RESUMEN
INTRODUCTION: Comorbid substance abuse is known to blunt response to treatment for underlying psychiatric disorders, but it has not been investigated in schizophrenia when comparing the effects of long-acting injectable antipsychotics with those of oral antipsychotics. METHODS: This exploratory analysis compared once-monthly paliperidone palmitate (PP1M) with daily oral antipsychotics on time to treatment failure in patients with schizophrenia and a history of incarceration. Subjects were stratified into substance abuse (reported substance or alcohol misuse in the past 30days on the baseline Addiction Severity Index-Lite Version and/or met criteria for a current MINI diagnosis of a substance abuse disorder) and nonabuse cohorts. RESULTS: In the substance abuse cohort, treatment failure was observed in 56.2% (73/130) and 64.2% (86/134) of subjects in the PP1M and oral antipsychotic groups, respectively. For the nonabuse cohort, treatment failure was observed in 36.5% (35/96) and 53.6% (45/84) of subjects in the PP1M and oral antipsychotic groups, respectively. Median (95% confidence interval [CI]) time to first treatment failure was 291 (179-428) days and 186 (94-296) days in the PP1M and oral antipsychotic groups, respectively. Median (95% CI) time to first treatment failure was >450 and 284 (147 to >450) days in the respective treatment groups. CONCLUSION: Greater treatment effects were evident with PP1M compared with oral antipsychotics in both cohorts. The observed beneficial effect of PP1M was attenuated in the substance-abuse cohort, further reinforcing both the need for and value of continued research to optimize patient care in these complex patient populations.
Asunto(s)
Antipsicóticos/administración & dosificación , Criminales , Preparaciones de Acción Retardada/administración & dosificación , Esquizofrenia/complicaciones , Esquizofrenia/tratamiento farmacológico , Trastornos Relacionados con Sustancias/complicaciones , Administración Oral , Adulto , Comorbilidad , Femenino , Humanos , Masculino , Palmitato de Paliperidona/administración & dosificación , Factores Socioeconómicos , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the effect of 1 oral and 2 distinct long-acting injectable (LAI) formulations of the same antipsychotic on times to relapse following medication discontinuation. METHODS: Data were drawn from 3 similarly designed, multicenter, double-blind, placebo-controlled, randomized-withdrawal studies of paliperidone in adults with a schizophrenia diagnosis (according to DSM-IV criteria for ≥ 1 year before screening): once-daily extended-release oral paliperidone (ORAL paliperidone), once-monthly paliperidone palmitate (PP1M), and once-every-3-months paliperidone palmitate (PP3M). In a post hoc analysis, we compared median time to relapse across the treatment-withdrawal arms of the 3 studies using final analysis datasets. Time to relapse in the withdrawal arm of each study was examined using log-rank tests and Cox proportional hazards models. RESULTS: Four hundred forty-nine patients were withdrawn from 3 paliperidone formulations: 101 from ORAL paliperidone, 203 from PP1M, and 145 from PP3M. Postwithdrawal median (95% confidence interval [CI]) days to relapse were 58 days (42-114 days) for ORAL paliperidone, 172 days (134-222 days) for PP1M, and 395 days (274 days-not reached) for PP3M (P < .0001, pairwise comparisons). Relapse risk was significantly lower (P < .001) for patients who withdrew from either PP formulation relative to ORAL paliperidone and additionally for patients who withdrew from PP3M relative to PP1M. CONCLUSIONS: Results demonstrate that 50% of patients who withdrew treatment from ORAL paliperidone, PP1M, or PP3M remained relapse free for approximately 2 months, 6 months, and 13 months, respectively. This may be relevant for risk mitigation strategies in schizophrenia, a condition in which interruptions in maintenance antipsychotic treatment are commonplace and unpredictable. LAI antipsychotic formulations may provide substantial delays over oral equivalents in times to relapse when patients discontinue therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00086320, NCT00111189, and NCT01529515.
Asunto(s)
Palmitato de Paliperidona/administración & dosificación , Palmitato de Paliperidona/farmacocinética , Esquizofrenia/sangre , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Síndrome de Abstinencia a Sustancias/sangre , Administración Oral , Adulto , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Semivida , Humanos , Inyecciones Intramusculares , Masculino , Palmitato de Paliperidona/efectos adversos , Recurrencia , Medición de Riesgo , Relación Estructura-ActividadRESUMEN
The suprachiasmatic nucleus (SCN) controls the circadian rhythm of physiological and behavioural processes in mammals. Here we show that prokineticin 2 (PK2), a cysteine-rich secreted protein, functions as an output molecule from the SCN circadian clock. PK2 messenger RNA is rhythmically expressed in the SCN, and the phase of PK2 rhythm is responsive to light entrainment. Molecular and genetic studies have revealed that PK2 is a gene that is controlled by a circadian clock (clock-controlled). Receptor for PK2 (PKR2) is abundantly expressed in major target nuclei of the SCN output pathway. Inhibition of nocturnal locomotor activity in rats by intracerebroventricular delivery of recombinant PK2 during subjective night, when the endogenous PK2 mRNA level is low, further supports the hypothesis that PK2 is an output molecule that transmits behavioural circadian rhythm. The high expression of PKR2 mRNA within the SCN and the positive feedback of PK2 on its own transcription through activation of PKR2 suggest that PK2 may also function locally within the SCN to synchronize output.
Asunto(s)
Ritmo Circadiano/fisiología , Hormonas Gastrointestinales/metabolismo , Actividad Motora/fisiología , Neuropéptidos , Núcleo Supraquiasmático/fisiología , Células 3T3 , Animales , Relojes Biológicos/genética , Relojes Biológicos/fisiología , Línea Celular , Ritmo Circadiano/genética , Hormonas Gastrointestinales/genética , Eliminación de Gen , Regulación de la Expresión Génica , Humanos , Luz , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcripción GenéticaRESUMEN
Truncations at the carboxyl termini of G protein-coupled receptors result in defective receptor biogenesis and comprise a number of inherited disorders. In order to evaluate the structural role of the C-terminus in G protein-coupled receptor biogenesis, we generated a series of deletion and substitution mutations in the dopamine D1 receptor and visualized receptor subcellular localization by fusion to a green fluorescent protein. Alanine substitutions of several hydrophobic residues within the proximal C-terminus resulted in receptor transport arrest in the ER. Agonist binding and coupling to adenylyl cyclase was also abolished. In contrast, substitutions conserving C-terminal hydrophobicity produced normal cell surface receptor expression, binding, and stimulatory function. A mechanism for the role of the C-terminus in D1 receptor transport was investigated by searching for candidate protein interactions. The D1 receptor was found to co-precipitate and associate in vitro directly with the gamma-subunit of the COPI coatomer complex. In vitro pull-down assays confirmed that only the D1 C-terminus is required for COPI association, and that identical mutations causing disruption of receptor transport to the cell surface also disrupted binding to COPI. Furthermore, conservative mutations in the D1 C-terminus restored COPI association just as they restored cell surface transport. These results suggest that association between the coatomer complex and hydrophobic residues within the proximal C-terminus of the D1 receptor may serve an important role in receptor transport.