID-19 is warranted.

Introduction

The novel coronavirus (SARS-CoV-2) that causes coronavirus disease (COVID-19) impacts multiple organ systems.^[1] Mortality rates are staggering, and morbidity trends have been the focus of numerous investigations. Persisting symptoms following infection are increasingly reported, including psychiatric symptoms and cognitive concerns,^[2,3] which are likely salient contributors to morbidity and disability. Although the etiology is still largely unknown, cognitive deficits may arise from stroke, meningitis, hypoxia, and inflammatory injury^[4–8] or from the invasive interventions required to treat severe illness from COVID-19.^[9] Psychiatric illness may arise from a combination of biological, psychosocial, and environmental factors. Early findings on COVID-19 are consistent with existing literature on patients with severe and unexpected illness who experience psychiatric symptoms related to medical illness, functional disability, and psychosocial stressors.^[10]

Here, we review the nascent literature on the neuropsychological and psychiatric sequelae of COVID-19 among community-dwelling individuals. We included studies that reported on postacute infection, including individuals who were never hospitalized and those who were previously hospitalized. We highlight trends, discuss treatment implications, and provide a roadmap for further research on long-term psychiatric and cognitive impairment after COVID-19.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusion
References
Sidebar

Table 1. Overview of cited studies
Study	Population	Age (in years)	Race/ethnicity	Time of assessment	Measures	Findings	Limitations
Almeria et al. (2020)	35 patients without a history of prior cognitive impairment, psychiatric illness, or other CNS disease Barcelona, Spain 45.7% male	M=47.6 SD=8.9 Range=24-60	Not listed	10–35 days post discharge from hospital	TAVEC: list learning, interference, recognition WMS-IV: Visual reproduction Digit Span Letters and Numbers TMT SDMT Stroop Verbal fluency BNT HADS	34.3% of the patients reported cognitive complaints No differences in neuropsychological performance between patients who reported cognitive complaints compared to those who did not endorse cognitive complaints Higher levels of anxiety and depression were found among individuals who endorsed cognitive complaints Neurological symptoms such as headache as well as loss of smell and taste were strongly associated with impaired attention, memory, and executive function	Small sample size Older individuals were excluded to avoid age-related cognitive impairment. Assessed shortly after discharge home Some data was extracted from the EMR rather than being assessed directly
Bellan et al. (2021)	238 previously hospitalized patients Italy 59.7% male	Median=61 Range=50-71	Not listed	3–4 months post discharge from hospital	IES-R	Most patients did not endorse posttraumatic stress: 57.1% were within normal range, 25.6% reported mild symptoms, 11.3% reported moderate, and 5.9% reported severe symptoms Male sex was the only factor independently associated with the presence of moderate to severe PTS symptoms	Only contacted patients who necessitated inpatient hospitalization High rate of patients declining participation Evaluation was limited to assessment of posttraumatic stress
Bonazza et al. (2020)	261 previously hospitalized patients (35.2% received intensive care) Italy 68.2% male	M=58.9 SD=13.3	Not listed	2 months post discharge from hospital	HADS IES-R	High prevalence of patients reported anxiety (28%), depression (16%), as well as posttraumatic stress (36.4%) Psychological distress was associated with female gender. Younger patients are more likely to have anxiety No correlations were found between duration of hospitalization or the intensity of care, and psychological outcomes	Participants assessed within quarantine setting Underlying reasons for high endorsement of PTS remains unclear
Bowles et al. (2020)	1409 hospitalized patients New York, US 51% male	M=67 SD=15	27% White; 28% Black; 35% Hispanic; 9% other	Not listed	OASIS-D1 mandatory assessment tool	Improvements in cognitive functioning and anxiety usually within one month post hospital discharge 16% increase in cognitive functioning and 35% decrease in anxiety	Information on rehospitalization and death after hospital discharge was not available
Cai et al. (2020)	126 hospitalized patients Shenzhen, China 47.6% male	M=45.7 SD=14	Not listed	Not listed	Self-report of PTSD Self-report of depression Self-report of anxiety	54% reported psychiatric distress Comorbidity of clinically significant stress response, anxiety and depression was 11.9% 31% had clinically significant stress response; 22.2% had clinical anxiety; 38.1% had clinical depression Older survivors (over age 60) reported lower levels of stress response than younger individuals Significantly higher rates of psychiatric symptoms than seen following previous major disasters	23 participants had prior history of psychiatric illness All patients were discharged from hospital into a mandatory quarantine facility, and were assessed while in quarantine
Daher et al. (2020)	33 hospitalized patients not requiring mechanical ventilation Germany 67% male	M=64 SD=3	Not listed	6 weeks post discharge from hospital	EQ-5D-5L PHQ-9 GAD-7	Most common endorsement was mild depression and anxiety On quality-of-life measures, patients reported slight to moderate difficulties with mobility, self-care, completing ADLs as well as elevated levels of pain/discomfort and anxiety/depression	Patients had multiple medical comorbidities, and did not identify premorbid psychiatric disorders Primary outcome was respiratory function; assessment of psychiatric concerns was secondary aim
de Graaf et al. (2021)	81 hospitalized patients (42% requiring ICU admission); only 59 completed psychological assessments Netherlands 51% male	M=60.8 SD=13 Range=27-88	Not listed	6 weeks post discharge from hospital	GAD-7 PHQ-9 PCL-5 Cognitive Failures Questionnaire IQ Code-N semi structured clinical interview	17% reported elevated symptoms of depression; 5% endorsed elevated anxiety; 10% met criteria for PTSD 40% reported previous mental health treatment 25% of patients endorsed cognitive impairments	Small Sample size Less than 50% of sample were admitted to the hospital participated in the study Lack of baseline data
De Lorenzo et al. (2020)	185 patients (68.1% requiring inpatient hospitalization) Italy 66.5% male	M=57 Range=48-67	90.8% European; 8.6% Hispanic; 0.5% African-American	Median of 23 days post discharge from hospital	WHOQOL-BREF IES-R STAI-Y WHIIRS Unstructured clinical interview	Cognitive impairment was observed in 25% of patients despite no history of cognitive disorder 22.2% of patients met criteria for PTSD	Lack of objective assessment of cognition Use of unstructured clinical interviews Only previously hospitalized patients were recruited
Garrigues et al. (2020)	129 hospitalized patients France 75% male	M=63.2 SD=15.7	Not listed	Mean of 110.8 (SD=11.1) days post admission	EQ-5D-5L Brief phone interview of clinical symptoms	Most patients reported persistent symptoms of fatigue (55%), memory loss (34%) concentration difficulties (24%), and sleep disorders (30.8%)	Exclusive use of self-reported measures Lack of baseline functioning Only previously hospitalized patients were recruited
Guo et al. (2020)	259 patients China 46.9% male	<18=1.6% 18–46=53.1% 46–49=43.3% >69=2%	Not listed	One month post discharge from hospital	SF-36	Role limitations due to emotional problems were related to male sex and positive nucleic acid duration Significant differences were found in vitality and mental health of patients aged 46–69 with positive nucleic acid duration longer than 14 days	High rate of attrition across follow-up period Lack of standardized, granular mental assessment Only previously hospitalized patients were recruited
Huang et al. (2021)	1733 patients China 52% male	M=57	Not listed	Median of 184 (Range=175–199) days after symptom onset	mMRC EQ-5D-5L EQ-VAS	23% of reported depression or anxiety 63% reported fatigue/muscle weakness 25% reported sleep difficulties	Lack of baseline functioning Exclusion of patients with mild symptoms
Islam et al. (2021)	1002 patients (21% were previously hospitalized) Bangladesh 57.9% male	M=34.7 SD=13.9 Range=18-81	Bangladeshi	Not listed	PHQ-9 Self-report treatment history Assessment of fear of reinfection	30.4% endorsed minimal symptoms of depression, 21.5% endorsed mild symptoms, 24.2% endorsed moderate symptoms, 19.4% endorsed moderate-severe symptoms, 4.6% endorsed severe symptoms 52.2% reported sleep disturbance Lower SES, poor health, sleep disturbance, asthma/respiratory problems, and fear of reinfection were associated with moderate-severe depression	Time of assessment was not provided Diagnostic status determined by self-report rather than utilization of PCR test
Janiri et al. (2020)	61 patients who were referred to postacute care clinic (9% previously required ICU admission) Italy 59% male	>60	Italian	Mean of 41 days (SD=19) post discharge from hospital	TEMPS-A-39 Difficulties in Emotion Regulation Scale Kessler Questionnaire-10	High likelihood of psychological distress was associated with female gender, Cyclothymic and Depressive scales of TEMPS, self-reported impulse control difficulties and lack of emotional clarity scales of DERS	Small sample size Statistical models in (ANCOVA with 7 covariates) in light of sample size
Jeong et al. (2020)	234 patients who were admitted to nonhospital facilities for isolation and monitoring (28.2% were asymptomatic and 71.8% were mildly symptomatic) South Korea 39.7% male	M=37.78 SD=15.57	South Korean	Not listed	HADS	During first week of quarantine, 19.8% endorsed mild depression or anxiety symptoms At 1 week follow-up, 14% reported depression or anxiety symptoms; significant decline in anxiety but not depression 20% of the asymptomatic group endorsed mood difficulties Anxiety and depression levels positively associated with quarantine durations	Small sample size Clinical outcomes of all the patients were not included Mental health data was collected via mobile-phone based survey. Patients without access was contacted by physicians via direct questioning
Liu et al. (2020)	675 previously hospitalized patients (21.5% had mild symptoms, 60.1% had moderate symptoms, 17.2% had severe symptoms, 1.2% were critically ill) Wuhan, China 47% male	Median=55 Range=41-66	Not listed	Mean of 36.75 days post discharge from hospital	PHQ-9 GAD-7 PCL-5 5-item Perceived discrimination scale	12.4% of patients were provisionally diagnosed with clinically significant PTSD symptoms 10.4% were categorized as having moderate to severe anxiety symptoms, with 32.3% reporting mild symptoms 19% were categorized as having moderate to severe depression symptoms, with 46.7% reporting mild symptoms Perceived discrimination, disease severity, living with children, and death of family member were predictors of mental health symptoms; mechanical ventilation was not associated with mental health outcomes	Cross-sectional study which limits causal inference Mental health outcomes were cut off based on sum-score of diagnostic criteria, presenting potential threat to validity Medical comorbidities were not examined directly Lack of baseline psychological data
Liu et al. (2021)	324 patients: 6% asymtomatic, 73% had mild or moderate symptom 19% had severe/critical symptoms Shenzhen, China 47.8% male	Asymptomatic: M=23.44 Mild/moderate: M=38.61 Severe/critical: M=57 Total: Range=0.3–86	Not listed	Not listed	Not listed	Rates of anxiety was as follows: 11.94% among patients with mild/moderate symptoms, 10% among patients with severe/critical symptoms Rates of headache or insomnia were: 8.96% among patients with mild/moderate symptoms and 22.5% among patients with severe/critical symptoms	Anxiety measure was not reported, outcome was subsequently described as 'anxiety/depression' Timing of anxiety assessment remains unclear
Mandal et al. (2020)	384 previously hospitalized patients (14.5% required ICU admission) UK 62% male	M=59.9 SD=16.1	43% ethnic minority	Median of 54 days post discharge from hospital	PHQ-2	14.6% of patients endorsed depression a median of 54 days post discharge	Abbreviated measure of depressive symptoms
Mannan et al. (2021)	1021 patients (10.9% were asymptomatic and 89.1% were symptomatic) 384 previously hospitalized patients (14.5% required ICU admission) Bangladesh 75% male	0–9: N=18 10–19: N=50 20–29: N=248 30–39: N=309 40–49: N=171 50–59: N=126 >60: N=96	Not listed	Received negative PCR result at least 4 weeks prior to the study	Phone interview	Most prevalent postrecovery complications included sleep disturbance (32%), weakened attention span (24.4%), anxiety and depression (23.1%), memory loss (19.5%), and complications with mobility (17.7%) Patients with medical comorbidity were found to be more likely to experience mobility problem (26%), weakness and problems performing usual activities (14%), anxiety and depression (28.5%), sleep disturbances (41.3%), concentration difficulties (28.5%), and memory loss (24.6%) than those without any comorbid conditions	Measures used to assess cognitive and psychological functioning were not reported
Mazza et al. (2020)	402 patients who were presented to ED (74.6% were admitted for inpatient hospitalization and 25.4% were discharged home) Milan, Italy 65.7% male	M=57.8 Range=18-87	Not listed	Mean of 31.29 (SD=15.7) days post discharge from hospital, or mean of 28.56 (SD=11.73) days after ED admission	IES-R PCL-5 BDI-13 STAI-Y WHIIRS Obsessive-Compulsive Inventory Zung Depression Scale Medical Outcomes Study Sleep Scale	Rates of clinically significant psychopathology based on self-report: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for obsessive-compulsive symptoms, and 40% for insomnia 55.7% endorsed clinical levels on at least 1 psychopathological dimension, with 36.8% endorsing clinical levels across 2 dimensions, 20.6% across 3 dimensions, and 10% across 4 dimensions Female patients with a previous psychiatric history, and patients who were discharged home reported greater difficulties on most measures	Cross-sectional study
Park et al. (2020)	10 patients South Korea 80% male	M=62.6 SD=14.9	Not listed	1 month post discharge from hospital (median=25 days, range=13–50 days)	PHQ-9 GAD-7 IES-R	50% endorsed depressive symptoms during treatment 100% of patients denied significant anxiety after discharge At 1 month postdischarge, 10% endorsed symptoms of depression and PTSD Patients with high perceived stigma reported higher levels of PTSD symptoms Patients with a history of prior psychiatric treatment reported higher levels of PTSD symptoms, whereas levels of depression and anxiety did not differ as a function of treatment history	Small sample size
Raman et al. (2021)	58 hospitalized patients (95% required mechanical ventilation, 36% required ICU admission) 30 uninfected matched controls UK 58.6% male	M=55.4 SD=13.2	77.6% White, 22.4% Nonwhite	Median of 2.3 months from disease-onset, median of 1.6 months post discharge from hospital	PHQ-9 GAD-7 SF-36 MoCA MRC Fatigue Severity Scale	Executive/visuospatial impairments were greater among patients compared to controls. Severity of illness did not predict levels of depression or anxiety At 2–3 months from disease-onset, patients reported significantly reduced quality of life and endorsed greater levels of depression, anxiety, and fatigue than controls did	Small sample size Cross-sectional assessment Lack of correction for multiple comparisons Given that controls were not hospitalized, group differences may not be specific to COVID-19 infection
Soldati et al. (2021)	Soldati et al. (2021) 23 patients who were previously treated in the ICU Brazil 78.3% male	M=53.6 SD=11.7	Not listed	Ranged 43–136 days post discharge from hospital	TICS EuroQol	60.9% of patients fell within normal limits on cognitive assessments 13% met criteria for MCI MCI diagnosis was negatively associated with EuroQol scores No one exhibited severe levels of cognitive impairment on TICS Quality of education was inversely associated with cognitive functioning	Lack of control group
Speth et al. (2020)	114 patients Switzerland 45.6% male	M=44.6 SD=16.1	Not listed	M=12.3 days (SD=7.2, range=0–31) following onset of COVID-19 symptoms	PHQ-2 GAD-2	Depressed mood and anxiety were positively associated with chemosensory dysfunction but not positively associated with symptoms of fever, cough and shortness of breath Older age and preexisting depressive and anxiety symptoms were positively associated with levels of depression and anxiety across disease course	Cross-sectional assessment Utilization of retrospective report Lack of objective measures of olfactory dysfunction
Sykes et al. (2021)	134 hospitalized patients (87% required supplemental oxygen or respirator support, 20% required ICU admission) UK 65.7% male	M=59.6 SD=14	91% White, 1.5% Black, 6% Asian, 1.5% Mixed/other	Median of 113 days (range: 46–167) post discharge from hospital	MRC EQ-5D-5L	86% reported at least one residual symptom, with the most frequently reported complaint being fatigue Illness severity was not associated with self-reported symptom burden Female sex was positively correlated with level of residual symptoms, particularly anxiety and fatigue Persistent COVID-related complications may not be directly attributable to SARS-CoV2 infection but, rather, the neuropsychiatric sequelae of the virus	Severity of persistent symptoms was not Assessed
Tomasoni et al. (2021)	105 hospitalized patients (72% received minimal oxygen therapy whereas 22% were treated with CPAP, NIV or OTI) Milan, Italy 73.3% male	Median=55	Not listed	1–3 months (Median=46 days) after virological clearance	HADS MMSE	Among 25 patients who completed MMSE, 40% indicated cognitive impairment, which ranged from mild to severe Many patients continued to endorse anxiety (29%) and depression (11%) 1–3 months after virological clearance Clinical levels of HADS-A/D scores were positively associated with physical complaints	Small sample size Only included patients with confirmed virological recovery, patients with persistent positive PCR after clinical recovery were excluded Lack of baseline psychological data
Townsend et al. (2020)	128 patients (55.4% were hospitalized, 44.6% were outpatients) Dublin, Ireland 46.1% male	M=49.5 SD=15	Not listed	Outpatients: at least 6 weeks after abatement of acute COVID-19 symptoms Hospitalized patients: date of discharge	Chalder Fatigue Scale	Mean psychological fatigue was 4.72 (SD=1.99) Treatment factors (hospitalization status, need for respiratory treatments) were not associated with fatigue levels Fatigue was positively associated with pre-existing depression and use of antidepressant medications	Cross-sectional assessment
Van den borst et al. (2020)	124 patients (21.7% with mild disease, 41.1% with moderate, 20.9% with severe, 16.1% with critical disease); 78.2% required inpatient hospitalization Nijmegen, Netherlands 60% male	M=59 SD=14	Not listed	Outpatients: M=13.0 weeks (SD=2.2) symptom onset Hospitalized patients: M=9.1 weeks (SD=1.6) after discharge home	HADS TICS PCL-5 IES-R SF-36 Cognitive Failures Questionnaire Nijmegen Clinical Screening Instrument	Approximately 33% exhibited cognitive difficulties or atypical mental status Disease severity grade was not associated with mental or cognitive status in this study Many patients reported chronic, and severe, problems across health domains Referred mild disease patients displayed a female predominance and reported more frequently severe problems than moderate-to-critical disease, in the domains of physical functioning, quality of life, and energy	Skewed distribution of prior health difficulties across disease severity groups; participants with mild disease had longstanding health impairments Diagnostic status not confirmed by PCR test for all participants
Wang, et al. (2020)	215 hospitalized patients Cleveland, US	Not listed	Not listed	Not listed	PTSD-5 GAD-7 CES-D10	57% screened positive for PTSD, anxiety, or depression. Specific rates were as follows: 34% for PTSD, 24% for anxiety, and 42% for depression Among patients without a prior psychiatric history, 42% screened positive for one psychiatric disorder Among patients with a prior psychiatric history, 78% screened positive for one disorder	Utilization of self-report to characterize psychiatric history Not all patients were initially hospitalized due to COVID-19
Weerhandi et al. (2021)	152 hospitalized patients (45.3% required ICU admission, 36.7% required mechanical ventilation) New York, US 62.7% male	Median=62 Range=50–67	44.1% White, 21.7% Hispanic, 9/9% Asian, 11.2% Black, 8.7% Mixed/other, 4.4% unknown	Median of 37 days (range: 30–43) post discharge from hospital	the PROMIS Global Health-10	Poorer physical health and mental health were reported after hospital discharge compared to baseline functioning	Strict exclusion criteria
Woo et al. (2020)	18 patients with mild to moderate disease (61% required inpatient hospitalization) 10 age-matched healthy controls Hamburg, Germany 42.1% male	M=42.2 SD=14.3	Not listed	Median of 85 days (Range=20–105 days) after recovery	TICS-M PHQ-9 Fatigue Assessment Scale	Patients exhibited greater difficulties on TICS-M as compared to healthy controls in the areas of short-term memory, attention, concentration/language 50% reported attention deficits, 44.4% reported short-term memory deficits, 27.8% reported word-finding difficulties, 16.7% reported fatigue, 11.1% reported mood swings, and 5.6% reported fatigue, phonophobia, or incoherent thoughts Cognitive functioning was not associated with somatic symptoms Disease severity and treatment factors were not associated with cognitive impairments	Small sample size Screening measure of cognitive functioning
Zarghami et al.(2020)	50 outpatients with mild symptomatology Fasa City, Iran	M=43.62 SD=15.81	Not listed	During home quarantine	PHQ-9 GAD-7 PSS-14 Semi-structured psychiatric interview	17.3% patients had prior history of psychiatric disorders Based on self-report measure, 34.6% endorsed depressive symptoms, 32.7% endorsed anxiety, and mean score for PSS-14 is 11.8 (scores range from 0–56) Based on clinical interview, 18.8% met criteria for a psychiatric disorder; specific rates were as follows: 5.8% for GAD, 21.2% for insomnia, 3.8% for MDD, and 9.6% for an adjustment disorder	Small sample size
Zhou et al. (2020)	29 recovered patients 29 healthy controls Zhejiang, China 62% male	M=47 SD=10.54 Range=30-64	Chinese Han	2–3 weeks after infection	TMT Digit Span Sign Coding Test CPT GAD-7 PHQ-9	Cognitive impairments among patients with SARS-CoV-2 were mild and most prominent in the domain of sustained attention No significant difference between patient and healthy controls in TMT, SCT, or DST	Small sample size Participants excluded if they received fewer than nine years of education
Zhu et al. (2020)	432 previously hospitalized patients China 51% male	Median=49, range=35-60	Chinese Han and Tibetan	Not listed	Lawton IADL scale Barthel Index Zung's self-reported anxiety scale	36.8% of patients reported at least one IADL limitation, with 16.4% reporting moderate dependence and 5.6% reporting severe dependence 28.7% of patients met criteria for a probable anxiety disorder diagnosis Disease severity was associated with greater prevalence of disability and anxiety and was an independent risk factor for all outcomes	Lack of baseline data Lack of control group Reliance on self-report measures Cross-sectional assessment

BDI-13, Beck's Depression Inventory; BNT, Boston Naming Test; CESD-10, Center for Epidemiological Studies Depression Scale; CPT, Continuous Performance Test; EQ-5D-5L, Euro Quality of Life-5 Dimensions-5 Levels; EQ-VAS, Euro Quality of Life- Visual Analogue Scale; GAD-7, Generalized Anxiety Disorder Scale; HAD, Hospital Anxiety and Depression Scale; IES-R, Impact of Event Scale–Revised; IQ Code-N, Informant Questionnaire on Cognitive Functioning in the Elderly; mMRC, modified British Medical Research Council dyspnea scale; MoCA, Montreal Cognitive Assessment; PCL, Posttraumatic Stress Disorder Checklist; PHQ-9, Patient Health Questionnaire 9; PSS-14, Perceived Stress Scale-14; SDMT, Symbol Digit Modalities Test; SF-36, 36-Item Short Form Survey; STAI-Y, State-Trate Anxiety Inventory form Y; TAVEC, Test de Aprendizaje Verbal España-Complutense; TEMPS, Temperament Evaluation of Memphis, Pisa, Paris, and San Diego; TICS, Telephone Interview of Cognitive Status; TMT, Trail Making Test A and B; WHIIRS, Women's Health Initiative Insomnia Rating scale; WHOQOL-BREF, World Health Organization Quality of Life; WMS , the Wechsler Memory Scale.