Sampling over diﬀerent dis- tances will often reveal a hierarchy of scale-dependent processes that depend on the epidemiology and demography of the parasite cheap kamagra 50 mg free shipping erectile dysfunction with age. It may be common to ﬁnd spatial isolation at longer scales buy generic kamagra 100mg line erectile dysfunction jack3d, mixing in dense aggre- gations at local scales, and occasional swaths of genome-wide linkage at varying scales caused by population bottlenecks or the rapid spread of epidemic strains. The relative scaling of these processes will diﬀer greatly among parasites. Diﬀerent phylogenetic histories of genomic components. Very in- tense selection on antigenic loci can occur in parasites. This focused selection can cause diﬀerent components of the genome to have dif- ferent genetic structures and phylogenetic histories. I brieﬂy mention one example to provide hints about what may happen and to encourage further work. Idescribed earlier in this chapter the example of inﬂuenza. By contrast, the other six segments ap- peared to mix their lineages relative to the single line of cotransmitted 170 CHAPTER 10 antigenic segments. Thus, epidemically bound linkage groups may oc- cur against a mixing genetic background. More data of this sort might show diﬀerent genomic components changing their population struc- tures relative to each other over diﬀerent temporal and spatial scales. Such data could provide insight into the scale-dependent eﬀects of de- mographic, genetic, and selective processes. Variant alleles at antigenic loci ap- pear to trace their phylogenetic history back to common ancestors more recent than the putative bottleneck event. This pattern suggests intense natural selection favoring novel diversity at antigenic sites against a background of low genome-wide diversity caused by a recent bottleneck. Alternatively, the antigenic variants could trace their history back to ancestors that predated the bottleneck (Hughes 1992; Hughes and Hughes 1995; Hughes and Verra 2001). This pattern arises when natural selection strongly favors rare variant antigens, holding diverse antigens in the population through the bottleneck that reduced variation in the rest of the genome. Ancient polymorphisms of this sort suggest that natural selection preserves existing variants rather than favors de novo generation of new variants (Ayala 1995; O’hUigin et al. If this estimate applies to the var genes aswellas thelocistudied by Volkman et al. Further studies of diﬀerent genomic regions will contribute to understanding the speed of diversiﬁcation in the var archival library. Many classical genetic models develop the island structure for populations(Wright 1978). However, those general studies of migration, selection, and stochastic perturbation provide little guid- ance for the genetic structure of parasites. Studies for parasites must account for the density and variability of host immune memory, the longevity of infections, the genetic diversity of inocula, and the patterns of genetic mixing between parasites. STRUCTURE OF PARASITE POPULATIONS 171 Much insight can be gained by island models focused speciﬁcally on the special biology of parasites (Hastings and Wedgwood-Oppenheim 1997). Rouzine and Coﬃn’s (1999) study shows how a clear model of population genetic process can lead to predictions about the expected patterns in the data. This suggestshowone could couple process- oriented theory with the problem of statistical inference. PART V STUDYING EVOLUTION Classiﬁcations by Antigenicity and 11 Phylogeny In this chapter, I compare immunological and phylogenetic classiﬁca- tions of antigenic variation. Contrasts between these classiﬁcations pro- vide insight into how natural selection shapes observed patterns of di- versity. Following chapters take up other methods to infer processes of selection. The ﬁrst section describes immunological measures of antigenicity. These measures summarize the ability of speciﬁc antibodies to recog- nize diﬀerent antigenic variants. The reactivities for various antibodies tested against diﬀerent antigenic isolates form a matrix of antigenic or immunological distances between parasite variants. These distances can be used to classify antigenic variants into related clusters. The second section notesthatantigenic variants can also be classiﬁed by phylogeny. This classiﬁcation scheme measures relatedness between variants by distance back in time to a common ancestor. Such distances arise from the patterns of nucleotide or amino acid diﬀerences in ge- nomic sequences. The third section deﬁnes possiblerelationsbetween antigenic and phylogenetic classiﬁcations. Concordance commonly occurs because antigenic distance often increases with time since a common ancestor, reﬂecting the natural tendency for similarity by common descent. A particular pattern of discord between antigenic and phylogenetic clas- siﬁcations suggests hypotheses about evolutionary process. Suppose, for example, that phylogenetically divergent parasites are antigenically close at certain epitopes. This suggests asahypothesis that selective pressure by antibodies has favored recurrent evolution of a particular antigenic variant. The fourth section presents ﬂaviviruses as an example of concor- dant antigenic and phylogenetic classiﬁcations. This example compares strains that diﬀer by relatively long phylogenetic distances with anti- genicity measured by averaging reactivity over many diﬀerent epitopes. Aggregate antigenicity tends to diverge steadily over time as amino acid 176 CHAPTER 11 diﬀerences accumulate (Benjamin et al. Particular details of nat- ural selectionwithregardtoeachaminoacid substitution disappear in the averaging over many independent events. The ﬁfth section shows a mixture of discordance and concordance between antigenic and phylogenetic classiﬁcations for inﬂuenza A. The classiﬁcations cover a history of transfers between diﬀerent host spe- cies. Antigenicity and phylogeny bothseparate isolates from pigs into two groups, the classical swine types and avian-like swine types more recently transferred from birds to pigs. Two bird isolates group phylo- genetically with the avian-like swine types, as expected. However, anti- genic measures separate the bird isolates as distinct from the relatively similar classical swine and avian-likeswinegroups.
The phase 3 trial demonstrated overall safety and product and complicating reliable synthesis for consistent effective- efﬁcacy buy online kamagra icd 9 code erectile dysfunction due diabetes. In the phase 1 trial buy 100mg kamagra mastercard erectile dysfunction viagra not working, there was one serious adverse event ness. A new approach involving targeted, site-speciﬁc PEGylation reported as probably being related to N9-GP, a hypersensitivity has signiﬁcant advantages. For FVIII, the PEGylation was resis, but no changes in blood pressure or pulse) that occurred highly speciﬁc and the site of PEGylation on the FVIII molecule during administration of N9-GP in a 25-year-old male patient who was critical to PEGylation efﬁciency, preservation of the coagula- had no history of inhibitors nor allergic reactions to his previous tion activity, and improvement in pharmacokinetic parameters. After the event, the patient continued with his previous plasma-derived FIX product without any Nearly a dozen PEGylated protein therapeutics have been approved 15 for use, including anti-TNF mAb Fab fragment,49 VEGF-aptamer, complications. The therapeutics, appropriate clinical observations will be needed as the increase in t1/2 mediated by albumin fusion proteins also results from clinical trials for the coagulation proteins progress. There are their interaction with the salvage neonatal Fc-receptor present on several PEGylated coagulation factors that are in clinical develop- many cell types, in addition to the slower renal clearance for ment. In hemophilia animal models of bleeding, all of these newer larger-sized molecules. Therefore, during the activation events, toxicity, and/or immunogenicity in previously treated per- of the coagulation cascade at the site of clotting, the FIX activation sons with hemophilia. Extensive safety data for PEGylated proteins peptide is cleaved, releasing the albumin part of the fusion so that containing high-molecular-weight PEG do not indicate any safety only the native FIX remains at the site of clotting. Animal studies, concerns after chronic use in animal models or patients. However, toxicology, and the phase 1 clinical trials have demonstrated safety there are differences in how the PEGylation is achieved and subtle and efﬁcacy with extended t. Small PEG molecules are more rapidly cleared than large ones. FVIII extended t1/2 products Larger PEG molecules do not penetrate into tissues as well as In June 2014, the ﬁrst extended t1/2 FVIII product to receive smaller ones. With 10-kDa PEG, there is increased pinocytotic approval for clinical use, FVIII-Fc (efraloctocog alfa) was approved uptake into macrophages and Kupffer cells; with 30-kDa PEG, for clinical use in the United States for adults and children with renal clearance decreases; and with 50-kDa PEG, liver clearance hemophilia A. Similar to the FIXFc product discussed above, increases. For example, there was no toxicity associated with acute high-dose administration of BAY As for FIX, recent efforts to extend the t1/2 of FVIII have pursued 94-9027, a site-speciﬁc PEG-conjugated FVIII molecule, or upon conjugating the factor protein at one or a few speciﬁc sites with repeated dosing with up to 11 mg/kg every other day for 4 weeks in polyethylene glycol (PEG), a hydrophilic polymer, or use recombi- rats. The PEG amount in BAY 94-9027 is 4 g/kg in a dose of 60 nant technology to fuse the factor protein with either albumin or the IU/kg rFVIII. Over a 1-year period, a 50-kg patient would receive Fc fragment of IgG. Fusion of FVIII to albumin failed so far to 11 mg of PEG. Most experts consider PEG to be inert in the preserve effective coagulation activity. Previous the A2-domain of FVIII reduced inhibitory activity for a monoclo- studies demonstrated that FIX clearance is likely mediated through nal antibody that reacts to this highly immunogenic region of FVIII, interaction of the aminoterminal Gla domain residues 3-11 with suggesting that such modiﬁcations may limit the activity of endothelial/collagen IV sites, although the speciﬁc mechanism inhibitory antibodies. In the presence of VWF, FVIII is stabilized in the plasma results for BAX 855, a full-length rFVIII that 2 20 kDa branched with a t1/2 of 12 hours. The clearance of FVIII from the plasma is pegylation molecules added nonspeciﬁcally by chemical means at likely dependent on the dominant role that VWF plays in regulating lysine residues. Assessment of animal toxicity was based on the clearance of FVIII, so, conversely, VWF interaction may limit mortality, clinical observations, clinical pathology, male fertility in the effectiveness of the different methods to extend the t1/2 of FVIII. No PEG-related Hematology 2014 359 effects were observed. One of these, rFVIIa-FP, uses the same trial with results expected to be reported in 2015. It may be a promising extended t1/2 product for patients with FVII deﬁciency; however, A B-domain-deleted FVIII product has been PEGylated at a whether the extended t1/2 also provides extended coagulation site-speciﬁc mutation to cysteine with a 40 kDa pegylation mole- protection in hemophilia patients with high responding inhibitors cule. Again, no safety signals have been seen in extensive toxicol- remains to be tested in planned clinical trials62 ogy studies. This extended t1/2 FVIII, BAY 94-9027, is in a phase 3 clinical trial with results expected to be submitted for regulatory Other novel approaches for hemophilia therapies approval in 2015. There are also several novel approaches being pursued in preclinical work or early phase 1 trials. These novel approaches are intriguing, In a phase 1 clinical trial, Novo Nordisk demonstrated a glycoPEG- but much remains to be determined as they enter clinical ylated FVIII that increased plasma t1/2 by 1. Further details will be needed to assess the signiﬁcance FVIIIa serves as a cofactor for FIXa to increase the Vmax and of this ﬁnding. It is possible that small molecules might this discussion. One is rhFVIII-hCL, a recombinant FVIII manufac- replace the FVIII function by promoting the assembly of FIXa and tured in a human cell line and currently in phase 3 in adults and FX in a manner that stimulates the rate of FXa generation. Such a children and in clinical trial for previously untreated patients with 55,56 small molecule could be delivered subcutaneously or even orally. The potential advantages are improved t1/2 and this direction, a humanized bispeciﬁc mAb to FIXa and FX was possibly a lower rate of inhibitor development in previously derived (hBS23) that displayed a 2-week t1/2 in a cynomolgus untreated patients due to human glycosylation patterns. A phase 1 study in 64 new FVIII product was modiﬁed by recombinant technology so that Japanese and Caucasian healthy adults indicated that ACE910 the FVIII is a single chain molecule, scFVIII. It has a higher afﬁnity (hBS23 with additional minor molecular engineering) at doses up to to VWF, which may translate into a longer t1/2, and it is currently in 18,39,57,58 1 mg/kg had medically acceptable safety and tolerability proﬁles a phase 3 clinical trial. The 2 recently approved the antithrombotic pathways that control coagulation. The tissue 1/2 products were also approved for use in surgery. The phase 3 clinical factor/FVIIa/FXa complex forms small amounts of thrombin to trials for each product include an arm for use in surgery, but all of initiate coagulation. The tissue factor pathway inhibitor (TFPI) the results have not yet been reported. Nonetheless, it is reasonable inhibits this complex through its 2 Kunitz domains: Kunitz domain to conclude that the extended t products can be used for surgery 1 interacts with FVIIa and Kunitz domain 2 interacts with FXa. Dosing considerations should target the same monoclonal antibody to the second Kunitz domain neutralizes the peak and trough factor activity levels as for currently used factor inhibitory effect of TFPI on extrinsic pathway activation. One is a nucleic acid ate assays to monitor factor activity after infusion will need to be aptamer that binds tightly and speciﬁcally to TFPI and inhibits its function in vitro and in vivo. The US Food and Drug Administration (FDA)- charide (NASP) BAX 513 demonstrated efﬁcacy in hemophilia dogs. There is some concern that inhibition of TFPI by products currently in phase 3 clinical trials. Further studies planned or under way to provide more detailed guidance for assays in animals and humans will be needed to sort out the therapeutic to monitor the new products as they receive approval for clinical opportunities of these potentially exciting approaches. Targeting antithrombin FVIIa products in clinical trials Another novel approach is represented by the development of FVIIa has been used commonly for nearly 20 years for the treatment ALN-AT3, a synthetic, GalNAc-conjugated RNAi therapeutic de- of patients with inhibitory antibodies and now there are other FVIIa signed to suppress liver production of antithrombin (AT) mRNA 360 American Society of Hematology after subcutaneous injection.
The supply of AB respectively discount kamagra 50 mg with visa fluoride causes erectile dysfunction, of citrate cheap 100mg kamagra amex erectile dysfunction even with cialis, phosphate, and dextrose anticoagulant. This plasma can be expanded by collecting 600 mL units by apheresis dilutes the suspending plasma but leaves the RBC volume un- from specially recruited donors as frequently as 24 times a year, and changed. The whole blood in anticoagulant is then gently spun, the deﬁnition of universal donor plasma can be expanded to include precipitating the RBCs, and most of the platelet-rich plasma units of A plasma with low hemagglutinin titers of anti-B (eg, supernatant is expressed off the top of the collection bag into an 1:250). RBCs in this format store poorly and ﬂow required to prevent coagulopathy in various surgical situations are like molasses, so 110 mL of RBC nutrient additive solution is largely a matter of opinion, being generally formulated as expert added. The resulting suspension now has the 200 mL of RBCs in 40 group guidelines because no large clinical trials exist in this area. Loss Pathologists state that major elective surgery can be performed of 35 mL of this mixture in a leukocyte reduction ﬁlter results in the along anatomic planes when the PT and PTT are not 1. Typically, the division is 50 mL for the platelet concentrate lines can be safely performed with the PT or PTT prolonged to and 270 mL for the platelet-poor plasma. With the most severe injuries, the anecdotal experience and mixing one unit of RBCs with one unit of plasma and one unit of clinical series of our military surgeons using fresh whole blood platelets, a 1:1:1 ratio. In this mixture, there are 180 mL of RBCs in Hematology 2013 665 a 645 mL total volume for a hematocrit of 28%. The 465 mL of has failed to improve outcome in 2 large clinical trials when given remaining ﬂuid contains only 288 mL of plasma for a coagulation late in dilutional coagulopathy. Platelet losses in the leukocyte reduction ﬁlters reduce the ﬁnal count of platelets in 9 Resuscitation of TIC with clotting factor concentrates a whole blood derived unit of platelets to 600 to 800 10 or their 9 An alternative form of treatment for TIC is the administration of ﬁnal concentration in the mixture to 90 to 120 10 /L. The in vivo pharmaceutically prepared plasma-derivative coagulation factor recovery of radioactively labeled fresh platelets is 50% in storage concentrates. The idea is that the intrinsic coagulation system can be studies, and 5-day stored platelets have a recovery 30% less than largely reconstituted in the injured patient with 4-factor prothrom- that. The of the starting number, their individual function is degraded, and the 4-factor PCCs provide factors VII, IX, X, and II and recently plasma they are suspended in will have lost some activity too. Factor VIII, produced by the also lose viability during storage, so that only 90% of transfused endothelium, is rarely deﬁcient, and factor V is present in platelet RBCs actually circulate, reducing the effective concentration from alpha granules. Fibrinogen concentrates contain enough factor XIII 28% to 25%. One is essentially at the transfusion trigger for all 3 proteins can be kept on the anesthetist’s cart, reconstituted quickly, components. Adding more of one component merely dilutes the and given early. Austrian researchers claim that their use has other 2 and adding any other ﬂuid dilutes all 3. Some have argued that giving other ratios might be just as good and Randomized clinical trials are needed. The products have only have suggested adding 2 units of RBC to every unit of plasma and recently become available in the United States and for other platelets as an obvious choice (2:1:1). The clinical consequences for the severely injured of the concentration of RBCs in the administered ﬂuid goes up and that low concentrations of VWF and other plasma proteins not present in of plasma and platelets goes down. There is a general need for better clinical hematocrit of 37%, a plasma concentration of 52%, and a platelet blood products and clinical effectiveness research. Again, because in vivo recover- ies of the platelets are only 50%, the effective administered platelet 9 Making resuscitation of TIC a trauma center concentrations are 31 to 46 10 /L, values well below the accepted quality issue transfusion trigger and with no potential to raise platelet concentra- The American College of Surgeons Committee on Trauma runs the tions above it. One of its goals for this year is to try to improve the availability and timeliness of It is possible to take advantage of the small differences in available plasma-based resuscitation, not only for patients seen in level 1 components, such as choosing apheresis platelet concentrates that trauma centers, but also for patients cared for in less intensively are collected in doubly concentrated anticoagulant so their plasma 37 resourced settings. This means that, as a condition of accredita- concentration is 93% rather than the 80% of whole blood derived tion, we will all need a plan to recognize and treat TIC. The advantages are marginal and can be lost if a transfusion protocols from just providing universal donor RBCs to blood bank issues one of the new units of platelets in additive creating systems that can quickly mobilize and issue balanced solution containing 200 mL of saline and 100 mL of plasma rather amounts of RBCs, plasma, and platelets. Five years ago, most than the conventional units with 300 mL of plasma. In the future, the standards will be It is important to recognize that even if volume replacement with a more exacting. These new standards will drive changes in your 1:1:1 ratio of RBCs, plasma, and platelets is the optimal way to transfusion service that will need to be carefully considered to resuscitate patients with uncontrolled hemorrhage and TIC, such optimize patient care and minimize blood component waste. It is patients represent only a small fraction, perhaps 2% of those hoped hematologists will support this effort in practice and through admitted to a trauma center. The use of diagnostic algorithms to their transfusion services, transfusion committees, and local blood increase diagnostic speciﬁcity while maintaining sensitivity will provider networks. The most Disclosures impressive example comes from the National Institutes of Health’s Conﬂict-of-interest disclosure: The author is on the board of trauma glue grant consortium, where earlier use of plasma and 30 directors or an advisory committee for CSL Behring. Off-label drug platelets reduced mortality and total blood use. Adjuvants to the use: ﬁbrinogen concentrate and 4-factor prothrombin complex resuscitation of TIC include tranexamic acid and, rarely, rVIIa. Tranexamic acid is a lysine analog and inhibitor of plasmin- medicated ﬁbrinolysis. It provided a signiﬁcant survival beneﬁt in the large CRASH II trial when given in the ﬁrst 3 hours after Correspondence injury. Hess, Box 359743, Blood Bank, 325 Ninth Ave North, factor VII consumed with the massive exposure of tissue factor. It Seattle, WA 98104; Phone: 206-897-6121; e-mail: hessj3@uw. ASA Task Force on Perioperative Blood Transfusion and Adju- 1. Practice guidelines for perioperative blood transfu- thy. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, 208. Acute traumatic coagulopathy: initiated by hypoperfu- 21. Plasma, Cryoprecipitate, and Platelets Administration Practice 3. The incidence and Guidelines Development Task Force of the College of Ameri- magnitude of ﬁbrinolytic activation in trauma patients. The coagulopathy of trauma: a management in a large urban academic medical center: a review of mechanisms. Wang QY, Song J, Gibbs RA, Boerwinkle E, Dong JF, Yu FL. Fresh whole blood use Characterizing polymorphisms and allelic diversity of von by forward surgical teams in Afghanistan is associated with Willebrand factor gene in the 1000 Genomes. J Thromb improved survival compared to component therapy without Haemost. Hess JR, Lindell AL, Stansbury LG, Dutton RP, Scalea TM. Comparison of platelet prevalence of abnormal results of conventional coagulation tests transfusion as fresh whole blood versus apheresis platelets for on admission to a trauma center. Slichter SJ, Bolgiano D, Corson J, Jones MK, Christoffel T, battleﬁeld (2001-2011): implications for the future of com- Pellham E.
Results of head-to-head efficacy trials of atypical antipsychotics in patients with behavioral and psychological symptoms of dementia purchase kamagra in india erectile dysfunction best medication. kamagra 50 mg free shipping erectile dysfunction medication online............................................................................................. Trials comparing atypical antipsychotics with conventional antipsychotics in patients with behavioral and psychological symptoms of dementia............................................................................ Placebo-controlled trials of atypical antipsychotics in patients with behavioral and psychological symptoms of dementia..................................................................................................... Adverse events in head-to-head trials of atypical antipsychotics in patients with behavioral and psychological symptoms of dementia.............................................................................................. Placebo-controlled trials of atypical antipsychotics in children and adolescents with pervasive developmental disorders........................................................................................................................ Placebo-controlled trials of atypical antipsychotics in children and adolescents with disruptive behavior disorders.................................................................................................................................. Weight gain reported in short-term trials of atypical antipsychotics in children and adolescents with pervasive developmental disorders or disruptive behavior disorders............................................. Adverse events reported in longer-term studies of risperidone in children and adolescents. Rates of death in observational studies of atypical antipsychotics........................................ Risk of cerebrovascular adverse events reported in comparative observational studies of atypical antipsychotics in elderly patients with dementia....................................................................... Incidence of diabetes mellitus in comparative observational studies..................................... Incidence of tardive dyskinesia with olanzapine and risperidone in longer-term studies....... Risk of rehospitalization with olanzapine compared with risperidone....................................... Risk of rehospitalization with olanzapine compared with immediate-release quetiapine......... Relative risk of early discontinuation of olanzapine compared with risperidone (symbol size represents sample size)........................................................................................................................... Pooled risk of new-onset diabetes mellitus with olanzapine compared with risperidone....... Atypical antipsychotic drugs Page 10 of 230 Final Report Update 3 Drug Effectiveness Review Project Acknowledgments We would like to thank Ron Heintz, MD for clinical and technical advice during the writing of the original report. We also thank our peer reviewers of each of the versions of this report; see http://www. We would also like to recognize the important contributions of Kathy Hamm, Pharm D (candidate) for assistance with background research, and Michelle Freeman, MPH for data abstraction in the original report. Update 1: We would like to thank Carol Roberts, BS; Sarah Lopez, BA; Po-Yin Yen, MS; and Barbara Ray for their work on data abstraction, organization, and formatting of Update #1 of this report. Update 2: We would like to recognize the contributions of Leah Williams and Arkady Mak, PhD, MD for editing work; Vi Pham, Pharm D (candidate) for background research; Trish Theida, MA; Laura Morgan, MA; Janet Dailey, Pharm D; Peggy Nygren, MA; Miranda Walker, BA; and Susan Norris, MD, MPH for their assistance with data abstraction and quality assessment of studies; and Theresa Nguyen for work on article retrieval, organization, editing and formatting of Update #2 of this report. Update 3: We thank Leah Williams, our publications editor, for putting this report into its present form for you to read; Laurie Huffman, MS; Trish Thieda, MA; Miranda Walker, MA; Michele Freeman, MPH; Haley Holmer, MPH; and Jenny Chen MSc for assistance with data abstraction and quality assessment of studies; and Theresa Nguyen and Jennifer Nguyen for retrieval of articles and assistance with editing and formatting. Suggested citation for this report McDonagh MS, Peterson K, Carson S, Fu R, Thakurta S. These organizations selected the topic and had input into the Key Questions for this review. The content and conclusions of the review are entirely determined by the Evidence-based Practice Center researchers. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in this report. Atypical antipsychotic drugs Page 11 of 230 Final Report Update 3 Drug Effectiveness Review Project INTRODUCTION “Atypical” antipsychotic agents are used to treat the symptoms of schizophrenia and bipolar disorder (see Table 1 for details). In general, atypical antipsychotics produce antipsychotic responses with fewer acute extrapyramidal side effects than “conventional” antipsychotic drugs. Extrapyramidal side effects are a set of movement disorders such as akathisia, dystonia, and pseudoparkinsonism that resolve when the drug is discontinued or the dosage is lowered. Tardive dyskinesia is a movement disorder that can develop with more prolonged use and may persist even after cessation of the antipsychotic agent. Atypical antipsychotics are associated with lower rates of the development of this neurological side effect in comparison with the older, conventional agents. Atypical antipsychotics may also treat negative symptoms and improve cognitive functioning. Table 1 describes drug indications approved by the US Food and Drug Administration, dosing, and mechanisms of action based on the current product labels for the 10 atypical antipsychotics available in the United States and Canada. Clozapine, the prototypic atypical antipsychotic, was introduced in 1989. Since then, 9 other atypical antipsychotics have been brought to market: risperidone (1993), risperidone long-acting injection (2003), olanzapine (1996), quetiapine (1997), ziprasidone (2001), aripiprazole (2002), extended-release paliperidone (2006), asenapine (2009), iloperidone (2009), and paliperidone long-acting injection (2009). Atypical antipsychotics vary from one another in receptor interaction selection and affinity. These differences in receptor activity are hypothesized to account for differences in efficacy, safety, and tolerability among atypical antipsychotics, as well as in comparison with conventional antipsychotics. Clozapine is an antagonist at dopamine (D1-5) receptors with relatively low affinity for D and D receptors and high affinity for D receptors. Its greater1 2 4 activity at limbic (opposed to striatal) dopamine receptors and lower affinity for D receptors2 may explain the low incidence of extrapyramidal side effects. The antipsychotic effect of risperidone, olanzapine, quetiapine, and ziprasidone is proposed to be primarily via D and serotonin (5-HT ) receptor antagonism. However, each drug2 2 has varying effects on these and other receptors (see Table 1). Antagonism of the 5-HT2 receptors is thought to reduce the extent of D receptor antagonism in the striatum and cortex2 while leaving blockade of D receptors in the limbic area unaffected. These properties are2 thought to account for fewer extrapyramidal side effects and better effects on the negative symptoms of schizophrenia compared with conventional antipsychotics. However, in doses higher than 6 mg daily, the profile for risperidone may become more similar to a conventional antipsychotic due to increased D receptor blockade. Aripiprazole is a partial agonist at D receptors; thus it is an antagonist in the2 presence of high levels of endogenous dopamine and, conversely, acts as an agonist when minimal dopamine is present. Aripiprazole is also a partial agonist at 5-HT1A receptors that may contribute to improvements in anxiety, depression, negative symptoms, and lower incidence of extrapyramidal side effects. Paliperidone is a major active metabolite of risperidone. While risperidone is subject to drug interactions affecting the CYP2D6 enzyme, in vivo studies suggest this isozyme plays a limited role in the clearance of paliperidone. Paliperidone does not require dose adjustments in mild to moderate hepatic impairment, but awaits studies for use in patients with severe hepatic impairment. Iloperidone is an antagonist at the D and 5-HT receptors.