Top 10 papers in geriatric psychiatry Dr. Akshya Vasudev November 2014 Disclosures • No aid was received for composing or delivering this presentation • PI’s Research funding agencies have no conflict of interest with this presentation. Current grants from • • • • • Academic Medical Organisation of Southwestern Ontario Academic Development Fund, Western Department of Psychiatry and Pediatrics, Western Institute of Clinical Evaluative Sciences, Toronto Schulich Research Opportunities Project An exciting year as ever • CIT-AD study • No new drug for dementia! • New ways of diagnosing Alzheimer’s : disturbance in olfactory responses as well as retinal and lens changes in the eye. Exercise is protective and is dose related. (AAIC 2014) • Porsteinsson, A. P., et al. (2014). "Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial." Jama 311(7): 682-691 • MPORTANCE: Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. • OBJECTIVE: The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. • DESIGN, SETTING, AND PARTICIPANTS: The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. • INTERVENTIONS: Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. • MAIN OUTCOMES AND MEASURES: Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRSA) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. • RESULTS: Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCSCGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to 0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. • CONCLUSIONS AND RELEVANCE: Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. Objectives: Impaired insight into illness is a prevalent feature of schizophrenia, which negatively influences treatment adherence and clinical outcomes. Little is known about the effects of aging on insight impairment. We aimed to review the available research literature on the effects of aging on insight into illness in schizophrenia, in relation to positive, negative, and cognitive symptoms. Ultimately, we propose a trajectory of insight in schizophrenia across the lifespan. Method: A systematic Medline® literature search was conducted, searching for English language studies describing the relationship of insight into illness in schizophrenia with aging. • Results: We identified 62 studies. Insight impairment is associated with illness severity, premorbid intellectual function (i.e. IQ), executive function, and memory. Insight impairment improves modestly during midlife, worsening again in late life. It tends to fluctuate with each episode of psychosis, likely in relation to worsening positive symptoms that improve with antipsychotic treatment. The relationship between insight impairment and cognitive dysfunction appears to attenuate with age, while the relationship with lower premorbid intellectual function is preserved. The association between impaired insight and negative symptoms is unclear. • Conclusions: The available literature suggests that the course of insight impairment follows a U-shaped curve, where insight impairment is severe during the first episode of psychosis, modestly improves over midlife, and declines again in late life. Future studies are required to investigate the trajectory of insight into illness and its core domains across the lifespan from prodromal phase to late life. B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial Osvaldo P. Almeida, Andrew H. Ford, Varsha Hirani, Vash Singh, Frank M. vanBockxmeer, Kieran McCaul, and Leon Flicker BJP bjp.bp.114.145177; published ahead of print September 25, 2014, • Background: Depression is common and the efficacy of antidepressants is suboptimal. High plasma homocysteine has been consistently associated with depression, and treatment with certain B vitamins demonstrably reduces its concentration. • Aims: To determine whether vitamins B6, B12 and folic acid enhance response to antidepressant treatment over 52 weeks. • Method: Randomised, double-blind, placebo-controlled trial of citalopram (20-40 g) together with 0.5 mg of vitamin B12, 2 mg of folic acid and 25 mg of vitamin B6 for 52 weeks. Participants were community-dwelling adults aged 50 years or over with DSM-IV-TR major depression.. The primary outcome was remission of the depressive episode after 12, 26 and 52 weeks. Secondary outcomes included reduction of MADRS scores over time and relapse of major depression after recovery by week 12. • Results: In total, 153 people were randomised (76 placebo, 77 vitamins. Remission of symptoms was achieved by 78.1 and 79.4% of participants treated with placebo and vitamins by week 12 (P = 0.840), by 76.5 and 85.3% at week 26 and 75.8 and 85.5% at week 52 (effect of intervention over 52 weeks: odds ratio (OR) = 2.49, 95% CI 1.12-5.51). Group differences in MADRS scores over time were not significant (P = 0.739). The risk of subsequent relapse among those who had achieved remission of symptoms at week 12 was lower in the vitamins than placebo group (OR = 0.33, 95% CI 0.120.94). • Conclusions: B vitamins did not increase the 12-week efficacy of antidepressant treatment, but enhanced and sustained antidepressant response over 1 year. Replication of these findings would mandate that treatment guidelines adopt the adjunctive use of B vitamins as a safe and inexpensive strategy to manage major depression in middle-aged and older adults. • Disabato, B. M., et al. (2014). "Comparison of Brain Structural Variables, Neuropsychological Factors, and Treatment Outcome in Early-Onset Versus Late-Onset Late-Life Depression." The American Journal of Geriatric Psychiatry 22(10): 1039-1046. • Objective: To compare differences in gray matter volumes, white matter and subcortical gray matter hyperintensities, neuropsychological factors, and treatment outcome between early- and late-onset late-life depressed (LLD) subjects. • Methods: We conducted a prospective, nonrandomized, controlled trial at the outpatient clinics at Washington University and Duke University on 126 subjects, aged 60 years or older, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received neuropsychological testing and magnetic resonance imaging. Subjects were excluded for cognitive impairment or severe medical disorders. After 12 weeks of sertraline treatment, subjects' MADRS scores over time and neuropsychological factors were studied. • Results: Left anterior cingulate thickness was significantly smaller in the late-onset depressed group than in the earlyonset LLD subjects. The late-onset group also had more hyperintensities than the early-onset LLD subjects. No differences were found in neuropsychological factor scores or treatment outcome between early-onset and late-onset LLD subjects. • Conclusion: Age at onset of depressive symptoms in LLD subjects are associated with differences in cortical thickness and white matter and subcortical gray matter hyperintensities, but age at onset did not affect neuropsychological factors or treatment outcome. • Mulsant, B. H., et al. (2014). "A systematic approach to pharmacotherapy for geriatric major depression." Clin Geriatr Med 30(3): 517-534. • The broadening use of antidepressants among older Americans has not been associated with a notable decrease in the burden of geriatric depression. This article, based on a selective review of the literature, explores several explanations for this paradox. The authors propose that the effectiveness of antidepressants depends in large part on the way they are used. Evidence supports that antidepressant pharmacotherapy leads to better outcomes when guided by a treatment algorithm as opposed to attempting to individualize treatment. Several published guidelines and pharmacotherapy algorithms developed for the treatment of geriatric depression are reviewed, and an updated algorithm proposed. • Background: There are conflicting results on the impact of anxiety on depression outcomes. The impact of anxiety has not been studied in major depression with psychotic features (“psychotic depression”). Aims: We assessed the impact of specific anxiety symptoms and disorders on the outcomes of psychotic depression. Methods: We analyzed data from the Study of Pharmacotherapy for Psychotic Depression that randomized 259 younger and older participants to either olanzapine plus placebo or olanzapine plus sertraline. We assessed the impact of specific anxiety symptoms from the Brief Psychiatric Rating Scale (“tension”, “anxiety” and “somatic concerns” and a composite anxiety score) and diagnoses (panic disorder and GAD) on psychotic depression outcomes using linear or logistic regression. Age, gender, education and benzodiazepine use (at baseline and end) were included as covariates. • Results: Anxiety symptoms at baseline and anxiety disorder diagnoses differentially impacted outcomes. On adjusted linear regression there was an association between improvement in depressive symptoms and both baseline “tension” (coefficient = 0.784; 95% CI: 0.169–1.400; p = 0.013) and the composite anxiety score (regression coefficient = 0.348; 95% CI: 0.064–0.632; p = 0.017). There was an interaction between “tension” and treatment group, with better responses in those randomized to combination treatment if they had high baseline anxiety scores (coefficient = 1.309; 95% CI: 0.105–2.514; p = 0.033). In contrast, panic disorder was associated with worse clinical outcomes (coefficient = −3.858; 95% CI: –7.281 to −0.434; p = 0.027) regardless of treatment. • Conclusions: Our results suggest that analysis of the impact of anxiety on depression outcome needs to differentiate psychic and somatic symptoms. • Gerhard, T., et al. (2014). "Comparative mortality risks of antipsychotic medications in community-dwelling older adults." Br J Psychiatry 205(1): 44-51. • BACKGROUND: All antipsychotic medications carry warnings of increased mortality for older adults, but little is known about comparative mortality risks between individual agents. AIMS: To estimate the comparative mortality risks of commonly prescribed antipsychotic agents in older people living in the community. METHOD: A retrospective, claims-based cohort study was conducted of people over 65 years old living in the community who had been newly prescribed risperidone, olanzapine, quetiapine, haloperidol, aripiprazole or ziprasidone (n = 136 393). Propensity score-adjusted Cox proportional hazards models assessed the 180-day mortality risk of each antipsychotic compared with risperidone. • RESULTS: Risperidone, olanzapine and haloperidol showed a dose-response relation in mortality risk. After controlling for propensity score and dose, mortality risk was found to be increased for haloperidol (hazard ratio (HR) = 1.18, 95% CI 1.06-1.33) and decreased for quetiapine (HR = 0.81, 95% CI 0.73-0.89) and olanzapine (HR = 0.82, 95% CI 0.74-0.90). CONCLUSIONS: Significant variation in mortality risk across commonly prescribed antipsychotics suggests that antipsychotic selection and dosing may affect survival of older people living in the community. • Gildengers, A. G., et al. (2014). "Longer lithium exposure is associated with better white matter integrity in older adults with bipolar disorder." Bipolar Disorders • OBJECTIVES: Bipolar disorder (BD) is associated with cognitive dysfunction and structural brain abnormalities. In human and non-human studies, lithium has been related to neuroprotective and neurotrophic effects. We explored whether lithium treatment is related to better brain integrity and cognitive function in older adults with BD. • METHODS: We examined cognitive and neuroimaging data in 58 individuals with BD [mean (standard deviation) age = 64.5 (9.8) years] and 21 mentally healthy comparators (controls) of similar age and education. Subjects received comprehensive neurocognitive assessment and structural brain imaging, examining total gray matter volume, overall white matter integrity (fractional anisotropy), and total white matter hyperintensity burden. • RESULTS: In comparison to controls, subjects with BD had worse overall cognitive performance, lower total gray matter volume, and lower white matter integrity. Among subjects with BD, longer duration of lithium treatment was related to higher white matter integrity after controlling for age and vascular disease burden, but not with better cognitive performance. • CONCLUSIONS: Lithium treatment appears to be related to better brain integrity in older individuals with BD, in particular, in those who take lithium long-term. While intriguing, these findings need to be confirmed in a larger sample. • Kryscio, R. J., et al. (2014). "Self-reported memory complaints: Implications from a longitudinal cohort with autopsies." Neurology. • Objective: We assessed salience of subjective memory complaints (SMCs) by older individuals as a predictor of subsequent cognitive impairment while accounting for risk factors and eventual neuropathologies. • Methods: Subjects (n = 531) enrolled while cognitively intact at the University of Kentucky were asked annually if they perceived changes in memory since their last visit. A multistate model estimated when transition to impairment occurred while adjusting for intervening death. Risk factors affecting the timing and probability of an impairment were identified. The association between SMCs and Alzheimer-type neuropathology was assessed from autopsies (n = 243). • Results: SMCs were reported by more than half (55.7%) of the cohort, and were associated with increased risk of impairment (unadjusted odds ratio = 2.8, p < 0.0001). Mild cognitive impairment (dementia) occurred 9.2 (12.1) years after SMC. Multistate modeling showed that SMC reporters with an APOE ε4 allele had double the odds of impairment (adjusted odds ratio = 2.2, p = 0.036). SMC smokers took less time to transition to mild cognitive impairment, while SMC hormone-replaced women took longer to transition directly to dementia. Among participants (n = 176) who died without a diagnosed clinical impairment, SMCs were associated with elevated neuritic amyloid plaques in the neocortex and medial temporal lobe. • Conclusion: SMC reporters are at a higher risk of future cognitive impairment and have higher levels of Alzheimer-type brain pathology even when impairment does not occur. As potential harbingers of future cognitive decline, physicians should query and monitor SMCs from their older patients. • Kuźma, E., et al. "History of Alcohol Use Disorders and Risk of Severe Cognitive Impairment: A 19-Year Prospective Cohort Study." The American Journal of Geriatric Psychiatry 22(10): 1047-1054. • OBJECTIVE: To assess the effects of a history of alcohol use disorders (AUDs) on risk of severe cognitive and memory impairment in later life. • METHODS: We studied the association between history of AUDs and the onset of severe cognitive and memory impairment in 6,542 middle-aged adults born 1931 through 1941 who participated in the Health and Retirement Study, a prospective nationally representative U.S. cohort. Participants were assessed at 1992 baseline and follow-up cognitive assessments were conducted biannually from 1996 through 2010. History of AUDs was identified using the three-item modified CAGE questionnaire. Cognitive outcomes were assessed using the 35-item modified Telephone Interview for Cognitive Status at last follow-up with incident severe cognitive impairment defined as a score </=8, and incident severe memory impairment defined as a score </=1 on a 20-item memory subscale. • RESULTS: During up to 19 years of follow-up (mean: 16.7 years, standard deviation: 3.0, range: 3.5-19.1 years), 90 participants experienced severe cognitive impairment and 74 participants experienced severe memory impairment. History of AUDs more than doubled the odds of severe memory impairment (odds ratio [OR] = 2.21, 95% confidence interval [CI] = 1.27-3.85, t = 2.88, df = 52, p = 0.01). The association with severe cognitive impairment was statistically nonsignificant but in the same direction (OR = 1.80, 95% CI = 0.973.33, t = 1.92, df = 52, p = 0.06). • CONCLUSION: Middle-aged adults with a history of AUDs have increased odds of developing severe memory impairment later in life. These results reinforce the need to consider the relationship between alcohol consumption and cognition from a multifactorial lifespan perspective. • Lopez, O. L., et al. (2014). "Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldestold." Neurology. • Objective: To examine the association between brain structural changes and β-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later. • Methods: Subjects had a brain structural MRI scan and a PET scan with 11C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011. • Results: At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB+, had small hippocampal volume (<25th percentile), or had high white matter lesion (WML) volume (>75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB+. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB+, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores. • Conclusions: The prevalence of β-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia. • Rej, S., et al. "Prevalence and Correlates of Renal Disease in Older Lithium Users: A Population-Based Study." The American Journal of Geriatric Psychiatry 22(11): 1075-1082. • OBJECTIVE: Lithium is an important treatment for mood disorders, but concern about its association with renal disease has contributed to its limited use, particularly in older adults. Because high-quality evidence examining renal disease in this population is lacking, this study aims to quantify the prevalence and identify clinical correlates of renal disease in geriatric lithium users. • METHODS: In a population-based cross-sectional study on 2,480 lithium users aged 70 or more years, the authors searched the provincial administrative health data from Ontario, Canada between April 1, 2005 and March 31, 2011. Prevalence of chronic kidney disease (CKD), acute kidney injury (AKI), and nephrogenic diabetes insipidus (NDI) was measured using International Classification of Diseases, Tenth Revision codes. Logistic regression analyses were used to identify independent correlates of renal disease. • RESULTS: The 6-year prevalence rates of CKD, AKI, and NDI were 13.9%, 1.3%, and 3.0%, respectively. Hypertension (odds ratio [OR]: 2.05; 95% confidence interval [CI]: 1.50-2.79), diabetes mellitus (OR: 1.86; 95% CI: 1.45-2.38), ischemic heart disease (OR: 1.65; 95% CI: 1.24-2.20), NDI (OR: 2.54; 95% CI: 1.47-4.40), AKI (OR: 11.7; 95% CI: 5.26-26.1), lithium use for more than 2 years (OR: 1.71; 95% CI: 1.052.81), loop diuretic use (OR: 1.74; 95% CI: 1.26-2.41), hydrochlorothiazide use (OR: 1.48; 95% CI: 1.07-2.05), and atypical antipsychotic use (OR: 1.49; 95% CI: 1.17-1.89) were all independently associated with CKD. • CONCLUSION: Older lithium users have high rates of CKD. Lithium use duration was independently associated with CKD. Longitudinal studies including individuals without lithium exposure will be necessary to confirm whether lithium is indeed a risk factor for CKD in older adults. • Robinson, M., et al. (2014). "Acute and Long-term Treatment of Late-Life Major Depressive Disorder: Duloxetine Versus Placebo." The American Journal of Geriatric Psychiatry 22(1): 34-45. • Objective: To compare the efficacy of duloxetine with placebo on depression in elderly patients with major depressive disorder. • Design: Multicenter, 24-week (12-week short-term and 12-week continuation), randomized, placebo-controlled, double-blind trial. Setting United States, France, Mexico, Puerto Rico. Participants Age 65 years or more with major depressive disorder diagnosis (one or more previous episode); Mini-Mental State Examination score ≥20; Montgomery-Asberg Depression Rating Scale total score ≥20. Intervention Duloxetine 60 or 120 mg/day or placebo; placebo rescue possible. Measurements Primary-Maier subscale of the 17item Hamilton Depression Rating Scale (HAMD-17) at week 12. Secondary-Geriatric Depression Scale, HAMD-17 total score, cognitive measures, Brief Pain Inventory (BPI), Numeric Rating Scales (NRS) for pain, Clinical Global Impression-Severity scale, Patient Global Impression of Improvement in acute phase and acute plus continuation phase of treatment. • Results: Compared with placebo, duloxetine did not show significantly greater improvement from baseline on Maier subscale at 12 weeks, but did show significantly greater improvement at weeks 4, 8, 16, and 20. Similar patterns for Geriatric Depression Scale and Clinical Global Impression-Severity scale emerged, with significance also seen at week 24. There was a significant treatment effect for all BPI items and 4 of 6 NRS pain measures in the acute phase, most BPI items and half of the NRS measures in the continuation phase. More duloxetine-treated patients completed the study (63% versus 55%). A significantly higher percentage of duloxetine-treated patients versus placebo discontinued due to adverse event (15.3% versus 5.8%). • Conclusions: Although the antidepressant efficacy of duloxetine was not confirmed by the primary outcome, several secondary measures at multiple time points suggested efficacy. Duloxetine had significant and meaningful beneficial effects on pain. • Sampson, E. L., et al. (2014). "Behavioural and psychiatric symptoms in people with dementia admitted to the acute hospital: prospective cohort study." Br J Psychiatry 205(3): 189-196. • Background: Dementia is common in older people admitted to acute hospitals. There are concerns about the quality of care they receive. Behavioural and psychiatric symptoms of dementia (BPSD) seem to be particularly challenging for hospital staff. • Aims: To define the prevalence of BPSD and explore their clinical associations. • Method: Longitudinal cohort study of 230 people with dementia, aged over 70, admitted to hospital for acute medical illness, and assessed for BPSD at admission and every 4 (+/- 1) days until discharge. Other measures included length of stay, care quality indicators, adverse events and mortality. • Results: Participants were very impaired; 46% at Functional Assessment Staging Scale (FAST) stage 6d or above (doubly incontinent), 75% had BPSD, and 43% had some BPSD that were moderately/severely troubling to staff. Most common were aggression (57%), activity disturbance (44%), sleep disturbance (42%) and anxiety (35%). • Conclusions: We found that BPSD are very common in older people admitted to an acute hospital. Patients and staff would benefit from more specialist psychiatric support.