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1.
Psychol Med ; : 1-6, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31576781

RESUMO

BACKGROUND: Group-based trajectory modeling holds promise for the study of prognostic indicators in the mood disorders because the courses that the individuals with these disorders follow are so highly variable. However, trajectory analyses of major depressive disorder have so far not included some of the more robust predictors of mood disorder outcome, nor have they described interactions between these predictors. METHODS: A group of 186 individuals aged 15-20 years with past or current depressive symptoms, who had recently begun taking a serotonin reuptake inhibitors antidepressant, underwent extensive baseline evaluations and were then followed for up to 2 years. Trajectory analyses used weekly ratings of depressive symptoms and the resulting groups were compared by the risk factors of sex, psychiatric comorbidity, negative emotionality, and childhood adversity. RESULTS: A three-group solution provided the best statistical fit to the 2-year symptom trajectory. Negative emotionality and childhood adversity, though correlated, independently predicted membership in higher-morbidity groups. Female sex and comorbidity with generalized anxiety disorder (GAD) were also significantly more likely in the trajectory groups with higher symptom levels. However, the presence of GAD, rather than female sex, was the most important determinant of group membership. Negative emotionality was predictive of group membership only among women. CONCLUSIONS: Trajectory analyses indicated that week-to-week variations in depressive symptoms across individuals could best be condensed into low, remitting and persistent symptom patterns. Female sex, anxiety symptoms, negative emotionality and childhood adversity were each independently associated with trajectories of higher morbidity but negative emotionality may be prognostically important only among women.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31131922

RESUMO

OBJECTIVE: We have previously shown that the severity of anxiety symptoms during major depressive episodes is associated in a linear fashion with the proportion of weeks in depressive episodes during a subsequent 25 years of follow-up. Here, we test whether the negative prognostic implications of anxiety comorbidity extend to higher likelihoods of suicidal behavior. METHODS: We used the NIMH Collaborative Depression Study (CDS) cohort to test both the severity of eight anxiety symptoms and the presence or absence of four anxiety disorders as risk factors for suicide attempts or completions over a mean (SD) follow-up of 16.6 (8.5) years. Separate analyses tested potential predictors of events that occurred within 2 years and those that occurred later. RESULTS: None of the baseline anxiety manifestations were significantly associated with overall risks for past or future suicide attempts. Only the diagnosis of phobic disorder was overrepresented in the 36 who committed suicide. Psychic anxiety was a risk factor for suicide attempts beyond 2 years of follow-up, and phobic anxiety was protective of suicides within this period. CONCLUSIONS: These results did not show anxiety comorbidity to be an important risk factor for suicide attempts or completions.

4.
Handb Exp Pharmacol ; 250: 3-33, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31004226

RESUMO

This section provides summaries of the epidemiology, phenomenology, nosology, and the suspected biological substrates of the depressive disorders. It particularly emphasizes the historical evolution of the pertinent diagnostic constructs and the prognostic import both of the various diagnostic groupings and of the individual symptoms and symptom clusters.


Assuntos
Transtorno Depressivo , Transtorno Depressivo/epidemiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Humanos , Síndrome
5.
J Affect Disord ; 246: 775-782, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30623823

RESUMO

OBJECTIVES: To determine whether the risk of suicidal ideation or behavior during mixed states exceeds that attributable to the depressive components of these states alone in bipolar disorder. METHODS: We utilized real-world, longitudinal clinical data collected on 290 patients with bipolar disorders (bipolar I, bipolar II, and bipolar not otherwise specified (NOS)) from the National Network of Depression Centers (NNDC) Clinical Care Registry (CCR) seen for 891 visits over a mean of 27.5 weeks. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9), manic symptoms with the Altman Self-Rating Mania (ASRM), and suicidal ideation and behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), obtained as part of the routine, measurement-based care provided across the NNDC. The relations between depressive symptoms, manic symptoms, and the interaction thereof (mixed symptoms) on coinciding suicidal ideation and behavior were modeled in generalized linear mixed models. RESULTS: Depressive symptoms, as measured by the PHQ-9, were strongly associated with suicidal ideation and behavior (p < 0.0001), while there was no significant association with manic symptoms as measured by the ASRM or the interaction between depressive and manic symptoms. Similar results were observed when the outcome was restricted to suicidal behavior and when mood was modeled categorically. There was evidence of a gender by ASRM interaction (p = 0.011) and risk of suicidal ideation or behavior was significant for women, but not men with manic symptoms. LIMITATIONS: Diagnoses were based on clinician assessment and not structured interview. Mood assessments were self-reported rather than clinician-administered. Suicidal ideation was more frequently observed than suicidal behavior (23/272 visits where outcome positive). CONCLUSIONS: Depression represents the primary mood state accounting for suicide risk in bipolar disorder. Co-occurring symptoms of mania (mixed symptoms) do not appear to convey an elevated risk for suicidal ideation or behavior beyond that explained by the depressive symptoms alone.


Assuntos
Transtorno Bipolar/psicologia , Depressão/psicologia , Ideação Suicida , Suicídio/psicologia , Adulto , Afeto , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Autorrelato , Suicídio/estatística & dados numéricos
6.
Artigo em Inglês | MEDLINE | ID: mdl-30503783

RESUMO

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.

7.
Int J Bipolar Disord ; 6(1): 24, 2018 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-30415424

RESUMO

BACKGROUND: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. RESULTS: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. CONCLUSION: Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30487653

RESUMO

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

9.
J Psychiatr Res ; 106: 38-42, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30261413

RESUMO

BACKGROUND: Increased inflammatory markers have been linked to suicidal behavior in numerous studies. Measures of aggression and of impulsivity also comprise risks factors for suicidal behavior and there is evidence that inflammatory markers correlate with these traits. The following analyses compare suicide attempters and non-attempters to determine whether inflammatory markers mediate relationships between aggression or impulsivity and proclivities to suicidal behavior. METHODS: Investigators at three academic centers recruited patients in major depressive episodes who had a history of two or more suicide attempts (n = 79), or who had no history of suicide attempts (n = 123). Analyses compared these groups by five inflammatory marker levels and by measures of aggression and of impulsivity. RESULTS: These results did not confirm the hypotheses that cytokine levels would explain relationships between aggressive behavior and suicide attempt history. However, scores for aggressive behavior and for impulsivity were significantly higher among suicide attempters. One of five of the inflammatory markers, (IL-1ß), distinguished the two groups with lower values in the suicide attempt group. IL-1ß levels correlated inversely with measures of aggression but neither impulsivity or aggressive behavior appear to explain the association between IL-1ß levels and suicide attempt status. CONCLUSION: These results identify recent aggressive behavior, higher levels of impulsivity, and lower levels of IL-1ß as risk factors for a history of multiple suicide attempts in a group suffering from major depressive episodes. These measures appear to be additive in their effects.

10.
Am J Psychiatry ; 175(9): 897-904, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29792050

RESUMO

OBJECTIVE: The authors conducted a systematic review and meta-analysis to determine whether the risk of psychosis is higher in past or future episodes in patients with major depression with psychotic features than in patients with nonpsychotic depression. METHOD: PubMed, Embase, and PsycINFO were searched, and studies were selected that 1) identified patients with unipolar major depression, 2) made diagnoses of psychosis based on the presence of delusions or hallucinations, 3) characterized past or subsequent episodes as psychotic or nonpsychotic, and 4) were published in English. Two meta-analyses were then conducted using data from patients having index depressive episodes with or without psychosis at study entry to determine the risk of any prior or subsequent psychotic episode and the risk of psychosis in all episodes. RESULTS: Twelve studies met the inclusion criteria, and altogether they included 546 psychotic and 1,583 nonpsychotic patients with unipolar depression. In seven of the studies, the risk ratio for a prior or subsequent psychotic episode in patients whose index depressive episode was psychotic compared with those whose index episode was nonpsychotic was 9.98 (95% CI=4.75, 20.94). In eight studies, the risk ratio for psychosis among all episodes of depression in the subgroups with psychotic and nonpsychotic index episodes was 7.24 (95% CI=5.03, 10.43). Differences in risk of psychosis between these subgroups remained robust when potential sources of heterogeneity were explored. CONCLUSIONS: The findings support the hypothesis that psychotic depression runs true to form, and they support the distinction between psychotic and nonpsychotic depression. Because patients with psychotic depression are at high risk for psychosis in future episodes, determination of effective preventive treatments is imperative.

11.
Bipolar Disord ; 20(1): 35-41, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28833953

RESUMO

OBJECTIVE: To assess whether suicidal behavior during mixed states exceeds that expected from the manic or depressive components alone. METHODS: This study included 429 participants with bipolar disorder from the National Institute of Mental Health Collaborative Depression Study (CDS). Mood and suicidal behavior were captured using the Longitudinal Interval Follow-up Evaluation and the Schedule of Affective Disorders and Schizophrenia. Suicidal behavior during each mood state, relative to euthymia, was analyzed using Cox regression to allow for repeated events, with a frailty term to account for intra-participant correlation. Mixed states were modeled as a depression-by-mania interaction. RESULTS: Individuals with a history of mixed states were at higher risk of suicidal behavior and spent more time depressed, compared to subjects with no such history. In bipolar I disorder, risk increased during episodes of mania (hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.28-2.99, P = .0019) and depression (HR: 5.49, 95% CI: 4.01-7.51, P < .0001) and there was a less than additive effect of mixed states. In bipolar II disorder, risk was increased during episodes of depression (HR: 3.66, 95% CI: 2.51-5.35, P < .0001) and there was no excess risk during mixed states beyond that attributable to the depressed component. Most of the excess risk (71%) among those with a history of mixed states was attributable to a depression predominant course of illness. CONCLUSIONS: Individuals with mixed states are at high risk of suicidal behavior, largely due to more time spent depressed. Clinicians should aggressively treat depression to mitigate suicide risk for patients with or without mixed states.


Assuntos
Transtorno Bipolar , Depressão , Suicídio/psicologia , Adulto , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/psicologia , Transtorno Bipolar/complicações , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Depressão/diagnóstico , Depressão/psicologia , Depressão/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Medição de Risco , Índice de Gravidade de Doença , Ideação Suicida , Suicídio/prevenção & controle
12.
J Bone Miner Res ; 32(12): 2367-2374, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28815738

RESUMO

The purpose of this study was to prospectively examine the independent contribution of major depressive disorder (MDD), generalized anxiety disorder (GAD), and selective serotonin reuptake inhibitors (SSRIs) use to changes in bone metabolism in older adolescents and emerging adults. Medically healthy 15- to 20-year-olds who were unmedicated or within 1 month of starting an SSRI were prospectively followed. Psychiatric functioning and medication treatment were assessed monthly. Every 4 months, trabecular and cortical volumetric bone mineral density (vBMD) at the radius and markers of bone metabolism were evaluated. Every 8 months, total body less head areal bone mineral content and lumbar spine (LS) areal BMD (aBMD) were determined. Linear mixed-effects regression analysis examined associations between bone measures on the one hand and MDD, GAD, and SSRI indices on the other. A total of 264 participants were followed for 1.51 ± 0.76 years. After adjusting for age, sex, vitamin D concentration, physical activity, lean mass or grip strength, and time in the study, MDD severity was associated with increasing LS aBMD. Similarly, SSRI use was associated with increasing LS aBMD and bone formation in female participants. In contrast, SSRI use was associated with decreasing LS aBMD in males. After accounting for depression, GAD was independently, albeit weakly, associated with increased bone mineralization. In older adolescents and emerging adults, MDD and GAD are associated with increasing bone mass, particularly in the lumbar spine and in females, whereas SSRIs are associated with increasing bone mass in females but decreasing bone mass in males. © 2017 American Society for Bone and Mineral Research.


Assuntos
Ansiedade/tratamento farmacológico , Osso e Ossos/metabolismo , Depressão/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Adulto , Ansiedade/complicações , Osso e Ossos/efeitos dos fármacos , Demografia , Depressão/complicações , Feminino , Humanos , Modelos Lineares , Masculino , Inibidores de Captação de Serotonina/farmacologia , Caracteres Sexuais , Adulto Jovem
13.
Pediatrics ; 140(1)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28759400

RESUMO

OBJECTIVES: To examine the independent contribution of major depressive disorder (MDD), generalized anxiety disorder (GAD), and selective serotonin reuptake inhibitors (SSRIs) to changes in body composition in older adolescents. METHODS: Medically healthy 15- to 20-year-olds who were unmedicated or within 1 month of starting an SSRI were prospectively followed. Psychiatric functioning and medication treatment were assessed monthly. Body Mass Index (BMI) was measured every 4 months. Every 8 months, a whole-body dual-energy radiograph absorptiometry scan was obtained to determine lean BMI, fat mass index, and visceral fat mass. Linear mixed effects regression analysis examined associations between MDD, GAD, and SSRI use variables and body composition measures. RESULTS: Over 1.51 ± 0.76 years of follow-up, 264 participants contributed 805 observations. After adjusting for age, sex, physical activity, dietary intake, and time in the study, MDD severity was inversely associated, prospectively, with BMI, fat mass index, and lean BMI z scores, whereas cumulative SSRI treatment duration and dose were positively associated with these outcomes. GAD severity and diagnosis were not significantly associated with any body composition outcome. Moreover, citalopram and escitalopram were most strongly associated with the increase in all body composition measures, including visceral fat mass, whereas the associations with fluoxetine were somewhat weaker. Sertraline was not different from no SSRI treatment. CONCLUSIONS: Depression severity was associated with a decrease in measures of body composition in older adolescents over a mean of 1.5 years, whereas SSRI treatment was positively associated with these outcomes, with differential effects across treatment groups.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Composição Corporal/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacologia , Adolescente , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Inibidores de Captação de Serotonina/uso terapêutico , Adulto Jovem
14.
Psychiatry Res ; 256: 305-311, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28666200

RESUMO

Childhood experiences, personality, and polyunsaturated essential fatty acid (PUFA) composition have all been shown to affect the likelihood of depressive symptoms. Few studies have addressed relationships between these factors in their influence on the occurrence or course of depressive symptoms. The following analysis was designed to do so. Subjects, 15-20 years old, had either begun antidepressant treatment within the preceding month (n = 88), or had never taken psychiatric medications (n = 92). Baseline assessments included a structured diagnostic interview, the self-completed Multiphasic Personality Questionnaire, and a determination of plasma PUFA phospholipid composition. Depressive symptom levels were assessed at baseline and again at 4, 8 and 12 months. Omega-3 composition and general childhood trauma scores were unrelated to each other but both correlated, in predicted directions, with negative emotionality. Low omega-3 composition and history of childhood trauma were associated with persistence of depressive symptoms during follow-up, largely through their effects on negative emotionality. Negative emotionality appears to comprise a final common pathway to depressive disorder through which the diverse risk factors of childhood adversity and low omega-3 composition are expressed.


Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Depressão/sangue , Depressão/psicologia , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Insaturados/sangue , Adolescente , Emoções , Feminino , Seguimentos , Humanos , Masculino , Adulto Jovem
15.
Psychiatry Res ; 256: 162-168, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28645075

RESUMO

Pathological gambling (PG) is a common and costly public health problem associated with impaired quality of life and high suicide rates. Despite its frequency in the general population, PG course is poorly understood in older adults who are especially vulnerable to its devastating consequences. We enrolled 175 subjects in a longitudinal study of gambling behavior: our case group of 53 older adults with PG (≥ 60 years), and two comparison groups including 72 younger adults with PG (< 40 years) and 50 older adults without PG (≥ 60 years). Subjects with PG met lifetime criteria for DSM-IV PG and had a South Oaks Gambling Screen (SOGS) and National Opinion Research Center DSM Screen for Gambling Problems (NODS) scores ≥ 5. Subjects were evaluated at intake and reassessed every 6 months and drop outs were replaced. Follow-up lasted a mean (SD) of 2.6 (1.4) years. At intake older PGs were more likely to be female, Caucasian, divorced, and to have a lower level of education. Older and younger PGs were similar in gambling severity, but older PGs were more likely to have sought PG treatment. Older PGs had lower rates of lifetime drug use disorders, attention deficit/hyperactivity disorder, and obsessive-compulsive disorder. They preferred slots, were more likely to receive PG treatment, and were less likely to discontinue participation in the study. Week by week gambling activity levels showed a significant general downward movement for older and younger PGs, although there were no differences between the groups. Elders without PG had no change in their level of gambling activity. We conclude that younger and older PGs moved toward a reduced level of gambling activity during follow-up. Our data challenge the notion that PG is chronic and progressive.


Assuntos
Jogo de Azar/diagnóstico , Qualidade de Vida/psicologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Feminino , Seguimentos , Jogo de Azar/complicações , Jogo de Azar/psicologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem
16.
Hum Mol Genet ; 25(15): 3383-3394, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27329760

RESUMO

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.

17.
BMC Psychiatry ; 16: 129, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27150464

RESUMO

BACKGROUND: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. METHODS/DESIGN: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response. DISCUSSION: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Compostos de Lítio/uso terapêutico , Idoso , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Estudos Prospectivos , Estudos Retrospectivos , Prevenção Secundária , Ácido Valproico/uso terapêutico
18.
Bipolar Disord ; 18(4): 352-62, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27237705

RESUMO

OBJECTIVES: Patients diagnosed with bipolar disorder (BP) may experience hippocampal atrophy. Lithium exposure has been associated with increased hippocampal volumes. However, its effects on hippocampal subfields remain to be clarified. METHODS: We investigated the effects of short- and long-term lithium exposure on the hippocampus and its subfields in patients affected by bipolar I disorder (BP-I). Hippocampal subfields and total hippocampal volumes were measured in 60 subjects divided into four groups: 15 patients with BP-I who were never exposed to lithium [no-exposure group (NE)], 15 patients with BP-I exposed to lithium for < 24 months [short-exposure group (SE)], 15 patients with BP-I exposed to lithium for > 24 months [long-exposure group (LE)], and 15 healthy control subjects (HC). RESULTS: The SE and NE groups showed smaller total hippocampal volumes and smaller bilateral cornu ammonis CA2-3, CA4-dentate gyrus (DG), presubiculum, and subiculum volumes compared with HC. The LE group showed larger total hippocampal volumes and bilateral CA2-3, left CA4-DG, left presubiculum, and right subiculum volumes compared with the NE group, and larger volumes of the right CA2-3, left CA4-DG, left presubiculum, and right subiculum compared with the SE group. No differences were found between the LE group and HC or between the SE and NE groups. CONCLUSIONS: Long-term, but not short-term, exposure to lithium treatment may exert neuroprotective effects on specific hippocampal subfields linked to disease progression.


Assuntos
Transtorno Bipolar , Hipocampo , Lítio , Adulto , Atrofia , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Progressão da Doença , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Lítio/administração & dosagem , Lítio/farmacocinética , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacocinética , Tamanho do Órgão/efeitos dos fármacos , Testes Psicológicos , Tempo
20.
Arch Suicide Res ; 20(4): 605-13, 2016 Oct-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27045220

RESUMO

Latent infection with toxoplasmosis is a prevalent condition that has been linked in animal studies to high-risk behaviors, and in humans, to suicide and suicide attempts. This analysis investigated a relationship between suicide attempt history and toxoplasmosis titers in a group of older adolescents who had recently begun treatment with an SSRI. Of 108 participants, 17 (15.7 %) had a lifetime history of at least one suicide attempt. All were given structured and unstructured diagnostic interviews and provided blood samples. Two individuals (11.9%) with a past suicide attempt, and two (2.1%) without this history, had toxoplasmosis titers ≥ 10 IU/ml (p = 0.166). Those with a past suicide attempt had mean toxoplasmosis titers that were significantly different (p = 0.018) from those of patients who lacked this history. An ROC analysis suggested a lower optimal threshold for distinguishing patients with and without suicide attempts (3.6 IU/ml) than that customarily used to identify seropositivity. Toxoplasmosis titers may quantify a proneness to suicidal behavior in younger individuals being treated with antidepressants.


Assuntos
Inibidores de Captação de Serotonina/uso terapêutico , Tentativa de Suicídio , Toxoplasma/isolamento & purificação , Toxoplasmose , Adolescente , Infecções Assintomáticas , Feminino , Humanos , Entrevista Psicológica/métodos , Masculino , Curva ROC , Fatores de Risco , Testes Sorológicos/métodos , Testes Sorológicos/estatística & dados numéricos , Tentativa de Suicídio/prevenção & controle , Tentativa de Suicídio/estatística & dados numéricos , Toxoplasmose/sangue , Toxoplasmose/diagnóstico , Toxoplasmose/epidemiologia , Toxoplasmose/psicologia
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