RESUMO
OBJECTIVE: To evaluate the efficacy and safety of mirtazapine in depressed outpatients who have shown nonresponse or intolerance to selective serotonin reuptake inhibitor (SSRI) therapy. METHOD: In this open-label, 8-week study, the efficacy and safety of mirtazapine among 103 outpatients with DSM-IV major depressive disorder who had failed previous therapy with an SSRI (fluoxetine, paroxetine, or sertraline) were evaluated. The primary efficacy measure was the 17-item Hamilton Rating Scale for Depression (HAM-D-17), and safety assessments included reported adverse events, routine laboratory assessments, physical examinations, and assessments of vital signs. A 4-day washout period followed by mirtazapine treatment was compared with an immediate switch from the SSRI to mirtazapine. RESULTS: Based on mean HAM-D-17 scores at endpoint and response rates of 48% based on the criterion of > or = 50% reduction in HAM-D-17 score, mirtazapine was found to be an effective treatment for a substantial proportion of patients for whom an SSRI was ineffective and/or poorly tolerated. Mirtazapine was well tolerated, with sedation and appetite increase/weight gain the most commonly reported adverse events. In addition, no difference in efficacy, safety, or tolerability was observed for patients undergoing an immediate switch from an SSRI (after having been tapered to the minimal effective dose) to mirtazapine, compared with those undergoing the imposition of a 4-day drug-free washout. CONCLUSION: These results suggest that an immediate switch to mirtazapine may be a valid therapeutic option among patients who cannot tolerate or do not respond to SSRIs.
Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Mianserina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto , Assistência Ambulatorial , Antidepressivos Tricíclicos/efeitos adversos , Transtorno Depressivo/diagnóstico , Método Duplo-Cego , Feminino , Nível de Saúde , Humanos , Masculino , Mianserina/efeitos adversos , Mianserina/análogos & derivados , Pessoa de Meia-Idade , Mirtazapina , Pacientes Desistentes do Tratamento , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Qualidade de Vida , Falha de Tratamento , Resultado do Tratamento , Aumento de PesoAssuntos
Clozapina/sangue , Triazóis/farmacocinética , Adulto , Clozapina/análogos & derivados , Clozapina/metabolismo , Clozapina/uso terapêutico , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Monitoramento de Medicamentos , Quimioterapia Combinada , Humanos , Masculino , Oxigenases de Função Mista/antagonistas & inibidores , Oxigenases de Função Mista/metabolismo , Piperazinas , Esquizofrenia Paranoide/sangue , Esquizofrenia Paranoide/tratamento farmacológico , Triazóis/administração & dosagem , Triazóis/uso terapêuticoRESUMO
The objective of this study was to assess in both young and elderly volunteers the pharmacokinetics of fluoxetine and norfluoxetine and effects on cytochrome P450 (CYP) 2C19. Male volunteers aged 18 to 40 years (N = 14) or older than 65 years (N = 16) received fluoxetine 20 mg/day for 6 weeks and fluoxetine 40 mg/day for an additional 6 weeks. Blood was drawn over a 24-hour period after the initial dose and after 6 weeks and 12 weeks to determine AUC0-24, Cmax, and tmax; weekly to evaluate predose levels (C0); and over a 3-week period after discontinuation to evaluate washout (t1/2). Mephenytoin was used to assess CYP2C19 activity before and after 6 weeks and 12 weeks of fluoxetine. Fluoxetine AUC0-24, C0, and Cmax did not differ in young and elderly subjects. The norfluoxetine C0 was 22% lower in elderly subjects (p < .05), with comparable decreases in AUC0-24 and Cmax. In the elderly volunteers, the t1/2 for fluoxetine was 25% longer (5.0 vs. 4.0 days) and for norfluoxetine was 33% longer (20 vs. 15 days), although variability and sample size precluded statistical significance. Fluoxetine dosing inhibited CYP2C19 activity in both age groups, increasing the (S)- to (R)-mephenytoin ratio 3- to 4-fold (p < .01). The half-lives of fluoxetine and norfluoxetine at 40 mg/day were longer than commonly reported in the literature and may be longer in elderly subjects. Fluoxetine substantially inhibited the metabolism of the CYP2C19 substrate (S)-mephenytoin.
Assuntos
Hidrocarboneto de Aril Hidroxilases , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Fluoxetina/análogos & derivados , Fluoxetina/sangue , Oxigenases de Função Mista/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/sangue , Adulto , Fatores Etários , Idoso , Análise de Variância , Área Sob a Curva , Citocromo P-450 CYP2C19 , Sistema Enzimático do Citocromo P-450/urina , Fluoxetina/farmacocinética , Humanos , Masculino , Oxigenases de Função Mista/urina , Inibidores Seletivos de Recaptação de Serotonina/farmacocinéticaAssuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/economia , Pirenzepina/análogos & derivados , Idoso , Antipsicóticos/uso terapêutico , Benzodiazepinas , Depressão/prevenção & controle , Interações Medicamentosas , Feminino , Fluoxetina/efeitos adversos , Fluoxetina/economia , Fluoxetina/uso terapêutico , Haloperidol/efeitos adversos , Haloperidol/economia , Haloperidol/uso terapêutico , Custos de Cuidados de Saúde , Humanos , Olanzapina , Doença de Parkinson/tratamento farmacológico , Pirenzepina/efeitos adversos , Pirenzepina/economia , Pirenzepina/uso terapêutico , Selegilina/farmacologia , Selegilina/uso terapêutico , Triexifenidil/farmacologia , Triexifenidil/uso terapêuticoAssuntos
Anticonvulsivantes/farmacocinética , Carbamazepina/farmacocinética , Transtorno Depressivo/tratamento farmacológico , Sertralina/uso terapêutico , Adulto , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Transtorno Depressivo/psicologia , Esquema de Medicação , Interações Medicamentosas , Feminino , Humanos , Masculino , Transtornos Psicóticos/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/sangue , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Sertralina/sangue , Sertralina/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVE: To describe the pharmacokinetics and safety of nefazodone (NFZ) in depressed children and adolescents. METHOD: Depressed youths aged 7 to 17 years were eligible to participate. Intensive sampling for pharmacokinetic analyses of NFZ and 3 of its active metabolites was performed after single and multiple dose administration. Treatment was continued for 6 more weeks and titrated to maximize clinical response. RESULTS: Twenty-eight patients were enrolled. Systemic exposure to NFZ and 3 metabolites was generally higher in children than adolescents. NFZ and metabolite disposition profiles showed high intra- and interpatient variability. Compared to published data in adults, the half-life of NFZ and 2 of its metabolites appears shorter in children and adolescents. Meta-chlorphenylpiperazine pharmacokinetic parameters were different in 5 patients determined to be poor metabolizers of cytochrome P450 2D6 (CYP2D6). NFZ was well tolerated, and administration was associated with significant reductions (p < .001) in depressive symptoms. CONCLUSIONS: The pharmacokinetics of NFZ in pediatric patients is highly variable. NFZ appears to be safe in this small, short-term study. Pediatric patients who are poor metabolizers of CYP2D6 do not appear to be at increased risk for NFZ-associated adverse events. Open-label treatment of NFZ is associated with reductions in depressive symptoms.
Assuntos
Antidepressivos de Segunda Geração/farmacocinética , Transtorno Depressivo/sangue , Triazóis/farmacocinética , Adolescente , Adulto , Fatores Etários , Antidepressivos de Segunda Geração/sangue , Antidepressivos de Segunda Geração/uso terapêutico , Área Sob a Curva , Criança , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo/tratamento farmacológico , Feminino , Meia-Vida , Humanos , Masculino , Piperazinas , Resultado do Tratamento , Triazóis/sangue , Triazóis/uso terapêuticoAssuntos
Comportamento/efeitos dos fármacos , Transtorno Bipolar/psicologia , Adulto , Antipsicóticos/uso terapêutico , Benzodiazepinas , Benzotropina/uso terapêutico , Interações Medicamentosas , Humanos , Masculino , Antagonistas Muscarínicos/uso terapêutico , Olanzapina , Pirenzepina/análogos & derivados , Pirenzepina/uso terapêutico , Risperidona/efeitos adversos , Risperidona/uso terapêuticoRESUMO
BACKGROUND: Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake. METHODS: Healthy male volunteers aged 18 to 45 years received either 75 mg or 375 mg of venlafaxine hydrochloride per day, the 5-HT uptake inhibitor sertraline hydrochloride (50 mg/d), or the NE uptake inhibitor maprotiline hydrochloride (150 mg/d) (n = 8 for each of 4 treatment groups). Changes in platelet 5-HT uptake and the pressor response to intravenous tyramine were assessed following the initial dose and after 1 and 2 weeks of drug administration. RESULTS: Platelet 5-HT uptake was inhibited by venlafaxine across the dose range and by sertraline but not maprotiline. Inhibition was competitive, related to increases in affinity and not related to capacity. Steady-state drug levels were associated with a 5-HT uptake inhibition of 87% or more in subjects taking venlafaxine or sertraline. The pressor response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine. CONCLUSION: This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antidepressivos de Segunda Geração/farmacologia , Cicloexanóis/farmacologia , Norepinefrina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , Adolescente , Inibidores da Captação Adrenérgica/farmacocinética , Adulto , Antidepressivos de Segunda Geração/farmacocinética , Transporte Biológico Ativo/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Cicloexanóis/farmacocinética , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Injeções Intravenosas , Masculino , Maprotilina/farmacocinética , Maprotilina/farmacologia , Pessoa de Meia-Idade , Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Sertralina/farmacocinética , Sertralina/farmacologia , Sístole/efeitos dos fármacos , Tiramina/administração & dosagem , Tiramina/farmacologia , Cloridrato de VenlafaxinaAssuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Tônico-Clônica/tratamento farmacológico , Fluoxetina/efeitos adversos , Fenitoína/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Síndrome de Abstinência a Substâncias/psicologia , Adulto , Anticonvulsivantes/farmacocinética , Interações Medicamentosas , Epilepsia Tônico-Clônica/complicações , Humanos , Masculino , Fenitoína/farmacocinéticaRESUMO
Despite evidence to support its potential benefit in clinical practice, therapeutic drug monitoring (TDM) is under-utilised and underdeveloped in the field of psychiatry. In antidepressant pharmacotherapy drug dose is emphasised as the critical treatment variable. However, dose in, and of, itself can be a strikingly misleading predictor of drug concentration and, hence, treatment effect. For antidepressant drugs, plasma concentrations at a given dose have been shown to vary in excess of 40-fold. The clinical relevance of this variability is that at a standard antidepressant dosage only some patients will have tissue drug concentrations associated with an optimal response whereas others will have either low, ineffective drug concentrations or unnecessarily high concentrations which may be poorly tolerated. Among clinicians and healthcare agencies there is an under-appreciation of the degree of pharmacokinetic variability found in patients and how that might impact on the patients response to pharmacotherapy. Hence there is a perception that TDM is an unnecessary, complicated and costly procedure. This is actually unfounded. There are data to suggest that TDM can favourably affect the outcome of antidepressant treatment by providing a rational alternative to the inherently slower, trial and error practice of dosage titration based on clinical response. It is unlikely that TDM will become a standard of care for all antidepressant agents and all patients. Therefore the question becomes for which antidepressant agents, for which patients and under what circumstances, is TDM more cost-effective than traditional dose titration. The use of TDM to optimise the efficient use of selected antidepressant agents could potentially free up healthcare resources to fund other equally deserving treatments. This article provides a discussion of the major classes of antidepressant drugs with regard to their pharmacological features that predict the utility of TDM in clinical practice. Recommendations are made for the practical application of TDM and the directions for further research.
Assuntos
Antidepressivos/uso terapêutico , Monitoramento de Medicamentos/estatística & dados numéricos , Antidepressivos/classificação , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/economia , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/normas , Humanos , FarmacogenéticaRESUMO
This article summarizes the basic and clinical pharmacology of the available antidepressants to aid the busy primary care practitioner in anticipating and predicting the effects of different antidepressants on patients; choosing a specific antidepressant for each patient based on these effects; selecting a sequential antidepressant for the patient who has not benefited from a trial of a specific type of antidepressant, either because of inadequate effect or treatment-limiting adverse effects; and avoiding adverse drug interactions when choosing an antidepressant for patients on other drug therapy.
Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Antidepressivos/classificação , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Masculino , Atenção Primária à Saúde , Síndrome de Abstinência a Substâncias/patologiaRESUMO
In 1993, it was first proposed that an important difference between selective serotonin reuptake inhibitors (SSRIs) was the degree of inhibition of the cytochrome P450 (CYP) enzyme 2D6 that they produced under usually dosing conditions (Preskorn, 1993). Specifically, fluoxetine and paroxetine, in contrast to sertraline, were identified as causing substantial increases in the plasma levels of coadministered drugs, which were principally dependent on CYP 2D6 for their metabolism. Over the next 5 years, this position was hotly contested (Preskorn and Nemeroff, 1997). However, an extensive body of research has now accumulated, which incontrovertibly supports the original position. This paper will reviews this research and extends the discussion to all five SSRIs and four other important CYP enzymes: 1A2, 2C9/10, 2C19, and 3A3/4.