Search

Children reared in institutional settings experience early deprivation that has lasting implications for multiple aspects of neurocognitive functioning, including executive function (EF). Changes in brain development are thought to contribute to these persistent EF challenges, but little research has used fMRI to investigate EF-related brain activity in children with a history of early deprivation. This study examined behavioral and neural data from a response conflict task in 12-14-year-olds who spent varying lengths of time in institutional care prior to adoption (N = 84; age at adoption - mean: 15.85 months, median: 12 months, range: 4-60 months). In initial analyses, earlier- and later-adopted (EA, LA) youth were compared to a group of children raised in their biological families (non-adopted, NA). NA youth performed significantly more accurately than LA youth, with EA youth falling in between. Imaging data suggested that previously institutionalized (PI) youth activated additional frontoparietal regions, including dorsolateral prefrontal cortex, as compared to NA youth. In addition, EA youth uniquely activated medial prefrontal regions, and LA uniquely activated parietal regions during this task. A separate analysis in a larger group of PI youth examined whether behavioral or brain measures of EF varied with the duration of deprivation experienced. Duration of deprivation was negatively associated with activation of default mode network (DMN) regions. Overall, results suggest that there are lasting effects of deprivation on EF, but that those who are removed from institutional care earlier may be able to recruit additional neural resources as a compensatory mechanism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Because of constrained personnel time, the Philadelphia Department of Public Health (Philadelphia, PA, USA) adjusted its COVID-19 contact tracing protocol in summer 2021 by prioritizing recent cases and limiting staff time per case. This action reduced required staff hours to prevent each case from 21-30 to 8-11 hours, while maintaining program effectiveness.

Psychotic symptoms typically emerge in adolescence. Age-associated thalamocortical connectivity differences in psychosis remain unclear. We analyzed diffusion-weighted imaging data from 1254 participants 8-23 years old (typically developing (TD):N = 626, psychosis-spectrum (PS): N = 329, other psychopathology (OP): N = 299) from the Philadelphia Neurodevelopmental Cohort. We modeled thalamocortical tracts using deterministic fiber tractography, extracted Q-Space Diffeomorphic Reconstruction (QSDR) and diffusion tensor imaging (DTI) measures, and then used generalized additive models to determine group and age-associated thalamocortical connectivity differences. Compared to other groups, PS exhibited thalamocortical reductions in QSDR global fractional anisotropy (GFA, p-values range = 3.0 × 10 -6 -0.05) and DTI fractional anisotropy (FA, p-values range = 4.2 × 10 -4 -0.03). Compared to TD, PS exhibited shallower thalamus-prefrontal age-associated increases in GFA and FA during mid-childhood, but steeper age-associated increases during adolescence. TD and OP exhibited decreases in thalamus-frontal mean and radial diffusivities during adolescence; PS did not. Altered developmental trajectories of thalamocortical connectivity may contribute to the disruptions observed in adults with psychosis., (© 2023. The Author(s).)

Although reinfections with SARS-CoV-2 have occurred in the United States with increasing frequency, U.S. epidemiologic trends in reinfections and associated severe outcomes have not been characterized. Weekly counts of SARS-CoV-2 reinfections, total infections, and associated hospitalizations and deaths reported by 18 U.S. jurisdictions during September 5, 2021-December 31, 2022, were analyzed overall, by age group, and by five periods of SARS-CoV-2 variant predominance (Delta and Omicron [BA.1, BA.2, BA.4/BA.5, and BQ.1/BQ.1.1]). Among reported reinfections, weekly trends in the median intervals between infections and frequencies of predominant variants during previous infections were calculated. As a percentage of all infections, reinfections increased substantially from the Delta (2.7%) to the Omicron BQ.1/BQ.1.1 (28.8%) periods; during the same periods, increases in the percentages of reinfections among COVID-19-associated hospitalizations (from 1.9% [Delta] to 17.0% [Omicron BQ.1/BQ.1.1]) and deaths (from 1.2% [Delta] to 12.3% [Omicron BQ.1/BQ.1.1]) were also substantial. Percentages of all COVID-19 cases, hospitalizations, and deaths that were reinfections were consistently higher across variant periods among adults aged 18-49 years compared with those among adults aged ≥50 years. The median interval between infections ranged from 269 to 411 days by week, with a steep decline at the start of the BA.4/BA.5 period, when >50% of reinfections occurred among persons previously infected during the Alpha variant period or later. To prevent severe COVID-19 outcomes, including those following reinfection, CDC recommends staying up to date with COVID-19 vaccination and receiving timely antiviral treatments, when eligible., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Introduction: Early non-motor symptoms in Huntington's disease (HD), including visual perceptual difficulties, can have profound negative impacts on quality of life. In particular, deficits in emotion recognition may contribute to misinterpretation of social cues, and may adversely affect interpersonal relationships, work relationships and/or general well-being. This may be particularly salient during the pre-manifest period, a period prior to the onset of motor symptoms. We sought to evaluate impairments in emotion recognition in gene-positive individuals who did not meet criterial for a diagnosis of HD; we also sought to determine associations between emotion recognition processing and altered cortico-striatal circuitry., Methods: We used a standardized battery to evaluate performance on a facial expression recognition task in a cohort of motor pre-manifest HD (Pre-HD) individuals (N = 21). Functional MRI (fMRI) was then used to assess the face processing network in a subset (N = 15)., Results: We found significantly decreased response accuracy to certain facial expressions, particularly of negative emotions (p < 0.001) in Pre-HDs. When Pre-HDs viewed faces with different emotions, activation within the Superior Temporal Sulcus (fSTS) was reduced compared to controls; in contrast, the level of evoked response within other face-selective cortical regions was comparable., Conclusion: Early deficits in emotion recognition in Pre-HD appear to be associated with alterations in the fSTS response, a distinctly different pathway from that involved in face perception and provide support for early cognitive and behavioral interventions., Competing Interests: Declaration of competing interest None of the authors has any financial or personal relationships with organizations that could bias the work., (Copyright © 2023. Published by Elsevier Ltd.)

Importance: The COVID-19 pandemic has claimed nearly 6 million lives globally as of February 2022. While pandemic control efforts, including contact tracing, have traditionally been the purview of state and local health departments, the COVID-19 pandemic outpaced health department capacity, necessitating actions by private health systems to investigate and control outbreaks, mitigate transmission, and support patients and communities., Objective: To investigate the process of designing and implementing a volunteer-staffed contact tracing program at a large academic health system from April 2020 to May 2021, including program structure, lessons learned through implementation, results of case investigation and contact tracing efforts, and reflections on how constrained resources may be best allocated in the current pandemic or future public health emergencies., Design, Setting, and Participants: This case series study was conducted among patients at the University of Pennsylvania Health System and in partnership with the Philadelphia Department of Public Health. Patients who tested positive for COVID-19 were contacted to counsel them regarding safe isolation practices, identify and support quarantine of their close contacts, and provide resources, such as food and medicine, needed during isolation or quarantine., Results: Of 5470 individuals who tested positive for COVID-19 and received calls from a volunteer, 2982 individuals (54.5%; median [range] age, 42 [18-97] years; 1628 [59.4%] women among 2741 cases with sex data) were interviewed; among 2683 cases with race data, there were 110 Asian individuals (3.9%), 1476 Black individuals (52.7%), and 817 White individuals (29.2%), and among 2667 cases with ethnicity data, there were 366 Hispanic individuals (13.1%) and 2301 individuals who were not Hispanic (82.6%). Most individuals lived in a household with 2 to 5 people (2125 of 2904 individuals with household data [71.6%]). Of 3222 unique contacts, 1780 close contacts (55.2%; median [range] age, 40 [18-97] years; 866 [55.3%] women among 1565 contacts with sex data) were interviewed; among 1523 contacts with race data, there were 69 Asian individuals (4.2%), 705 Black individuals (43.2%), and 573 White individuals (35.1%), and among 1514 contacts with ethnicity data, there were 202 Hispanic individuals (12.8%) and 1312 individuals (83.4%) who were not Hispanic. Most contacts lived in a household with 2 to 5 people (1123 of 1418 individuals with household data [79.2%]). Of 3324 cases and contacts who completed a questionnaire on unmet social needs, 907 (27.3%) experienced material hardships that would make it difficult for them to isolate or quarantine safely. Such hardship was significantly less common among White compared with Black participants (odds ratio, 0.20; 95% CI, 0.16-0.25)., Conclusions and Relevance: These findings demonstrate the feasibility and challenges of implementing a case investigation and contact tracing program at an academic health system. In addition to successfully engaging most assigned COVID-19 cases and close contacts, contact tracers shared health information and material resources to support isolation and quarantine, thus filling local public health system gaps and supporting local pandemic control.

Introduction: Most individuals with Down syndrome (DS) have the neuropathological changes of Alzheimer's disease (AD) by age 40 and will have developed dementia by age 60. Alterations of the intrinsic connectivity of the default mode network (DMN) are associated with AD in the neurotypical population. In this study, we sought to determine whether, and how, connectivity between the hubs of the DMN were altered in cognitively stable adults with DS who did not have evidence of either mild cognitive impairment or AD., Methods: Resting state functional MRI scans were collected from 26 healthy adults with DS and 26 healthy age-matched non-DS controls. Nodes comprising the DMN were generated as ROI's (regions of interest) and inter-nodal correlations estimated., Results: Analysis of intra-network connectivity of the DMN revealed anterior-posterior DMN dissociation and hyper- and hypo-connectivity, suggesting "accelerated aging" in DS., Discussion: Disruption of the DMN may serve as a prelude for AD in DS., Competing Interests: The authors report no conflicts of interest., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objective: This study examined patterns of diagnosis, consultation, and treatment of persons who screened positive for bipolar disorder., Methods: An impact survey was mailed to a representative subset of 3,059 individuals from a large U.S.-population-based study that utilized the Mood Disorder Questionnaire (MDQ)., Results: Respondents who screened positive on the MDQ (reported the presence of seven of 13 symptoms of bipolar disorder, the co-occurrence of at least two symptoms, and moderate or severe symptom-related impairment) (N=1,167) had consulted a health care provider more often in the previous year than those who screened negative (reported six or fewer symptoms regardless of symptom co-occurrence or impairment) (N=1,283). Psychiatrists and primary care physicians failed to detect or misdiagnosed bipolar disorder among 53 percent and 78 percent of patients, respectively, who screened positive for bipolar disorder. The most commonly used psychotropic medications during the previous 12 months among those who screened positive were antidepressants alone (32 percent), followed by lithium and anticonvulsant mood stabilizers (20 percent), antidepressants in combination with other psychotropics (19 percent), hypnotics (19 percent), and antipsychotics (9 percent). In the preceding 12 months, respondents who screened positive on the MDQ had greater use of psychiatric hospitals, emergency departments, and urgent care centers and also had more outpatient visits to primary care physicians, psychiatrists, and alcohol treatment centers than those who screened negative., Conclusions: The results of this study suggest that bipolar disorder is an underdiagnosed and often inappropriately treated illness associated with significant use of health care resources.

Objective: The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research., Data Sources: Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors., Study Selection/data Extraction: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed., Conclusions: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Diffusion of small molecules into glassy polymers is quite complicated and almost always non-Fickian. Little work has been done with the diffusion of low molecular weight polymers that are liquids at room temperature (such as poly(dodecyl acrylate)) into their miscible monomers. We have studied three molecular weights under 20 000 to determine if poly(dodecyl acrylate) diffusion into dodecyl acrylate could be treated with Fick's law and if so to determine the values of the diffusion coefficients. We compare two methods for measuring the diffusion of dodecyl acrylate into poly(dodecyl acrylate): We used laser line deflection (Wiener's method) and improved upon the method from published reports. We also used the dependence of pyrene's fluorescence on the viscosity to measure the concentration distribution, and thus to extract the diffusion coefficient. After an initial relaxation period, diffusion in all cases followed Fick's law with a single concentration-independent diffusion coefficient. Comparison of the diffusion coefficients obtained by both methods yielded the same order of magnitude for the diffusion coefficients (10(-7) cm2/s) and showed the same trend in the dependence on the average molecular weight of the polymer (a decrease in the diffusion coefficient with an increase in the molecular weight).

Objective: The authors' goal was to assess the adequacy of control, quality of life, and treatment experiences of patients with chronic, recurrent depression being treated by primary care physicians., Method: The sample comprised 1,001 patients 18 years old or older who had chronic, recurring depression and were currently being treated with a single antidepressant prescribed by a primary care physician. These patients had responded positively to questions regarding the presence of clinical depression and prescription of a single antidepressant by a primary care physician during a telephone survey conducted in two stages separated by 18 to 24 months. The 1,001 patients participated in a structured, 20-minute, anonymous interview conducted by trained personnel., Results: Most patients had recurrent depression (median=5 episodes), and most had taken their current antidepressant for more than 1 year. The mean age at onset of depression was 33.8 years, and the mean age at time of diagnosis was 38.0 years, with treatment following a mean of 2 years later. Most patients were satisfied with the care they received from their primary care physician, but many also reported incomplete symptom resolution and substantial side effects from medications that were not discussed with or by their primary care physician. A majority of patients reported that treatment decisions were made in conjunction with their physician, a method that was preferred by three-quarters of the group. Although 752 patients reported that they had mild or moderate depression, 729 were satisfied with their life and 600 said they were in good or excellent health., Conclusions: Despite being mostly satisfied with the care received from their primary care physician, patients with chronic, recurring depression had substantial levels of continuing dysfunction, distress, unrelieved symptoms, and medication side effects, which suggests several possible physician-centered, patient-centered, or system-centered barriers to treatment to full function and wellness.

Objective: To focus attention on the critical unmet needs of children and adolescents with mood disorders and to make recommendations for future research and allocation of healthcare resources., Method: The 36-member Consensus Development Panel consisted of experts in child/adolescent or adult psychiatry and psychology, pediatrics, and mental health advocacy. Reviews of the literature concerning youth mood disorders were performed on the subjects of risk factors, prevention, diagnosis, treatment, and services delivery, and opinions and experiences of mental health advocates were obtained., Results: The Consensus Development Panel listened to presentations and participated in discussions. Independent workgroups of clinicians, scientists, and mental health advocates considered the evidence and prepared preliminary statements. Workgroup leaders presented drafts for discussion by the Consensus Development Panel. The final document was reviewed by the entire group and edited to incorporate input from all participants., Conclusions: Evidence suggests high rates of unmet needs for children and adolescents with depression or bipolar disorder. Training is largely limited to child mental health specialists; general psychiatrists, pediatricians, and other primary care physicians receive little or no training. As a result, treatment patterns may reflect adult treatment plans that are not validated for youths. Effective treatments have been identified and some preliminary prevention models have been developed, but they are not yet widely applied. Patients experience limited exposure to clinicians adequately trained to address their problems and little information to guide care decisions, particularly concerning bipolar disorder. National efforts are required to restructure healthcare delivery and provider training and to immediately develop more advanced research on pathophysiology, prevention, and services delivery effectiveness.

Objectives: To review progress made during the past decade in late-life mood disorders and to identify areas of unmet need in health care delivery and research., Participants: The Consensus Development Panel consisted of experts in late-life mood disorders, geriatrics, primary care, mental health and aging policy research, and advocacy., Evidence: (1) Literature reviews addressing risk factors, prevention, diagnosis, treatment, and delivery of services and (2) opinions and experiences of primary care and mental health care providers, policy analysts, and advocates., Consensus Process: The Consensus Development Panel listened to presentations and participated in discussions. Workgroups considered the evidence and prepared preliminary statements. Workgroup leaders presented drafts for discussion by the Consensus Development Panel. The final document was reviewed and edited to incorporate input from the entire Consensus Development Panel., Conclusions: Despite the availability of safe and efficacious treatments, mood disorders remain a significant health care issue for the elderly and are associated with disability, functional decline, diminished quality of life, mortality from comorbid medical conditions or suicide, demands on caregivers, and increased service utilization. Discriminatory coverage and reimbursement policies for mental health care are a challenge for the elderly, especially those with modest incomes, and for clinicians. Minorities are particularly underserved. Access to mental health care services for most elderly individuals is inadequate, and coordination of services is lacking. There is an immediate need for collaboration among patients, families, researchers, clinicians, governmental agencies, and third-party payers to improve diagnosis, treatment, and delivery of services for elderly persons with mood disorders.

Background: Bipolar disorder is a chronic psychiatric illness characterized by depression and at least 1 manic or hypomanic episode during the lifetime of the illness. Bipolar symptoms have been associated with significant functional impairment. We conducted a study to determine the psychosocial impact of bipolar disorder in a U.S. community sample., Method: 3059 subjects were selected from a large epidemiologic study of bipolar prevalence that used the Mood Disorder Questionnaire (MDQ) to screen for bipolar I and II disorder. Subjects were surveyed from April 24, 2001, to August 6, 2001, using the Sheehan Disability Scale and the Social Adjustment Scale-Self Report. Comorbid disease data were also collected., Results: Of the 3059 subjects surveyed, 2450 (80%) returned completed surveys: 1167 (48%) subjects screened positive for bipolar disorder based on MDQ scores; 1283 (52%) screened negative. MDQ-positive subjects reported significantly (p <.0001) more difficulties with work-related performance, social/leisure activities, and social/family interactions compared with MDQ-negative subjects. Younger subjects, aged 18 to 34 years, reported significantly (p =.003) more symptom days than did older MDQ-positive subjects. MDQ-positive women reported more disruption in social and family life, while MDQ-positive men reported being jailed, arrested, and convicted for crimes. Anxiety (30% vs. 6%), panic attacks (18% vs. 4%), migraine (24% vs. 11%), asthma (17% vs. 10%), and allergies (42% vs. 29%) were significantly (p <.05) more common in MDQ-positive versus MDQ-negative subjects., Conclusion: Bipolar disorder, as identified in a community sample using the Mood Disorder Questionnaire, was significantly associated with negative impact on the performance of work-related, leisure, and interpersonal activities.

Objective: To assess the experience of selected individuals living with bipolar disorder and compare this experience with that of a similar group of individuals sampled in 1992., Method: In June 2000, 4192 self-administered questionnaires were sent to National Depressive and Manic-Depressive Association chapters for distribution to support group participants diagnosed with bipolar disorder. By July 31, 2000, the first 600 completed surveys were analyzed., Results: Over one third of respondents sought professional help within 1 year of the onset of symptoms. Unfortunately, 69% were misdiagnosed, with the most frequent misdiagnosis being unipolar depression. Those who were misdiagnosed consulted a mean of 4 physicians prior to receiving the correct diagnosis. Over one third waited 10 years or more before receiving an accurate diagnosis. Despite having underreported manic symptoms, more than half believe their physicians' lack of understanding of bipolar disorder prevented a correct diagnosis from being made earlier. In 2000, the respondents reported a greater negative impact of bipolar disorder on families, social relationships, and employment than did the respondents in 1992. Overall, respondents were satisfied with their current treatment, which often included medication, talk therapy, and support groups. Respondents who were highly satisfied with their treatment provider had a more positive outlook on their illness and their ability to cope with it., Conclusion: Individuals with bipolar disorder reported that the illness manifests itself early in life but that accurate diagnosis lags by many years. The illness exacts great hardships on the individual and the family and has a profoundly negative effect on careers. These findings are very similar to those reported nearly a decade ago.

Objective: This study tested the validity in the adult general population of the Mood Disorder Questionnaire, a screening instrument for bipolar I and II disorders. The Mood Disorder Questionnaire has been validated in a psychiatric outpatient study group., Method: A total of 711 subjects (stratified by Mood Disorder Questionnaire score) were randomly selected from a group of 85,358 adult respondents in a nationwide epidemiological general population sample that was balanced for key demographic variables. Of these, 695 subjects received a telephone interview involving an abbreviated version of the Structured Clinical Interview for DSM-IV., Results: A sensitivity of 0.281 and a specificity of 0.972 were obtained for the Mood Disorder Questionnaire., Conclusions: The Mood Disorder Questionnaire is a useful screening instrument for bipolar I and II disorders in the community. The operating characteristics of the Mood Disorder Questionnaire in the general population differ substantially from its characteristics in outpatient psychiatric settings.

Background: Our goal was to estimate the rate of positive screens for bipolar I and bipolar II disorders in the general population of the United States., Method: The Mood Disorder Questionnaire (MDQ), a validated screening instrument for bipolar I and II disorders, was sent to a sample of 127,800 people selected to represent the U.S. adult population by demographic variables. 85,358 subjects (66.8% response rate) that were 18 years of age or above returned the survey and had usable data. Of the nonrespondents, 3404 subjects matched demographically to the 2000 U.S. Census data completed a telephone interview to estimate nonresponse bias., Results: The overall positive screen rate for bipolar I and II disorders, weighted to match the 2000 U.S. Census demographics, was 3.4%. When adjusted for the nonresponse bias, the rate rose to 3.7%. Only 19.8% of the individuals with positive screens for bipolar I or II disorders reported that they had previously received a diagnosis of bipolar disorder from a physician, whereas 31.2% reported receiving a diagnosis of unipolar depression. An additional 49.0% reported receiving no diagnosis of either bipolar disorder or unipolar depression. Positive screens were more frequent in young adults and low income households. The rates of migraine, allergies, asthma, and alcohol and drug abuse were substantially higher among those with positive screens., Conclusion: The positive MDQ screen rate of 3.7% suggests that nearly 4% of American adults may suffer from bipolar I and II disorders. Young adults and individuals with lower income are at greater risk for this largely underdiagnosed disorder.

The burden of affective disorders includes costs and the pain and suffering of affected individuls. Burden can be perceived from social and private perspectives. Although no ideal measure of burden exists, ample evidence documents the extensive cost and other negative impacts of affective disorders. Affective disorders are associated with disruptive family relations, higher health care costs for comorbid conditions, elevated rates of suicide, and lower productivity. Reserch should focus on improving measures of burden in general and on quantifying burden from the standpoint of diverse population groups.

This paper summarizes 3 sets of barriers to reducing burden of affective disorders including factors that contribute to 1) the risk, course, and outcomes of affective disorders; 2) help-seeking and use of health and mental health services for affective and other mental disorders; and 3) the appropriateness of treatments used for affective disorders. On the basis of this review, the authors recommend research needed to identify modifiable barriers to reducing the burden of affective disorders and to identifying opportunities to reduce these barriers. This new research should focus on clarifying societal, family, and consumer, clinician, and system barriers to recognizing disorders, seeking and providing care, and adhering with guideline concordant care, and should include barriers that apply to both treatment and prevention services.

Affective disorders impose a substantial individual and societal burden. Despite availability of efficacious treatments and practice guidelines, unmet need remains high. To reduce unmet need and the burden of affective disorders, information is needed on the distribution of burden across stakeholders, on barriers to reducing burden, and on interventions that effectively reduce burden at the levels of practice, community, and policy. This article provides the report of the Working Group on Overcoming Barriers to Reducing the Burden of Affective Disorders, for the National Institute of Mental Health Strategic Plan on Mood Disorders. We review the literature, identify key gaps, and recommend new research to guide national efforts to reduce the burden of affective disorders.

A consensus conference on the use of placebo in mood disorder studies consisted of expert presentations on bioethics, biostatistics, unipolar depression, and bipolar disorder. Work groups considered evidence and presented statements to the group. Although it was not possible to write a document for which there was complete agreement on all issues, the final document incorporated input from all authors. There was consensus that placebo has a definite role in mood disorder studies. Findings of equivalence between a new drug and standard treatment in active control studies is not evidence of efficacy unless the new drug is also significantly more effective than placebo. Add-on studies in which patients are randomized to standard therapy plus the investigational drug or standard therapy plus placebo are especially indicated for high-risk patients. Mood disorders in elderly and pediatric patients are understudied, and properly designed trials are urgently needed. Research is needed on the ethical conduct of studies to limit risks of medication-free intervals and facilitate poststudy treatment. Patients must fully understand the risks and lack of individualized treatment involved in research.