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The economic and medical costs of alcohol- historically red viagra 200mg line erectile dysfunction pills for heart patients, alcohol detoxification has occurred in inpatient ism and alcohol abuse continue to escalate discount 200 mg red viagra free shipping 5 htp impotence. Most recent setting order 200mg red viagra impotence at age 70, increasingly alcohol detoxification is being con- figures put the economic costs of alcohol-related expenses ducted in ambulatory settings. 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. In alcohol-dependent patients, adverse events reported riod.

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Sertraline in the prevention of depres- response rates and high rates of undertreatment in the commu- sion purchase 200mg red viagra mastercard erectile dysfunction medication side effects. Psychopharmacological of 20 mg citalopram cheap red viagra 200 mg without prescription erectile dysfunction doctor near me, 40 mg citalopram and placebo in the pre- treatment response of patients with a DSM-III diagnosis of dys- vention of relapse of major depression order 200mg red viagra mastercard erectile dysfunction treatment in mumbai. Mirtazapine versus RO-11-1163 (moclobemide) and placebo in the treatment of amitriptyline in the long-term treatment of depression: a double- depression. International Collaborative Study substitution study of nefazodone in the prevention of relapse Group. Amisulpride versus fluoxetine in patients with dys- ders. WEISSMAN Epidemiology is the study of the distribution of diseases MAJOR DEPRESSION and disorders in human populations and the variation in Prevalence these distributions in different population subgroups. An observation that a disease is higher in one group or another Data on prevalence of unipolar MD based on epidemiologic helps to identify risk factors or correlates of these high rates community surveys using the same diagnostic assessment, whose alteration will interrupt the causal sequence that pro- the Diagnostic Interview Schedule (DIS), are now available duces the disorder. Epidemiologic methods have been from different parts of the world. These population-based grouped into descriptive studies, which provide basic esti- epidemiologic studies were conducted in the 1980s, and a mates of rates and their variation or increased risk in a popu- cross-national collaboration was formed to analyze the data lation; analytic studies, which explore the variations in rates together in a standardized way. Ten countries across the among different groups and identify risk factors; and experi- world, including North America, Europe, Asia, and New mental studies, which test an association between a risk Zealand, participated. These data provide the first informa- factor and a disorder and seek to control or reduce the tion on cross-national rates for risk factors using the same occurrence by controlling the risk factor. The lifetime prevalence rates of MD range from Epidemiologic methods used in psychiatry are identical 1. The results showed considerable variation in rates, but con- to those used in other branches of medicine. In psychiatry sistency in sex differences and age of onset. In the National Comorbidity analytic (family and high-risk offspring) studies. The former Survey (NCS) conducted a decade later in the United States, is useful as a first step because the samples include subjects a substantially higher lifetime prevalence of MD was re- regardless of treatment and thus are unbiased. All prevalence rates have been published are useful as they include control groups and can be used individually, but for the purpose of comparison between to calculate relative risks. Whether the differences are real (reflecting a substantial change in the prevalence rate over the decade) or artifactual (due to differences in methodology) has prompted careful examination. Hirschfeld: Department of Psychiatry and Behavioral difference is due to methodology (e. Weissman: College of Physicians and Surgeons of Columbia assessment, sample age, and size), and not to a true increase University, New York, New York. CROSS-NATIONAL LIFETIME PREVALENCE OF MAJOR DEPRESSIONa Lifetime Rate/100 Mean Age Country Overall Females Males F/M Ratio at Onset United States 5. All studies used the DIS with the exception of the NCS, which used the CIDI. Gender MD in female relatives of patients with MD by age 30 was less than 10% in individuals born before 1929. This rate Despite the variation in rates, the most consistent finding doubled in cohorts born between 1930 and 1949, and in the cross-national studies and the two U. The reasons The rate in males also increased in younger cohorts, but not for this disparity are not clear, but the disparity is also found nearly as dramatically as in women (Figs. Interestingly, prior to puberty there are An analysis of the ECA data by Wickramaratne and col- no sex differences in rates of depression. However, following leagues (5) showed an increase in the rate of MD in the puberty there is a dramatic shift in the prevalence rates, cohort born between 1935 and 1945. The rates for females with a twofold increase in the prevalence of depression stabilized after this increase. However, rates for males con- among women compared to men. A higher risk of depres- tinued to rise in the cohort born between 1945 and 1954, sion in women is probably accounted for primarily by the and then decreased in the most recent cohort of the study, higher risk of first onset in women. A series of analyses of the NCS data shows that there is little difference in the probability of acute recurrence in women and in men with a history of depression (3). Many theories, biological, psy- chosocial, and artifactual, attempt to explain this dramatic increase in the prevalence of depression among women, but none is fully satisfactory. Age Of Onset And Secular Changes The age of first onset of MD is fairly consistent across stud- ies (Table 70. Of the ten major population-based epide- miologic studies reported by Weissman et al. Although there is consis- tency across studies regarding the age of onset, there is some evidence that the age of onset of depression has decreased FIGURE 70. Cumulative probability of diagnosable major de- over the last half century (4). In 1985, using the data from pressive disorder in male relatives by birth cohort. Birth-cohort trends in rates the NIMH Collaborative Program on the Psychobiology of of major depressive disorder among relatives of patients with Depression, the cumulative probability of a first episode of affective disorder.

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Further discount red viagra 200 mg online erectile dysfunction at 25, the calculation of DALYs 'pre- drawn to the neighborhood) buy cheap red viagra 200 mg erectile dysfunction dr. hornsby, perform their own idiosyn- supposes that life years of disabled people are worth less cratic weighting of these factors proven 200mg red viagra erectile dysfunction kegel exercises, and decide if they are in than life years of people without disabilities' (46), and may favor of the park or not. In contrast to cost-utility analysis, cost-effectiveness anal- Schizophrenia brings with it an increased risk of suicide ysis does not reduce the impact of an intervention into one (48), which is consistent with DALYs ranking some lives measure. Some outcomes may be clearly preferential or as worse than death. However, assuming that person A and 'dominant choices' (e. Other outcomes are not as clearly dominant, and in fates are worse than death presumes an ecologic validity to these cases it may be useful to show the likely range of DALY ratings that may be unwarranted. One Cost-utility measures such as QALYs, DALYs, and mea- method of examining these ranges is to create sampling dis- sures like symptom-free days, have enormous appeal because tributions for costs and effectiveness measures to show the of their ability to reduce multiple effectiveness domains to precision of estimates as well as their mean. Where the measure is reduced to dollars (as in and plot these estimates as a cost-effectiveness plane. Boot- QALYs), one may even compare the values of interventions strapping techniques offer one means of describing confi- between different conditions (38), for example, if dollars dence intervals for incremental cost-effectiveness ratios expended on diabetes reap more benefits than dollars spent (ICERs) (49,50). Cost data are often highly positively on schizophrenia. But the assumptions built into such bullet skewed, and ICERs provide less biased estimates of confi- measures may have limited usefulness for informing deci- dence intervals in highly skewed cost data (43,51,52). Instead, these stakehold- cluster of points displays the sampling distribution of the ers are asking more specific questions. Most of the points fall in the lower-right quadrant, mental health commissioner asks, 'If I put an extra $3 mil- indicating that clozapine is most likely to be less costly and Chapter 57: The Economics of the Treatment of Schizophrenia 813 FIGURE 57. Ten thousand bootstrap replications plotted in the cost-effectiveness plane (intent-to-treat, N 136 clozapine and N 87 usual care; treatment crossovers excluded, N 89 clozapine and N 30usual care). The x-axis and y-axis, respec- tively, show the difference between clozapine and usual-care groups in estimated number of extrapyramidal side effects (EPS)-free months and total cost during a 2-year period. The quadrant to the lower right of the origin (0,0) contains those estimates where clozapine was found to be less costly and more effective than the usual care (80% of the estimates for the in- tent-to-treat analyses and 81% of the estimates when treat- ment crossovers are excluded). Cost-effectiveness of clozapine compared with conventional antipsychotic medication for patients in state hos- pitals. It is incumbent on mental health services re- the cost perspective (total societal cost) and for the effective- searchers to report their findings in ways that speak to fun- ness measure in question (reduction in EPS). Such displays ders and service system managers, which means providing of information give the reader/policy maker a sense of the estimates of the most likely outcome as well as the likelihood tightness of the point estimate and the risk of falling in a of alternative outcomes. One can use these sampling distributions to create cost- acceptability curves from the viewpoint of particular payers COST OF THE NEWER ANTIPSYCHOTIC for particular outcomes (e. These Saul Feldman (53) has held positions as the head of the acquisition costs are reflected in formulary budgets. Thus, he has past decade, and the market share of the newer agents has been in a position to make policy based on research, and risen as they have replaced the less costly conventional to inform policy makers with research. Distribution of (left circle) and total dollars paid (right circle) by Medicaid for antipsychotic medication prescriptions during 1998. Newer antipsychotic medications represented slightly over half of the total prescriptions, and they were responsible for 90% of the total cost. These also showed that clozapine is more effective than the usual data show that the newer agents account for 58% of all care in minimizing days hospitalized, enough so that the antipsychotic prescriptions paid for by Medicaid but for reduction in hospital days more than covers the increased $1. These charts dramatically But, from more narrow perspectives (e. For cost- This price difference between the older and the newer effectiveness studies to influence planning and policy mak- antipsychotic medications, which can be a 100-fold differ- ing, the perspectives of these different payers need to be ence (e. A hospi- than simply the cost of the medication was considered. For tal would have a great incentive to use clozapine for a heavy example, if using new and expensive medication X results user of hospital services if it has a fixed budget (the case in fewer days hospitalized than some alternative, then, all with most state hospitals), but a hospital paid a per diem else being equal, using X will reduce overall costs as long would have no such incentive. By the end of 6 months in the Connecticut study, only 11% of the Clozapine Cost Effectiveness Studies As usual care patients had begun a trial on clozapine, but by Case Examples the end of 24 months in the study, 66% had. In the VA The rub, of course, is that 'all else' is rarely equal in effec- clozapine study, 72% of the patients assigned to masked tiveness or cost-effectiveness studies, and the early cost pro- haloperidol had ceased taking the masked medication by jections concerning the impact of using clozapine often suf- the end of the 1-year study period, with 49 of 157 (31%) fered from faulty assumptions about what was equivalent. Be- amined changes in hospital use and lacked a comparison cause of the biases introduced by what is likely to be highly group (54–60). For example, the study by Meltzer and col- nonrandom discontinuation of the assigned treatment, the leagues (59) of patients with schizophrenia who were taking importance of intent-to-treat analyses and the unspecified clozapine collected retrospective cost data for 2 years before biases of crossovers-excluded analyses are well documented and after these 47 individuals began taking clozapine and (68). Regardless, when crossovers are common, analyses ex- concluded that clozapine was associated with a 23% drop cluding crossovers offer a proxy for the best-case scenarios in treatment costs. Critics focused on the who do well enough on treatment B to stay on it. Figure problem of the regression toward the mean that can be 57. The exclusion of treatment crossovers increases low point in their functioning (such as may have prompted the apparent effectiveness of clozapine (the crossovers- the initiation of clozapine), and on the other potential tem- excluded oval is shifted to the right of the intent-to-treat poral and case-mix confounds associated with mirror-image oval in Fig. For example, of conventional antipsychotics among long-term patients in in the VA study just cited, health care costs in the 6 months state hospitals (41,65,66), and in the 1-year masked trial prior to randomization were approximately $27,000 with comparing clozapine to haloperidol among veterans hospi- a standard deviation of about $17,000 (67). Each trial showed clozapine necticut clozapine study, the 95% confidence interval for to be somewhat more effective than the comparison agents, patients assigned to clozapine was $96,847 to $114,308 for and this increase in effectiveness comes at no additional cost year 2 versus $103,665 to $121,144 for those assigned to when costs are viewed from a societal perspective.

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Supersensitivity to in the mammalian suprachiasmatic nucleus order red viagra 200mg on-line erectile dysfunction pills cape town. BehavBrain Res light: possible trait marker for manic-depressive illness order 200mg red viagra otc erectile dysfunction vacuum pumps reviews. Photic and non-photic to melatonin suppression by light in young people at high risk circadian phase-shifting responses in a diurnal monkey generic red viagra 200mg mastercard female erectile dysfunction drugs, the for affective disorder. Jet lag: clinical light in euthymic bipolar and unipolar patients. Arch Gen Psy- features, validation of a new syndrome-specific scale, and lack chiatry 2000;57:572–579. Entrainment of totally Am J Psychiatry 1999;156:1392–1396. The etiology reviews the causes, consequences, and mechanisms of sleep of these symptoms has not been clearly delineated, however. This section pro- health concerns, and economic costs of sleep loss and sleepi- vides a review of the daytime sequelae of the insomnia and ness, it is imperative that researchers and practitioners strive a discussion of alternative mechanisms that may account to obtain a solid understanding of these consequences and for the daytime symptoms experienced. Several advances in the psychopharmacologic and behavioral treatments of the causes and consequences of sleep loss have recently evolved. Technologies are rapidly Consequences developing and showing promise for effective evaluation of Persons with insomnia report various somatic complaints these highly prevalent problems. The Advances and online monitoring and mathematical primary complaints among insomniacs include drowsiness modeling of sleepiness and associated neurobehavioral and tiredness on awakening, as well as sleepiness throughout forms are rapidly evolving novel behavioral and psychophar- the day (3,4). Insomniacs complain of physical ailments macologic treatments effective for the causes and conse- such as headache, diarrhea, stomach discomfort, heart palpi­ quences of sleep loss. Insomnia is characterized by difficulty initiating or main- The quality of life among insomniacs also appears to be taining sleep that results in psychological distress and im- diminished (8). Absenteeism, and work and social limita­ paired social or occupational functioning (1). Individuals tions are significantly more prevalent among insomniacs with insomnia report a myriad of interpersonal, cognitive, compared to normal sleepers (5,8). Insomniacs report re- affective, behavioral, and physical symptoms. Not only are stricted physical activities, poorer health, less vitality, and there consequences for the individual, but also are there a decreased amount of time spent reading and engaging in recreational activities (8). Insomniacs report more time watching television, relaxing, and shopping than do nonin- Jacqueline D. Kloss: Department of Psychology, Sociology, and Anthro- somniacs, whereas non-insomniacs work more, study more, pology, Drexel University; Department of Psychiatry, University of Pennsylva- and socialize more than do insomniacs. Insomnia is also nia School of Medicine, Philadelphia, Pennsylvania. Dinges: Department of Psychiatry, Uni- associated with dissatisfaction in interpersonal relationships versity of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. These data suggest that insomniacs avoid or are unable 1896 Neuropsychopharmacology: The Fifth Generation of Progress to participate in activities that require higher levels of con­ whether they suffer significant sleep loss compared to 'good centration or social engagement. Sleep sleep latency, that is, the time from lights out to the onset disruption is the single most common complaint of patients of electrophysiologically defined sleep, and underestimate in a major depressive episode (9). Some have speculated that chronic insomnia may mised sleep efficiencies and intermittent waking time (13), contribute to the development of major depressions (10, it is not clear that sleep is significantly disparate from that 11); however, prospective controlled studies are needed to of noncomplaining sleepers in the majority of insomniacs. Kales and associates (5) found that Second, studies consistently find that insomniacs do not insomniacs also exhibited symptoms mood changes, such demonstrate daytime sleepiness, as measured by the Multi­ as dysphoric mood, worry, tension, anxiety, and irritability. These results must physiologically aroused, but rather passive and calm. Inability to to hypothesize that there may be different types of insom­ initiate sleep may be a characteristic of insomniacs both niacs: (a) hypoactive, as described; and (b) hyperactive, who during the day and night. This measure is of dubious utility in the evaluation of sleepi­ The causal direction of the relationship between insom­ ness in those who cannot initiate sleep. We cannot To circumvent this measurement difficulty, Lichstein readily assume that psychiatric symptoms are merely se­ and colleagues have used an index of sleepiness that does quelae of insomnia, nor can we definitively assume that not depend on sleep ability, but rather diameter of the pupil insomnia is always a consequence of psychopathology. Although there is some evidence Clearly, we need to attend to the relationship between mood to suggest that insomniacs differ from noninsomniacs on and insomnia. Even if criteria for a diagnostic disorder are sleepiness as measured by pupillometry (19,20), the effects not met, the interplay between moods and insomnia need were marginal. The technique may be promising, but the to be examined in order to increase our knowledge of the results are inconclusive. One would expect that concentration and memory difficulties (4). Compared to a worsening of nighttime sleep would exacerbate daytime noninsomniacs, insomniacs also rate their attention, mem­ impairment. Although there is some evidence that insomniacs 15,20) do not always directly relate to measures of daytime have difficulty with semantic memory (13), reaction time, functioning. Interestingly, Sugerman and asso­ both insomniacs and noninsomniacs. What, then, could boration), displayed cognitive deficits. Thus, there may be account for the decrements in daytime functioning? First, these data lead one to question whether Hypothesized Mechanisms or not insomniacs are indeed sleep deprived; and second, to hypothesize what could account for these reported symp­ Several studies support the notion that insomniacs are not toms if not sleep deprivation. This chronic activa­ tion may account for the inability to fall asleep at night and Are Insomniacs Sleep Deprived? Bonnet Daytime symptoms may not solely be attributable to sleep and Arand (22) 'yoked' the sleep of controls to that of loss.

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