Depression

Depression is mood disorder that produces sadness, negative self-regard, loss of interest in life, and disruptions of sleep, appetite, thinking and energy level. These symptoms are classified as a depressive episode in both international (ICD; Dilling et al. Reference Dilling, Mombour and Schmidt1991) and American (APA, 2000) diagnostic systems when they are present for more than 2 weeks and interfere with daily living. Although diagnostic criteria encourage the categorization of specific subtypes and severity levels of depression, it is important to recognize that any depressive symptoms that impair cognition or activities of daily living (ADLs) are clinically significant (Koenig & Blazer, Reference Koenig, Blazer, Blazer, Steffens and Busse2004). In this review, the use of the term depression includes any constellation of depressive symptoms that is sufficient to impair cognition, social functioning or other important aspects of daily living, and we refer to the term major depression where it is important to make this clinical distinction.

Depression and neurocognitive function

Although dysfunction in concentration is one of the key diagnostic criteria of depression, the presentation of cognitive deficits is heterogeneous. While many depressed individuals have no cognitive complaints or objective findings on neurocognitive assessments, most research on neurocognitive function in depression has found that depressed individuals tend to have worse performance relative to non-depressed comparison groups on a number of neuropsychological measures (Veiel, Reference Veiel1997; Zakzanis et al. Reference Zakzanis, Leach and Kaplan1998), with the most consistent deficits occurring in the areas of processing speed (Nebes et al. Reference Nebes, Butters, Mulsant, Pollock, Zmuda, Houck and Reynolds2000; Sheline et al. Reference Sheline, Barch, Garcia, Gersing, Pieper, Welsh-Bohmer, Steffens and Doraiswamy2006); effortful tasks involving selective attention, response inhibition, and performance monitoring (i.e. executive functions) (Boone et al. Reference Boone, Lesser, Miller, Wohl, Berman, Lee and Palmer1995; Beats et al. Reference Beats, Sahakian and Levy1996); and the acquisition and retrieval of new information (i.e. episodic memory) (Beats et al. Reference Beats, Sahakian and Levy1996; Austin et al. Reference Austin, Mitchell, Wilhelm, Parker, Hickie, Brodaty, Chan, Eyers, Milic and Hadzi-Pavlovic1999). Deficits in information processing speed and executive functions appear to increase with severity of depression symptoms, particularly apathy (Boone et al. Reference Boone, Lesser, Miller, Wohl, Berman, Lee and Palmer1995; Feil et al. Reference Feil, Razani, Boone and Lesser2003). Neurocognitive deficits involving executive dysfunction are more common when first onset of depression occurs in late life and even more so in the presence of vegetative symptoms (Palmer et al. Reference Palmer, Boone, Lesser, Wohl, Berman and Miller1996); however, some research suggests that memory deficits may be more focally affected among older individuals with a history of recurrent depression beginning earlier in life (Rapp et al. Reference Rapp, Dahlman, Sano, Grossman, Haroutunian and Gorman2005).

The cognitive neuroscience of depression

Cognitive neuroscience has made important contributions to understanding how specific neural mechanisms in frontal and subcortical regions are associated with specific characteristics of cognitive processing among depressed individuals. This in turn provides insight into cognitive impairments that may occur as a result of brain changes in regions associated with depression. Although depression is influenced by a number of brain regions within larger neural systems (Phillips et al. Reference Phillips, Drevets, Rauch and Lane2003), we focus on four key regions: (1) the orbitofrontal cortex, (2) the anterior cingulate gyrus, (3) the dorsolateral prefrontal cortex, and (4) the hippocampus.

The orbitofrontal cortex (OFC) appears to have a cognitive role in the selective processing of affective stimuli, and is associated with the finding that depressed individuals show a more rapid reaction to sad words than to happy words (Elliott et al. Reference Elliott, Rubinsztein, Sahakian and Dolan2002). The OFC is also associated with a disproportionate response to negative feedback that is evidenced on tests involving learning of stimulus–reward associations (i.e. reversal learning) (Murphy et al. Reference Murphy, Michael, Robbins and Sahakian2003), which makes depressed individuals predisposed to cognitive errors if they have received negative feedback on preceding tasks. Structurally, neuroimaging studies have found smaller total OFC volumes, smaller OFC gray matter volumes, and more prominent hyperintense lesions in elderly depressed individuals relative to non-depressed (Lai et al. Reference Lai, Payne, Byrum, Steffens and Krishnan2000; MacFall et al. Reference MacFall, Payne, Provenzale and Krishnan2001; Ballmaier et al. Reference Ballmaier, Toga, Blanton, Sowell, Lavretsky, Peterson, Pham and Kumar2004).

The cognitive role of the anterior cingulate gyrus (ACC) appears to involve both initiation (Nemeth et al. Reference Nemeth, Hegedus and Molnar1988) and suppression (Paus et al. Reference Paus, Petrides, Evans and Meyer1993) of behavior through conflict monitoring (Carter et al. Reference Carter, MacDonald, Botvinick, Ross, Stenger, Noll and Cohen2000) and appraisal of motivational content (Devinsky et al. Reference Devinsky, Morrell and Vogt1995). In this role, the ACC is involved in the affective processing bias seen in depression, in which depressed individuals responding more rapidly to sad versus happy words also demonstrate an elevated neural response in the rostral anterior cingulate (Elliott et al. Reference Elliott, Rubinsztein, Sahakian and Dolan2002). In addition to cognitive-emotional processing, the ACC is involved in spatial planning and working memory, with depressed individuals demonstrating lower activation of this region than non-depressed controls while performing the Tower of London task (Elliott et al. Reference Elliott, Baker, Rogers, O'Leary, Paykel, Frith, Dolan and Sahakian1997). Structural changes include bilateral volume reductions of the ACC in geriatric depression (Ballmaier et al. Reference Ballmaier, Toga, Blanton, Sowell, Lavretsky, Peterson, Pham and Kumar2004), and a more specific finding of smaller left subgenual ACC volumes in non-geriatric depressed subjects (Hastings et al. Reference Hastings, Parsey, Oquendo, Arango and Mann2004). Functional imaging studies have identified decreased metabolism and cerebral blood flow in the subgenual ACC of depressed individuals (Drevets et al. Reference Drevets, Bogers and Raichle2002; London et al. Reference London, Simon, Berman, Mandelkern, Lichtman, Bramen, Shinn, Miotto, Learn, Dong, Matochik, Kurian, Newton, Woods, Rawson and Ling2004).

A major cognitive role of the dorsolateral prefrontal cortex (DLPFC) is to subserve the implementation of attentional control. Mood-disordered individuals have demonstrated reduced left cingulate activation and increased left DLPFC activation for both affective and non-affective tests of response inhibition (the Stroop test) relative to non-depressed controls (George et al. Reference George, Ketter, Parekh, Rosinsky, Ring, Pazzaglia, Marangell, Callahan and Post1997). Depressed individuals also evidence increased neural response in the DLPFC to an affective go/no-go task than non-depressed controls, which is presumed again to reflect an affective processing bias (Elliott et al. Reference Elliott, Rubinsztein, Sahakian and Dolan2002). Although the DLPFC is not the primary substrate of cognitive-emotional processing, it is involved in several higher-order cognitive functions, including working memory (Owen et al. Reference Owen, Herrod, Menon, Clark, Downey, Carpenter, Minhas, Turkheimer, Williams, Robbins, Sahakian, Petrides and Pickard1999), retrieval of episodic memory (Rugg et al. Reference Rugg, Fletcher, Chua and Dolan1999), planning (Dagher et al. Reference Dagher, Owen, Boecker and Brooks1999), and response monitoring (Blakemore et al. Reference Blakemore, Rees and Frith1998). On planning tests such as Tower of London-type tasks (e.g. CANTAB Stockings of Cambridge), depressed individuals demonstrate reduced perfusion in the right middle frontal cortex and left superior frontal gyrus relative to non-depressed individuals (Goethals et al. Reference Goethals, Audenaert, Jacobs, Van de Wiele, Ham, Pyck, Vandierendonck, Van Heeringen and Dierckx2005). The cognitive findings of the DLPFC in depression are consistent with the finding that depressed individuals demonstrate reduced metabolism in DLPFC relative to non-depressed individuals (Biver et al. Reference Biver, Goldman, Delvenne, Luxen, De Maertelaer, Hubain, Mendlewicz and Lotstra1994; Michael et al. Reference Michael, Erfurth, Ohrmann, Arolt, Heindel and Pfleiderer2003). Geriatric depression is associated with microstructural differences in the white matter of the DLPFC (Taylor et al. Reference Taylor, MacFall, Payne, McQuoid, Provenzale, Steffens and Krishnan2004) and reduced volumes of the superior and middle frontal cortices (Ballmaier et al. Reference Ballmaier, Toga, Blanton, Sowell, Lavretsky, Peterson, Pham and Kumar2004), which may play a particularly important role in late-onset depression.

The hippocampus plays a complex role in affective regulation and a vital role in learning and recall. Cognitively, depressed elderly individuals demonstrate reduced hippocampal volume in association with lower levels of performance on tests of both verbal and visual episodic memory, which is seen in both early and late-onset depression (Hickie et al. Reference Hickie, Naismith, Ward, Turner, Scott, Mitchell, Wilhelm and Parker2005). Although the hippocampus is most frequently associated with episodic memory (Moscovitch et al. Reference Moscovitch, Rosenbaum, Gilboa, Addis, Westmacott, Grady, McAndrews, Levine, Black, Winocur and Nadel2005), it may also regulate emotional responses to environmental stimuli (Phillips et al. Reference Phillips, Drevets, Rauch and Lane2003). Imaging studies of the hippocampus in depression are mixed; some studies have found decreased volume to be associated with depression among adults (Sheline et al. Reference Sheline, Wang, Gado, Csernansky and Vannier1996; Frodl et al. Reference Frodl, Meisenzahl, Zetzsche, Hohne, Banac, Schorr, Jager, Leinsinger, Bottlender, Reiser and Moller2004), while others have not (Hastings et al. Reference Hastings, Parsey, Oquendo, Arango and Mann2004). Reductions in hippocampal volume are more consistently found among individuals with recurrent depression (MacQueen et al. Reference MacQueen, Campbell, McEwen, Macdonald, Amano, Joffe, Nahmias and Young2003; Sheline et al. Reference Sheline, Gado and Kraemer2003), earlier age-of-depression onset (Sheline et al. Reference Sheline, Sanghavi, Mintun and Gado1999; MacQueen et al. Reference MacQueen, Campbell, McEwen, Macdonald, Amano, Joffe, Nahmias and Young2003), and longer duration of untreated depression (Sheline et al. Reference Sheline, Gado and Kraemer2003). Smaller hippocampal volume has been associated with subsequent cognitive decline in older patients with depression (Steffens et al. Reference Steffens, Bosworth, Provenzale and MacFall2002; O'Brien et al. Reference O'Brien, Lloyd, McKeith, Gholkar and Ferrier2004).

Vascular pathology and vascular depression

The preceding review of the cognitive neuroscience of depression highlights the crucial relationships between mood and structural changes in the aging brain. There are well-established associations between cerebrovascular pathology and development of depression in the elderly. Studies using magnetic resonance imaging (MRI) have suggested that subcortical ischemic changes may play a role in the pathology of geriatric depression, particularly in patients with late age of onset (Krishnan et al. Reference Krishnan, Goli, Ellinwood, Franz, Blazer and Nemeroff1988; Coffey et al. Reference Coffey, Figiel, Djang, Saunders and Weiner1989; Figiel et al. Reference Figiel, Krishnan, Doraiswamy, Rao, Nemeroff and Boyko1991; Salloway et al. Reference Salloway, Malloy, Kohn, Gillard, Duffy, Rogg, Tung, Richardson, Thomas and Westlake1996; Kumar et al. Reference Kumar, Bilker, Jin, Udupa and Gottleib1999; de Groot et al. Reference de Groot, de Leeuw, Oudkerk, Hofman, Jolles and Breteler2000). These findings led to the characterization of MRI-defined vascular depression (Krishnan et al. Reference Krishnan, Hays and Blazer1997; Steffens & Krishnan, Reference Steffens and Krishnan1998). Relative to depressed individuals without marked cerebrovascular pathology, individuals with vascular depression tend to be older, have higher levels of hypertension and other cerebrovascular risk factors, and less family history of depression (Krishnan et al. Reference Krishnan, Taylor, McQuoid, MacFall, Payne, Provenzale and Steffens2004; Taylor et al. Reference Taylor, Steffens and Krishnan2006). The contribution of underlying cerebrovascular risk factors (CVRFs) to depression and cognitive impairment in general is indicated in a study that found that individuals with two or more CVRFs (diabetes, hypertension or atrial fibrillation) and lower scores on a measure of initiation and perseveration had significantly higher levels of depressive symptomatology at baseline and 18 months than individuals with fewer CVRFs and better cognitive performance (Mast et al. Reference Mast, Yochim, MacNeill and Lichtenberg2004). These data suggest that individuals with higher levels of CVRF and lower executive function performances are at greater risk of developing depression, possibly as a result of structural brain changes. The influence of structural brain changes is supported by findings that depressed elders with greater prevalence of deep-white matter hyperintensities (DWMHs) demonstrate worse performance on tests of memory and executive functions than either depressed elders or normal controls without DWMHs (Kramer-Ginsberg et al. Reference Kramer-Ginsberg, Greenwald, Krishnan, Christiansen, Hu, Ashtari, Patel and Pollack1999). The characterization of cerebrovascular pathology in depression is an important area of continued research not only because it may result in an acquired and persistent dysfunction in affect and cognition but also because of its association with slowed treatment response (Hickie et al. Reference Hickie, Scott, Mitchell, Wilhelm, Austin and Bennett1995; Simpson et al. Reference Simpson, Jackson, Baldwin and Burns1997; Steffens et al. Reference Steffens, Conway, Dombeck, Wagner, Tupler and Weiner2001, Reference Steffens, Pieper, Bosworth, MacFall, Provenzale, Payne, Carroll, George and Krishnan2005), increased hospitalization (Yanai et al. Reference Yanai, Fujikawa, Horiguchi, Yamawaki and Touhouda1998), greater functional impairment (Steffens et al. Reference Steffens, Bosworth, Provenzale and MacFall2002), and increased mortality (Levy et al. Reference Levy, Steffens, McQuoid, Provenzale, MacFall and Krishnan2003).

Depression and mild cognitive impairment (MCI)

Detection of MCI is a key clinical issue in depression because it is associated with accelerated cognitive decline and possible conversion to dementia. It is important to clarify that MCI is not a formal diagnostic entity, but rather is frequently used to characterize a state of non-normal cognitive function that is not severe or pervasive enough to meet formal diagnostic criteria for dementia. We use the term MCI in this section to describe non-normal cognitive function not meeting criteria for dementia, but note that other terminologies such as cognitively impaired, not demented (CIND) provide a similar characterization. Reported co-morbid prevalence of depression and MCI ranges from approximately 25% to 50% (Lopez et al. Reference Lopez, Becker, Sweet, Klunk, Kaufer, Saxton, Habeych and DeKosky2003b; Adler et al. Reference Adler, Chwalek and Jajcevic2004; Lee et al. Reference Lee, Potter, Wagner, Welsh-Bohmer and Steffens2007), which is much greater than the 3–6% prevalence of amnestic MCI in studies of community samples (Lopez et al. Reference Lopez, Becker, Sweet, Klunk, Kaufer, Saxton, Habeych and DeKosky2003b; Ganguli et al. Reference Ganguli, Dodge, Shen and DeKosky2004). Research indicates that MCI or other clinically significant cognitive impairment evolving during an episode of depression may persist after the depression episode has remitted (Reischies & Neu, Reference Reischies and Neu2000; Lee et al. Reference Lee, Potter, Wagner, Welsh-Bohmer and Steffens2007). Although not using a specific MCI classification, other studies have found that the extent of cognitive impairment in depressed older adults prior to treatment is associated with persisting cognitive impairment after treatment (Butters et al. Reference Butters, Becker, Nebes, Zmuda, Mulsant, Pollock and Reynolds2000; Adler et al. Reference Adler, Chwalek and Jajcevic2004), particularly in the areas of processing speed and executive function (Nebes et al. Reference Nebes, Pollock, Houck, Butters, Mulsant, Zmuda and Reynolds2003; Murphy & Alexopoulos, Reference Murphy and Alexopoulos2004). Persistent cognitive deficits in the context of depression are a significant clinical concern because they may reflect underlying structural changes that increase an individual's risk of converting to Alzheimer's disease (Butters et al. Reference Butters, Becker, Nebes, Zmuda, Mulsant, Pollock and Reynolds2000) or another form of dementia.

Table 1.

Comparison of major depressive episode and provisional criteria of depression of Alzheimer's disease (AD)

Adapted from Olin et al. (Reference Olin, Katz, Meyers, Schneider and Lebowitz2002a, b). Also appears in Potter & Steffens (Reference Potter and Steffens2007).

Depression and dementia

Depression symptoms are a prominent clinical feature within a number of progressive dementing illnesses. The most common form of dementia is Alzheimer's disease (AD), and most studies report that 30–50% individuals with AD experience symptoms of depression, including low mood, apathy, social withdrawal and suicidal ideation (Zubenko et al. Reference Zubenko, Zubenko, McPherson, Spoor, Marin, Farlow, Smith, Geda, Cummings, Petersen and Sunderland2003). Major depression is common among patients with mild (11.5%) and moderate (10%) AD, but occurs at a lower rate in severe AD (4.5%) (Lopez et al. Reference Lopez, Becker, Sweet, Klunk, Kaufer, Saxton, Habeych and DeKosky2003a). Table 1 provides a comparison of major depression and the criteria for depression of AD. Depression symptoms are also common in patients with other forms of dementia, including vascular dementia (Sultzer et al. Reference Sultzer, Levin, Mahler, High and Cummings1993; Park et al. Reference Park, Lee, Lee, Lee, Jhoo, Youn, Choo, Choi, Jeong, Choe, Woo and Kim2007), dementia with Lewy bodies (Klatka et al. Reference Klatka, Louis and Schiffer1996; Papka et al. Reference Papka, Rubio and Schiffer1998; Ballard et al. Reference Ballard, Holmes, McKeith, Neill, O'Brien, Cairns, Lantos, Perry, Ince and Perry1999), Parkinson's disease (Tandberg et al. Reference Tandberg, Larsen, Aarsland and Cummings1996; Weintraub & Stern, Reference Weintraub and Stern2005) and Huntington's disease (Folstein et al. Reference Folstein, Abbott, Chase, Jensen and Folstein1983).

The close relationship of depression to many conditions causing dementia raises the question of why this relationship exists, and to what extent may different etiologies account for depression occurring before versus after the onset of dementia. One point of debate centers on whether depression is a risk factor or prodrome of dementia. Several studies have found that remote histories of depression (10–25 years before onset of dementia) do increase the risk of later diagnosis of dementia (Broe et al. Reference Broe, Henderson, Creasey, McCusker, Korten, Jorm, Longley and Anthony1990; Steffens et al. Reference Steffens, Plassman, Helms, Welsh-Bohmer, Saunders and Breitner1997; Green et al. Reference Green, Cupples, Kurz, Auerbach, Go, Sadovnick, Duara, Kukull, Chui, Edeki, Griffith, Friedland, Bachman and Farrer2003). While these studies do suggest that a prior history of depression increases dementia risk, the magnitude of risk ratios decreases with increasing time between depression onset and dementia diagnosis (Broe et al. Reference Broe, Henderson, Creasey, McCusker, Korten, Jorm, Longley and Anthony1990; Steffens et al. Reference Steffens, Plassman, Helms, Welsh-Bohmer, Saunders and Breitner1997; Green et al. Reference Green, Cupples, Kurz, Auerbach, Go, Sadovnick, Duara, Kukull, Chui, Edeki, Griffith, Friedland, Bachman and Farrer2003), which makes it more likely in these cases that later age of onset of depression may be either a prodromal symptom or a susceptibility factor for later dementia. Evidence suggesting that depression presents as a prodrome of dementia comes from a longitudinal, population-based study of dementia, which found that depression symptoms increased after onset of dementia, but that prior depression alone did not increase dementia risk (Chen et al. Reference Chen, Ganguli, Mulsant and DeKosky1999).

The question of whether dementia is a risk factor or prodrome of dementia does raise controversy, and there are putative biological explanations on both sides of the debate. For instance, hippocampal atrophy is associated with both depression and dementia, and studies have found that greater hippocampal atrophy is associated with both longer duration of depressive episodes (Sheline et al. Reference Sheline, Sanghavi, Mintun and Gado1999) and more recurrent depression (Shah et al. Reference Shah, Ebmeier, Glabus and Godwin1998). This would suggest that recurrent and chronic depression contribute to a degree of hippocampal atrophy that raises an individual's risk for later development of dementia, and there is neuropsychological evidence that individuals with chronic early onset of depression have greater relative deficits in hippocampally mediated processes of episodic memory than individuals with later onset of depression (Rapp et al. Reference Rapp, Dahlman, Sano, Grossman, Haroutunian and Gorman2005). One explanation that has been posited for the adverse effects of chronic depression on the hippocampus is that stress-related hypercortisolemia occurring during depression has a toxic effect on the hippocampus and disrupts regulation of glucocorticoid secretion, which results in a cascade effect of hippocampal atrophy leading to cognitive impairment and ultimately dementia. Although support for this hypothesis exists among non-depressed individuals (Lupien et al. Reference Lupien, Nair, Briere, Maheu, Tu, Lemay, McEwen and Meaney1999), the evidence is mixed in studies of depression (Mitchell & Dening, Reference Mitchell and Dening1996; Adler & Jajcevic, Reference Adler and Jajcevic2001), and there also does not seem to be strong evidence that the observed relationship between depression and hippocampal atrophy is related to cortisol levels (O'Brien et al. Reference O'Brien, Lloyd, McKeith, Gholkar and Ferrier2004).

Another possible explanation for the presence of depression in dementias such as AD may be related to loss of monoaminergic neurons in this disease (Lyness et al. Reference Lyness, Zarow and Chui2003). A third hypothesis is that depression exacerbates pre-existing cognitive impairment by depleting cognitive reserve or otherwise lowering the threshold for clinical manifestation of dementia (Jorm, Reference Jorm2001). Other operational definitions based on neuropathology or rate of cognitive decline associated with depression history remain to be studied. In our view, the ideas of depression as a risk factor or prodrome of dementia are not mutually exclusive, but rather reflect the heterogeneous presentations and etiologies of both conditions. The more important scientific issues are identifying factors that cause depression to become a risk factor for dementia and determining factors that cause depression to emerge in prodromal dementia.

Assessment of cognitive impairment in late-life depression

Regardless of whether depression is a risk or prodrome of dementia, the important clinical issue is that the depression tends to co-occur with cognitive impairment, particularly in late life, which highlights the importance of assessing cognitive impairment as part of a long-term approach to managing depression. Although the assessment of cognitive impairment in late-life depression is predicated on an accurate assessment of depression itself, we focus in this review on the research addressing: (1) clinical differences between major depression and depression in AD and (2) brief versus comprehensive cognitive evaluation in older depressed adults. We assume that the reader is likely to be familiar with the need to rule out medical factors (e.g. sleep apnea, hypothyroidism) and medications (e.g. steroids, beta blockers) that can produce either cognitive impairment or behavioral and physical symptoms similar to depression (Patten & Love, Reference Patten and Love1994; Houston & Bondi, Reference Houston and Bondi2005).

Brief versus comprehensive assessment of cognitive impairment in depression

One important aspect of the clinical assessment of cognitive impairment in depression should be identifying cognitive screening instruments that differentiate the cognitive deficits most characteristic of depression from those that are most likely to reflect dementia. Unfortunately, there are few empirical data on screening measures that effectively discriminate between the cognitive presentations of dementia and depression. In a study that illustrates the diagnostic problem, the Short Cognitive Evaluation Battery was found to demonstrate 94% sensitivity and 85% specificity for discriminating AD from non-demented and non-depressed controls, but there was only 63% sensitivity with 96% specificity discriminating AD from individuals with depression symptoms (Robert et al. Reference Robert, Schuck, Dubois, Olie, Lepine, Gallarda, Goni and Troy2003). Another study found that a screening test based on cued recall had 83% sensitivity and 85% specificity in discriminating individuals with AD from individuals with depression, but that this declined to 58% sensitivity and 85% specificity in discriminating MCI from depression, which was interpreted to reflect the greater heterogeneity in MCI (Dierckx et al. Reference Dierckx, Engelborghs, De Raedt, De Deyn and Ponjaert-Kristoffersen2007). Similar issues of test insensitivity in discriminating depression are present in the Mini-Mental State Examination (MMSE; Folstein et al. Reference Folstein, Folstein and Fanjiang2001), which is widely used to estimate the severity of cognitive impairment, but which is less sensitive to milder cognitive impairment that might be expected in depression because of a low ceiling of difficulty, narrow range of cognitive abilities assessed, and differential sensitivity to age, education and ethnicity (Tombaugh & McIntyre, Reference Tombaugh and McIntyre1992). Moreover, validity of the MMSE is reduced in psychiatric samples (Faustman et al. Reference Faustman, Moses and Csernansky1990), and there is limited assessment of the types of executive function deficits that characterize cognitive impairment in depression. Based on current evidence, there are no screening measures that are sufficiently valid for distinguishing among depression, MCI and dementia in a clinical setting, and this is even more of an issue when depression and cognitive impairment occur together. Currently, brief cognitive screening measures are most informative as complementary aspects of a thorough clinical assessment (Duff et al. Reference Duff, McCaffrey and Solomon2002; Robert et al. Reference Robert, Schuck, Dubois, Olie, Lepine, Gallarda, Goni and Troy2003), and the presence of impairment on such measures may warrant a more comprehensive evaluation. Table 2 summarizes clinical and cognitive presentations in typical cases of major depression and AD.

Table 2.

Typical clinical and cognitive presentations of major depression (MD) versus Alzheimer's disease (AD)

In the absence of effective screening instruments to differentiate the cognitive presentations of depression and dementia, neuropsychological assessment remains an important diagnostic tool for characterizing the cognitive profile of depressed individuals. Research has long indicated that sensitivity and specificity for differential diagnosis of conditions such as dementia and depression are improved when multiple cognitive measures are used (Chaves & Izquierdo, Reference Chaves and Izquierdo1992), and there are three important ways in which a neuropsychological assessment can inform diagnosis and treatment planning for depressed patients with cognitive impairment. First, comprehensive neuropsychological assessment can characterize a cognitive profile aiding differential diagnosis; for instance, whether an individual presents with frontally mediated deficits in memory retrieval and complex information processing that characterize a cognitive syndrome of depression or with hippocampally mediated deficits in memory storage and additional deficits in language or praxis that characterize AD (Butters et al. Reference Butters, Salmon, Butters, Storandt and VandenBos1994). Second, neuropsychological assessment can also identify areas of cognitive impairment, such as memory or problem solving, that may play a role in cognitive or behavioral interventions (e.g. Alexopoulos et al. Reference Alexopoulos, Raue and Arean2003, as discussed later), or executive function deficits that indicate a higher likelihood of functional impairment (Kiosses et al. Reference Kiosses, Klimstra, Murphy and Alexopoulos2001). Third, neuropsychological assessment is important in effectively tracking the extent to which cognitive deficits are either partially to fully reversible (as in depression and some medical conditions), stable (as in cerebrovascular event), or progressive (as in AD or other dementias).

Pharmacological management of cognitive impairment in late-life depression

In general, a clinician does not start pharmacological treatment specific for cognitive symptoms in acutely depressed patients when cognitive impairment is consistent with their depressive disorder. Furthermore, starting both an antidepressant medication and a cognitive medication will complicate the clinician's ability to manage side-effects and adverse events, particularly gastrointestinal complaints. The exception to this approach is when co-morbid dementia is suspected, though not confirmed, in an older depressed patient, in which case treatment with a cholinesterase inhibitor (e.g. donepezil, galantamine, rivastigmine) or an N-methyl-d-aspartic acid (NMDA) receptor antagonist (memantine) may be warranted, depending on the severity of the dementia. Nonetheless, many clinicians prefer a stepwise approach to treatment, choosing to initiate an antidepressant and achieve a therapeutic dose prior to adding an anti-dementia agent.

Even when clinicians may not immediately treat cognitive impairment in the context of geriatric depression, it is important to recognize that the presence of cognitive impairment can adversely influence the patient's response to treatment. Behaviors such as perseveration and decreased initiation are among the types of executive function deficits that are associated with lower acute response rates to pharmacological treatment (Kalayam & Alexopoulos, Reference Kalayam and Alexopoulos1999; Potter et al. Reference Potter, Kittinger, Wagner, Steffens and Krishnan2004) and also predict a higher likelihood of recurrent depression over a 2-year period (Alexopoulos et al. Reference Alexopoulos, Meyers, Young, Kalayam, Kakuma, Gabrielle, Sirey and Hull2000). However, executive dysfunction has not been found to be related to recurrent depression in all studies (Butters et al. Reference Butters, Bhalla, Mulsant, Mazumdar, Houck, Begley, Dew, Pollock, Nebes, Becker and Reynolds2004). Thus, depression and executive dysfunction may be independent among some individuals, but in others, the combination of executive dysfunction and persistent depression may reflect a common underlying dysfunction in the frontostriatal system. Nonetheless, the key point is that the presence of cognitive impairment may complicate management of depression in the older adult, and will necessitate more active monitoring of patient response.

Non-pharmacological intervention for depression and cognitive impairment

One reason that psychotherapy is an important component of depression treatment is that the combination of antidepressant medication and treatments, such as cognitive-behavioral therapy and interpersonal therapy, often produce better symptom improvement and maintenance of response than either psychotherapy or pharmacotherapy alone (Keller et al. Reference Keller, McCullough, Klein, Arnow, Dunner, Gelenberg, Markowitz, Nemeroff, Russell, Thase, Trivedi and Zajecka2000; Lenze et al. Reference Lenze, Dew, Mazumdar, Begley, Cornes, Miller, Imber, Frank, Kupfer and Reynolds2002; Lynch et al. Reference Lynch, Cheavens, Cukrowicz, Thorp, Bronner and Beyer2007). Non-pharmacological interventions are also important in treating geriatric depression because many individuals either do not respond to medications or discontinue them due to adverse side-effects (Lyketsos et al. Reference Lyketsos, Lopez, Jones, Fitzpatrick, Breitner and DeKosky2002). These outcomes may be more common in older depressed adults with cognitive impairment, and suggest that specific approaches to psychotherapy may mitigate some cognitive deficits associated with depression. One study found a 12-week trial of problem-solving therapy to be associated with higher remission rates and lower functional disability compared with supportive therapy when implemented in depressed older adults with demonstrated deficits in executive functions (Alexopoulos et al. Reference Alexopoulos, Raue and Arean2003). In this case, the key therapeutic agent appeared to be the focus on practical problem-solving strategies, which would be beneficial to individuals whose perseverative thinking and other deficits in executive functions might otherwise inhibit effective coping and problem solving.