The demography and phenomenology of depression in patients suffering from Alzheimer's disease (AD) have been the subject of considerable recent research. Unfortunately, most, studies have used markedly different diagnostic criteria for their diagnoses of depression and AI), thereby producing confounding results and considerable disagreement among researchers and clinicians. Indeed, until quite recently, a diagnosis of depression (as a cause of "pseudodementia") was considered almost exclusionary to a diagnosis of a primary neurodegenerative disorder.2
Various terminologies have been employed to describe the occurrence of depression in patients with AD. These include "depressive dementia," "depressive syndrome of dementia," "dementia with mood disorder," and "coexistent depression with dementia."1 Patients suffering from Alzheimer's disease may exhibit disorders of affect lie, emotional lability) as well as sustained alterations of mood consistent with a DSM-IV diagnosis of a major depressive disorder. In addition, the negative symptoms manifest in the natural clinical course of Alzheimer's disease (eg, apathy, social withdrawal, flat affect, and diminished psychomotor activity) are often misinterpreted as indicative of a major depressive disorder.2
INCIDENCE OF DEPRESSION IN ALZHEIMER'S DISEASE
As a consequence of their different methodologies, studies have varied widely in the reported prevalence of depression in patients with AD. Studies that have relied solely on the history reported by caretakers when making a diagnosis of major depression (according to DSM-III criteria) in patients with AD have reported an incidence between 30% and 86%3-5; however, studies that have used a direct examination of the patient by a clinician have reported a much lower incidence of major depression 10% and 13.9% ).2,6,7
The discrepancy between different studies is exemplified by the results of a recent retrospective chart review of 325 patients with probable AD (according to National Institute of Neurological and Communicative Disorders and Stroke |NINCDS| criteria) that reported a 1.3% 2-year incidence of major depression/ It is important to note, however, that this study excluded patients with a history of depression. These studies have all relied on a probable diagnosis of AD based on the criteria of the NINCDS and have not employed either standardized diagnostic interviews for diagnosis of depression or considered the stage of AD. In contrast, Rosen and Zubenko, employing an annual standardized clinical interview keyed to DSM-III criteria in a cohort of 32 patients with a confirmed histopathologic diagnosis of AD at autopsy, reported a prevalence of depression of 22%. 9 In addition, they reported that 47% of their cohort developed a psychosis that appeared to be an independent variable to the presence of a mood disorder.9
A recent study, employing a structured psychiatric interview of 103 patients with probable AD, reported that 23% were suffering from a major depressive disorder and 28% from a dysthymic disorder. Patients suffering from dysthymia tended to exhibir greater insight into the nature and extent of their cognitive deficits and developed dysthymia early in the course of their dementing illness.1" In this study, the prevalence of major depression was similar across all stages of the disease.10
RISK FACTORS FOR DEPRESSION IN ALZHEIMER'S DISEASE
Pearlson et al have reported that almost 50% of their depressed AD patients had a family history of major affective disorders compared with ll(/r of euthymic AD patients." In addition, the prevalence of major depression in relatives of depressed AD patients was similar to that found in the relatives of patients suffering from a primary major depression.11
In a recent study, Lawlor et al reported that AD patients with an earlier age of onset (defined as younger than 65 years) were more likely to manifest depression and other behavioral disorders compared with late-onset AD patients. In addition, patients with early onset AD were reported to exhibit more prominent language and praxis impairment.12 The more widespread and severe neurnpathologic and neurochemical derangements found in early onset AD have been postulated to account for this higher prevalence of behavioral disorders.1;i-M Other possibly important risk factors for depression, including premorbid personality structure, substance abuse, social functioning, and medication use, have not yet been assessed.
CLINICAL CHARACTERISTICS OF DEPRESSION ASSOCIATED WITH AD
Neurovegetative symptoms such as social withdrawal, apathy, anergia, decreased concentration, decreased libido, insomnia, and psychomotor agitation and retardation are frequent clinical manifestations in the natural course of AD.- Caretakers may frequently perceive that these symptoms are indicative of depression, and this may account for the higher incidence of depression in studies that have used caretakers as the primary information source. Therefore, one of the major challenges facing the clinician when making a diagnosis of major depression in a patient with AD is to distinguish these "negative" symptoms of AD from the emergence of a comorbid mood disorder.1 Several studies have emphasized the importance of considering intrapsychic rather than neurovégétative features when making a diagnosis of major depression in a patient with AD; however, a recent study has reported that self-reproach/guilt and difficulties with concentration have a low sensitivity and specificity as criteria for a diagnosis of major depression in AD !according to RDC criteria)."' The same study reported, however, that the AD patient's nonverbal manifestations of dysphoria I such as irritability, dcmandingness, dependency behavior, and complaining! are the most reliable indicators of depression. This finding is consistent with studies that have found that patients with AD often exhibit diminished insight and relative anosagnosia for their illness and their internal mood state.16
A sensitive, specific, and reliable clinical rating scale capable of identifying AD patients suffering from depression would be an extremely valuable tool that would have a significant impact on the care provided to this group of patients; however, several difficulties are encountered when attempting to develop such an instrument. First, self-report scales are likely to be extremely unreliable in AD patients whose progressive cognitive deficits preclude a reliable performance on a self-report questionnaire. In addition, as described previously, patients with AD frequently display little insight into their disease or its impact on their lives or personal well-being. Patients with AD live, and are cared for, in a wide range oí residential and institutional settings, and any questionnaire must be suitable for a wide variety of individuals.
Rating scales have been developed specifically to assess depression (the Cornell Scale for Depression in Demential and other psychopathology (the Behavior Pathology in Alzheimer's Disease Rating Scale [Behave-AD] and the Columbia University Scale for Psychopathology in Alzheimer's disease) in demented patients.1'·1* Although these scales are superior to those developed for younger nondemented population groups, they also exhibit some significant limitations. The Cornell Scale's narrow range of severity (ie, a 2-point scale 1 limits the ability of the scale to monitor subtle alterations in mental status. The Behave-AD scale does not include some items that are important markers for depression in AD patients, ie, loss of interest, loss of responsivity, and motor retardation. In addition, both scales are somewhat ambiguous in terms of their administration, which is likeiy to negatively impact interrater reliability among the wide range of possible informants who care for AD patients.
BIOLOGICAL MARKERS OF DEPRESSION IN AD
Considering the diagnostic ambiguity of signs and symptoms in AD and major depressive disorder, sensitive and specific biologic markers of depression would provide a valuable clinical tool. Although 70r/i of depressed geriatric patients with or without AD will exhibit early escape on the dexamethasone suppression test (DST), as many as SO'/r of euthymic AD patients will also exhibit early mmsuppression.111 Single photon omission computed tomography (SPECT) and positron emission tomography (PET) have consistently demonstrated characteristic pattern abnormalities in patients with AD and may provide a valuable tool for distinguishing between various types of dementia. Euthymic patients with AD typically demonstrate diminished bitemporal perfusión compared with the patchy hypoperfusion associated with multi-infarct dementia. Starkstein et al, in a recent study using ii9l"TcHMPAO SPECT, report that, compared with euthymic AD patients, patients suffering from AD with a concomitant major depression had significantly reduced regional cerebral flow (rCBF) over the left hemisphere (mainly involving the frontal. dorsal, temporal, and parietal cortices).-0 Furthermore, they reported that this pattern of diminished rCBF distinguished between depressed (DSM-III-R criteria) and dysthymic AD patients. Whether these SPECT changes in depressed AD patients represent a state or trait marker requires further evaluation. In addition, the qualitative estimation of abnormalities in rCBF as manifest on SPECT scanning may render the procedure too insensitive and inconsistent for routine dinicaï use.
Ventricular enlargement and cortical atrophy are found in both AD and in elderly depressed nondemented patients.''1 Structural brain imaging with CT and MRI do not, therefore, provide a useful tool for distinguishing between euthymic and depressed AD patients.
A recent study has reported that patients with AD exhibit lower total REM sleep density compared with a group of elderly depressed (DSM-III-R criteria) patients.-2 The sleep characteristics of depressed AD patients have not yet been investigated but may provide a valid (albeit cumbersome and expensive) clinical diagnostic tool.
Decreased cerebrospinal fluid (CSF) monoamine metabolites, ie, 3-methoxy-4-hydroxyphenylethylglycol (MHPG). 5-hydroxyindoleacetic acid (5-HIAA). homovanillic acid (HVA), and somatostatin-like immunoreactivity (SLI), have been reported in patients with primary depression and also in the CSF of patients with AD. In addition, depressed AD patients have been found to exhibit significantly decreased levels of 5-HIAA and SLI compared with euthymic AD controls.-·1" Whether these biogenic amines may have clinical use as possible early markers of depression remains to be ascertained. Markedly decreased levels of these two metabolites in depressed AD patients does, however, implicate 5-HT., receptor abnormalities in the pathophysiology of depression in AD.24
Several neuropathologic studies have reported consistent abnormalities in depressed compared with eutlwmic AD patients, including (U greater neuronal loss in the locus coeruleus, raphe nuclei, and substantia nigra, and (2i a 10to 20-fold reduction in the level of cortical norepinephrine concentrations but relative preservation of subcortical choline acetyltransferase activity.- Although these neuropathologic findings have no current clinical application, they do support the "catecholamine" hypothesis of depression.
MAKING A DIAGNOSIS QF DEPRESSION IN A PATIENT WITH AD
Making a definitive diagnosis of a major depressive disorder in a patient suffering from AD frequently presents a considerable challenge. The neurovegetative signs and symptoms of depression may be a manifestation of the typical progression of AD and cannot therefore be relied on solely to make a diagnosis of a mood disorder. The clinician must, therefore, also rely on the patient's nonverbal cues, such as irritability, "whining behavior," verbal aggression, and nonspecific somatization. It is extremely helpful if the physician has maintained contact with the patient over the preceding course of illness and maintained a detailed record of the patient's cognitive, physical, and behavioral status. In this regard, the authors recommend that the patient's primary physician schedule regular appointments with the patient, regardless of the patient's current status. A laissez-faire attitude to the follow-up of patients suffering from AD may result in therapeutic contacts that are "crisis driven'1 and fraught with confusion and diagnostic ambiguity.
A thorough clinical history obtained from caretakers who have maintained close contact with the patient over the preceding months will provide valuable clues. An escalating pattern of cognitive decline, personality change, and interpersonal aggression is particularly important. Attention should be addressed to identifying any occult or deteriorating medical disorder that may be contributing to the patient's decline, and a thorough neurologic examination should address the differential diagnosis. A comprehensive physical examination should be performed on any AD patient who presents with a rapid alteration in cognitive or functional capacity. The therapeutic rationale and potential side effects of the patient's medications (prescribed, "over-the-counter," and those prescribed by family or friends) should be evaluated. Any recent falls or syncopal events should alert the clinician to a possible subdural hematoma.
The decision to obtain further diagnostic studies will be driven by the findings obtained in the history and physical examination. Once again, the clinician's prior knowledge and sequential examinations of the patient will greatly enhance the yield of diagnostic studies. Unfortunately, despite adequate clinical evaluation, a diagnosis of depression in an AD patient is frequently empirical. In such circumstances, antidepressant medications should only be employed once specific markers of therapeutic outcome (eg, irritability, verbal aggression) have been identified and can be sequentially evaluated.
FUNCTIONAL CONSEOUENCES OF DEPRESSION IN ALZHEIMER1S DISEASE
Comorbid depression in AD, through its influence on motivation, motor responsivity, and cognition, produces excess disability in AD patients.25 Several studies have found that depressed AD patients, compared with euthymic AD patients, exhibit more impairment in the independent activities of daily living (ADLl such as managing home finances, shopping, and scheduling personal affairs.25-26 In fact, in patients with mild cognitive impairment, the presence and severity of depression are more powerful predictors of functional capacity than the patient's cognitive functioning or age.-7 In contrast, the level of cognition was the most important predictor of ADL and IADL capacity in patients with more severe cognitive deficits, and the presence and severity of depression played only a secondary role.-7
TREATMENT OF DEPRESSION IN AD
Although several reports have addressed the use of different agents in the treatment of depression in AD,28-31 only one study has employed a douhle-blind methodology.32 Reifler at al:ta reported that both imipramine and placebo were effective treatments for depression in patients with AD. The authors ascribed the therapeutic efficacy in the placebo group to the fact that patients were seen on a weekly basis by clinicians who provided encouragement and support. In an extension of this study, Teri et al:iH examined the therapeutic effect of imipramine (average dose, 82 ing/day) in two cohorts of depressed and euthymic AD patients. Although the depressed AD patients receiving imipramine exhibited a significant improvement in depression, this improvement was no more significant than that exhibited by the control group of depressed AD patients receiving placebo. Neither group exhibited any significant improvement in cognitive functioning.311 In fact, euthymic AD patients receiving imipramine exhibited a mild decline in cognition. :'3 Certainly, the anticholinergic effects of the tricyclic antidepressants would suggest that their use should be avoided, if possible, in AD patients. The benign side effect profile of the selective serotinergic reuptake inhibitors and selective serotoninergic and noradrenergic reuptake inhibitors appear to make them appropriate therapeutic options in depressed AD patients, but their therapeutic efficacy remains to be confirmed.28"111
A large (but uncontrolled) clinical literature suggests that ECT may provide a safe and rapidly effective treatment for depression in patients with Alzheimer's disease, especially those who have been unresponsive to or intolerant of antidepressant medications. ECT is well tolerated by depressed AD patients and does not appear to hasten the rate of their cognitive decline. Their tendency to exhibit more short-term confusion and amnesia can be minimized by various modifications in treatment technique (eg, no anticholinergic premedi cation, light unilateral electrode placement, brief pulse stimulus, and increased spacing of treatment intervals).34
DEPRESSION AMONG CARETAKERS
Caring for a loved one with AD places a tremendous physical, financial, and emotional burden on family caretakers. Witnessing the steady decline and ultimate demise of a loved one inevitably engenders a sense of hopelessness, helplessness, and ambivalence in those who courageously accept the task. As many as half of caregivers will experience significant depressive symptoms that are likely to have a negative impact on both their health and the person for whom they are caring. ;JS Several studies have found that caregivers are better able to handle cognitive deficits or disruptive behavior than the passive and negative behaviors associated with depression.1 It is not surprising, therefore, that caregiver depression is most strongly correlated with the severity of depression in the AD patient.1
It is critical that the clinician be available to provide support, assistance, and, if necessary, treatment to caregivers. Such treatment will enable patients with AD to remain in the familiar and comforting surroundings of their home and family. Caring for patients in the context of their extended social constellation will inevitably reap rich therapeutic benefits for both patients and their families. Indeed, several studies have reported that caregivers can learn effective behavioral strategies for treating mood and behavioral disturbances in the AD patient.1
Depression is a frequent, disabling, but treatable disorder in AD that is often overlooked. Rather than focus solely on identifying neurovégétative signs and symptoms or depressive statements, the clinician should remain alert for nonverbal cues of depression, such as irritability, passivity, and somatic preoccupation. A failure to diagnose and treat depression in AD patients will inevitably result in an escalating downward spiral of declining functional capacity in the patient and despair in the caregiver.
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