RESUMEN
The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.
Asunto(s)
Antidepresivos de Segunda Generación/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Morfolinas/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1 , Sustancia P/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Antidepresivos de Segunda Generación/efectos adversos , Antidepresivos de Segunda Generación/metabolismo , Antidepresivos de Segunda Generación/farmacología , Aprepitant , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Trastorno Depresivo/etiología , Trastorno Depresivo/metabolismo , Femenino , Gerbillinae , Cobayas , Humanos , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Morfolinas/metabolismo , Morfolinas/farmacología , Norepinefrina/fisiología , Paroxetina/uso terapéutico , Receptores de Neuroquinina-1/metabolismo , Serotonina/fisiología , Estrés Psicológico/tratamiento farmacológico , Sustancia P/metabolismo , Vocalización Animal/efectos de los fármacosRESUMEN
Following a 1-week, single-blind placebo washout, 150 patients were randomized to double-blind treatment with daily doses of either mianserin, 30 mg to 150 mg; amitriptyline, 60 mg to 300 mg; or placebo, 1 to 5 capsules taken at bedtime (qhs). Mianserin and amitriptyline were found to be comparable in efficacy, and both significantly more effective than placebo in the treatment of major depressive illness. Rating instruments, all of which showed significant improvement in the active drug groups over the placebo, included the 17- and 21-item Hamilton Rating Scale for Depression (HAM-D), Montgomery and Asberg Depression Rating Scale (MADRS), Self-rating Depression Scale (SDS) index, and the Clinical Global Impressions (CGI) Severity of Illness and Improvement rating scales. Furthermore, for most efficacy parameters in the efficacy-evaluable group, the earliest statistically significant difference vs. placebo could be observed at Visit 1 for the mianserin patients and at Visit 3 for the amitriptyline patients. The safety profile for mianserin was comparable with placebo with respect to laboratory values, electrocardiogram changes, vital signs, ophthalmologic evaluations, and most adverse clinical experiences. Complaints of somnolence and weight gain were comparable in the amitriptyline and mianserin groups. Mianserin was superior to amitriptyline in terms of vital signs; anticholinergic effects; and complaints of dizziness, dyspepsia, and tremor.