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Endocapillary proliferation and m acrophages within capillary loops are im portant features of acute transplantation glomerulopathy purchase ramipril now, which usually are absent in recurrent M CGN order ramipril 10mg mastercard. Endothelial Subendothelial Basement A cell deposits membrane Endothelial cell Basement membrane Podocyte Cell nucleus foot processes Capillary lumen Continuous band of electron-dense material B in basement membrane 17 order ramipril uk. In contrast, recurrent disease frequently causes nephrotic syn- with studies reporting incidences from 3% to 57% [4,37]. The major drome, developing within the first 2 years after transplantation. Data differential diagnosis is de novo membranous nephropathy in patients on the incidence of graft failure attributable to membranous disease with a different underlying renal pathology. Cyclosporine therapy has made no difference in the branous glomerulonephritis reported in 2% to 5% of transplantations incidence of the two entities, and hepatitis C virus infection may be is often asymptomatic and usually associated with chronic rejection associated with membranous disease after transplantation. FIGURE 17-30 FIGURE 17-31 (see Color Plate) H istologic slide of a biopsy showing extensive spike form ation H istologic slide showing deposition of anti–glom erular basem ent along the glomerular basement membrane. This woman had recurrent m em brane (GBM ) antibody along the GBM , which is seen in over membranous disease 8 months after transplantation. In most of these Both recurrent and de novo m em branous glom erulonephritis are cases no histologic abnormalities are seen within the glomerulus, how- indistinguishable from idiopathic m em branous nephropathy. The ever, and patients remain asymptomatic with normal renal function. Delaying transplantation for at least 6 m onths after antibodies have becom e undetectable reduces the recurrence rate to only 5% to 15%. Treatm ent of the prim ary disease with antibody deposition in anti-GBM disease is diffuse and global and, in plasm a exchange, cyclophospham ide, and steroids leads to rapid practice, is rarely confused with the nonspecific antibody deposition loss of circulating antibodies. Patients who need transplantation seen in other conditions. In chronic transplantation glom erulopathy while circulating antibodies are still detectable should be treated the antibody deposition is focal and segmental, and focal necrosis and with plasm a exchange before and after transplantation to m inim ize cellular crescents are extremely rare. The finding of linear antibody circulating antibody levels and with cyclophospham ide therapy for deposits on a transplantation biopsy should lead to testing for 2 m onths. A sim ilar approach should be used in patients with clini- circulating anti-GBM antibodies. Patients who have linear im m unoglobulin deposi- along with linear IgG staining, m ay be the first indication that a tion in the absence of focal necrosis, crescents, or renal dysfunction patient with an unidentified cause for end-stage renal disease has do not require treatm ent. After transplantation, approxim ately 15% of Chromosome Collagen Diseases caused by mutations patients develop linear deposition of im m unoglobulin G (IgG) along the glom erular basem ent m em brane (GBM ), and circulating 13 1 and 2 chains of type IV anti-GBM antibodies specific for the 3 or 5 chains of type IV 2 3 and 4 chains of type IV Autosomal recessive or dominant collagen [42–44]. Those patients who do develop proteinuria or hem aturia usually lose their grafts. In som e cases, treatm ent with cyclophospham ide did not prevent graft loss. The incidence of H US recurrence is difficult to assess. At one extrem e, five of 11 children suffered graft loss because of recurrent disease. H owever, m ost series have reported substantially lower recurrence rates: no recurrences in 16 adults and children, one of 34 grafts in 28 children, and two probable recurrences of 24 grafts in 20 children [4,45,46]. Graft loss occurs in 10% to 50% of patients with recurrence. HUS has been diagnosed 1 day to 15 months after transplantation (usually in less than 2 months), and the incidence of recurrence is increased in patients receiving grafts less than 3 months after their initial disease. Treatment of recurrent disease is plasma exchange for plasma or cryosupernatant, or plasma infusions, and dose reduction of cyclo- sporine. Recurrence may be prevented by aspirin and dipyridamole. FIGURE 17-36 DIFFERENTIAL DIAGNOSIS OF RECURRENT Blood film abnorm alities, m icroangiopathic hem olytic anem ia, HEM OLYTIC UREM IC SYNDROM E throm bocytopenia, and acute renal failure occur in accelerated hypertension and acute vascular rejection. A renal biopsy usually distinguishes acute vascular rejection, and malignant hypertension Thrombotic microangiopathy associated with cyclosporine should be obvious clinically. The m icroangiopathy of cyclosporine Acute vascular rejection can be difficult to differentiate from hemolytic uremic syndrome; however, glom erular pathology usually is less m arked and vascular Accelerated phase hypertension changes m ore obvious with cyclosporine toxicity. D e novo Tacrolimus- (FK-506) associated thrombotic microangiopathy hem olytic urem ic syndrom e also has been reported in patients treated with tacrolim us (FK-506). Very few patients with system ic sclerosis have received inhibitors after transplantation is unknown. Two of four patients transplantation, and the incidence of acute renal failure caused by with im m unotactoid glom erulopathy developed recurrent disease systemic sclerosis has declined with the widespread use of angiotensin- heralded by m assive proteinuria. About 20% of patients with a rarely leads to graft-related problem s; however, patients die from m alignant course of scleroderm a receiving a transplantation develop system ic com plications of ceram ide deposition. For patients with prim ary hyperoxaluria, Disease Treatment of recurrence m easures to prevent further deposition of oxalate have proved successful in controlling Focal segmental glomerulosclerosis Plasma exchange, immunoadsorption, steroids, recurrent renal oxalosis. In diabetes angiotensin-converting enzyme inhibitors, m ellitus, the pathophysiology of recurrent nonsteroidal anti-inflammatory drugs nephropathy undoubtedly reflects the sam e Immunoglobulin A nephropathy W ith crescents: plasma exchange, cytotoxics insults as those causing the initial renal failure, Henoch-Schonlein purpura? Steroids and good evidence exists that glycemic control Mesangiocapillary glomerulonephritis type I Aspirin, dipyridamole can slow the development of end-organ Mesangiocapillary glomerulonephritis type II?

Proton magnetic resonance function and negative symptoms in drug-free patients with spectroscopy: an in vivo method of estimating hippocampal neu- schizophrenia buy ramipril with american express. Br J Psy- ronal depletion in schizophrenia [published erratum appears in chiatry 1997;171:574–577 discount ramipril line. Hippocampal age-related changes in schizo- with positron Emission tomography and 76Br-bromolisuride buy ramipril overnight. Proton magnetic D2 receptors and negative symptoms of schizophrenia. Br J resonance spectroscopy of the left medial temporal and frontal Pharmacol 1994;164:27–34. Proton magnetic reso- studied with positron emission tomography. Am J Psychiatry nance spectroscopy in the frontal and temporal lobes of neuro- 2000;157:269–271. Biol Psychiatry 1998; lobe proton magnetic resonance spectroscopy of patients with 43:263–269. Proton lobe 1H MR spectroscopy in childhood-onset schizophrenia. J magnetic resonance spectroscopy of the temporal lobes in Magn Reson Imaging 1998;8:841–846. Psychiatry spectroscopy of the left temporal and frontal lobes in schizophre- Res 1999;92:45–56. It is in this arena that functional neuroimaging has had the broadest HISTORIC PERSPECTIVE application and greatest impact in psychiatry. This now ex- tensive body of work has left no doubt that schizophrenia Functional neuroimaging studies utilize the fact that neu- is associated with measurable, objective signs of altered brain ronal activation results in regionally increased blood flow function, and clinical and pathophysiologic correlations and metabolism. This can be measured either by radiotracer have begun to emerge. Increasingly, it appears that dysfunction oglobin to oxyhemoglobin imaged by magnetic resonance of a system of functionally and/or structurally intercon- techniques (the blood oxygenation level dependent [BOLD] nected cortical and limbic brain regions is present to lesser effect). This work began in earnest some 50 years ago with or greater degrees, producing more or less psychopathology the pioneering studies of Seymour Kety and colleagues who in individual patients, and that certain brain regions, such developed the first reproducible, quantitative technique for as frontal cortex, may play a special role in this larger picture. When this method was applied to ticularly cognitive impairment. Although it is likely that at schizophrenia (1), these investigators found no alteration in least some of the functional abnormalities are generative of the overall average CBF level in patients, a result that has these features and not simply a response to them, clarifica- largely been confirmed by more recent studies; however, tion of this 'chicken versus egg' issue must be a crucial this finding did not rule out the existence of neurophysio- component of any research program in this area, and the logically meaningful changes in specific brain structures. Current functional ment of rigorous methods that could differentiate the func- neuroimaging has much to offer in guiding this quest, par- tional level of specific cortical regions, albeit with only 2- ticularly when combined with new information now avail- cm anatomic accuracy at best (2). This method, administra- able from other fields such as genetics and cognitive science. The resulting findings delineate their relationship to other neurobiological and of functional abnormality in the frontal lobe spurred a shift clinical properties of the illness, discuss conceptual issues in focus throughout many research domains in the field that and controversies, examine methodologic considerations remains a prevailing force today. In the 1980s, the advent (including technical constraints), summarize new tech- of tomographic methods, such as single photon emission computed tomography (SPECT) and PET, which both use radioactive compounds as tracers, brought improved in- Karen Faith Berman: National Institute of Mental Health, Intramural terregional spatial resolution on the order of 5 to 6 mm Research Program, Bethesda, Maryland and allowed measurement of subcortical regional function. A particular advantage ing (fMRI) has emerged as the premier technique for neu- for research in schizophrenia is that neural activity during ropsychiatric functional neuroimaging. By taking advantage correct and incorrect trials can be measured separately and of the differential paramagnetic properties of oxyhemoglo- compared, allowing more incisive study of the mechanism bin versus deoxyhemoglobin and the altered ratio between of cognitive failure and better experimental control of po- them that occurs when blood volume and blood flow change tential confounds based in performance discrepancies that in response to neural activation, BOLD fMRI uses intrinsic often occur between patient and control groups. Event- properties of the blood itself rather than an extrinsic contrast related fMRI has very recently come into wide use in neu- or tracer agent, to generate maps of brain function. It is, roimaging of cognitive systems in healthy subjects, but as thus, entirely noninvasive, and measurements can be re- of this writing has had only limited application to the study peated over time, conferring significant advantage in experi- of schizophrenia. In this approach, blood flow and other measures advance brought further improvements in spatial resolution such as MR spectroscopy, neuroreceptor measurements, and as well as enhanced temporal resolution, which, although electrophysiology (with MEG or EEG) are determined in still slow (several seconds) compared to neuronal signaling the same patients. One example of the richness of the data (on the order of 200 ms), improved to the degree that event- that can be gleaned is the use of PET or fMRI to measure related neural activity could be recorded with anatomic blood flow in conjunction with EEG or MEG. PET and precision heretofore unavailable with electrophysiologic fMRI allow localization of the brain regions that work to- methods. On the other hand, EEG and MEG TECHNICAL PERSPECTIVE have relatively poorer spatial resolution, but provide fine time resolution (i. Combining these meth- As can be seen in the preceding brief history, over the years ods, together with the application of the advanced computa- the sophistication of the questions that could be asked and tional cross-registration and source localization techniques the hypotheses about schizophrenia that could be tested that now exist, provides exponentially more information have paralleled the development of new brain imaging tech- than any of these techniques alone. For example, this allows nologies and analytic methods.

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Meltzer: Bixler Professor of Psychiatry and Pharmacology generic ramipril 10mg without a prescription, ophrenia who fail to respond to typical neuroleptic drug; Vanderbilt University School of Medicine purchase 2.5mg ramipril otc, Nashville cheap ramipril on line, Tennessee. Thus, in patients with schizophrenia, especially secondary memory this chapter continues to use the term atypical to designate and semantic memory (verbal fluency) (9,11,13). These collective advantages of clozapine led to the ing some of the other highly valued advantages of these search for the mechanism(s) involved in these effects and agents, as well as their unique side effects. This chapter reviews the classified as atypical, by consensus, are, in order of their major hypotheses, which are based on the pharmacologic introduction, risperidone, olanzapine, sertindole, quetia- profiles of the numerous classes of agents with atypical prop- pine, and ziprasidone. Melperone, a butyrophenone, intro- erties as well as current theories of the action of drugs effec- duced at about the same time as clozapine, has also been tive in animal models of psychosis, but not yet adequately suggested to be an atypical antipsychotic drug because of tested in humans, e. Zotepine and amisulpride, both of which are for the D1, D2, D3, D4, 5-HT , 5-HT , 5-HT ,5- 1A 1D 2A widely used antipsychotic drugs in Europe, are also some- HT , 5-HT , 5-HT , , ,H, and muscarinic M1 2C 6 7 1 2 1 times grouped with the atypical antipsychotic drugs (9,10). Of these, the greatest interest is in the role of With the exception of aripiprazole, a partial DA agonist D2, D4, 5-HT , 5-HT , 5-HT , , and receptors. There are a very large number of drugs in development as antipsychotics that have the property of being active in ROLE OF D2 RECEPTORS various animal models that predict antipsychotic action, e. All of these drugs are routinely referred to as putative gest that they produce effective blockade of these receptors atypical antipsychotic drugs, at least by preclinical scientists, in vivo (23,24). The model for atypical antipsychotic drug because of their ability to produce an antipsychotic action action proposed by Meltzer et al. An exception to this may be induction of catalepsy, respectively. These drugs differ amperozide, with is a potent 5-HT2A antagonist and DA greatly in chemical structure and, to some extent, pharmaco- reuptake inhibitor with very low affinity for the D2 receptor logic profile, and thus cannot be referred to as a group by (25). Recently, NRA0045, which has potent 5-HT2A, D4, either chemical class or pharmacologic profile. However, and 1 but no D2 or D3 receptor blockade has been found some clinical investigators find the term atypical antipsy- to have atypical antipsychotic properties (26). Partial DA chotic drug misleading because there are important clinical agonists, which may act as agonists at presynaptic DA recep- differences among the compounds with regard to the six tors, and antagonists at postsynaptic DA receptors are a new clinical features of clozapine noted above, and they prefer class of antipsychotic drugs that has promise (15,27,28). However, this temporal-based nomenclature and current data support only the view that they are atypical is not routed in any meaningful or enduring characteristic in the classic sense, i. Others prefer to call them multireceptor anti- or clinical testing at doses that produce weak or absent EPSs. It is our view that these atypical antipsychotic drug activity will be discussed subse- other designations have no specific advantages and some quently. The in vitro affinity of a drug at the DA D2 recep- Chapter 58: Mechanism of Action of Atypical Antipsychotic Drugs 821 tor is a useful predictor of the dose that produces EPSs and parable to haloperidol in their rate of dissociation from the control of positive symptoms for typical neuroleptic drugs D2 receptor and are not displaced by raclopride or iodoben- (2,29), although it does not do so for some atypical antipsy- zamide, as are clozapine and quetiapine (24). Furthermore, there is no hypothesis could not explain the basis for their low EPSs. There is little agreement even on the best dose for to support this selectivity with regard to displacement as haloperidol, the most widely used antipsychotic drug. Although there is evidence for higher occupancy of wide range of 2 to 15 mg/day has been suggested, far re- extrastriatal D2 receptors by clozapine and quetiapine in moved from the 20 to 40 mg/day thought to be most effec- patients with schizophrenia (40,41), and for atypical anti- tive in 1966 (9,10). To date, no clinically proven antipsy- psychotic drugs that show more potent 5-HT2A receptor chotic with the possible exception of amperozide lacks blockade in rodents (42), the same appears to be true for significant D2 receptor antagonist properties. As will be olanzapine, which does not show the higher off-rates of discussed, the combination of D2 and 5-HT2A receptor clozapine and quetiapine (R. Meltzer, in blockade, in the right ratio, produces some of the effects of preparation). Because clozapine produces a greater increase clozapine and other atypical antipsychotic drugs in rodents, in DA release in the cortex than in the accumbens or stria- e. There have been in these regions than the cortex, but, as noted above, this only limited tests of this hypothesis in humans, mainly using is not the case. It is also not clear how this model could ritanserin, which is a mixed 5-HT2A/2B/2C antagonist (32). The evidence for this hypothesis will be dis- mimic the effects of the multireceptor antagonists such as cussed subsequently. Pharmacologic analysis of this impor- Counter to the hypothesis of the importance of 5-HT2A tant model for the action of atypical antipsychotic drugs receptor antagonism to the action of clozapine and other on cognition and negative symptoms strongly supports the atypical antipsychotic drugs is the proposal of Seeman and importance of combined blockade of 5-HT2A, D2, and pos- Tallerico (24) and Kapur and Seeman (38) that the basis sibly 1 receptors (36,37,44,45). It has also been proposed that rapid and extensive displacement of clozapine and que- tiapine from binding sites accounts for the reported low Ever since the cloning and characterization of the distribu- occupancy of striatal D2 receptors by these drugs (24). The tion of the D3 and D4 receptors, which revealed a limbic authors also suggested that this might account for more and cortical distribution, there has been considerable specu- rapid relapse following clozapine and quetiapine withdrawal lation about the role of these receptors in schizophrenia and (24). Although the evidence cited for clozapine-induced rel- the mechanism of action of antipsychotic drugs (19,46–48). See- cognition, and motor function, as well as to carry out some man and Tallerico found that the affinity for and rate of clinical trials in schizophrenia. Drugs with low affinity for the D2 recep- selectivity for the D3 receptor and good brain bioavailabil- tor, e. This com- higher dissociation rate constant than drugs with higher pound was active in preventing isolation-induced deficits in affinity, e. Rapid dissociation from the D2 prepulse inhibition but was not effective in blocking either receptor was reported to also permit easier displacement amphetamine- or phencyclidine (PCP)-induced locomotor of clozapine and quetiapine by endogenous DA, thereby activity or, by using microdialysis, to increase prefrontal avoiding side effects related to DA receptor blockade such cortical DA release in rats (49).

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EPSs in humans or a clear distinction between doses that 6 buy generic ramipril 2.5mg. Typical and atypical neuroleptics: dif- affect mesolimbic and striatal dopaminergic function in ro- ferential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons purchase cheapest ramipril. Clozapine was the first atypical antipsychotic drug 1607–1619 discount ramipril 10 mg without prescription. Haloperidol does not produce showed that antipsychotic drugs might also be effective in dopamine cell depolarization-block in paralyzed, unanesthetized some patients with schizophrenia whose positive symptoms rats. Striatal extracellular dopamine levels in rats with haloperidol-induced depolarization block of negative symptoms, cognitive impairment, depression, and substantia nigra dopamine neurons. J Neurosci 1998;18: possibly suicidality of schizophrenia and other psychotic 5068–5077. In: Psychopharmacol- partial agonist at dopamine D2/D3 receptors and potential anti- ogy: the fourth generation of progress. Functional profile in comparison to aripi- 1999:1277–1286. Antipsychotic drug vances in the neurobiology of schizophrenia, vol 1. England: Wiley, doses and neuroleptic/dopamine receptors. M100907, a tems; neurophysiology and electrophysiological pharmacology. New release in rat medial prefrontal cortex, but inhibits that in the York: Raven Press, 1987:113–126. Enhancement of and olanzapine on cognitive function in schizophrenia. Interactions of the 5-HT2/1C antagonist, and negative symptoms in schizophre- novel antipsychotic aripiprazole (OPC-14597) with dopamine nia. The role of 5-HT2A D2/D3 receptor antagonist, on the electrical activity of mid- receptors in antipsychotic activity. Classification of typical and relevance to schizophrenia. J Pharmacol Exp Ther 1989; Neuropsychopharmacology 1999;21(2 suppl):106S–115S. Do novel antipsychotics have similar phar- by psychotomimetic NMDA-receptor antagonists and the ef- macological characteristics? The role of serotonin in schizophrenia come off the dopamine D2 receptors. Implications for atypical and the mechanism of action of anti-psychotic drugs. New York: Marcel Dekker, 1996: pine withdrawal: effect of cyproheptadine plus neuroleptic. Limbic selectivity by a group II metabotropic glutamate receptor agonist in rats. Attenuation of specific striatal dopamine D2 receptor binding by the novel atypical PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, antipsychotic drug sertindole—a 123I IBZM single photon LY379268 and comparison with the atypical antipsychotic, clo- emission tomography. Characterization pared with new and reference antipsychotic drugs: in vitro and of typical and atypical antipsychotic drugs based on in vivo in vivo receptor binding. Rapid release of antipsychotic drugs frontal cortex compared with the caudate nucleus. Neuropsycho- from dopamine D2 receptors: an explanation for low receptor pharmacol 1999;20:403–412. Neuropsychopharmacology 1999;22: antipsychotic drug amperozide and its metabolite FG5620 with 140–147. Functional 5-HT1A relation to behavioral and clinical effects. Biol Psychiatry 1997; agonism, most likely produced by combined blockade of 5- 42:247–259. HT2A and D2 receptors, may be a mechanism by which atypical 26. In vivo receptor antipsychotic drugs preferentially increase dopamine release in occupancy of NRA0045, a putative atypical antipsychotic, in rat medial prefrontal cortex. D4 dopamine receptor Chapter 58: Mechanism of Action of Atypical Antipsychotic Drugs 829 binding affinity does not distinguish between typical and atypi- 65. The interactions of typical cal antipsychotic drugs. Psychopharmacology 1995;120: and atypical antipsychotics with the ( )2,5-dimethoxy-4- 365–368. Serotonin 2 (5-HT2) receptor binding receptor antagonist, SB-277011-A.

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Symptom-free days may be a poor health policy agenda purchase ramipril now. Policy makers need to know the im- measure within schizophrenia studies simply because order generic ramipril on-line, unlike pact of dollars invested in treatment—but not just in a with depression cost of ramipril, symptoms and functioning are poorly cor- 812 Neuropsychopharmacology: The Fifth Generation of Progress related, and the likelihood of having a completely symptom- lion in the pharmacy budget for medication X, what can I free day is rather small. What will it equals one lost year of healthy life, can also be used to buy me in terms of reductions in hospital use, improvements express years lost, both to premature death and to disabilities in vocational functioning, reductions in violent episodes, associated with living with schizophrenia (44). In a population my sexual functioning, and in my body movements? DALYs are calculated by adding together the than to others. An analogy is a proposal for a city park number of years between mortality and life expectancy to be funded from multiple sources. Calculating YLDs requires making as- park would impact the value of your property, your safety, sumptions about the relative impact of illness onset, dura- your recreational options, what you are called on to invest), tion, and severity on healthy living (for example, making the park may or may not be a good idea. And, depending an assumption that a first psychotic episode at age 15 is on who is paying for what, and which outcome domains worse than a first episode at age 25). As with QALYs, these are most important to you, you may stand to get a lot or metrics can be derived by surveying individuals with schizo- a little out of the dollars going into the park. The challenge phrenia or their proxies, with the accompanying assump- is to present the data on costs and effects in such a way that tions that how one weights hypothetical events is the same the various payers (the city, private foundations, neighbor- as the trade-offs one would make if one could trade fewer hood organizations, individual contributors) can each look days of healthy life for more days of life with particular from their own perspective, see what the expected gains and disabilities. Because such ratings are inherently untestable losses are in the outcome domains they care about most by rigorous methods, whether reliable or not, their validity (less street noise, more open space, more dogs, more people remains suspect. Further, the calculation of DALYs 'pre- drawn to the neighborhood), perform their own idiosyn- supposes that life years of disabled people are worth less cratic weighting of these factors, 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.

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