RESUMEN
OBJECTIVES: Behavioral emergencies are a common and serious problem for consumers, their communities, and the healthcare settings on which they rely to contain, assess, and ultimately help the individual in a behavioral crisis. Partly because of the inherent dangers of this situation, there is little research to guide provider responses to this challenge. Key constructs such as agitation have not been adequately operationalized so that the criteria defining a behavioral emergency are vague. The significant progress that has been made for some disease states with better treatments and higher consumer acceptance has not penetrated this area of practice. A significant number of deaths of patients in restraint has focused government and regulators on these issues, but a consensus about key elements in the management of behavioral emergencies has not yet been articulated by the provider community. The authors assembled a panel of 50 experts to define the following elements: the threshold for emergency interventions, the scope of assessment for varying levels of urgency and cooperation, guiding principles in selecting interventions, and appropriate physical and medication strategies at different levels of diagnostic confidence and for a variety of etiologies and complicating conditions. METHOD: In order to identify issues in this area on which there is consensus, a written survey with 808 decision points was developed. The survey was mailed to a panel of 52 experts, 50 of whom completed it. A modified version of the RAND Corporation 9-point scale for rating appropriateness of medical decisions was used to score options. Consensus on each option was defined as a non-random distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred choice, second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables were constructed describing the preferred strategies in key clinical situations. RESULTS: The expert panel reached consensus on 83% of the options. The relative appropriateness of emergency interventions was ascertained for a continuum of behaviors. When asked about the frequency with which emergency interventions (parenteral medication, restraints, seclusion) were required in their services, 47% of the experts reported that such interventions were necessary for 1%-5% of patients seen in their services and 32% for 6%-20%. In general, the consensus of this panel lends support to many elements of recent Health Care Financing Administration regulations, including the timing of clinician assessment and reassessment and the intensity of nursing care. However, the panel did not endorse the concept of "chemical restraint," instead favoring the idea that medications are treatments for target behaviors in behavioral emergencies even when the causes of these behaviors are not well understood. Control of aggressive behavior emerged as the highest priority during the emergency; however, preserving the physician-patient relationship was rated a close second and became the top priority in the long term. Oral medications, particularly concentrates, were clearly preferred if it is possible to use them. Benzodiazepines alone were top rated in 6 of 12 situations. High-potency conventional antipsychotics used alone never received higher ratings than benzodiazepines used alone. A combination of a benzodiazepine and an antipsychotic was preferred for patients with suspected schizophrenia, mania, or psychotic depression. There was equal support for high-potency conventional or atypical antipsychotics (particularly liquids) in oral combinations with benzodiazepines. Droperidol emerged in fourth place in some situations requiring an injection. CONCLUSIONS: To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data in comparing modalities with each other or in combination. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide some direction for addressing common clinical dilemmas in the management of psychiatric emergencies and can be used to inform clinicians in acute care settings regarding the relative merits of various strategies.
Asunto(s)
Antipsicóticos/uso terapéutico , Servicios Médicos de Urgencia , Hipnóticos y Sedantes/uso terapéutico , Psicoterapia , Trastornos Psicóticos/terapia , Agresión , Niño , Trastornos de la Conducta Infantil/terapia , Urgencias Médicas , Femenino , Humanos , Embarazo , Agitación Psicomotora , Restricción FísicaRESUMEN
Long-term depression (LTD) of synaptic transmission can be induced by several mechanisms, one thought to involve Ca2+-dependent activation of postsynaptic nitric oxide (NO) synthase and subsequent diffusion of NO to the presynaptic terminal. We used the stable NO donor S-nitroso-N-acetylpenicillamine (SNAP) to study the NO-dependent form of LTD at Schaffer collateral-CA1 synapses in vitro. SNAP (100 microM) enhanced the induction of LTD via a cascade that was blocked by the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonopentanoic acid (50 microM), NO guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (10 microM), and the PKG inhibitor KT5823 (1 microM). We further show that LTD induced by low-frequency stimulation in the absence of SNAP also is blocked by KT5823 or Rp-8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphorothioate (10 microM), cyclic guanosine 3',5' monophosphate-dependent protein kinase (PKG) inhibitors with different mechanisms of action. Furthermore SNAP-facilitated LTD was blocked when release from intracellular calcium stores was inhibited by ryanodine (10 microM). Finally, two cell-permeant antagonists of the cyclic ADP-ribose binding site on ryanodine receptors also were able to block the induction of LTD. These results support a cascade for induction of homosynaptic, NO-dependent LTD involving activation of guanylyl cyclase, production of guanosine 3',5' cyclic monophosphate and subsequent PKG activation. This process has an additional requirement for release of Ca2+ from ryanodine-sensitive stores, perhaps dependent on the second-messenger cyclic ADP ribose.
Asunto(s)
Adenosina Difosfato Ribosa/análogos & derivados , Calcio/metabolismo , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Óxido Nítrico/fisiología , Proteínas Quinasas/metabolismo , Adenosina Difosfato Ribosa/fisiología , Animales , ADP-Ribosa Cíclica , Proteínas Quinasas Dependientes de GMP Cíclico , Estimulación Eléctrica , Femenino , Guanilato Ciclasa/metabolismo , Masculino , Donantes de Óxido Nítrico/farmacología , Penicilamina/análogos & derivados , Penicilamina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiología , Rianodina/farmacología , Canal Liberador de Calcio Receptor de Rianodina/fisiología , S-Nitroso-N-Acetilpenicilamina , Sinapsis/fisiologíaRESUMEN
Although it is widely agreed that cyclic AMP is necessary for the full expression of long-term potentiation of synaptic strength, it is unclear whether cyclic AMP or cyclic AMP-dependent protein kinase (PKA) play roles in the induction of long-term depression (LTD). We show here that two PKA inhibitors, H-89 (10 microM) and KT5720 (1 microM), are unable to block induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Rather, H-89 enhanced the magnitude of LTD induced by submaximal low-frequency stimulation. Raising [cGMP] with zaprinast (20 microM), a selective type V phosphodiesterase inhibitor, reversibly depressed synaptic potentials. However, coapplication of H-89 plus zaprinast converted this to a robust LTD that depended critically on activation of cyclic GMP-dependent protein kinase (PKG). Chemically induced LTD is activity-independent because it could be induced without stimulation and in tetrodotoxin (0.5 microM). Additionally, chemical LTD did not require activation of N-methyl-D-aspartate or GABA receptors and could be reversed by LTP. Stimulus-induced LTD occluded chemical LTD, suggesting a common expression mechanism. In contrast to bath application, postsynaptic infusion of H-89 into CA1 pyramidal neurons did not enhance LTD, suggesting a presynaptic site of action. Further evidence for a presynaptic locus was supplied by experiments where H-89 applied postsynaptically along with bath application of zaprinast was unable to produce chemical LTD. Thus simultaneous presynaptic generation of cyclic GMP and inhibition of PKA is sufficient to induce LTD of synaptic transmission at Schaffer collateral-CA1 synapses.
Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Potenciación a Largo Plazo/fisiología , Proteínas Quinasas/metabolismo , Animales , GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico , Combinación de Medicamentos , Estimulación Eléctrica/métodos , Activación Enzimática/fisiología , Inhibidores Enzimáticos/farmacología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Hipocampo/fisiología , Técnicas In Vitro , Masculino , Óxido Nítrico Sintasa/fisiología , Terminales Presinápticos/enzimología , Ratas , Ratas Sprague-Dawley , Sinapsis/fisiologíaRESUMEN
Ca2+ released from presynaptic and postsynaptic intracellular stores plays important roles in activity-dependent synaptic plasticity, including long-term depression (LTD) of synaptic strength. At Schaffer collateral-CA1 synapses in the hippocampus, presynaptic ryanodine receptor-gated stores appear to mobilize some of the Ca2+ necessary to induce LTD. Cyclic ADP-ribose (cADPR) has recently been proposed as an endogenous activator of ryanodine receptors in sea urchin eggs and several mammalian cell types. Here, we provide evidence that cADPR-mediated signaling pathways play a key role in inducing LTD. We show that biochemical production of cGMP increases cADPR concentration in hippocampal slices in vitro, and that blockade of cGMP-dependent protein kinase, cADPR receptors, or ryanodine-sensitive Ca2+ stores each prevent the induction of LTD at Schaffer collateral-CA1 synapses. A lack of effect of postsynaptic infusion of either cADPR antagonist indicates a probable presynaptic site of action.
Asunto(s)
Adenosina Difosfato Ribosa/análogos & derivados , Antígenos CD , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Sulfonamidas , Sinapsis/fisiología , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1 , Adenosina Difosfato Ribosa/metabolismo , Adenosina Difosfato Ribosa/farmacología , Animales , Antígenos de Diferenciación/metabolismo , Calcio/metabolismo , ADP-Ribosa Cíclica , Corteza Entorrinal/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Isoquinolinas/farmacología , Masculino , Glicoproteínas de Membrana , Modelos Neurológicos , NAD+ Nucleosidasa/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Rianodina/farmacología , Transducción de Señal , Transmisión Sináptica/fisiologíaRESUMEN
The necessity for phospholipase C (PLC), the enzyme which produces the second messenger molecules inositol trisphosphate (IP3) and diacylglycerol, for the induction of long-term depression (LTD) was tested at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. We report here that bath application of a selective cell-permeant PLC inhibitor, U-73122 (10 microM), does block the induction of LTD. In contrast, neither the inactive analog U-73343 (10 microM), nor application of U-73122 during the maintenance phase of LTD, impaired expression of LTD. Furthermore, postsynaptic infusion of U-73122 (100 microM) into single CA1 pyramidal neurons also prevented the induction of LTD. Since mGluR5 is the only metabotropic glutamate receptor subtype coupled to inositide turnover in field CA1, we conclude that the postsynaptic calcium store necessary for the induction of homosynaptic LTD is gated by IP3, through activation of mGluR5 coupled to phospholipase C.