RESUMO
BACKGROUND: The allocation of any scarce health care resource, especially a lifesaving resource, can create profound ethical and legal challenges. Liver transplant allocation currently is based upon urgency, a sickest-first approach, and does not utilize capacity to benefit. While urgency can be described reasonably well with the MELD system, benefit encompasses multiple dimensions of patients' well-being. Currently, the balance between both principles is ill-defined. METHODS: This survey with 502 participants examines how urgency and benefit are weighted by different stakeholders (medical staff, patients on the liver transplant list or already transplanted, medical students and non-medical university staff and students). RESULTS: Liver transplant patients favored the sickest-first allocation, although all other groups tended to favor benefit. Criteria of a successful transplantation were a minimum survival of at least 1 year and recovery of functional status to being ambulatory and capable of all self-care (ECOG 2). An individual delisting decision was accepted when the 1-year survival probability would fall below 50%. Benefit was found to be a critical variable that may also trigger the willingness to donate organs. CONCLUSIONS: The strong interest of stakeholder for successful liver transplants is inadequately translated into current allocation rules.
Assuntos
Atitude , Transplante de Fígado/ética , Seleção de Pacientes , Ética Baseada em Princípios , Obtenção de Tecidos e Órgãos , Listas de Espera , Adulto , Idoso , Idoso de 80 Anos ou mais , Beneficência , Feminino , Humanos , Masculino , Corpo Clínico , Pessoa de Meia-Idade , Participação dos Interessados , Estudantes de Medicina , Inquéritos e Questionários , Universidades , Adulto JovemRESUMO
BACKGROUND: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. METHODS: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. RESULTS: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1ß (IL-1ß) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. CONCLUSIONS: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention.
Assuntos
Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/patologia , Inflamação/imunologia , Inflamação/patologia , Adulto , Idoso , Doenças Cardiovasculares/metabolismo , Moléculas de Adesão Celular/metabolismo , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Sistema Nervoso/metabolismo , Estudos Prospectivos , Fatores de RiscoRESUMO
The tryptophan metabolism and immune activation play a role in pathophysiology of major depressive disorders. The pro-inflammatory cytokine interferon-γ transcriptionally induces the indoleamine 2,3-dioxygenase enzyme that degrades the tryptophan and thus induces serotonin depletion. The polymorphism of certain cytokine genes was reported to be associated with major depression. We investigated the association between interferon-γ (IFNγ) gene CA repeat polymorphism, the profile of serotonin and tryptophan pathway metabolites and clinical parameters in 125 depressed patients and 93 healthy controls. Compared to controls, serum tryptophan and 5-hydroxyindoleacetic acid (5HIAA) concentrations in the patients were significantly lower and serum kynurenine concentrations were significantly higher at baseline (p<0.0001). The presence of IFNγ CA repeat allele 2 homozygous has significant association with higher kynurenine concentrations in controls (F=4.47, p=0.038) as well as in patients (F=3.79, p=0.045). The existence of interferon-γ CA repeat allele 2 (homo- or heterozygous) showed significant association with increase of tryptophan breakdown over time during the study period (F=6.0, p=0.019). The results indicated the association between IFNγ CA repeat allele 2, tryptophan metabolism and the effect of medication.
Assuntos
Transtorno Depressivo Maior/metabolismo , Interferon gama/genética , Triptofano/metabolismo , Adulto , Idoso , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/imunologia , Feminino , Humanos , Ácido Hidroxi-Indolacético/metabolismo , Imunogenética , Interferon gama/metabolismo , Cinurenina/genética , Cinurenina/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Serotonina/genética , Serotonina/metabolismo , Triptofano/genéticaRESUMO
OBJECTIVES: The effectiveness of electroconvulsive therapy (ECT) in pharmacotherapy-resistant major depressive disorder and schizophrenia has been shown for all age groups. Nevertheless, age-specific adverse effects such as greater cognitive impairment and higher somatic risks due to medical comorbidities and concomitant medication may be limiting factors in geriatric patients. METHODS: We retrospectively evaluated 4457 treatments in 380 patients to investigate the influence of age on ECT outcome, safety, and adverse effects. Clinical variables, treatment modalities, and neurophysiological parameters were analyzed. For modeling the influence of age on these variables of interest, linear and logistic regression models were performed. RESULTS: The mean (SD) age of our patients was 51.2 (15) years; 30% were older than 60 years. Diagnoses were major depressive disorder in 74.4% and schizophrenia in 25.6%. We found a considerable clinical improvement in all age groups. A higher severity of disease at admission corresponded to a better clinical response. Analyzing treatment modalities of elderly patients older than 60 years, no significant differences in need and number of concomitant psychotropic medications were seen, but significant differences were seen in medical co-medication. Ictal and postictal neurophysiological parameters were only in part predictive for clinical outcome, but age had a significant influence on most of them. Transient cardiovascular adverse effects and cognitive disturbances were more frequent in the elderly. In most cases, there was no need for any specific treatment. CONCLUSIONS: Our data confirm previous studies indicating the good effectiveness of ECT irrespective of age. We also found an excellent tolerability profile in the elderly in our patient sample. There was no mortality, and only transient and no life-threatening adverse events occurred.
Assuntos
Envelhecimento/fisiologia , Eletroconvulsoterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia , Eletroconvulsoterapia/efeitos adversos , Eletroencefalografia , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Estudos Retrospectivos , Convulsões/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
Experimental panic induction with cholecystokinin tetrapeptide (CCK-4) is considered as a suitable model to investigate the pathophysiology of panic attacks. While only a few studies investigated the brain activation patterns following CCK-4, no data are available on the putative involvement of the amygdala in the CCK-4 elicited anxiety response. We studied the functional correlates of CCK-4-induced anxiety in healthy volunteers by means of functional magnetic resonance imaging (fMRI) and region of interest (ROI) analysis of the amygdala. Sixteen healthy volunteers underwent challenge with CCK-4 compared with placebo in a single-blind design. Functional brain activation patterns were determined for the CCK-4-challenge, the placebo response and anticipatory anxiety (AA). CCK-4-induced anxiety was accompanied by a strong and robust activation (random effects analysis, P < 0.00001, uncorrected for multiple testing) in the ventral anterior cingulate cortex (ACC), middle and superior frontal gyrus, precuneus, middle and superior temporal gyrus, occipital lobe, sublobar areas, cerebellum, and brainstem. In contrast, random effects group analysis for placebo and AA using the same level of significance generated no significant results. Using a more liberal level of significance, activations could be observed in some brain regions such as the dorsal part of the ACC during AA (random effects analysis, P < 0.005). Overall functional responses did not differ between panickers and nonpanickers. Only 5 of 11 subjects showed strong amygdala activation. However, ROI analysis pointed towards higher scores in fear items in these subjects. In conclusion, while overall brain activation patterns are not related to the subjective anxiety response to CCK-4, amygdala activation may be involved in the subjective perception of CCK-4-induced fear.
Assuntos
Encéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Transtorno de Pânico/fisiopatologia , Adulto , Tonsila do Cerebelo/anatomia & histologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Ansiedade/induzido quimicamente , Ansiedade/fisiopatologia , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico , Medo/efeitos dos fármacos , Medo/fisiologia , Giro do Cíngulo/anatomia & histologia , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/fisiopatologia , Humanos , Sistema Límbico/anatomia & histologia , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/anatomia & histologia , Rede Nervosa/efeitos dos fármacos , Transtorno de Pânico/induzido quimicamente , Tetragastrina/farmacologia , Adulto JovemRESUMO
BACKGROUND: Among the neuroactive steroids, dehydroepiandrosterone sulfate (DHEA-S) is at least in part produced in the adrenal gland and is therefore under the control of the hypothalamic-pituitary-adrenocortical (HPA)-system. In the present study, the impact of mirtazapine on DHEA-S and cortisol (COR) levels was investigated in relation to clinical response in depressed patients. METHODS: A total of 23 inpatients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/day). Plasma samples were taken weekly at 0800 h and quantified for COR and DHEA-S levels. RESULTS: Mirtazapine significantly reduced both COR and DHEA-S concentrations, but had no impact on the COR/DHEA-S ratio. The percentage decrease of DHEA-S, but not that of COR was significantly and positively correlated with the percentage reduction in the sum score of the Hamilton Depression Rating Scale at week 5, suggesting a relationship between DHEA-S reduction and clinical efficacy of mirtazapine. There was a significant positive correlation between the decline in COR and DHEA-S levels. CONCLUSIONS: Apparently, the decrease in COR and DHEA-S concentrations conjointly reflects an attenuating impact of mirtazapine on HPA axis activity, thereby decreasing the adrenal secretion of COR and DHEA-S.
Assuntos
Antidepressivos Tricíclicos/sangue , Sulfato de Desidroepiandrosterona/sangue , Transtorno Depressivo/sangue , Hidrocortisona/sangue , Mianserina/análogos & derivados , Adulto , Idoso , Análise de Variância , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Sulfato de Desidroepiandrosterona/química , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/tratamento farmacológico , Feminino , Humanos , Masculino , Mianserina/sangue , Mianserina/farmacologia , Mianserina/uso terapêutico , Pessoa de Meia-Idade , Mirtazapina , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
RATIONALE: Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder. In line with the serotonin (5-HT)-hypothesis of panic disorder it has been suggested that the panicogenic effects of CCK-4 are mediated in part through the 5-HT system. The analysis of the loudness dependency of the auditory evoked potentials (LDAEP) is a valid non-invasive indicator of central serotonergic activity. METHODS: We investigated the correlation between LDAEP and behavioral, cardiovascular and neuroendocrine panic responses to CCK-4in 77 healthy volunteers and explored whether differences in LDAEP paralleled subjective panic severity. Behavioral panic responses were measured with the panic symptom scale (PSS). Heart rate and ACTH/cortisol plasma concentrations were assessed concomitantly. RESULTS: LDAEP did not differ between panickers and nonpanickers. Furthermore, LDAEP did not correlate with the behavioral panic response. However, a significant positive correlation between LDAEP and CCK-4 induced HPA-axis activation, which was uniform in panickers and nonpanickers, could be detected. CONCLUSIONS: The psychological effects of CCK-4 rather are mediated by neurotransmitters others than the endogenous 5-HT system. However, the extent of the neuroendocrine activation related to the CCK-4 panic provocation was correlated with the LDAEP, thereby suggesting that central 5-HT mechanisms are involved in the HPA-axis activation during this challenge paradigm.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Potenciais Evocados Auditivos , Hidrocortisona/sangue , Percepção Sonora , Pânico/fisiologia , Tetragastrina/toxicidade , Estimulação Acústica/métodos , Hormônio Adrenocorticotrópico/biossíntese , Adulto , Eletroencefalografia , Potenciais Evocados Auditivos/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrocortisona/biossíntese , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Percepção Sonora/efeitos dos fármacos , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiopatologia , Radioimunoensaio , Índice de Gravidade de Doença , Estatística como Assunto , Tetragastrina/administração & dosagemRESUMO
Copeptin, the C-terminal part of the hypothalamic arginine vaspopressin (AVP) precursor, closely mirrors the production of AVP and was proposed as an easily measured novel marker of the individual stress level in man. First data in male volunteers proposed copeptin as a potential endocrine surrogate marker of cholecystokinin-tetrapeptide (CCK-4)-induced panic. We tried to replicate these pilot data and to extend them to the other sex. 46 healthy human subjects (29 men, 17 women) were given an intravenous bolus of 50⯵g CCK-4. Basal and stimulated plasma copeptin was measured and panic symptoms were assessed using the Acute Panic Inventory (API). Basal copeptin was significantly lower in women vs. men, while men showed a significantly higher CCK-4-induced increase of copeptin. In contrast, female subjects displayed a signifcantly higher increase of API ratings by CCK-4. No significant correlations of panic symptoms and copeptin release induced by CCK-4 could be found, neither in man, nor in women, nor in the total sample. A sexual dimorphism in copeptin secretion and in panic response was demonstrated. Prior unexpected findings of copeptin release as an objective read-out of panic could not be replicated. The role of the vasopressinergic system in panic anxiety needs further study in panic patients and in healthy man, using also other panic provocation paradigms.
Assuntos
Glicopeptídeos/sangue , Transtorno de Pânico/induzido quimicamente , Transtorno de Pânico/diagnóstico , Pânico/efeitos dos fármacos , Caracteres Sexuais , Tetragastrina/efeitos adversos , Adaptação Psicológica/efeitos dos fármacos , Adulto , Biomarcadores/sangue , Feminino , Glicopeptídeos/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Transtorno de Pânico/sangue , Via Secretória/efeitos dos fármacos , Adulto JovemRESUMO
Core symptoms of depression are a combination of psychological and somatic symptoms, often combined with psychomotor and cognitive disturbances. Diagnostic classification of depression including the concepts of melancholic, endogenous, or severe depression describe severely depressed patients suffering from most of the core symptoms, together with clinical characteristics of a cyclic unipolar or bipolar course, lower placebo response rates, higher response rates to electroconvulsive therapy, to antidepressant treatments with dually or mixed modes of action, or to lithium augmentation. Higher rates of hypothalamic-pituitary-adrenal axis hyperactivity and specific electroencephalographic patterns have also been shown in this patient group. Summarizing the symptomatology of depression in these patients, a broad overlap between the abovementioned subgroups can be suggested. Because the positive diagnosis of those core symptoms of depression may include clinical consequences, it would be of use to integrate all the mentioned concepts in the upcoming new versions of the diagnostic systems DSM-V and ICD-11.
Assuntos
Depressão/classificação , Depressão/terapia , Antidepressivos/uso terapêutico , Depressão/fisiopatologia , Eletroconvulsoterapia , HumanosRESUMO
Antidepressants such as SSRIs or mirtazapine have been demonstrated to increase the concentrations of 3alpha-reduced neuroactive steroids throughout several weeks of treatment. However, no data are available on the impact of mood stabilizers such as lithium or carbamazepine on neuroactive steroid levels in depressed patients. Study 1 was performed in 26 drug-free depressed inpatients who were treated with either mirtazapine monotherapy (n=13) or combination therapy with mirtazapine and addition of lithium (n=13). Twenty drug-free depressed inpatients were included in study 2, receiving either mirtazapine monotherapy (n=10) or combination treatment with mirtazapine and carbamazepine (n=10). Plasma samples were taken weekly at 0800 h in the morning and quantified for neuroactive steroids by means of combined gas chromatography/mass spectrometry analysis. In study 1, the mirtazapine-induced rises in 3alpha,5alpha-tetrahydroprogesterone and 3alpha,5beta-tetrahydroprogesterone were abolished by additional lithium administration, as compared to mirtazapine monotherapy. In study 2, the mirtazapine-evoked increase in 3alpha,5alpha-tetrahydroprogesterone was reversed after additional administration of carbamazepine, presumably due to lowered mirtazapine levels after induction of cytochrome P450 enzymes. Apparently, the mood stabilizers lithium and carbamazepine do not enhance but rather reverse the increase in plasma concentrations of 3alpha-reduced neuroactive steroids in depressed patients pretreated with antidepressants such as mirtazapine.
Assuntos
Depressão/sangue , Depressão/tratamento farmacológico , Mianserina/análogos & derivados , Esteroides/sangue , Tranquilizantes/administração & dosagem , Tranquilizantes/farmacologia , Adulto , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/farmacologia , Quimioterapia Combinada , Feminino , Humanos , Compostos de Lítio/administração & dosagem , Compostos de Lítio/farmacologia , Masculino , Mianserina/administração & dosagem , Mianserina/farmacologia , Pessoa de Meia-Idade , Mirtazapina , Pregnanolona/análogos & derivados , Pregnanolona/sangue , Progesterona/análogos & derivados , Progesterona/sangueRESUMO
RATIONALE: Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder and might serve as a tool to asses the antipanic potential of novel anxiolytic compounds. However, assessment of CCK-4-induced panic does not follow consistent rules. OBJECTIVES: To provide a basis for the use of the CCK-4 model in proof-of-concept studies, we investigated CCK-4-induced panic according to different criteria in 85 healthy volunteers who underwent a CCK-4 bolus injection. METHODS: We assessed panicker/non-panicker ratios according to different panic criteria and explored whether differences in cardiovascular and neuroendocrine responses to CCK-4 paralleled subjective panic responses. Subjective panic responses were measured with the Acute Panic Inventory (API) and the Panic Symptom Scale (PSS). Heart rate, blood pressure, adrenocorticotropic hormone (ACTH) and cortisol were assessed concomitantly. RESULTS: The API-derived panic rate was 10.6% higher than that derived from the PSS. CCK-4 induced an increase in heart rate, systolic blood pressure and ACTH/cortisol plasma levels, which did not differ between panickers and non-panickers. CONCLUSIONS: The panic criterion applied appears to be of major importance for the panic rate achieved, whereas CCK-4-induced cardiovascular and hormonal alterations are not valuable as an objective "read out". The CCK-4 challenge might serve as a useful model to study putative anxiolytic effects of novel compounds during the early phase of drug development if the challenge procedure is carried out according to strictly comparable conditions.
Assuntos
Transtorno de Pânico/fisiopatologia , Tetragastrina , Hormônio Adrenocorticotrópico/sangue , Adulto , Análise de Variância , Pressão Sanguínea , Frequência Cardíaca , Humanos , Hidrocortisona/sangue , Masculino , Modelos Biológicos , Modelos Psicológicos , Transtorno de Pânico/induzido quimicamente , Transtorno de Pânico/psicologia , Inventário de Personalidade , Valores de ReferênciaRESUMO
Depressive disorders are of the highest socioeconomic and health-economic importance, as they are the psychiatric disorders that most frequently cause psychosocial disability. Despite the progress that has been made, currently available pharmacotherapies for depression still have a limited antidepressant efficacy with a delayed onset of several weeks, and still cause side effects; these unmet needs represent important reasons to continue to search for novel treatment options. A disorganization of circadian rhythms has been suggested to play an important role in the pathophysiology of major depression, and complaints regarding disturbed sleep are frequent in depressed patients. As endogenous melatonin secretion underlies the regulation of circadian rhythms, compounds with activity at melatonergic receptors have been proposed as potential novel therapeutics. Agomelatine (S-20098), a compound with agonistic properties at MT1 and MT2 receptors and antagonistic properties at the 5-HT2C receptor, has been shown preclinically to exhibit robust antidepressant effects in several experimental paradigms. Clinical trials, including phase III studies, have now demonstrated the superior efficacy of agomelatine in comparison with placebo, and a similar efficacy in comparison with active comparators, for the treatment of major depression. Agomelatine was even effective in severely depressed patients. In all studies published so far, agomelatine was found to be safe and its overall tolerability profile was superior to that of selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors.
Assuntos
Acetamidas/uso terapêutico , Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Acetamidas/efeitos adversos , Ansiolíticos/efeitos adversos , Antidepressivos/efeitos adversos , Ritmo Circadiano , Transtorno Depressivo/fisiopatologia , Humanos , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Antagonistas do Receptor 5-HT2 de SerotoninaRESUMO
BACKGROUND: There is preliminary evidence that the atypical antipsychotic aripiprazole, which is a partial agonist at D(2) and 5-HT(1A) receptors and a potent antagonist at 5-HT(2A) receptors, may be useful as an augmentation strategy in treatment-resistant depression. METHOD: In this 4-week open-label non-randomized parallel-group study, the safety and efficacy of aripiprazole as add-on treatment strategy in patients suffering from non-delusional depression was investigated. Forty drug-free depressed inpatients without psychotic symptoms (13 men, 27 women), suffering from a major depressive episode or bipolar disorder, depressive state (DSM-IV criteria), were included in the study. The patients were treated either with mirtazapine monotherapy (45 mg/day) or combination therapy (mirtazapine 45 mg/day plus aripiprazole 15 mg/day) for 4 weeks. Safety and efficacy were assessed weekly using the Hamilton Depression Rating Scale, the Simpson-Angus Scale and the Barnes Akathisia Scale. RESULTS: Mirtazapine monotherapy and combined treatment with mirtazapine and aripiprazole showed comparable antidepressant effects as assessed at the endpoint of the study period. However, additional administration of aripiprazole accelerated the onset of antidepressant action in patients suffering from treatment-resistant depression. Additive use of aripiprazole reduced the mirtazapine-induced increase in the body mass index. Moreover, mirtazapine had favourable effects on aripiprazole-induced akathisia. No other extrapyramidal side effects were seen in the combination therapy group. CONCLUSION: Combined therapy with mirtazapine and aripiprazole is a safe and well-tolerated treatment option which may be useful especially in treatment-resistant depression. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole in depressed patients.
Assuntos
Antidepressivos Tricíclicos/administração & dosagem , Antipsicóticos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Mianserina/análogos & derivados , Piperazinas/administração & dosagem , Quinolonas/administração & dosagem , Adulto , Idoso , Antidepressivos Tricíclicos/efeitos adversos , Antipsicóticos/efeitos adversos , Aripiprazol , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Mianserina/administração & dosagem , Mianserina/efeitos adversos , Pessoa de Meia-Idade , Mirtazapina , Exame Neurológico/efeitos dos fármacos , Inventário de Personalidade , Piperazinas/efeitos adversos , Quinolonas/efeitos adversosRESUMO
Data suggest that both neurotrophic and hypothalamic-pituitary-adrenocortical (HPA) systems are involved in the pathophysiology of depression. The aim of the present study was to investigate whether the non-conservative brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has an impact on HPA axis activity in depressed patients. At admission, the dexamethasone/CRH (DEX/CRH) test was performed in 187 drug-free in-patients suffering from major depression or depressed state of bipolar disorder (DSM-IV criteria). Moreover, genotyping of BDNF Val66Met polymorphism was carried out using the fluorescence resonance energy transfer method (FRET). Homozygous carriers of the Met/Met genotype showed a significantly higher HPA axis activity during the DEX/CRH test than patients carrying the Val/Val or Val/Met genotype (ACTH, cortisol). Our results further contribute to the hypothesized association between HPA axis dysregulation and reduced neuroplasticity in depression and are consistent with the assumption that BDNF is a stress-responsive intercellular messenger modifying HPA axis activity.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Hormônio Liberador da Corticotropina , Transtorno Depressivo/genética , Transtorno Depressivo/psicologia , Dexametasona , Hormônio Adrenocorticotrópico/sangue , Adulto , Substituição de Aminoácidos , Transtorno Bipolar/psicologia , Transtorno Depressivo Maior/psicologia , Feminino , Genótipo , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Escalas de Graduação PsiquiátricaRESUMO
RATIONALE: In healthy subjects, cortisol and ACTH secretion are acutely stimulated by reboxetine and inhibited by mirtazapine. However, it was not investigated so far whether reboxetine and mirtazapine may also differ in their impact on hypothalamic-pituitary-adrenocortical (HPA) axis activity in depressed patients and whether these effects are related to clinical outcome. OBJECTIVES: In the present study, we investigated the impact of 5-week treatment with reboxetine or mirtazapine on the combined dexamethasone suppression/corticotropin releasing hormone (DEX/CRH) test results in depressed patients. METHODS: Forty drug-free patients suffering from a major depressive episode (Diagnostic and Statistical Manual of Mental Disorders-IV criteria) were treated with either reboxetine (8 mg/day; n=20) or mirtazapine (45 mg/day; n=20) for 5 weeks. Before, after 1 and 5 weeks of therapy, the DEX/CRH test was performed and cortisol and ACTH concentrations were measured. RESULTS: During reboxetine treatment, a gradual and significant reduction in HPA axis activity as measured by the DEX/CRH test was seen, which was most pronounced after 5 weeks of treatment. In contrast, mirtazapine significantly reduced the cortisol and ACTH concentrations during the DEX/CRH test within 1 week. However, after 5 weeks of mirtazapine treatment, the cortisol and ACTH responses to the DEX/CRH test partially increased again both in responders and nonresponders. CONCLUSIONS: This is the first study demonstrating differential effects of various antidepressants on the time course of serial DEX/CRH test results in depressed patients.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Mianserina/análogos & derivados , Morfolinas/uso terapêutico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Antidepressivos/farmacologia , Hormônio Liberador da Corticotropina , Transtorno Depressivo Maior/sangue , Dexametasona , Feminino , Glucocorticoides , Humanos , Hidrocortisona/sangue , Masculino , Mianserina/farmacologia , Mianserina/uso terapêutico , Pessoa de Meia-Idade , Mirtazapina , Morfolinas/farmacologia , Escalas de Graduação Psiquiátrica , Reboxetina , Fatores de TempoRESUMO
Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABAA) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety- and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of 3alpha-reduced neuroactive steroids have been observed during major depression. This disequilibrium can be corrected by successful treatment with antidepressant drugs. However, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition independently from the clinical response. Further research is needed to clarify whether enhancement of neuroactive steroid levels might represent a new therapeutical approach in the treatment of affective disorders. Nevertheless, the first studies investigating the therapeutical effects of exogenously administered dehydroepiandosterone revealed promising results in the treatment of major depression. In addition, in various anxiety disorders alterations of neuroactive steroid levels have been observed. In panic disorder, in the absence of panic attacks, neuroactive steroid composition is opposite to that seen in depression, which may represent counter-regulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimentally induced panic attacks, there was a pronounced decline in GABAergic neuroactive steroids, which might contribute to the pathophysiology of panic attacks. In conclusion, neuroactive steroids contribute to the pathophysiology of affective disorders and the mechanisms of action of antidepressants. They are important endogenous modulators of depression and anxiety and may provide a basis for the development of novel therapeutic agents in the treatment of affective disorders.
Assuntos
Sulfato de Desidroepiandrosterona/farmacologia , Desidroepiandrosterona/farmacologia , Pregnanos/farmacologia , Animais , Ansiolíticos/sangue , Ansiolíticos/farmacologia , Antidepressivos/sangue , Antidepressivos/farmacologia , Depressão/sangue , Depressão/tratamento farmacológico , Humanos , Transtorno de Pânico/sangue , Pregnanos/sangueRESUMO
Anxiety disorders are highly prevalent and disabling disorders which are commonly treated with pharmacotherapy and/or psychotherapy. While benzodiazepines are of great value for the treatment of acute anxiety states, their long-term use is hampered by their well-known side effect profile. Meanwhile, antidepressants represent first line treatment options for anxiety disorders. However, their slow onset of action is a disadvantage for their use in these disorders. Therefore, there is need for novel anxiolytics with a rapid onset of action and a favourable side effect profile. Currently, there is a renaissance of gamma-aminobutyric acid type A (GABAA) receptors as targets for the development of novel anxiolytic drugs. While compounds structurally related to GABA, e.g., pregabalin, have already entered large scale clinical development, GABA transporter inhibitors, subtype specific benzodiazepines and GABAA receptor modulating neuroactive steroids are promising new candidates. However, their clinical efficacy has still to be shown in clinical trials.
Assuntos
Ansiolíticos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Receptores de GABA-A/efeitos dos fármacos , Animais , Ansiolíticos/química , Humanos , CamundongosRESUMO
BACKGROUND: A major problem in the treatment of severe depression is the onset latency until clinical improvement. So far, electroconvulsive therapy (ECT) is the most effective somatic treatment of depression. This holds especially true for treatment-refractory disturbances. However, not all patients respond to conventional unilateral ECT. In certain cases, subsequent clinical response can be achieved using bilateral or high-dose unilateral ECT. Also, a concomitant pharmacotherapy can be utilized to augment therapeutic effectiveness. Surprisingly, data in this field are widely lacking and only few studies showed advantages of an ECT/tricyclic antidepressant combination. METHOD: We retrospectively evaluated 5482 treatments in 455 patients to investigate possible therapeutic advantages in combination therapies versus ECT monotherapy. Main outcome criteria were clinical effectiveness and tolerability. Moreover, treatment modalities and ictal neurophysiological parameters that might influence treatment outcome were analysed. RESULTS: A total of 18.2% of our treatments were ECT monotherapy, 8.87% were done with one antidepressant. Seizure duration was unaffected by the most antidepressants. SSRI caused a lengthened seizure activity. Postictal suppression was lower in mirtazapine and higher in SSRI and SNRI treated patients. A significant enhancement of therapeutic effectiveness could be seen in the patient group receiving tricyclics, SSRI or mirtazapine. Serious adverse events were not recorded. CONCLUSION: Our study supports the hypothesis that mirtazapine can be used to enhance the therapeutic effectiveness of ECT. Controlled studies are necessary to further investigate the possible advantages of ECT and pharmacotherapy combinations, especially the use of modern dually acting antidepressants which have proven their good effectiveness in treatment-resistant depression.
Assuntos
Antidepressivos/normas , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/terapia , Tolerância a Medicamentos/fisiologia , Eletroconvulsoterapia , Adulto , Idoso , Anestesia/métodos , Terapia Combinada , Eletroconvulsoterapia/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/uso terapêutico , Estudos Retrospectivos , Segurança , Convulsões/epidemiologiaRESUMO
BACKGROUND: Electroconvulsive therapy (ECT) is still considered to be the most efficacious treatment option in major depressive disorder and treatment-resistant schizophrenia. Unfortunately, in some cases patients do not respond sufficiently to conventional unilateral ECT, or even to bilateral or high dose ECT. In these cases, concomitant pharmacotherapy can be a useful augmentation strategy to improve clinical effectiveness. Interestingly, there is not much data about ECT and concomitant neuroleptic medication. METHOD: We evaluated 5482 treatments in 455 patients in our retrospective study to see whether there might be differences between combination therapies (ECT and concomitant neuroleptic medication) and ECT monotherapy. We focused on clinical effectiveness and tolerability; furthermore we investigated treatment modalities and ictal neurophysiological parameters that might influence the treatment. RESULTS: A total of 18.2% of all treatments were done with no psychotropic medication, 2.8% with a neuroleptic monotherapy. Seizure duration according to EEG derivations turned out to be significantly longer in patients treated with neuroleptics of lower antipsychotic potency, whereas seizure duration in EMG was shorter in treatments done with atypical substances. Postictal suppression was highest in treatments done with atypical neuroleptics, whereas the same group was lowest regarding convulsion energy and convulsion concordance indices. The best therapeutic effectiveness was seen in treatments done with atypical substances. Adverse effects were not influenced significantly by concomitant neuroleptic medication. CONCLUSION: Our study suggests that there might be a clinical benefit by combining ECT treatment with neuroleptic medication; especially atypical substances seem to enhance improvement. The tolerability of ECT treatment was not influenced by concomitant neuroleptic medication.