RESUMO
Background: QUALIFY was a 28-week, randomized, open-label, head-to-head trial that assessed improvements across multiple measures in stable patients with schizophrenia with aripiprazole once-monthly 400 mg vs paliperidone palmitate. Methods: Secondary effectiveness assessments included physician-rated readiness for work using the Work Readiness Questionnaire, the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales, and quality of life with the rater-blinded Heinrichs-Carpenter Quality of Life Scale. Patients assessed their treatment satisfaction and quality of life with Subjective Well-Being under Neuroleptic Treatment-short version and Tolerability and Quality of Life questionnaires. Results: Odds of being ready for work at week 28 were significantly higher with aripiprazole once-monthly 400 mg vs paliperidone palmitate (adjusted odds ratio, 2.67; 95% CI, 1.39-5.14; P=.003). Aripiprazole once-monthly 400 mg produced numerically or significantly greater improvements from baseline vs paliperidone palmitate in all Quality of Life Scale items. With aripiprazole once-monthly 400 mg vs paliperidone palmitate at week 28, there were significantly more Clinical Global Impression-Severity and Clinical Global Impression-Improvement responders (adjusted odds ratio, 2.26; P=.010, and 2.51; P=.0032) and significantly better Clinical Global Impression-Improvement scores (least squares mean treatment difference, -0.326; 95% CI, -0.60 to -0.05; P=.020). Numerically larger improvements with aripiprazole once-monthly 400 mg vs paliperidone palmitate were observed for patient-rated scales Subjective Well-Being under Neuroleptic Treatment-short version and Tolerability and Quality of Life. Partial correlations were strongest among clinician-rated and among patient-rated scales but poorest between clinician and patient-rated scales. Conclusions: Consistently greater improvements were observed with aripiprazole once-monthly 400 mg vs paliperidone palmitate across all measures. Partial correlations between scales demonstrate the multidimensionality of various measures of improvement. More patients on aripiprazole once-monthly 400 mg were deemed ready to work by the study end. Trial registry: National Institutes of Health registry, NCT01795547, https://clinicaltrials.gov/ct2/results?id=NCT01795547).
Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Palmitato de Paliperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Emprego , Feminino , Humanos , Masculino , Palmitato de Paliperidona/efeitos adversos , Satisfação do Paciente , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Índice de Gravidade de Doença , Método Simples-Cego , Inquéritos e Questionários , Resultado do TratamentoRESUMO
In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies.
Assuntos
Transtorno Depressivo Maior/genética , Proteínas Heterotriméricas de Ligação ao GTP/genética , Polimorfismo Genético/genética , Receptores de Ácido Caínico/genética , Adulto , Idoso , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Resultado do TratamentoRESUMO
INTRODUCTION: Treatment resistance constitutes the highest burden of disease within schizophrenia. We hypothesized that the synergistic activity of Lu AF35700 at dopamine D1 and D2 receptors might provide superior antipsychotic effects versus first-line antipsychotic therapy in patients with treatment resistant schizophrenia (TRS), with a benign tolerability profile. METHODS: This was a randomized, double-blind, active-controlled clinical trial (NCT02717195) followed by a one year open-label safety extension (NCT02892422). Following prospective confirmation of treatment resistance, patients were randomized (1:1:1) to 10 weeks double-blind treatment with Lu AF35700 10 mg or 20 mg, or active comparator (risperidone or olanzapine). RESULTS: 1628 patients were screened for TRS, of which 1092 entered the prospective confirmation period. Of these, 697 were randomized (Lu AF35700 10 mg n = 235, 20 mg n = 232, comparator n = 230) and 395 discontinued before randomization, including 264 (24 %) who responded to treatment. 586 patients completed the double-blind phase, of which 524 entered the open-label extension and 318 completed 1-year of open-label treatment. At the end of the double-blind phase, the mean ± SE change in positive and negative syndrome scale (PANSS) total score was -10.1 ± 0.96 for Lu AF35700 10 mg, -8.22 ± 0.98 for Lu AF35700 20 mg, and - 9.90 ± 0.97 for the comparator group. Treatment differences [95 % CI] versus comparator treatment were non-significant (-0.12 [-2.37; 2.13] and 1.67 [-0.59; 3.94], respectively). The most common adverse events with Lu AF35700 were increased weight and headache. Prolactin values decreased by ≥50 % in both sexes treated with Lu AF35700. CONCLUSIONS: Despite evidence of antipsychotic efficacy, treatment with Lu AF35700 failed to differentiate from conventional antipsychotic treatment for patients with TRS.
Assuntos
Antipsicóticos , Esquizofrenia , Feminino , Humanos , Masculino , Antipsicóticos/efeitos adversos , Dopamina , Método Duplo-Cego , Olanzapina/uso terapêutico , Prolactina , Estudos Prospectivos , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/induzido quimicamente , Esquizofrenia Resistente ao Tratamento , Resultado do TratamentoRESUMO
Melanin concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight. Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and, after chronic administration to rats with diet-induced obesity, resulted in a marked, sustained decrease in body weight. In addition, after mapping the binding sites for [(3)H]SNAP-7941 in rat brain, we evaluated its effects in a series of behavioral models. SNAP-7941 produced effects similar to clinically used antidepressants and anxiolytics in three animal models of depression/anxiety: the rat forced-swim test, rat social interaction and guinea pig maternal-separation vocalization tests. Given these observations, an MCH1-R antagonist may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Depressores do Apetite/farmacologia , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/metabolismo , Linhagem Celular , Dieta , Feminino , Cobaias , Humanos , Hormônios Hipotalâmicos/química , Hormônios Hipotalâmicos/metabolismo , Masculino , Melaninas/química , Melaninas/metabolismo , Estrutura Molecular , Hormônios Hipofisários/química , Hormônios Hipofisários/metabolismo , Distribuição Aleatória , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Wistar , Receptores do Hormônio Hipofisário/metabolismoRESUMO
In the present study, aimed at investigating whether a set of single nucleotide polymorphisms (SNPs) within PTGS2 gene (rs4648276, rs2066826 and rs689466) could be associated with antidepressant response, remission and treatment resistance in a sample of major depression patients, we did not find evidence supporting any of such associations.
Assuntos
Antidepressivos/uso terapêutico , Ciclo-Oxigenase 2/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , FarmacogenéticaRESUMO
OBJECTIVE: To evaluate long-term safety and effectiveness of continued treatment with aripiprazole once-monthly 400mg (AOM 400) in patients with schizophrenia. METHODS: Patients who completed the QUALIFY study (NCT01795547) in the AOM 400 arm were eligible for 6 additional once-monthly injections of AOM 400 during an open-label, 24-week extension (NCT01959035). Safety data were collected at each visit. Effectiveness measures included change from baseline in health-related qualify of life and functioning on the Heinrichs-Carpenter Quality of Life scale (QLS) and Clinical Global Impression - Severity (CGI-S) scale. RESULTS: Of the 88 patients enrolled, 77 (88%) completed the extension study. Most common treatment-emergent adverse events (incidence ≥2%) were weight increased (6/88, 7%), toothache (3/88, 3%) and headache (3/88, 3%). Effectiveness was maintained during the extension study, with small but continued improvements from baseline: the least squares mean (LSM) change (95% CI) from baseline to week 24 was 2.32 (-1.21 to 5.85) for the QLS total score and -0.10 (-0.26 to 0.06) for the CGI-S score. The aggregated LSM change (95% CI) from baseline of the lead-in study to week 24 of the extension study was 11.54 (7.45 to 15.64) for the QLS total score and -0.98 (-1.18 to -0.79) for the CGI-S score. CONCLUSIONS: AOM 400 was well tolerated in patients continuing AOM treatment during the extension phase of the QUALIFY study. Robust and clinically meaningful improvements in health-related quality of life and functioning were maintained, further supporting the long-term clinical benefits of AOM 400 for the treatment of patients with schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Humanos , Cooperação Internacional , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Adulto JovemRESUMO
Melanin-concentrating hormone (MCH) is involved in the regulation of feeding, water balance, energy metabolism, general arousal and attention state, memory, cognitive functions, and psychiatric disorders. Herein, two new chemical series exemplified by N-[5-(1-{3-[2,2-bis-(4-fluoro-phenyl)-acetylamino]-propyl}-piperidin-4-yl)-2,4-difluoro-phenyl]-isobutyramide (SNAP 102739, 5m) and N-[3-(1-{3-[(S)-2-(4-fluoro-phenyl)-propionylamino]-propyl}-piperidin-4-yl)-4-methylphenyl]-isobutyramide ((S)-6b) are reported. These compounds were designed to improve the pharmacokinetic properties of the high-throughput screening lead compound 1 (SNAP 7941). The MCH1 receptor antagonists 5m and (S)-6b show reasonable pharmacokinetic profiles (rat bioavailability = 48 and 81%, respectively). Compounds 5m and (S)-6b demonstrated the inhibition of a centrally administered MCH-evoked drinking effect, and compound 5m exhibited oral in vivo efficacy in the rat social interaction model of anxiety, with a minimum effective dose = 0.3 mg/kg.
Assuntos
Acetamidas/síntese química , Anilidas/síntese química , Ansiolíticos/síntese química , Proteínas do Citoesqueleto/antagonistas & inibidores , Piperidinas/síntese química , Pirimidinas/química , Acetamidas/farmacocinética , Acetamidas/farmacologia , Anilidas/farmacocinética , Anilidas/farmacologia , Animais , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiedade/psicologia , Disponibilidade Biológica , Encéfalo/metabolismo , Cálcio/metabolismo , Linhagem Celular , Proteínas do Citoesqueleto/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Humanos , Masculino , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Comportamento Social , EstereoisomerismoRESUMO
A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.
Assuntos
Ansiolíticos/síntese química , Proteínas do Citoesqueleto/antagonistas & inibidores , Haloperidol/análogos & derivados , Piperidinas/síntese química , Animais , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiedade/psicologia , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular , Proteínas do Citoesqueleto/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Haloperidol/síntese química , Haloperidol/farmacocinética , Haloperidol/farmacologia , Humanos , Ligantes , Masculino , Atividade Motora/efeitos dos fármacos , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Comportamento SocialRESUMO
In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a single diagnostic entity; the needs for in depth clinical phenotyping to leverage the findings of schizophrenia genetics and advance the understanding of the disease biology; the symptom domains that are the major sources of disability in order to improve functional outcomes beyond current treatment options. In spite of the progress achieved during the last century the task ahead is still daunting and will require the efforts of scientists and clinicians through inclusive public-private partnerships and consortia to create the scientific basis for new therapeutic approaches to schizophrenia.
Assuntos
Antipiréticos , Antagonistas dos Receptores de Dopamina D2 , Descoberta de Drogas/métodos , Esquizofrenia/tratamento farmacológico , Animais , Antipiréticos/efeitos adversos , Antipiréticos/farmacologia , Antipiréticos/uso terapêutico , Disfunção Cognitiva/induzido quimicamente , Transtorno Depressivo/induzido quimicamente , Antagonistas dos Receptores de Dopamina D2/efeitos adversos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Indústria Farmacêutica , Humanos , Transtornos Mentais , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologiaRESUMO
Schizophrenia is a chronic disease with negative impact on patients' employment status and quality of life. This post-hoc analysis uses data from the QUALIFY study to elucidate the relationship between work readiness and health-related quality of life and functioning. QUALIFY was a 28-week, randomized study (NCT01795547) comparing the treatment effectiveness of aripiprazole once-monthly 400 mg and paliperidone palmitate once-monthly using the Heinrichs-Carpenter Quality-of-Life Scale as the primary endpoint. Also, patients' capacity to work and work readiness (Yes/No) was assessed with the Work Readiness Questionnaire. We categorized patients, irrespective of treatment, by work readiness at baseline and week 28: No to Yes (n = 41), Yes to Yes (n = 49), or No at week 28 (n = 118). Quality-of-Life Scale total, domains, and item scores were assessed with a mixed model of repeated measures. Patients who shifted from No to Yes in work readiness showed robust improvements on Quality-of-Life Scale total scores, significantly greater than patients not ready to work at week 28 (least squares mean difference: 11.6±2.6, p<0.0001). Scores on Quality-of-Life Scale instrumental role domain and items therein-occupational role, work functioning, work levels, work satisfaction-significantly improved in patients shifting from No to Yes in work readiness (vs patients No at Week 28). Quality-of-Life Scale total scores also significantly predicted work readiness at week 28. Overall, these results highlight a strong association between improvements in health-related quality of life and work readiness, and suggest that increasing patients' capacity to work is an achievable and meaningful goal in the treatment of impaired functioning in schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Emprego , Palmitato de Paliperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona/administração & dosagem , Esquizofrenia/fisiopatologiaRESUMO
Sexual dysfunction, a common side effect of antipsychotic medications, may be partly caused by dopamine antagonism and elevation of prolactin. In QUALIFY, a randomized study, aripiprazole once-monthly 400 mg (AOM 400), a dopamine D2 receptor partial agonist, showed noninferiority and subsequent superiority versus paliperidone palmitate (PP), a dopamine D2 receptor antagonist, on the Heinrichs-Carpenter Quality-of-Life Scale (QLS) in patients with schizophrenia aged 18-60 years. Sexual dysfunction (Arizona Sexual Experience Scale) and serum prolactin levels were also assessed. Odds for sexual dysfunction were lower with AOM 400 versus PP [week 28 adjusted odds ratio (95% confidence interval), 0.29 (0.14-0.61); P=0.0012] in men [0.33 (0.13-0.86); P=0.023], women [0.14 (0.03-0.62); P=0.0099], and patients aged 18-35 years [0.04 (<0.01-0.34); P=0.003]. Among patients shifting from sexual dysfunction at baseline to none at week 28, there was a trend toward greater improvement in the QLS total score. The mean (SD) prolactin concentrations decreased with AOM 400 [-150.6 (274.4) mIU/l] and increased with PP [464.7 (867.5) mIU/l] in both men and women. Six PP-treated patients experienced prolactin-related adverse events. In addition to greater improvement on QLS, patients had a lower risk for sexual dysfunction and prolactin elevation with AOM 400 versus PP in QUALIFY.
Assuntos
Aripiprazol/efeitos adversos , Palmitato de Paliperidona/efeitos adversos , Esquizofrenia/tratamento farmacológico , Disfunções Sexuais Fisiológicas/induzido quimicamente , Adolescente , Adulto , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona/uso terapêutico , Prolactina/sangue , Qualidade de Vida , Esquizofrenia/sangue , Adulto JovemRESUMO
The importance of melanin concentrating hormone (MCH) in the control of energy balance has been confirmed by findings of lean phenotypes of mice with targeted deletion of the melanin concentrating hormone receptor 1 (MCH1-R). The recent publications of anorectic and antiobesity effects of the first two selective MCH1-R antagonists have confirmed the notion that pharmacological blockade of MCH1-R is a viable therapeutic approach for obesity. In addition, MCH1-R antagonists have been found to have antidepressant and anxiolytic properties.
Assuntos
Encefalopatias/fisiopatologia , Comportamento Alimentar/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Receptores do Hormônio Hipofisário/fisiologia , Animais , Encefalopatias/tratamento farmacológico , Comportamento Alimentar/efeitos dos fármacos , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Humanos , Receptores do Hormônio Hipofisário/agonistas , Receptores do Hormônio Hipofisário/antagonistas & inibidoresRESUMO
OBJECTIVE: To directly compare aripiprazole once-monthly 400mg (AOM 400) and paliperidone palmitate once-monthly (PP) on the Heinrichs-Carpenter Quality-of-Life Scale (QLS), a validated health-related quality of life and functioning measure in schizophrenia. METHOD: This 28-week, randomized, non-inferiority, open-label, rater-blinded, head-to-head study (QUALIFY) of AOM 400 and PP in adult patients (18-60 years) comprised oral conversion, initiation of AOM 400 or PP treatment, and continuation with intramuscular injections every 4weeks. The primary endpoint assessed non-inferiority and superiority on QLS total score analyzed using a mixed model for repeated measurements. RESULTS: Of 295 randomized patients, 100/148 (67.6%) of AOM 400 and 83/147 (56.5%) of PP patients completed 28weeks of treatment. A statistically significant least squares mean difference in change from baseline to week 28 on QLS total score (4.67 [95%CI: 0.32;9.02], p=0.036) confirmed non-inferiority and established superiority of AOM 400 vs PP. There were also significant improvements in Clinical Global Impression - Severity scale and the Investigator's Assessment Questionnaire for AOM 400 vs PP, and pre-defined sub-group analyses revealed a consistent pattern of significance favoring AOM 400 in patients ≤35years. Common treatment-emergent adverse events in the treatment continuation phase were more frequent with PP vs AOM 400, and adverse events were the most frequent reason for discontinuation (27/137 [19.7%] for PP and 16/144 [11.1%] for AOM 400). All-cause discontinuation was numerically lower with AOM 400. CONCLUSION: Superior improvements on clinician-rated health-related quality of life and a favorable tolerability profile suggest greater overall effectiveness for aripiprazole once-monthly vs paliperidone palmitate. ClinicalTrials.gov identifier:NCT01795547.
Assuntos
Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Palmitato de Paliperidona/administração & dosagem , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Palmitato de Paliperidona/efeitos adversos , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Método Simples-Cego , Resultado do TratamentoRESUMO
Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study. They were genotyped for COX-2 and OXTR SNPs. Treatment resistance (according to two different definitions), response and remission were recorded. We did not observe any association between the genotypes or alleles of the selected SNPs within COX-2 and OXTR genes and treatment resistance, response and remission in the whole sample. Our results are consistent with those of some studies but not with those of other ones. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, and different definitions of treatment resistance.
Assuntos
Ciclo-Oxigenase 2/genética , Depressão/genética , Depressão/terapia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Ocitocina/genética , Depressão/epidemiologia , Feminino , Predisposição Genética para Doença/prevenção & controle , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Falha de Tratamento , Resultado do TratamentoRESUMO
Our study aims at replicating our previous finding of an association between COMT rs4680 G/A polymorphism and early onset major depression (MD). We included 462 MD, 147 bipolar disorders (BD) subjects and 295 healthy controls. We could partially replicate previous findings. In particular, rs4680 GG+AG genotypes were more represented in the subgroup of early onset MD patients (p=0.04). Additionally, we observed an association between rs737865 alleles and early onset MD (p=0.04). Rs4680 genotype was associated with early onset BD as well (p=0.01). In conclusion, we partially replicated our previous findings confirming a possible influence of COMT variants in MD and BD, particularly in early onset subjects, though not with the same risk genotypes.
Assuntos
Idade de Início , Transtorno Bipolar/genética , Catecol O-Metiltransferase/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Adulto , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has pivotal roles in neuronal survival, proliferation, and synaptic plasticity in the brain. Both clinical and pharmacological studies have implicated the common single nucleotide polymorphism (SNP) at position 196, Val66Met in the pathophysiology of major depressive disorder (MDD), and antidepressant response. However, inconsistent results were found between Val66Met (rs6265) polymorphism and treatment response phenotypes in genetic association studies. The functional Val66Met polymorphism and seven other tagging SNP markers selected to capture the major allelic variations across BDNF locus were analyzed in depressed patients, treated with antidepressants, and 76 control patients. Two hundred and six patients with Diagnostic and Statistical Manual of Mental Disorders-IV MDD were recruited for this study and genotyped for eight BDNF tagging SNPs (rs11030096, rs925946, rs10501087,rs6265, rs12273363, rs908867, rs1491850, and rs1491851)to investigate the functional impact of genotypes/haplotypes in the susceptibility of depression and on treatment response. None of the eight SNPs, including the rs6265, were significantly associated with MDD after permutation correction. However, we found an association for rs10501087, rs6265 with nonresponse to antidepressant treatment (corrected permutation P:0.03599; 0.0399 and power: 0.1420; 0.1492, respectively).Analysis of each two-marker, three-marker, and four-marker sliding window haplotypes showed significance in haplotype combinations. Especially rs10501087 (C), rs6265 (A), and rs149,1850 (C) together or with the other SNP haplotypes showed a similar pattern in all treatment response phenotypes. Despite the limited power of analysis, our results suggest that these three SNPs may play a role in antidepressant treatment response phenotypes in MDD.
Assuntos
Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Transtorno Depressivo Maior/tratamento farmacológico , Alelos , Transtorno Depressivo Maior/genética , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Indução de Remissão , Resultado do TratamentoRESUMO
BACKGROUND: The transcription factor Cyclic adenosine monophosphate Response Element Binding (CREB) protein has been repeatedly involved in the aetiology and pharmacotherapy of major depression (MD). The aim of this study was to investigate the potential association of a set of single nucleotide polymorphisms (SNPs) in CREB1 gene and both MD and response, remission and treatment resistance to antidepressants. METHODS: One hundred-ninety MD patients collected in the context of a resistant depression study and treated with antidepressants for at least 4weeks were genotyped for 5 CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). Response, remission and treatment resistance were recorded. RESULTS: An allele of rs7569963 as well as rs2253206-rs7569963 A-A and rs7569963-rs4675690 A-C haplotypes were associated with the status of treatment resistance. Additionally, rs7569963 GG genotype was positively associated with remission. No further significant associations were observed. LIMITATIONS: Limitations of the present study include a relatively small sample size and the incomplete ascertainment of data which could influence the outcome. CONCLUSIONS: Our results preliminary suggest that some genetic polymorphisms in CREB1 could be associated to treatment resistance. Although such finding needs to be replicated in larger samples, it increases current knowledge about the genetic predictors of response to antidepressants that will probably lead to enhance treatment outcomes by addressing each individual to the most appropriate treatment strategy in the early stages of treatment.
Assuntos
Antidepressivos/uso terapêutico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Resistência a Medicamentos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Indução de Remissão , Fatores de Risco , Estudos de Amostragem , Resultado do TratamentoRESUMO
OBJECTIVES: Dystrobrevin binding protein 1 (Dysbindin) is a plausible candidate gene for major depressive disorders (MDD) due to its involvement in synaptic signaling, plasticity and localization in the brain. METHODS: Two intronic SNPs of DTNBP1; rs760761 (P1320) and rs2619522 (P1763) were analyzed in 206 patients with DSM-IV MDD to investigate the functional impact of genotypes on susceptibility for depression and some clinical phenotypes. The Sequenom iPLEX assay (Sequenom, Cambridge, MA) was used for genotyping. RESULTS AND CONCLUSIONS: Despite the limited power of analysis, our results showed that these two SNPs in DTNPB1 gene were not related to clinical phenotypes such as melancholia, age at onset, suicidality and co-morbid anxiety disorders, as well as to treatment response phenotypes.
Assuntos
Proteínas de Transporte/genética , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idade de Início , Idoso , Alelos , Antidepressivos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Comorbidade , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Transtorno Depressivo Maior/tratamento farmacológico , Resistência a Medicamentos/genética , Disbindina , Proteínas Associadas à Distrofina , Feminino , Frequência do Gene , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Ideação SuicidaRESUMO
The 5HT2A (5HTR2A) and 5HT1A receptor (5HTR1A) genes are plausible candidate genes for major depressive disorders. Two single nucleotide polymorphisms, the rs7997012 in 5HTR2A and the -1019C/G in 5HTR1A, were analyzed in 206 patients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder. Patients were retrospectively characterized for clinical response to antidepressant treatment. We found a significant difference in the rs7997012 allele frequency between resistant and nonresistant patients. However, following the Bonferroni correction we could not find any association between this single nucleotide polymorphism and treatment resistance phenotype. Nevertheless, given the limited power of our analysis, we are not able to conclude that these results reflect a lack of association. Additional studies are needed to confirm or to disprove our result.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Polimorfismo de Nucleotídeo Único/genética , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Transtorno Depressivo Maior/diagnóstico , Resistência a Medicamentos , Frequência do Gene/genética , Genótipo , Humanos , Farmacogenética , Fenótipo , Escalas de Graduação Psiquiátrica , Indução de Remissão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
An alpha1a-adrenoceptor-selective antagonist has the potential to be a new benign prostatic hyperplasia drug with reduced side-effects. Modification of the non-selective antagonist BE2254 led to the development of a series of tetralin analogs. Evaluation of these compounds in cloned human alpha1-adrenoceptors resulted in the discovery of an analog that showed selectivity toward the human alpha1a-adrenergic receptor subtype. The compound also showed moderate potency to block human prostate muscle contraction.