REVIEW

Diagnosing and Treating Depression in Patientswith Alzheimer’s Disease

Anna D. Burke . Danielle Goldfarb . Padmaja Bollam .

Sehar Khokher

Received: May 22, 2019 / Published online: August 21, 2019� The Author(s) 2019

ABSTRACT

Although cognitive and functional impairmentare the hallmark features of Alzheimer’s disease(AD), neuropsychiatric symptoms associatedwith AD account for increased rates of disabilityand profoundly impact the quality of life ofboth patients and their caregivers. This narra-tive review of current evidence provides practi-cal guidance in diagnosing and managingdepression in patients with AD using pharma-cological and nonpharmacological interven-tions. After apathy, depression is the secondmost common neuropsychiatric symptom inAD. Diagnosing late-life depression (LLD), par-ticularly in those affected by AD, is complicatedbecause older patients may not meet the criteriafor a major depressive disorder. Clinically, late-life depression and dementia can be indistin-guishable. Although these two entities are now

thought to be related, the pathologic mecha-nisms remain unclear. Evidence suggests thatLLD may be a prodromal symptom of neu-rodegenerative disease. The various geropsy-chiatric measures currently used to diagnose,rate the severity of, and monitor the progress oftreatment for depression are imperfect. Neu-roimaging represents a promising avenuetoward understanding the complex pathophys-iologic relationships between dementia andLLD, and will support the pursuit of biomarker-driven diagnosis and treatment. Nonpharma-cologic interventions to relieve depression inpersons with cognitive impairment anddementia include emotion-oriented therapies,behavioral and cognitive-behavioral modifica-tion programs, and structured activity pro-grams. Sensory-stimulation therapies andmultisensory approaches show some promisefor successfully treating depression in patientswith dementia, but further rigorous research isneeded to establish their validity. Clinical con-sensus and research appear to support selectiveserotonin reuptake inhibitors as a first choicefor the pharmacological treatment of depres-sion in patients with dementia. However, initialsupport for these therapies remains variable,and further investigation is needed. Extra care isrequired in prescribing to this populationbecause of the generally high level of medicaland psychiatric comorbidity and the potentialdifficulty in assessing the cognitively impairedpatient’s response.

Enhanced digital features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.8982449.

A. D. Burke (&) � P. BollamDepartment of Neurology, Barrow NeurologicalInstitute, St. Joseph’s Hospital and Medical Center,350 W. Thomas Rd., Phoenix, AZ 85013, USAe-mail: Neuropub@barrowneuro.org

D. GoldfarbBanner Alzheimer’s Institute, Phoenix, AZ, USA

S. KhokherWellspan Philhaven, Mount Gretna, PA, USA

Neurol Ther (2019) 8:325–350

https://doi.org/10.1007/s40120-019-00148-5

Keywords: Alzheimer’s disease; Behavioral andpsychological symptoms in dementia;Dementia; Depression; Geriatric depression;Late-life depression; Neuroimaging indepression; Neuropsychiatric symptoms indementia; Sleep and depression; Vasculardepression

AbbreviationsAD Alzheimer’s diseaseCBT Cognitive behavioral therapyCSDD Cornell Scale for Depression in

DementiaCSF Cerebrospinal fluidCT Computed tomographyDMN Default mode networkDSM Diagnostic and Statistical Manual

of Mental DisordersFDG FluorodeoxyglucoseGDS Geriatric Depression ScaleLLD Late-life depressionMCI Mild cognitive impairmentMMSE Mini-Mental State ExaminationMRI Magnetic resonance imagingNACC National Alzheimer’s

Coordinating CenterNIMH-dAD National Institute of Mental

Health diagnostic criteria fordepression in AD

NPS Neuropsychiatric symptomNREM Non-rapid eye movementPET Positron emission tomographyREM Rapid eye movementSCN Suprachiasmatic nucleusSPECT Single-photon emission

computerized tomographySSRI Selective serotonin reuptake

inhibitorSWS Slow-wave sleepWML White matter lesion

INTRODUCTION

Alzheimer’s disease (AD) is the most commonform of dementia. This disorder currentlyaffects an estimated 5.6 million Americans; afigure that is expected to increase to nearly 16million by 2050 [1]. Although the hallmark

cognitive and functional impairment features ofthe disorder are most often emphasized, theneuropsychiatric symptoms associated with thedisease account for increased rates of disabilityand profoundly decrease the quality of life ofboth patients and their caregivers.

Neuropsychiatric symptoms (NPS) affectnearly all patients with AD (97%) [2]. Thesesymptoms are associated with impairment inactivities of daily living [3], poor quality of life[4], earlier institutionalization [5], accelerateddisease progression, increased mortality [6],caregiver stress [7], and increased costs of care[8].

Apathy and depression are the most com-mon forms of NPS in Alzheimer’s disease.Although many geropsychiatric measures areavailable to diagnose, rate the severity of, andmonitor the progress of treatment for depres-sion, these measures remain imperfect. Addi-tionally, numerous pharmacological andnonpharmacological treatments are used fordepression in patients with AD. The purpose ofthis narrative review is to provide practicalguidance in diagnosing and managing depres-sion in patients with AD using both pharma-cological and nonpharmacologicalinterventions. The data for the narrative werecompiled from the Medline and Pubmed data-bases using the terms ‘‘depression,’’ ‘‘Alzhei-mer’s disease,’’ ‘‘dementia,’’ ‘‘neuropsychiatricsymptoms,’’ and ‘‘behavioral and psychologicalsymptoms in dementia.’’ The data were col-lected from 2/1/2019 to 5/15/2019.

Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

DEPRESSION IN PATIENTSWITH ALZHEIMER’S DISEASE

Depression is second to apathy as the mostcommon NPS in patients with AD. Depression iscommon in mild cognitive impairment (MCI)

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stages. A meta-analysis of 57 studies found aprevalence of 32% in patients with MCI, withdepressive symptoms being more prevalent inclinical (40%) versus community-based (25%)samples [9].

Depression is also a predictor of progressionfrom normal cognition to MCI and from MCI todementia. One study showed that 16% ofpatients in population-based AD studies and44% of patients in hospital-based studies sufferfrom depression [10]. There is evidence thatdepression may be an early manifestation of AD[11]. The presence of MCI in depression hasbeen shown to predict later development of AD[11].

Patients with AD and depression appear tohave more severe neuropathology (tau, amy-loid, and vascular burden) than those withoutdepression and show more severe loss of sero-tonin receptors and serotonin transporterbinding, which may have implications fortreatment [12].

Older adults with late-onset depression aremore likely to have vascular risk factors (in-cluding a history of cerebrovascular disease)[13]. Neuroimaging changes such as whitematter hyperintensities or leukoencephalopa-thy, particularly those affecting the frontal-striatal and frontal-limbic brain pathways, arecommon among patients with late-onsetdepression [14]. Other risk factors for thedevelopment of depression in patients with ADinclude a previous history of depression [15],ApoE4 positivity [14, 16], a family history ofdepression, and female sex [3]. The use of cer-tain medications such as beta-blockers, corti-costeroids, and benzodiazepines as well asprolonged exposure to dopamine agonists,stimulants, anticonvulsants, hormone-alteringdrugs, proton pump inhibitors and H2 blockers,statins or lipid-lowering drugs, and anticholin-ergic medications such as dicyclomine alsoincrease the likelihood of developing a depres-sive disorder.

The stage of dementia may also impact therisk of developing depression. Forsell et al. sug-gested that depression becomes more frequentas AD progresses from mild to moderatedementia, and becomes less common in severedementia [17]. However, Lyketsos et al. found

no significant differences in the frequencies ofmajor and minor depression among the stagesof mild, moderate, and severe AD [3]. Starksteinet al. [18] and Lopez et al. [19] found that majordepression was less frequent in AD patients withsevere cognitive deficits than in those with mildor moderate cognitive deficits. These differencesmay be related to the challenges involved indiagnosing depression in the context of AD.

DIAGNOSIS OF DEPRESSION

Prevalence

Approximately 52% of patients have their firstonset of depression at age 60 or older [20].According to some epidemiological studies, thepoint prevalence of major depression is4.6%–9.3% in patients older than 75 years,which increases to 27% in those older than85 years [21, 22].

The diagnosis of depression in seniors, andin particular, in those affected by AD, is com-plicated by additional challenges. Elderlypatients may not meet full Diagnostic and Sta-tistical Manual of Mental Disorders (DSM)-5[23] criteria for a major depressive disorder(Table 1). They frequently do not report adepressed mood, but instead present with lessspecific symptoms such as insomnia, anorexia,treatment-resistant pain symptoms, and fatigue.Older patients, particularly women, may havevegetative symptoms and cognitive dysfunctionthat overlap with symptoms of AD [24]. Somefeatures that suggest depression include fre-quent office visits or use of medical services;persistent reports of pain, fatigue, insomnia,and headache; changes in sleep or appetite;unexplained gastrointestinal symptoms; andsigns of social isolation and increased depen-dency. Elderly individuals may also dismiss lesssevere depression as an acceptable response tolife stressors or a normal part of aging.

Impact of Depression

Late-life depression (LLD) remains underdiag-nosed and inadequately treated—in late life,

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this is associated with higher rates of morbidityand mortality. The rates of cognitive, social, andphysical impairment, as well as the resultingdecrease in independence, significantly impactthe lives of seniors suffering from depression[25, 26]. Compared to non-depressed counter-parts, severely depressed older adult patientshave elevated rates of mortality (controlling forsex, preexisting chronic health problems,socioeconomic status, and fitness) [25–28].

Diagnostic Criteria

In 2001, the National Institute of Mental Healthconvened an expert panel that developed aprovisional set of diagnostic criteria for depres-sion in AD (NIMH-dAD; Table 2) [29, 30]. Thesecriteria were derived from DSM-IV criteria formajor depression, with a few modifications. Thenumber of symptoms required for a diagnosis ofdepression was decreased from five to three. Theduration and frequency of depressive symptomswere also decreased; symptoms need only bepresent together within the same 2-week

period, as compared with the DSM-IV require-ment that symptoms be present ‘‘most of theday, nearly every day’’ for at least2 weeks. Cognitive complaints such as adecreased ability to think and to concentratewere eliminated. Anhedonia criteria were mod-ified to focus on decreased affect and pleasureassociated with social and other activities.Symptoms distinct to this population, includ-ing withdrawal, social isolation, and irritability,were added as new symptoms. These changeswere believed to reflect the clinical features ofdepression in patients with AD better [29, 30].

Teng et al. evaluated a cohort of 101patients, diagnosing depression at baseline andafter 3 months using NIMH-dAD criteria andthe Structured Clinical Interview for DSM-IVAxis I Disorders [31]. Depressive symptoms alsowere assessed with the Cornell Scale forDepression in Dementia (CSDD), the GeriatricDepression Scale (GDS), and the Neuropsychi-atric Inventory Questionnaire. The use ofNIMH-dAD criteria allowed the investigators toidentify a greater proportion of AD patients asdepressed than when several other established

Table 1 DSM-5 diagnostic criteria for depression

Criteria The individual must be experiencing five or more symptoms during the same 2-week period, and at least one of

the symptoms should be either (1) depressed mood or (2) loss of interest or pleasure

Symptoms 1. Depressed mood most of the day, nearly every day

2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day

3. Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day

4. A slowing down of thought and a reduction of physical movement (observable by others, not merely

subjective feelings of restlessness or being slowed down)

5. Fatigue or loss of energy nearly every day

6. Feelings of worthlessness or excessive or inappropriate guilt nearly every day

7. Diminished ability to think or concentrate, or indecisiveness, nearly every day

8. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a

specific plan for committing suicide

Diagnosis To receive a diagnosis of depression, these symptoms must cause the individual clinically significant distress or

impairment in social, occupational, or other important areas of functioning. The symptoms must also not be

a result of substance abuse or another medical condition

Adapted from [23]

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assessment tools for depression were applied.These results are consistent with the resultsfrom a previous study that interpolated NIMH-dAD diagnoses from data collected using astructured interview from another diagnosticinstrument [31].

Variants of Depression

The validity of existing criteria for geriatricdepressive disorders, particularly the DSM-5,continues to be questioned. Data suggest thatthere are qualitative differences in the clinicalpresentation of depression in younger and olderadults and that the different presentations ofdepression in older adults are not fully assessed

by the current measures of depression[26, 32, 33]. These differences are even furtherpotentiated in cognitively impaired seniors.

In a study comparing major depressive fea-tures between patients with AD and cognitivelynormal older adults, several significant differ-ences were noted. Patients with AD had moreprominent difficulties with concentration andindecisiveness, fewer sleep disturbances, andfewer reports of feelings of worthlessness orexcessive guilt. However, patients with AD werenoted to have higher rates of psychotic symp-toms, such as delusions and hallucinations.There was also a trend toward higher rates ofpsychomotor agitation/retardation and fatigue/

Table 2 National Institute of Mental Health Diagnostic Criteria for Depression in AD

Criteria

A. Three (or more) of the following symptoms must be present during the same 2-week period and represent a change

from previous functioning. At least one of the symptoms must either be (1) depressed mood or (2) decreased positive

affect or pleasure

1. Clinically significant depressed mood

2. Decreased positive affect or pleasure in response to social contacts and usual activities

3. Social isolation or withdrawal

4. Disruption in appetite

5. Disruption in sleep

6. Psychomotor changes

7. Irritability

8. Fatigue or loss of energy

9. Feelings of worthlessness, hopelessness, or excessive or inappropriate guilt

10. Recurrent thoughts of death, suicidal ideation, plan or attempt

B. All criteria are met for dementia of the Alzheimer type (DSM-IV)

C. The symptoms cause clinically significant distress or disruption in functioning

D. The symptoms do not occur exclusively in the course of delirium

E. The symptoms are not due to the direct physiological effects of a substance

F. The symptoms are not better accounted for by other conditions such as major depressive disorder, bipolar disorder,

bereavement, schizophrenia, schizoaffective disorder, psychosis of Alzheimer disease, anxiety disorders, or substance-

related disorders

Adapted from [29]

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loss of energy in patients with more advancedAD [34].

The variability in the cognitive profile ofgeriatric depression also suggests that this syn-drome represents a heterogeneous group ofdisorders requiring careful neuropsychiatricassessment and treatment planning [35].Attempts have been made to define and cate-gorize the different presentations of depressionin seniors. Several geriatric-specific variants ofdepression have been proposed. One of these,the ‘‘depletion syndrome,’’ is characterized byhopelessness, loss of appetite, thoughts ofdeath, and lack of interest [36, 37]. Anothervariant is the ‘‘depression-executive dysfunctionsyndrome’’ [38]. In this syndrome, cognitiveperformance is typically impaired on measuresof verbal fluency, naming, and initiation/per-severation; psychomotor retardation and anhe-donia are included, but vegetative symptoms,agitation, and guilt are less severe than in othertypes of depression.

Diagnostic Assessment Tools

Although a structured clinical interviewremains the cornerstone of diagnosis, a varietyof geropsychiatric measures have been devel-oped to help diagnose depression, rate theseverity of the disease, and monitor treatmentprogress (Table 3).

In general, current test measures were foundto underestimate the depletion syndrome,although they generally inflated the extent towhich depression was found in older adults.Therefore, current measures may underestimatedepression in older adults because they do notmeasure the most common subtype of geriatricdepression [39].

Many of the available geropsychiatric testsremain imperfect. Most existing depression self-report scales used for older adults (e.g., BeckDepression Inventory-II, Center for Epidemio-logic Studies Depression Scale, Zung Self-RatingDepression Scale) fail to consider the level ofcognitive impairment along with visual deficitsof older patients. The validity of certaindepression rating scales is considerablydecreased in patients with a Mini-Mental State

Examination (MMSE) score equal to or less than15 [40].

With the exceptions of the GDS and CSDD,which were specifically developed for use ingeriatric patients and contain fewer somaticitems, most existing depression rating scalescurrently used for older adults have beendeveloped and validated in younger popula-tions. No current self-report assessment toolsdiscriminate between subtypes of geriatricdepression [41].

Most self-report depression scales currentlyused for older adults, e.g., the Beck DepressionInventory-II, contain items tapping somaticsymptoms. When there is considerable overlapbetween depressive symptoms and physicalconditions, failure to take the physical illnessinto account may result in an overestimation ofdepression in such populations [41]. This over-lap may affect the assessment of treatmentefficacy.

Cognitively impaired patients also underre-port symptoms on patient-focused depressionscales such as the GDS, as they are unable torecall or are not aware of the depressive symp-toms reported by the caregivers [34]. As thereliability of GDS diminishes with MMSE scoresbelow 15, input from caregivers becomes moreimportant as the patient’s cognitive statusdeclines [40]. Therefore, an assessment tool thatincorporates caregiver input, such as the CSDD,may be more appropriate in patients withdementia [42]. Patients with CSDD scores above12 require treatment, and those with scoresabove 8 require close follow-up and possiblytreatment [43].

NEUROIMAGING IN ADAND DEPRESSION

The clinical picture of LLD can be indistin-guishable from that of dementia. There isincreasing awareness of a relationship betweenthese two entities, yet the pathologic mecha-nisms remain unclear. Evidence is growing thatsuggests that LLD may be a prodromal symptomof neurodegenerative disease. The ability todistinguish between LLD and dementia, partic-ularly early in the disease course, has significant

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implications for clinical care, along with ourunderstanding of the neurobiological systemsimplicated. Neuroimaging represents a promis-ing avenue to elucidate these two potentiallyoverlapping pathologies.

Various imaging techniques, structural andfunctional, are currently used in research andclinical settings for the evaluation of dementia,LLD, or both. Clinical consensus guidelines [44]

recommend the use of structural brain imag-ing—either magnetic resonance imaging (MRI)(preferred) or computed tomography (CT)—forthe evaluation of a cognitive/dementia syn-drome in order to rule out structural andpotentially treatable causes and to assess atro-phy. The most characteristic structural imagingbiomarker of AD is hippocampal atrophy[45, 46]; however, this finding is not specific for

Table 3 Depression scales used in geriatric psychiatry

Scales Description

Geriatric Depression Scale (GDS) Self-report questionnaire with ‘‘yes’’ or ‘‘no’’ responses. Different versions are

available, with the number of questions ranging from 30 to 4. The 5-item

GDS is reported to be as effective as the 15-item GDS for the screening of

depression in cognitively intact older individuals

Cornell Scale for Depression in Dementia

(CSDD)

Developed specifically for the assessment of depression in dementia. It is a

19-item comprehensive interview of both patient and informant and

includes the clinician’s impression

Assesses signs and symptoms during the week preceding the interview

NIMH-dAD The NIMH Provisional Diagnostic Criteria for Depression in Alzheimer’s

Disease, a provisional set of diagnostic criteria for depression in AD,

developed in 2001 in order to better reflect the clinical features of

depression in AD

Center for Epidemiologic Studies

Depression Scale (CES-D), NIMH

A 20-item self-report questionnaire on symptom frequency during the past

week. Responses range from rarely or none to most or all the time

Neuropsychiatric Inventory (NPI) Useful to assess 10 behavioral areas and 2 neurovegetative areas. Assessment is

based on informant (caregiver) observations. Scores for the areas reveals

frequency and severity and caregiver distress

Hamilton Rating Scale of Depression

(HAM-D)

Gold standard of observer-rated depression rating scales. Requires training to

administer. Is helpful in assessing the severity of depression

Montgomery-Asberg Depression Rating

Scale (MADRS)

Administered by a trained interviewer. Helpful to measure progress. Useful

for assessment of depression in individuals with physical illness

Beck Depression Inventory (BDI) A 21-item, self-report, multiple choice inventory. Revised version is BDI-II.

Helps to assess severity of depression

Patient Health Questionnaire (PHQ) PHQ-9—self-report questionnaire: helps screen, diagnose, monitor, and

measure severity of depression. PHQ-2—‘‘first step’’ approach: enhances

routine enquiry

Zung Self-Rating Depression Scale (SDS) A 20-item self-report questionnaire to screen affective, psychological, and

somatic symptoms associated with depression

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AD and is seen in other neurodegenerative dis-eases. Smaller hippocampal volumes are associ-ated with memory performance [47].

MRI

MRI morphometric studies in LLD demonstrateatrophy of various brain structures includinglower gray matter volumes in the frontal–tem-poral lobes, hippocampus, parahippocampalgyrus, amygdala, putamen, pallidum, and tha-lamus compared to controls [48]. Another studyshowed that LLD is associated with corticalthinning, which is associated with age atdepression onset, sex, and level of cognitivefunctioning [49]. Volumetric hippocampalchanges in LLD can reflect one or more patho-physiological processes, including early neu-rodegenerative disease, vascular disease, and(duration-related) treatment of depressive ill-ness [50, 51]. Based on an imaging meta-analy-sis, patients with LLD and AD both demonstrateabnormalities in hippocampal volume andventricular enlargement [52].

One potential shared pathway to dementiaand depression is vascular disease. Neuroimag-ing is essential to our understanding of thiscomplex relationship. Alexopoulos et al. firstdescribed the vascular hypothesis for LLD,positing that cerebrovascular disease plays acritical role in provoking and perpetuatingdepressive symptoms as a result of structuraldamage to frontal–subcortical circuits [53].However, the diagnosis of vascular depressionremains controversial, without definitive bio-logical or neuroanatomical substrates, and theterm is used more often in research than in theclinical setting. The diagnosis is driven largelyby neuroimaging findings of white matterhyperintensities on T2-weighted or fluid-atten-uated inversion recovery MRI, subcorticallacunes, microinfarcts, and microhemorrhagesalong with frontal and hippocampal gray mat-ter atrophy [54]. LLD with these imaging find-ings has been termed ‘‘MRI-defined vasculardepression’’ [55].

Functional Imaging

Functional imaging is used in the clinicaldementia evaluation in atypical cases, early-onset cases, or other uncertain cases where fur-ther specificity is warranted despite standardstructural imaging [44]. The most commonlyused functional scans in this setting are fluo-rodeoxyglucose positron emission tomography(FDG-PET) or single-photon emission computedtomography (SPECT). FDG-PET technologydemonstrates glucose metabolism, which is asurrogate for neuronal and synaptic activityalong with neurodegeneration. SPECT incorpo-rates CT with a radioactive tracer to demon-strate cerebral blood flow or perfusion.

Perfusion imaging techniques, such asSPECT, may provide a promising approach todifferentiating depression from dementia.Amen et al. evaluated perfusion neuroimagingusing SPECT in more than 4500 subjects with adiagnosis of depression, dementia, or both [56].Subjects with dementia had lower regionalcerebral blood flow, specifically seen in theamygdala and hippocampus, compared to sub-jects with depression, and these changes weremagnified in those with both depression anddementia. Overall, SPECT distinguishedbetween depression and dementia with 86%accuracy.

White Matter Lesions

The pathophysiology of white matter lesions(WMLs) has not been fully elucidated. It isgenerally accepted that WMLs are caused, atleast in part, by small-vessel ischemia. However,given that WMLs are found in some individualswith no major vascular risk factors (hyperten-sion, hyperlipidemia, diabetes, heart disease,smoking, and obesity), other non-vascular fac-tors must play a role [50]. One autopsy studycompared 20 older subjects with a history ofmajor depression to age-matched controls. Atautopsy, deep WMLs were found to be ischemicin nature for all depressed subjects compared toless than one-third of control subjects. Fur-thermore, in the depressed subjects, ischemiclesions were significantly more present in the

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dorsolateral prefrontal cortex compared withthe non-depressed group. Of note, the non-de-pressed group had more clinical vascular diseaseduring life than the depressed group. Onhistopathologic analysis, ischemic deep WMLsrevealed infarction, gliosis, axonal loss,ischemic demyelination, or a combination ofthese, supporting the vascular hypothesis ofdepression [57].

One multimodal imaging study evaluatedbrain MRI features associated with late-lifedepressive symptoms in older community-dwelling adults, analyzing whole-brain vari-ables including white matter hyperintensityburden, fractional anisotropy (a measure ofwater movement), and gray matter volume. Theloss of gray matter volume was most significantin the bilateral insula and anterior cingulatecortex. The insula has been previously impli-cated in major depressive disorder [58] and,furthermore, is a brain region known to besensitive to hypoperfusion, supporting a cere-brovascular pattern for depressive symptoms inolder adults.

The causal relationship between WML bur-den, cognitive changes, and LLD remainsunclear. One population-based study of olderadults [59] analyzed the relationship betweenWMLs and cortical atrophy on CT and laterdevelopment of depression or dementia incommunity-dwelling adults over a 10-year per-iod. The authors found that WML and temporallobe atrophy independently predicted laterdevelopment of depression and dementia, pos-sibly suggesting shared pathogenetic pathways.There remains a considerable debate, regardingwhether shared versus distinct pathophysio-logic pathways exist between dementia andLLD. While evidence supports the presence ofhippocampal atrophy in LLD, one study showeda lack of identifiable Ab pathology in LLD basedon [18F]flutemetamol amyloid PET findings [60].Another study assessed cortical Ab with18F-florbetapir PET and showed that depressedpatients with moderate-to-severe treatmentresistance had higher 18F-florbetapir standard-ized uptake value ratios than healthy controls inthe parietal regions [61, 62]. As well, the ele-vated amyloid burden in depressed olderpatients with moderate-to-severe treatment

resistance was seen in the precuneus, parietal,temporal, and occipital regions. Overall amy-loid PET findings in the more treatment-resis-tant depressed group were similar to typicalfindings in confirmed AD subjects. Hence,treatment-refractory depression in older indi-viduals may represent early changes in AD-re-lated pathophysiology.

CSF Biomarkers

Liguori et al. sought to evaluate whether cere-brospinal fluid (CSF) AD biomarkers and 18F-FDG PET findings in older adults (n = 256) withconcomitant dementia and untreated depres-sion could differentiate AD from LLD [63]. CSFwas collected, and FDG-PET was completed atbaseline and after a 2-year interval. The authorsfound that CSF Ab42 levels were significantlyhigher in LLD (range, 550–1204 pg/mL) com-pared to AD patients (range, 82–528 pg/mL).Furthermore, CSF AD biomarkers (Ab42 and tauproteins) in LLD patients were similar to thoseof controls. Regarding 18F-FDG PET, patientswith AD showed a significant reduction in 18F-FDG PET uptake in temporoparietal regionscompared to both controls and LLD subjects,whereas the LLD and control groups had similar18F-FDG PET findings. It should be noted thatLLD subjects showed nonspecific, heteroge-neous patterns of glucose hypometabolisminvolving various cortical and subcortical brainareas.

Neural Networks

While structural and functional neuroimagingstudies have elucidated gray matter volumetricchanges (network nodes), white matter tractdisruptions (network edges), and rest- and task-related changes in network dynamics, increas-ing evidence points to the importance of dis-rupted functional neural network connectivityin the pathophysiology and symptomatology ofboth cognitive impairment and LLD [64, 65].Intrinsic neural networks found to be involvedin LLD include the default mode network(DMN), executive control network, and saliencenetwork. These networks become active in the

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resting state (not doing a task) and inactivewhen a person is engaged in any attention-de-manding tasks, which is called task-induceddeactivation [59]. Imaging these intrinsic net-works requires either functional PET scans orresting-state functional MRI to evaluate regio-nal cerebral blood flow. During the resting state,functional MRI shows an increased regionalblood flow or blood oxygenation level depen-dent signal within the set of brain regions,while there is a decrease in this signal duringattention-demanding tasks.

Increasing evidence suggests that the DMNcould be the neural basis of the connectionbetween LLD and AD [66]. The DMN, firstdescribed by Raichle et al. [65], is involved inwakeful rest, mind-wandering, and self-referen-tial thinking, and is considered to involve cer-tain spatially distributed brain regions withsynchronized activity patterns, including theposterior cingulate cortex/precuneus, superiorfrontal gyrus, medial prefrontal cortex, inferiorparietal lobule, lateral temporal cortex, angulargyrus, hippocampus, and cerebellum [64, 66].

Sheline et al. proposed that a failure todeactivate the DMN during cognitive or emo-tional tasks is a network-based mechanism indepression [67]. DMN overactivity has beenlinked to negative rumination in depression[68]. Negative ruminations are a type of self-referential thinking, which is common indepression in both early and late life. Thoughnot a core diagnostic feature, higher levels ofrumination are predictive of more severedepressive symptoms in depressed individuals[69]. Increased functional connectivity betweenthe subgenual prefrontal cortex and the DMNhas been shown in major depressive disorder,and is posited to be a neural substrate ofdepressive rumination [70].

It is hypothesized that DMN activity corre-lates with increased neuronal and synapticactivity along with increased Ab and possiblytau release, which, in a vulnerable individual,could predispose to and propagate AD pathol-ogy. One study of cognitively normal individ-uals with Pittsburgh compound B PET-confirmed Ab deposition found that elevated Abdisrupted DMN functional connectivity even inthe absence of a task. Connectivity between the

precuneus and hippocampus was significantlylower in nondemented older adults with Abdeposition compared to those without Ab pla-ques [71]. Hence, there appears to be a bidirec-tional relationship between abnormal DMNfunctional connectivity and AD pathology,where one begets the other.

Future of Neuroimaging in ADand Depression

Many questions remain unanswered, but neu-roimaging represents a promising and vitalavenue toward understanding the complexpathophysiologic relationships betweendementia and LLD and for supporting the pur-suit of biomarker-driven diagnosis andtreatment.

SLEEP AND DEPRESSION

Causes of Sleep Disruption

Numerous sleep changes occur with normalaging, including advanced sleep timing,increased sleep fragmentation, more fragilesleep, and less time in deeper non-rapid eyemovement (NREM) sleep [72]. Aging leads tochanges in the structures involved in generatingor entraining circadian rhythms, and con-tributes to altered circadian rhythm timing withadvancing age. Characteristic age-related chan-ges in rest-activity circadian rhythms includelower amplitude [73, 74], fragmentation of lossof rhythms, and decreased sensitivity tosuprachiasmatic nucleus (SCN) time cues suchas light exposure [75]. In dementing neurode-generative diseases, these sleep and circadianchanges are magnified along with others such asdecreased rapid eye movement (REM) sleep [72],all of which contribute to worsening dementiasymptoms and brain pathology.

While the sleep–wake cycle is the best-char-acterized circadian rhythm, many other formsof circadian disruption are also common. Indementia, circadian dysfunction worsens as thedisease progresses, which often results insleep–wake rhythm disorders, such as irregular

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sleep–wake rhythm disorder [76]. The patho-physiology of circadian disruption in dementiais yet to be fully elucidated; however, internaland external factors have been implicated,including SCN dysfunction, abnormal SCNinput, and disrupted environmental factors (so-called zeitgebers). The integrity of the SCN (thecentral pacemaker) and the monosynapticpathway from the retina to the SCN (known asthe retinohypothalamic tract) are essential forproper circadian function. SCN degenerationresults in an inability to consolidate wakeful-ness and the development of an abnormal 24-hrhythm. Autopsy studies of brains from patientswith severe AD reveal SCN degeneration,namely neuronal loss and neurofibrillary tangleformation [77].

Disrupted environmental factors, such aslight exposure, social cues, activity, and meal-times, influence the period, phase, and ampli-tude of circadian rhythms. Without sufficientexposure to timed light, the biological clockbecomes desynchronized with the solar day,resulting in deleterious effects on variousphysiological functions, neurobehavioral per-formance, and sleep [78]. Older adults and, to agreater extent, those institutionalized are morelikely to be exposed to less robust daytime light[79]. Ancoli-Israel and colleagues demonstratedthat lower daytime light levels contribute toincreasingly abnormal circadian rhythms asmeasured by actigraphy and were associatedwith an increase in night-time awakenings,even after controlling for the level of dementia[80]. Gehrman et al. hypothesized that in theearly stages of dementia, SCN damage results ina decline in circadian rhythmicity, at whichpoint environmental cues take on a larger role,contributing to a resynchronization of circadianrhythms [81]. When dementia becomes severe,environmental cues lose their potency.

Sleep Disruption and Depression

Meanwhile, sleep disruption is a core feature ofdepression, with up to 90% of depressed indi-viduals having subjective sleep complaints [82].Depressed patients often show altered circadianrhythms, sleep disturbances, and diurnal mood

variation. Sleep disruption is a risk factor in thedevelopment of depression [83, 84], is often thefirst subjective symptom, and is associated withan increased risk of relapse along with anincreased risk of suicide [85]. In polysomno-graphic studies, individuals with major depres-sive disorder have prolonged sleep latency(longer time to fall asleep), frequent nocturnalawakenings, and poor sleep efficiency (per-centage of time sleeping while in bed) [86].Additionally, sleep architecture in depressedindividuals shows decreased REM latency (timefrom sleep onset to first epoch of REM) and anincreased proportion of REM sleep overall [87].Paradoxically, some studies have demonstratedthat sleep deprivation interventions can acutelyreverse depressive symptoms in approximately50–60% of patients with major depression, butthis remission was temporary, and diseaserelapsed following subsequent rebound sleep[88, 89].

Biochemical Factors in Sleep Dysfunction

It is established that soluble Ab levels fluctuatediurnally—they increase during awake time anddecrease during sleep [90]. These fluctuationsare thought to be related to neuronal activityand metabolic demand. Sleep disruption anddeprivation, specifically decreased NREM slow-wave sleep (SWS) at\ 1 Hz, is associated withaggregation of Ab and tau neurofibrillary tan-gles [91, 92]. Decreased NREM SWS is associatedwith impaired overnight memory consolidationand weaker hippocampal-neocortical memorytransformation [91]. Lucey and colleaguesrecently demonstrated elevated tau levels inboth CSF and PET analysis in cognitivelyasymptomatic or mildly impaired subjects withdecreased NREM SWS [93].

Evidence increasingly supports the role ofdysfunctional Ab and tau clearance systems inthe development of AD. A sleep-dependentbrain clearance system has been described,which is a whole-brain perivascular networkfacilitating the clearance of interstitial solutes,including Ab and tau. The CSF-interstitial fluidsystem is also known as the glymphatic systembecause of its hypothetical reliance on glial cells

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for interstitial transport [94, 95]. In rodentstudies, Xie and colleagues found that the CSF-interstitial fluid clearance system was mainlyactive during sleep, specifically SWS [96]. Theauthors theorize that this occurs because, dur-ing sleep, neurons are less active and shrink insize, which results in a 60% increase in theinterstitial space volume relative to the awakestate. With more volume and less resistance,CSF flow and clearance is hypotheticallygreater.

Functional neuroimaging studies demon-strate that DMN connectivity is decreased dur-ing sleep [97]. Specific brain regions that show adecrease in activity with progression fromwakefulness to SWS include the posterior cin-gulate cortex, parahippocampal gyrus, andmedial prefrontal cortex [98]. The DMNbecomes less active during SWS, indicating adrop in neuronal activity and metabolicdemand. Ju et al. posit that poor sleep qualityresults in increased neuronal activity, con-tributing to chronically increased soluble Ab,which leads to an increased risk of amyloidplaque formation over time [99].

Links Among Sleep Dysfunction,Depression, and Dementia

The relationship between sleep dysfunction,depression, and dementia appears to bedynamic and synergistic, though the pathome-chanisms remain unclear. Both sleep disruptionand depression are common in dementia,independently and co-occurring, and both canbe prodromal symptoms of neurodegenerativedisease. While the relationship between sleepdysfunction and AD is often described as bidi-rectional, bringing depression into the equationcould lead to a tridirectional relationship,which is challenging to disentangle [99].

Burke et al. used a syndemic approach toanalyze the associative effects of depression,anxiety, and sleep disturbance on the risk oflater development of symptomatic AD in acognitively asymptomatic cohort of more than11,000 individuals in the National Alzheimer’sCoordinating Center (NACC) [100]. The authorsdescribe the syndemic approach as ‘‘reaching

beyond a person’s biology and takes account ofstress, inequality, the community, and theenvironment, all over time, as potential cofac-tors in the exacerbation of illnesses’’ [100]. Theauthors showed strong independent hazards ofAD development for depression, sleep distur-bance, and anxiety independently. The additiveinteraction and risk of eventual AD diagnosiswere significant for those experiencing recentdepression symptoms and sleep disturbances,current or lifetime, as compared to those with-out either symptom. Those with clinician-veri-fied depression and sleep disturbance showedthree times greater risk of eventual AD diagnosisthan those without these symptoms. Anotherstudy by the same group using NACC datashowed that these independent risk relation-ships between sleep, dementia, and depressionwere even stronger for APOE4 carriers, indicat-ing a genetic role [101].

Treatment for Sleep Dysfunctionin Patients with Dementia and Depression

Sleep represents a promising area for the dis-covery of diagnostic markers and novel treat-ment approaches in dementia and LLD.Pharmacologic and nonpharmacologic approa-ches to improve NREM SWS may serve todecrease or delay the aggregation of toxic Aband tau proteins. One recent retrospective studyevaluated whether the use of trazodone, acommonly used sleep medication in olderadults, resulted in less cognitive decline com-pared to non-trazodone users. Trazodone wasoriginally developed as an antidepressant,though it was found to be less effective for thatindication [102]. Trazodone has been previouslyshown to significantly increase NREM SWS onpolysomnography [103]. Analyzing NACC data,a study showed that trazodone non-usersdeclined 2.6-fold faster on the MMSE than tra-zodone users over 4 years. Other hypnotics,including melatonin, ramelteon, and mirtazap-ine, have not produced such an improvementin NREM SWS [104].

Beyond medications, sleep and circadiandysfunction in older adults can be targetedthrough nonpharmacologic and behavioral

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approaches. Such therapies include cognitivebehavioral therapy, chronotherapies such asbright-light exposure, and social rhythm thera-pies for the illness. Evidence suggests thataddressing sleep impairment in older adults,particularly before the development of cogni-tive symptoms, could have disease-modifyingeffects. However, more research is needed.

TREATMENT OF DEPRESSIONIN PATIENTS WITH AD

Currently, no clearly established consensusguidelines exist regarding the treatment ofdepression in patients with AD. However, alarge body of literature has documented thedifferent approaches and medications that havebeen investigated. Both pharmacological andnonpharmacological interventions have beenshown to help reduce depressive symptoms incognitively impaired patients and in improvingtheir quality of life. These interventions canbroadly be divided into nonpharmacologicaltherapies and lifestyle interventions andpsychopharmacology.

Nonpharmacological Therapiesand Lifestyle Interventions

The National Institute for Health and CareExcellence (NICE) guideline published in June2018 regarding the assessment and manage-ment of dementia has a section on managingnoncognitive symptoms [105]. It suggests con-sidering psychological treatments for peoplewith mild-to-moderate dementia who havemild-to-moderate depression. Per these recom-mendations, antidepressants should not beroutinely offered unless they are indicated for apreexisting severe mental health problem. Goodclinical practice requires the use of nonphar-macological approaches for NPS, includingdepression, before the initiation of pharmaco-logical interventions [106, 107]. Nonpharma-cological therapies that specifically targetdepression or its symptoms include emotion-oriented therapies, brief psychotherapies, andsensory-stimulation therapies. Regardless of the

specific therapy chosen, it is advised that thesebe used as an acute and short-term intervention[108, 109].

Emotion-Oriented TherapiesEmotion-oriented therapies aim to fit the ther-apy to the emotional needs of people withdementia by utilizing approaches such as vali-dation, reminiscence, reality, and simulated-presence therapy. Reminiscence therapy usesmemory aids such as old family photos andpersonal objects while encouraging patients totalk about their pasts [110]. Reality-orientationtherapy hypothesizes that confusion can bereduced by giving repeated orientation clues,such as the date, time of day, season, or names.It is based on the theory that the inability toorient one’s self reduces the ability of those withdementia to function. Validation therapyadopts the concept that cognitively impairedindividuals withdraw to an inner reality basedon emotions, rather than trying to face thechallenges of their faltering cognitive abilities.The therapist accepts the subsequent disorien-tation of the patient and validates his or herfeelings, providing a background for meaning-ful conversations addressing their emotions[111]. Simulated-presence therapy involvesexposing a patient to audio or videotapedrecordings of loved ones [112].

Despite several positive clinical reports ofefficacy for these interventions, there is cur-rently insufficient evidence for their effective-ness in reducing any NPS, and almost noresearch providing data on their effects ondepression. However, numerous anecdotal andresearch reports of clinical effectiveness and thepatient-centered nature of these individualizedtherapies suggest that they might yet prove tobe of value [113–119].

Brief PsychotherapiesSeveral brief psychotherapeutic interventionshave also been shown to be particularly effec-tive in this population [120, 121]. Behavioraltherapies are more commonly applied in thelater stages of dementia, while modified cogni-tive-behavioral strategies appear to be moresuccessful with those in the earlier stages of

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cognitive decline [122]. Cognitive behavioraltherapy (CBT) requires a period of detailedassessment to identify the triggers, behaviors,and reinforcers (also known as ABC: ante-cedents, behaviors, and consequences). Theirrelationships are discussed with the patient.Interventions are then based on an analysis ofthese findings. CBT in AD patients withdepression focuses on identifying and reframingnegative thoughts and increasing participationin social and pleasurable activities.

Although CBT is more commonly used withcaregivers of patients with dementia than withthe patients themselves, a few studies have tes-ted the effects of individual or group CBT onNPS, and on depression in particular. Teri et al.used cognitive therapy in adults with milddementia to challenge the patients’ negativecognitions in order to reduce distortions andenable the patients to generate more adaptiveways of viewing specific situations and events[123, 124].

Most CBT programs for persons withdementia involve their caregivers, both as CBTcoaches for the care recipient and as treatmentpartners who frequently benefit from theintervention as well [123–125]. ImplementingCBT with persons suffering from dementiarequires a highly structured format and con-tinuous monitoring of the person’s under-standing of the therapeutic material. Thestrongest evidence is for short-term CBT andproblem-solving therapy [109].

Sensory Stimulation TherapiesSensory stimulation therapies, including musictherapy, art therapy, pet therapy, aromather-apy, activity therapies, and multisensoryapproaches (such as Snoezelen), have thepotential for benefit in depressed patients withcognitive impairment. Similar to the emotion-oriented therapies, few rigorous studies havebeen performed, and efficacies are mixed,although reports from clinical observers aregenerally very positive [126].

Lifestyle ModificationsOther lifestyle modifications, such as anincrease in physical activity, may provide

additional benefits through nonpharmacologi-cal means. A meta-analysis of eight studiesfound that moderate daily exercise was effectiveat reducing symptoms of depression in theelderly [127]. Exercise has also been associatedwith a decrease in hippocampal atrophy, whichis believed to be related to improved cerebralperfusion as well as the release of brain-derivednerve growth factor [127]. These studies did notexclusively focus on AD, but it is reasonable toextrapolate these results to depression inpatients with AD.

Psychopharmacology

Recent guidelines for pharmacotherapy in geri-atric patients with depression (Table 4) havebeen recommended by the French Associationfor Biological Psychiatry and Neuropsy-chopharmacology and the foundation Fon-daMental [128].

Pharmacokinetics and PharmacodynamicsPharmacological treatment of depression incognitively impaired patients presents uniquechallenges due to physiologic changes thataccompany normal aging as well as the neu-rodegenerative process itself. Significant changesin pharmacokinetics and pharmacodynamicsdictate that vigilance be exercised to avoiddrug–drug interactions and accidental over-doses. The presence of medical comorbiditiesalso influences both the therapeutic and adverseeffects of antidepressant medications.

Hepatic metabolism and renal clearancedecrease with advancing age. The decrease inmesenteric blood flow also decreases gastroin-testinal absorption. Neurodegenerative changesalso lead to decreased production of acetyl-choline as well as a decreased number ofcholinergic neurons in the basal forebrain,which leads older individuals to show markedsensitivity to developing anticholinergicadverse effects.

Given their physical and cognitive frailty,individuals with dementia may be particularlysusceptible to the adverse effects of medications;therefore, the old adage ‘‘start low and go slow’’applies when dosing the elderly. Comorbid

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Table 4 Therapeutic strategies in geriatric depression

Clinical features First intention Second intention Contraindications

Mild to moderate

intensity

SSRI

a2 Antagonist

SNRI

Agomelatine

Irreversible MAOI

Bupropion

Association with an ATD from the same

pharmacological class

Anticonvulsant

ECT

Moderate to severe

intensity

SSRI

SNRI

a2 Antagonist

Imipramine Bupropion

Association with an ATD from the same

pharmacological class

Anticonvulsant

First-generation antipsychotic

Severe cognitive

impairments

SSRI

SNRI

a2 Antagonist

Agomelatine

Severe psychomotor

agitation

SSRI

a2 Antagonist

SNRI

Potentiation with

AAP

Bupropion

Tianeptine

Irreversible MAOI

Association with an ATD from the same

pharmacological class

Severe psychomotor

retardation

SSRI

SNRI

a2 Antagonist

Imipramine

ECT in association

Tianeptine

Bupropion

Association with an ATD from the same

pharmacological class

First-generation antipsychotic

Severe sleep disorders SSRI

a2 Antagonist

SNRI

Agomelatine

Tianeptine

Irreversible MAOI

Bupropion

Association with an ATD from the same

pharmacological class

Severe anhedonia SSRI

SNRI

a2 Antagonist

Imipramine

Agomelatine

Association with an ATD from the same

pharmacological class

Anticonvulsant

First-generation antipsychotic

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medical conditions including diabetes, history offalls, renal and hepatic insufficiency, cardiacarrhythmias, and cerebrovascular risk factorsshould all be considered before initiation ofpharmacotherapy. It is also important to notethat the patient’s cognitive limitations mayaffect their ability to communicate regarding theemergence of adverse effects. Hence, close mon-itoring by the prescriber and caregivers isindicated.

Use of Antidepressants in Patientswith DementiaAntidepressants are frequently prescribed forthe treatment of depression in patients withdementia. The 2007 practice guidelines issuedby the Work Group on Alzheimer’s Disease andOther Dementias of the American PsychiatricAssociation recommend selective serotoninreuptake inhibitors (SSRIs) as the first pharma-cological treatment of choice for depression indementia [129]. SSRIs tend to be better toleratedthan other antidepressants because they havefewer serious adverse effects. The Work Groupsuggests that if patients with dementia cannot

tolerate higher dosages when needed for theremission of depression, trials of alternativeantidepressants such as bupropion, venlafaxine,and mirtazapine may be considered [129].

The evidence regarding the efficacy of theseagents, however, remains conflicting. Reviewsof research on the pharmacological treatment ofNPS in general [106, 107, 130] indicate positiveeffects of various antidepressants (includingsertraline, fluoxetine, citalopram, trazodone,and moclobemide) on depression in patientswith dementia, with citalopram and sertralinebeing the most commonly prescribed[131–133]. Case reports and small pilot studiesindicate that other antidepressants, includingtrazodone, buspirone, and mirtazapine, mayimprove depression in patients with dementia,but no large trials have been performed inindividuals with dementia to date[106, 107, 134].

Lyketsos et al. examined depressive symp-toms using the CSDD in a 12-week double-blind, placebo-controlled trial of sertraline. Theresults were encouraging and indicated thatsertraline had a clear advantage over placebo,

Table 4 continued

Clinical features First intention Second intention Contraindications

Psychotic symptoms SNRI

Potentiation with

AAP

SSRI

a2 Antagonist

Imipramine

ECT in association

Tianeptine

Irreversible MAOI

Bupropion

Association with an ATD from the same

pharmacological class

High suicidal risk SSRI

SNRI

a2 Antagonist

Imipramine

ECT in association

Potentiation with

AAP

Tianeptine

Bupropion

Association with an ATD from the same

pharmacological class

First-generation antipsychotic

Data adapted from [128]AAP AAP gene, ATD antidepressant, ECT electroconvulsive therapy, MAOI monoamine oxidase inhibitor, SNRI dualserotonin and norepinephrine reuptake inhibitors, SSRI selective serotonin reuptake inhibitor

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with the bulk of the antidepressant effect seenin the first 3 weeks after starting therapy.Improvements were also noted in activities ofdaily living, but no significant effect was notedin cognition [135].

Lyketsos et al. expanded this study with alarger group recruited from two different sites.Once again, the results demonstrated sertralineas being superior to placebo at 12 weeks. Inaddition, the researchers noted improvementsin activities of daily living as well as non-moodbehavioral disturbances. The improvement inactivities of daily living, as well as non-moodbehavioral disturbances, lagged behind theimprovement in depressive symptoms. Theimprovement in symptoms was hypothesized tobe due to an improvement in depression, ratherthan being a direct response to sertraline. It wasalso noted that there was no improvement incognitive functioning [131].

The Depression in Alzheimer’s Disease Study(DIADS)-2 work group [136, 137] continued toinvestigate the role of sertraline in treatingdepression in AD, publishing data collected at12 weeks and again at 24 weeks. Neither of thesedemonstrated sertraline as being superior toplacebo. They did agree that the previouslyproposed dose range of 90–100 mg a day wassafe and appropriate.

An analysis by Dudas et al. [138] of thefindings from these three studies [131, 136, 137]indicated overall little or no benefit from treat-ment with an antidepressant (MD - 0.10points, 95% CI - 0.99 to 0.78; 433 participants;3 studies).

One landmark study [139] examined 150 mgsertraline or 45 mg mirtazapine per day versusplacebo. Decreases in depression scores at13 weeks did not show a statistically significantdifference between patients receiving mirtaza-pine or sertraline versus placebo. It was con-cluded that the overall effectiveness ofantidepressants in patients with AD is small.However, a meta-analysis trended toward treat-ment response; hence, the possible clinicaladvantages of antidepressants could not be fullyruled out [140].

Effect of Antidepressants on Cognitive DeclineMore recent studies have focused on dulox-etine, vortioxetine, and brexpiprazole. Vortiox-etine demonstrated a significant positiveimprovement in cognitive function comparedto placebo [141]. Brexpiprazole, when used asan adjunctive agent in an open-label safety andtolerability study (26 weeks), was shown to bewell tolerated in elderly patients, withimprovements noted in depression and socialfunctioning.

Earlier studies gave conflicting resultsregarding efficacy, safety, and effects on cogni-tive function. Most of the existing studies dif-fered in study design, rating scales used, andseverity of symptoms addressed. Only twocomparative studies have been published. Tar-ango et al. [142] compared fluoxetine toamitriptyline, and Katona et al. [143] comparedparoxetine to imipramine. One of the earlieststudies by Roth and colleagues in 1996 [144]demonstrated that moclobemide was effectivein treating symptoms of depression; however,no improvement in cognitive function wasfound. In 1995, Tollefson et al. [145] demon-strated the efficacy of fluoxetine versus placebo.However, in 2001, Petracca et al. [146] foundthat it was not superior to placebo. In contrast,in 1992, Nyth et al. [147] demonstrated thatcitalopram improved both cognitive and emo-tional functioning in a 6-week double-blindplacebo-controlled trial. Tricyclic antidepres-sants were also studied [148, 149], and bothclomipramine and imipramine were shown tobe superior to placebo. Clomipramine seemedto lower scores on the MMSE. Despite incon-clusive data regarding treatment, there wasagreement that untreated depression in patientswith AD and an impaired level of functioningresulted in increased impairment of quality oflife, a higher decline in activities of daily living,an increased likelihood of being dischargedfrom assisted living facilities, an increased like-lihood of needing a nursing home level of care,and increased mortality and suicidal ideations.

Perhaps the more significant future directionof psychopharmacology is exploring the rela-tionship between antidepressants and progres-sion of cognitive decline. Bartels et al. [150]demonstrated that long-term SSRI treatment

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might delay progression from mild cognitiveimpairment to AD. Zhou et al. [151] observedthat fluoxetine delayed the cognitive functionaldecline and synoptic changes in a transgenicmouse model of early AD. However, the clinicalstudies published at this time are insufficient todraw conclusions.

Adverse Effects of Antidepressants in Patientswith DementiaAs noted previously, the selection of a particularantidepressant should encompass the consider-ation of potential adverse effects.

SSRIs include fluoxetine, paroxetine, sertra-line, citalopram, and escitalopram. Potentialadverse effects of these agents include nausea andvomiting, agitation, anxiety, indigestion, diar-rhea or constipation, dizziness, blurred vision,dry mouth, diaphoresis, loss of appetite andweight loss, insomnia or sedation, headaches,and sexual adverse effects. However, these drugshave less marked anticholinergic and antia-drenergic properties, and therefore, may be lesslikely to cause confusion or falls [152].

Both citalopram and escitalopram have beenassociated with a prolonged QTc interval, par-ticularly if combined with other medicationsthat prolong QTc. The risk also increases whenthose drugs are combined with medications(e.g., cimetidine, omeprazole) that decrease themetabolism of those drugs, thus raising theirserum blood levels.

Selective serotonergic and noradrenergicreuptake inhibitors such as venlafaxine,desvenlafaxine, and duloxetine, tetracyclicantidepressants such as trazodone and mapro-tiline, and reversible monoamine oxidase inhi-bitors such as moclobemide are alternativeoptions to SSRIs. Another often-used example ofthe newer antidepressants is the a2 antagonistmirtazapine. The adverse effect profiles of thesemedications are similar to that of SSRIs.

The oldest class of antidepressants is the tri-cyclic antidepressants. They are associated withpotentially problematic adverse effects for olderpatients. In particular, their anticholinergicproperties are associated with a negative impacton cognition [153]. Other problematic anti-cholinergic effects would include increasedintraocular pressure, urinary retention, dry

mouth, and constipation. Because of theirantiadrenergic adverse effects, they can alsocause postural hypotension [154] and dizziness,thereby increasing the risk of fall. In general,this class of antidepressants should be avoidedin patients with cognitive impairment.

APATHY

Although this review focuses on depression, it isimportant to understand the distinctionbetween apathy and depression as the underly-ing causes of symptoms, and patients’ responsesto antidepressant treatment vary significantly.Apathy is characterized by lack of motivation,decreased initiative, akinesia, and emotionalindifference. It is the most common NPS asso-ciated with AD and a primary cause of caregiverdistress [155]. It frequently emerges in the pre-cognitive impairment stages of AD, increases infrequency as the disease progresses, and predictsconversion from normal cognition to MCI andfrom MCI to dementia [156]. In 2009, aninternational task force published diagnosticcriteria for apathy which require that two ofthree dimensions of diminished motivationmust be present for at least 4 weeks with iden-tifiable associated functional impairment [157].The Apathy Evaluation Scale is commonly usedto assess apathy across the AD continuum [158].The Neuropsychiatric Inventory also includesan apathy subscale, but it has not yet beenvalidated for use on its own. Apathy can occuralone or as a symptom of depression [159].

In neuroimaging studies, apathy has beenassociated with cortical dysfunction in theposterior cingulate or inferior temporal cortex.It has also been associated with atrophy, hypo-metabolism, and hypoperfusion in theseregions. High levels of tau and phospho-tau inthe CSF and abnormalities in cholinergic,GABAergic, and dopaminergic function havealso been associated with apathy [160].Dopaminergic circuits have been targeted intreatment trials using methylphenidate, with asignificant reduction in apathy symptoms andimprovement in global cognition in a 6-weekstudy [161]. Open-label studies of cholinesteraseinhibitors (donepezil, galantamine, and

342 Neurol Ther (2019) 8:325–350

rivastigmine) showed improvements in apathywith all three medications [162].

In the clinical setting, patients sufferingfrom apathy will frequently deny feeling ‘‘de-pressed,’’ and may not endorse the typicalsymptoms of depression. Their caregivers mayreport that their engagement, motivation, andinterest has dwindled and, as a result of theseobservations, express concerns over their lovedone being depressed.

CONCLUSION

When treating patients with AD, the impact ofneuropsychiatric symptoms, particularly depres-sion, on the patients’ quality of life should not beoverlooked. Diagnosing depression in this patientpopulation can be challenging. Thus, additionalresearch and development of assessment toolsfocused on a geriatric population are needed.Neuroimaging may represent a promising avenuetoward understanding the complex pathophysi-ologic relationships between dementia and LLD,and may support the pursuit of biomarker-drivendiagnosis and treatment.

Additional future research into the pathologi-cal mechanisms of depression and AD will enablea better understanding of these diseases and theirrelationship, leading to better pharmacologicaland nonpharmacological treatments. Largerclinical trials assessing pharmacological andnonpharmacological interventions are necessaryfor the development of comprehensive consensusguidelines regarding the treatment of depressionin patients with AD. Improving interventions fordepression in patients with AD can help todecrease disability and improve the quality of lifeof patients and their caregivers.

ACKNOWLEDGMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Medical Writing, Editorial, and OtherAssistance. The authors thank the staff of

Neuroscience Publications at Barrow Neurolog-ical Institute for assistance with manuscriptpreparation.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Dr. Burke, Dr. Goldfarb, Dr.Bollam, and Dr. Khokher have no personal,financial, commercial, or academic conflicts ofinterest.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors. Approval from the local institutionalreview board was not required for this review.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproductionin any medium, provided you give appropriatecredit to the original author(s) and the source,provide a link to the Creative Commons license,and indicate if changes were made.

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