Posttraumatic Distress Symptoms and Their Response to Treatment in Adults With Prolonged Grief Disorder.

OBJECTIVE: Posttraumatic stress disorder and prolonged grief disorder (PGD) arise following major life stressors and may share some overlapping symptomatology. This study aimed to examine the presence and response to treatment of posttraumatic stress symptoms (PTSS) in bereaved adults with a primary diagnosis of PGD. METHODS: A randomized controlled trial of 395 adults with PGD (defined as an Inventory of Complicated Grief score ≥ 30 plus confirmation on structured clinical interview) randomly assigned participants to either complicated grief treatment (CGT) with citalopram, CGT plus placebo, citalopram, or placebo between March 2010 and September 2014. This secondary analysis examined the presence of PTSS (per the Davidson Trauma Scale) at baseline and change in PTSS with treatment using longitudinal mixed-effects regression and examined the role of violent compared to nonviolent deaths (loss type). RESULTS: High levels of PTSS were present at baseline, regardless of loss type, and were associated with increased functional impairment (P < .001). CGT with placebo demonstrated efficacy for PTSS compared to placebo in both threshold (OR = 2.71; 95% CI, 1.13-6.52; P = .026) and continuous (P < .001; effect size d = 0.47) analyses, and analyses were suggestive of a greater effect for CGT plus citalopram compared to citalopram alone (threshold analysis: OR = 2.84; 95% CI, 1.20-6.70; P = .017; continuous analysis: P = .053; d = 0.25). In contrast, citalopram did not differ from placebo, and CGT plus citalopram did not differ from CGT plus placebo. CONCLUSIONS: Bereavement-related PTSS are common in bereaved adults with PGD in the context of both violent and nonviolent death and are associated with poorer functioning. CGT shows efficacy for PTSS, while the antidepressant citalopram does not. TRIAL REGISTRATION: : ClinicalTrials.gov identifier: NCT01179568.

Biomarkers to predict antidepressant response.

During the past several years, we have achieved a deeper understanding of the etiology/pathophysiology of major depressive disorder (MDD). However, this improved understanding has not translated to improved treatment outcome. Treatment often results in symptomatic improvement, but not full recovery. Clinical approaches are largely trial-and-error, and when the first treatment does not result in recovery for the patient, there is little proven scientific basis for choosing the next. One approach to enhancing treatment outcomes in MDD has been the use of standardized sequential treatment algorithms and measurement-based care. Such treatment algorithms stand in contrast to the personalized medicine approach, in which biomarkers would guide decision making. Incorporation of biomarker measurements into treatment algorithms could speed recovery from MDD by shortening or eliminating lengthy and ineffective trials. Recent research results suggest several classes of physiologic biomarkers may be useful for predicting response. These include brain structural or functional findings, as well as genomic, proteomic, and metabolomic measures. Recent data indicate that such measures, at baseline or early in the course of treatment, may constitute useful predictors of treatment outcome. Once such biomarkers are validated, they could form the basis of new paradigms for antidepressant treatment selection.

Mobile interventions for severe mental illness: design and preliminary data from three approaches.

Mobile devices can be used to deliver psychosocial interventions, yet there is little prior application in severe mental illness. We provide the rationale, design, and preliminary data from 3 ongoing clinical trials of mobile interventions developed for bipolar disorder or schizophrenia. Project 1 used a personal digital assistant to prompt engagement in personalized self-management behaviors based on real-time data. Project 2 employed experience sampling through text messages to facilitate case management. Project 3 was built on group functional skills training for schizophrenia by incorporating between-session mobile phone contacts with therapists. Preliminary findings were of minimal participant attrition, and no broken devices; yet, several operational and technical barriers needed to be addressed. Adherence was similar to that reported in nonpsychiatric populations, with high participant satisfaction. Therefore, mobile devices seem feasible and acceptable in augmenting psychosocial interventions for severe mental illness, with future research in establishing efficacy, cost effectiveness, and ethical and safety protocols.

Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease.

BACKGROUND: Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. METHODS: In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. RESULTS: There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). CONCLUSIONS: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].).

Medication augmentation after the failure of SSRIs for depression.

BACKGROUND: Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach. METHODS: We randomly assigned 565 adult outpatients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy (mean final dose, 55 mg per day) to receive sustained-release bupropion (at a dose of up to 400 mg per day) as augmentation and 286 to receive buspirone (at a dose of up to 60 mg per day) as augmentation. The primary outcome of remission of symptoms was defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of this study; scores were obtained over the telephone by raters blinded to treatment assignment. The 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR-16) was used to determine the secondary outcomes of remission (defined as a score of less than 6 at the end of this study) and response (a reduction in baseline scores of 50 percent or more). RESULTS: The sustained-release bupropion group and the buspirone group had similar rates of HRSD-17 remission (29.7 percent and 30.1 percent, respectively), QIDS-SR-16 remission (39.0 percent and 32.9 percent), and QIDS-SR-16 response (31.8 percent and 26.9 percent). Sustained-release bupropion, however, was associated with a greater reduction (from baseline to the end of this study) in QIDS-SR-16 scores than was buspirone (25.3 percent vs. 17.1 percent, P<0.04), a lower QIDS-SR-16 score at the end of this study (8.0 vs. 9.1, P<0.02), and a lower dropout rate due to intolerance (12.5 percent vs. 20.6 percent, P<0.009). CONCLUSIONS: Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings. Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events. (ClinicalTrials.gov number, NCT00021528.).

Performance-based and subjective measures of functioning in middle-aged and older adults with bipolar disorder.

Performance-based measures may be useful in quantifying functional impairment associated with bipolar disorder, particularly among older adults. Among 30 outpatients with bipolar disorder and 31 normal comparison subjects (NCs), we administered the UCSD Performance-Based Skills Assessment (UPSA) and 2 subjective measures of functioning. The UPSA simulates real-world everyday tasks, such as financial management. We compared UPSA scores between groups and, within the bipolar group, examined associations between UPSA scores and subjective functioning, cognitive functioning, and depressive, and manic symptoms. By large effect sizes, the bipolar disorder group had lower scores on the UPSA and its subscales compared with NCs. Within the bipolar group, UPSA scores correlated strongly with Quality of Well-Being Scale but not SF-36 scores, and the UPSA was not related to depressive or manic symptoms, but was associated with cognitive functioning. Given its relative independence from symptoms, the UPSA may be useful in gauging the effectiveness of rehabilitation for bipolar disorder.

Disability and self-management practices of people with bipolar disorder: a web-based survey.

In a web-based survey asking adults diagnosed with bipolar disorder about illness management, we obtain frequency of self-reported usage and perceived helpfulness of 27 self-management strategies. We correlated the strategy use and perceived helpfulness with demographic and clinical characteristics, along with the Illness Intrusiveness Scale total score. Completed surveys were obtained from 1,024 individuals. Perceived helpfulness of 18 of 27 strategies was correlated negatively with illness intrusiveness at the P < 0.001 level. Given limitations of web-based surveys, our study underscores the substantial negative impact of bipolar disorder, along with the potential of the Internet to enhance the use of self-management strategies.

Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.

BACKGROUND: The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. METHODS: A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. RESULTS: Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. CONCLUSIONS: The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

Short-term course of neuropsychological abilities in middle-aged and older adults with bipolar disorder.

OBJECTIVES: There are few longitudinal studies of neurocognition in bipolar disorder, and the short-term course of cognitive deficits in later-life bipolar disorder is unknown. METHODS: We administered a battery of neurocognitive tests, repeated 1-3 years after baseline, to 35 community-dwelling outpatients with bipolar disorder (mean age = 58), and compared their performance on a composite measure of cognitive functioning to that of demographically matched samples of normal comparison subjects (NCs; n = 35) and patients with schizophrenia (n = 35). Using regression analyses, we examined group differences in baseline performance, trajectory of change over time, and variability in performance across time. Within the bipolar group, we examined the impact of baseline severity and change in severity of psychiatric symptoms on intra-individual change in neurocognitive performance. RESULTS: At baseline, the group with bipolar disorder differed in overall neurocognitive functioning from the NCs, but did not differ significantly from the schizophrenia group. The bipolar group did not differ from the NCs or schizophrenia group in the mean trajectory of change between time-points, but the bipolar patients showed more intra-individual variability over time than the NCs or schizophrenia group. In the bipolar group, change in neurocognitive function was not related to baseline or change in psychiatric symptom severity. CONCLUSIONS: Middle-aged and older community-dwelling adults with bipolar disorder have greater short-term variability in level of neurocognitive functioning relative to NCs or people with schizophrenia. The developmental course of and risk factors for cognitive deficits in bipolar disorder should be examined in future longitudinal studies.

Public-academic partnerships: improving care for older persons with schizophrenia through an academic-community partnership.

Translating evidence-based mental health interventions designed in research settings into community practice is a priority for multiple stakeholders. Partnerships between academic and public institutions can facilitate this translation. To improve care for middle-aged and older adults with schizophrenia, the authors developed a collaboration between a university research center and a public mental health service system using principles from community-based participatory research and cultural exchange theory. They describe the process that has led to a number of mutually beneficial products. Despite the challenges involved, building and maintaining academic-public collaborations will be essential for improving mental health care for persons with schizophrenia.

Psychosocial interventions and medication adherence in bipolar disorder.

Recent research has indicated that psychosocial interventions can have a valuable role in reducing the substantial psychosocial disability associated with bipolar disorder. Randomized controlled trials of these interventions indicate that improvements are seen in symptoms, psychosocial functioning, and treatment adherence. These interventions, systematically presented in the form of standardized treatment manuals, vary in format, duration, and theoretical basis. All are meant to augment pharmacotherapy, which represents the standard of treatment in the field. Modalities that have gathered the most empirical support include cognitive-behavioral therapy, family-focused therapy, interpersonal and social rhythms therapy, and psychoeducation. The enhancement of adherence to pharmacotherapy is a common therapeutic target, due to the association of nonadherence with higher relapse rates, hospitalization, and health care costs among people with bipolar disorder. Given the complexity of nonadherence behavior, multicomponent interventions are often required. In this review, we provide an overview of the rationale, evidence base, and major psychotherapeutic approaches in bipolar disorder, focusing on the assessment and enhancement of medication adherence.

Medical comorbidity in complicated grief: Results from the HEAL collaborative trial.

OBJECTIVE: To describe medical comorbidity in persons with Complicated Grief (CG) and to test whether medical comorbidity in individuals with CG is associated with the severity and duration of CG, after adjusting for age, sex, race, and current depressive symptoms. METHODS: In exploratory analyses, we compared data from participants in an NIMH-sponsored multisite clinical trial of CG ("HEAL": "Healing Emotions After Loss") to archival data from participants matched on age, gender, and race/ethnicity, stratified by the presence or absence of current major depression. We used the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) as a measure of medical polymorbidity. We investigated the association between CG and medical comorbidity via multiple linear regression, adjusting for sociodemographic and clinical variables, including severity of depressive symptoms. RESULTS: Chronological age and severity of co-occurring symptoms of major depression correlated with cumulative medical polymorbidity in persons with Complicated Grief. The severity of CG and the time since loss did not correlate with global medical polymorbidity (CIRS-G score). Nor was there an interaction between severity of depressive symptoms and severity of CG symptoms in predicting global CIRS-G score. Cumulative medical comorbidity, as measured by CIRS-G scores, was greater in subjects with current major depression ("DEPRESSED") than in CG subjects, and both DEPRESSED and CG subjects had greater medical morbidity than CONTROLS. CONCLUSION: Medical comorbidity is prevalent in Complicated Grief, associated with increasing age and co-occurring depressive symptoms but apparently not with chronicity and severity of Complicated Grief per se. This observation suggests that treating depression in the context of CG may be important to managing medical conditions in individuals with Complicated Grief to attenuate or prevent the long-term medical sequelae of CG.

Neurocognitive impairment in middle-aged and older adults with bipolar disorder: comparison to schizophrenia and normal comparison subjects.

BACKGROUND: The frequency, pattern, and correlates of neurocognitive impairment in older patients with bipolar disorder have received little study. We examined neurocognitive abilities in middle-aged and older adults with bipolar disorder to groups with schizophrenia or normal subjects, as well as the relation of neurocognition to clinical characteristics. METHOD: We administered a battery of neurocognitive and clinical measures to older (45-85 years) outpatients with bipolar disorder (n=67), schizophrenia (n=150), and normal comparison subjects (n=85). Within the bipolar group, we assessed the association between neurocognitive performance and psychiatric symptoms, quality of life, and medication status. RESULTS: The group with bipolar disorder differed on nearly all neuropsychological tests compared to normal subjects, with medium effect sizes. Bipolar patients as impaired as those with schizophrenia on half of the tests administered, and performed better on the remaining tests, with small effect sizes. Neurocognitive deficits in bipolar disorder group related to lower quality of life, but not to psychiatric symptom severity or duration of illness. LIMITATIONS: Samples were outpatients with mild-moderate symptoms, and findings may not generalize to acutely ill populations. We lacked data on illness history to examine the cumulative impact of psychopathology. CONCLUSIONS: Among clinically stable middle-aged and older outpatients, bipolar disorder was associated with substantial neurocognitive impairment, with a pattern that was somewhat distinct from that found in schizophrenia. Deficits in the bipolar group were not related to severity or duration of psychiatric symptoms, but were related to quality of life. Bipolar disorder often involve disabling and enduring cognitive impairments in older outpatients.

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

OBJECTIVE: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of or=11 (HRSD(17)>or=14) defined relapse. RESULTS: The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. CONCLUSIONS: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

Treatments in depression.

Major depression is believed to be a multifactorial disorder involving predisposing temperament and personality traits, exposure to traumatic and stressful life events, and biological susceptibility. Depression, both unipolar and bipolar, is a "phasic" disease. Stressful life events are known to trigger depressive episodes, while their influence seems to decrease over the course of the illness. This suggests that depression is associated with progressive stress response abnormalities, possibly linked to impairments of structural plasticity and cellular resilience. It therefore appears crucial to adequately treat depression in the early stages of the illness, in order to prevent morphological and functional abnormalities. While evidence suggests that a severely depressed patient needs antidepressant drug therapy and that a non-severely depressed patient may benefit from other approaches (ie, "nonbiological"), little research has been done on the effectiveness of different treatments for depression. The assertion that the clinical efficacy of antidepressants is comparable between the classes and within the classes of those medications may be true from a statistical viewpoint, but is of limited value in practice. The antidepressant drugs may produce differences in therapeutic response and tolerability. Among the possible predictors of outcome in depression treatment, those derived from clinical assessment, neuroendocrine investigations, polysomnographic sleep parameters, genetic variables, and brain imaging techniques have been extensively studied. This article also reviews therapeutic strategies used when initial treatment fails, and describes briefly new concepts in antidepressant therapies such as the regulation of disturbances in circadian rhythms. The treatment of depressive illness does not stop with treatment of acute episodes, and has to be envisaged as a continuous therapeutic intervention, of which we are still not able to determine the optimal duration of treatment and the moment that it should be ceased.

Schizophrenia in late life: emerging issues.

Schizophrenia in late life is emerging as a major public health concern worldwide. We discuss several areas of research and clinical care that are particularly pertinent to older persons with schizophrenia, including the public health challenge and the cost of care. We then discuss clinical issues relevant to late-life schizophrenia (course of illness and cognition), medical care and comorbidity in older psychiatric patients (general and illness-related), and treatment concerns related to the use of atypical antipsychotics in older persons with psychosis (efficacy and side effects). Clinical care for this ever-increasing segment of our population requires special consideration of the unique characteristics of older persons with schizophrenia.

Late-life depression: a model for medical classification.

Geriatric psychiatric syndromes might serve as the starting point for a medical classification of psychiatric disorders, because their medical and neurological comorbidity and their clinical, neuropsychological, and neuroimaging features often reflect specific brain abnormalities. Geriatric syndromes, however, consist of complex behaviors that are unlikely to be caused by single lesions. We propose a model in which aging-related changes in specific brain structures increase the propensity for the development of certain psychiatric syndromes. The predisposing factors are distinct from the mechanisms mediating the expression of a syndromic state, much like hypertension is distinct from stroke, but constitutes a morbid vulnerability. We argue that research seeking to identify both brain abnormalities conferring vulnerability as well as the mediating mechanisms of symptomatology has the potential to lead to a medical classification of psychiatric disorders. In addition, a medical classification can guide the effort to improve treatment and prevention of psychiatric disorders as it can direct therapeutic efforts to the underlying predisposing abnormalities, the syndrome-mediating mechanisms, and to development of behavioral skills needed for coping with adversity and disability.

Depression and Bipolar Support Alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life.

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.

Enhancing the technology of clinical trials and the trials model to evaluate newly developed, targeted antidepressants.

Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on "improving the technology of clinical trials." The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on "whole" disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) , Unites States and Food and Drug Administration (FDA), Unites States participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants.

Approaches to multisite clinical trials: the National Institute of Mental Health perspective.

The Division of Services and Intervention Research of the National Institute of Mental Health (NIMH) utilizes a variety of methodologies and approaches in the development of its clinical trials program. In this article, we describe the need for large multisite trials; the mechanisms for addressing this need; and the various approaches that have been used. In the course of carrying out this initiative, we have created opportunities for the Institute and its trial investigators to receive advice and input from the field. We describe the role and function of the trial coordinating center and NIMH staff. We identify the first steps to be taken in the initiation of a trial and highlight the opportunity for ancillary studies. Finally, we enumerate some of the pitfalls of large clinical trials and discuss measures taken to anticipate and address them.