Defined as an acquired global decline of cognition. Diagnosis and treatment of depression in Alzheimer s disease: impact on mood and cognition

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1 PANMINERVA MED 2007;49: Diagnosis and treatment of depression in Alzheimer s disease: impact on mood and cognition B. S. APPLEBY, P. ROY, A. VALENTI, H. B. LEE Depression, a common neuropsychiatric syndrome associated with lower quality of life (QOL), higher mortality, and higher caregiver burden, is estimated to occur in 20-50% of Alzheimer s disease (AD) patients. Recent research suggests that depression in AD (dad) may differ from major depression phenomenologically and etiologically. Treatment options for dad include behavioral modifications, pharmacotherapy, and electroconvulsive therapy. Successful treatment of dad has been reported to improve patients mood and QOL, as well as lower caregiver burden. Further research is needed in therapeutics of dad to enhance treatment options and effectiveness. KEY WORDS: Alzheimer disease - Depression, diagnosis - Cognition. Defined as an acquired global decline of cognition in the setting of clear consciousness resulting in functional impairment, dementia is a common disease of the elderly and is associated with dramatic social burden in the aging society. In 2005, the worldwide prevalence of dementia was estimated to be 24.3 million people with an average of one new case every 7 s. 1 In 2004, Alzheimer s disease (AD) was classified as the 7 th leading cause of death in the USA 2 and was the 5 th leading cause of disease burden in the world in people over the age of 65 in AD is the most common cause of dementia, accounting for over half of all cases. 4 The prevalence of AD increases with age, and as life expectancy increases in our society, so will the incidence of AD. While primarily considered a cognitive disorder, non-cognitive behavioral symptoms frequently accompany AD. In one sample, 61% of dementia patients were found to Address reprint requests to: B. Appleby, M.D., Meyer 279, The Johns Hopkins Hospital, 600 North Wolfe St., Baltimore, MD 21287, USA. E- mail: applebyb77@yahoo.com Department of Psychiatry and Behavioral Sciences Johns Hopkins University, School of Medicine Baltimore, MD, USA have psychiatric symptoms, such as apathy, depression, agitation/aggression, hallucinations, and delusions. 5 When combined with another study, the 18- month prevalence rate of neuropsychiatric symptoms was estimated to be 88.6%. 6 Symptoms appear to be quite persistent as 81% of those who initially had symptoms continued to have symptoms 18 months later. 7 One particular study conducted in Brazil found a 78% prevalence rate of neuropsychiatric symptoms in AD patients. 8 Similar rates have been reported in Canada and China. 9, 10 Depression is among the most common non-cognitive psychiatric symptoms of AD; and its proper diagnosis and treatment among AD patients can lead to improved quality of life (QOL) for patients and caregivers. In this paper, we will review epidemiology, diagnostic features, etiology, and treatment for depression in AD (dad). Epidemiology Most studies report a 20-50% prevalence rate of depressive symptoms in AD The psychiatric diagnoses for depressive symptoms in AD vary widely as they seldom precisely meet Diagnostic and Statistical Manual of Mental Disorders-4 th edition (DSM-IV) diagnostic criteria. Also, reported variability of depression rates likely reflects different population samples as well Vol N. 3 PANMINERVA MEDICA 139

2 APPLEBY DEPRESSION IN ALZHEIMER S DISEASE as different detection instruments and criteria. For example, in a Chinese sample of 141 AD patients, the rate of major depression was 5%, dysthymia (7.8%), and depressive disorder not otherwise specified (3.5%). 14 Landes et al. reported an 8.4% prevalence rate of major depressive disorder in mostly mild to moderate AD, while another study reported rates of 23% and 28% for major depression and dysthymia, respectively. 11, 15 Likewise, Starkstein et al. found a 26% prevalence rate for both major and minor depression separately. 16 Findings comparing depressive symptoms to dementia severity have been mixed. One study found that prevalence of dad declines over the lifespan and is often preceded by functional decline, but not necessarily cognitive impairment. 17 Two studies reported that increased cognitive impairment resulted in fewer mood symptoms. 18, 19 However, it is unclear if this represents a true decline in illness or if depressive symptoms are less likely to be conveyed by the aphasic patient. Some studies have reported an association between dementia severity and neuropsychiatric symptoms, including depression, 8, 20 while another study found no association between the two. 21 One study did show that there was an increased incidence of major depression before and after the diagnosis of dementia. 22 Because of this, some researchers have suggested that depression may be part of the preclinical prodome of AD, implicating a shared biological mechanism between the two diseases. 23 This could also be the result of the diagnosis being a major life stressor, though there appears to be no correlation between depression and self awareness of the diagnosis. 21 The presence of depression in AD has been shown to increase the rate of other neuropsychiatric symptoms, including psychosis. 24 Delusions are much more common in dad patients as opposed to non-demented depressed elderly patients, 25 and depressed patients with AD have an elevated risk of developing delusions when compared to non-depressed patients with AD. 26, 27 Like other neuropsychiatric symptoms in this population, depression is a persistent and recurring phenomenon. 28 There are several predictors of depression in AD. Most studies have found that family history, personal history, or both increases the risk of developing dad Female gender was also associated with a higher risk of developing dad, and age was found to be inversely proportional to mood symptoms. 11, 18 One study found that neuroticism, as reported by an informant, was also a potential risk factor. 18 Impact of depression on Alzheimer s disease patients and their caregivers Besides affecting mood, depressive symptoms in AD patients have a profoundly negative impact on their lives. QOL decreases in AD patients with depression. 32 Depression in AD also adds to disability and impaired functioning beyond what is accounted for by cognitive decline By causing a decrease in functional capacity, particularly in activities of daily living (ADLs), depression hastens the transition from the community and assisted living facilities to nursing homes, thereby raising the cost of care Mortality also increases in dad. Suh et al. found that depression was an independent risk factor for mortality among AD patients. 39 In addition, suicidal ideation in AD patients was strongly associated with sad mood. 16 A case-controlled study by Rubio et al. reported that severe AD was over-represented in elderly patients who had completed suicide. 40 Psychiatric co-morbidity has been described in caregivers of patients with AD as well. 41 Caregivers for patients with dementia have more depressive symptoms than non-caregivers, even when controlling for age and gender. 42, 43 Caregivers of patients suffering from dementia exhibit significantly more depressive symptoms than caregivers for patients who are not demented. 44, 45 Many stressors negatively impact caregiver depression. Neundorfer et al. noted that the more rapidly patients became dependent in their ADLs, the more caregivers endorsed depressive symptoms. 46 This was significant even when controlling for the caregiver s health, gender, and relationship to the patient. Accelerated progression of patients depression was noted to have a negative impact on caregiver depression, whereas a decelerated progression of depression resulted in little or no change on caregiver depression. Women caregivers are at greater risk of depression as their QOL is worse and they have more depressive symptoms when compared to men. 47 However, nursing home placement was delayed by 1.5 years when caregivers received counseling. 48 Thus, dad may oftentimes affect individuals other than the patient. Etiology Several studies have found similarities between idiopathic depression and dad. Some have discovered alterations in neurotransmitter systems, such as a 140 PANMINERVA MEDICA September 2007

3 DEPRESSION IN ALZHEIMER S DISEASE APPLEBY degenerative loss of noradrenergic neurons in the locus ceruleus and serotonergic neurons in the dorsal raphe nucleus in AD. 53 Also, genotypic variability related to serotonergic neurotransmission may be associated with dad. Holmes et al. have found that different genotypes of the 5-HT2A and 5-HT2C receptor genes increases the likelihood of dad. 54 According to the bioamine hypothesis of depression, such alteration of neurotransmitter systems may lead to depression. Though reductions of acetylcholine occur in AD, there are likely other neurotransmitter deficiencies. Gamma-amino butyric acid (GABA) and glutamate have been implicated in both mood disorders and AD. Garcia-Alloza et al. reported that GABA concentration and the GABA/glutamate ratio are negatively correlated with depression in AD. 55 Similarly, raised interleukin 1-β (IL-β) levels have been linked to idiopathic depression which may also be true of dad, as a common polymorphism in the promoter region of IL-β has been linked to dad. 56 Positron emission computed imaging studies have also detected hypometabolism in the dorsolateral prefrontal and right superior frontal gyri in dad, a finding similar in idiopathic depression. 57, 58 Depression in AD is phenotypically similar to idiopathic depression, but the underlying etiology of dad may be distinct. Another putative pathophysiological mechanism underlying the etiology of idiopathic depression is hypothalamic-pituitary dysfunction, leading to increased cortisol levels. However, Hoogendijk et al. did not find a difference in cortisol levels in depressed and non-depressed AD patients. 59 There are also important neuropathologic findings in dad that are absent in idiopathic depression. For example, AD patients with a history of depression have been shown to have more plaques and tangles in their hippocampi compared to AD patients without a history of depression. 60 This is also true for those individuals whose AD and depression were diagnosed at approximately the same time. This does not appear to be true of cortical plaques and tangles. 61 Lewy bodies, particularly when located in the amydala, also increases the risk of dad. 62 Assessment of depression in Alzheimer s disease The implementation of scales in neuropsychiatric research has led to some inconsistencies in reported prevalence rates. For example, the Beck Depression Inventory (BDI), a widely used scale in depression, has been shown to underdiagnose dad. 63 One study examined the use of 4 different scales: the Geriatric Depression Scale (GDS), Montgomery and Åsperg Depression Scale (MADRS), Cornell Scale for Depression in Dementia (CSDD), and Nurses Observation Scale for Geriatric Patients (NOS-GER). 64 All scales shared internal consistency. However, internal consistency decreased with severity of dementia in the GDS and NOS-GER. The CSDD and MADRS were found to be the most consistent tools in evaluating depression in AD. In another study, the CSDD was found to be more sensitive compared to the Hamilton Depression Rating Scale and the Neuropsychiatry Inventory-Mood Scale. 65 Hence, the current evidence points to the CSDD as the best available instrument for screening patients for dad. Though scales can be useful in detecting depressive symptomatology, they are seldom used for the purpose of making clinical diagnoses of depression. There are many classification systems that can be used for the diagnosis of dad, including the International Classification of Disease, 10 th edition (ICD-10), DSM- IV, Cambridge Examination for Mental Disorder in the Elderly (CAMDEX), Neuropsychiatric Inventory (NPI), and the Provisional Diagnostic Classification for Depression in Alzheimer s Disease (PDC-dAD). Vilalta-Franch et al. compared these classification systems and found the κ to be <0.52, indicating moderate concordance among them. 66 Self-esteem and irritability were the two most discordant symptoms. The study concluded that generic diagnostic criteria as found in the ICD-10 and DSM-IV should be replaced by the more specific criteria of the PDC-dAD, as an AD patient may require fewer or different depressive symptoms in the setting of a significant depressive disorder. To meet the diagnostic criteria of dad based on the PDC-dAD (Figure 1), the patient must first have dementia of Alzheimer s type. The clinician must then consider whether or not the depressive symptoms can be better accounted for by some other entity such as a idiopathic depression, other psychiatric condition, medical illness, or medications. Once these two conditions have been met, the clinician should compare the patient s symptoms to the criteria. The PDC-dAD differs from the DSM-IV diagnosis of major depressive disorder by revising the loss of pleasure or interest criteria to decreased positive affect or pleasure as one of the two required symptoms for diagnosis. The requirement of the presence of 3 or more depressive Vol N. 3 PANMINERVA MEDICA 141

4 APPLEBY DEPRESSION IN ALZHEIMER S DISEASE A. Three or more of the following symptoms occurring during the same 2-week period, one of which must be depressed mood, decreased positive affect, or diminished pleasure capacity: 1. depressed mood; 2. decrease in positive affect or pleasure capacity; 3. social isolation and/or withdrawal; 4. changes in appetite; 5. changes in sleep; 6. irritability; 7. fatigue or low energy levels; 8. feelings of worthlessness, hopelessness, and/or excessive guilt; 9. recurrent thoughts of death, suicidal ideation, or presence of a suicide plan or attempt. B. All criteria are met for the dementia of Alzheimer s type. C. Symptoms cause clinically significant distress or decrease in functioning. D. Symptoms do not occur exclusively during the course of a delirium. E. The symptoms are not due to direct physiological effects of a substance. F. The symptoms are not better accounted for by another condition. Specifiers: Co-occurring onset: onset antedates or coincides with Alzheimer s disease symptoms. Post-Alzheimer s disease onset: onset occurs after Alzheimer s disease symptoms. With psychosis of Alzheimer s disease. With other significant behavioral signs or symptoms. With past history of mood disorder. Figure 1. Clinical criteria for diagnosis of depression of Alzheimer s disease. [Adapted from Olin et al.67 ]. symptoms in dad (i.e. changes in appetite, energy levels, sleep, etc.) is less than the 5 or more symptoms required by DSM-IV. Additional items include irritability and social isolation or withdrawal. Finally, the patient must experience significant distress or a decrease in functioning, and a diagnosis of dad cannot occur exclusively during an episode of delirium. The PDC-dAD also differs from other classification systems in that it allows caregiver input. Caregivers may be the most reliable source of history due to patients cognitive impairment. They often play a vital role in reporting symptoms to physicians, especially since depressive symptoms may be underreported by patients due to failure to recognize depressive symptoms or underestimating the severity of their depression. 68, 69 However, discrepancy often exists between patient and caregiver mood symptom ratings. 70 This may be due to the fact that AD patients report fewer depressive symptoms as their insight decreases On the other hand, caregivers may over-report patients depressive symptoms due to factors such as caregiver depression. 70, 73 Caregiver variables have been demonstrated to account for 33% of variance in patient mood ratings in one study. 73 Another study found that patient and caregiver agreement over reported symptoms occurred 58% of the time and patient responses were confirmed 75% of the time by caregivers. 70 Therefore, physicians need to be aware of this discrepancy and are cautioned not to rely entirely on caregiver reports, as many factors may influence their ratings. These facts should prompt the physician to take two histories, one from the patient and one from the caregiver. Another diagnostic challenge involves the differential diagnosis of depression in AD. Apathy, for example, can present similarly to depression or frequently co-occur. However, apathy usually remains after the resolution of depressive symptoms. 74 Agitation in dementia can appear similar to an irritable depression of Alzheimer s disease, but dad is accompanied by other depressive symptoms as mentioned above. 142 PANMINERVA MEDICA September 2007

5 DEPRESSION IN ALZHEIMER S DISEASE APPLEBY Another important differential diagnosis is hypoactive/hypoalert delirium, which can present with psychomotor retardation, lethargy, and decreased arousal. This can be distinguished from dad by the fact that consciousness fluctuates in delirium, but is stable in dad. In general, non-pharmacological interventions are generally safer and have fewer side effects compared to pharmacologic and somatic treatments. Because of its safety profile, behavioral interventions should be first line treatments for dad and may be combined with somatic treatment if necessary. Behavioral treatment of depression in Alzheimer s disease There are several behavioral strategies that can be implemented in the treatment of dad. One major difference between the treatment of dad and idiopathic depression is the role of psychotherapy. Supportive and cognitive behavioral therapy are commonly used in idiopathic depression, but its use is limited in the cognitively impaired dad population. However, in mild to moderate AD, cognitive therapy has been reported to improve mood. 75 Other strategies focus on caregivers and the patient s environment. Basic dementia care, such as maintaining a routine and providing frequent orientation, can be useful in treating depressive symptoms in AD. Trained nurses and occupational therapists can teach caregivers various problem solving skills tailored to the patient s needs. There are other non-pharmacologic treatments specifically designed for patients with dementia and depression. Exercise is often prescribed in other depressive disorders and may actually be protective for dad in addition to improving mood. 76, 77 Engaging in pleasurable activities has been found to be especially important, as reduced pleasant events have been associated with dad. 78 The Pleasant Events Schedule-AD (PES- AD) can be used as an aide for identifying pleasant activities for patients with AD. The PES-AD inventory recognizes everyday activities that are pleasant, such as making crafts, taking a car ride, and listening to music. Depressed patients frequently dwell on negative thoughts, which can be remedied with redirection. 79 Photoalbums, as a reminiscing on past enjoyable events, may help distract patients from their low mood. Encouraging social activities, such as visiting friends or family, going to church, and going to workshops, ensures that the patient continues to be interactive. Because dementia results in functional decline, patients frequently cannot engage in tasks at which they once excelled. This can be frustrating, and diverting the patient s attention from these challenging tasks to more realistic ones may prevent disappointment. Pharmacologic treatment of depression in Alzheimer s disease There are several psychopharmacologic options for treating dad, with antidepressants being the most studied. Table I lists all the published placebo-controlled antidepressant trials in dad, the results of which have varied. There have been 8 such trials resulting in 5 positive and 3 negative findings. The earlier trials with tricyclic antidepressants (TCA), such as imipramine and clomipramine, resulted in mixed findings. 80, 81 Clomipramine was reportedly effective in treating depressive symptoms in a double-blind crossover designed study of 21 AD patients; however, the study duration was only for 6 weeks and clomipramine was associated with lower Mini Mental State Examination (MMSE) score. Another TCA, imipramine, was not shown to be more efficacious when compared to placebo. Moclobemide, a monoamine oxidase inhibitor, was efficacious in treating dad in another trial without significant side effects. 82 Multiple selective serotonin reuptake inhibitors (SSRIs) trials have been conducted. There have been two positive trials utilizing sertraline 83, 88 and one study that did not find a statistically significant difference when compared to placebo. 84 The two studies that demonstrated improvement in mood also found a decreased rate of decline in ADLs. Two placebo-controlled trials of citalopram have revealed both positive and negative findings. 85, 86 One study by Petracca et al. found no difference between placebo and fluoxetine. 87 A few comparative trials of antidepressant medications used in the treatment of dad have also been conducted. In all 3 trials (fluoxetine vs amitriptyline, paroxetine vs imipramine, and tianeptine vs fluoxetine), both agents were found to be effective. However, there was no significant difference between the two medications Several uncontrolled studies have examined efficacy of newer antidepressants as well. Escitalopram and milnacipran demonstrated clinical efficacy in two case series studies. 92, 93 A case report of successful treatment of dad with mirtazapine has also Vol N. 3 PANMINERVA MEDICA 143

6 APPLEBY DEPRESSION IN ALZHEIMER S DISEASE TABLE I. Pharmacologic treatments for depression in Alzheimer s disease. Placebo Drug No. Dose range Cognitive Affective rating Outcome Other findings controlled studies (mg) Dx scale Reifler et al. 80 Petracca et al. 81 Roth et al. 82 Lyketsos et al. 83 Magai et al. 84 Nyth et al. 85 Nyth et al. 86 Petracca et al. 87 Imipramine Clomipramine Moclobemide Sertraline Sertraline Citalopram Citalopram Fluoxetine DSM-III NINCDS DSM-III NINCDS NINCDS GBS <5 DSM-III Probable AD, MMSE >9 HDRS HDRS HDRS CSDD, HDRS CSDD, GS, FB HDRS, CGI, MADRS MADRS HDRS No difference 9/11 patients achieved remission Significant improvement Significant full and partial response No difference Significant improvement No difference No difference Confusion in one patient Few adverse events Less decline of ADLs Cognitive improvement Mild side effects Mild tremor DSM-III: Diagnostic and Statistical Manual of Mental Disorders-3 rd edition; HDRS: Hamilton Depression Rating Scale; NINCDS: National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer s Disease and Related Disorders Association; CSDD: Cornell Scale for Depression in Dementia; GS: Gestalt Scale; FB: Facial Behaviors; MADRS: Montgomery Asberg Depression Rating Scale; GBS: Gottfries-Bråne-Steen geriatric rating scale. been described. 94 Some researchers have attempted to identify predictors of response to sertraline, but have been unable to find any statistically significant factors. 95 Efficacy and safety concerns should be considered when using antidepressants in dad. Presently, the class of antidepressants with the most evidence of efficacy is the SSRIs, such as sertraline and citalopram. When considering which medication to prescribe, the clinician should weigh the potential benefits against known side effects. For example, TCAs could be intolerable in AD patients who are more susceptible to anticholinergic side effects, such as orthostasis, urinary retention, constipation, and confusion. Also, the dietary requirements of monoamine oxidase inhibitors (MAOIs) can be difficult to follow for cognitively impaired patients, potentially resulting in a hypertensive crisis. Moreover, drug interactions of MAOIs with other antidepressants, CNS depressants, narcotics, and other common medications, are difficult to avoid in AD patients who are often on multiple medications. In general, SSRIs are more tolerable antidepressants compared to TCAs and MAOIs, and are the first line of treatment for depression. 96 Accordingly, those SSRIs that have been shown to be efficacious in treating dad should be the initial treatment. Several classes of antidepressants have not had placebo-controlled trials, such as selective norepinephrine reuptake inhibitors, buproprion, nefazodone, and mirtazapine. There are augmentation strategies that have not been studied in this population, including lithium, anticonvulsants, neuroleptics, and levothyroxine. Long-term treatments have not been studied and more studies need to be done to clarify long term strategies. Other somatic therapies Besides behavioral interventions and pharmacotherapy, the option of electroconvulsive therapy (ECT) should be considered in cases of severe or treatment-resistant depression in AD. Depression remission rates have been reported to be as high as 88.2% in the geriatric population when using ECT. 97 In a case-series study of 31 dementia patients with depression, Rao et al. reported that ECT is a safe and effective treatment, leading to improvements in both mood and cognition. 98 A potential drawback to ECT is its propensity for causing delirium and transient amnesia. Although the use of vagus nerve stimulators (VNS) has been studied in the treatment of cognitive impairment in AD, neither study demonstrated any effects on mood. 99, 100 Studies that examine mood as a primary 144 PANMINERVA MEDICA September 2007

7 DEPRESSION IN ALZHEIMER S DISEASE APPLEBY TABLE II. Antidepressant effects on cognition in depression in Alzheimer s disease. Citation Design and duration Sample size Sample characteristics Study medication Cognitive measure Cognitive outcome Caballero et al. 113 Retrospective chart review over a minimum of 9 months 99 (58 received an antidepressant, 41 did not) Outpatients with Alzheimer s disease receiving anticholinesterase inhibitors. Com-pared patients prescribed antidepressants to those not prescribed antidepressants Sertraline, Citalopram, Paroxetine, Fluoxetine, Escitalopram, Venlafaxine, Bupropion MMSE No significant difference in cognition Finkel et al. 114 Randomized, double-blind, placebo-controlled trial over 12 weeks 244 (124 received donepezil and study drug, 120 received donepezil and placebo.) Outpatients with probable or possible diagnosis of Alzheimer s disease and no current primary psychiatric diagnosis other than Alzheimer s disease Sertraline MMSE, ADAS- Cog No significant difference between study drug and placebo Lyketsos et al. 83 Munro et al. 112 Randomized, placebo-controlled, 12-week clinical trial 41 (18 received placebo and 23 received the study drug) Outpatients with probable Alzheimer s disease and depression Sertraline Neuropsycholog ical battery No significant difference between study drug and placebo Petracca et al. 87 Double-blind, randomized, placebo-controlled trial 41 (17 received study drug and 24 received placebo) Patients with probable Alzheimer s disease meeting DSM-IV criteria for major or minor depression Fluoxetine MMSE No significant improvement in cognition. Petracca et al. 81 Double-blind, randomized, crossover, placebo-controlled trial for 6 weeks with washout period 21 (11 received clomipramine, then placebo, 10 received placebo, then clomipramine). Patients with probable Alzheimer s disease and depression Clomipramine MMSE Significantly lower MMSE on clomipramine compared with placebo Taragano et al. 89 Double-blind, randomized, with 45 days of follow-up 37 initially randomized, 18 to fluoxetine and 19 to amitriptyline; 11 of the subjects treated with amitriptyline dropped out of the study compared with 4 taking fluoxetine Outpatients meeting criteria for probable Alzhei-mer s disease and major depressive disorder Fluoxetine, Amitriptyline MMSE Improvement in MMSE in both treatment groups, but no significant difference found between the two drugs Teri et al. 115 Reifler et al. 80 Double-blind, randomized, placebo-controlled trial lasting 8 weeks 61 (28 were diagnosed with depression and dementia, 13 received study drug and 15 received placebo; 33 were diagnosed with de-mentia, 14 recei-ved study drug and 19 received placebo) Outpatients diagnosed with probable Alzheimer s disease, with and without depression Imipramine MMSE, DRS, WMS, FOME No significant difference in MMSE, WMS and FOME between study drug and placebo. Greater decline in DRS in those taking imipramine MMSE: Mini-Mental State Examination; ADAS-Cog: Alzheimer s Disease Assessment Scale-Cognitive Subscale; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders-4th edition; DRS: Dementia Rating Scale; WMS: Wechsler Memory Scale; FOME: Fuld Object Memory Evaluation. Vol N. 3 PANMINERVA MEDICA 145

8 APPLEBY DEPRESSION IN ALZHEIMER S DISEASE outcome measure are needed to determine the efficacy of VNS in this population. Deep brain stimulation has also been shown to improve depressive symptoms as a secondary outcome measure in patients with Parkinson s disease, but it has not been studied in dad. Cognitive effects of repetitive transmagnetic stimulation has been studied in AD. Specifically, stimulation of the dorsolateral prefrontal cortices was shown to improve accuracy in action naming. 105 To date, no studies have examined its use in dad. Treatment of depression in Alzheimer s disease on cognition Major depression, uncomplicated by dementia, is known to be associated with neurocognitive deficits, 106 which raises clinical questions regarding whether depression worsens or accelerates cognitive decline in AD. Studies have not consistently shown that depressive symptoms contribute to worsening of cognitive functioning in AD, but there does appear to be a relationship between depression and cognition in AD. A longitudinal study of AD patients found that depression does not contribute to decline in cognitive performance in patients with mild dementia. 107 Another longitudinal study found that patients with probable AD meeting criteria for major depression had no significant difference in cognitive functioning compared with controls without depression. 108 However, an Oxford study, which confirmed sole Alzheimer-type pathology, found that depressive symptoms were associated with cognitive impairment in patients in the intermediate stages of AD, but not in the early or late stages. 109 Interestingly, Modrego et al. reported that comorbidity of MDD among patients with amnestic mild cognitive impairment (MCI) increased the risk of conversion to AD substantially. 110 The cohort was followed prospectively for 3 years and it was found that of the depressed patients with amnestic MCI, 85% went on to develop AD compared to 32% of the nondepressed patients with MCI. Mowla et al. did a placebo-controlled trial with fluoxetine on non-depressed patients with MCI and demonstrated enhanced cognition compared to placebo. 111 Statistically significant improvements were found in immediate and delayed logical memory as well as on the MMSE in patients with MCI treated with fluoxetine. These studies raise interesting questions about the relationship between depression, cognition, and AD, an area that requires more research to fully understand their associations. Numerous studies have looked at the impact of antidepressants on cognition in AD and in dad. Some studies have suggested that cognition improves with mood, 82, 85, 89 but others fail to report a change. 80, 81, 112, 113 To date, studies show no significant benefit of antidepressants on cognition in AD. TCAs may have detrimental effects in patients with AD, most likely due to anticholinergic side effects. Taragano et al. compared fluoxetine to amitriptyline in a randomized, double-blind clinical trial in patients diagnosed with MDD and AD. 89 The dropout rate among the patients taking amitriptyline was high (58%), mostly due to central nervous system side effects, such as confusion and disorientation. These studies support the premise that depression does not directly impact performance on cognitive tests in AD, since improvement in depressive symptoms did not impact performance. Table II summarizes these studies. Conclusions There have been many advancements in the study of dad. With the recent establishment of provisional diagnostic criteria, diagnosis of dad has become more reliable and research more uniform. Recent neuropathological findings from depression of AD offer hopes of elucidating the relationship between AD and depression. Such research not only helps us to understand dad, but also our investigation on neurobiological aspect of idiopathic depression as well. In parallel, clinical research continues to help establishment of diagnostic and treatment guidelines that leads to improved care for the patients with dad. Linking basic science studies and clinical studies together, future translational research will be crucial in refining diagnostic criteria, understanding symptomatology, and treating dad in an effective manner. References 1. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366: Minino AM, Heron MP, Smith BL, Division of Vital Statistics. Deaths: preliminary data for Statistics Reports NVSS; 2006.p Peden M, McGee K, Krug E, editors. Injury: a leading cause of global burden of disease, Geneva: World Health Organization; Caselli RJ, Boeve BF. The degenerative dementias. In: Goetz CG, 146 PANMINERVA MEDICA September 2007

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