RESUMEN
BACKGROUND: Current medications for alcohol dependence (AD) show only modest efficacy. None target brain noradrenergic pathways. Theory and preclinical evidence suggest that noradrenergic circuits may be involved in alcohol reinforcement and relapse. We therefore tested the alpha-1 adrenergic receptor antagonist, prazosin, as a pharmacotherapy for AD. METHODS: We randomized 24 participants with AD but without posttraumatic stress disorder to receive either prazosin or placebo in a 6-week, double-blind pilot study. Medication was titrated to a target dose of 4 mg QAM, 4 mg QPM, and 8 mg QHS by the end of week 2. Participants received 5 medical management treatment sessions. Participants were reminded 3 times each day via a text pager to take medications and to call a telephone monitoring system once daily to provide self-reports of alcohol consumption and craving, the primary outcome measures. Results were analyzed using mixed linear regression adjusted for drinking days per week at baseline and week number. RESULTS: Twenty of the 24 (83%) subjects completed. Among the completers, the prazosin group reported fewer drinking days per week than the placebo group during the final 3 weeks of the study. Since only 1 woman was randomized to placebo and only three women completed the trial, the following results focus on the 17 male completers. The prazosin group reported fewer drinking days per week and fewer drinks per week during the final 3 weeks of the study; average total number of drinking days for the placebo group 5.7 (SEM 1.9) versus 0.9 (SEM 0.5) for the prazosin group, and average total number of drinks 20.8 (SEM 6.5) for the placebo group versus 2.6 (SEM 1.3) for the prazosin group. Rates of adverse events were equivalent across conditions. CONCLUSIONS: Prazosin holds promise as a pharmacologic treatment for AD and deserves further evaluation in a larger controlled trial.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Alcoholismo/tratamiento farmacológico , Prazosina/uso terapéutico , Adolescente , Antagonistas Adrenérgicos alfa/efectos adversos , Adulto , Afecto , Anciano , Alcoholismo/psicología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Proyectos Piloto , Prazosina/efectos adversos , Escalas de Valoración Psiquiátrica , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: Agitation/aggression in Alzheimer disease (AD) is a major cause of patient distress, caregiver burden, and institutionalization. Enhanced behavioral responsiveness to central nervous system norepinephrine (NE) release may contribute to the pathophysiology of agitation/aggression in AD. Prazosin, a nonsedating generic medication used for hypertension and benign prostatic hypertrophy, antagonizes NE effects at brain postsynaptic alpha-1 adrenoreceptors. This pilot study examined the efficacy and tolerability of prazosin for behavioral symptoms in patients with agitation/aggression in AD. DESIGN: Double-blind, placebo controlled, parallel group study. SETTING: A university AD center and a nursing home in Seattle, WA. PARTICIPANTS: Twenty-two nursing home and community-dwelling participants with agitation/aggression and probable or possible AD (mean age: 80.6 +/- 11.2). INTERVENTION: Randomization to placebo (N = 11) or prazosin (N = 11). Medication was initiated at 1 mg/day and increased up to 6 mg/day using a flexible dosing algorithm. MEASUREMENTS: The Brief Psychiatric Rating Scale (BPRS) and Neuropsychiatric Inventory (NPI) at Weeks 1, 2, 4, 6, and 8. The Clinical Global Impression of Change (CGIC) at Week 8. RESULTS: Participants taking prazosin (mean dose: 5.7 +/- 0.9 mg/day) had greater improvements than those taking placebo (mean dose: 5.6 +/- 1.2 mg/day) on the NPI (mean change: -19 +/- 21 versus -2 +/- 15, chi = 6.32, df = 1, p = 0.012) and BPRS (mean change: -9 +/- 9 versus -3 +/- 5, chi = 4.42, df = 1, p = 0.036) based on linear mixed effects models and the CGIC (mean: 2.6 +/- 1.0 versus 4.5 +/- 1.6, z = 2.57, p = 0.011 [Mann-Whitney test]). Adverse effects and blood pressure changes were similar between prazosin and placebo groups. CONCLUSION: Prazosin was well tolerated and improved behavioral symptoms in patients with agitation/aggression in AD.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Síntomas Conductuales/tratamiento farmacológico , Prazosina/uso terapéutico , Anciano , Anciano de 80 o más Años , Agresión/efectos de los fármacos , Agresión/psicología , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Escalas de Valoración Psiquiátrica Breve , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Proyectos Piloto , Agitación Psicomotora/tratamiento farmacológico , Agitación Psicomotora/psicología , Estadísticas no Paramétricas , Resultado del Tratamiento , WashingtónRESUMEN
Studies of traumatic brain injury from all causes have found evidence of chronic hypopituitarism, defined by deficient production of one or more pituitary hormones at least 1 year after injury, in 25-50% of cases. Most studies found the occurrence of posttraumatic hypopituitarism (PTHP) to be unrelated to injury severity. Growth hormone deficiency (GHD) and hypogonadism were reported most frequently. Hypopituitarism, and in particular adult GHD, is associated with symptoms that resemble those of PTSD, including fatigue, anxiety, depression, irritability, insomnia, sexual dysfunction, cognitive deficiencies, and decreased quality of life. However, the prevalence of PTHP after blast-related mild TBI (mTBI), an extremely common injury in modern military operations, has not been characterized. We measured concentrations of 12 pituitary and target-organ hormones in two groups of male US Veterans of combat in Iraq or Afghanistan. One group consisted of participants with blast-related mTBI whose last blast exposure was at least 1 year prior to the study. The other consisted of Veterans with similar military deployment histories but without blast exposure. Eleven of 26, or 42% of participants with blast concussions were found to have abnormal hormone levels in one or more pituitary axes, a prevalence similar to that found in other forms of TBI. Five members of the mTBI group were found with markedly low age-adjusted insulin-like growth factor-I (IGF-I) levels indicative of probable GHD, and three had testosterone and gonadotropin concentrations consistent with hypogonadism. If symptoms characteristic of both PTHP and PTSD can be linked to pituitary dysfunction, they may be amenable to treatment with hormone replacement. Routine screening for chronic hypopituitarism after blast concussion shows promise for appropriately directing diagnostic and therapeutic decisions that otherwise may remain unconsidered and for markedly facilitating recovery and rehabilitation.