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By H. Ortega. Center for Creative Studies College of Art and Design.

In acute settings when renal water losses are extensive purchase 250 mg antabuse with mastercard medicine queen mary, aqueous vasopressin (pitressin) is Condition Drug Dose useful purchase 500mg antabuse with visa symptoms youre pregnant. It has a short duration of action that allows for careful m on- itoring and avoiding com plications like water intoxication. This Complete central DI dDAVP 10–20 (g intranasally q 12–24 h drug should be used with caution in patients with underlying coro- Partial central DI Vasopressin tannate 2–5 U IM q 24–48 h nary artery disease and peripheral vascular disease, as it can cause Aqueous vasopressin 5–10 U SC q 4–6 h vascular spasm and prolonged vasoconstriction. For the patient Chlorpropamide 250–500 mg/d with established central DI, desm opressin acetate (dDAVP) is the Clofibrate 500 mg tid–qid agent of choice. It has a long half-life and does not have significant Carbamazepine 400–600 mg/d vasoconstrictive effects like those of aqueous vasopressin. It can be conveniently adm inistered intranasally every 12 to 24 hours. It is safe to use in pregnancy and resists degradation by circulating vasopressinase. In patients with partial DI, agents that potentiate release of antidiuretic horm one can be used. These include chlorpropam ide, clofibrate, and carbam azepine. They work effectively only if com bined with horm one therapy, decreased solute intake, or diuretic adm inistration. FIGURE 1-37 T T S A M Extracellular P * S L M –NH2 Congenital nephrogenic diabetes insipidus, P S H V A 1 S L L G P X-linked–recessive form. This is a rare dis- N S P S ease of m ale patients who do not concen- S F trate their urine after adm inistration of Q R E D R antidiuretic horm one. The pedigrees of R T G P A P A E P affected fam ilies have been linked to a L P L F W G L D D K D C R group of Ulster Scots who em igrated to R T W A A S G G P E A P A L W G E R H alifax, N ova Scotia in 1761 aboard the R A V T D L A L C C V Y * W E ship called “H opewell. Recent studies, howev- A L H V M T A L V V L I T L Y A * * L I L V F M S er, disproved this hypothesis. The A P R D P E R R S S F L C C R A H R I V S A gene defect has now been traced to 87 dif- R H V L R R W A N A T S S G ferent m utations in the gene for the vaso- G H W S K S E L R R R R G I H S A pressin receptor (AVP-R2) in 106 presum - C L V T R A V H A V P G * A A ably unrelated fam ilies. In the autosom al recessive form of N DI, m utations D N A T G A 8 P G have been found in the gene for the antiiuretic horm one (ADH )– R L N K sensitive water channel, AQ P-2. This form of N DI is exceedingly I S M F D N S D rare as com pared with the X-linked form of N DI. Thus far, a A S 13 C D total of 15 AQ P-2 m utations have been described in total of 13 P T G H T 6 T T W fam ilies. The acquired form of N DI occurs in various kidney I A Y V Q A L P E G H F diseases and in association with various drugs, such as lithium S V H L Q I W P W L L A T V G L L I G and am photericin B. Hypernatremia always Causes and mechanisms of acquired nephrogenic diabetes insidpidus. It usually diabetes insipidus occurs in chronic renal failure, electrolyte imbalances, with certain drugs, occurs in a hospital setting (reported inci- in sickle cell disease and pregnancy. The exact mechanism involved has been the subject of dence 0. The prim ary goal in the treatm ent Muscle twitching of hypernatrem ia is restoration of serum tonicity. H ypovolem ic hypernatrem ia in the con- Spasticity text of low total body sodium and orthostatic blood pressure changes should be m anaged Hyperreflexia with isotonic saline until blood pressure norm alizes. Thereafter, fluid m anagem ent general- ly involves adm inistration of 0. The goal of therapy for hypervolem ic hypernatrem ias is to rem ove the excess sodium , which is achieved with diuretics plus 5% dextrose. Patients who have renal im pairm ent m ay need FIGURE 1-41 dialysis. In euvolem ic hypernatrem ic patients, water losses far exceed solute losses, and the Signs and sym ptom s of hypernatrem ia. To correct the hypernatrem ia, the total body water H ypernatrem ia always reflects a hyperosm o- deficit m ust be estim ated. This is based on the serum sodium concentration and on the lar state; thus, central nervous system sym p- assum ption that 60% of the body weight is water. SYM PTOM ATIC HYPERNATREM IA* Patients with severe sym ptom atic hypernatrem ia are at high risk of dying and should be treated aggressively. An initial step is estim at- ing the total body free water deficit, based on the weight (in kilo- Correct at a rate of 2 mmol/L/h gram s) and the serum sodium. During correction of the water Replace half of the calculated water deficit over the first 12–24 hrs deficit, it is im portant to perform serial neurologic exam inations. Replace the remaining deficit over the next 24–36 hrs Perform serial neurologic examinations (prescribed rate of correction can be decreased as symptoms improve) Measure serum and urine electrolytes every 1–2 hrs *If UNa + U K is less than the concentration of PNa, then water loss is ongoing and needs to be replaced. Jacobson H R: Functional segm entation of the m am m alian nephron. Berl T, Schrier RW : Disorders of water m etabolism. Berl T, Anderson RJ, M cDonald KM , Schreir RW : Clinical Disorders Publishing Co. Kokko J, Rector F: Countercurrent m ultiplication system without 18.

Towbin and co-workers offered operational crite- and occurrence during childhood and considered schizo- ria and preliminary validating evidence for the concept and phrenic psychoses to be an early onset of the same disease generic antabuse 500mg online medicine to reduce swelling, criteria and used the term multiple complex developmental which appeared to be on a continuum phenomenologically purchase antabuse 500 mg fast delivery symptoms 28 weeks pregnant, disorder (42). Furthermore, and co-workers was that multiple complex developmental it has been shown that schizophrenic psychoses can be diag- disorder was a higher-functioning type of pervasive develop- nosed reliably in children using the same criteria as for adults mental spectrum disorder. Very few studies to date have dealt with the ticular outcome, Towbin and coworkers suggested that mul- long-term outcome in childhood-onset schizophrenia. Most tiple complex developmental disorder was a nonspecific risk studies have followed children for between 1 and 5 years factor for a poor adaptation in adult life but with a myriad (52). Because of methodologic difficulties, there is a striking of adult diagnostic outcomes such as schizophrenia, bipolar absence of data before the age of 11 years on the long- illness, or any of the more severe unstable personality disor- term course of psychosis. Further elaboration of these criteria have shown sup- importance' of long-term follow-up data for establishing port for the concept and validated that children with perva- the validity of psychotic symptoms manifested in early sive developmental disorder not otherwise specified and childhood (53). This is especially important because chil- autism can be meaningfully separated from those with mul- dren often describe 'hearing voices,' especially in clinical tiple complex developmental disorder (43). An astute clinician will delve into this symp- tion of the concept of multiple complex developmental dis- tom in greater depth, to obtain a qualitative appreciation order has received support from neurophysiologic studies of these 'voices. He most likely will not hear this voice project on early schizophrenia culled children for a study of through his ears and seems affectively not to be too troubled clozapine. The most common referrals were children whose by it. Conversely, a child experiencing true auditory halluci- symptoms closely resembled those of multiple complex de- nations is frightened, puzzled, and unable to be reassured. The NIMH group suggested the term This differentiation is especially important because manage- multidimensionally impaired (45,46) and offered criteria that ment of these youngsters often includes the use of psycho- were analogous to those described by Towbin and co-work- tropic medications, which, in and of themselves, require ers. However, despite findings that many of these children serious consideration because of their long-term adverse ef- met partial criteria for pervasive developmental disorder not fects. If the phenomenology of these so-called psychotic Chapter 45: Psychosis in Childhood 617 symptoms is not clarified, many youngsters with pseudohal- contamination with symptoms and deficits belonging to the lucinations will be prescribed psychotropic medication early phase of the disease. In addition, they will wrongly be labeled with a on the early course is also made accessible to empiric re- psychotic disorder. Other instruments that have been used for assessing Premorbid developmental peculiarities have been re- psychotic symptoms in youngsters have been the Interview ported in children with childhood-onset schizophrenia who Schedule for Children (58), the Diagnostic Interview have been followed into their thirties. These peculiarities Schedule for Children (59), the Schedule for Affective Dis- are primarily internalizing such as shyness, isolatory behav- orders and Schizophrenia for School-Aged Children (60, iors, lack of interest, awkwardness, being fickle with peculiar 61). These signs have been reported to be much more phrenia. These include deficits in smooth pursuit eye move- common than externalizing, acting-out behaviors such as ments and autonomic responsivity (62,63). Neuroimaging temper tantrums, aggression, opposition, and hostility (22). However, the ring in the frontal and temporal regions (64–67). Others predictive relevance in prepsychotic symptoms in children findings reported in the literature are a smaller total cerebral seems to be extremely uncertain because of the high variabil- volume, correlated with negative symptoms (37), and fron- ity of developmental peculiarities. The nature of the diagnostic subtypes varies markedly Schizophrenia with childhood onset is usually a severe across the course of the illness. In patients with continuous and chronic disorder with a more guarded prognosis and predominantly catatonic symptoms, the outcome is poor. New research to illuminate the heterogeneous psychopathology of child- and data will help to clarify the origin and pathogenesis of hood-onset schizophrenia (22). These investigators found schizophrenia in children. Subsequently, development of that various temporary premorbid behavioral peculiarities more effective treatments and preventive measures may re- were precursors of childhood-onset schizophrenia. Their findings contradicted the assump- can often be accompanied by psychotic symptoms. Over tion that childhood-onset schizophrenia is characterized the past several decades, the prevalence of mood disorders only by negative symptoms, because a differentiation be- appears to have been increasing (69). Although information tween premorbid and prodromal signs proved to be arbi- on the epidemiology of psychotic depression in children is trary. The psychotic symptoms 1889, the onset and course of schizophrenia relied heavily usually are mood congruent, but at times they can be quite on first admission data and on the subsequent course of the like those seen in childhood schizophrenia (20,70–72). Sometimes, the used as premorbid characteristics (57). In an attempt sys- negative symptoms of schizophrenia in children can be mis- tematically to account for the age and gender distribution taken for those of depression. However, it has been shown of the true onset and the symptoms and pattern of the early that children with schizophrenia have poorer premorbid ad- and later course, Hafner et al. This instrument allows an objective, reliable, der (50). It is therefore prudent to make only a tentative and valid assessment of the symptoms, psychological im- diagnosis at the outset that must be confirmed longitudi- pairments, demographic and social characteristics, and the nally. Careful follow-up of psychotic patients is needed to referring points in time of the early course of psychosis. This issue can be compounded, Their findings suggested that the IRAOS provides informa- however, if the symptoms resolve with antipsychotic medi- tion on the earliest course of the disease and enables them cations. It becomes unclear whether the child improves be- to separate premorbid characteristics, possibly the most cause of treatment or spontaneous remission. Approxi- powerful predictors of the later course and outcome, from mately one-half of adolescents with bipolar disorder may 618 Neuropsychopharmacology: The Fifth Generation of Progress be originally diagnosed as having schizophrenia (20,70). Brief Reactive Psychosis Therefore, it is extremely important that longitudinal reas- Occasionally, children and adolescents suddenly develop sessment is needed to ensure accuracy of the diagnosis. De- psychotic symptoms that can last from a few hours or days.

NE order 250 mg antabuse overnight delivery treatment tendonitis, cortisol generic 500mg antabuse with mastercard treatment modalities, and CRH thus appear tightly decrease; DST, dihydrostreptomycin; HPA, hypothalamic pituitary linked as a functional system that offers a homeostatic mech- adrenal axis; inc. A clinical phenomenon of anxiety disorders that may be specifically regulated by interactions between NE and glucocorticoid secretion involves the acquisition and consol- idation of traumatic memories. A characteristic feature of PTSD and PD is that memories of the traumatic experience development of PTSD and may comprise a risk factor for or the original panic attack, respectively, persist for decades developing PTSD in response to traumatic stress. In PD, the results of studies examining CRH-receptor In experimental animals, alterations of both brain catechol- and HPA-axis function have been less consistent (Table amine and glucocorticoid levels affect the consolidation and 63. Elevated plasma cortisol levels were reported in one retrieval of emotional memories (50,51). Glucocorticoids study (244), but not in another (245), and the results of influence memory storage by activation of glucocorticoid studies assessing urinary free cortisol have been similarly receptors in the hippocampus, whereas NE effects are me- inconsistent (177,246). In a study of 24-hour secretion of diated in part through -adrenoreceptor stimulation in the ACTH and cortisol, PD subjects had subtle elevations of amygdala (255). In humans, adrenocortical suppression nocturnal cortisol secretion and greater amplitude of ul- blocks the memory-enhancing effects of amphetamine and traradian secretory episodes relative to control subjects epinephrine (256), and propranolol impairs memory for an (247), but these findings await replication. Both normal emotionally provocative story, but not for an emotionally and elevated rates of cortisol nonsuppression after dexa- 'neutral' story (257). These data suggest that the acute methasone administration have been reported in PD (248). It is axis response was higher in PD subjects than in healthy conceivable that long-term alterations in these systems may controls, but the magnitude of this abnormality was less account for memory distortions seen in PTSD, such as the than that seen in depressed samples (249,250). The ACTH memory fragmentation, hypermnesia, and deficits in declar- ative memory. The extent to which pathophysi- ologic heterogeneity within PD samples may account for Several lines of preclinical and clinical evidence have estab- the inconsistency of these findings remains unclear. Central BZD receptors are ex- mediated through a GABAergic mechanism. These agents pressed are present throughout the brain, but they are most are effective for the treatment of a spectrum of anxiety disor- densely concentrated in the cortical gray matter. The BZD ders including social anxiety disorder, generalized anxiety and GABAA receptors form parts of the same macromolecu- disorder, PD, and PTSD. One of the multiple secondary lar complex, and although they constitute distinct binding effects of these agents involves potentiation of GABAergic sites, they are functionally coupled and regulate each other function. For example, in rats, the effective dose of phenel- in an allosteric manner (258). Central BZD-receptor ago- zine (15mg/kg) on the elevated plus maze administered nists potentiate and prolong the synaptic actions of the in- produces a more than twofold increase in whole-brain level hibitory neurotransmitter, GABA, by increasing the fre- GABA concentrations, whereas an ineffective dose of phe- quency of GABA-mediated chloride channel openings (258, nelzine (5. Microinjection of BZD-receptor agonists in limbic (267). Moreover, the N-acetylated metabolite of phenelzine, and brainstem regions such as the amygdala and the PAG N-2-acetylphenelzine, which potently inhibits monoamine exert antianxiety effects in animal models of anxiety and fear oxidase but does not change whole-brain GABA concentra- (260). Conversely, administration of BZD-receptor inverse tions, does not produce anxiolytic effects in the elevated agonists, such as -carboline-3-carboxylic acid ethylester, plus-maze test (267). Transgenic mouse studies have identified behavioral roles for specific GABAA-receptor subunits. The anxiolytic action of diazepam appears absent in mice with 2 subunit point Effects of Stress on Benzodiazepine-GABAA mutations, but it is present in mice with 1 or 3 subunit Receptors point mutations (264,265). These data suggest that the an- xiolytic effect of BZD agonists is at least partly mediated BZD- and GABA-receptor function can be altered by expo- by the GABA -receptor subunit, which is largely ex- sure to stress in some brain regions. In experimental animals A 2 pressed in the limbic system, but not by the subunit, exposed to inescapable stress in the form of cold swim or 3 which is predominately expressed in the reticular activating foot shock, the BZD-receptor binding decreases in the fron- system, or the subunit, which is implicated in mediating tal cortex, with less consistent reductions occurring in the 1 the sedative, amnestic, and anticonvulsive effects of BZDs hippocampus and hypothalamus, but no changes in the oc- (265,266). These findings hold clear implications for inves- cipital cortex, striatum, midbrain, thalamus, cerebellum, or tigations of the pathophysiology of anxiety disorders and for pons (268). Chronic stress in the form of repeated foot the development of anxioselective BZD-receptor agonists. The neurosteroid, allopregnenolone, ex- in BZD-receptor binding were associated with deficits in erts antianxiety effects in conflict paradigms that serve as maze escape behaviors that may have reflected alterations putative animal models of anxiety. The anticonflict effects in mnemonic processing (269,270). Some of these stress of allopregnenolone are reversed by either isopropylbicyclo- effects may be mediated by glucocorticoids, because chronic phosphate, which binds at the picrotoxinin site on the exposure to stress levels of CORT alters mRNA levels of GABAA receptors, or RO15-4513 (ethyl-8-azido-5,6-dihy- multiple GABAA-receptor subunits (271). Consistent with dro-5-methyl-6-oxo-4H-imidazo[1,5- ]-[1,4]benzodiaze- the effects of chronic stress on BZD-receptor expression, pine-3-carboxylate), a BZD-receptor inverse agonist that the Maudsley 'genetically fearful' rat strain shows decreased inhibits GABAA-activated chloride flux in neuronal mem- BZD-receptor density relative to other rats in several brain branes. In contrast, administration of the BZD-receptor an- structures including the hippocampus (272). Allopregnenolone may thus exert reduced BZD-receptor sites in the LC, the NTS, the frontal anxiolytic-like effects by stimulating the chloride channel cortex, and the CE and the LA of the amygdala, and reduced in GABAA receptors by binding at the picrotoxinin site or mRNA levels for the 2 subunit of the GABAA-receptor at a site specific for RO15-4513. The The antianxiety effects of antidepressant drugs with pri- extent to which these developmental responses to early-life Chapter 63: Neurobiological Basis of Anxiety Disorders 917 stress may alter the expression of fear and anxiety in adult- global reduction in BZD site binding in seven study subjects hood remains unclear. Anxiety Disorders found no differences in the Bmax, Kd or bound/free values The central BZD receptor has been implicated in anxiety for [11C]flumazenil in any brain region in ten unmedicated disorders on the basis of the anxiolytic and anxiogenic prop- PD study subjects relative to healthy controls (283). Hypotheses advanced regarding the role Acute stress increases DA release and turnover in multiple of GABAA-BZD–receptor function in anxiety disorders brain areas. The dopaminergic projections to the mPFC have proposed either that changes in the GABAA-BZD mac- appear particularly sensitive to stress, because brief or low- romolecular complex conformation or that alterations in the concentration or properties of an endogenous ligand intensity stressors (e.

Amgdaloid sclerosis cal outcome following selective amygdalohippocampectomy generic antabuse 250 mg mastercard medicine used to stop contractions. Stereotactic amygdalohippocampo- in experimental and human temporal lobe epilepsy purchase 250mg antabuse with visa symptoms for pneumonia. Epilepsy Res tomy for the treatment of medial temporal lobe epilepsy. Erkrankung des Ammonshorns als aetiologisches correlated with long-term, free recall of emotional information. Arch Psychiatr Nervenkrankh 1880;10: Proc Natl Acad Sci USA 1996;93:8016–8021. The histopathology of convulsive disorders patients with complex partial seizures of left temporal origin. Interictal cerebral glucose of subtotal temporal lobectomy. Quantitative magnetic of the brain in epilepsy, with particular reference to the temporal resonance imaging in temporal lobe epilepsy: relationship to lobes. Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganiza- 1876. Rapid kindling with recurrent in rats: visualization after retrograde transport of biocytin. J hipocampal seizures: effect of stimulus frequency and train dura- Comparative Neurology 1995;352:515–534. Neurosurgery 1978;3: rent excitatory circuits in the dentate gyrus of hippocampal 234–252. Subcortical structures and pathways involved in convul- campal kainate in the rat. Possible functional consequences of synaptic reor- 46. FAST and SLOW amyg- ganization in the dentate gyrus of kainate-treated rats. Neurosci dala kindling rat strains: comparison of amygdala, hippocampal, Lett 1992;137:91–96. Limbic seizure and brain damage produced by kainic 1854 Neuropsychopharmacology: The Fifth Generation of Progress acid: mechanisms and relevance to human temporal lobe epi- epileptogenesis: does disinhibition play a role? Permanently altered hippocampal structure, excita- of pilocarpine in rats: structural damage of the brain triggers bility, and inhibition after experimental status epilepticus in kindling and spontaneous recurrent seizures. Epilepsia 1991;32: the rat: the 'dormant basket cell' hypothesis and its possible 778–782. Hip- campus versus a chronic, kainate rat model of hippocampal pocampus 1996;6:347–470. Recurrent sponta- aminobutyric acid type A receptor function in CA1pyramidal neous hippocampal seizures in the rat as a chronic sequela to neurons. A new model of chronic GABA A receptor subunits in the hippocampus of the rat after temporal lobe epilepsy induced by electrical stimulation of the kainic acid-induced seizures. Self-sustaining induced by lowering extracellular [Mg2 ] in combined hippo- status epilepticus after brief electrical stimulation of the perfor- campal-entorhinal cortex slices: modulation by receptors for ant path. The TINS/TIPS lecture The molecular biology lepsy Res 1995;20:93–104. Model of chronic spontaneous limbic 1993;16:359–365. J entorhinal cortex are epileptiform in an electrogenic rat model Pharmacol Exp Ther 1995;274:1113–1121. Hyperexcitability of entorhinal cortex and hip- sion in young and adult rats. Expression of the medial entorhinal cortex in combined entorhinal and hippo- glutamate transporters in human temporal lobe epilepsy. Shortened duration GABA A receptor Neuroscience 1996;72:399–408. Spontaneous in a chronic model of temporal lobe epilepsy. Neuroscience 1997; recurrent seizures in rats: amino acid and monamine determina- 80:1101–1111. Neuropeptide Y: emerging tor subunits GluR1and GluR2/3 distribution shows reorganiza- evidence for a functional role in seizure modulation. GABA receptors in human epileptic neocortical tissue: quantita- 81. Hyperexcitability in combined entorhinal/hip- tive in vitro receptor autoradiography. Neuroscience 1999;94: pocampal slices of adult rat after exposure to brain-derived neu- 1051–1061. Effects of kainic acid on of the NMDAR1glutamate receptor subunit in human tem- messenger RNA levels of IL1IL6, TNF , and Lif in the rat poral lobe epilepsy. Increased neuronal - so dormant in temporal lobe epilepsy: a critical reappraisal of the amyloid precursor protein expression in human temporal lobe dormant basket cell hypothesis. Evidence of functional mossy fiber Neurochem 1994;63:1872–1879.

The proportion of respondents agreeing or strongly agreeing that PRISM had enabled them to change they worked had fallen to < 30% cheap 250mg antabuse overnight delivery medications quizzes for nurses. Lack of time to use PRISM was an issue antabuse 500mg with visa nioxin scalp treatment, and few practices agreed that they were working together as a team to use it. Future Predictive RIsk Stratification Model use At the end of the trial, we asked respondents how they expected to use PRISM over the following 6 months; 13 out of 31 responded with free-text answers. There was a range of responses, from those who did not expect to use it at all, to those who had definite plans: We will continue to use PRISM to identify patients at risk and patients who should be included in our palliative register. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 99 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. P R IS M do es a us efulj b fiden ifyin g a t ien w ih a high rik f em ergen cy a dm i i n ho ia l W e a re us in g R IS M get hera s a ea m in ur ra ct ice Strongly agree W e la ck he im e us e R IS M Agree No opinion P R IS M ha s en a b led us cha n ge he w a y w e w o rk in hi Disagree p ra ct ice Strongly disagree P R IS M iden ifi es dem a n ds w hich w e ca n n a t ify P R IS M r vides us w ih us efulin f rm a t i n a b ut a t ien 0 R es n e ra t in g FIGURE 10 Looking back over the past 3 months, what difference has PRISM made to the way you work? PRISM does a useful job of identifying patients with a high risk of emergency admission to hospital We are using PRISM together as a team in our practice Strongly agree We lack the time to use PRISM Agree PRISM has enabled us to change the way we work in this No opinion practice Disagree Strongly disagree PRISM identifies demands which we cannot satisfy PRISM provides us with useful information about patients 0 10 20 30 40 50 60 70 80 90 100 Response rating (%) FIGURE 11 Looking back over the past 9 months, what difference has PRISM made to the way you work? All stakeholder groups seemed to be aware of a lack of certainty about the intended role and function of PRISM, with its original purpose being identified as supporting service planning, while later implementation focused on individual case-finding. General practitioners and practice staff showed a willingness and open-mindedness about trying the PRISM risk prediction tool as a way to move away from current reactive practice, which was seen as unsustainable. However, there were concerns expressed – both before implementation and after – by all stakeholder groups about its ability to support change in patient care without associated investment in new community services or resources. Almost all practices that responded to the end-of-trial survey reported that they made some use of PRISM, although the total number of logins was not high and became less frequent during the course of the intervention period, with only two practices reporting that they were still using it at the end. The extent to which PRISM was used varied greatly across practices. A range of ways of using the PRISM information was reported, with some practices printing off PRISM data (lists) for later discussion. Generally, patients were discussed in practice meetings (often initiated by QOF requirements), some of which were attended by staff from other disciplines and organisations. The introduction of PRISM to general practices coincided with contractual requirements (QOF) to select 0. The QOF requirement appears to have been a major driver of PRISM use, and also to have shaped the exact way in which practices used the tool – focusing on those patients in the highest risk group. After the QOF reporting period ended, use of PRISM appears to have fallen away. General practitioners cited as barriers to using PRISM: the lack of time to work prospectively; inadequate referral services; limited internet access; out-of-date data; and the PRISM data not being integrated with practice records. They said that they needed financial incentives alongside additional community-based services for identified patients in order to regularly use the tool. Respondents felt that PRISM changed their awareness of patients and focused them on targeting at-risk patients to reassure themselves all steps were taken to prevent a possible crisis. All had concentrated on high-risk patients, despite feeling these were least suitable for proactive management, yet they believed that they had provided more attention and treatment, which was reassuring to patients. Strengths and limitations of qualitative strand of study Strengths The multiple data collection methods (interviews, focus groups, survey, login information) allowed us to triangulate findings, which helped interpretation of quantitative findings. Collection of data at different time points allowed us to track how attitudes to and use of PRISM changed over time. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 101 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. STAKEHOLDER VIEWS: THE PREDICTIVE RISK STRATIFICATION MODEL IMPLEMENTATION AND USE Using the NPT framework to interpret interview data enabled us to fully consider the stages and actions associated with implementing an intervention in a health-care setting to increase our understanding of the ways they responded in this study. Limitations Interviews with policy and health board staff about the story of PRISM took place some years after PRISM was developed, potentially affecting their memory of events because of the time period and role changes. In most cases, we talked to only one respondent from participating general practices. This was usually the GP responsible for leading use of PRISM, and their knowledge and use of PRISM was not always shared by other staff. In a minority of practices, the PRISM lead GP changed between the three data collection points, because they retired or moved practice. We were unable to gather the views of community health staff after the tool was implemented, as most staff declined to attend a follow-up focus group because their roles had changed. Only one health services manager agreed to be interviewed at the end of the study. General practitioners taking part in the PRISMATIC trial volunteered for the study. In interviews, several identified themselves as interested in, or supportive of, research and wanted to contribute to knowledge generation by participating. They were therefore likely to be atypical of many GPs and their response to PRISM may not be that of other members of their profession. A summary of service user involvement can be found in Table 42. TABLE 42 Summary of service user involvement in the PRISMATIC trial Type of involvement activity Role Process Comments Supporting Service users were actively Information, guidance, honoraria, Named individual (BAE) supported service user involved across all activities expenses and briefing sessions the trial manager (MRK) to ensure involvement associated with delivering were provided to facilitate active active involvement. In addition, the PRISMATIC trial involvement provided single contact for service users Service users recruited through the SUCCESS group: membership of this group gave access to mutual support and a wider service user perspective Mid-study meeting held to review involvement and further support needed Long time scales enabled strong relationships across all research partners RMG Two service users were 24 meetings scheduled (2010–16) One individual remained involved meetings invited to be members of throughout the study; the second the RMG, and contributed Two service users were at almost place was taken by four different to all decisions about all meetings; just one meeting individuals managing and undertaking took place without a service user the study member present Individuals received induction before starting role and were offered pre-meeting briefings Service user perspectives were sought at all stages, especially when developing patient consent process, preparing patient information and questionnaires, holding a prize draw for questionnaire respondents, interpreting final results TSC meetings Two service users were Five meetings held (2013–15) Service users received training before invited to be members of joining the TSC which covered the the six-person TSC, and Three out of the five meetings role of a TSC and provided provided independent attended by at least one service background about the PRISMATIC study scrutiny and user trial oversight Opportunity provided for briefing before each TSC meeting Qualitative One service user was Two meetings held (2013–14) analysis and invited to the qualitative write-up of subcommittee to develop Both meetings were attended by results coding framework and one service user and three review drafts of qualitative researchers. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 103 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. SERVICE USER INVOLVEMENT TABLE 42 Summary of service user involvement in the PRISMATIC trial (continued) Type of involvement activity Role Process Comments Writing events To contribute service user Six meetings held (2012–15) Workshop sessions held at two perspective to all meetings to consider potential study discussions about Two service users were invited to outputs for service user audience communications and each meeting: at least one dissemination attended each meeting Discussions held about how to describe the PRISMATIC trial service user involvement in final report Service users contributed to all discussions as equal team members and agreed publications plan Publicity and Service users contributed to Service users reviewed and One service user contributed to dissemination publicity and dissemination contributed to seven PRISMATIC edition 6, writing about her materials about PRISMATIC newsletters, aimed at participating experience of being involved in GP practices and health services research managers One service user contributed to edition 7, explaining how risk prediction tools can help patients, especially those with early-stage chronic illness who can expect their condition to deteriorate Two newsletters contained articles by GP champions linked to the research team The SUCCESS group members advised on, and reviewed, the patient information pages of the PRISMATIC trial website Service users involved in Service users suggested production publicising PRISMATIC to patients and distribution of a poster about the PRISMATIC trial, for display in GP practices, to inform patients about the study One service user and one GP champion were interviewed by a TV crew about the study.

Most recent setting purchase antabuse 500 mg otc medications gout, increasingly alcohol detoxification is being con- figures put the economic costs of alcohol-related expenses ducted in ambulatory settings quality antabuse 250 mg medications not covered by medicare. Except in the case of medical at $176 billion annually in the United States (2). This in- or psychiatric emergencies, outcome studies generally show cludes the economic costs of increased health care expenses, that successful detoxification can safely and effectively be lost productivity at work, and legal expenses. Similarly, al- carried out in ambulatory setting using medications such though there have been some reductions in the number of as benzodiazepines (5,6). In addition, the use of anticonvul­ motor vehicle deaths attributed to excessive alcohol drink- sants has received recent interest. Benzodiazepines Current psychosocial approaches to alcohol addiction are moderately effective, with perhaps as many as half the pa- Benzodiazepines are �-aminobutyric acid (GABA) agonists tients receiving treatment becoming abstinent or signifi- that metaanalysis of placebo-controlled double-blind studies cantly reducing episodes of binge drinking (4). In the past have consistently shown to be safe and effective (7). Benzo­ two decades significant progress has been made in under- diazepines differ widely in their pharmacologic half-life, and standing the pharmacology of alcohol and why some people this has been a factor in the choice of which benzodiazepines become dependent. This has led to the development of sev- to use for detoxification. For example, one popular ap­ eral medications that have been shown in research studies proach is to use a benzodiazepine with a long half-life such to improve treatment outcomes. This chapter reviews some as chlordiazepoxide as a loading dose and let the benzodiaze­ of the possible neurobiological mechanisms involved in al- pine self-taper (8). We introduce precludes problems with patience noncompliance. A second future directions for research such as the use of combina- approach is to use shorter acting benzodiazepines and titrate tions of medications that may have additive or synergistic the dose depending on symptoms. In a recent study, oxaze­ effects on improving treatment, and discuss the role of psy- pam was used as needed depending on the severity of with­ chosocial support to facilitate the effectiveness of pharmaco- drawal symptoms as assessed by the Clinical Institute With- therapy. As needed oxazepam resulted in effective alcohol withdrawal management with a lower total amount of oxazepam over a shorter duration compared to routine dosing (9). Volpicelli: Department of Psychiatry, University of Pennsylva- Anticonvulsants nia, Veterans Affairs Medical Center, Philadelphia, Pennsylvania. Anticonvulsants have the 1446 Neuropsychopharmacology: The Fifth Generation of Progress advantage of no abuse potential and a theoretical advantage drinking (17–33). These studies have consistently demon­ of reducing kindling, a sensitization of withdrawal symp­ strated that alcohol enhances the release of endogenous toms that occurs after multiepisodes of alcohol withdrawal. For example, Gia­ of less hostility in the phenobarbital group (10). Carbamaze­ noulakis and colleagues (34) have found that in humans pine has also been used as an alternative to benzodiazepines peripheral levels of �-endorphin increase in family his­ to attenuate alcohol withdrawal symptoms (11). Although tory–positive subjects following a moderate dose of alcohol, its mechanism of action remains unknown, research gener­ whereas there is no increase in �-endorphin for social drink­ ally shows that carbamazepine is as effective as benzodiaze­ ers without a family history of alcoholism. Disadvantages of carbamazepine include a rather nar­ lich and colleagues (36) have also demonstrated that alco­ row therapeutic window, the need to monitor serum levels, hol-induced �-endorphin responses both prior to and and hepatotoxic effects. For patients with a history of alco­ following alcohol administration are significantly heritable. Nonpreferring (NP) rats exhibit differences in the densities of � opioid receptors in certain brain reward regions compared to alcohol-preferring rats. PHARMACOLOGIC TREATMENTS TO Transgenic mice lacking �-endorphin have been shown to REDUCE ALCOHOL RELAPSE exhibit decreased preference for alcohol compared with wild-type mice (39). Disulfiram Nonspecific and specific opioid antagonists have been The aversive agent disulfiram has been available for the found to reduce alcohol self-administration in rodents and treatment of alcoholism since 1949. Preclinical studies have also inhibiting the liver enzyme that catalyzes the oxidation of evaluated the efficacy of antagonists specific for the � and � acetaldehyde, a toxic by-product of alcohol, resulting in an opioid receptors in reducing alcohol drinking. The � opioid aversive reaction to alcohol consumption. In this way, disul­ receptor antagonist �-funaltrexamine (B-FNA) and the � firam is thought to deter drinking by making the negative opioid receptor antagonists naltrindole (NTI) and naltriben consequences of drinking more certain, immediate, and (NTB) have all been shown to reduce alcohol drinking (17, aversive than they would be otherwise. Recent evidence also suggests a role for the � opioid patient takes the disulfiram, the decision about whether or receptors in mediating the aversive effects of alcohol as indi­ not to drink is probably shifted toward abstinence when cated by an increase in conditioned taste aversion in alcohol faced with opportunities to drink based on the knowledge preferring (P) rats in the presence of the � opioid receptor of the disulfiram-ethanol interaction. With supervi­ ing at least in part because of its effects on enhancing the sion and positive contingencies for taking disulfiram, how- release of endogenous opioids. The use of opioid antagonists ever, the effectiveness of disulfiram appears to be enhanced as an effective agent in the treatment of alcoholism is (14). As an alternative to behavioral methods for enhancing strongly predicted by these preclinical studies. However, these efforts have been unsuc­ Pharmacokinetics, Pharmacodynamics, and cessful perhaps because these implants have not yielded ade­ Safety quate disulfiram blood concentration required to produce a reaction to alcohol (15,16). Naltrexone, an opioid antagonist, was originally developed for use in the prevention of relapse in detoxified opiate addicts. Naltrexone has a half-life of approximately 4 hours, Opioid Antagonists and 6-�-naltrexol, its major metabolite, has a half-life of 12 hours. Rapidly absorbed, naltrexone reaches peak plasma Background levels between 60 and 90 minutes. Naltrexone undergoes The role of the alcohol-induced activation of the endoge­ first-pass hepatic metabolism, and there is some evidence nous opioid system in the reinforcing effects of alcohol has of dose-related hepatotoxicity at doses four to five times been well established in dozens of animal models of alcohol higher than the currently recommended 50-mg daily dos- Chapter 101: Alcoholism Pharmacotherapy 1447 age.

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