diagnosis and treatment of depression and cognitive

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue:Qatar Clinical Neuroscience Conference

Diagnosis and treatment of depression and cognitiveimpairment in late lifeSarah Shizuko Morimoto,1 Dora Kanellopoulos,1 Kevin J. Manning,2and George S. Alexopoulos11Institute of Geriatric Psychiatry, Weill Cornell Medical College, White Plains, New York. 2Department of Psychiatry, Universityof Connecticut Health Center, Farmington, Connecticut

Address for correspondence: Sarah Shizuko Morimoto, Psy.D., Institute of Geriatric Psychiatry, Weill Cornell Medical College,21 Bloomingdale Road 7 South, White Plains, NY 10605. [email protected]

Cognitive impairment in late-life depression is prevalent, disabling, and heterogeneous. Although mild cognitiveimpairment indepressiondoesnotusually progress todementia, accurate assessment of cognition is vital to prognosisand treatment planning. For example, executive dysfunction often accompanies late-life depression, influencesperformance across cognitive domains, and is associated with poor antidepressant treatment outcomes. Here, wereviewhowassessment can capturedysfunction across cognitive domains anddiscuss cognitive trajectories frequentlyobserved in late-life depression in the context of the neurobiology of this disorder. We also review the efficacy of asample of interventions tailored to specific cognitive profiles.

Keywords: geriatric depression; cognitive impairment; older adults; cognitive control; psychotherapy; antidepressants

IntroductionMajor depression in the elderly often presentswith cognitive impairment. Mild cognitive deficitsin memory, processing speed, and executivefunctioning are particularly common in late-lifedepression.1,2 Executive functions are controlmech-anisms that modulate aspects of emotion andcognition, and disruption to these processes is asso-ciated with poor course of illness and worse clinicaloutcomes of late-life depression.37 In some cases,depression may present concomitantly with,8 oreven precede,9 dementing disorders characterizedby diffuse cognitive deficits. The variability in thecognitive profile of geriatric depression suggests thatthis syndrome represents a heterogeneous groupof disorders requiring careful treatment planningand close neuropsychiatric follow-up. In this paper,we discuss the relevance of cognitive impairmentto the care of geriatric depression, first by describ-ing the various cognitive trajectories and associatedclinical manifestations of cognitive impairment inthese disorders. We next discuss current assessmentand treatment practices and recommendations forclinicians treating patients with late-life depression.

Cognitive impairments in late-lifedepressionMajor depressive disorder in the elderly is accom-panied by structural and functional abnormalitiesin the frontal lobes and their connections with lim-bic and striatal systems (see Refs. 10 and 11 fordetailed reviews). Disruption of the cognitive con-trol network, which encompasses the dorsolateralprefrontal cortex, dorsal and rostral regions of theanterior cingulate, and parietal association regions,is especially prominent.12,13 Clinically, disruptionin this network results in symptoms of executivedysfunction, including a tendency to attend toirrelevant information, impaired concentration,disorganization, difficulty shifting attention, andperseveration, or the inability to disengage fromearlier behavioral responses.10 Roughly 3040% ofnondemented older adults with major depressionexhibit signs of executive dysfunction on cognitiveexamination.10,14 Depressed older adults often per-formpoorly on tests of verbal fluency, theWisconsinCard SortingTest (ameasure of problem solving andcognitive flexibility), the Tower of London (a test ofplanning), and the Stroop ColorWord Interference

doi: 10.1111/nyas.12669

1Ann. N.Y. Acad. Sci. xxxx (2015) 111 C 2015 New York Academy of Sciences.

Depression and cognitive impairment in late life Morimoto et al.

Test (a measure of cognitive inhibition).15 Otherexecutive functions, including planning and seman-tic organization, may account for observed deficitsin select aspects of episodic memory and visuospa-tial abilities.16,17 For example, geriatric depressionpatients frequently perform poorly on word-listmemory and recall, mediated by executive func-tioning, while memory in recognition and cued re-call conditions and narrative contextual memorytasks that do not depend on executive functionsare often intact.16,18

Depression with reversible dementiasyndromeSome older adults with late-life depression maydevelop a dementia syndrome (previously termedpseudodementia), that is, a cognitive impairmentreaching the severity of dementia but subsidesupon remission of depression. These patientsusually present with a severe, late-onset depressionand a mild dementia syndrome. When comparedwith depressed patients with Alzheimers disease,patients with depression and reversible dementiaexhibit more psychic and somatic anxiety, earlymorning awakening, and loss of libido.19 Althoughthe dementia syndrome subsides after remissionof depression, a large percentage of depressionpatients with reversible dementia progress intoirreversible dementia within 23 years.20

Cognitive impairment and clinicaloutcomes in late-life depressionCognitive-control dysfunction is associated withpoor response of geriatric depression to antide-pressants. For example, poor performance onmeasures of executive functioning, such as verbalfluency and cognitive inhibition, predict poorand slow antidepressant response, relapse, andgreater levels of functional disability.3,7,2123 Poorperformance on tests of cognitive control is alsoassociated with greater lethality of suicide attemptsin older adults.24,25 Using the Clinical DementiaRating Scale, a global screening test of cognitivefunctioning, we found that impaired performancein semantic organization during a verbal fluencytask predicted poor treatment response in depressedolder patients.4 These findings were statisticallyindependent of processing speed. We followed upthese findings with a second study that demon-strated deficits; semantic organizational strategy

use (clustering like words together during recall)on a verbal memory task accounted for both verbalmemory performance and treatment response.26

These studies showed that semantic organizationpredicts poor response to antidepressant drug treat-ment regardless of the task by which it is elicited.26

Failure to achieve remission following treat-ment with escitalopram in late-life depression isassociated with decreased gray matter volume inthe dorsal and rostral anterior cingulate27 andwith microstructural white matter abnormalities,likely contributing to disconnection between thesebrain regions and to poor treatment response.28

In late-life depression, low functional connectivitybetween the anterior cingulate and dorsolateralprefrontal cortices has been found to be associatedwith poor remission rate during treatment withescitalopram.12

Prognosis of cognitive impairment inlate-life depressionMild cognitive impairment during depressiveepisodes in late life does not progress to dementiain most cases. Instead, it is often a stable distur-bance that either persists or improves only whendepressive symptoms are ameliorated.3,2931 How-ever, severe cognitive symptoms in geriatric depres-sion patients do appear to result in an increasedrisk for developing dementia.20 The variability inthe cognitive abnormalities seen in geriatric depres-sion suggests that this syndrome represents hetero-geneousdisorders.29Manydepressedolder adultsdonot have significant cognitive impairment.2 In thosewith depression and cognitive impairment, the twosyndromesmay have a common cause (e.g., vasculardisease11) or simply coexist and have distinct causes(e.g., a recurrence of early-onset depression in anolder patient with early-stage Alzheimers disease).8

Depressive symptomsmay also be aprodrome (earlysymptom) of a dementing disorder. Finally, depres-sive disorder with an onset in early life can be arisk factor for both Alzheimers disease and vasculardementia.3032

Neuropsychological assessment can aid in thedifferential diagnosis of geriatric patients withdepression and cognitive impairment (Table 1).Notably, select cognitive deficits may help differen-tiate depressed patients who are likely to experiencecognitive decline compared to depressed patientswho remain cognitively stable. Rushing et al.9

2 Ann. N.Y. Acad. Sci. xxxx (2015) 111 C 2015 New York Academy of Sciences.

Morimoto et al. Depression and cognitive impairment in late life

Table 1. Clinical assessment of cognitive function: sample of cognitive domains, measures, and associated cognitivefunctionsa

Neuropsychological tests

Cognitive function Bedside examination Measure Cognitive function

General cognitive

function

Mini Mental State

Examination (MMSE)

Mattis Dementia Rating

Scale 2 (MDRS-2)

Montreal Cognitive

Assessment (MOCA)

Repeatable Battery for

Assessment of

Neuropsychological

Status (RBANS)

Attention Cannot hold a telephone

number in mind

Digit Span (WAIS-IV) Auditory attention/working

memory

Easily distracted Brief Test of Attention

(BTA)

Auditory attention

Tasks take too long Digit Symbol Coding Divided attention/working

memory

Poor concentration LetterNumber Sequencing

(WAIS-IV)

Working memory

Memory Poor recall of recent events Benton Visuospatial

Memory TestRevised

(BVMT-R)

Nonverbal learning &

memory

Need of reminders California Verbal Learning

Test-II (CVLT-II)

Verbal list learning &

memory

Repeats self Hopkins Verbal Learning

TestRevised (HVLT-R)

Verbal list learning &

memory

Logical Memory Subtest

(WMS-IV)

Verbal contextual learning

& memory

Language Word-finding difficulty Boston Naming Test 2

(BNT-2)

Confrontation naming

Use of vague generic terms Token Test Comprehension

Syntactic errors Boston Diagnostic Aphasia

Examination3rd

Edition (BDAE-3)

Comprehensive language

assessment

Comprehension difficulty Animal Naming Test Semantic fluency

Difficulty keeping up with

conversation

Controlled Oral Word

Association Test

(COWAT)

Phonemic fluency

Praxis,

somatosensory,

& motor

functions

Difficulty with use of

familiar tools (e.g., pen,

toothbrush)

Apraxia Exam Praxis

Difficulty with sequencing

of actions (e.g., Show me

how you would cut your

meat?)

RightLeft Orientation Somatosensory

Finger Localization Somatosensory

Finger Tapping Test Fine motor

Grooved Pegboard Fine motor

Continued



Table 1. Continued

Neuropsychological tests

Cognitive function Bedside examination Measure Cognitive function

Visuospatial

functions

Difficulty navigating

familiar environment

Clock Drawing Test Planning, construction

Judgment of Line

Orientation

Visuospatial perception

Hooper Visual Organization

Test

Visuospatial integration

Facial Recognition Test

Executive functions Multistage projects are

effortful or avoided

Trail Making Test Set shifting

Poor task persistence

Perseverates

Stroop Test Cognitive

inhibition/processing

speed

Double alternating hand

movements

Controlled Oral Word

Association Test

(COWAT)

Strategy

Wisconsin Card Sorting Test

(WCST)

Perseveration, flexibility

Iowa Gambling Task (IGT) Reward-based decision

making

Social awareness Impaired recognition of

social cues

Apathy Evaluation Scale

(AES)

Takes unusual liberties

Apathetic

Insistent, overbearing

aThis is not an exhaustive list of neuropsychological functions andmeasures, but rather a sample of measures that maybe used to assess aspects of cognitive function in older adults.

contrasted baseline performance on multiple cog-nitive measures and found that only recall of nar-rative contextual information (i.e., short stories)predicted conversion to dementia in the 15 out of120 older adults with major depression who devel-oped Alzheimers disease up to 13 years later. Testsof executive functioning and executive-dependentword-list recall did not add significant value to thedementia prediction model. Thus, impaired mem-ory for verbal contextual information, dependenton intact hippocampal functioning, may predictconversion to Alzheimers disease in geriatricdepression, whereas mild impairment in frontallymediated executive functions may not. This isconsistent with evidence from nondepressed olderadults; namely, that the amnestic subtype of mildcognitive impairment is associated with a progres-sion to Alzheimers disease whereas the dysexecutivesubtype is associated with vascular disease.33

Evaluation of cognitive impairment in theelderly

Evaluation of depressive syndromes in cognitivelyimpaired patients is complicated by the symptomoverlap with dementia, the instability of depres-sive symptoms over time, and the poor ability ofelderly patients to report their symptoms. If crite-ria for one of the depressive syndromes are met, anantidepressant treatment trial should be offered.37

Beyond the benefits of alleviating the sufferingand complications of depression, remission of thedepressive syndrome can increase the cliniciansability to evaluate the severity of the remaining cog-nitive impairment and plan for further treatmentand follow-up. Screening tests and questionnairescan be useful for detecting select aspects of cognitiveimpairment.While theMiniMental State Examina-tion (MMSE) and Montreal Cognitive Assessment



(Table 1) are relatively ubiquitous screening mea-sures for gross cognitive impairment, otherinstruments, including the Mattis Dementia RatingScale (MDRS-2; Table 1)34 and Executive Interview(EXIT),35 may be more sensitive to generalized cog-nitive decline.36 The Cornell Scale for Depressionin Dementia may also aid in quantifying depressivesymptoms and signs; this scale integrates informantwith patient reports.37 Among patients with sus-pected executive dysfunction who perform well ontraditional measures of executive functioning, theFrontal Systems Behavior Scale (FrSBe)38 can helpcharacterize behavioral manifestations of executivedeficits. For instance, on the FrSBe, patients and in-formants rate the presence of behavioral syndromesof apathy and disinhibition as well as difficultiesin working memory, planning, sequencing, orga-nizing, and abstracting. In addition to character-izing executive dysfunction, preliminary evidencesuggests that behavioral abnormalities identified bytheFrSBe are associatedwith slower responseof late-life depression to escitalopram.39 The usefulness ofscreening measures and questionnaires is limitedin situations where the cognitive deficits are subtle,there is concern about a comorbid dementia, or thepatient and/or familymember is not a reliable infor-mant with respect to questionnaires. In such cases,clinicians concerned about cognitive dysfunctionshould refer for a neurological and/or neuropsy-chological consultation (see Table 1 for examples ofcognitive functions that should be assessed).40 Vari-ability in the course of elderly patients with depres-sion and cognitive impairment suggests the need forcareful follow-up.

Pharmacologic treatmentThe Expert Consensus Guideline recommends an-tidepressant drug therapy combinedwith psychoso-cial intervention as the treatment of choice forgeriatric depression.41 Tricyclic antidepressantshave not been found to improve cognitive functionin depressed older adults. In fact, nortriptyline wasshown to compromise verbal learning performanceof depressed older adultsmore than placebo.42 Con-versely, some selective serotonin reuptake inhibitors(SSRIs) may improve cognitive function mainly inpatients whose depressive symptoms subside aftertreatment. Specifically, sertraline has been shown toimprove performance on tests of attention, episodicmemory, and executive function, but only in

treatment responders.43 Similarly, depressed olderpatients with an antidepressant response to citalo-pram showed improvement in psychomotor speedand visuospatial functioning. However, citalopramtreatment appeared to worsen verbal learning andprocessing speed in patients who remained de-pressed despite treatment.44 In contrast, there ismounting preliminary evidence from both animaland human studies45,46 showing improvement ofboth mood and cognitive functioning with vortiox-etene; however, studies in humans are limited, andadditional research is needed in humans to substan-tiate the effects on cognition.

Nevertheless, a substantial number of depressedolder patients continue to experience residual de-pressive symptoms and neuropsychological deficitsafter antidepressant treatment. Abnormal executivefunctions, processing speed, and working mem-ory persist after remission of mood symptoms inmany patients with geriatric depression.4749 Inaddition, some demographic variables may leavepatientsmore vulnerable to persistent cognitive dys-function despite treatment: old age, high vascu-lar risk score, and low baseline MMSE scores allpredicted less cognitive improvement in depressedolder adults treated with citalopram.43 Treatmentof depression with sertraline50 or mirtazapine51 inAlzheimers disease does not improve depressivesymptoms more than placebo. Further, SSRI treat-ment is associated with increased adverse events,suggesting that their use for first-line treatment fordepression should be reconsidered.51

Psychotherapies for late-life depressionwith cognitive impairmentNonpharmacological interventions should be con-sidered in conjunction with pharmacotherapy orgiven alone in depression of mild-to-moderateseverity.52 Specific psychotherapies have also beendeveloped to remedy the behavioral deficits of de-pressed older adults with cognitive impairmentsassociated with poor response to antidepressants(Table 2).5360 As an example, problem-solving ther-apy (PST) was modified to address the behav-ioral deficits of patients with late-life depressionand executive dysfunction61 and has been effica-cious in reducing depression and disability in cog-nitively unimpaired depressed older adults and inolder adults with cognitive impairment.53,54,62 PSTis basedon the premise that helping patients become



Table 2. Psychotherapies for depressed older adults

Name of Location of

psychotherapy Target population delivery Duration Specific techniques

Problem-solving

therapy for executive

dysfunction

(PST-ED)54

Depressed,

nondemented older

adults with executive

dysfunction

Outpatient

setting

12 weekly

sessions

Problem solving skills:

problem definition,

goal setting,

generation of

alternative solutions,

decision making,

planning

Problem adaptation

therapy (PATH)53Depressed, disabled

older adults with

significant cognitive

impairment

Patients

home

12 weekly

sessions

Problem-solving skills,

caregiver

involvement,

environmental

adaptation tools

(e.g., notebooks,

calendars, pill boxes,

alarms, timers,

checklists, and

step-by-step

breakdown of tasks)

Cognitive behavioral

therapy for mild

dementia

(CBTmild

dementia)58

Depressed older adults

with mild dementia

Outpatient

setting

1620 weekly

sessions

Cognitive strategies

(e.g., examining the

evidence, listing pros

and cons, cognitive

restructuring),

behavioral

activation, memory

aids

Behavior

therapypleasant

events (BT-PE)59


with moderate to

severe dementia and

their caregivers

Outpatient

setting

9 weekly

sessions

Behavioral strategies

(e.g., identifying,

planning, and

carrying out positive

activities, as well as

identifying and

eliminating

obstacles)

Behavior

therapyproblem

solving (BT-PS)59


with moderate to

severe dementia and

their caregivers

Outpatient

setting

9 weekly

sessions

Problem-solving skills

training to

caregivers;

education, advice,

and support to

caregivers

Interpersonal

psychotherapy for

mild cognitive

impairment

(IPT-CI)60


with mild cognitive

impairment

Outpatient

setting

1216 weekly

sessions

Interpersonal skills,

joint caregiver

patient sessions

Continued



Table 2. Continued

Name of Location of

psychotherapy Target population delivery Duration Specific techniques

Personalized adherence

intervention for

depression and

COPD (PID-C)55


with COPD

Outpatient

setting

9 weekly

sessions

Skills to target barriers

to adherence (i.e.,

misconceptions,

misunderstanding of

recommendations,

misattribution of

symptoms, stigma,

hopelessness,

dissatisfaction with

treatment

experience, logistic

barriers)

Ecosystem-focused

therapy (EFT)57Older adults with

poststroke

depression

Patients

home

12 weekly

sessions

New perspective,

adherence

enhancement

structure,

problem-solving

structure,

re-engineering goals

and plans of family,

coordination of

specialized

therapists

Engage56 Depressed older adults Outpatient

setting

9 weekly

sessions

Reward exposure

(action planning to

increase rewarding

activities);

behavioral

techniques targeting

barriers (negativity

bias, apathy,

emotional

dysregulation) to

reward exposure

COPD, chronic obstructive pulmonary disease.

better managers of their lives reduces stress andthus ameliorates depression. Patients are instructedto identify problems, brainstorm different waysto solve problems, create action plans, perform acostbenefit analysis, and evaluate the effectivenessof potential solutions. PST improves skills neededin interpersonal relationships, remedies commu-nication deficits, and increases behavioral activa-tion by enhancing exposure to pleasurable activities.

Further, therapies have recently been developed fordepressed elderly patients that incorporate themod-ification of the patients environment or ecosys-tem, which includes the patient, the caregiver, andthe patients home environment (see ecosystem-focused therapy (EFT) in Table 2).57 In additionto utilizing PST as a basic therapeutic frame-work, problem adaptation therapy (PATH; Table 2)integrates environmental adaptation tools and the



primary caregiver in order to help the patient cir-cumvent their cognitive impairment and engage inproblem resolution and adaptive functioning.53

Computerized cognitive remediationCertain types of computerized cognitive remedi-ation (CCR) can improve brain functioning byinducing neuroplasticity (nCCR).63,64 We have pro-posed that CCR that relies on the induction of neu-roplasticity and targets brain networks associatedwith clinical outcomes in late-life depression hasthe potential to improve treatment response. Re-cently, we developed a novel treatment model us-ing nCCR to improve the functioning of cerebralnetworks responsible for executive functioning andassociated with poor response to antidepressants.65

Our nCCR treatment model is based on the as-sumption that neuroplastic changes that improvethe function of cerebral network abnormalities con-tributing to antidepressant resistance (i.e., dorsalneocortical structures participating in the cognitivecontrol network) would improve symptoms andsigns of late-life depression. Preliminary evidencesuggests that nCCR treatment induces a clinicallymeaningful improvement of both cognitive and af-fective symptoms in depressed elderly patients whofailed to remit using conventional antidepressants.In fact, 72% of patients reached remission after 4weeks of treatment with nCCR.66

Future investigationsClassic neuropsychological tests of executivefunctioning primarily assess the cognitive controlnetwork and offer little information on theventromedial prefrontal regions, including theorbitofrontal cortex, the ventralrostral anteriorcingulate, and their connections with the amygdala.These regions mediate divergent functions, such asprocessing of emotional information, utilization ofcues in the environment to predict rewarding oraversive events, and the regulation of behavioralresponses.67 The ventromedial region also mediatesreward-related decision making, a complex taskinvolving option generation, evaluation of risksand consequences, and choice of a course ofaction.68 Ventromedial dysfunction is prominentin major depression,69 yet behavioral abnormalitiesmediated by ventromedial regions have seldombeen investigated in late-life depression.We recentlytreated an elderly woman with major depression

who presented with mood lability, distractibility,poor self-monitoring, and impulsivity, yet demon-strated no impairment on classic tests of executivefunction.70 Behavioral disturbances mediated byventromedial regions, potentially dissociable fromcognitive-control dysfunction, may characterizea subgroup of late-life depression patients whoseneurobiology, treatment response, and course ofillness require further investigation.

The need to assess ventromedial functioningled to the development of Stroop-like emotionalconflict tasks (e.g., categorizing facial affect whileignoring overlaid affect label words)71 and decision-making paradigms, such as the Iowa GamblingTask.72 When performing this task, individuals se-lect cards, one at a time, fromone of four decks.Halfof the decks are disadvantageous (i.e., higher im-mediate rewards but long-term negative outcomes)and the other half are advantageous (i.e., lower im-mediate rewards but long-term positive outcomes).Overall, older adults with major depression donot differ from age-matched controls on the Iowaor other gambling paradigms.73,74 However, olderadults with major depression and clinical evidenceof poor decision making (as evidenced by a his-tory of attempted suicide) performworse on a gam-bling task when compared to older depressed adultswith no history of suicide.73 In contrast, apathetic,depressed elderly patients are not influenced byimmediate reinforcers (the high rewards of the dis-advantageous decks) and demonstrate an advanta-geous strategy on the IowaGambling Task (selectingcards from the conservative decks) when comparedto nonapathetic, depressed older adults.74 Elucidat-ing the neurocognitive outcome of geriatric depres-sion patientswith behavioral disturbancesmediatedby ventromedial regions remains ongoing.

ConclusionsMajor depression in elderly patients is oftenaccompanied by impairment75 spanning multiplecognitive domains.14 Most depressedolder adults donot develop neurodegenerative diseases, yet somecases of late-onset depression represent the firstbehavioral abnormalities of dementia syndromes.In some cases, depression and cognitive impairmentmay be related to a single underlying illness (e.g.,cerebrovascular disease), while in others, neurode-velopmental disease and depression simply coexist.Deficits in executive functions (i.e., susceptibility



to interference, semantic strategy) have importantclinical implications, such as poor, slow, andunstable response of depression to antidepressantdrugs, early relapse and recurrence, increased riskof suicidality, and disability disproportional to theseverity of depression. In the majority of patients,pharmacological treatment does not lead to majorimprovement in cognition, although there are a fewexceptions. Therefore, it is important to clarify thepatients cognitive status early so that appropriatetreatment recommendations can be made.

Psychotherapies have been developed to addressthe behavioral deficits of depression with executivedysfunction (e.g., PST), as well as in patients withdepression and dementia (e.g., PATH) and patientswith poststroke depression (e.g., EFT). These ap-proaches have been found to be effective in improv-ing depression and disability. Neuroplasticity-basedCCR that targets brain networks responsible for ex-ecutive functioning has been developed, and pre-liminary studies are encouraging. More studies areneeded in this emerging area.

Conflicts of interestThe authors declare no conflicts of interest.

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