Depression: An Important Risk Factor for Cognitive Decline No conflicts of interest Sarah K. Tighe, M.D. Assistant Professor University of Iowa Carver College of Medicine Department of Psychiatry Institute of Medicine Public Health Dimensions of Cognitive Aging April 11, 2014
Objectives 1. Impact of depression on cognitive decline 2. Prevention and treatment for depression-related cognitive decline 3. Gaps in current knowledge Sperling et al., Alzheimer s & Dementia, 2011
Major depression: most common mental illness in U.S. GAD: Generalized anxiety disorder PTSD: Post-traumatic stress disorder ADHD: Attention deficit hyperactivity disorder ODD: Oppositional defiant disorder Kessler et al., Arch Gen Psychiatry 2005
Depression increases dementia risk Da Silva et al., British Journal of Psychiatry 2013
Depression is heterogeneous across adulthood Highly variable clinical presentation Age of onset Symptomatology Illness course Important implications for study of cognitive outcomes Timing of depression matters
Timing of depression effects cognitive decline Timing of depression Early onset depression (EOD) < 65 years* Late-life depression (LLD) > 65 years* *Variable cutoff
EOD and LLD increase dementia risk through different mechanisms 1. EOD is a risk factor for cognitive decline Early onset depression Neuropathology Cognitive decline 2. LLD is a prodrome of cognitive decline Age-related pathologic process Late-life depression Cognitive decline EOD: Early onset depression LLD: Late-life depression Butters et al., Dialogues Clin Neurosci 2008; Byers and Yaffe. Nat Rev Neurol 2011
EOD and LLD increase dementia risk through different mechanisms 1. EOD is a risk factor for cognitive decline Early onset depression Neuropathology Cognitive decline EOD: Early onset depression LLD: Late-life depression Butters et al., Dialogues Clin Neurosci 2008; Byers and Yaffe. Nat Rev Neurol 2011
Dementia risk increases with number of EOD episodes EOD: Early onset depression Dotson et al., Neurology 2010
Reduced hippocampal volumes in EOD EOD: Early onset depression Sheline et al., J Neurosci 1999
Inflammation Increased glucocorticoids Impaired neurogenesis Disrupted growth factors Theoretical pathway 1 Early onset depression Hippocampal atrophy Cognitive decline Butters et al., Dialogues Clin Neurosci 2008; Byers and Yaffe. Nat Rev Neurol 2011
Antidepressant treatment associated with larger hippocampal volumes in EOD * * p=0.08 Huang, et al. Biol Psychiatry 2013
EOD and LLD increase dementia risk through different mechanisms 2. LLD is a prodrome of cognitive decline Age-related pathologic process Late-life depression Cognitive decline EOD: Early onset depression LLD: Late-life depression Butters et al., Dialogues Clin Neurosci 2008; Byers and Yaffe. Nat Rev Neurol 2011
LLD increases dementia risk nearly 2-fold Meta-analysis of 23 studies Age 50+ years at baseline LLD associated with significant risk of all-cause dementia (1.85, 95% CI 1.67-2.04) Diniz et al., British Journal of Psychiatry 2013
LLD associated with increased WMHs White matter hyperintensities Brain marker of vascular disease Associated with cognitive decline and dementia Roughly 2 times more common in LLD than controls WMHs: White matter hyperintensities Debette and Markus, BMJ 2010; Taylor et al., Molecular Psychiatry 2013
Theoretical White matter hyperintensities pathway 2 Vascular disease Late-life depression Cognitive decline Butters et al., Dialogues Clin Neurosci 2008; Byers and Yaffe. Nat Rev Neurol 2011
Standard LLD treatment is suboptimal for mood and cognition Cognitive impairment often persists despite remission of depression Addition of donepezil to anti-depressant treatment increases risk of LLD recurrence In elders with Alzheimer s dementia, greater exposure to psychotropic medications was associated with more rapid cognitive and functional decline Bhalla et al., Am J Geri Psych 2006; Reynolds et al., Arch Gen Psych 2011; Rosenberg et al., Int J Geri Psych 2012
Early evidence that statins have a protective effect against depression Parsaik et al. Journal of Affective Disorders 2014
Gaps in current knowledge Refine important terms Age cutoff for LLD Enrich phenotypes Several disease mechanisms Incorporate biomarkers (CSF, MRI, PET)
Gaps in current knowledge Effect of treating mid-life vascular disease risk factors on LLD Include depression as outcome measure vascular disease studies Better understanding of mechanisms to guide development of prevention strategies and rational therapeutics Needed for mood and cognitive symptoms Examine impact of other chronic mental illnesses on cognitive decline Autism Psychiatric comorbidity (e.g. substance use disorders + depression)