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.

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.

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.

Physical Exercise for Late-Life Major Depression.

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

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.

Prefrontal dysfunction and treatment response in geriatric depression.

BACKGROUND: This study investigated the relationship of clinical, neuropsychological, and electrophysiological measures of prefrontal dysfunction with treatment response in elderly patients with major depression. METHODS: Forty-nine depressed elderly subjects were studied before and after 6 weeks of adequate antidepressant treatment and compared with 22 psychiatrically normal controls. The psychomotor retardation item of the Hamilton Depression Rating Scale, the initiation/perseveration subscore of the Mattis Dementia Rating Scale, and the latency of the P300 auditory evoked potential were used as indices of prefrontal dysfunction. The intensity of antidepressant drug treatment was classified and monitored for a 6-week period. RESULTS: Abnormal initiation/perseveration score, psychomotor retardation, and long P300 latency predicted 58% of the variance in change of depression scores from baseline to 6 weeks (F3= 20.1, P<.001). Depressed patients who remained symptomatic (n = 25) had more abnormal initiation/perseveration scores and longer P300 latency compared with depressed patients who achieved remission (n = 24) and control subjects. There were no differences between the last 2 groups. The association between psychomotor retardation, initiation/perseveration scores, P300 latency, and response to antidepressant treatment could not be explained by differences in demographic and clinical characteristics or treatment intensity between remitted and nonremitted depressed patients. CONCLUSIONS: Prefrontal dysfunction was associated with poor or delayed antidepressant response in depressed elderly patients. This observation, if confirmed, may aid clinicians in identifying candidates for aggressive somatic therapies and for interventions offering structure of daily activities.

'Vascular depression' hypothesis.

We propose that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. The "vascular depression" hypothesis is supported by the comorbidity of depression, vascular disease, and vascular risk factors and the association of ischemic lesions to distinctive behavioral symptoms. Disruption of prefrontal systems or their modulating pathways by single lesions or by an accumulation of lesions exceeding a threshold are hypothesized to be central mechanisms in vascular depression. The vascular depression concept can generate studies of clinical and heuristic value. Drugs used for the prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurologic recovery from ischemic lesions. Research can clarify the pathways to vascular depression by focusing on the site of the lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors.

Plasma immunoreactive beta-endorphin levels in depression. Effect of electroconvulsive therapy.

Immunoreactive (ir) plasma beta-endorphin level was assayed in ten symptomatic patients with a unipolar major depressive disorder and in 16 psychiatrically normal controls matched for age and sex. Plasma ir-beta-endorphin level in depressed patients was similar to that in controls. All depressed patients was similar to that in controls. All depressed patients had a transient, approximately threefold increase in ir-beta-endorphin after each use of electroconvulsive therapy (ECT). The increase of plasma ir-beta-endorphin level after ECT parallels the transient elevation of adrenocorticotropic hormone level reported by others and probably reflects a hypothalamic response to ECT.

Recovery in geriatric depression.

BACKGROUND: Clinical characteristics of depression, age at illness onset, medical burden, disability, cognitive impairment, lack of social support, and poor living conditions may influence the course of depression. This study investigates the timetable of recovery and the role of the above factors in predicting recovery in elderly patients with major depression. METHODS: Recovery was studied in 63 elderly (age >63 years) and 23 younger patients with depression who were followed up for an average of 18.2 months (SD, 13.1 months) under naturalistic treatment conditions. Diagnosis was assigned according to Research Diagnostic Criteria after administration of the Schedule for Affective Disorders and Schizophrenia. The Longitudinal Follow-up Interval Examination was used to identify recovery. RESULTS: The recovery rate of depressed elderly patients was similar to that of younger depressed patients. In the elderly patients, age, antidepressant treatment, age at onset, and chronicity of episode were significantly associated with time to recovery since entry. Among these parameters, late age at onset was the strongest predictor of slow recovery. In younger patients, long time to recovery was predicted by weak social support, younger age, cognitive impairment, and low intensity of antidepressant treatment. In the elderly, the intensity of antidepressant treatment began to decline within 16 weeks from entry and approximately 10 weeks prior to recovery. CONCLUSIONS: These findings challenge the view that geriatric depression has a worse outcome than depression in younger adults. However, depressed patients with onset of first episode in late life may be at higher risk for chronicity. Antidepressant treatment prescribed by clinicians may decline prior to recovery despite evidence that high treatment intensity is effective in preventing relapse.

Clinical determinants of suicidal ideation and behavior in geriatric depression.

BACKGROUND: The aim of this study was to find clinical characteristics that can identify elderly patients with depression at risk for suicidal ideation and to determine their prognosis. METHOD: Suicidal ideation, past suicidal behavior, severity of depression, cognitive impairment, medical burden, disability, and social support were studied in 354 patients with depression aged 61 to 93 years. The patients had in-person evaluations every 6 months and telephone evaluations for a mean of 1.8 years (SD, 2.2). RESULTS: During the index episode, suicidal ideation was predicted by previous suicide attempts with serious intent (odds ratio [OR], 2.82; 95% confidence interval [CI], 1.37-5.80), severity of depression (OR, 1.09; 95% CI, 1.03-1.16), and poor social support (OR, 1.77; 95% CI, 1.18-2.65). Suicide attempts during the year prior to entry were reported by patients with a severe index episode (OR, 1.05; 95% CI, 1.00-1.11), impaired instrumental activities of daily living (OR, 0.78; 95% CI, 0.67-0.93), and limited impairment in activities of daily living (OR, 1.53; 95% CI, 1.10-2.14). At the initial evaluation, severity of depression, previous attempts, and seriousness of suicidal intent during previous attempts predicted the course of suicidal ideation (concordance correlation, 0.78). During follow-up, contemporaneous severity of depression was the most important determinant of suicidal ideation over time (concordance correlation, 0.88). CONCLUSIONS: Elderly individuals with severe depression, history of suicide attempts with serious intent, and poor social support are most likely to have suicidal ideation and should be targeted for appropriate interventions. Severity of depression is the strongest predictor of the course of suicidal ideation.

Executive dysfunction and long-term outcomes of geriatric depression.

BACKGROUND: This study investigated the relationship of executive and memory impairment to relapse, recurrence, and course of residual depressive symptoms and signs after remission of geriatric major depression. METHODS: Fifty-eight elderly subjects remitted from major depression received continuation nortriptyline treatment (plasma levels 60-150 ng/mL) for 16 weeks and then were randomly assigned to either nortriptyline maintenance therapy or placebo for up to 2 years. Diagnosis was made using the Research Diagnostic Criteria and the DSM-IV criteria after an interview using the Schedule for Affective Disorders and Schizophrenia. Executive dysfunction and memory were assessed with the Dementia Rating Scale, disability and social support were rated with the Philadelphia Multiphasic Instrument, and medical burden was assessed with the Cumulative Illness Rating Scale. RESULTS: Abnormal initiation and perseveration scores, but not memory impairment, were associated with relapse and recurrence of geriatric depression and with fluctuations of depressive symptoms in the whole group and in subjects who never met criteria for relapse or recurrence during the follow-up period. Memory impairment, disability, medical burden, social support, and history of previous episodes did not significantly influence the outcome of depression in this sample. CONCLUSIONS: Executive dysfunction was found to be associated with relapse and recurrence of geriatric major depression and with residual depressive symptoms. These observations, if confirmed, will aid clinicians in identifying patients in need of vigilant follow-up. The findings of this study provide the rationale for investigation of the role of specific prefrontal pathways in predisposing or perpetuating depressive syndromes or symptoms in elderly patients.

Consensus statement on the upcoming crisis in geriatric mental health: research agenda for the next 2 decades.

It is anticipated that the number of people older than 65 years with psychiatric disorders in the United States will increase from about 4 million in 1970 to15 million in 2030. The current health care system serves mentally ill older adults poorly and is unprepared to meet the upcoming crisis in geriatric mental health. We recommend the formulation of a 15- to 25-year plan for research on mental disorders in elderly persons. It should include studies of prevention, translation of findings from bench to bedside, large-scale intervention trials with meaningful outcome measures, and health services research. Innovative strategies are needed to formulate new conceptualizations of psychiatric disorders, especially those given scant attention in the past. New methods of clinical and research training involving specialists, primary care clinicians, and the lay public are warranted.

Geriatric depression: age of onset and dementia.

Age of depression onset was studied in 183 consecutively hospitalized elderly patients with major depression. Patients with both depression and dementia had onset of depression at a significantly later age than patients with depression alone. Depressives with reversible dementia had age of onset comparable to that of depressives with irreversible dementia. These findings suggest that late-onset depression is a heterogeneous syndrome and includes a considerable number of patients who develop depression as part of a dementing illness.

Brain computed tomography findings in geriatric depression and primary degenerative dementia.

Brain computed tomography (CT) scans were performed in hospitalized geriatric patients with major depression (n = 45) or primary degenerative dementia (n = 21). Depressed patients with onset of illness at age 60 years or older (n = 32) had greater ventricular size than geriatric depressives with earlier age of illness onset (n = 13). CT parameters of late-onset depressives were comparable to those of patients with primary degenerative dementia. However, early-onset geriatric depressives had significantly smaller ventricles and less sulcal widening than demented patients. The findings suggest that late-onset depression may have a stronger association with neurological dementing disorders than early-onset depression.

Cornell Scale for Depression in Dementia.

The Cornell Scale for Depression in Dementia is introduced. This is a 19-item clinician-administered instrument that uses information from interviews with both the patient and a nursing staff member, a method suitable for demented patients. The scale has high interrater reliability (kw = 0.67), internal consistency (coefficient alpha: 0.84), and sensitivity. Total Cornell Scale scores correlate (0.83) with depressive subtypes of various intensity classified according to Research Diagnostic Criteria.