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1.
JAMA Psychiatry ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31532468

RESUMO

Importance: Infection-associated immune activation and inflammation are increasingly recognized in the pathophysiology of bipolar disorder. Objective: To determine whether antibodies to common infectious agents, including cytomegalovirus (CMV), Toxoplasma gondii, and measles, as well as the inflammatory marker C-reactive protein, in serum samples differ between patients with bipolar disorder and control individuals without bipolar disorder. Design, Setting, and Participants: In this case-control study, antibody titers were measured in serum samples from 1207 patients with bipolar disorder and 745 controls that were obtained from biobanks with participating sites in Rochester and Minneapolis, Minnesota (n = 1537), and Cincinnati, Ohio (n = 415), from January 5, 2009, through May 12, 2014. A subset of case patients and controls from Minnesota were matched by age, sex, and educational level. Bipolar type, age at onset, and history of psychosis were assessed for case patients as well as current drug treatment at the time of blood sample obtainment from the biobank. Data were analyzed from February 5, 2018, to January 4, 2019. Exposures: The CMV and T gondii antibodies with IgM titers were expressed as z scores and IgG titers dichotomized into seropositive and seronegative based on expected prevalence in the US population and further classified based on the joint CMV-positive/T gondii-negative IgG status, C-reactive protein z score, and drug treatments with antitoxoplasma activity. Main Outcomes and Measures: Patients were stratified by bipolar disorder type I or type II, nonearly (>19 years of age) and early (≤19 years of age) onset, and history of psychosis during mania or no psychosis. Results: Of 1207 patients with bipolar disorder (mean [SD] age, 43.2 [15.1] years; 742 [61.5%] female), the CMV-positive/T gondii-negative IgG status was significantly higher (odds ratio [OR], 1.33; 95% CI, 1.09-1.62; P = .004) compared with that in the 745 controls (mean [SD] age, 44.5 [15.5] years; 444 [59.6%] female). The CMV-positive/T gondii-negative IgG status was associated with bipolar cases type I (OR, 1.41; 95% CI, 1.14-1.75; P = .001), nonearly age at onset (OR, 1.41; 95% CI, 1.16-1.72; P = .001), and history of manic psychosis (OR, 1.46; 95% CI, 1.13-1.88; P = .004). Patients with bipolar disorder who received drug treatment with antitoxoplasma activity (n = 272) had significantly lower T gondii IgM titers (median, 1.59; interquartile range, 1.30-2.07) compared with those (n = 900) who did not receive this treatment (median, 1.69; interquartile range, 1.35-2.25) (P = .03). Conclusions and Relevance: In this sample, increased long-term antibody response to CMV and decreased long-term antibody response to T gondii were associated with bipolar disorder and the subphenotypes of bipolar type I, nonearly disease onset, and manic psychosis. Further work appears to be needed to better understand genetic vs environmental disease risk and infection or immune activation contribution to overall disease pathogenesis with particular reference to disease onset.

2.
Transl Psychiatry ; 9(1): 149, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123248

RESUMO

Glutamatergic dysregulation is implicated in the neurobiology of mood disorders. This study investigated the relationship between the anterior cingulate cortex (AC) glutamate, as measured by proton magnetic resonance spectroscopy (1H-MRS), and single-nucleotide polymorphisms (SNPs) from four genes (GLUL, SLC1A3, SLC1A2, and SLC1A7) that regulate the extracellular glutamate in 26 depressed patients with major depressive disorder (MDD; n = 15) and bipolar disorder (BD; n = 11). Two SNPs (rs3812778 and rs3829280), in perfect linkage disequilibrium, in the 3' untranslated region of the EAAT2 gene SLC1A2, were associated with AC glutamate, with minor allele carriers having significantly higher glutamate levels (p < 0.001) in comparison with common allele homozygotes. In silico analysis revealed an association of minor allele carriers of rs3812778/rs382920 with an upregulation of the astrocytic marker CD44 localized downstream of SLC1A2 on chromosome 11. Finally, we tested the disease relevance of these SNPs in a large group of depressed patients [MDD (n = 458); BD (n = 1473)] and found that minor allele carriers had a significantly higher risk for rapid cycling (p = 0.006). Further work is encouraged to delineate the functional impact of excitatory amino acid transporter genetic variation on CD44 associated physiology and glutamatergic neurotransmission, specifically glutamate-glutamine cycling, and its contribution to subphenotypes of mood disorders.

3.
Aust N Z J Psychiatry ; : 4867418808382, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30378461

RESUMO

OBJECTIVE:: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD:: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS:: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION:: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

4.
Bipolar Disord ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30422375

RESUMO

OBJECTIVES: A sizable fraction of people with bipolar I disorder (BDI) experience a deteriorating clinical course with increasingly frequent mood episodes and chronic disability. This is believed to result from neurobiological illness progression, or neuroprogression. Excessive weight gain predicts neuroprogression across multiple brain illnesses, but no prospective studies have investigated this in BDI. The objective of this study was to determine whether BDI patients who experienced clinically significant weight gain (CSWG; gaining ≥7% of baseline weight) over 12 months had greater 12-month brain volume loss in frontal and temporal regions important to BDI. METHODS: In 55 early-stage BDI patients we measured (i) rates of CSWG, (ii) the number of days with mood symptoms, using NIMH LifeCharts, and (iii) baseline and 12-month brain volumes, using 3T MRI. We quantified brain volumes using the longitudinal processing stream in FreeSurfer v6.0. We used general linear models for repeated measures to investigate whether CSWG predicted volume loss, adjusting for potentially confounding clinical and treatment variables. RESULTS: After correction for multiple comparisons, CSWG in patients predicted greater volume loss in the left orbitofrontal cortex (effect size [ES; Cohen's d] = -1.01, P = 0.002), left cingulate gyrus (ES = -1.31, P < 0.001), and left middle temporal gyrus (ES = -0.96, P = 0.004). Middle temporal volume loss predicted more days with depression (ß = -0.406, P = 0.010). CONCLUSIONS: These are the first prospective data on weight gain and neuroprogression in BDI. CSWG predicted neuroprogression, and neuroprogression predicted a worse clinical illness course. Trials of weight loss interventions are needed to confirm the causal direction of the weight gain-neuroprogression relationship, and to determine whether weight loss is a disease-modifying treatment.

5.
J Affect Disord ; 245: 679-685, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30447566

RESUMO

BACKGROUND: Increased circulating inflammatory cytokines is a replicated finding in bipolar I disorder (BDI). Pro-inflammatory cytokines such as TNFα, IL-6 and IL-1 have also been associated with poorer cognitive functioning in patients with longer illness duration. However, the effect of inflammatory cytokines on cognition in early stage patients is not yet known. Here, we investigate the relationship between cytokines and cognition in BDI patients within three years of diagnosis. METHODS: Serum pro-inflammatory (TNFα, IL-6 and IL-1α) and anti-inflammatory (IL-4 and IL-10) cytokine levels were compared between 51 early stage BDI patients and 20 healthy controls. 46 patients completed neuropsychological testing, and multiple regression analysis was used to assess the association between cytokine levels and cognition after accounting for relevant clinical and demographic variables. RESULTS: TNFα was elevated at trend level significance in BDI patients compared to healthy controls, and was negatively associated with global cognition, processing speed, and working memory in patients. IL-6, IL-1α, IL-4 and IL-10 levels were comparable between groups and were not significantly associated with cognition. LIMITATIONS: Direct causation cannot be established in this cross-sectional study; in addition, cytokine levels were not taken on the same day as neuropsychological testing for all patients. CONCLUSIONS: TNFα may negatively impact cognition in early BDI. While replication is required in larger samples, these results suggest that inhibition of TNFα activity might be a strategy to preserve cognition in newly diagnosed BDI patients.

7.
Transl Psychiatry ; 8(1): 188, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30201969

RESUMO

Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke's R2 = 0.021; p = 0.045), BD-I cases without psychosis (R2 = 0.015; p = 0.007), BD-II cases without psychosis (R2 = 0.014; p = 0.017), and controls (R2 = 0.065; p = 2 × 10-13). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system.

8.
Nat Commun ; 9(1): 2343, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29904055

RESUMO

Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.

9.
Bipolar Disord ; 20(2): 97-170, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29536616

RESUMO

The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

10.
Int J Neuropsychopharmacol ; 21(2): 108-113, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29016993

RESUMO

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods: In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results: Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.

11.
J Psychiatr Res ; 95: 208-212, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28886448

RESUMO

In a prior discovery study, increased levels of serum Growth Differentiation Factor 15 (GDF15), Hepsin (HPN), and Matrix Metalloproteinase-7 (MMP7) were observed in bipolar depressed patients vs controls. This exploratory post-hoc analysis applied a proteomic-informed genomic research strategy to study the potential functional role of these proteins in bipolar disorder (BP). Utilizing the Genotype-Tissue Expression (GTEx) database to identify cis-acting blood expression quantitative trait loci (cis-eQTLs), five eQTL variants from the HPN gene were analyzed for association with BP cases using genotype data of cases from the discovery study (n = 58) versus healthy controls (n = 777). After adjusting for relevant covariates, we analyzed the relationship between these 5 cis-eQTLs and HPN serum level in the BP cases. All 5 cis-eQTL minor alleles were significantly more frequent in BP cases vs controls [(rs62122114, OR = 1.6, p = 0.02), (rs67003112, OR = 1.6, p = 0.02), (rs4997929, OR = 1.7, p = 0.01), (rs12610663, OR = 1.7, p = 0.01), (rs62122148, OR = 1.7, P = 0.01)]. The minor allele (A) in rs62122114 was significantly associated with increased serum HPN level in BP cases (Beta = 0.12, P = 0.049). However, this same minor allele was associated with reduced gene expression in GTEx controls. These exploratory analyses suggest that genetic variation in/near the gene encoding for hepsin protein may influence risk of bipolar disorder. This genetic variation, at least for the rs62122114-A allele, may have functional impact (i.e. differential expression) as evidenced by serum HPN protein expression. Although limited by small sample size, this study highlights the merits of proteomic informed functional genomic studies as a tool to investigate with greater precision the genetic risk of bipolar disorder and secondary relationships to protein expression recognizing, and encouraging in subsequent studies, high likelihood of epigenetic modification of genetic disease risk.


Assuntos
Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Proteômica/métodos , Locos de Características Quantitativas/genética , Serina Endopeptidases/sangue , Serina Endopeptidases/genética , Bases de Dados Genéticas , Humanos
12.
Clin Schizophr Relat Psychoses ; 11(2): 103-112, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28742394

RESUMO

The diagnoses of serious psychiatric illnesses, such as schizophrenia, schizoaffective disorder, and bipolar disorder, rely on the subjective recall and interpretation of often overlapping symptoms, and are not based on the objective pathophysiology of the illnesses. The subjectivity of symptom reporting and interpretation contributes to the delay of accurate diagnoses and limits effective treatment of these illnesses. Proteomics, the study of the types and quantities of proteins an organism produces, may offer an objective biological approach to psychiatric diagnosis. For this pilot study, we used the Myriad RBM Discovery Map 250+ platform to quantify 205 serum proteins in subjects with schizophrenia (n=26), schizoaffective disorder (n=20), bipolar disorder (n=16), and healthy controls with no psychiatric illness (n=23). Fifty-seven analytes that differed significantly between groups were used for multivariate modeling with linear discriminant analysis (LDA). Diagnoses generated from these models were compared to SCID-generated clinical diagnoses to determine whether the proteomic markers: 1) distinguished the three disorders from controls, and 2) distinguished between the three disorders. We found that a series of binary classification models including 8-12 analytes produced separation between all subjects and controls, and between each diagnostic group and controls. There was a high degree of accuracy in the separations, with training areas-under-the-curve (AUC) of 0.94-1.0, and cross-validation AUC of 0.94-0.95. Models with 7-14 analytes produced separation between the diagnostic groups, though less robustly, with training AUC of 0.72-1.0 and validation AUC of 0.69-0.89. While based on a small sample size, not adjusted for medication state, these preliminary results support the potential of proteomics as a diagnostic aid in psychiatry. The separation of schizophrenia, schizoaffective disorder, and bipolar disorder suggests that further work in this area is warranted.


Assuntos
Transtorno Bipolar/metabolismo , Proteínas/metabolismo , Transtornos Psicóticos/metabolismo , Esquizofrenia/metabolismo , Adolescente , Adulto , Área Sob a Curva , Estudos de Casos e Controles , Análise Discriminante , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Proteômica , Reprodutibilidade dos Testes , Adulto Jovem
13.
Br J Psychiatry ; 210(6): 403-407, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28385704

RESUMO

BackgroundKetamine has emerged as a novel therapeutic agent for major depressive episodes, spurring interest in its potential to augment electroconvulsive therapy (ECT).AimsWe sought to update our preliminary systematic review and meta-analysis, focusing on randomised controlled trials (RCTs) involving an index course of ECT, and testing the hypothesis that lack of efficacy is due to barbiturate anaesthetic co-administration.MethodWe searched EMBASE, CENTRAL and Medline to identify RCTs examining the efficacy of ketamine during a course of ECT. Data were synthesised from ten trials (ketamine group n = 333, comparator group n = 269) using pooled random effects models.ResultsElectroconvulsive therapy with ketamine was not associated with greater improvements in depressive symptoms or higher rates of clinical response or remission, nor did it result in pro-cognitive effects. This held true when limiting analysis to trials without barbiturate anaesthetic co-administration. Increased rates of confusion were reported.ConclusionsOverall, our analyses do not support using ketamine over other induction agents in ECT.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia , Ketamina/uso terapêutico , Terapia Combinada , Confusão/induzido quimicamente , Humanos , Ketamina/efeitos adversos
14.
Aust N Z J Psychiatry ; 51(1): 65-74, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26792829

RESUMO

OBJECTIVE: Previous studies reported decreased N-acetyl aspartate and increased Glx (the sum of glutamate plus glutamine) in bipolar disorder. Since these studies included patients at different stages of illness, it is unknown whether these changes have a causal role or a consequence of multiple episodes and treatments. The studies in early-stage bipolar disorder patients have the potential to provide answers to these issues. Therefore, we evaluated N-acetyl aspartate and Glx levels in hippocampi of first-episode bipolar disorder patients and health subjects at baseline and at 12 months, and examined the impact of episode recurrence on these measures. METHOD: We used single-voxel proton magnetic resonance spectroscopy to compare the hippocampal neurometabolites ( N-acetyl aspartate and Glx) levels between 41 patients with bipolar disorder following recovery from their first-manic episode and 27 matched healthy subjects at recruitment and 12 months later. We also compared N-acetyl aspartate and Glx levels between patients who had a recurrence of a mood episode and those who did not. RESULTS: There was no main effect of either group (diagnosis) or time for hippocampal N-acetyl aspartate and Glx levels in bipolar disorder patients and healthy subjects. We also did not find any group-by-time interaction for the levels of these metabolites. There were also no differences in N-acetyl aspartate and Glx between patients who experienced a recurrence of a mood episode and those who did not over 12-month follow-up. CONCLUSION: Our data suggest that N-acetyl aspartate and Glx levels are not altered in early stage bipolar disorder. Further, these data suggest that episode recurrence in early stages does not have a significant impact on the levels of these metabolites. These may suggest that there may be an early window for intervention to potentially arrest neuroprogression of the disease.


Assuntos
Ácido Aspártico/análogos & derivados , Transtorno Bipolar/metabolismo , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Hipocampo/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adulto , Ácido Aspártico/metabolismo , Feminino , Humanos , Masculino , Estudos Prospectivos , Adulto Jovem
15.
J Clin Psychiatry ; 78(4): 441-448, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27780338

RESUMO

OBJECTIVE: There is a bidirectional relationship between obesity and mood disorders, with each increasing the risk of developing the other. This relationship suggests that they have overlapping pathophysiologic mechanisms. Adipose tissue-derived hormones, or adipokines, regulate appetite and metabolism and have activity in limbic brain regions, making them potential shared etiologic factors between elevated body mass index (BMI) and mood disorders. However, the precise relationships between BMI, mood, and adipokines are unknown. METHODS: We measured the serum levels of adiponectin, lipocalin-2, resistin, adipsin, and leptin in 53 people with early-stage DSM-IV-defined bipolar disorder, diagnosed with the Mini-International Neuropsychiatric Interview, and 22 healthy comparison subjects. Participants were followed at the University of British Columbia Mood Disorders Centre between June 2004 and June 2012. We were primarily interested in determining, in patients, (1) whether BMI and recent mood episodes predicted adipokine levels and (2) whether adipokine levels in turn predicted subsequent mood relapses and change in BMI. RESULTS: Using linear regression, we found that (1) past-6-month mood episodes predicted lower adiponectin (ß = -0.385, P = .04) and adipsin (ß = -0.376, P = .03) levels and higher lipocalin-2 levels (ß = 0.411, P = .03), (2) BMI did not predict adipokine levels, and (3) treatment with second-generation antipsychotics was associated with higher resistin levels (ß = 0.482, P < .01). Furthermore, lower adiponectin (ß = -0.353, P = .01) and leptin (ß = -0.332, P = .02) levels predicted depressive relapse over 12 months, while higher adipsin (ß = 0.496, P < .01) and leptin (ß = 0.421, P < .01) levels predicted BMI gain. CONCLUSIONS: Our results suggest that mood episodes and medication treatment contribute to adipokine abnormalities in bipolar disorder and that adipokines influence psychiatric illness course and BMI change. Adipokines may represent a novel pathophysiologic mechanism linking elevated BMI and mood disorders and deserve further study as potential mood-regulating molecules.


Assuntos
Adipocinas/sangue , Afeto/fisiologia , Transtorno Bipolar/sangue , Transtorno Bipolar/fisiopatologia , Índice de Massa Corporal , Adolescente , Adulto , Transtorno Bipolar/tratamento farmacológico , Feminino , Humanos , Estudos Longitudinais , Masculino , Recidiva , Adulto Jovem
16.
J Affect Disord ; 208: 291-297, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27794253

RESUMO

BACKGROUND: Overweight/obesity is common in patients with bipolar disorder (BD). However, little is known about longitudinal trends in body mass index (BMI) in patients with BD. Furthermore, most studies on the association between BMI and clinical outcomes are restricted by retrospective and cross-sectional designs. This study uses prospectively-gathered data from a first episode mania (FEM) cohort to examine the trajectories of BMI change and analyze their association with clinical outcomes during a 3-year period. METHODS: A total of 110 FEM patients receiving maintenance treatment and 57 healthy subjects were included. The comparisons of BMI trajectories were examined using linear mixed-effects models. The effects of BMI on time to any mood episode were assessed by Cox proportional-hazards models. RESULTS: The estimated mean BMI in FEM patients significantly increased from 24.0kg/m2 to 25.4kg/m2 within 6 months. FEM patients had a significant BMI increase trend over the entire 3 years follow-up, which was not observed in the control group. No significant difference in BMI trajectory between patient subgroups (baseline normal-weight vs. overweight/obese; male vs. female) was observed. BMI increase predicted an increased risk of recurrence during follow-up visits (HR=1.50, 95% CI: 1.06-2.13; p=0.02). LIMITATIONS: Naturalistic design does not allow the accurate assessments of the impact of pharmacologic treatments on BMI. CONCLUSIONS: FEM patients showed a significantly increased BMI trajectory compared to healthy subjects. Furthermore, BMI increase is independently associated with an increased risk of recurrence to a new mood episode during 3-year follow-up. Thus, weight control prevention is needed in the early course of BD.


Assuntos
Transtorno Bipolar/fisiopatologia , Índice de Massa Corporal , Peso Corporal/fisiologia , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Adolescente , Adulto , Transtorno Bipolar/complicações , Transtorno Bipolar/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Obesidade/complicações , Sobrepeso/complicações , Recidiva , Fatores Sexuais , Adulto Jovem
17.
Bipolar Disord ; 18(6): 511-519, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27759214

RESUMO

OBJECTIVES: Bipolar I disorder (BD-I) is associated with gray matter volume (GMV) alterations in neural regions important for emotional regulation. Reductions found in patients with multiple episodes are not seen at illness onset, suggesting that changes occur with illness progression, although no prospective studies to date have examined this. In the present study, we assessed GMV at baseline and one year following a first manic episode, examining the impact of episode recurrence on the trajectory of change. METHODS: A total of 41 recently remitted first manic episode patients with BD-I and 25 healthy subjects (HS) underwent 3T magnetic resonance imaging at baseline and one year later. Using voxel-based morphometry, we compared GMV change between HS, patients who experienced a recurrence of a mood episode (BDrecurr ), and patients in sustained remission (BDwell ). RESULTS: The GMV change from baseline to one year did not differ significantly between HS and the full BD-I group or BDwell and HS. However, the BDrecurr group had greater GMV loss than HS in left frontal and bilateral temporal regions, and BDwell patients involving bilateral frontal, temporal and left parietal regions. CONCLUSIONS: GMV change early in the course of BD-I is associated with clinical outcome, such that neuroprogression found in patients who experience a recurrence of a mood episode is not seen in those with sustained remission. These findings have important implications for the treatment of BD-I as they suggest that prevention of recurrence might minimize neuroprogression of the disease, possibly requiring a multipronged early intervention approach to achieve this goal.


Assuntos
Transtorno Bipolar , Emoções/fisiologia , Substância Cinzenta , Adulto , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , Progressão da Doença , Cuidado Periódico , Feminino , Seguimentos , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Tamanho do Órgão , Estudos Prospectivos , Prevenção Secundária/métodos
18.
J Affect Disord ; 201: 95-8, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27195513

RESUMO

OBJECTIVE: To determine whether bipolar spectrum disorder with binge eating behavior (BE) is an important clinical sub-phenotype. METHODS: Prevalence rates and correlates of different levels of BE were assessed in 1114 bipolar spectrum patients participating in a genetic biobank. BE and eating disorders (EDs) were assessed with the Eating Disorder Diagnostic Scale (EDDS). Psychiatric illness burden was evaluated with measures of suicidality, psychosis, mood instability, anxiety disorder comorbidity, and substance abuse comorbidity. Medical illness burden was evaluated with body mass index (BMI) and the Cumulative Index Rating Scale (CIRS). RESULTS: Thirty percent of patients had any BE and 27% had BE plus an ED diagnosis. Compared with bipolar spectrum patients without BE, bipolar spectrum patients with BE were younger and more likely to be female; had significantly higher levels of eating psychopathology, suicidality, mood instability, and anxiety disorder comorbidity; had a significantly higher mean BMI and a significantly higher rate of obesity; and had a significantly higher medical illness burden. Bipolar spectrum patients with BE but no ED diagnosis were more similar to bipolar spectrum patients without BE than to those with an ED. Nonetheless, the positive predictive value and specificity of BE predicting an ED was 0.90 and 0.96, respectively. LIMITATIONS: As only two patients had co-occurring anorexia nervosa, these results may not generalize to bipolar spectrum patients with restricting EDs. CONCLUSION: Bipolar spectrum disorder with broadly-defined BE may not be as clinically relevant a sub-phenotype as bipolar spectrum disorder with an ED but may be an adequate proxy for the latter when phenotyping large samples of individuals.


Assuntos
Transtorno da Compulsão Alimentar/diagnóstico , Transtorno Bipolar/diagnóstico , Adulto , Transtornos de Ansiedade/epidemiologia , Transtorno da Compulsão Alimentar/epidemiologia , Transtorno da Compulsão Alimentar/psicologia , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/psicologia , Índice de Massa Corporal , Comorbidade , Efeitos Psicossociais da Doença , Comportamento Alimentar/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/psicologia , Prevalência , Inquéritos e Questionários
19.
Bipolar Disord ; 18(3): 205-20, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27112231

RESUMO

OBJECTIVES: Approximately 3.5 million Americans will experience a manic episode during their lifetimes. The most common causes are psychiatric illnesses such as bipolar I disorder and schizoaffective disorder, but mania can also occur secondary to neurological illnesses, brain injury, or neurosurgical procedures. METHODS: For this narrative review, we searched Medline for articles on the association of mania with stroke, brain tumors, traumatic brain injury, multiple sclerosis, neurodegenerative disorders, epilepsy, and neurosurgical interventions. We discuss the epidemiology, features, and treatment of these cases. We also review the anatomy of the lesions, in light of what is known about the neurobiology of bipolar disorder. RESULTS: The prevalence of mania in patients with brain lesions varies widely by condition, from <2% in stroke to 31% in basal ganglia calcification. Mania occurs most commonly with lesions affecting frontal, temporal, and subcortical limbic brain areas. Right-sided lesions causing hypo-functionality or disconnection (e.g., stroke; neoplasms) and left-sided excitatory lesions (e.g., epileptogenic foci) are frequently observed. CONCLUSIONS: Secondary mania should be suspected in patients with neurological deficits, histories atypical for classic bipolar disorder, and first manic episodes after the age of 40 years. Treatment with antimanic medications, along with specific treatment for the underlying neurologic condition, is typically required. Typical lesion locations fit with current models of bipolar disorder, which implicate hyperactivity of left-hemisphere reward-processing brain areas and hypoactivity of bilateral prefrontal emotion-modulating regions. Lesion studies complement these models by suggesting that right-hemisphere limbic-brain hypoactivity, or a left/right imbalance, may be relevant to the pathophysiology of mania.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/fisiopatologia , Encefalopatias/complicações , Encefalopatias/fisiopatologia , Lesões Encefálicas/complicações , Lesões Encefálicas/fisiopatologia , Antimaníacos , Transtorno Bipolar/psicologia , Encéfalo/fisiopatologia , Encefalopatias/diagnóstico , Encefalopatias/psicologia , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/psicologia , Mapeamento Encefálico , Diagnóstico Diferencial , Feminino , Humanos , Masculino
20.
Psychoneuroendocrinology ; 65: 76-83, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26731572

RESUMO

Bipolar I disorder (BD) is associated with increased inflammation, which is believed to be central to disease etiology and progression. However, BD patients also have high rates of obesity, itself an inflammatory condition, and the relative contributions of mood illness and obesity to inflammation are unknown. Moreover, the impact of inflammation on clinical illness course has not been well studied. The objectives of this analysis were therefore: (1) to determine if inflammation in BD is mood illness-related or secondary to elevated body mass index (BMI), and (2) to investigate the impact of inflammation on prospectively-ascertained relapse into depression and mania. We measured the serum levels of 7 inflammatory cytokines (TNF-α, γ-interferon, monocyte chemoattractant protein-1 [MCP-1], IL-1α, IL-2, IL-6, and IL-8) and 2 anti-inflammatory cytokines (IL-4 and IL-10) in 52 early-stage BD patients and 22 healthy subjects. In patients, a multivariate multiple regression model that controlled for psychotropic medications found that higher BMI, but not recent (past-6-month) mood episodes, predicted greater inflammatory cytokines (p=.05). Healthy subjects also had a BMI-related increase in inflammatory cytokines (p<.01), but it was counter-balanced by a compensatory increase in anti-inflammatory cytokines (p=.02), reducing their total inflammatory burden from higher BMI. In patients, linear regression showed that two inflammatory cytokines predicted depressive relapse in the 12 months after cytokine measurement: IL-1α (p<.01) and MCP-1 (p<.01). These results suggest that elevated BMI is a significant contributor to inflammation in BD, more so even than recent mood illness severity. They also point to inflammation as an important predictor of illness course, particularly depressive relapse.


Assuntos
Transtorno Bipolar/imunologia , Transtorno Depressivo/imunologia , Inflamação/psicologia , Afeto/fisiologia , Transtorno Bipolar/sangue , Transtorno Bipolar/patologia , Transtorno Bipolar/psicologia , Índice de Massa Corporal , Estudos de Casos e Controles , Citocinas/sangue , Citocinas/imunologia , Transtorno Depressivo/sangue , Transtorno Depressivo/patologia , Transtorno Depressivo/psicologia , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Inflamação/patologia , Masculino , Obesidade/sangue , Obesidade/imunologia , Obesidade/patologia , Recidiva , Adulto Jovem
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