RESUMO
ABSTRACT: The identification of single-nucleotide polymorphisms (SNPs) in genes putatively related to pathophysiological processes in major depressive disorder (MDD) might improve both diagnosis and personalized treatment strategies eventually leading to more effective interventions. Considering the important role of the glucocorticoid receptor and the related FK506 binding protein 51 (FKBP51) in the pathophysiology of MDD, we aimed to investigate putative associations between variants of FKBP5, the coding gene of FKBP51, with antidepressant treatment resistance and MDD susceptibility.Nine common SNPs of the FKBP5 gene prioritized based on location and, putative or known functions were genotyped in Han Chinese population, including MDD patients with or without antidepressant-treatment resistance and healthy controls. Associations of FKBP5 SNPs with MDD susceptibility and treatment response were examined in the whole group of MDD patients, as well as in subgroups stratified by antidepressant treatment resistance, compared with healthy controls.In total, 181 Han Chinese patients with MDD and 80 healthy controls were recruited. No significant SNP or haplotype associations were observed in the whole patient group. There were nominal significant differences both for the haplotype block with SNPs in strong LD (r2â>â0.8, Pâ=â.040) and haplotype block with SNPs in moderate LD (r2â>â0.1, Pâ=â.017) between the haplotype distributions of patients with antidepressant treatment resistance (nâ=â81) and healthy controls, but both significances did not survive multiple testing correction. Furthermore, no specific haplotype could be observed causing a significant difference in any combination between all comparisons.No associations were observed of FKBP5 variants with MDD or antidepressant treatment response. The lack of associations might be due to the relatively small sample size of this study (power ranged from 0.100 to 0.752). A follow-up study will need larger, better phenotyped, and more homogeneous samples to draw a definitive conclusion regarding the involvement of this gene in MDD.
Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Predisposição Genética para Doença , Proteínas de Ligação a Tacrolimo/genética , Adolescente , Adulto , Idoso , Povo Asiático , Estudos de Casos e Controles , China , Transtorno Depressivo Maior/genética , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: Understanding how genetic polymorphisms are associated with the pathophysiology of major depressive disorder (MDD) may aid in diagnosis and the development of personalized treatment strategies. CNR1 is the gene coding Cannabinoid type 1 receptor which is highly involved in emotional processing and in regulating neurotransmitter releases. We aimed to investigate the associations of CNR1 single-nucleotide polymorphisms (SNPs) with MDD susceptibility and treatment response. METHODS: The study reported data on 181 Han Chinese with MDD and 80 healthy controls. The associations of CNR1 genetic polymorphisms with MDD susceptibility and treatment response were examined, wherein the MDD patients were subgrouped further by responding to antidepressant treatment, compared with healthy controls separately. RESULTS: The CNR1 SNPs rs806367 and rs6454674 and haplotype C-T-T-C of rs806366, rs806367, rs806368, and rs806370 were associated with increased susceptibility for MDD and antidepressant treatment resistance, but the association was not detected in other SNPs or the haplotype block of rs806368 and rs806370. CONCLUSION: The CNR1 is a promising candidate for the genetic association study of MDD. Larger and well-characterized samples are required to confirm the genetic association of CNR1 with MDD because of the limitations such as relatively small sample size and lack of information for correcting confounding factors.
Assuntos
Transtorno Depressivo Maior/genética , Transtorno Depressivo Resistente a Tratamento/genética , Polimorfismo de Nucleotídeo Único , Receptor CB1 de Canabinoide/genética , Adolescente , Adulto , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
BACKGROUND: Hypoandrogenic men showed a higher prevalence of major depressive disorder (MDD), which could be ascribed to overlapping symptoms such as sexual dysfunction, or additionally to core emotional symptoms such as sadness and anhedonia. We examined whether androgen levels 1) differ between men with and without MDD cross-sectionally, 2) are associated with an elevated risk for onset of MDD prospectively, and 3) associate with all individual MDD symptoms, or only with hypogonadism overlapping symptoms. METHODS: In 823 men (mean age 43.5 years), baseline plasma levels of total testosterone, 5α-dihydrotestosterone (5α-DHT), and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulphate (DHEAS) and sex hormone binding globulin with radioimmunoassay, whereas free testosterone was calculated. MDD status was assessed at baseline and after two years using structured interviews and individual MDD symptoms were self-rated at baseline, and after one and two years. RESULTS: None of the androgen levels were associated with current or onset (incidence or recurrence) of MDD. Free testosterone was only inversely associated with interest in sex. Also, androstenedione and DHEAS were positively associated with some individual MDD symptoms, and 5α-DHT levels showed non-linear associations (both with low and high levels) with MDD symptom severity and several individual MDD symptoms. CONCLUSIONS: These results support the idea that circulating androgens synthesised by the testes are of limited clinical relevance to MDD in adult men, but levels of androstenedione, DHEAS and 5α-DHT may be associated with some individual MDD symptoms.
Assuntos
Androgênios , Transtorno Depressivo Maior , Adulto , Androstenodiona , Sulfato de Desidroepiandrosterona , Depressão , Di-Hidrotestosterona , Humanos , Masculino , Globulina de Ligação a Hormônio Sexual , TestosteronaRESUMO
Major depressive disorder (MDD) has a higher prevalence in women with supraphysiologic androgen levels. Whether there is also an association between depression and androgen levels in the physiological range, is unknown. This study examined if women with current MDD have higher androgen levels compared to women who have never had MDD, and if androgen levels are associated with onset and remission of MDD. In 1659 women (513 current MDD, 754 remitted MDD, and 392 never MDD), baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulfate and sex hormone binding globulin (SHBG) with radioimmunoassays. Free testosterone was calculated. MDD status was assessed at baseline, and at 2 and 4 years follow-up. Women were aged between 18 and 65 years (mean age 41) with total testosterone levels in the physiological range (geometric mean 0.72 nmol/L [95% CI 0.27-1.93]). After adjusting for covariates and multiple testing, women with current MDD had a higher mean free testosterone than women who never had MDD (adjusted geometric mean 8.50 vs. 7.55 pmol/L, p = 0.0005), but this difference was not large enough to be considered clinically meaningful as it was consistent with statistical equivalence. Levels of other androgens and SHBG did not differ and were also statistically equivalent between the groups. None of the androgens or SHBG levels predicted onset or remission of MDD. Our findings support the idea that plasma androgens within the physiological range have no or only limited effects on depressive disorders in women.
Assuntos
Androgênios , Transtorno Depressivo Maior , Adolescente , Adulto , Idoso , Androstenodiona , Depressão , Feminino , Humanos , Pessoa de Meia-Idade , Globulina de Ligação a Hormônio Sexual , Testosterona , Adulto JovemRESUMO
Despite major expansions of evidence-based treatments of common mental disorders in recent decades, especially antidepressant medication, the point prevalence of depression has not decreased; instead it probably increased in young adults. We question whether antidepressants (AD)-monotherapy and low-fidelity-to-guideline psychological treatment (PT) might have no effect or even adverse effects in some patients and contexts that dilute the benefits of treatment at the population level, making it harder for population-based studies to detect treatment-driven prevalence reductions. Randomized Clinical Trial (RCT)s have not identified these effects because AD-monotherapy and low-fidelity PT are uncommon in RCTs where treatment protocols are specified and carefully monitored, unlike treatment in real-world settings. Second, RCTs may have missed the bigger picture of ultimate outcomes due to too short follow-ups. We elaborate two mechanisms through which AD-monotherapy and low-fidelity PT could produce adverse effects on long-term illness course. Both mechanisms are speculative and we outline how to test.
Assuntos
Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Depressão/epidemiologia , Depressão/terapia , Depressão/psicologia , Humanos , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto JovemRESUMO
BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, and its dysregulation has been associated with the pathogenesis of mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone which is also produced as a cytokine by immune cells and could be a neurotrophic factor regulating the functional activity of stress-related mechanisms. AIM: To investigate the possible relationship between depressive state and BDNF and PRL genotypes or levels with special reference to severity of depression. METHODS: Participants of 18-70 years with a clinical diagnosis of depressive disorder of at least moderate severity were included. These patients had not been treated with antidepressant drugs before admission to hospital during the preceding period of the last 6 months, and 54.5% had never been treated with antidepressant drugs during their entire life. The DNA was genotyped for rs1341239 within the prolactin and for rs6265, rs7124442, and rs11030104 within the BDNF gene. Rs11030104 violated the Hardy-Weinberg equilibrium distribution and was excluded from further analyses. BDNF and prolactin concentration was measured in serum by MAGPIX multiplex analyzer (Luminex, USA) using MILLIPLEX® MAP kit (Merck, Germany). Genetic associations were determined by sequentially regressing prolactin, BDNF, 17-items Hamilton's Depression (HAMD-17) and Clinical Global Impression scale, Severity (CGI-S) ratings, and depression (absent/present) on the available SNPs. Genetic associations were evaluated assuming an additive model. RESULTS: A total of 186 depressed patients (of which 169 were women) and 94 healthy controls (67 women) were genotyped. After excluding subjects without genetic information on all three study SNPs, 217 remained of whom 138 suffered from depression. Within depressed patients we observed an association of rs6265 with HAMD-17: mean difference (MD) 2.33 (95%CI 0.49; 4.16; p = 0.014) and CGI-S: MD 0.38 (95%CI 0.09; 0.66; p = 0.011). No significant association was observed between the prolactin SNP rs1341239 and prolactin levels. Similarly the mean differences of BDNF SNPs did not show an association with BDNF: rs6265 -0.042 ln(pg/ml) (95%CI -0.198; 0.113), and rs7124442 0.006 ln(pg/ml) (95%CI -0.117; 0.130). No other association reached statistical significance. CONCLUSION: We observed a significant association between BDNF gene variant rs6265 and the severity of depression in newly admitted, antidepressant treatment-free, depressed patients. Actual PRL and BDNF levels were not elevated sufficiently in depressed patients to reach statistical significance and were not associated with the studied genotypes.
RESUMO
BACKGROUND: Brain-derived neurotrophic factor (BDNF) is associated with response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with behavioural effects, acting as a neurotrophic factor within the brain and may be involved in antidepressant response. OBJECTIVES: To investigate the relationship between BDNF and PRL genotypes with antidepressant drug response. METHODS: Prospective inception cohort of 186 Russian treatment-free participants (28 men and 158 women) between 18 and 70 years clinically diagnosed with depressive disorder who initiated antidepressant medication. DNA polymorphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442. Primary outcome was measured by differences in Hamilton Depression Rating Scale (∆HAM-D) scores between baseline/week two, week two/week four, and baseline/week four. Linear regression and independent t-test determined the significance between polymorphisms and ∆HAM-D. RESULTS: Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment. In the latter two weeks, BDNF rs7124442 homozygous C patients responded significantly worse in comparison to homozygous T patients during this period. Further analysis within women and in post-menopausal women found a similar comparison between alleles. LIMITATIONS: Study lasted four weeks, which may be considered short to associate genuine antidepressant effects. CONCLUSIONS: Patients taking tricylic antidepressants were noted to have a significant improvement in ∆HAM-D compared to patients taking SSRIs. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment.
Assuntos
Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Prolactina/efeitos dos fármacos , Adolescente , Adulto , Idoso , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Estudos Prospectivos , Federação Russa , Resultado do Tratamento , Adulto JovemRESUMO
Major Depressive Disorder (MDD) is a heterogeneous disorder with a considerable symptomatic overlap with other psychiatric and somatic disorders. This study aims at providing evidence for association of a set of serum and urine biomarkers with MDD. We analyzed urine and serum samples of 40 MDD patients and 47 age- and sex-matched controls using 40 potential MDD biomarkers (21 serum biomarkers and 19 urine biomarkers). All participants were of Caucasian origin. We developed an algorithm to combine the heterogeneity at biomarker level. This method enabled the identification of correlating biomarkers based on differences in variation and distribution between groups, combined the outcome of the selected biomarkers, and calculated depression probability scores (the "bio depression score"). Phenotype permutation analysis showed a significant discrimination between MDD and euthymic (control) subjects for biomarkers in urine (Pâ¯<â¯.001), in serum (Pâ¯=â¯.02) and in the combined serum plus urine result (Pâ¯<â¯.001). Based on this algorithm, a combination of 8 urine biomarkers and 9 serum biomarkers were identified to correlate with MDD, enabling an area under the curve (AUC) of 0.955 in a Receiver Operating Characteristic (ROC) analysis. Selection of either urine biomarkers or serum biomarkers resulted in AUC values of 0.907 and 0.853, respectively. Internal cross-validation (5-fold) confirmed the association of this set of biomarkers with MDD.
Assuntos
Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/urina , Adulto , Algoritmos , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROCRESUMO
BACKGROUND: A substantial percentage of depressed patients do not respond satisfactorily to conventional antidepressant treatment. This treatment resistant depression (TRD) may be partly related to inflammatory processes in the central nervous system. Accordingly, peripheral inflammatory markers might serve to predict treatment response with novel but still experimental forms of antidepressant treatment. METHODS: A literature search on treatment of TRD and inflammatory markers was performed using the PubMed/Medline database on November 8th 2018, and 95 articles were retrieved initially, which were subsequently screened and selected only when the inclusion and exclusion criteria were met. RESULTS: Ten studies were recruited. In five studies higher baseline interleukin-6 (IL-6) or C-reactive protein (CRP)/high-sensitivity-CRP (hsCRP) in blood predicted better response to medication with anti-inflammatory characteristics, such as ketamine and infliximab. One study found that higher IL-6 predicted worse response to antidepressant treatment in patients with TRD. No evidence was found for the predictive value of other inflammatory markers (e.g., Tumor Necrosis Factor-α, Interferon-γ). LIMITATIONS: The number of available studies was limited; included studies showed considerable methodological variation and used different definitions for TRD. CONCLUSION: The inflammatory markers IL-6 and CRP/hsCRP could hold promise as markers for the prediction of treatment response in TRD. Clearly, this field of research is still far from mature but it could pave the way for novel and efficacious treatments for at least the inflammatory type of TRD with more well-designed studies and more convincing results.
Assuntos
Antidepressivos/uso terapêutico , Proteína C-Reativa/análise , Transtorno Depressivo Resistente a Tratamento/sangue , Mediadores da Inflamação/sangue , Interleucina-6/sangue , Adulto , Biomarcadores/sangue , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Feminino , Humanos , Infliximab/uso terapêutico , Interferon gama/sangue , Ketamina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVES: Older age and major depressive disorder (MDD) are both risk factors for the development of cardiovascular diseases. Testosterone has been associated with MDD and metabolic syndrome (MetS) in men, although associations in women are less clear. Therefore, we investigated whether testosterone is associated with MetS and whether this association is different for depressed and non-depressed older men and women. METHODS: In this prospective cohort study, 478 participants (349 patients with MDD and 129 controls) aged between 60 and 93 years from the Netherlands Study of Depression in Older Persons were included. Total testosterone (TT) and sex-hormone binding globulin levels were measured using a second-generation radioimmune assay. Free testosterone (FT) was calculated based on TT. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: A higher risk for MetS was found in men with low FT and TT (odds ratio [OR]: 0.67, 95% confidence interval [95%CI]: 0.47-0.95 and OR: 0.51, 95%CI: 0.34-0.75), and in women with high FT (OR: 1.41, 95%CI: 1.08-1.82). Strong associations in the same direction were found with adiposity, glucose, and plasma lipid MetS components at baseline, but not with changes in these components at 2-year follow-up. The associations did not significantly differ between MDD patients and controls. CONCLUSIONS: Independently of having MDD, low testosterone levels in men and, in contrast, high testosterone levels in women were significantly associated with MetS and its components.
Assuntos
Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/complicações , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Testosterona/sangue , Adiposidade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Razão de Chances , Estudos Prospectivos , Fatores de Risco , Globulina de Ligação a Hormônio Sexual/análiseRESUMO
BACKGROUND: Etiological research of depression and anxiety disorders has been hampered by diagnostic heterogeneity. In order to address this, researchers have tried to identify more homogeneous patient subgroups. This work has predominantly focused on explaining interpersonal heterogeneity based on clinical features (i.e. symptom profiles). However, to explain interpersonal variations in underlying pathophysiological mechanisms, it might be more effective to take biological heterogeneity as the point of departure when trying to identify subgroups. Therefore, this study aimed to identify data-driven subgroups of patients based on biomarker profiles. METHODS: Data of patients with a current depressive and/or anxiety disorder came from the Netherlands Study of Depression and Anxiety, a large, multi-site naturalistic cohort study (n = 1460). Thirty-six biomarkers (e.g. leptin, brain-derived neurotrophic factor, tryptophan) were measured, as well as sociodemographic and clinical characteristics. Latent class analysis of the discretized (lower 10%, middle, upper 10%) biomarkers were used to identify different patient clusters. RESULTS: The analyses resulted in three classes, which were primarily characterized by different levels of metabolic health: 'lean' (21.6%), 'average' (62.2%) and 'overweight' (16.2%). Inspection of the classes' clinical features showed the highest levels of psychopathology, severity and medication use in the overweight class. CONCLUSIONS: The identified classes were strongly tied to general (metabolic) health, and did not reflect any natural cutoffs along the lines of the traditional diagnostic classifications. Our analyses suggested that especially poor metabolic health could be seen as a distal marker for depression and anxiety, suggesting a relationship between the 'overweight' subtype and internalizing psychopathology.
Assuntos
Transtornos de Ansiedade/classificação , Depressão/classificação , Adulto , Transtornos de Ansiedade/sangue , Transtornos de Ansiedade/diagnóstico , Biomarcadores/análise , Biomarcadores/sangue , Estudos de Coortes , Depressão/sangue , Depressão/diagnóstico , Feminino , Frequência Cardíaca , Humanos , Análise de Classes Latentes , Masculino , Países Baixos , Escalas de Graduação Psiquiátrica , Saliva/químicaRESUMO
BACKGROUND: A subgroup of depressed patients with increased inflammatory activity was shown to be more susceptible to develop Treatment Resistant Depression (TRD). Earlier studies with anti-inflammatory drugs have shown benefits in the treatment of major depressive disorder (MDD), but the effects are expected to be higher in patients with increased inflammatory activity. Supplementation of N-acetylcysteine (NAC) to ongoing antidepressant therapy may positively influence outcome of depression treatment in these patients. Therefore, this study aims to investigate the efficacy of NAC supplementation in patients with insufficient response to standard antidepressant treatment, and to explore potential roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD. METHODS/DESIGN: A double-blind randomized placebo-controlled study comparing NAC versus placebo as add-on medication to antidepressant treatment with 12-week treatment and 8-week follow up in patients with TRD and increased inflammatory activity. Apart from clinical efficacy defined as the change in Hamilton Depression Rating Scale (HAMD)-17 score, secondary outcomes include changes in pathophysiological mechanisms related to depression as well as changes in local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). Importantly, sole patients with CRP levels with values between 0.85 and 10 mg/L will be included. DISCUSSION: This is the first clinical trial taking both TRD and increased inflammatory activity as inclusion criteria. This study will provide reliable evidence for the efficacy of NAC in patients with TRD displaying increased inflammatory activity. And this study also will help explore further the roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD. TRIAL REGISTRATION: The trial protocol has been registered on "ClinicalTrials.gov"with protocol ID "NAC-2015-TJAH" and ClinicalTrials.gov ID " NCT02972398 ".
Assuntos
Acetilcisteína/administração & dosagem , Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Adulto , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/metabolismo , Imagem de Tensor de Difusão/métodos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Sequestradores de Radicais Livres/administração & dosagem , Humanos , Inflamação/diagnóstico por imagem , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Psicoterapia/métodos , Resultado do TratamentoRESUMO
OBJECTIVE: The current diagnostic criteria for major depressive disorder (MDD) do not allow prediction of prognosis and therapeutic response. A possible strategy to improve this situation is the identification of depression subtypes on the bases of biomarkers reflecting underlying pathological processes such as neuro-inflammation. METHODS: The PubMed/Medline database was searched until Apr 25th, 2017. In the initial search 1018 articles were retrieved, which were subsequently screened and only selected when the inclusion and exclusion criteria were fulfilled. RESULTS: Eight eligible studies were found. Overall, serum interleukin-6 and 1ß values were increased in the melancholic MDD subtype compared to controls and the non-melancholic MDD subtype. C-reactive protein was increased in non-melancholic MDD in 2 out of 4 studies, while there was no difference for tumor necrosis factor-α and interleukin-2 and 10. CONCLUSION: Given the paucity of eligible studies the tentative conclusion must be drawn that peripheral inflammation markers have limited added value thus far to distinguish between melancholic and non-melancholic depression. To allow for a more definitive conclusion, further research is warranted using a broader panel of inflammatory markers in MDD subtypes, preferably based on a general consensus regarding diagnostic criteria and subtype definitions.
Assuntos
Proteína C-Reativa/metabolismo , Depressão/sangue , Transtorno Depressivo Maior/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Biomarcadores/sangue , Depressão/diagnóstico , Depressão/psicologia , Transtorno Depressivo/sangue , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/psicologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Cálcio/metabolismo , Pirazinas/farmacologia , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/fisiologia , Digitonina/farmacologia , Humanos , Leucócitos Mononucleares , Lipopolissacarídeos/farmacologia , Polimorfismo de Nucleotídeo Único/fisiologia , Serotonina/análogos & derivados , Serotonina/farmacologiaRESUMO
Electroconvulsive therapy (ECT) is an effective treatment for depression, but can have negative side effects including amnesia. The mechanisms of action underlying both the antidepressant and side effects of ECT are not well understood. An equivalent manipulation that is conducted in experimental animals is electroconvulsive seizure (ECS). Rodent studies have provided valuable insights into potential mechanisms underlying the antidepressant and side effects of ECT. However, relatively few studies have investigated the effects of ECS in animal models with a depression-relevant manipulation such as chronic stress. In the present study, mice were first exposed to chronic social stress (CSS) or a control procedure for 15 days followed by ECS or a sham procedure for 10 days. Behavioral effects were investigated using an auditory fear conditioning (learning) and expression (memory) test and a treadmill-running fatigue test. Thereafter, immunohistochemistry was conducted on brain material using the microglial marker Iba-1 and the cholinergic fibre marker ChAT. CSS did not increase fear learning and memory in the present experimental design; in both the control and CSS mice ECS reduced fear learning and fear memory expression. CSS induced the expected fatigue-like effect in the treadmill-running test; ECS induced increased fatigue in CSS and control mice. In CSS and control mice ECS induced inflammation in hippocampus in terms of increased expression of Iba-1 in radiatum of CA1 and CA3. CSS and ECS both reduced acetylcholine function in hippocampus as indicated by decreased expression of ChAT in several hippocampal sub-regions. Therefore, CSS increased fatigue and reduced hippocampal ChAT activity and, rather than reversing these effects, a repeated ECS regimen resulted in impaired fear learning-memory, increased fatigue, increased hippocampal Iba-1 expression, and decreased hippocampal ChAT expression. As such, the current model does not provide insights into the mechanism of ECT antidepressant function but does provide evidence for pathophysiological mechanisms that might contribute to important ECT side-effects.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Depressão/psicologia , Eletroconvulsoterapia/efeitos adversos , Hipocampo/imunologia , Proteínas dos Microfilamentos/metabolismo , Estresse Psicológico/psicologia , Animais , Condicionamento Psicológico , Depressão/imunologia , Depressão/terapia , Modelos Animais de Doenças , Teste de Esforço , Masculino , Aprendizagem em Labirinto , Camundongos , Estresse Psicológico/imunologia , Estresse Psicológico/terapiaRESUMO
Replication has been poor for previously reported candidate genes involved in Major Depressive Disorder (MDD). One possible reason is phenotypic and genetic heterogeneity. The present study replicated genetic associations with MDD as defined in DSM-IV and with a more narrowly defined MDD subtype with a chronic and severe course. We first conducted a systematic review of genetic association studies on MDD published between September 2007 and June 2012 to identify all reported candidate genes. Genetic associations were then tested for all identified single nucleotide polymorphisms (SNPs) and the entire genes using data from the GAIN genome-wide association study (MDD: n = 1,352; chronic MDD subsample: n = 225; controls: n = 1,649). The 1,000 Genomes database was used as reference for imputation. From 157 studies identified inthe literature, 81 studies reported significant associations with MDD, involving 245 polymorphisms in 97 candidate genes, from which we were able to investigate 185 SNPs in 89 genes. We replicated nine candidate SNPs in eight genes for MDD and six in five genes for chronic MDD. However, these were not more than expected by chance. At gene level, we replicated 18 genes for MDD and 17 genes for chronic MDD, both significantly more than expected by chance. We showed that replication rates were improved for MDD compared to a previous, highly similar, replication study based on studies published before 2007. Effect sizes of the SNPs and replication rates of the candidate genes were improved in the chronic subsample compared to the full sample. Nonetheless, replication rates were still poor.
Assuntos
Transtorno Depressivo Maior/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos TestesRESUMO
Major depressive disorder is a heterogeneous disorder, mostly diagnosed on the basis of symptomatic criteria alone. It would be of great help when specific biomarkers for various subtypes and symptom clusters of depression become available to assist in diagnosis and subtyping of depression, and to enable monitoring and prognosis of treatment response. However, currently known biomarkers do not reach sufficient sensitivity and specificity, and often the relation to underlying pathophysiology is unclear. In this review, we evaluate various biomarker approaches in terms of scientific merit and clinical applicability. Finally, we discuss how combined biomarker approaches in both preclinical and clinical studies can help to make the connection between the clinical manifestations of depression and the underlying pathophysiology.
Assuntos
Transtorno Depressivo Maior , Animais , Biomarcadores/metabolismo , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/etiologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , HumanosRESUMO
Individual differences in coping style emerge as a function of underlying variability in the activation of a mesocorticolimbic brain circuitry. Particularly serotonin seems to play an important role. For this reason, we assessed serotonin-2A receptor (5-HT2A R) binding in the brain of rats with different coping styles. We compared proactive and reactive males of two rat strains, Wild-type Groningen (WTG) and Roman high- and low avoidance (RHA, RLA). 5-HT2A R binding in (pre)frontal cortex (FC) and hippocampus was investigated using a radiolabeled antagonist ([(3) H]MDL-100907) and agonist ([(3) H]Cimbi-36) in binding assays. No differences in 5-HT2A R binding were observed in male animals with different coping styles. [(3) H]MDL-100907 displayed a higher specific-to-nonspecific binding ratio than [(3) H]Cimbi-36. Our findings suggest that in these particular rat strains, 5-HT2A R binding is not an important molecular marker for coping style. Because neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5-HT2A R is co-varying with levels of aggression or active avoidance in WTG, RHA and RLA.
Assuntos
Adaptação Psicológica/efeitos dos fármacos , Agressão/fisiologia , Encéfalo/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Benzilaminas/farmacocinética , Encéfalo/efeitos dos fármacos , Fluorbenzenos/farmacocinética , Masculino , Fenetilaminas/farmacocinética , Piperidinas/farmacocinética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Ratos , Ratos Endogâmicos , Serotonina/metabolismo , Antagonistas da Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/farmacocinética , Trítio/farmacocinéticaRESUMO
Many patients with major depression do not respond to selective serotonin reuptake inhibitors (SSRIs). Lack of response could be due to inhibition of dopamine (DA) release by serotonin (5-HT) through 5-HT2C receptors. Combining an SSRI with a 5-HT2C antagonist may result in improved efficacy by causing simultaneous increases of 5-HT and DA. In order to test this augmentation strategy, male Wistar rats were treated (s.c.) with an acute dose of the SSRI citalopram (Cit, 5 mg/kg), the 5-HT2C antagonist SB 242084 (SB, 2 mg/kg), or Cit + SB, and the effect on 5-HT and DA release in the nucleus accumbens (NAcc) was assessed by microdialysis. In a separate experiment, animals were treated with vehicle, Cit (20 mg/kg/d), SB (2 mg/kg/d) or Cit + SB for a period of 2 days (s.c.), and the impact on the release of 5-HT and DA in the ventral tegmental area (VTA) and NAcc was studied. On the day of microdialysis, 5-HT2C receptor sensitivity was assessed with an SB challenge. Acutely administered Cit + SB increased 5-HT release in the NAcc more than Cit alone. SB alone increased DA release in the NAcc (not in the VTA), but when administered together with Cit, this effect was abolished. A 2-day treatment with Cit or Cit + SB increased 5-HT release in both VTA and NAcc. Combining Cit with SB augmented the effect of Cit in the VTA. DA release in VTA and NAcc was only significantly increased after 2-days of treatment with Cit + SB. In conclusion, Cit + SB had synergistic effects on 5-HT and DA release after 2-days of treatment, probably related to a decreased tonic inhibition of DA release via 5-HT2C receptors. Regional differences occur and future studies should elucidate if this augmentation strategy is beneficial at the behavioral level.