Literature Review Resources

International Review of Psychiatry, August 2008; 20(4): 382–388

Depression in Alzheimer’s disease: Phenomenology, clinical correlates and treatment

SERGIO E. STARKSTEIN 1,2

, ROMINA MIZRAHI 3,4

, & BRIAN D. POWER 1,2

1 School of Psychiatry and Clinical Neurosciences, University of Western Australia,

2 Fremantle Hospital,

Western Australia, Australia, 3 Faculty of Medicine, University of Toronto, Ontario, Canada, and

4 Center for Addiction and Mental Health, PET centre, Toronto, Ontario, Canada

Abstract Depression is one of the most frequent comorbid psychiatric disorders in Alzheimer’s disease and other dementias, and is associated with worse quality of life, greater disability in activities of daily living, a faster cognitive decline, a high rate of nursing home placement, relatively higher mortality, and a higher frequency of depression and burden in caregivers. Depression in Alzheimer’s disease is markedly under-diagnosed, and most patients with depression are either not treated or are on subclinical doses of antidepressants. This is related to the lack of validated diagnostic criteria and specific instruments to assess depression in dementia. Apathy and pathological affect-crying are the main differential diagnoses of depression in Alzheimer’s disease. Left untreated, major depression in Alzheimer’s disease may last for about 12 months. Recent randomized controlled trials demonstrated the efficacy of sertraline and moclobemide to treat depression in Alzheimer’s disease. Other psychoactive compounds may be useful as well, but careful consideration must be given to potentially serious side-effects.

Introduction

Depression is increasingly recognized as one of the

most frequent psychiatric disorders of Alzheimer’s

disease (AD). For the past ten years several studies

have examined the epidemiology, mechanism, clin-

ical correlates and treatment of depression in AD

(Lyketsos & Olin, 2002). Nevertheless, important

issues regarding the phenomenon of depression in

AD remain to be properly clarified. First, there is no

general consensus on the most valid method to assess

and diagnose depression in AD. There is a major

overlap between symptoms of depression and symp-

toms of AD, and there are few instruments that

were specifically designed to assess depression in

dementia. These diagnostic limitations may at least

partially account for the high variability on the

frequency of depression in AD reported in several

studies (Lyketsos & Olin, 2002). Second, patients

with AD often show a variety of psychological and

behavioural problems such as anxiety, apathy, dis-

inhibition, irritability, and poor insight, among

others. Depression in AD rarely occurs in isolation

and is usually comorbid with one or more of the

above. Finally, there is a paucity of treatment studies

for depression in AD, although recent controlled

studies suggest that several antidepressant com-

pounds and psychological treatments may be

effective.

The aim of the present review is to provide a

critical analysis of the methods currently used to

diagnose depression in AD, to review the most

important clinical and psychiatric comorbidities of

this condition, and to examine the efficacy of

different treatment modalities for depression in AD.

Diagnostic approaches to depression

in dementia

There are four main approaches to diagnose depres-

sion in chronic degenerative neurological conditions.

For the ‘inclusive approach’ (Cohen-Cole &

Stoudemire, 1987) symptoms which may or may

not be related to the physical illness are counted

towards the diagnostic criteria. For the ‘exclusive

approach’ symptoms specifically associated with the

neuropsychiatric disorder are counted but symptoms

that the interviewer feels are related to the physical

illness are not counted (Gallo, Rabins, Lyketsos,

Tien, & Anthony, 1997). For the ‘substitutive

Correspondence: Professor Sergio E. Starkstein, Education Building T-7, Fremantle Hospital, Fremantle, 6959 WA, Australia. Tel: 61 8 9431 2013.

E-mail: [email protected]

ISSN 0954–0261 print/ISSN 1369–1627 online � 2008 Informa Healthcare USA, Inc. DOI: 10.1080/09540260802094480

approach’ non-overlapping symptoms of depression

(e.g. psychological symptoms) are substituted for the

overlapping diagnostic criteria (Olin, Katz, Meyers,

Schneider, & Lebowitz, 2002a). Finally, the ‘specific

symptom approach’ only considers those symptoms

which are significantly more frequent in patients with

sad mood as compared to those without sad mood,

and the diagnostic criteria are modified to include

only specific symptoms (Starkstein, Jorge, Mizrahi,

& Robinson, 2005b). The question now arises as to

the best strategy to diagnose depression in AD.

A work group convened by the National Institutes

of Mental Health (NIMH) suggested that depression

in AD should be diagnosed using the inclusive

approach, which may minimize the rate of false

negatives (Olin et al., 2002a; Olin et al., 2002b).

This is an important suggestion given that depression

in AD largely goes unrecognized. On the other hand,

the inclusive strategy will maximize the rate of

false positives, with the concomitant over-diagnosis

and unnecessary treatment of depression. Therefore,

the ‘specific symptom approach’ is clinically more

appropriate, although its implementation will depend

on appropriate validation studies of depressive

symptoms in AD.

Diagnostic criteria for depression in AD

One of the main limitations to a valid diagnosis of

depression in dementia is the overlap between

symptoms of depression and symptoms of cognitive

and functional decline. For instance, insomnia,

psychomotor retardation, loss of energy, loss of

libido, and poor appetite are common among

patients with dementia, but are also clinical criteria

for a DSM-IV diagnosis of major depression. Several

studies examined the specificity of symptoms of

depression in AD. Chemerinski and co-workers

(2001) assessed a series of 233 patients with AD,

47 patients with depression without dementia, and

20 age-comparable healthy individuals for the fre-

quency of depressive symptoms. The main finding

was that the presence of sad mood was associated

with significantly higher scores on the HAM-D items

rating guilt, suicide, insomnia, loss of interest,

retardation, agitation, worry, anxiety, loss of

energy, loss of libido, and hypochondriasis, but not

loss of appetite. This finding demonstrates that both

physical and psychological symptoms of depression

are frequent among AD patients with sad mood.

Another important finding of this study was that

AD patients without sad mood had no more

symptoms of depression than did age-comparable

healthy individuals, demonstrating that physical

and psychological symptoms of depression should

not be necessarily construed as mere epiphenomena

of a chronic neurological disease, but may be specific

to depression in AD. Furthermore, only 2% of

the AD patients met the DSM-IV criteria for

major depression without having sad mood or loss

of interest, confirming that symptoms of depression

are uncommon among AD patients without

sad mood.

Lyketsos and co-workers (2001) suggested an

empirically based taxonomy of psychiatric disorders

in AD. They suggested that the ‘individual symptom

approach’ may ignore the high comorbidity of

psychiatric symptoms and syndromes in AD and

should not be used. The authors examine a large

series of AD patients living in the community,

and using latent class analysis they identified a

group (27% of the participants) who exhibited

affective symptoms of depression, anxiety, irritability

and apathy. Based on these findings, they proposed

specific diagnostic criteria for AD-associated

affective disorder (Table I).

The NIMH workgroup proposed standardized

diagnostic criteria for depression in AD (Olin et al.,

2002a, 2002b) (Table II). These are similar to the

DSM-IV criteria for major depression, but with the

inclusion of irritability and social isolation replacing

loss of libido, and with loss of pleasure in response to

social contact replacing loss of interest. The NIMH

criteria require three symptoms for the diagnosis

of depression instead of the five required by the

DSM-IV criteria for a major depressive episode, and

symptoms are not required to be present nearly

every day (Table II).

Table I. Diagnostic criteria for AD-associated neuropsychiatric

disturbance (adapted from Lyketsos et al., 2001).

A. Meeting NINCDS/ADRDA criteria for probable AD.

B. A prominent disturbance of affect, disruptive to the patient

or the care environment and representing a change from

the patient’s baseline, as evidenced by the presence of one

or more of the following symptoms: 1. Depression

2. Iritability

3. Anxiety

4. Euphoria

C. One or more of the following associated symptoms must

be present:

1. Aggression

2. Psychomotor agitation

3. Delusions

4. Hallucinations

5. Sleep disturbance

6. Appetite disturbance

D. Symptoms from B and C co-occur most days, and

the disturbance has a duration of at least 2 weeks.

E. The disturbance has its first onset within two years or after

the onset of dementia.

F. The disturbance cannot be explained in its entirety by

another cause (e.g. a general medical condition,

medication, life stressors).

Depression in Alzheimer’s disease 383

Few studies have examined the validity of the

NIMH criteria. Starkstein and co-workers (2005b)

found that 41% of depressed AD patients in the stage

of severe dementia had no sad mood (i.e. depression

was diagnosed based on the presence of loss of

interest/anhedonia) suggesting that the NIMH

criteria may have low specificity for depression in

the late stages of dementia. A recent study by Vilalta-

Franch et al. (2006) compared the frequencies of

depression resulting from using 4 different diagnostic

schemes for depression in a sample of 491 patients

with AD. Frequencies of major or severe depression

were 5% for the International Classification of

Diseases, 10th Revision (ICD-10) criteria, 10% for

the Cambridge Examination for Mental Disorder of

the Elderly (CAMDEX) diagnostic criteria, 13% for

the DSM-IV criteria for major depression, and 27%

for the NIMH work group criteria. The authors

stressed that the requirements of loss of confidence/

self-esteem and irritability accounted for a large

variance of the discrepancies.

In a recent study Starkstein and co-workers

(2005c) examined the temporal stability of symptoms

of depression in a series of 65 AD patients with

depression at baseline that were re-assessed for

depression an average of 17 months later. At

follow-up about half of the sample had no depression

and showed a significant improvement in the

symptoms of sadness, guilt, suicidal ideation, dis-

ruption in sleep, loss of interest, loss of energy,

thoughts of death, social withdrawal, psychomotor

changes, changes in appetite/weight, and symptoms

of anxiety. On the other hand, no significant

between-group changes were found on scores of

irritability or apathy. The finding that symptoms

of anxiety co-varied over time with the presence of

depression suggests that anxiety is attributable

to depression rather than to dementia. On the other

hand, the lack of changes on scores of irritability

among patients with remission of depression suggests

that irritability should not be construed as a criterion

for depression in AD.

One limitation to assess mood changes in demen-

tia is that patients with AD may under-report

depressive symptoms due to poor awareness of

their behavioural and emotional changes.

Chemerinski and colleagues (2001) examined dis-

crepancies between patients’ and caregivers’ reports

of depressive symptoms, and found that AD patients

under-rated the severity of their depressive

symptoms as compared to reports provided by their

respective caregivers. Another confounder is that

depression in caregivers may influence depression

ratings of patients. However, while some studies

found a significant influence of caregivers’ depres-

sion on patients’ own ratings of depression (Teri &

Truax, 1994) other studies showed no significant

impact (Loewenstein et al., 2001). In a recent

12-week study on the efficacy of sertraline among

AD patients with depression, Rosenberg and cow-

orkers (2005) found that both caregiver depression

and burden decreased during the three months of

the study, although these changes were not asso-

ciated with improvement in patient mood as rated

by the caregivers.

Taken together, these findings suggest that both

physical and psychological symptoms of depression

are frequent in AD. However, in the absence of

sad mood, symptoms of depression are no more

prevalent in AD than in age-comparable individuals

without dementia, suggesting that physical and

psychological symptoms of depression are not

epiphenomena of a chronic neurological disease,

but constitute specific symptoms of a mood disorder.

The diagnosis of depression in dementia should be

based on a systematic mental status examination

leading to a psychiatric diagnosis based on the

presence of a syndromic symptom cluster using the

inclusive approach, until specific criteria are properly

validated. Future studies will provide specific

Table II. Provisional diagnostic criteria for depression of AD

(adapted from (Olin et al., 2002b).

A. Three or more of the following symptoms have been present

during the same 2-week period and represent a change from

previous functioning: at least one of the symptoms is either

(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 met for dementia of the Alzheimer type.

C. The symptoms cause clinically significant distress or disrup-

tion in functioning.

D. The symptoms do not occur exclusively during the course of

a 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

psychiatric conditions.

Specify if: Co-occurring onset: if onset antedates or co-occurs with

the AD symptoms

Post-AD onset: if onset occurs after AD symptoms

Specify: With psychosis of AD

With other significant behavioral signs or symptoms

With past history of mood disorders

384 S. E. Starkstein et al.

diagnostic criteria for a valid (i.e. clinically mean-

ingful) diagnosis of depression in AD.

Depression in AD: Diagnostic instruments

The presence of psychiatric signs and symptoms

should be assessed with a structured psychiatric

interview that includes questions for a variety of

behavioural and emotional symptoms, as well as

specific items to rate the presence and severity of

observed abnormal behaviours. The Structured

Clinical Interview for DSM-IV (SCID) is a semi-

structured psychiatric interview for making the major

Axis I diagnoses (Spitzer, Williams, Gibbon, & First

1992). This instrument includes an overview of the

present psychiatric complaint and past episodes of

psychopathology. This is followed by specific sec-

tions with open-ended questions to obtain symptom

description from the patient and caregivers. The

examiner should use all sources of information

available at the time of the evaluation, and use her/

his own judgement about the presence of a given

symptom. The full SCID usually takes from 60 to 90

minutes to complete and has been validated for use

in AD (Chemerinski, Petracca, Sabe, Kremer, &

Starkstein, 2001).

Depression rating scales are useful to rate the

severity of depressive disorders and may also be used

as screening instruments to determine the likelihood

of the presence or absence of mood disorders in

dementia. The Hamilton Depression Rating Scale

(HAM-D) is a 17-item interviewer-rated scale that

measures psychological and autonomic symptoms of

depression (Hamilton, 1960). This instrument

assesses the individual’s mood, self-esteem, suicidal

ideation and interest in daily life activity and work

productivity. Other HAM-D items, such as those

rating sleep problems, psychomotor retardation,

poor concentration, loss of energy, and hypochon-

driasis may be difficult to assess in patients with AD.

The Geriatric Depression Scale (GDS) is a short

screening instrument for depression in the elderly

that focuses on psychosocial aspects of depression,

avoiding symptoms that may overlap with medical

disorders or aging (Yesavage et al., 1982). One

limitation of the GDS is that it is a self-report

instrument, and some of the questions may be

difficult for patients with moderate or severe demen-

tia to answer reliably. The Cornell Scale for

Depression in Dementia (CSDD) was developed to

specifically assess depressive symptoms in dementia

and is based on information provided by a caregiver

and the patient (Alexopoulos, Abrams, Young, &

Shamoian, 1988). If the examiner considers that

some of the symptoms are secondary to the cognitive

deficits, those symptoms should not be considered

for the final score.

Frequency of depression in Alzhiemer’s

disease

Estimates of depression in AD depend on sampling

issues, diagnostic methods, and clinical manifesta-

tions. The prevalence of major and minor depression

has been estimated to range between 30% to 50%

(Olin et al., 2002a). Population studies reported a

prevalence of dysphoria of 20% and an 18-month

incidence of 18% (Lyketsos & Olin, 2002).

Clinical correlates of depression in

Alzheimer’s disease

Depression in AD has been associated with worse

quality of life, greater disability in activities of

daily living (ADLs), a faster cognitive decline,

and relatively higher mortality (Kales, Chen, Blow,

Welsh, & Mellow, 2005; Lee & Lyketsos, 2003).

Kales and coworkers recently demonstrated that

demented patients with coexistent depression have

significantly higher rates of nursing home placement

than patients with either depression or dementia

alone (Kales et al., 2005). Starkstein and coworkers

(2005b) examined the clinical correlates of major

and minor depression in a consecutive series of 670

patients with AD. They found that patients meeting

DSM-IV criteria for either major or minor depres-

sion had more severe social dysfunction and greater

impairment in activities of daily living than AD

patients without depression, suggesting that even

mild levels of depression are significantly associated

with more functional impairment in AD. Patients

with major depression also showed more severe

anxiety, apathy, delusions and Parkinsonism than

those with minor depression, demonstrating that

the severity of depression is significantly associated

with increased psychopathology and neurological

impairments.

Differential diagnosis of depression in AD

Apathy

Apathy is defined as diminished activity due to lack

of motivation (Starkstein, Ingram, Garau, & Mizrahi,

2005a). Among patients with AD, apathy is mani-

fested as diminished drive to perform their daily

chores, low interest about family activities, and

emotional indifference to positive or negative

events. AD patients with apathy put little effort into

their usual chores and need help from a caregiver to

structure their routines. Depression is frequently

associated with apathy in AD, an expected finding

given that loss of interest and motivation is a cardinal

symptom of both apathy and depression. For

instance, key symptoms of apathy such as loss of

interest and psychomotor retardation are specific

Depression in Alzheimer’s disease 385

DSM-IV diagnostic criteria for depression, and

about two thirds of AD patients with apathy also

have depression.

In a recent study Starkstein and co-workers

examined the association between apathy and

depression in the context of a longitudinal study

that included 247 patients with AD (Starkstein,

Jorge, Mizrahi, & Robinson, 2006). In a cross-

sectional analysis about one quarter of patients

without depression had apathy, demonstrating that

depression is not necessary for apathy in AD. On the

other hand, about half of the patients with depression

had apathy, demonstrating that depression is not

sufficient for apathy in AD. After a mean follow-up

period of 18 months there was a significant increase

on apathy scores over time, but syndromal depres-

sion at baseline (i.e. major or minor depression) was

not significantly associated with more severe

apathy at follow-up. On the other hand, the presence

of apathy at baseline was a significant predictor of

increasing depression during follow-up, suggesting

that apathy may be an early marker or a prodromal

stage of depression in AD.

Pathological affective display

Pathological affective display is another important

differential diagnosis of depression in AD (Starkstein

et al., 1995). Patients with dementia may present

with sudden episodes of crying that may be classified

into two different categories: (1) ‘Emotional lability’,

which is defined as the sudden onset of crying that

the patient is unable to suppress, which generally

occurs in appropriate situations and is accompanied

by a congruent emotion (e.g. sadness); and (2)

‘Pathological crying’, which is defined as the sudden

onset of crying episodes that do not correspond

to an underlying congruent emotional change

(e.g. crying episodes in the context of normal

mood). Pathological affective display-crying was

present in about 50% of patients with AD

(Starkstein et al., 1995). Patients with pathological

affective display-crying showed significantly higher

depression and anxiety scores and a significantly

higher frequency of major and minor depression than

patients with no pathological affect. Taken together,

these findings suggest that pathological affect-crying

in AD may be a marker of an underlying depression.

Longitudinal evolution of depression in

Alzheimer’s disease

A personal history of psychiatric disorders is a strong

predictor of major depression in AD (Migliorelli

et al., 1995; Garre-Olmo et al., 2003). Left

untreated, major depression in AD may last for

about 12 months, whereas minor depression has a

shorter course (Starkstein et al., 1997; Garre-Olmo

et al., 2003). Longitudinal studies suggest that the

incidence (i.e. new cases) of depression in AD is

about 20% during a 12-month period, suggesting

that most patients with AD will develop depression at

some stage of their illness (Starkstein et al., 1997).

Treatment of depression in Alzheimer’s

disease

Pharmacological treatments

Most randomized control trials (RCT) and a recent

meta-analysis have shown that antidepressants are

superior to placebo for both treatment response and

remission of depression (Thompson, Herrmann,

Rapoport, & Lanctot, 2007).

Randomized controlled trials using selective ser-

otonergic re-uptake inhibitors (SSRIs) demonstrated

a significant efficacy over placebo for citalopram and

sertraline, but not for fluoxetine (Lyketsos & Lee,

2004) (Petracca, Chemerinski, & Starkstein, 2001).

Whereas SSRIs are better tolerated than tricyclics,

they may induce agitation, anxiety, tremor and

sleep problems. Autonomic changes such as dry

mouth, sweating, loss of weight and diarrhoea may

also occur. Concurrent administration of opiates or

monoamine oxidase inhibitors increases the risk

of serotonin syndrome and the concomitant use of

these medications should be avoided.

Tricyclics are rarely used to treat depression in AD

given their relatively frequent side-effects among

elderly individuals, important contra-indications and

high lethality index. A randomized controlled trial

using the tricyclic clomipramine demonstrated a

greater efficacy of the active compound over placebo

(Petracca, Teson, Chemerinski, Leiguarda, &

Starkstein, 1996). On the other hand, other studies

found no significant differences between the tricyc-

lics maprotiline or imipramine over placebo

(Lyketsos & Lee, 2004). Side-effects are frequently

reported in elderly individuals on tricyclics. The

most dangerous adverse event is a delay in cardiac

conduction and a potential heart block. Orthostatic

hypotension is a frequent problem with tricyclics,

and other anticholinergic side-effects include dry

mouth, reduced tear flow, impaired visual accom-

modation, constipation, urinary retention and cog-

nitive changes characterized by confusion or overt

delirium. Sedation and weight gain are other

frequent problems. Contraindications to the use of

tricyclics are myocardial infarction within the past

6 months, first- or second-degree heart block or

life threatening arrhythmias, history of prostatic

hypertrophy, difficult to treat seizures and glaucoma.

A randomized controlled trial using the reversible

monoamine oxidase inhibitor (MAOI) moclobemide

386 S. E. Starkstein et al.

demonstrated a significant efficacy of this medication

over placebo (Roth, Mountjoy, & Amrein, 1996).

Side effects for moclobemide were mild and mostly

included restlessness, dizziness, nausea and

constipation.

In summary, the current strategy to treat depres-

sion in AD is to start with a SSRI (Lyketsos & Olin,

2002), although the patient’s psychiatric and phar-

macological history (e.g. positive response to tricyc-

lics in the past) may suggest other therapeutic

alternatives. Medically compromised elderly patients

may not be suitable for either tricyclics or MAOIs.

In addition, the patient’s living situation should be

carefully evaluated (e.g. nursing homes with reduced

staff may warrant the use of treatments that would

require less nursing needs).

Non-pharmacological treatments for

depression in AD

Psychotherapy

A recent systematic review of psychological

approaches to the management of neuropsychiatric

symptoms of dementia (Livingston, Johnston,

Katona, Paton, & Lyketsos, 2005) suggests that

behaviour management therapies, and specific types

of caregiver and residential care staff education are

among the most effective to treat neuropsychiatric

symptoms in patients with dementia. A recent study

has demonstrated the effectiveness of specific treat-

ment guidelines for AD delivered through a collab-

orative care model, which included active screening

for cognitive impairment, active case finding and

treatment for depression, psychoses, behavioural

disturbances, and active monitoring and support

of the caregiver’s emotional and physical health

(Callahan et al., 2006).

Electroconvulsive therapy (ECT)

There is anecdotal evidence that ECT may be a

useful treatment for demented patients with major

depression that are refractory to medication (Rao &

Lyketsos, 2000). On the other hand, confusion

post-ECT is very frequent among depressed

patients with dementia undergoing ECT, and the

severity of confusion is significantly associated

with the severity of pre-ECT cognitive deficits

(Rao & Lyketsos, 2000).

Conclusions

Depression is one of the most frequent comorbid

psychiatric disorders in AD.

The diagnosis of depression in AD should be

made after a thorough mental status examination

with a specific evaluation for the signs and symptoms

of mood disorders. The best strategy to diagnose

depression in dementia is to use a standardized

psychiatric interview and structured diagnostic

criteria.

Depression rating scales are useful to screen

patients for depressive disorders, to determine

the relative severity of depressive symptoms, and to

quantify changes in depression after specific

treatment.

Depressive symptoms are not rampant among

patients with dementia, but are specific to the

presence of sad mood.

Depression in AD is associated with worse quality

of life, greater disability in activities of living, a faster

cognitive decline, a high rate of nursing home

placement, relatively higher mortality, and a higher

frequency of depression and burden in caregivers.

Depression in Alzheimer’s disease is markedly

under-diagnosed, and most patients with depression

are either not treated or are on subclinical doses of

antidepressants.

Several antidepressants are effective to treat

depression in AD. SSRIs are currently the first

choice, given their acceptable efficacy and relatively

low rate of side-effects.

Acknowledgements

This study was partially supported with grants

from the National Health and Medical Research

Council.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the paper.

References

Alexopoulos, G. S., Abrams, R. C., Young, R. C., &

Shamoian, C. A. (1988). Cornell Scale for Depression in

Dementia. Biological Psychiatry, 23, 271–284.

Callahan, C. M., Boustani, M. A., Unverzagt, F. W., Austrom,

M. G., Damush, T. M., Perkins, A. J., et al. (2006).

Effectiveness of collaborative care for older adults with

Alzheimer disease in primary care: A randomized controlled

trial. JAMA, 295, 2148–2157.

Chemerinski, E., Petracca, G., Sabe, L., Kremer, J., &

Starkstein, S. E. (2001). The specificity of depressive symptoms

in patients with Alzheimer’s disease. American Journal of

Psychiatry, 158, 68–72.

Cohen-Cole, S. A., & Stoudemire, A. (1987). Major depression

and physical illness. Psychiatric Clinics of North America, 10,

1–17.

Gallo, J. J., Rabins, P. V., Lyketsos, C. G., Tien, A. Y., &

Anthony, J. C. (1997). Depression without sadness: Functional

outcomes of nondysphoric depression in later life. Journal of the

American Geriatrics Society, 45, 570–578.

Depression in Alzheimer’s disease 387

Garre-Olmo, J., López-Pousa, S., Vilalta-Franch, J., Turon-

Estrada, A., Hernàndez-Ferràndiz, M., Lozano-Gallego, M.,

et al. (2003). Evolution of depressive symptoms in Alzheimer

disease: one-year follow-up [Comment]. Alzheimer Disease &

Associated Disorders, 17, 77–85.

Hamilton, M. (1960). A rating scale for depression. Journal of

Neurology Neurosurgery and Psychiatry, 23, 56–62.

Kales, H. C., Chen, P., Blow, F. C., Welsh, D. E., &

Mellow, A. M. (2005). Rates of clinical depression diagnosis,

functional impairment, and nursing home placement in

coexisting dementia and depression. American Journal of

Geriatric Psychiatry, 13, 441–449.

Lee, H. B., & Lyketsos, C. G. (2003). Depression in Alzheimer’s

disease: Heterogeneity and related issues. Biological Psychiatry,

54, 353–362.

Livingston, G., Johnston, K., Katona, C. L., Paton, J., &

Lyketsos, C. G. (2005). Systematic review of psychological

approaches to the management of neuropsychiatric symptoms

of dementia. American Journal of Psychiatry, 162, 1996–2021.

Loewenstein, D. A., Arguelles, S., Bravo, M., Freeman, R. Q.,

Arguelles, T., Acevedo, A., et al. (2001). Caregivers’ judgments

of the functional abilities of the Alzheimer’s disease patient: A

comparison of proxy reports and objective measures. Journals of

Gerontology Series B-Psychological Sciences & Social Sciences, 56,

P78–P84.

Lyketsos, C. G., Breitner, J. C., & Rabins, P. V. (2001). An

evidence-based proposal for the classification of neuropsychia-

tric disturbance in Alzheimer’s disease [Comment].

International Journal of Geriatric Psychiatry, 16, 1037–1042.

Lyketsos, C. G., & Lee, H. B. (2004). Diagnosis and treatment of

depression in Alzheimer’s disease. A practical update for the

clinician. Dementia & Geriatric Cognitive Disorders, 17, 55–64.

Lyketsos, C. G., & Olin, J. (2002). Depression in Alzheimer’s

disease: Overview and treatment. Biological Psychiatry, 52,

243–252.

Migliorelli, R., Teson, A., Sabe, L., Petrachi, M., Leiguarda, R.,

& Starkstein, S. E. (1995). Prevalence and correlates of

dysthymia and major depression among patients with

Alzheimer’s disease. American Journal of Psychiatry, 152, 37–44.

Olin, J. T., Katz, I. R., Meyers, B. S., Schneider, L. S., &

Lebowitz, B.D. (2002a). Provisional diagnostic criteria for

depression of Alzheimer disease: Rationale and background.

American Journal of Geriatric Psychiatry, 10, 129–141.

Olin, J. T., Schneider, L. S., Katz, I. R., Meyers, B. S.,

Alexopoulos, G. S., Breitner, J. C., et al. (2002b). Provisional

diagnostic criteria for depression of Alzheimer disease.

American Journal of Geriatric Psychiatry, 10, 125–128.

Petracca, G., Teson, A., Chemerinski, E., Leiguarda, R., &

Starkstein, S. E. (1996). A double-blind placebo-controlled

study of clomipramine in depressed patients with Alzheimer’s

disease. Journal of Neuropsychiatry & Clinical Neurosciences, 8,

270–275.

Petracca, G. M., Chemerinski, E., & Starkstein, S. E. (2001).

A double-blind, placebo-controlled study of fluoxetine in

depressed patients with Alzheimer’s disease. International

Psychogeriatrics, 13, 233–240.

Rao, V., & Lyketsos, C. G. (2000). The benefits and risks of ECT

for patients with primary dementia who also suffer from

depression [Comment]. International Journal of Geriatric

Psychiatry, 15, 729–735.

Rosenberg, P. B., Mielke, M. M., & Lyketsos, C. G. (2005).

Caregiver assessment of patients’ depression in Alzheimer

disease: Longitudinal analysis in a drug treatment study.

American Journal of Geriatric Psychiatry, 13, 822–826.

Roth, M., Mountjoy, C. Q., & Amrein, R. (1996). Moclobemide

in elderly patients with cognitive decline and depression:

An international double-blind, placebo-controlled trial.

British Journal of Psychiatry, 168, 149–157.

Spitzer, R. L., Williams, J. B., Gibbon, M., & First, M. B. (1992).

The Structured Clinical Interview for DSM-III-R (SCID).

I: History, rationale, and description. Archives of General

Psychiatry, 49, 624–629.

Starkstein, S. E., Chemerinski, E., Sabe, L., Kuzis, G.,

Petracca, G., Teson, A., et al. (1997). Prospective longitudinal

study of depression and anosognosia in Alzheimer’s disease.

British Journal of Psychiatry, 171, 47–52.

Starkstein, S. E., Ingram, L., Garau, M. L., & Mizrahi, R.

(2005a). On the overlap between apathy and depression

in dementia. Journal of Neurology, Neurosurgery & Psychiatry,

76, 1070–1074.

Starkstein, S. E., Jorge, R., Mizrahi, R., & Robinson, R. G.

(2005b). The construct of minor and major depression in

Alzheimer’s disease. American Journal of Psychiatry, 162,

2086–2093.

Starkstein, S. E., Jorge, R., Mizrahi, R., & Robinson, R. G.

(2006). A prospective longitudinal study of apathy in

Alzheimer’s disease. Journal of Neurology Neurosurgery &

Psychiatry, 77, 8–11.

Starkstein, S. E., Migliorelli, R., Teson, A., Petracca, G.,

Chemerinsky, E., Manes, F., et al. (1995). Prevalence and

clinical correlates of pathological affective display in

Alzheimer’s disease. Journal of Neurology, Neurosurgery &

Psychiatry, 59, 55–60.

Starkstein, S. E., Mizrahi, R., & Garau, L. M. (2005c). Specificity

of symptoms of depression in Alzheimer disease: A longitudinal

analysis. American Journal of Geriatric Psychiatry, 13, 803–807.

Teri, L., & Truax, P. (1994). Assessment of depression in

dementia patients: Association of caregiver mood with depres-

sion ratings. Gerontologist, 34, 231–234.

Thompson, S., Herrmann, N., Rapoport, M. J., & Lanctot, K. L.

(2007). Efficacy and safety of antidepressants for treatment of

depression in Alzheimer’s disease: A metaanalysis. Canadian

Journal of Psychiatry – Revue Canadienne de Psychiatrie, 52,

248–255.

Vilalta-Franch, J., Garre-Olmo, J., Lopez-Pousa, S., Turon-

Estrada, A., Lozano-Gallego, M., Hernandez-Ferrandiz, M.,

et al. (2006). Comparison of different clinical diagnostic criteria

for depression in Alzheimer disease. American Journal of

Geriatric Psychiatry, 14, 589–597.

Yesavage, J. A., Brink, T. L., Rose, T. L., Lum, O., Huang, V.,

Adey, M., et al. (1982). Development and validation of a

geriatric depression screening scale: A preliminary report.

Journal of Psychiatric Research, 17, 37–49.

388 S. E. Starkstein et al.