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1.
J Clin Psychiatry ; 80(4)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31318184

RESUMO

BACKGROUND: Suicidal ideation is a frequent and difficult-to-treat clinical challenge among patients with major depressive disorder (MDD). However, little is known regarding the differential development during antidepressant treatment and whether some patients may suffer from persistent suicidal ideation. METHODS: Among 811 patients with Schedules for Clinical Assessment in Neuropsychiatry (SCAN)-verified MDD from 2004-2007 assessed weekly for 12 weeks of escitalopram or nortriptyline antidepressant treatment, we applied item response theory to integrate a suicidality score based on 3 rating scales. We performed latent growth mixture modeling analysis to empirically identify trajectories. Multinomial logistic regression analyses estimated associations with potential predictors. RESULTS: We identified 5 distinct classes of suicidal ideation. The Persistent-low class (53.7%) showed no suicidal ideation whereas the Persistent-high class (9.8%) had high suicidal ideation throughout 12 weeks. Two classes showed a fluctuating course: the Fluctuating class (5.2%) ended at a low level of suicidal ideation, whereas the Slow-response-relapse class (4.8%) initially responded slowly but then experienced a large increase to a high level of suicidal ideation after 12 weeks. The Fast-response class (26.5%) had a high baseline severity similar to the Persistent-high class but responded quickly within a few weeks and remained at a low level. Previous suicide attempts and higher mood symptom severity were associated with worse suicidal ideation trajectories, whereas living with a partner showed a trend toward better response. CONCLUSION: Approximately 1 of 5 patients with MDD showed high or fluctuating suicidal ideation despite antidepressant treatment. Studies should investigate whether suicidal ideation may persist for longer periods and more targeted treatment possibilities. TRIAL REGISTRATION: ISRCTN​​ identifier: ISRCTN03693000​​​​.

2.
Am J Psychiatry ; 176(8): 651-660, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164008

RESUMO

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

3.
Br J Psychiatry ; 215(2): 494-501, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30698114

RESUMO

BACKGROUND: For patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).AimsTo compare the switch between the TCA nortriptyline and the SSRI escitalopram. METHOD: Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 (https://eudract.ema.europa.eu/) and ISRCTN No.03693000 (http://www.controlled-trials.com)). Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery-Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting ß-coefficients with 95% CIs. RESULTS: Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, ß = -0.38, 95% CI -0.51 to -0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, ß = -0.34, 95% CI -0.41 to -0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions. CONCLUSIONS: These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.Declarations of interestK.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.

4.
Nord J Psychiatry ; 73(2): 96-103, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30654674

RESUMO

BACKGROUND: Neurotrophin-3 (NTF3) and neurotrophin-4 (NTF4) play a crucial role in the neurodevelopment, differentiation, survival, and protection of neurons in different brain regions. Schizophrenia and depression are highly associated with metabolic abnormalities. Longitudinal and cross-sectional comparisons of NTF3 and NTF4 levels, as well as clinical and metabolic parameters, were studied in schizophrenia, first-episode depression, and control groups. MATERIALS AND METHODS: Serum NTF3 and NTF4 levels, body mass index (BMI), fasting serum glucose and lipid profile: cholesterol, triglyceride, high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) were measured at baseline and week 8 in 133 women: 55 patients with schizophrenia (19 with first-episode and 36 chronic), 30 patients with a first-episode depression and 48 healthy controls. The severity of the symptoms was evaluated with the Positive and Negative Syndrome Scale, 17-item Hamilton Depression Rating Scale and the Beck Depression Inventory. RESULTS: Longitudinal and cross-sectional comparisons did not detect any differences in the serum levels of NTF3 and NTF4 between studied groups. NTF3 and NTF4 levels were strongly correlated. Correlation of NTF3 and HDL-C levels at baseline was observed. Significant changes in cholesterol and fasting serum glucose levels in first-episode depression patients during 8 weeks of treatment were detected. Significant differences in BMI and LDL-C levels between schizophrenia and first-episode depression patients were discovered. CONCLUSIONS: To our knowledge, this is the first research which correlates NTF3 and NTF4 with metabolic parameters. Our study does not support the theory that the peripheral levels of NTF3 and NTF4 are disturbed in schizophrenia or first-episode depression.


Assuntos
Índice de Massa Corporal , Depressão/sangue , Fatores de Crescimento Neural/sangue , Esquizofrenia/sangue , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Colesterol/sangue , Estudos Transversais , Depressão/diagnóstico , Depressão/epidemiologia , Jejum/metabolismo , Jejum/psicologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Adulto Jovem
5.
Psychiatry Res ; 271: 89-95, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30472511

RESUMO

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of psychiatric disorders. Schizophrenia is associated with metabolic abnormalities and BDNF regulates energy homeostasis and glucose metabolism in peripheral tissues. The aim of this study was to examine serum levels of BDNF in schizophrenic women during 8 weeks of treatment and control group, and its correlation with clinical and metabolic parameters. The study was performed on a group of 96 women: 55 diagnosed with paranoid schizophrenia according to DSM-IV criteria, and 41 healthy controls. Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of schizophrenia. BDNF serum levels and metabolic parameters: fasting serum glucose, total cholesterol, triglyceride (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) were measured at baseline and week 8 of treatment. BDNF serum levels were significantly elevated in medicated patients with schizophrenia comparing to controls. After 8 weeks of antipsychotic treatment, BDNF levels did not significantly change. Increase in TG and TG/HDL-C ratio and a decrease in HDL-C was detected in medicated patients. Correlation between BDNF and lipid profile as well as symptoms severity was found. In our study we detected abnormalities in BDNF levels and lipid profile in medicated schizophrenic women in Polish population.

6.
Transl Psychiatry ; 8(1): 150, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104601

RESUMO

A key feature of major depressive disorder (MDD) is anhedonia, which is a predictor of response to antidepressant treatment. In order to shed light on its genetic underpinnings, we conducted a genome-wide association study (GWAS) followed by investigation of biological pathway enrichment using an anhedonia dimension for 759 patients with MDD in the GENDEP study. The GWAS identified 18 SNPs associated at genome-wide significance with the top one being an intronic SNP (rs9392549) in PRPF4B (pre-mRNA processing factor 4B) located on chromosome 6 (P = 2.07 × 10-9) while gene-set enrichment analysis returned one gene ontology term, axon cargo transport (GO: 0008088) with a nominally significant P value (1.15 × 10-5). Furthermore, our exploratory analysis yielded some interesting, albeit not statistically significant genetic correlation with Parkinson's Disease and nucleus accumbens gray matter. In addition, polygenic risk scores (PRSs) generated from our association analysis were found to be able to predict treatment efficacy of the antidepressants in this study. In conclusion, we found some markers significantly associated with anhedonia, and some suggestive findings of related pathways and biological functions, which could be further investigated in other studies.

7.
J Psychiatr Res ; 105: 17-22, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30130674

RESUMO

BACKGROUND: Inflammation may play an important role in depression and its treatment. A previous study found that increased C-reactive protein (CRP), a marker of systemic inflammation, is associated with worse response to the serotonergic antidepressant escitalopram and better response to the noradrenergic antidepressant nortriptyline. It is unclear whether this reflects genetic disposition to inflammation. METHODS: We analyzed genotype data and weekly Montgomery-Åsberg Depression Rating Scale scores (MADRS) from 755 unrelated individuals obtained over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. We calculated a polygenic risk score for CRP level based on genome-wide meta-analysis results from the CHARGE Consortium. RESULTS: A higher polygenic risk score for CRP was associated with slightly better response to escitalopram and slightly worse response to nortriptyline, reflected in a statistically significant interaction between polygenic risk score and drug (beta = 1.07, 95% CI = 0.26-1.87, p = 0.0093). DISCUSSION: A differential association between CRP-PRS and antidepressant drug that is in a direction opposite to that found with serum CRP measurement suggests that previously observed effect of inflammation on antidepressant efficacy may be driven by state factors distinct from genetic influences on systemic inflammation.

8.
J Affect Disord ; 241: 142-146, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30121446

RESUMO

BACKGROUND: Psychiatric comorbidity affects 24-65% patients with bipolar disorder (BD), 45% of which have alcohol abuse/dependence (AAD). Despite the fact that BD has an equal incidence in both genders, AAD more often occurs in men. We hypothesized that the presence of BD and AAD, reported as a secondary diagnosis, may result from a common genetic background. However, specific genetic factors predispose to gender differences. METHODS: Based on the relationship between circadian clock genes pathway and BD/AAD we decided to test the connection of four core clock genes with common genetic background of both diseases. We analyzed 436 patients with BD, among which 17% were diagnosed with AAD. The control group consisted of 417 healthy subjects. We analyzed 44 SNPs of the previously described core molecular clock genes: CLOCK, ARNTL, TIMELESS and PER3. RESULT: We found association of ARNTL gene (rs11600996) and PER3 gene (rs228642) polymorphisms with an increased risk of BD/AAD in a group of male patients. We also found that two other polymorphisms of PER3 gene, rs228682 and rs2640909, were associated with both AAD and family history of affective disorders. LIMITATIONS: Possible factors that could have influenced the results are: relatively small sample size, gender disproportion and unverifiable data form the patient interview. CONCLUSIONS: Our study confirms the existence of a link between clock genes and increased risk of alcohol abuse/dependence in male patients and the accumulation of risk genes in patients with a positive family history.

9.
Eur Neuropsychopharmacol ; 28(8): 945-954, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30135031

RESUMO

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2-4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19-0.66) and higher remission rates (OR = 1.55, CI = 1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08-1.47), neurological (OR = 1.28, CI = 1.07-1.53) and sexual side effects (OR = 1.52, CI = 1.23-1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).

10.
Front Psychiatry ; 9: 207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29904359

RESUMO

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

11.
Sci Rep ; 8(1): 5530, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615645

RESUMO

Individuals with depression differ substantially in their response to treatment with antidepressants. Specific predictors explain only a small proportion of these differences. To meaningfully predict who will respond to which antidepressant, it may be necessary to combine multiple biomarkers and clinical variables. Using statistical learning on common genetic variants and clinical information in a training sample of 280 individuals randomly allocated to 12-week treatment with antidepressants escitalopram or nortriptyline, we derived models to predict remission with each antidepressant drug. We tested the reproducibility of each prediction in a validation set of 150 participants not used in model derivation. An elastic net logistic model based on eleven genetic and six clinical variables predicted remission with escitalopram in the validation dataset with area under the curve 0.77 (95%CI; 0.66-0.88; p = 0.004), explaining approximately 30% of variance in who achieves remission. A model derived from 20 genetic variables predicted remission with nortriptyline in the validation dataset with an area under the curve 0.77 (95%CI; 0.65-0.90; p < 0.001), explaining approximately 36% of variance in who achieves remission. The predictive models were antidepressant drug-specific. Validated drug-specific predictions suggest that a relatively small number of genetic and clinical variables can help select treatment between escitalopram and nortriptyline.

12.
Psychiatr Pol ; 52(1): 21-32, 2018 Feb 28.
Artigo em Inglês, Polonês | MEDLINE | ID: mdl-29704411

RESUMO

OBJECTIVES: Suicide is an important clinical problem in psychiatric patients. The highest risk of suicide attempts is noted in affective disorders. In this study we tested 20 factors described in the literature (sociodemographic and clinical factors as well as family burden) in association with suicidal behavior and we analyzed whether the significance of those factors differs between males and females. METHODS: In the study we included patients with major depressive disorder (MDD; n = 249) and bipolar affective disorder (BP; n = 582). The Structured Clinical Interview for DSM-IV Axis I (SCID I), the Operational Criteria Diagnostic Checklist (OPCRIT) and a questionnaire of family history were used. RESULTS: In the study population we observed an association between suicidal attempts and the following factors: family history of psychiatric disorders, affective disorders and psychoactive substance abuse/dependence; family history of attempted/completed suicide; occurrence of specific symptoms in the course of depressive episode (inappropriate guilt, sense of worthlessness, early morning awakening); and psychotic symptoms. Having children was also associated with suicide attempts. The risk factors of suicide attempt differ between males and females. The age of onset of MDD and coexistence of substance abuse/dependence with affective disorder were significant for lifetime risk of attempted suicide only in female group. Having children was associated with suicide attempts in the whole group and in the male subgroup, but not in the female subgroup. CONCLUSIONS: Suicide attempts are significantly associated with 10 out of 20 analyzed clinical factors in our group of affective patients, however, the significance (or lack of it) of these factors differed in female and male groups in half the cases.


Assuntos
Transtorno Bipolar/psicologia , Transtorno Depressivo/psicologia , Transtornos da Personalidade/prevenção & controle , Tentativa de Suicídio/psicologia , Adulto , Feminino , Culpa , Humanos , Masculino , Fatores de Risco , Fatores Sexuais , Transtornos Relacionados ao Uso de Substâncias/psicologia
13.
Bipolar Disord ; 2018 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-29578315

RESUMO

OBJECTIVES: In mood disorders, chronic stimulation with stress results in aberrant regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Lithium was shown to influence HPA axis function. The underlying genetic background as well as environmental context may influence the stress response, and therefore lithium efficacy. The aim of the present study was to analyze if genetic variants located in genes involved in HPA axis regulation affect the response to long-term lithium treatment in bipolar patients. METHODS: We included 93 patients with bipolar disorder (32 males and 61 females), aged 31-80 years. The patients had been treated with lithium carbonate for at least 5 years. The magnitude of the lithium response was assessed using the Alda scale. Genotyping was performed for 28 polymorphisms in the genes encoding the following proteins involved in HPA axis regulation: corticotropin-releasing hormone receptor 1 (CRHR1), arginine vasopressin receptor 1B (AVPR1b), FK506 binding protein (FKBP) 5, FKBP4, BCL2-associated athanogene 1 (BAG1), stress induced phosphoprotein 1 (STIP1), glucocorticoid-induced transcript 1 (GLCC1), dual specificity phosphatase 1 (DUSP1) serine and arginine rich splicing factor (SRSF) 3, SRSF9, SRSF5, and acid phosphatase 1 (ACP1). Linkage disequilibrium and haplotype analysis were then performed, followed by statistical analysis (Statistica v.12; Stasoft, Krakow, Poland). RESULTS: We found a correlation between stressful life events at first episode and worse response to lithium (P=.019). In single marker analysis, we observed a significant association between three FKBP5 polymorphisms (rs1360780, rs7748266 and rs9296158), one ACP1 variant (rs300774) and one glucocorticoid-induced transcript 1 gene (GLCC1) variant (rs37972) and the degree of lithium response. Five out of seven FKBP5 polymorphisms showed strong linkage with one haplotype demonstrating an association with lithium efficacy (P=.008). No relationship was found between the other analyzed polymorphisms and lithium response. CONCLUSION: The response to lithium may depend on the variants of genes regulating the HPA axis and stressful life events in bipolar patients.

14.
Pharmacol Rep ; 70(1): 55-59, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29331787

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) influences neuron differentiation during development as well as the synaptic plasticity and neuron survival in adulthood. BDNF has been implicated in the pathogenesis of schizophrenia and depression. Val66Met polymorphism and BDNF serum level are potential biomarkers in neuropsychiatric disorders. The aim of this study was to determine the effect of BDNF gene Val66Met functional polymorphism on serum BDNF concentration in patients with schizophrenia, during depression episode and in healthy control group. METHODS: 183 participants were recruited (61 patients with depressive episode, 56 females with schizophrenia, 66 healthy controls) from Polish population. Serum BDNF levels were measured using ELISA method. Val66Met polymorphism was genotyped using PCR- RFLP method. RESULTS: Serum BDNF levels were not associated with Val66Met polymorphism in either of the groups. A significant increase of BDNF level in schizophrenia (p = 0.0005) and depression (p = 0.026) comparing to the control group has been observed. CONCLUSIONS: Our results suggest that the functional Val66Met BDNF polymorphism is not associated with BDNF serum levels, which is in line with previous findings. Replication studies on larger groups are needed.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/sangue , Depressão/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/sangue , Esquizofrenia/genética , Adulto , Afeto , Estudos de Casos e Controles , Depressão/diagnóstico , Depressão/psicologia , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polônia , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico
15.
JAMA Psychiatry ; 75(1): 65-74, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29121268

RESUMO

Importance: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). Objectives: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. Design, Setting, and Participants: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. Main Outcomes and Measures: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. Results: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. Conclusions and Relevance: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

16.
J Affect Disord ; 228: 20-25, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29197740

RESUMO

BACKGROUND: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. METHODS: We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. RESULTS: Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. LIMITATIONS: Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. CONCLUSIONS: Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.


Assuntos
Transtorno Bipolar/genética , Encéfalo/crescimento & desenvolvimento , Proteína Adaptadora GRB2/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais , Algoritmos , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Encéfalo/metabolismo , Feminino , Proteína Adaptadora GRB2/genética , Expressão Gênica , Genes erbB-2/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA/metabolismo
17.
Pharmacopsychiatry ; 51(4): 148-152, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29141255

RESUMO

BACKGROUND: Conflicting data regarding the efficacy of antidepressants of different mechanism of action on unexplained painful physical symptoms (UPPS) in depression have been published so far. OBJECTIVE: The aim of this study was to compare the impact of escitalopram (ESC), nortriptyline (NOR), and venlafaxine (VEN) on UPPS in patients with major depression. MATERIALS AND METHODS: Sixty patients, participants in the GENDEP study, with a diagnosis of depression according to the ICD-10 criteria were randomly assigned to treatment with ESC (10-30 mg, mean dose 15.2, standard deviation [SD]±9.2) or NOR (50-150 mg, mean dose 106.2, SD±8.2). Additionally, 30 patients who were treated with VEN (75-225 mg, mean dose 181.3, SD±8.8) were included. Before inclusion (day 0) and throughout the study (days 14, 28, 42, 56), the severity of pain was monitored using the visual analog scale. RESULTS: The patients treated with ESC, NOR, and VEN did not differ in the intensity of pain at days 0, 14, 28, 42, and 56. CONCLUSION: Our results do not support the hypothesis suggesting the superiority of VEN over ESC and NOR in the management of UPPS in major depression.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/complicações , Dor/tratamento farmacológico , Dor/etiologia , Adulto , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nortriptilina/uso terapêutico , Medição da Dor , Escalas de Graduação Psiquiátrica , Fatores de Tempo , Cloridrato de Venlafaxina/uso terapêutico
18.
Nord J Psychiatry ; 72(3): 191-196, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29235396

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) influences neuron differentiation during development, as well as the synaptic plasticity and neuron survival in adulthood. BDNF has been implicated in the pathogenesis of psychiatric disorders and its serum level is a potential biomarker for depression. The aim of this study was to examine serum levels of BDNF in first-episode depression and its correlation with clinical and metabolic parameters. MATERIALS AND METHODS: The study was performed on a group of 60 women: 30 diagnosed with a first-episode of depression and 30 healthy controls. 17-Item Hamilton Depression Rating Scale (HDRS-17) was used to assess the severity of depression. Patients were randomly chosen for treatment with sertraline or venlafaxine. BDNF serum levels and metabolic parameters: fasting serum glucose, cholesterol, triglyceride (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) were measured at baseline and week 8 of treatment. RESULTS: There were no differences between BDNF level in depressed patients compared with the healthy controls. Lack of differences in medication effect of sertraline or venlafaxine on HDRS-17 scores during 8 weeks of treatment was observed. Correlation of BDNF at baseline and fasting serum glucose at baseline and week 8 was detected. CONCLUSIONS: Correlations of BDNF serum levels with metabolic parameters were observed.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Depressão/sangue , Depressão/diagnóstico , Adulto , Biomarcadores/sangue , Estudos Transversais , Depressão/tratamento farmacológico , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Inibidores de Captação de Serotonina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Sertralina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico
19.
Psychiatry Res ; 257: 446-449, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28837935

RESUMO

Former findings indicate that suicidal behavior in bipolar disorder is associated with clock genes. Additionally, numerous non-genetic risk factors are potentially associated with suicidal behavior. Therefore, we conducted an analysis of the relationship between clock genes (as distal risk factors) with clinical characteristics and the course of bipolar disorder. We also tried to obtain a predictive model for suicide attempts based on clinical and genetic data. We found associations between selected polymorphisms and.


Assuntos
Fatores de Transcrição ARNTL/genética , Transtorno Bipolar/genética , Proteínas CLOCK/genética , Proteínas de Ciclo Celular/genética , Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Circadianas Period/genética , Polimorfismo de Nucleotídeo Único , Suicídio/psicologia , Adulto , Transtorno Bipolar/psicologia , Relógios Circadianos/genética , Feminino , Humanos , Masculino , Fatores de Risco
20.
Psychiatry Res ; 256: 396-402, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28689143

RESUMO

AIM: Neurotrophic factors have been implicated in neuropsychiatric disorders, including schizophrenia and depression. Glial Cell Line-Derived Neurotrophic Factor (GDNF) promotes development, differentiation, and protection of dopaminergic, serotonergic, GABAergic and noradrenergic neurons as well as glial cells in different brain regions. This study examined serum levels of GDNF in schizophrenia and depression and its correlation with metabolic parameters during 8 weeks of treatment. METHODS: Serum GDNF level, fasting serum glucose and lipid profile were measured at baseline and week 8 in 133 women: 55 with schizophrenia, 30 with a first episode depression and 48 healthy controls. The severity of the symptoms was evaluated using Positive and Negative Syndrome Scale (PANSS), 17-item Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). RESULTS: There was statistically significant higher GDNF level in schizophrenia at baseline when compared with week 8. Correlations of GDNF with PANSS in schizophrenia and cholesterol level in depression have also been detected. CONCLUSIONS: To our knowledge, this is the first study which correlates GDNF levels with metabolic parameters. Our results show no differences in GDNF serum level between schizophrenia, a first depressive episode, and healthy controls. GDNF serum level did not correlate with metabolic parameters except for total cholesterol in depression.


Assuntos
Depressão/sangue , Transtorno Depressivo/sangue , Fator Neurotrófico Derivado de Linhagem de Célula Glial/sangue , Esquizofrenia/sangue , Adulto , Glicemia/metabolismo , Feminino , Humanos , Lipídeos/sangue , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica
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