Brain charts for the human lifespan.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Physical Exercise for Late-Life Major Depression.

(Reprinted with permission from Br J Psychiatry 2005; 207: 235-242).

Stabilization treatment of remitted psychotic depression: the STOP-PD study.

OBJECTIVE: We conducted a 12-week double-blind study of stabilization pharmacotherapy in patients with remitted psychotic depression (PD). METHODS: Seventy-one persons aged 18 years or older who had achieved remission of PD when randomized to either olanzapine plus sertraline or olanzapine plus placebo were continued on the double-blind treatment associated with remission. Symptoms of depression and psychosis, and weight, were measured once every 4 weeks. Cholesterol, triglycerides, and glucose were measured at stabilization phase baseline and Week 12/termination. RESULTS: The effect of treatment did not significantly change with time for depression, weight, or metabolic measures in the stabilization phase. Eight of the 71 participants (11.3%; 95% CI: 5.8, 20.7) experienced a relapse of major depression, psychosis, or both. Treatment groups did not differ in the frequency of relapse. In the entire study group, the adjusted estimate for change in weight was an increase of 1.66 kg (95% CI: 0.83, 2.48) and the adjusted estimate for change in total cholesterol was a decrease of 14.8 mg/dL (95% CI: 3.5, 26.1) during the 12-week stabilization phase; the remaining metabolic measures did not significantly change. CONCLUSION: Continuation of acute treatment was associated with stability of remission.

Physical exercise for late-life major depression.

BACKGROUND: Interventions including physical exercise may help improve the outcomes of late-life major depression, but few studies are available. AIMS: To investigate whether augmenting sertraline therapy with physical exercise leads to better outcomes of late-life major depression. METHOD: Primary care patients (465 years) with major depression were randomised to 24 weeks of higher-intensity, progressive aerobic exercise plus sertraline (S+PAE), lower-intensity, non-progressive exercise plus sertraline (S+NPE) and sertraline alone. The primary outcome was remission (a score of ≤10 on the Hamilton Rating Scale for Depression). RESULTS: A total of 121 patients were included. At study end, 45% of participants in the sertraline group, 73% of those in the S+NPE group and 81% of those in the S+PAE group achieved remission (P = 0.001). A shorter time to remission was observed in the S+PAE group than in the sertraline-only group. CONCLUSIONS: Physical exercise may be a safe and effective augmentation to antidepressant therapy in late-life major depression.

Cognitive control, reward-related decision making and outcomes of late-life depression treated with an antidepressant.

BACKGROUND: Executive processes consist of at least two sets of functions: one concerned with cognitive control and the other with reward-related decision making. Abnormal performance in both sets occurs in late-life depression. This study tested the hypothesis that only abnormal performance in cognitive control tasks predicts poor outcomes of late-life depression treated with escitalopram. METHOD: We studied older subjects with major depression (N = 53) and non-depressed subjects (N = 30). Executive functions were tested with the Iowa Gambling Test (IGT), Stroop Color-Word Test, Tower of London (ToL), and Dementia Rating Scale - Initiation/Perseveration domain (DRS-IP). After a 2-week placebo washout, depressed subjects received escitalopram (target daily dose: 20 mg) for 12 weeks. RESULTS: There were no significant differences between depressed and non-depressed subjects on executive function tests. Hierarchical cluster analysis of depressed subjects identified a Cognitive Control cluster (abnormal Stroop, ToL, DRS-IP), a Reward-Related cluster (IGT), and an Executively Unimpaired cluster. Decline in depression was greater in the Executively Unimpaired (t = -2.09, df = 331, p = 0.0375) and the Reward-Related (t = -2.33, df = 331, p = 0.0202) clusters than the Cognitive Control cluster. The Executively Unimpaired cluster (t = 2.17, df = 331, p = 0.03) and the Reward-Related cluster (t = 2.03, df = 331, p = 0.0433) had a higher probability of remission than the Cognitive Control cluster. CONCLUSIONS: Dysfunction of cognitive control functions, but not reward-related decision making, may influence the decline of symptoms and the probability of remission of late-life depression treated with escitalopram. If replicated, simple to administer cognitive control tests may be used to select depressed older patients at risk for poor outcomes to selective serotonin reuptake inhibitors who may require structured psychotherapy.

Pharmacological treatment of depression in older patients with chronic obstructive pulmonary disease: impact on the course of the disease and health outcomes.

Over 40 % of older chronic obstructive pulmonary disease (COPD) patients suffer from clinically significant depressive symptoms, which may interfere with their daily activities. Untreated depression may increase physical disability, social isolation, hopelessness and healthcare utilization. This review examined the impact of depression on the course of COPD, and the efficacy of antidepressant drug therapy and its implications for clinical practice. The efficacy of antidepressants in published trials in patients with COPD has been inconclusive. Specifically, there has been no clear evidence that antidepressants can induce remission of depression or ameliorate dyspnoea or physiological indices of COPD. Both selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) studies conducted in depressed COPD patients have been significantly limited by methodological weaknesses including small sample size, sample heterogeneity and variability in the scales used to diagnose and monitor the treatment of depression. For this reason, it remains unclear which SSRIs or TCAs should be favoured in the treatment of depressed COPD patients and what are appropriate dosages and duration ranges. Simply offering antidepressant drugs to older depressed COPD patients is unlikely to improve their condition. Promising treatment strategies such as a collaborative treatment approach and cognitive behavioural therapy should be considered for depressed COPD patients, with or without antidepressant drug therapy. Further studies are needed, including large, randomized, controlled trials with long-term follow-up, to examine the efficacy of antidepressants in patients with COPD.

A model for streamlining psychotherapy in the RDoC era: the example of 'Engage'.

A critical task for psychotherapy research is to create treatments that can be used by community clinicians. Streamlining of psychotherapies is a necessary first step for this purpose. We suggest that neurobiological knowledge has reached the point of providing biologically meaningful behavioral targets, thus guiding the development of effective, simplified psychotherapies. This view is supported by the Research Domain Criteria (RDoC) Project, which reflects the field's consensus and recognizes the readiness of neurobiology to guide research in treatment development. 'Engage' is an example of such a streamlined therapy. It targets behavioral domains of late-life depression grounded on RDoC constructs using efficacious behavioral strategies selected for their simplicity. 'Reward exposure' targeting the behavioral expression of positive valence systems' dysfunction is the principal therapeutic vehicle of 'Engage'. Its first three sessions consist of direct 'reward exposure', but the therapists search for barriers in three behavioral domains, that is, 'negativity bias' (negative valence), 'apathy' (arousal) and 'emotional dysregulation' (cognitive control), and add strategies targeting these domains when needed. The end result is a structured, stepped approach using neurobiological constructs as targets and as a guide to personalization. We argue that the 'reduction' process needed in order to arrive to simplified effective therapies can be achieved in three steps: (1) identify RDoC constructs driving the syndrome's psychopathology; (2) create a structured intervention utilizing behavioral and ecosystem modification techniques targeting behaviors related to these constructs; (3) examine whether the efficacy of the new intervention is mediated by change in behaviors related to the targeted RDoC constructs.

The vascular depression hypothesis: mechanisms linking vascular disease with depression.

The 'Vascular Depression' hypothesis posits that cerebrovascular disease may predispose, precipitate or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between LLD, vascular risk factors and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in LLD, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor, influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression, but also provide guidance on the potential repurposing of pharmacological agents that may improve LLD outcomes.

The prognostic significance of subsyndromal symptoms emerging after remission of late-life depression.

BACKGROUND: Attainment of remission is viewed as the optimal outcome of acute antidepressant treatment. However, some patients experience subsyndromal symptoms after they achieve remission. This study examines the prognostic significance of subsyndromal symptoms occurring during the first 6 months after remission of late-life depression. METHOD: Older (age 60-89 years) in-patients and out-patients with unipolar major depression were followed until remission (asymptomatic or almost asymptomatic for 3 consecutive weeks). Two hundred and forty-two achieved remission after uncontrolled antidepressant treatment. This analysis focused on remitted patients who had follow-up data over a 2.5-year period (n = 185). RESULTS: Approximately 18% of patients relapsed. Of the remainder (n = 152), 42.8% had subsyndromal depressive symptoms during the 6 months following remission. Cox's proportional survival analysis demonstrated that longer duration of subsyndromal symptoms [number of weeks with the Longitudinal Follow-up Examination (LIFE) Psychiatric Status Rating Scale (PSR) score of 3 or 4] in the first 6 months after remission was significantly associated with shorter time to recurrence and higher recurrence rate [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.08-1.24]. Based on our analysis, patients with 0, 4, 8 and 12 weeks of subsyndromal symptoms in the first 6 months after remission have estimated recurrence rates of 28, 45, 66 and 86% respectively during the ensuing 2 years. CONCLUSIONS: These findings highlight the clinical importance of subsyndromal symptoms occurring after remission in late-life depression. They also argue that studies of geriatric depression may complement the definition of remission with information on subsyndromal symptoms occurring after the initial asymptomatic period.

Diurnal variation of endothelial function and arterial stiffness in hypertension.

The onset of cardiovascular events presents a circadian variation that may be mediated by similar temporal patterns of vascular function. Blood pressure also follows circadian variation. We investigated the possible diurnal variation of endothelial function and arterial stiffness in patients with hypertension. Thirty-five individuals with recently diagnosed hypertension (mean age 48.3 years, range 30-60 years, 14 men) were examined. Flow-mediated vasodilatation (FMD), nitrate-mediated vasodilatation (NMD) and carotid-femoral (cf) pulse wave velocity (PWV) were measured at three different occasions: at 0700 hours immediately after awaking, at 1200 hours and at 2100 hours. FMD was markedly lower in the morning (0700 hours, 2.22+/-1.58%; 1200 hours, 4.37+/-2.25%; 2100 hours, 4.28+/-2.12%; P<0.001), whereas NMD was similar at the same time points. This difference remained significant after adjustment for baseline brachial artery diameter and reactive hyperaemia. PWVcf progressively increased from morning to evening (0700 hours, 9.8+/-1.9 m s(-1); 1200 hours, 10.2+/-2.2 m s(-1); 0900 hours, 10.5+/-1.9 m s(-1); P=0.013 for linear trend). Similar temporal patterns were observed in systolic and diastolic blood pressures peaking in the evening. PWVcf changes lost significance after adjustment for changes in mean blood pressure. Endothelial function is decreased in the early morning in hypertensive patients, whereas arterial stiffness is increased in the evening. Changes in BP-dependent passive artery distension may be involved in this phenomenon.

Cognitive impairment in bipolar disorder in old age: literature review and findings in manic patients.

BACKGROUND: Descriptions of aged patients with bipolar (BP) disorder have commented on cognitive impairments. However, the literature regarding cognitive test performance in this population has apparently been scant. METHOD: 1. We reviewed studies reporting cognitive performance in aged BP patients. 2. We compared the performance of elderly BP manic patients and aged community comparison subjects on the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (DRS). RESULTS: 1. Seven published studies of cognitive measures in aged BP patients were identified. They utilized different assessment methods and addressed different illness states, but they indicate impairments in these patients. 2. In our sample, the manic patients (n=70) had lower MMSE scores and DRS scores than did the comparison subjects (n=37). In these patients, cognitive scores were not significantly associated with Mania Rating Scale scores. LIMITATIONS: The patients in our study were assessed cross-sectionally, and they were treated naturalistically. CONCLUSIONS: Manic or depressed BP elders have impaired cognitive function; in some patients these impairments may persist. Research characterizing these impairments and their clinical implications is warranted.

Continuation treatment of delusional depression in older adults.

Delusional depression responds poorly to acute antidepressant monotherapy but appears to respond to intensive combination pharmacotherapy, however with poor short-term outcomes after initial improvement, particularly in later life. The authors compared the efficacy and safety of continuation combination therapy to monotherapy among older patients after remission from a delusional depression. Twenty-nine older adults with SCID-diagnosed major depression with delusions received continuation treatment with nortriptyline-plus-perphenazine or nortriptyline-plus-placebo under randomized double-blind conditions after achieving remission after ECT. Of the 28 subjects included in efficacy analyses, 25% suffered relapses. The relapse frequency was nonsignificantly greater in combination therapy than in monotherapy subjects. However, combination subjects had significantly more extrapyramidal symptoms, an increased incidence of tardive dyskinesia, and a greater number of falls. Continuation treatment with a conventional antipsychotic does not decrease relapse rates but is associated with significant untoward adverse events in older persons after recovery from a delusional depression.

Stigma as a barrier to recovery: Perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence.

OBJECTIVE: Major depression is undertreated despite the availability of effective treatments. Psychological barriers to treatment, such as perceived stigma and minimization of the need for care, may be important obstacles to adherence to the pharmacologic treatment of major depression. The authors examined the impact of barriers that were present at the initiation of antidepressant drug therapy on medication adherence in a mixed-age sample of outpatients with major depression. METHODS: A two-stage sampling design was used to identify adults with a diagnosis of major depressive disorder, as determined by the Structured Clinical Interview for Diagnosis, who sought mental health treatment at outpatient clinics. Additional instruments were administered to 134 newly admitted adults who had been taking a prescribed antidepressant medication for at least a week to assess perceived stigma, self-rated severity of illness, and views about treatment. The patients were reinterviewed three months later and were classified as adherent or nonadherent on the basis of self-reported estimates of the number and frequency of missed doses. RESULTS: Medication adherence was associated with lower perceived stigma, higher self-rated severity of illness, age over 60 years, and absence of personality pathology. No other characteristics of treatment or illness were significantly related to medication adherence. CONCLUSIONS: Perceived stigma associated with mental illness and individuals' views about the illness play an important role in adherence to treatment for depression. Clinicians' attention to psychological barriers early in treatment may improve medication adherence and ultimately affect the course of illness.

Comorbidity of depression and anxiety disorders in later life.

Since psychiatric disorders differ throughout the lifespan in phenomenology, course, and treatment, there is need for study of comorbidity of such disorders in geriatric populations. Prior findings of low prevalence of comorbid late-life anxiety disorders in depressed elderly are now disputed by recent studies. Risk factors for comorbid late-life depression and anxiety may be different from those for depression without anxiety. Similar to adults, elderly depressives with comorbid anxiety symptoms present with more severe pathology and have a more difficult course of illness, including decreased or delayed treatment response. In this paper, we review the literature on anxiety and depression comorbidity in late life, and we make recommendations for the assessment and treatment of comorbid late-life anxiety and depression. We also recommend directions for future research in the area of psychiatric comorbidity in late life.

A short-term inpatient program for agitated demented nursing home residents.

OBJECTIVE: This case series describes the various contributors of disruptive behavior in demented nursing home residents and outlines the necessary steps to identify and treat them. DESIGN: Evaluation of overall clinical improvement and agitation at discharge from the hospital and at follow-up. SETTING: Nursing home residents consecutively admitted to the geriatric psychiatry service of a psychiatric university hospital in the New York metropolitan area. PATIENTS: 15 elderly demented nursing home residents with agitation. MEASURES: Overall clinical improvement was assessed with the 'global assessment of functioning scale'. Agitation was evaluated with the 'brief agitation rating scale' and the 'nursing home scale for agitation'. Medication side-effects were measured with the 'Simpson-Angus scale' and the 'abnormal involuntary movement scale'. RESULTS: The patients showed significantly more overall clinical improvement at discharge compared with admission. Additionally, agitation scores were significantly lower at discharge and at follow-up compared with admission. CONCLUSION: A comprehensive medical and neurological assessment, an accurate identification of comorbid psychopathology, evaluation of drug toxicity, and a thorough history of psychotropic medication trials are essential steps for a successful treatment.

Chronic depression in the elderly: approaches for prevention.

Depression in old age frequently follows a chronic and/or relapsing course, related to medical comorbidity, cognitive impairment and depletion of psychosocial resources. As endorsed by the US National Institutes of Health (NIH) Consensus Development Conference on the Diagnosis and Treatment of Late Life Depression, a major goal of treatment is to prevent relapse, recurrence and chronicity. We believe that most, if not all, elderly patients with major depressive episodes are appropriate candidates for maintenance therapy, because of the vulnerability to relapse and recurrence and because of the favourable benefit to risk ratio of available treatments. Antidepressant pharmacotherapy is the mainstay of this therapeutic goal, but psychosocial approaches (especially interpersonal psychotherapy) have also been shown to contribute significantly to prevention of a chronic depressive illness and to prevention of the disability that attends depression. Studies published to date have established the long term or maintenance efficacy of the tricyclic antidepressant nortriptyline. Current, ongoing studies are addressing the maintenance efficacy of paroxetine and citalopram to prolong recovery in depression associated with old age. These studies are focusing particularly on patients aged 70 years and above, who are at high risk of recurrence, and on patients in primary care settings, where under-recognition and under-treatment of depression in the elderly have been costly from a public health perspective in terms of increased medical utilisation, burden to patients and families, and high rates of suicide. Depression in old age is a major contributor to the global burden of illness-related disability, but it is extremely treatable if appropriate pharmacotherapy is prescribed and accepted by patients and their caregivers.

Executive dysfunction and disability in elderly patients with major depression.

The authors studied 126 elderly patients without dementia and with unipolar major depression. Impairment in instrumental activities of daily living (IADLs) was significantly associated with age (P<0.0001), gender (P<0.001), medical burden (P=0.013), severity of depression (P=0.01), initiation/perseveration (IP; P=0.035), and IP x depression (P=0.029). Depression was associated with IADL impairment mainly in patients with impaired IP. Among the cognitive impairments, IP-only contributed significantly to IADL impairment, whereas attention, construction, conceptualization, and memory did not. Attention to executive function and disability may guide clinical management and lead to development of innovative pharmacological and behavioral interventions.

Hippocampal and anterior cingulate activation deficits in patients with geriatric depression.

OBJECTIVE: The authors assessed frontotemporal function in patients with geriatric depression, a debilitating and increasingly prevalent disorder that has not been examined with brain activation paradigms. METHOD: Six depressed elderly patients and five healthy comparison subjects underwent high-sensitivity [(15)O]H(2)O positron emission tomography scans during a paced word generation task and a resting condition. RESULTS: Bilateral activation deficits were noted in the dorsal anterior cingulate gyrus and hippocampus of the depressed geriatric patients relative to the comparison subjects. Patients had memory deficits that correlated with lower hippocampal activity during both rest and activation. CONCLUSIONS: These initial findings suggest that hippocampal and dorsal anterior cingulate hypoactivation may constitute contributing neural substrates of geriatric depression. They also suggest that hippocampal dysfunction is related to the memory dysfunction characteristic of this disorder.