Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

/pdf/biological-insights-from-108-schizophrenia-associated-3rfvth8dm9.pdf

Biological insights from 108 schizophrenia-associated genetic loci

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.

/pdf/effectiveness-of-antipsychotic-drugs-in-patients-with-8hte8vymdc.pdf

Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia

Dementia prevention, intervention, and care

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 ≤5 on the Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR 16 ) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression [HRSD 17 ]) defined remission; a QIDS-SR 16 total score of ≥11 (HRSD 17 ≥14) defined relapse. Results: The QIDS-SR 16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, t...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.2006.163.11.1905

Acute and Longer- Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report

Although several psychological theories predict that members of stigmatized groups should have low global self-esteem, empirical research typically does not support this prediction. It is proposed here that this discrepancy may be explained by considering the ways in which membership in a stigmatized group may protect the self-concept It is proposed that members of stigmatized groups may (a) attribute negative feedback to prejudice against their group, (b) compare their outcomes with those of the ingroup, rather than with the relatively advantaged outgroup, and (c) selectively devalue those dimensions on which their group fares poorly and value those dimensions on which their group excels. Evidence for each of these processes and their consequences for self-esteem and motivation is reviewed. Factors that moderate the use of these strategies and implications of this analysis for treatment of stigmas are also discussed. For more than three decades, social psychological research on prejudice, stereotyping, and discrimination has examined both the content of stereotypes about a variety of social groups

Social stigma and self-esteem: The self-protective properties of stigma.

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.

/pdf/public-academic-partnerships-improving-care-for-older-52rzkzumem.pdf

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

This article, based on a Lawton Award Lecture, addresses the subject of the need to enhance the evidence base in our field in order to influence processes of policy development. Four issues are identified as critical to this: theory-driven targets of public health significance, use of appropriate and sophisticated approaches to research design and statistical modeling, development of instruments and measures, and conclusions that make a difference. Incentives are discussed with particular attention to regulatory approaches. A broad view of research is taken, with examples from studies of Alzheimer's disease and depression in late life. I conclude that new approaches to methodology will enhance our capacity to translate exciting new findings from the basic sciences into the development of therapeutics and that this will, in turn, enhance our capacity to inform the development of public policy.

Clinical Trials in Late Life: New Science in Old Paradigms

In July 1995, the American Association for Geriatric Psychiatry (AAGP) sponsored the first annual week-long Summer Research Institute (SRI) in Geriatric Psychiatry, at the University of California, San Diego. The NIMH-funded SRI was intended for promising postresidency and postdoctoral fellows, as well as junior faculty persons interested in research careers in geriatric psychiatry. The SRI focused on the tools needed to begin, maintain, and succeed on that career path and has been followed by continued communication between trainees and faculty. The SRI was highly successful, judging from the participants' evaluations, as well as the trainees' accomplishments in terms of publications and research funding during 1 year of follow-up. The SRI provides a useful model for an approach to bridging and shortening the transition period from fellowship to first research funding and of ensuring a continued flow of new investigators in geriatric psychiatry.

The First Summer Research Institute in Geriatric Psychiatry

The death of a loved one is one of life's greatest stressors. Most bereaved individuals experience a period of acute grief that diminishes in intensity as they adapt to the changes brought about by their loss. Over the past four decades, a growing body of research has focused on a form of prolonged grief that is painful and impairing. There is a substantial and growing evidence base that supports the validity and significance of a grief-related disorder, including the clinical value of being able to diagnose it and provide effective targeted treatment. ICD-11 will include a new diagnosis of prolonged grief disorder (PGD). DSM-5 called this condition persistent complex bereavement disorder (PCBD) and included it in Section III, signaling agreement that a diagnosis is warranted while further research is needed to determine the optimal criteria. Given the remaining uncertainties, reading this literature can be confusing. There is inconsistency in naming the condition (including complicated grief as well as PGD and PCBD) and lack of uniformity in identifying it, with respect to the optimal threshold and timeframe for distinguishing it from normal grief. As an introductory commentary for this Depression and Anxiety special edition on this form of grief, the authors discuss the history, commonalities, and key areas of variability in identifying this condition. We review the state of diagnostic criteria for DSM-5 and the current ICD-11 diagnostic guideline, highlighting the clinical relevance of making this diagnosis.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/da.22985

Commentary on evidence in support of a grief-related condition as a DSM diagnosis.

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.

Barry D. Lebowitz

Papers

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

Clinical Trials in Late Life: New Science in Old Paradigms

The First Summer Research Institute in Geriatric Psychiatry

Commentary on evidence in support of a grief-related condition as a DSM diagnosis.

Approaches to Multisite Clinical Trials: The National Institute of Mental Health Perspective