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.

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.

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

Mental Health Center Services for the Elderly: The Impact of Coordination with Area Agencies on Aging

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.

Treatments in depression.

Medication nonadherence is a key clinical concern in bipolar disorder (BD) across the life span. Cognitive deficits in older adults with BD may hinder medication management ability, which, in turn, may lead to nonadherence. Using an innovative performance-based measure of medication management ability, the Medication Management Ability Assessment (MMAA), we compared performance of 29 middle-aged older community-dwelling outpatients with BD who were clinically stable (mean age, 61 years; SD, 11 years; range, 45-86 years) with those of 59 normal control subjects (NCs) and 219 outpatients with schizophrenia. The MMAA is a role-play task that simulates a medication regimen likely to be encountered by older adults. Within the BD group, we examined the relationships of MMAA scores to demographic, psychiatric symptoms severity, and the Mattis Dementia Rating Scale (DRS) scores. The BD group made 2.8 times the errors on the MMAA than NCs (BD group, 6.2; SD, 5.5 vs NCs, 2.2; SD, 2.5) and did not significantly differ from the Schizophrenia group in errors on the MMAA. Errors in the BD group were more likely to be taking in too few medications as taking in too many. Within the BD group, a significant correlation was seen between MMAA scores and the DRS Total score, but not with age, education, Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, number of psychiatric medications, or medical conditions. Among DRS subscales, the Memory Subscale correlated most strongly with MMAA errors. This small cross-sectional study suggests that deficits in medication management ability may be present in later-life BD. Neurocognitive deficits may be important in understanding problems with unintentional nonadherence.

Barry D. Lebowitz

Papers

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

Mental Health Center Services for the Elderly: The Impact of Coordination with Area Agencies on Aging

Treatments in depression.

Assessment of medication management ability in middle-aged and older adults with bipolar disorder

Treatment research at the millennium: from efficacy to effectiveness.