RESUMEN
BACKGROUND: Deficits in neuropsychological performance are found in patients with bipolar disorder and represent a potential treatment target for novel therapeutic strategies. We have previously demonstrated a beneficial effect on spatial working memory (SWM) of treatment for 1 week with the progesterone and glucocorticoid receptor antagonist mifepristone, evident 2 weeks after the cessation of treatment. METHODS: We examined the longer-term efficacy of 600 mg/day of mifepristone as an adjunctive treatment, for 1 week, in a placebo-controlled, randomized, double-blind trial in 60 patients with bipolar depression, with SWM as the primary outcome measure. A comparator group of healthy control subjects was also recruited. RESULTS: At baseline, neuropsychological performance of patients was impaired, but hypothalamic-pituitary-adrenal axis function did not differ from that of control subjects. Mifepristone treatment was associated with a time-limited increase in cortisol awakening response and with a sustained improvement in SWM performance, which was evident 7 weeks after the cessation of treatment. The magnitude of this neuropsychological response was predicted by the magnitude of the cortisol response to mifepristone. The response occurred in the absence of a significant improvement in depressed mood. CONCLUSIONS: These data accord with the findings of animal studies and demonstrate that brief treatment with mifepristone is associated with a sustained improvement in SWM, an effect that might be mediated by a persistent enhancement in hippocampal mineralocorticoid receptor function.
Asunto(s)
Afecto/efectos de los fármacos , Trastorno Bipolar/tratamiento farmacológico , Antagonistas de Hormonas/uso terapéutico , Memoria a Corto Plazo/efectos de los fármacos , Mifepristona/uso terapéutico , Adulto , Atención/efectos de los fármacos , Trastorno Bipolar/fisiopatología , Trastorno Bipolar/psicología , Método Doble Ciego , Función Ejecutiva/efectos de los fármacos , Femenino , Antagonistas de Hormonas/farmacología , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Persona de Mediana Edad , Mifepristona/farmacología , Pruebas Neuropsicológicas , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/fisiopatología , Resultado del Tratamiento , Aprendizaje Verbal/efectos de los fármacosRESUMEN
RATIONALE: Hypothalamic-pituitary-adrenal axis dysregulation predicts poor clinical and biochemical response to antidepressants. Antiglucocorticoids have therapeutic benefits but most have a troublesome adverse event profile. Aspects of neuropsychological performance, notably working memory, are susceptible to corticosteroid modulation and are impaired in depression. Aspirin has been shown to attenuate the adrenocorticotropic hormone (ACTH) and cortisol response to physiological challenge suggesting its potential to act as an augmenting agent in depression. OBJECTIVES: To examine the effect of sub-acute (300 mg daily for 7 days) aspirin pre-treatment on the cortisol awakening response and the effect of acute (600 mg) and sub-acute aspirin on the neuroendocrine and neuropsychological response to the arginine vasopressin analogue, desmopressin. RESULTS: We demonstrated that aspirin pre-treatment did not attenuate the cortisol or ACTH response to desmopressin but, as hypothesised, significantly reduced the cortisol awakening response and improved working memory. CONCLUSIONS: Further studies to examine the impact of aspirin on neuropsychological performance and HPA axis function are warranted.