RESUMO
BACKGROUND: Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia. METHODS: For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected. RESULTS: The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail. CONCLUSIONS: The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes.
Assuntos
Coleta de Dados/métodos , Fenótipo , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/diagnóstico , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Estudos Transversais , Bases de Dados Genéticas/estatística & dados numéricos , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Psicologia do EsquizofrênicoRESUMO
RATIONALE: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. OBJECTIVE: The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). METHODS: Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. RESULTS: The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. CONCLUSION: The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.
Assuntos
Citalopram/administração & dosagem , Hormônio Liberador da Corticotropina/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Barreira Hematoencefálica/efeitos dos fármacos , Citalopram/farmacocinética , Transtorno Depressivo Maior/líquido cefalorraquidiano , Transtorno Depressivo Maior/psicologia , Dexametasona/farmacologia , Feminino , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Prognóstico , Retratamento , Falha de TratamentoRESUMO
Reliability and validity of the Quality of Life (QoL) construct were investigated in healthy controls (N=346), patients with depression (N=114) and patients with schizophrenia (N=91) using two different QoL instruments: the Short-Form 36 (SF-36), a well-established generic instrument measuring eight dimensions; and the Modular System for Quality of Life (MSQoL), a recently developed instrument measuring seven core dimensions and four specific modules (objective data, partnership, family, occupation). The MSQoL and the SF-36 were administered at three intervals (hospital admission, discharge and 4-month follow-up). Reliability, group profiles (clinical specificity), responsiveness, discriminant validity (with regard to sociodemographic, psychopathological, clinical and state variables) and convergent validity were tested. At admission, patients with depression had the lowest QoL level, patients with schizophrenia had an intermediate level, and controls had the highest QoL level. At discharge and follow-up, the two patient groups did not differ from each other, but still had lower levels than controls. Both patient groups improved significantly in QoL from admission to discharge. This improvement was confounded by improvement in depressive symptoms, but not in positive or negative symptoms. Current mood state influenced QoL assessments in all three samples substantially. In conclusion, QoL can be measured reliably and with sufficient responsiveness by the MSQoL and the SF-36 in psychiatric and non-clinical populations, although discriminant validity with regard to depression and current mood is questionable.
Assuntos
Transtorno Depressivo Maior/psicologia , Qualidade de Vida , Esquizofrenia , Psicologia do Esquizofrênico , Inquéritos e Questionários , Adulto , Doença Crônica , Transtorno Depressivo Maior/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Análise Discriminante , Feminino , Seguimentos , Humanos , Masculino , Ocupações , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
Neuropeptides appear to play a role in the pathophysiology of depression and electroconvulsive treatment and lithium affect these compounds in human cerebrospinal fluid (CSF) and rodent brain. Consequently, we investigated whether long-term treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram (Cit) would also affect neuropeptides in CSF of depressed patients. Changes in CSF monoamine metabolites were also explored. CSF concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity (-LI), neuropeptide Y (NPY)-LI, and Cit were determined in 21 patients with major depression. Lumbar puncture was performed in the morning at baseline and was repeated after at least 4 wk of Cit treatment (40 mg/d). The severity of depression was assessed by the Hamilton Rating Scale for Depression (HAMD). Cit treatment was associated with a significant increase in NPY-LI and decrease in CRH-LI. An evaluation of the relationship between changes in concentrations of NPY-LI, CRH-LI, and the clinical response showed significant correlations between these parameters. Significant NPY and CRH changes in CSF following treatment as well as correlations to changes in HAMD support the hypothesis that these two peptides play a role in affective disorders and are markers of therapeutic response.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Hormônio Liberador da Corticotropina/líquido cefalorraquidiano , Depressão/tratamento farmacológico , Neuropeptídeo Y/líquido cefalorraquidiano , Adulto , Análise de Variância , Hormônio Liberador da Corticotropina/sangue , Depressão/sangue , Depressão/líquido cefalorraquidiano , Feminino , Humanos , Imunoensaio/métodos , Masculino , Pessoa de Meia-Idade , Neuropeptídeo Y/sangue , Fatores de TempoRESUMO
Plasma and cerebrospinal fluid (CSF) concentrations of the enantiomers of citalopram (CIT), its N-demethylated metabolite demethylcitalopram (DCIT) and its deaminated metabolite citalopram propionic acid derivative (CIT-PROP) were measured in plasma and CSF in 22 depressed patients after a 4-week treatment with 40 mg/d citalopram, which was preceded by a 1-week washout period. CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured at baseline and after the 4-week CIT medication period. Patients were assessed clinically, using the Hamilton Depression Rating Scale (21-item HAM-D): at baseline and then at weekly intervals. CSF concentrations of S-CIT and R-CIT were 10.6 +/- 4.3 and 20.9 +/- 6 ng/mL, respectively, and their CSF/plasma ratios were 52% +/- 9% and 48% +/- 6%, respectively. The CIT treatment resulted in a significant decrease (28%) of 5-HIAA (P < 0.0001) and a significant increase (41%) of HVA in the CSF. Multiple linear regression analyses were performed to identify the impact of plasma and CSF CIT enantiomers and its metabolites on CSF monoamine metabolites and clinical response. There were 10 responders as defined by a > or =50% decrease of the HAM-D score (DeltaHAM-D) after the 4-week treatment. DeltaHAM-D correlated (Spearman) significantly with CSF S-CIT (r = - 0.483, P < 0.05), CSF S-CIT-PROP (r = -0.543, P = 0.01) (a metabolite formed from CIT by monoamine oxidase [MAO]) and 5-HIAA decrease (Delta5-HIAA) (r = 0.572, P = 0.01). The demonstrated correlations between pharmacokinetic parameters and the clinical outcome as well as 5-HIAA changes indicate that monitoring of plasma S-CIT, CSF S-CIT and CSF S-CIT-PROP may be of clinical relevance.