Investigation of genetic determinants of cognitive change in later life.

Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10-8 with slope 1) and rs34743896 (p = 5 × 10-10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change.

Identifying individuals with non-Alzheimer's disease co-pathologies: A precision medicine approach to clinical trials in sporadic Alzheimer's disease.

INTRODUCTION: Biomarkers remain mostly unavailable for non-Alzheimer's disease neuropathological changes (non-ADNC) such as transactive response DNA-binding protein 43 (TDP-43) proteinopathy, Lewy body disease (LBD), and cerebral amyloid angiopathy (CAA). METHODS: A multilabel non-ADNC classifier using magnetic resonance imaging (MRI) signatures was developed for TDP-43, LBD, and CAA in an autopsy-confirmed cohort (N = 214). RESULTS: A model using demographic, genetic, clinical, MRI, and ADNC variables (amyloid positive [Aß+] and tau+) in autopsy-confirmed participants showed accuracies of 84% for TDP-43, 81% for LBD, and 81% to 93% for CAA, outperforming reference models without MRI and ADNC biomarkers. In an ADNI cohort (296 cognitively unimpaired, 401 mild cognitive impairment, 188 dementia), Aß and tau explained 33% to 43% of variance in cognitive decline; imputed non-ADNC explained an additional 16% to 26%. Accounting for non-ADNC decreased the required sample size to detect a 30% effect on cognitive decline by up to 28%. DISCUSSION: Our results lead to a better understanding of the factors that influence cognitive decline and may lead to improvements in AD clinical trial design.

Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects.

AIMS: TAK-071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071. METHODS: TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect. RESULTS: TAK-071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK-071 demonstrated a long mean (% coefficient of variation) half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition. CONCLUSIONS: PK and safety profiles of TAK-071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK-071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK-071 is warranted.

An 8-Week, Randomized, Phase 2, Double-Blind, Sequential Parallel-Group Comparison Study of Two Dose Levels of the GABAA Positive Allosteric Modulator PF-06372865 Compared With Placebo as an Adjunctive Treatment in Outpatients With Inadequate Response to Standard of Care for Generalized Anxiety Disorder.

BACKGROUND: Generalized anxiety disorder (GAD) is a common psychiatric disorder, but many patients experience only partial relief of symptoms with existing therapies. Benzodiazepines are effective in many cases but are limited by a number of significant adverse effects. PF-06372865 is a subtype-selective gamma-aminobutyric acid A (GABAA)-positive allosteric modulator lacking in functional activity at alpha 1-containing receptors that are believed to mediate many of these adverse effects. METHODS: PF-06372865 was evaluated as an adjunct to current GAD treatment in a double-blind, placebo-controlled, sequential parallel comparison study in patients with GAD who showed an incomplete response to current standard-of-care pharmacotherapy. A total of 90 subjects (of the planned 384) were randomized into the study before the decision to terminate the study. Two doses of PF-06372865 (2.5 mg twice daily and 7.5 mg twice daily) were compared with placebo. RESULTS: Neither dose of PF-06372865 differentiated from placebo on week 4 Hamilton Anxiety Inventory total (primary end point) or on the Sheehan Disability Scale total score (secondary end point). Adverse events including dizziness, headache, and somnolence were observed, and the 7.5 mg dose demonstrated some impairment on the Digit Symbol Substitution test and the Epworth Sleepiness Scale relative to placebo and the 2.5 mg dose. CONCLUSIONS: Factors contributing to the negative results include the limited sample size and failure to explore a broader range of doses.

Audio Recording for Independent Confirmation of Clinical Assessments in Generalized Anxiety Disorder.

Objective: The assessment of patients with generalized anxiety disorder (GAD) to deteremine whether a medication intervention is necessary is not always clear and might benefit from a second opinion. However, second opinions are time consuming, expensive, and not practical in most settings. We obtained independent, second opinion reviews of the primary clinician's assessment via audio-digital recording. Design: An audio-digital recording of key site-based assessments was used to generate site-independent "dual" reviews of the clinical presentation, symptom severity, and medication requirements of patients with GAD as part of the screening procedures for a clinical trial (ClinicalTrials.gov: NCT02310568). Results: Site-independent reviewers affirmed the diagnosis, symptom severity metrics, and treatment requirements of 90 moderately ill patients with GAD. The patients endorsed excessive worry that was hard to control and essentially all six of the associated DSM-IV-TR anxiety symptoms. The Hamilton Rating Scale for Anxiety scores revealed moderately severe anxiety with a high Pearson's correlation (r=0.852) between site-based and independent raters and minimal scoring discordance on each scale item. Based upon their independent reviews, these "second" opinions confirmed that these GAD patients warranted a new medication intervention. Thirty patients (33.3%) reported a previous history of a major depressive episode (MDE) and had significantly more depressive symptoms than patients without a history of MDE. Conclusion: The audio-digital recording method provides a useful second opinion that can affirm the need for a different treatment intervention in these anxious patients. A second live assessment would have required additional clinic time and added patient burden. The audio-digital recording method is less burdensome than live second opinion assessments and might have utility in both research and clinical practice settings.

The role of genes involved in stress, neural plasticity, and brain circuitry in depressive phenotypes: Convergent findings in a mouse model of neglect.

Early life neglect increases risk for the development of psychopathologies during childhood and adulthood, including depression and anxiety disorders. We recently reported epigenetic changes in DNA derived from saliva in three genes predicted depression in a cohort of maltreated children: DNA-binding protein inhibitor ID-3 (ID3), Glutamate NMDA Receptor (GRIN1), and Tubulin Polymerization Promoting Protein (TPPP). To validate the role of these genes in depression risk, secondary analyses were conducted of gene expression data obtained from medial prefrontal cortex (mPFC) tissue of mice subjected to a model of maternal neglect which included maternal separation and early weaning (MSEW). Anxiety and depression-like phenotype data derived using the elevated plus maze (EPM) and forced swimming test (FST), respectively, were also available for secondary analyses. Behavioral tests were conducted in MSEW and control adult male mice when they were between 65 and 80days old. ID3, GRIN1 and TPPP gene expression in the mPFC were found to significantly predict behavioral differences in the EPM and FST. These results further support the role of these genes in the etiology of depressive and anxiety phenotypes following early life stress.

A randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day residual effects of zopiclone.

OBJECTIVES: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability. METHODS: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design. RESULTS: Evening administration of 7.5 mg zopiclone increased next-day standard deviation of lateral lane position (SDLP) by 2.62 cm on average compared with evening administration of placebo, and caused significant effects on symmetry analysis. The magnitude of the change in SDLP is highly similar to changes previously observed using on-the-road driving methods. CONCLUSIONS: Further validation of the CRCDS Mini-Sim is warranted to develop this platform for drug safety studies.

Efavirenz modulation of sleep spindles and sleep spectral profile.

Non-nucleoside reverse transcriptase inhibitors are important antiretroviral agents for the treatment of human immunodeficiency virus. Some non-nucleoside reverse transcriptase inhibitors, in particular efavirenz, have prominent effects on sleep, cognition and psychiatric variables that limit their tolerability. To avoid confounds due to drug-drug and drug-disease interactions, we assessed the effects of efavirenz in healthy volunteers on sleep, cognition and psychological endpoints during the first week of treatment. Forty healthy male subjects were randomized to receive placebo or efavirenz 600 mg nightly for 7 days after completion of a 3-day placebo run-in period. Treatment with efavirenz was associated with reduced time to sleep onset in the Maintenance of Wakefulness Test, an increase in non-rapid eye movement sleep, a large exposure-related decrease in sigma band spectral density and sleep spindle density during non-rapid eye movement sleep, and reduced performance on an attention switching task. Because efavirenz has been shown to have serotonin 2A receptor partial-agonist properties, we reasoned that antagonism of serotonin 2A receptor signalling in the thalamic reticular nucleus, which generates sleep spindles and promotes attention, may be responsible. Consistent with predictions, treatment of healthy volunteers with a single dose of a serotonin 2A receptor antagonist was found to significantly suppress sigma band spectral density in an exposure-related manner and modulated the overall spectral profile in a manner highly similar to that observed with efavirenz, consistent with the notion that efavirenz exhibits serotonin 2A receptor partial-agonist pharmacology in humans.

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex.

The pattern of neurodegeneration in Alzheimer's disease (AD) is very distinctive: neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau selectively affect pyramidal neurons of the aging association cortex that interconnect extensively through glutamate synapses on dendritic spines. In contrast, primary sensory cortices have few NFTs, even in late-stage disease. Understanding this selective vulnerability, and why advancing age is such a high risk factor for the degenerative process, may help to reveal disease etiology and provide targets for intervention. Our study has revealed age-related increase in cAMP-dependent protein kinase (PKA) phosphorylation of tau at serine 214 (pS214-tau) in monkey dorsolateral prefrontal association cortex (dlPFC), which specifically targets spine synapses and the Ca(2+)-storing spine apparatus. This increase is mirrored by loss of phosphodiesterase 4A from the spine apparatus, consistent with increase in cAMP-Ca(2+) signaling in aging spines. Phosphorylated tau was not detected in primary visual cortex, similar to the pattern observed in AD. We also report electron microscopic evidence of previously unidentified vesicular trafficking of phosphorylated tau in normal association cortex--in axons in young dlPFC vs. in spines in aged dlPFC--consistent with the transneuronal lesion spread reported in genetic rodent models. pS214-Tau was not observed in normal aged mice, suggesting that it arises with the evolutionary expansion of corticocortical connections in primates, crossing the threshold into NFTs and degeneration in humans. Thus, the cAMP-Ca(2+) signaling mechanisms, needed for flexibly modulating network strength in young association cortex, confer vulnerability to degeneration when dysregulated with advancing age.

Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry.

OBJECTIVES: To determine whether epigenetic markers predict dimensional ratings of depression in maltreated children. METHOD: A genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 healthy nontraumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible. RESULTS: Methylation in 3 genes emerged as genome-wide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (ID3); Glutamate Receptor, Ionotropic N-methyl-D-aspartate (NMDA) 1 (GRIN1); and Tubulin Polymerization Promoting Protein (TPPP) (p < 5.0 × 10(-7), all analyses). These genes are all biologically relevant with ID3 involved in the stress response, GRIN1 involved in neural plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different ß values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5). CONCLUSIONS: This study suggests that epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. The study adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. Although epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed.

Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels.

BACKGROUND: Disrupted in schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulates cyclic adenosine monophosphate (cAMP) signaling by increasing type 4 phosphodiesterase catabolism of cAMP when cAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons. METHODS: We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by short hairpin RNA viral knockdown or in vitro by dialysis of DISC1 antibodies. RESULTS: We found that DISC1 disruption resulted in an increase of metabotropic glutamate receptor-induced intracellular calcium (Ca2+) waves, small-conductance K+ (SK)-mediated hyperpolarization and a decrease of transient receptor potential C (TRPC)-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of cAMP signaling, forskolin-induced cAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine, an α2A-noradrenergic agonist, normalized the function of SK and TRPC channels. CONCLUSIONS: Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of prefrontal cortex activity through the loss of cAMP regulation of metabotropic glutamate receptor-mediated intracellular Ca2+ waves, SK and TRPC channel activity.

Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.

Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.

A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence.

Alcohol dependence (AD) is a common neuropsychiatric disorder with high heritability. A number of studies have analyzed the association between the Taq1A polymorphism (located in the gene cluster ANKK1/DRD2) and AD. In the present study, we conducted a large-scale meta-analysis to confirm the association between the Taq1A polymorphism and the risk for AD in over 18,000 subjects included in 61 case-control studies that were published up to August 2012. Our meta-analysis demonstrated both allelic and genotypic association between the Taq1A polymorphism and AD susceptibility [allelic: P(Z) = 1.1 × 10(-5), OR = 1.19; genotypic: P(Z) = 3.2 × 10(-5), OR = 1.24]. The association remained significant after adjustment for publication bias using the trim and fill method. Sensitivity analysis showed that the effect size of the Taq1A polymorphism on AD risk was moderate and not influenced by any individual study. The pooled odds ratio from published studies decreased with the year of publication, but stabilized after the year 2001. Subgroup analysis indicated that publication bias could be influenced by racial ancestry. In summary, this large-scale meta-analysis confirmed the association between the Taq1A polymorphism and AD. Future studies are required to investigate the functional significance of the ANKK1/DRD2 Taq1A polymorphism in AD.

Maternal separation with early weaning: a rodent model providing novel insights into neglect associated developmental deficits.

Child neglect is the most prevalent form of child maltreatment in the United States, and poses a serious public health concern. Children who survive such episodes go on to experience long-lasting psychological and behavioral problems, including higher rates of post-traumatic stress disorder symptoms, depression, alcohol and drug abuse, attention-deficit/hyperactivity disorder, and cognitive deficits. To date, most research into the causes of these life-long problems has focused on well-established targets such as stress responsive systems, including the hypothalamus-pituitary-adrenal axis. Using the maternal separation and early weaning model, we have attempted to provide comprehensive molecular profiling of a model of early-life neglect in an organism amenable to genomic manipulation: the mouse. In this article, we report new findings generated with this model using chromatin immunoprecipitation sequencing, diffuse tensor magnetic resonance imaging, and behavioral analyses. We also review the validity of the maternal separation and early weaning model, which reflects behavioral deficits observed in neglected humans including hyperactivity, anxiety, and attentional deficits. Finally, we summarize the molecular characterization of these animals, including RNA profiling and label-free proteomics, which highlight protein translation and myelination as novel pathways of interest.

Hypermethylation of OPRM1 promoter region in European Americans with alcohol dependence.

The µ-opioid receptor mediates rewarding effects of alcohol and illicit drugs. We hypothesized that altered DNA methylation in the µ-opioid receptor gene (OPRM1) might influence the vulnerability to alcohol dependence (AD). Genomic DNA was extracted from the peripheral blood of 125 European Americans with AD and 69 screened European American controls. Methylation levels of 16 CpGs in the OPRM1 promoter region were examined by bisulfite sequencing analysis. A multivariate analysis of covariance was conducted to analyze AD-associated methylation changes in the OPRM1 promoter region, using days of intoxication in the past 30 days, sex, age, ancestry proportion and childhood adversity (CA) as covariates. Three CpGs (80, 71, and 10 bp upstream of the OPRM1 translation start site) were more highly methylated in AD cases than in controls (CpG-80: P=0.033; CpG-71: P=0.004; CpG-10: P=0.008). Although these sites were not significant after correction for multiple comparisons, the overall methylation level of the 16 CpGs was significantly higher in AD cases (13.6%) than in controls (10.6%) (P=0.049). Sex and CA did not significantly influence OPRM1 promoter methylation levels. Our findings suggest that OPRM1 promoter hypermethylation may increase the risk for AD and other substance dependence disorders.

Genetic variation in Hyperpolarization-activated cyclic nucleotide-gated channels and its relationship with neuroticism, cognition and risk of depression.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) and, through activation by cyclic AMP (cAMP), represent a point of convergence for several psychosis risk genes. On the basis of positive preliminary data, we sought to test whether genetic variation in HCN1-4 conferred risk of depression or cognitive impairment in the Generation Scotland: Scottish Family Health Study. HCN1, HCN2, HCN3, and HCN4 were genotyped for 43 haplotype-tagging SNPs and tested for association with DSM-IV depression, neuroticism, and a battery of cognitive tests assessing cognitive ability, memory, verbal fluency, and psychomotor performance. No association was found between any HCN channel gene SNP and risk of depression, neuroticism, or on any cognitive measure. The current study does not support a genetic role for HCN channels in conferring risk of depression or cognitive impairment in individuals from the Scottish population.

Neuroanatomical changes in a mouse model of early life neglect.

Using a novel mouse model of early life neglect and abuse (ENA) based on maternal separation with early weaning, George et al. (BMC Neurosci 11:123, 2010) demonstrated behavioral abnormalities in adult mice, and Bordner et al. (Front Psychiatry 2(18):1-18, 2011) described concomitant changes in mRNA and protein expression. Using the same model, here we report neuroanatomical changes that include smaller brain size and abnormal inter-hemispheric asymmetry, decreases in cortical thickness, abnormalities in subcortical structures, and white matter disorganization and atrophy most severely affecting the left hemisphere. Because of the similarities between the neuroanatomical changes observed in our mouse model and those described in human survivors of ENA, this novel animal model is potentially useful for studies of human ENA too costly or cumbersome to be carried out in primates. Moreover, our current knowledge of the mouse genome makes this model particularly suited for targeted anatomical, molecular, and pharmacological experimentation not yet possible in other species.

Early life stress inhibits expression of a novel innate immune pathway in the developing hippocampus.

Childhood maltreatment represents a major risk factor for the development of numerous childhood psychopathologies that in many cases linger as chronic mental illnesses in adulthood. Exposing rodents or non-human primates to early life stress increases anxiety-like behaviors and impairs cognitive function in adulthood, suggesting that animal models may provide important insights into parallel developmental processes in humans. Using an unbiased genomic screen, we found that expression of lipopolysaccharide binding protein (LBP), a member of the innate immune system, is dramatically decreased in the hippocampus of pups exposed to early life stress. LBP levels peak in the normally developing hippocampus at a period of intense synaptic pruning, during which LBP is colocalized with the synaptic marker PSD95 and is found in close proximity to processes of microglia cells. Expression of LBP declines to low levels seen in adulthood at around postnatal day 30. Importantly, 30-day-old LBP knockout (k.o.) mice show increased spine density and abnormal spine morphology, suggesting that peak levels of LBP during the second and third weeks of life are necessary for normal synaptic pruning in the hippocampus. Finally, LBP k.o. mice show impaired hippocampal-dependent memory and increased anxiety-like behaviors in a manner that resembles that seen in animals exposed to early life stress. These findings describe a novel role for LBP in normal hippocampal development and raise the possibility that at least some of the behavioral sequelae of early life stress are mediated by reduced expression of LBP during a critical period of neurodevelopment.

Under-treatment of depression in older persons.

BACKGROUND: Due to the cross-sectional design of most existing studies, longitudinal characterization of treatment for depression in older persons is largely unknown. METHOD: Seven hundred fifty-four men and women (aged 70+ years) underwent monthly assessments of mental health professional use and 18-month assessments of antidepressant medication use and depressive symptoms over 9 years. Scores of ≥20 on the Center for Epidemiological Studies-Depression (CES-D) scale denoted depression. We evaluated trends in depression treatment over time in the entire sample and among the depressed participants. Using generalized linear models, we determined characteristics associated with receiving treatment for depression in these groups and among those with persistent depression. RESULTS: During the 9-year follow-up period (1998-2007), 339 (45.0%) of the participants reported depression treatment. Over time, antidepressant use alone decreased (p trend<0.001) while treatment with both antidepressants and a mental health professional increased (p trend=0.002). Of the 286 (27.9%) depressed participants, between 43% and 69% did not receive depression treatment during any 18-month interval. 30.5% of the 121 participants with persistent depression did not receive treatment during the study period. Increasing number of years of education, decreasing cognitive status score, and being physically frail were associated with a higher likelihood of receiving treatment in all models. LIMITATIONS: Pre-baseline depression, pre-baseline treatment, and indication for treatment were unavailable. CONCLUSIONS: Our findings indicate that the profile of treatment for depression in older persons has changed over time, that depressed older persons, including those with persistent depression, are under-treated, and that patient characteristics influence receipt of treatment.