Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Hyperprolactinemia and medications for bipolar disorder: systematic review of a neglected issue in clinical practice.

Drug-induced changes in serum prolactin (sPrl) levels constitute a relevant issue due to the potentially severe consequences on physical health of psychiatric patients such as sexual dysfunctions, osteoporosis and Prl-sensitive tumors. Several drugs have been associated to sPrl changes. Only antipsychotics have been extensively studied as sPrl-elevating agents in schizophrenia, but the extent to which bipolar disorder (BD) treatments affect sPrl levels is much less known. The objective of this systematic review is to summarize the evidence of the effects of drugs used in BD on Prl. This review followed the PRISMA statement. The MEDLINE/PubMed/Index Medicus, EMBASE, and Cochrane Library databases were systematically searched for articles in English appearing from any time to May 30, 2014. Twenty-six studies were included. These suggest that treatments for BD are less likely to be associated with Prl elevations, with valproate, quetiapine, lurasidone, mirtazapine, and bupropion reported not to change PRL levels significantly and lithium and aripiprazole to lower them in some studies. Taking into account the effects of the different classes of drugs on Prl may improve the care of BD patients requiring long-term pharmacotherapy. Based on the results of this review, lithium and valproate appear to be safer due to their low potential to elevate sPrL; among antipsychotics, quetiapine, lurasidone and aripiprazole appear to be similarly safe.

Psicoeducación, el litio de las psicoterapias Algunas consideraciones sobre su eficacia y su implementación en la práctica diaria* / Psycho-education, the Lithium of Psycho-therapies. Some Considerations Regarding its efficiency and Implementation in Daily Practice

La relación entre el médico y su paciente debe evolucionar hacia una mayor interactividad y fomentar la proactividad. Para ello, es imprescindible contar con programas de educación terapéutica de los pacientes. El pronóstico de muchas patologías no psiquiátricas (cardiopatías, enfermedades respiratorias, diabetes, asma) mejora claramente con estas intervenciones, y lo mismo ocurre con las psiquiátricas, como el trastorno bipolar. Los primeros programas psicoeducativos se centraban en la información, mientras que los actuales hacen énfasis en un enfoque más terapéutico, que incluye trabajar con el significado de la enfermedad, identificar los desencadenantes individuales y los pródromos, manejar los síntomas y superar los problemas de adherencia a los fármacos. Hoy la psicoeducación forma parte de las rutinas de tratamiento del trastorno bipolar, y encaja en su modelo médico. Así mismo, ha mostrado su eficacia en la profilaxis de todo tipo de recaídas a los dos y a los cinco años, con lo cual se ha reducido de forma notoria la duración de los episodios, las hospitalizaciones y los problemas de adherencia. Además, no pierde eficacia con el paso del tiempo, algo que sí ocurre con otras psicoterapias, y su implementación conlleva un ahorro de recursos sanitarios. No obstante, se recomienda implementar este tipo de programas lo antes posible en el curso de la enfermedad. El presente artículo presenta una serie de evidencias y reflexiones prácticas acerca de la implementación de la psicoeducación, que es a la psicoterapia del trastorno bipolar lo que el litio es a su farmacoterapia.

The physician-patient relationship must evolve towards greater interactivity and the promotion of pro-activity. For such a purpose, it is indispensable to have therapeutic educational programs for patients. Prognosis of many non-psychiatric pathologies i.e., cardiopathies, breathing diseases, diabetes, asthma) clearly improves with such programs and the same happens with psychiatric pathologies, such as bipolar disorder. The first psycho-educational programs were focused on information, while current approaches have a much more therapeutic focus, including work on the disease significance, identifying personal triggers as well as prodromes, managing symptoms and overcoming problems of adherence to pharmaceutical drugs. Today, psychoeducation is part of the routine of bipolar treatment, suitable to the physician's model. Psycho-education has likewise demonstrated its efficiency in the prophylaxis of all sorts of two and five-year relapses, remarkably reducing episode duration, hospitalizations and adherence problems. Besides, as time passes, its efficiency is maintained, something that does not occur with other sorts of psycho-therapies. Furthermore, its implementation saves health resources. However, this type of programs is recommended as soon as possible, in the course of the disease. This article introduces a series of evidences and practical considerations on the implementation of psycho-education, which in the bipolar disorder psychotherapy has the same role than lithium in pharmacotherapy.

Long-term mental health resource utilization and cost of care following group psychoeducation or unstructured group support for bipolar disorders: a cost-benefit analysis.

OBJECTIVE: To explore the short- and long-term mental health resource utilization and cost of care in a sample of 120 individuals with bipolar disorders who participated in a randomized controlled efficacy trial of group psychoeducation versus unstructured group support. METHOD: Prospective, independent monitoring of DSM-IV bipolar disorder type I or II patients aged 18 to 65 years was conducted during the intervention phase (6 months) and follow-up phase (5-year postintervention) of a randomized controlled trial reporting clinical outcomes and inpatient and outpatient mental health service utilization, with estimation of cost of treatment per patient. The study was conducted from October 1997 through October 2006. RESULTS: Compared with individuals with bipolar disorder receiving the control intervention, psychoeducated patients had twice as many planned outpatient appointments, but the estimated mean cost of emergency consultation utilization was significantly less. There were trends for psychoeducated patients to opt for self-funded psychotherapy after completing group psychoeducation and to utilize more medications. However, inpatient care accounted for 40% estimated total cost in the control group but only about 15% in the psychoeducation group. CONCLUSIONS: This study demonstrates the importance of taking a long-term overview of the cost versus benefits of adjunctive psychological therapy in bipolar disorders. If viewed only in the short-term, the psychoeducation group used more mental health care resources without clear additional health gain. However, extended follow-up demonstrated a long-term advantage for psychoeducated individuals, such that, compared to an unstructured support group intervention, group psychoeducation is less costly and more effective.

Comparison of rapid-cycling and non-rapid-cycling bipolar I manic patients during treatment with olanzapine: analysis of pooled data.

INTRODUCTION: Rapid-cycling (RC) bipolar disorder patients experience high levels of morbidity, typically respond unsatisfactorily to available treatments, and, so, require additional studies of novel treatments. We report on the first controlled study comparing acute and continuous clinical outcomes in RC and non-RC manic patients treated with olanzapine. METHOD: We analyzed data pooled from 2 placebo-controlled, double-blind, 3- to 4-week trials of olanzapine in mania (N = 254), 1 with an open-label extension up to 1 year (N = 113) and controlled supplementation with lithium or fluoxetine as needed, to compare demographic, clinical, and outcome measures between RC and non-RC subgroups of 254 DSM-IV bipolar I manic subjects. RESULTS: RC (N = 90, 35%) versus non-RC subjects (N = 164, 65%) were younger at intake (p = .02), less often psychotic (p < .0001), and more likely to have familial bipolar disorder (p < .0001), abused substances (p = .01), more previous hospitalizations (p = .004), and many more illness episodes (p < .001). In initial blinded trial outcomes, relative responses (> or = 50% improvement of mania) to olanzapine/placebo were similar in RC and non-RC subjects, though early responses to olanzapine favored RC over non-RC subjects (p = .003), and long-term outcomes favored non-RC subjects (p = .05). Fewer RC subjects achieved strictly defined initial symptomatic remission (p = .014) within a year; RC subjects were more likely to experience recurrences (p = .002), especially of depressive illness (< .001), and had more rehospitalizations (p = .01) and suicide attempts (p = .03). CONCLUSIONS: RC bipolar I patients showed major initial differences and more rapid initial clinical changes, especially toward depression, with less favorable long-term outcomes than non-RC cases during treatment with olanzapine. Inclusion of RC bipolar disorder patients can complicate therapeutic trials, but these patients require further study for differential responsiveness to innovative treatments with methods of assessing clinical response that take their mood instability into account.

Melhorando o desfecho do transtorno bipolar usando estratégias não farmacológicas: o papel da psicoeducação / Improving the outcome of bipolar disorder through non-pharmacological strategies: the role of psychoeducation

O presente artigo avalia a eficácia da psicoeducação e estratégias relacionadas nos transtornos bipolares. Vários ensaios clínicos aleatorizados demonstraram, recentemente, a eficácia de intervenções psicológicas - a saber: a identificação de sinais prodrômicos, terapia cognitivo-comportamental, psicoeducação e intervenções focadas na família - como um acréscimo profilático à medicação. Todos esses estudos são aqui apresentados, conjuntamente com os estudos pioneiros na área. Há vários tópicos que todo programa psicoeducacional deve incluir para assegurar sua utilidade e eles serão resumidos em doze pontos. Grosso modo, a psicoeducação deve conter informações gerais sobre a doença bipolar, elementos para a aumentar a adesão ao tratamento, ensinar o reconhecimento rápido de recaídas e questões sobre a regularidade do modo de vida. Hoje em dia, várias diretrizes para o tratamento incluem a psicoeducação como uma ferramenta profilática crucial. Os clínicos devem estar conscientes disso e começar a praticar a psicoeducação em sua prática clínica cotidiana.