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By H. Goran. Haskell Indian Nations University. 2018.

But the assumptions built into such bullet skewed purchase nifedipine 20 mg mastercard, and ICERs provide less biased estimates of confi- measures may have limited usefulness for informing deci- dence intervals in highly skewed cost data (43 cheap 30mg nifedipine otc,51 cheap nifedipine 20mg on line,52) buy nifedipine 20 mg with mastercard. Instead buy nifedipine 20 mg, 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. With such variability, cost differences are Chapter 57: The Economics of the Treatment of Schizophrenia 815 very difficult to detect, even with the relatively large sample than or the same as the usual care and the effectiveness sizes of the VA and Connecticut trials (N 423 and 227, measures favor clozapine or are neutral). Even for individuals who are heavy service data to such a point estimate belies the broad distribution users at study entry, mounting a trial powered to detect cost of possible outcomes that are likely to occur across patients. If the trial were a study of outpatients who are infre- treating clinicians, need a sense of the range of possible quent users of expensive services like hospitals, it would outcomes and their relative likelihood to inform their deci- require even larger samples to detect cost differences apart sions about what chances they want to take. From a public health perspective, an emphasis on point Costs Associated with Risperidone, estimates of costs and effectiveness is misguided when the Olanzapine, and Quetiapine confidence intervals are so broad. Economists would call clozapine the dominant alternative in these randomized Figure 57. Distribution of (left circles) and total dollars paid (right circles) by Medicaid for antipsychotic medication prescriptions in Cali- fornia, Ohio, and New York during 1998. Because Medicaid formularies allow unrestricted and colleagues (74) and Foster and Goa (75) would not be access to any of these medications independent of location expected among treatment-refractory patients, even though in the country and the same financial incentives apply, one these patients are heavy users of inpatient services.

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Stress induced sensitization of ment of hippocampal volume in combat-related posttraumatic norepinephrine release in the medial prefrontal cortex purchase 30 mg nifedipine with visa. Prior exposure surement of hippocampal volume in posttraumatic stress disor- to chronic stress results in enhanced synthesis and release of der related to childhood physical and sexual abuse: a preliminary hippocampal norepinephrine in response to a novel stressor generic 20mg nifedipine mastercard. Presynaptic alterations asso- nance imaging study of hippocampal volume in chronic com- ciated with enhancement of evoked release and synthesis of NE bat-related posttraumatic stress disorder generic 30 mg nifedipine amex. Biol Psychiatry 1996; in hippocampus of chronically cold stressed rats buy nifedipine 20mg with visa. Altered activity of the locus coeruleus in women victimized by childhood sexual abuse buy generic nifedipine 20 mg online. Science 1996; In: Usdin E, Kvetnansky R, Axelrod J, eds. Fear-potentiated startle conditioning J Neurosci 1995;15:12–29. Severe disturbance of higher cogni- patients with agoraphobia and panic disorder. Arch Gen Psychia- tion after bilateral frontal lobe ablation: patient EVR. Reciprocal links of the corpus striatum with the mechanisms of panic anxiety: biochemical and behavioral corre- cerebral cortex and limbic system: a common substrate for lates of yohimbine-induced panic attacks. Alterations in brain tion of locus coeruleus neurons: anatomy, physiology and phar- norepinephrine metabolism and behavior induced by environ- macology. During naturalistic Neurobiological and clinical consequences of stress: from normal behaviors and in response to simple and complex stimuli. Brain adaptation to PTSD New York: Raven, 1995:291–314. Studies of the nucleus locus coeruleus in mon- of cortisol, norepinephrine, testosterone, and melatonin in panic key and hypotheses for neuropsychopharmacology. Sympathetic adrenergic binding sites in posttraumatic stress disorder. Am J activity in patients with panic disorder at rest, under laboratory Psychiatry 1987;144:1511–1512. Altered alpha2-adrenoceptor sensitivity in panic disor- 1341–1343. Uncoupling of the noradren- vascular responses during phobic anxiety. Psychosom Med 1985; ergic-hypothalamus-pituitary adrenal axis in panic disorder pa- 47:320–332. Persistence of blunted inephrine responsivity to orthostatic challenge in anxiety disor- human growth hormone response to clonidine in fluoxetine- ders: comparison of patients with panic disorder and social pho- treated patients with panic disorder. Am J Psychiatry 1995;152: bia and normal control subjects. Effects of thyrotropin-releas- phenylethylene glycol (MHPG) and growth hormone responses ing hormone on blood pressure and heart rate in phobic and in panic disorder patients and normal controls. Hypercortisolism and its possible Arch Psychiatry 1992;241:337–344. Effects of chronic stress ronal dysregulation in panic disorder: the effects of intravenous on plasma corticosterone, ACTH and prolactin. Physiol Behav yohimbine and clonidine in panic disorder patients. Effects of yohimbine rine and plasma corticosterone following acute and chronic on heart rate variability in panic disorder patients and normal stressors: influence of social isolation and handling. Pharmacol controls: a study of power spectral analysis of heart rate. PET measurement of ACTH secretion: effect of stress-induced corticosterone secre- tion on subsequent stress responses in the rat. Endocrinology central metabolic correlates of yohimbine administration in 1973;92:1367–1375. Temporal and social factors Psychiatry 1993;50:266–274. Psychoneuroendocrinology and serotonergic function in posttraumatic stress disorder. Abuse-related PTSD: evidence for campal glucocorticoid receptors and hypothalamic-pituitary- chronic neuroendocrine activation in women. Urinary catechola- thalamic corticotropin-releasing factor mRNA medial CRF con- mines and cortisol in recent-onset posttraumatic stress disorder text, and stress induced release in adult rats. Bennett Re- corticotropin releasing factor systems due to early life stress: search Award: developmental traumatology. Biological stress relationship to pathophysiology of major depression and post- systems. Changes in plasma releasing factor in adult nonhuman primates exposed to early- norepinephrine to combat-related stimuli among Vietnam vet- life stressors: implications for the pathophysiology of mood and erans with post traumatic stress disorder.

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Trends can be identified from the analysis of At this latter time purchase nifedipine 30mg mastercard, 90% of conventional hemodialysis (HD) was per- medical and obstetric causes by the Chandigarh Study generic 30mg nifedipine mastercard. These rates are those and colleagues showed how obstetric (septic abortion) and hemolytic of a developed country cheap 20 mg nifedipine otc. In developing countries nifedipine 20mg with amex, dialysis should be (mainly herbicide toxicity) causes tended to decrease as economic performed according to the available facilities and each individual power and availability of hospitalization improved with time safe 20mg nifedipine. PD— peritoneal dial- causes of ARF, however, did not completely disappear. By contrast, ysis; CRRT— continuous renal replacem ent technique; diarrheal causes of ARF, such as cholera and other gastrointestinal dis- UF— isolated ultrafiltration. In conclusion, gastrointestinal causes of ARF; B data from the M adrid ARF Study. Educational programs and changes in gynecological attention, focused on controlled medical abortion and contraceptive measures, should be promoted to eradicate other forms of ARF that constitute a plague in Third W orld countries. Hospital-Related Epidemiologic Data FIGURE 8-18 P<0. A, O f the 50 patients included in an ARF epidem iologic study 39% had a 40 norm al SCr concentration (less than 1. It is worth noting that only 22% of the patients had 30 clearly established ARF (SCr greater than 3 m g/dL) when adm it- 20 ted (no acute-on-chronic case was included). M ortality was 10 significantly higher in patients with norm al SCr at adm ission. In conclusion, the hospital could be considered an ARF ATN 41. A, two reasons: 1) polytraum a patients are now treated in the ICU Initial departm ental location of ARF patients in a hospital in a and 2) early and effective treatm ents applied today to traum a W estern country. The m ajority of the cases initially were seen in patients at the accident scene, and quick transfer to hospital, have m edical, surgical, and intensive care units (ICUs). B, M ortality was greater for patients initially treated in nephrology departm ents were com m unity initially treated in the ICU and lower in the nephrology setting acquired, whereas the ARF patients in the other settings generally than rates observed in other departm ents. O bstetric-gynecologic ARF cases obtained from 748 ARF patients adm itted to 13 different adult have alm ost disappeared. ARF of traum atic origin is also rare, for hospitals. The incidence of hospital-acquired acute renal failure (ARF) depends on what epidem iologic m ethod is used. In case-control studies the incidence varied between 49 and 19 per Acute Renal Failure in Hospitalized Patients thousand. W hen the real occurrence was m easured in large popula- Investigator, Year (per 1000 admissions) tions over longer intervals, the incidence of hospital-acquired ARF decreased to 1. The criteria for estim ating prognosis in developm ent of m ultivariable analysis. Theoretically, few of these acute renal failure can be classified into four periods. They have not Classical or heuristic way is sim ilar to that used since the been used for triage. The next step will need a great deal of H ippocratic aphorism s. The Traditional one based on sim ple work to design and im plem ent adequate tools to stratify risks statistical procedures, is not useful for individual prognosis. Renal insult 100 Cumulative trend M ean 80 60 ARF Outcome 40 20 16 13 13 20 11 11 911 1110 9 10 Number 6 5 7 5 7 8 5 5 6 5 5 4 78 6 5 6 8 of 10 2 331 3 4 2 3 2 4 publi- 0 cations Prognosis 1951 55 60 65 70 75 80 85 1990 Year FIGURE 8-23 M ortality trends in acute renal failure (ARF). This figure shows the evolution of mortality during a 40-year period, starting in 1951. The graphic was elaborated after reviewing the outcome of 32,996 ARF FIGURE 8-22 patients reported in 258 published papers. As can be appreciated, Ideally, prognosis should be established as the problem , the episode mortality rate increases slowly but constantly during this follow-up, of acute renal failure (ARF), starts. Correct prognostic estim ation despite theoretically better availability of therapeutic armamentarium gives the real outcom e for a patient or group of patients as precisely (mainly antibiotics and vasoactive drugs), deeper knowledge of dialy- as possible. In this ideal scenario, this fact is illustrated by giving sis techniques, and wider access to intensive care facilities. This the sam e surface area for the concepts of outcom e and prognosis. A complementary explanation could be that the patients treat- ed now are usually older, sicker, and more likely to be treated more aggressively.

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However cheap nifedipine 30mg online, combined purchase nifedipine 20mg on line, unilateral lesions of in the way in which a US representation (e nifedipine 30 mg line. Patients with late- or early-onset lesions of sion from the basolateral nucleus to the hippocampus buy cheap nifedipine 30 mg on line. For example buy discount nifedipine 30 mg, on a gambling task, they choose Cortex Pathway as It Relates to Emotion high, immediate reward associated with long-term loss rather than low, immediate reward associated with positive Importance of the Bla in US Representation long-term gains. They also show severe deficits in social After pavlovian conditioning, presentation of a conditioned behavior and make poor life decisions. For dicate that cells in both the Bla and the orbitofrontal cortex example, the sound of a refrigerator door opening or an fire differentially to an odor, depending on whether the electric can opener may bring the family cat into the kitchen odor predicts a positive (e. These differential responses emerge before the Bla, perhaps by connections with cortical areas such as the development of consistent approach or avoidance behavior perirhinal cortex (93), is critical for these US representations elicited by that odor (220). Many cells in the Bla reverse based on studies using a procedure called US devaluation. Some animals then have the food paired with something (221), although this has not always been observed (217). After such treat- In contrast, many fewer cells in the orbitofrontal cortex ment, these animals show a reduction in the conditioned showed selectivity before the behavioral criterion was response to the light compared with animals that did not reached, and many fewer reversed their selectivity during experience US devaluation. This result suggests that, after reversal training (221). These investigators suggest that cells conditioning, animals have a representation of the value of in the Bla encode the associative significance of cues, a reinforcement that is elicited by the cue paired with that whereas cells in the orbitofrontal cortex are active when US. When that representation is changed, then the behavior that information, relayed from the Bla, is required to guide elicited by the cue also is changed in the same direction. Lesions of the basolateral, but not the CeA, block US deval- Taken together, these data suggest that the connection uation (112). In a related paradigm, rats are trained to be between the Bla and the frontal cortex may be involved in fearful of a weak shock in the presence of a tone. When determining choice behavior based on how an expected US this is followed by presentation of a stronger shock, without is represented in memory. The necessity for communication further tone-shock pairing, more freezing occurs to the tone. Because the Second-order conditioning also depends on a US repre- reciprocal connections between the two structures are ipsi- sentation elicited by a CS. In this procedure, cue 1 is paired lateral, this procedure completely eliminated activity of the with a particular US (e. After such training, cue 2 elicits a similar each structure. Using this approach in rhesus monkeys, Bax- behavior as that elicited by cue 1, depending on the US ter et al. Thus, it may elicit approach neurotoxic lesions of the basolateral nucleus in combination behavior if cue 1 was formerly paired with food and avoid- with unilateral aspiration of orbital prefrontal cortex (22). This indicates that These monkeys continued to approach a food on which cue 1 elicits a representation of the US that then becomes they had recently been satiated, whereas control monkeys associated with cue 2. Lesions of the Bla, but not the CeA, consistently switched to the other food. More distal threats activate the ventral PAG and generate As reviewed by Whalen (244), neuroimaging studies in nor- passive or preparatory defensive behaviors such as freezing mal human subjects have shown activation of the amygdala and analgesia. From a similar perspective, Deakin and by presentation of biologically relevant sensory stimuli that Graeff et al. For exam- inhibit the dorsal PAG (66,104), but this inhibition is over- ple, the functional magnetic resonance imaging (fMRI) sig- come with more extreme danger, thus allowing active de- nal intensity within the amygdala is greater when subjects fense or panic behaviors to emerge. Positron emission tomography metabolic ac- paulis and colleagues showed that chemical or electrical tivity within the amygdala increased to negative material stimulation of PAG regions lateral to the aqueduct produces presented by film clips (199), and the amount of amygdala active behaviors such as forward avoidance, defensive aggres- activity during film clips predicted later recall (47). In addi- sion, and cardiovascular activation (67,68), whereas stimu- tion, fMRI signal intensities in humans during classic fear lation of more ventral regions of the PAG elicits passive conditioning increased in response to stimuli that predicted responses such as behavioral arrest and decreased cardiovas- an aversive event (45,150,179). Electrical stimulation of the dorsal Amygdala activation also seems to be greater during pre- PAG in humans produces a pattern of cardiovascular effects sentations of fearful faces compared with neutral facial that resemble those seen during a natural panic attack, and expressions (40,180), happy facial expressions (180,246), or patients often experience fear, anxiety, and the desire to when subjects looked at a fixation point on an otherwise terminate stimulation (162). Most study subjects reported seeing neutral Based on these and other data, several investigators have 'expressionless' faces, but not any afraid or smiling faces. In addition, subjects reported that these The dorsal PAG has heavy innervation of the panicogenic masked stimuli did not induce any noticeable changes in peptide CCK, which has been shown to excite the majority their state of emotional arousal. CCK antagonists functionally de- (244), 'this study offers preliminary support for the notion crease the effects of electrical stimulation of the dorsal PAG, that the amygdala constantly monitors the environment for as does elevating serotonin, perhaps relevant to the use of such signals. More than functioning primarily for the pro- serotonin reuptake inhibitors in the treatment of panic dis- duction of strong emotional states, the amygdala would be order. Whether these effects depend on connections be- poised to modulate the moment-to-moment vigilance level tween the amygdala and the PAG or whether they represent of an organism.