RESUMO
INTRODUCTION: The pathophysiological mechanisms of acute schizophrenia are largely unknown, but it is widely accepted that dopamine D2 receptors (DRD2s) are involved in psychosis treatments for schizophrenic patients. We suggest that genetic variation in these receptors may play a role in patients' responses to commonly used antipsychotics, particularly D2-blockers. METHODS: This study included adult patients with ICD-10 diagnoses of schizophrenia and current acute psychosis who were treated with antipsychotics. All patients underwent genotyping for DRD2 rs2514218 polymorphism. The definition of overall treatment response was based on changes in treatment scheme: no changes indicated a good response, and changes indicated a limited response. RESULTS: There were 275 inpatients (38.1% of whom were female; mean age = 32.7 years, SD = 11.1 years) who met the inclusion criteria. Of the participants, 99 were good responders (34% of whom were female), and 176 were limited responders (40% of whom were female). No differences in demographic, premorbid, or disease characteristics were found. The number of patients that were homozygous for the risk allele was significantly greater in the limited response group than in the good response group. CONCLUSION: Our findings suggest that the risk variant at the DRD2 locus can be used as an indicator for patients' responses to antipsychotics without direct DRD2-blocking, thereby shortening the time needed for drug selection.
Assuntos
Antipsicóticos , Esquizofrenia , Adulto , Alelos , Antipsicóticos/uso terapêutico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pacientes Internados , Masculino , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genéticaRESUMO
BACKGROUND: Treating patients who experience residual psychotic symptoms during remission of schizophrenia remains one of the most challenging problems. The mechanisms underlying these symptoms differ from those of acute hallucinations and delusions. 5-HT6 receptor antagonists have been considered promising agents in treatment of residual psychotic symptoms and cognitive dysfunction. The aim of the study was to assess the efficacy of a selective 5-HT6 inhibitor Avisetron in the reduction of residual psychotic symptoms in patients with schizophrenia on stable antipsychotic therapy. METHODS: Eighty clinically stable outpatient subjects with schizophrenia with residual psychotic symptoms were randomized in a double-blind manner to 6 weeks of Avisetron or placebo at 1:1 ratio. Subjects received 8 mg of Avisetron or placebo on top their stable antipsychotic treatment. Standard clinical scales and cognitive tests were used for endpoint assessment. The primary efficacy endpoint was the mean reduction of total Positive and Negative Syndrome Scale score after 6 weeks of treatment. RESULTS: No significant differences in the primary and secondary endpoints were found between the groups. However, based on the subgroup analysis, the significant improvement of total Positive and Negative Syndrome Scale score and residual psychotic symptoms was observed in female patients. CONCLUSIONS: It was a negative study with unexpected benefits of the drug only in females. We hypothesized that the role of patients' sex can impact the treatment response to serotonergic drugs in general. We suggest a possible synergistic interaction between estrogen and Avisetron by means of modulating the effect of estrogens on the serotonergic system. Future studies targeting the sex-related effects of serotonergic drugs are warranted.
Assuntos
Flavonoides/uso terapêutico , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Receptores de Serotonina , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas da Serotonina/administração & dosagem , Fatores SexuaisRESUMO
UNLABELLED: The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia. OBJECTIVE: To clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive effects to stable antipsychotic treatment. METHODS: A randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic medication was performed. Seventeen patients from the study drug group and 25 patients from the placebo group completed the trial. Treatment effects were measured using clinical rating scales and attention tests. RESULTS: With no differences at baseline, there was a significant difference between the groups in Positive and Negative Syndrome Scale (PANSS) positive subscale score (p = 0.058) in favor of patients in the treatment group at the endpoint. The PANSS positive subscore (p = 0.0068) and Clinical Global Impression-Severity (CGI-S) (p = 0.048) score significantly changed only in the treatment group. Only in the placebo group were significant changes in Calgary Depression Rating Scale (CDRS) total score registered. The indices of attention tests at endpoint did not show differences between the groups, with the exception of the scope of change in the results of the subtest VIII of the Wechsler Adult Intelligence Scale (WAIS), which showed difference between the groups (p = 0.02) and was significantly larger in the treatment group. Only inside the study drug group, significant changes in selectivity and continuous attention were observed regarding total correct responses (p = 0.0038) and reaction time (p = 0.058) in the Continuous Attention Task (CAT) test. CONCLUSION: Selective 5HT6 antagonist AVN-211 (CD-008-0173) added antipsychotic and some procognitive (attention) effects to antipsychotic medication.
Assuntos
Antipsicóticos/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Serotonina , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Antagonistas da Serotonina/uso terapêutico , Adulto , Animais , Atenção , Comportamento Animal/efeitos dos fármacos , Antagonistas Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologia , Cognição , Donepezila , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Indanos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Projetos Piloto , Piperidinas/farmacologia , Inibição Pré-Pulso/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Tempo de Reação , Reflexo de Sobressalto/efeitos dos fármacos , Escopolamina/farmacologia , Antagonistas da Serotonina/farmacologia , Tacrina/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
Generalized anxiety disorder (GAD) is associated with an imbalance in the functioning of the stimulating neurotransmitter systems in human's brain. We studied the safety and therapeutic efficacy of aviandr, the new noradrenergic and specific serotonergic antidepressant, for GAD patients in the phase II, double-blind, placebo-controlled, randomized, multicenter, pilot trial at 17 clinical sites of the Russian Federation. 129 eligible patients were 18 years and older and met the criteria for GAD diagnosis. The patients were randomly assigned (1:1:1) to receive oral aviandr at daily dose of 40 mg (cohort 1, n = 41) or 60 mg (cohort 2, n = 43) or placebo (cohort 3, n = 43) for 8 weeks. The patients were assessed by the Hamilton anxiety scale (HAM-A), Hamilton Depression Scale (HAM-D), Clinical Global Impression Scale (CGI-S), Visual Analogue Scale and vital signs. At week 8, the decreases of the HAM-A score were achieved in 53â7%, 47â7% and 16â3% in cohorts 1, 2 and 3, respectively. Changes of HAM-A, HAM-D, CGI-S, and CGI-I scores in aviandr-treated patients were superior to placebo (p < 0â001). The psychic components of anxiety decreased on the first day, throughout the 8 weeks of treatment and on a follow-up week after aviandr discontinuation. Aviandr (40 mg daily dose) reduced drowsiness compared to baseline, was safe, well-tolerated and did not cause serious or severe adverse events or signs of withdrawal syndrome within one week after treatment completion. Aviandr at both 40 and 60 mg daily doses demonstrated therapeutic efficacy in GAD patients over placebo.