Treatment of Depression in Patients with Dementia

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1 Treatment of Depression in Patients with Dementia / /dementia-drugs-approved-for-mild-azlheimer-s-disease Rachel Basinger, PharmD PGY1 Pharmacy Practice Resident CHRISTUS Santa Rosa Health System Pharmacotherapy Rounds Pharmacotherapy Education and Research Center The University of Texas Health Science Center at San Antonio The University of Texas at Austin College of Pharmacy May 4, 2012 Objectives 1. Describe the pathophysiology of dementia and depression 2. List the difficulties of identifying and treating depression in dementia 3. Evaluate available literature on the treatment of antidepressants for depression in dementia 4. Create a treatment plan for a patient diagnosed with depression in dementia Basinger 1

2 Dementia I. Background 1-3 a. 5 million Americans have dementia and this number will triple by 2050 b. Incidence of dementia increases with age 2 i. 13% of patients 65 years ii. 43% of patients 85 years c. DSM IV criteria for dementia of the Alzheimer s type i. Chronic decline from baseline in memory with at least one of the following: 1. Aphasia- language disturbance 2. Apraxia- impaired motor ability despite desire and physical ability 3. Agnosia- failure to recognize objects despite intact sensory function 4. Disturbances in executive functioning ii. Must impair daily functioning iii. Not due to another condition or substance II. Types of dementia 1,3 Table 1. Types of Dementia Type Pathophysiology Characteristic Alzheimer s Disease (AD) Amyloid plaques and neurofibrillary tangles Insidious onset of impaired memory and functioning Lewy Body Dementia Lewy bodies Visual hallucinations, delirium, gait imbalance Frontotemporal Dementia Pick inclusion bodies Personality changes and loss of behavior inhibition Vascular Dementia Cerebrovascular disease Abrupt onset decline in executive function Other Parkinson s disease, Huntington s disease, HIV, mixed Reversible Drug toxicity, metabolic changes, thyroid disease, subdural hematoma, normal-pressure hydrocephalus III. Symptoms 1,3 Figure 1. Alterations in Alzheimer s Disease 4 a. Cognitive i. Memory loss, aphasia, apraxia, agnosia, impaired executive function b. Non-Cognitive i. Depression, behavior disturbances, sleep disturbances, psychosis c. Functional i. Unable to perform activities of daily living (ADL) d. Behavior conditions associated with dementia are a large cause of healthcare expenditures, nursing home placements, and caregiver burden Basinger 2

3 Depression IV. Background a. Affects 16% of the American population 5 i. Up to 19% of Americans 65 years old 2 b. DSM IV Criteria 5 i. Change from baseline of 5 of the following symptoms during same 2 week period occurring nearly every day, with at least 1 symptom being depressed mood or loss of interest or pleasure 1. Depressed mood 2. Loss of interest or pleasure 3. Significant change in weight or anorexia 4. Insomnia or somnolence 5. Observable psychomotor agitation or retardation 6. Fatigue or loss of energy 7. Feelings of worthlessness or inappropriate guilt 8. Decreased ability to think or make decisions 9. Recurrent thoughts of death, suicidal ideation, plan, or attempt ii. Symptoms disrupt daily function iii. Not due to other condition or substance V. Pathophyisology 5 a. Combination of genetic, biologic, and environmental factors b. Changes in brain monoamine neurotransmitters Figure 2. Neurotransmitters in Depression 6 VI. Clinical Presentation a. SIGECAPS i. Suicidal thoughts ii. Interest decreased iii. Guilt iv. Energy decreased v. Concentration decreased vi. Appetite disturbance vii. Psychomotor changes viii. Sleep disturbances VII. Antidepressant medications a. Increase neurotransmitters b. Inhibit reuptake of neurotransmitter dopamine (DA), serotonin (5HT), norepinephrine (NE) from the synapse Table 2. Most Common Antidepressant Medications 7 SSRI SNRI TCA MAOI OTHER Fluoxetine Venlafaxine Amitriptyline Isocaboxazid Bupropion Paroxetine Duloxetine Nortriptyline Phenelzine Mirtazapine Fluvoxamine Desvenlafaxine Doxepin Tranylcypromine Trazodone Sertraline Milnacipran Desipramine Citalopram Clomipramine Escitalopram Imipramine selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), monoamine oxidase inhibitor (MAOI) Basinger 3

4 Depression in Patients with Dementia VIII. Background a. About 40% of patients with AD are diagnosed with depression 2 b. Depression in patients with dementia is associated with 8 i. Poorer quality of life ii. Greater disability in activities of daily living iii. Faster cognitive decline iv. Higher nursing home placement v. Higher mortality rate vi. Higher burden in caregivers c. Complex nature of depression and dementia 9 i. Depression in older people can present as pseudodementia ii. Depression is often associated with deteriorating cognitive function 1. May not be reversible with antidepressant treatment iii. First depressive episodes presenting in later life is associated with increased risk of dementia iv. Both disorders common in the elderly and can be expected to occur together solely by chance v. Both DSM criteria include loss of pleasure and poor concentration d. National Institute of Mental Health Depression in Alzheimer s Disease (NIMN-dAD) 10 i. Criteria for diagnosis 1. 3 of the following must be present during the same 2 week period and represent a change from previous functioning. At least one symptom must be either depressed mood or loss of pleasure. a. Depressed mood b. Loss of pleasure c. Social isolation or withdraw d. Disruption in appetite e. Disruption in sleep f. Psychomotor changes g. Irritability h. Fatigue or loss of energy i. Feeling or worthlessness, hopelessness, or excessive or inappropriate guilt j. Recurrent thoughts of death, suicidal ideation, plan, or attempt 2. All criteria are met for Dementia of the Alzheimer Type (DSM IV) 3. The symptoms cause clinically significant distress or disrupt functioning 4. The symptoms do not occur exclusively in the course of delirium 5. The symptoms are not due to the physiological effect of a substance 6. The symptoms are not accounted for by other psychiatric conditions ii. When compared to other validated scales (DSM IV, CSDD, CDS, NIP), the NIMNdAD identified more cases of depression Most likely due to less stringent requirements for frequency and duration of symptoms Basinger 4

5 IX. The Cornell Scale for Depression in Dementia (CSDD) 11 a. CSDD is a provider-rated scoring system from information elicited through separate interviews with a caregiver and the patient (See Appendix, Figure 3) b. Areas addressed (19 symptoms total) i. Mood related signs: anxiety, sadness, lack of pleasure, irritability ii. Behavioral: agitation, retardation, physical complaints, loss of interest iii. Physical signs: appetite loss, weight loss, lack of energy iv. Cyclic functions: diurnal variation of mood, difficulty falling asleep, multiple awakenings during sleep, early morning awakenings v. Ideational disturbance: suicide, self-depreciation, pessimism, mood congruent delusions c. Each item is rated for severity of symptom i. 0 = absent, 1 = mild to moderate, 2 = severe d. Interpretation of results i. Score < 6 = absence of significant major depressive symptoms ii. Score = probable major depression iii. Score 18 = definite major depression e. Other common rating scales (Appendix, Table 11) Antidepressant Efficacy and Safety for Depression in Dementia X. Background a. Response not as robust to antidepressant medication in patients with dementia 12 b. Studies have failed to identify predictors of response to treatment XI. Other benefits of antidepressants in dementia disease a. Amitriptyline showed improvement in short- and long-term memory in mice 15 b. Increased serotonin associated with lower amyloid-β levels and plaques 16 c. Decrease agitation and psychosis with better tolerability than antipsychotics XII. Summary of available data Table 3. Trials evaluating the use of antidepressants for depression in dementia 8-9,20-22,26-35 Study Drugs Result Bains TCA, MAOI, SSRI Non-significant trend Petracca Fluoxetine vs. placebo Both significant improvements, efficacy similar Magai Sertraline vs. placebo Both significant improvements, efficacy similar Sobow Tianeptine vs. fluoxetine Both significant improvements, efficacy similar, tianeptine better tolerated Taragano Fluoxetine vs. amitriptyline Both significant improvements, efficacy similar, fluoxetine better tolerated Roth Moclobemide vs. placebo Moclobemide superior and well tolerated Mizukami Milnacipran Significant improvement and well tolerated Rosenberg Sertraline vs. placebo No significant difference and increased adverse events Weintraub Sertraline vs. placebo No significant difference and increased adverse events Lyketos Sertraline vs. placebo Significant improvement and well tolerated Roa Escitalopram Significant improvement and well tolerated Bergh Discontinue SSRI Significant decline Banejee Sertraline vs. mirtazapine vs. No difference and increased adverse events with active drug placebo Nelson TCA, SSRI, SNRI Trend but no significant difference Katona Paroxetine vs. imipramine Both significant improvements, paroxetine better tolerated Basinger 5

6 XIII. Recommendations for treatment based on limited and conflicting evidence and expert opinion 8 a. Screen all patients with dementia for depression 33,38 b. Rule out and treat other possible causes i. Pain, medication side effects c. Non-pharmacologic approaches for mild to moderate depression i. Cognitive behavioral therapy ii. Planned day time activity iii. Diet and exercise iv. Electroconvulsive therapy (ECT) 36 d. Pharmacological Therapies i. Reserve for moderate to severe depression 1. More robust response with more severe baseline depression ii. SSRI preferred agent e. Cleveland Clinic Guide (based on practice experience) Table 10. Treatment of depression in dementia 7 Comorbid Condition Consider None SSRI, SNRI, bupropion Hyponatremia, bradycardia, Bupropion, SNRI, or nortriptyline risk of bleeding Renal failure Sertraline or ½ dose of other SSRI Liver failure ¼ dose of sertraline, citalopram, or escitalopram Seizure SSRI Cardiac conduction SSRI (if not bradycardic) or SNRI (if not HTN) abnormalities Parkinsonian symptoms Mirtazapine Weight loss, failure to thrive Mirtazapine, or methylphenidate for rapid response Agitation SSRI (citalopram, escitalopram) Difficulty sleeping Low dose Trazodone ( 100 mg) Unable to tolerate or not Nefazodone with monitoring of liver function responding to options above Basinger 6

7 XIV. Design Search Method Selection Criteria Primary Results Evaluation of the literature Table 4. Antidepressants for treating depression in dementia 9 Bains J, et al. Cochrane Database Syst Rev. 2002;(4):CD Meta-analysis Trails included in the Cochrane Dementia & Cognitive Improvement Group (CDCIG) Specialized Register Inclusion Exclusion Randomized, double-blind, placebocontrolled trials in patients diagnosed combination treatments, or other drugs Use of adjunctive therapies, with dementia and depression not regarded as antidepressants according to established criteria with depression longer than 4 weeks Change from baseline at 12 weeks: depression, cognitive function, ADL Trial Characteristics 4 studies included for efficacy data with 137 patients total 7 trials included for safety data with 769 patients total Mean age 75 years, severity of dementia greatly varied Antidepressants investigated: 3 TCA, 3 SSRI, 1 MAOI 1 trial with positive and 3 with negative outcomes No improvement in depression, cognitive function, or ADL scores at 12 weeks Mean Difference 95% CI Depression Cognitive function ADL Significantly more reports of total, nervous system, and GI AE, but no difference in AE involving other systems or specific symptoms OR 95% CI Number of dropouts AE CNS AE GI AE Authors Conclusions Critique Insufficient evidence for the efficacy and safety of antidepressants of depression in dementia. Available evidence offers weak support that antidepressants are effective for patients with depression and dementia. However, only 4 studies are included in the meta-analysis relating to efficacy and sample sizes are small. Strengths Study design Limitations Most studies used medications no longer commonly used Limited number of trials Basinger 7

8 Design Intervention Subjects Primary Results Authors Conclusions Critique Table 5. DIADS Trial: Sertraline versus Placebo 21 Lyketsos, et al. Arch Gen Psychaitry. 2003;60 (7): Randomized, placebo-controlled, parallel trial Placebo wash-out phase Sertraline 150 mg vs. placebo X 12 weeks Inclusion Criteria Exclusion Criteria Probable AD, MMSE 10, MDD, Schizophrenia, bipolar, anxiety, community resident, caregiver substance abuse, suicidal, participation, stable condition contraindications to sertraline Response rates and scores on HAMD, CSDD, PGDRS-ADL, NPI, and MMSE Baseline Characteristics Mean age 77.7 years, 68% female More women in sertraline group (p=0.03) Sertraline trending correlation with partial or full response (p=0.06) Significantly improved scores on HAMD and CSDD in sertraline group Placebo (n=20) Sertraline (n=24) P value CSDD 14.9 (5.5) 10.3 (7.7) HAMD 17.3 (6.8) 13.2 (9.0) PGDRS-ADL 9.9 (9.4) 6.5 (7.9) 0.7 NPI 18.1 (14.9) 14.0 (17.0) 0.32 MMSE 16.8 (7.1) 16.1 (8.5) 0.22 No difference in the frequency of AE between the two groups Sertraline is superior to placebo for treatment of major depression in Alzheimer s disease. Strengths Study design Limited to MDD Limitations Unknown effect of gender discrepancy at baseline Basinger 8

9 Design Intervention Subjects Primary Results Table 6. DIADS-2 Trial: Sertraline versus Placebo - 24 week 33 Weintraub D, et al. Am J Geriatric Psychiatry. 2010;18(4): Randomized, placebo-controlled, parallel trial Placebo run-in phase Sertraline 150 mg vs. placebo X 24 weeks Inclusion Criteria Exclusion Criteria AD, MMSE 10-26, dad, community Schizophrenia, bipolar, anxiety, substance resident, caregiver participation, stable abuse, suicidal, contraindications to condition sertraline Scores on CGI-I, CSDD, ADRQL, ADCS-ADL, and MMSE Baseline Characteristics (n=131) 78 years, 54% female, 40% MDD Significantly more years of formal higher education in the sertraline group No significant difference in any efficacy outcome Placebo (n=67) Sertraline (n=64) CGI-I OR 1.23 (95% CI, ) CSDD Mean Difference 0.6 ( 95%, CI ) NPI Treatment Effect 7.9 (p=0.01) ADRQL Treatment Effect 0.9 (p=0.30) ADCS-ADL Treatment Effect (p=0.99) MMSE Treatment Effect 0.5 (p=0.5) Significant increased frequency of AE with sertraline Placebo Sertraline OR (95% CI) P Value (n=66) (n=63) Diarrhea 22 (33%) 36 (57%) 2.22 ( ) Dizziness 26 (39%) 44 (70%) 2.86 ( ) Dry Mouth 23 (35%) 37 (59%) 2.22 ( ) Authors Conclusions Critique Sertraline is not associated with long-term benefit, and with lack of efficacy and increased adverse events, SSRIs cannot be recommended for treatment of depression in Alzheimer s disease. Strengths Included all severities of depression Limitations Changed inclusion criteria and outcomes from original 12 week study Unknown effect of education discrepancy at baseline Basinger 9

10 Design Search Methods Selection Criteria Primary Results Authors Conclusions Critique Table 7. Meta-analysis of placebo-controlled antidepressant studies 35 Nelson JC, et al. J Am Geriatr Soc. 2011;59(4): Meta-analysis Medline (1966-May 2010) and Cochrane Controlled Trials Registry (May 2010) search using terms antidepressant, depression, and dementia Parallel group, double-blind, random assignment, placebo-controlled trials of antidepressants marketed in the US Criterion-based diagnosis of dementia and depression Use of objective measurements of outcomes Rates of response, remission, discontinuation, and change in depression symptoms Trial Characteristics 7 trials from included with 330 participants total Mean age 70-89, female %, duration 6-12 weeks, baseline severity varied Antidepressants investigated: 2 TCA, 4 SSRI, 1 SNRI 2 trials with positive and 5 with negative outcomes No significant difference in any outcome Rates Reported OR (95% CI) P value Response 2.12 ( ) 0.07 Remission 1.97 ( ) 0.11 Discontinuation 1.12 ( ) 0.71 D/C due to SE 1.52 ( ) 0.32 Change in symptoms 0.29 ( ) 0.60 Sensitivity analysis Rates Reported OR (95% CI) P value Limited to MDD 1 of 2 trials showed significant difference Less Severe Depression 1.22 ( ) 0.28 Not limited to MDD 1.39 ( ) 0.23 Trial duration 12 weeks 1 of 2 trials showed significant difference Removal of highest OR for remission rates OR 2.52 ( ) The evidence for antidepressant treatment of people with depression and dementia is suggestive but not confirmatory. With limited power due to small sample sizes, these findings, however, do not establish that antidepressants are ineffective. Strengths Strict inclusion criteria to ensure high quality studies Preformed sensitivity analysis Limitations Majority of patients from TCA trials Significant heterogeneity Basinger 10

11 Design Intervention Subjects Primary Results Authors Conclusions Critique Table 8. HTA-SADD Trial: Sertraline verus Mirtazapine 8 Banerjee, et al. Lancet. 2011;378(9789): Parallel-group, double-blind, placebo-controlled trial Sertraline 150 mg, mirtazapine 45 mg, or placebo with usual care Inclusion Criteria Exclusion Criteria Probable or possible AD, depression 4 Clinically critical, contraindication to weeks, CSDD 8 drugs, on antidepressants, in another trial, or has no caregiver Reduction in CSDD score at 13 weeks and 39 weeks Baseline Characteristics Mean age 79 years, 32% males, 93% white, 68% depressed > 6 mo No difference between groups No difference in change in CSDD scores between treatment groups and placebo or between treatment groups Significantly fewer total AE and serious AE in placebo group versus study drug (p=0.017 and 0.003, respectively) Placebo (n=111) Sertraline (n=107) Mirtazapine (n=108) Baseline 13.6 (5.2) 12.8 (3.6) 12.5 (3.7) 13 weeks 7.7 (4.1) 8.6 (4.9) 7.6 (5.0) 39 weeks 8.5 (5.5) 8.5 (5.5) 7.7 (6.2) Mean Difference from placebo (p value) 13 weeks 1.17 (0.72) 0.01 (0.99) 39 weeks 0.37 (0.62) (0.37) Mean difference from mirtazapine (p value) 13 weeks 1.16 (0.11) 39 weeks 1.04 (0.17) Adverse events (p value) Total 26% 43% (0.010) 41% (0.031) Serious 20% 67% 71% Did not enroll the 113 patient per arm as needed per power calculation Patients did not reach target doses (mean dose: 70 mg sertraline, 24 mirtazepine) Because of the absence of benefit compared with placebo and increase risk of AE, the present practice use of antidepressants, with usual care, for first-line treatment of depression in AD should be reconsidered. Strengths Study design Mimic clinical practice Limitations Lacked power Patients of old-age psychiatry services Did not reach target drug doses Basinger 11

12 Design Intervention Subjects Table 9. Discontinuation of antidepressants 34 Bergh S, et al. BMJ. 2012;344:e1566 Multicenter, randomized, double blind, parallel group, placebo controlled trial Discontinuation (taper over 1 week) or continuation of antidepressant Inclusion Criteria Exclusion Criteria AD, vascular dementia, dementia, Depression, schizophrenia, severe neuropsychiatric symptoms somatic disease, terminal illness, unable Nursing home resident > 4 weeks to take medications as prescribed Citalopram, escitalopram, sertraline, paroxetine 3 months Score difference in CSDD and NPI at 25 weeks Primary Outcome Results Baseline Characteristics (n = 128) Escitalopram 72 (56%), citalopram 47 (37%), sertraline 5 (4%), paroxetine 4 (3%) Mean age 85.7 years, 75% female, 54.6 % AD, 20.3% vascular, 25% mixed No significant difference noted at baseline Significantly increased scores on the CSDD in the discontinuation group Increased scores on the NPI in the discontinuation group Significantly more patients in the discontinuation group had >30% worsening on CSDD and increase in neuropsychiatric symptoms Outcome Discontinue (n=35) Continue (n=46) P value Authors Conclusions Critique CSDD score (SD) 6.03 (4.76) 4.42 (3.77) NPI score (18.58) (9.15) CSDD score > 30% 13 (22%) 19 (33%) improvement CSDD score +/- 30% 14 (24) 22 (38) CSDD score > 30% 32 (54) 17 (29) deterioration NPI score > 30% 18 (31) 18 (31) improvement NPI score +/- 30% 28 (48) 34 (59) NPI score > 30% 13 (22) 6 (10) deterioration Withdrew 28 (44) 19 (29) NS Increased neuropsychiatric 13 (21) 4 (6) Sig symptoms Did not enroll the 76 patient per arm as needed per power calculation Discontinuation of antidepressant treatment in patients with dementia and neuropsychiatric symptoms leads to an increase in depressive symptoms, compared with those patients who continue with treatment. Strengths Study design Significance detected despite not reaching power Limitations Large dropout rate (36.7 %) Allowed change of dose of other psychotropic medications Basinger 12

13 Summary of Study Results XV. The 7 trials reviewed a. In support of antidepressant therapy i. Efficacious and well tolerated ii. DIADs trial iii. Discontinuation trial (Bergh) b. Against the use of antidepressant therapy i. Lacked efficacy and increased side effects ii. DIADS-2 trial iii. HTA-SADD trial c. Neither in support nor against i. Lacked quality evidence ii. Cochrane review iii. Meta analysis (Nelson) Proposed Treatment Algorithm XVI. XVII. XVIII. XIX. XX. Screen all patients with dementia for depression Rule out and treat other possible causes Non-pharmacologic approaches for mild to moderate depression Pharmacological Therapies a. Reserve for moderate to severe depression b. Start sertraline i. Justification 1. Most efficacy and safety data in dementia and non-dementia Generic 3. Low drug interaction (2C19, 2D6) ii. Dose mg daily, titrated by 12.5 mg weekly to mg (if tolerated) iii. Side effects 1. Dry mouth, HA, diarrhea, nausea, insomnia, somnolence, constipation, dizziness, sweating, taste abnormality Treatment duration c. Continue even if in remission i. May benefit other behavioral disturbances ii. May lose efficacy if stop medication and try to restart when behavioral disturbances reappear Basinger 13

14 References 1. Delirium, dementia, amnestic and other cognitive disorders. In: American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4 th ed. Arlington, VA: American Psychiatric Association; American Geriatrics Society. A guide to dementia diagnosis and treatment [Internet]. New York: American Geriatrics Society;[cited 2012 April]. Available from: 3. Rabins PV, et al. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer s disease and other dementias. 2 nd ed. Am J Psychiatry. 2007;[cited 2012 April]. Available from: 4. Brunton L, et al. Goodman & Gilman s The Pharmacological Basis of therapeutics, 12 th ed;[cited 2012 April]. Available from: 5. Gleneberg, et al. American Psychiatric Association practice guideline for the treatment of patients with major depression disorder. 3 rd ed. Am J Psychiatry. 2010;[cited 2012 April]. Available from: 6. Euthymics Bioscience. [cited 2012 April]. Available from: 7. Schwab, et al. Psychiatric symptoms of dementia: treatable, but no silver bullet. Cleve Clin J Med. 2009;76(3): Banerjee, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomized, multicenter, double-blind, placebo-controlled trial. Lancet. 2011;378(9789): Bains J. Antidepressants for treating depression in dementia. Cochrane Database Syst Rev. 2002;(4):CD Teng E, et al. Diagnosing depression in Alzheimer disease with the national institute of mental health provisional criteria. Am J Geriatr Psychiatry. 2008;16(6): Alexopoulos GA, et al. Cornell scale for depression in dementia. Biol Psych. 1998;23: Karlsson, et al. A randomized, double-blind comparison of the efficacy and safety of citalopram compared to mianserin in elderly, depressed patients with or without mild to moderate dementia. Int J Geriatr Psychiatry. 2000;15(4): Steinburg, et al. Patient predictors of response to treatment of depression in Alzheimer s disease: the DIADS study. Int J Geriatr Psychiatry. 2004;19: Drye, et al. Do treatments effects vary among differing baseline depression criteria in depression in Alzheimer s disease study +/- 2 (DIADS-2)? Int J Geriatr Psychiatry. 15. Chadwick, et al. Amitripyline-mediated cognitive enhancement in aged 3xTg Alzheimer s disease mice is associated with neurogenesis and neurotrophic activity. PLOSONE. 2011;6(6):e Cirrito, et al. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci USA. 2011; 108(36): Seitz DP, et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev. 2011;(2):CD Siddique H, et al. Effect of a serotonin reuptake inhibitor on irritability, apathy, and psychotic symptoms in patients with Alzheimer s disease. J Clin Psychaitry. 2009;70(6): Finkel SI, et al. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer s disease in outpatients treated with donepezil. Int J Geriatr Psychiatry. 2004;9(1): Magai, et al. A controlled clinical trial of sertraline in the treatment of depression in nursing home patients with late-stage Alzheimer s disease. Am J Geriatr Psychiatry. 2000;8(1): Basinger 14

15 21. Lyketsos CG, et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry. 2003;60(7): Roa, et al. An open-label study for escitalopram (Lexapro ) for the treatment of Depression of Alzheimer s disease (dad). Int J Geriatr Psychiatry. 2006;21(3): Cipriani A, et al. Sertraline versus other antidepressive agents for depression. Cochrane Database Syst Rev (4):CD Sobow TM, et al. Tianeptine versus fluoxetine in the treatment of depression complicating Alzheimer s disease. Int J Geriatr Psychiatry. 2011;16(11): Katona CL, et al. A double-blind comparison of the efficacy and safety of paroxetine and imipramine in the treatment of depression with dementia. Int J Geriatr Psychiatry. 1998;13(2): Brodaty H. Antidepressants treatment in Alzheimer s disease. Lancet. 2011; 378(9789): Petracca GM. A double-blind, placebo-controlled study of fluoxetine in depressed patients with Alzheimer s disease. Int Psychogeriatr 2010;13(3): Taragano FE. A double-blind, randomized, fixed-dose trail of fluoxetine vs. amitriptyline in the treatment of major depression complicating Alzheimer s disease. Psychosomatics. 1997;38(3): Roth M, et al. Moclobemide in elderly patients with cognitive decline and depression. Br J Psychiatry. 1996;168(2); Mizukami K, et al. Efficacy of milnacipran on the depressive state in patients with Alzheimer s disease. Prog Neuro Psychopharmcol Biol Psychiatry. 2006;30(2): Rosenberg, et al. Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry. 2010;18(2): Weintraub D, et al. Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes. Am J Geriatric Psychiatry. 2010;18(4): Bergh S, et al. Discontinuation of antidepressants in patients with dementia and neuropsychiatric symptoms: double blind, randomized, parallel group, placebo controlled trial. BMJ. 2012;344:e Nelson JC, et al. Systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J AM Geriatr Soc. 2011;59(4): Oudman E. Is electroconvulsive therapy (ECT) effective and safe for treatment of depression in dementia? J ECT. 2012;28(1): Lenze EJ. Treating depression in older adults with dementia. J Am Geriatr Soc. 2011;59(4): Ballard C, et al. Neuropsychiatric symptoms in dementia: importance and treatment considerations. Int Rev Psychiatry. 2008;20(4): Doody R, et al. Practice parameter: management of dementia (an evidence based review). Neurology. 2000;56: Eccles M, et al. North England evidence based guidelines development project: guideline for the primary care management of dementia. BMJ 1998;317: National Institute for Clinical Excellence/Social Care Institute for Excellence. Dementia: supporting people with dementia and their carers in health and social care. London, UK: Department of Health Muijser BR, et al. Spotlight on sertraline in the management of major depressive disorder in the elderly patients. CNS Drugs. 2002;16(11): Forlenza OV, et al. Antidepressant efficacy of sertraline and imipramine for the treatment of major depression in elderly outpatients. Sao Paulo Med J. 2000;118(4): Basinger 15

16 43. Schniderhan ME, et al. Evaluation of Psychiatric Illness: In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophyiologic Approach, 8 th ed. New Yourk, NY: McGraw-Hill; Berg L. Clinical dementia rating (CDR). Psychopharmacol Bull. 1988;24: Debruyne H, et al. Is the geriatric depression scale a reliable screening tool for depression symptoms in elderly patients with cognitive impairment? Int J Geriatr Psychiatry. 2009;24: Cummings JL, et al. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994:44: Basinger 16

17 Appendix Figure 3. Cornell Scale for Depression in Dementia 11 Basinger 17

18 Table 11. Commonly Used Rating Scales 8,43-46 Rating Scales Notes Mini-Mental Status Exam 8 items, 30 point scale (MMSE) >25 = normal, = mild, = moderate, 9 = severe Geriatric Depression Scale 30 items (1 point for each depressed symptom) (GDS) 9 = normal, = mild, = severe Cornell Scale for Depression 19 items, 3 point scale in Dementia (CSDD) <6 = normal, = probable, >18 = definite General Medical Health Seriousness of medical comorbidities Rating (GMHR) Clinician Global Impression 7 point scale Severity Scale (GCI-S) 1= normal, 7= most extremely ill Clinician Global Impression 7 point scale Improvement Scale (GCI-I) 1=very much improved, 7 = much worse Hamilton Depression Scale 17 items (HAMD) <6 = normal, = moderate, >25 = severe Montgomery-Asberg 10 items, 7 point scale (0= absent, 6 = severe) Depression Rating Scale <6 = normal, 7-19 = mild, = moderate, >34 = severe (MADRS) NeuroPsychiatric Inventory 12 items, 4 point frequency scale, 3 point severity scale, 6 point distress scale (NPI) 4 = clinically relevant symptom, 9 = severe symptom Activity of Daily Living 23 items, 1-4 rating scale (ADCS-ADL) (higher number = more independent) Alzheimer s Disease Related 40 items, (0-100%) Quality of Life (ADRQL) (higher % = higher quality of life) Gottfries, Brane, and Steen 27 items, 7 point scale (0-162) Scale (GBS) (higher number = clinical deterioration) Clinical Dementia Rating 6 items, 5 point scale Scale (CDRS) (higher score = more severe) Psychogeriatric Dependency Rating Scale-ADL subscale Higher scores = more severe impairment of activities of daily living (PGDRS-ADL) Basinger 18