Risk Of Metabolic Side Effects Research Articles

Effect of Risperidone and Olanzapine on blood glucose levels and lipid profile among individuals with schizophrenia

Background: Treatment of schizophrenia requires use of antipsychotics for considerable time. Studies established that patients have risk of metabolic side effects. Objectives: To study fasting blood glucose levels and lipid profile in schizophrenic patients and to see that same was present in study population. Methods: This study was conducted at psychiatry outpatient department, Nobel Medical College and Teaching Hospital Kanchanbari Biratnagar from October 2018 till august 2019 after due approval from college ethics committee. A total of 50 consenting drug naive schizophrenia patients 17- 60 years of age, with no comorbidity, were divided alternatively into two groups. group 1 was treated with olanzapine, group 2 with risperidone for eight weeks. With flexible dosage for ease of the therapy and individual patient requirement. Fasting blood glucose and lipid profile was measured at day baseline, four, eight weeks. Results: There was rise of fasting blood glucose in both groups but more in olanzapine group with no statistically significant intergroup difference (The p-value after eight weeks was 0.504). In lipid profile, mean total cholesterol levels were higher in the group 1, (p = 0.005 after eight weeks). Triglycerides, on intergroup comparison significant difference (p = 0.002) was noted. Higher values in group 1 were recorded. However, very low-density lipoprotein was elevated (p = 0.003) in group1 only. Conclusion: olanzapine and risperidone cause non-significant rise in fasting blood sugar. Olanzapine caused statistically significant rise of total cholesterol, triglycerides, very low-density lipoprotein as compared to risperidone.

Olanzapine Use in Schizophrenia and the Modulation of Its Response by Genetic Variations

Schizophrenia is a chronic disease with diverse psychopathology and multiple phases of illness. Consequently, numerous factors must be considered when assessing the benefits of a given treatment over short- and long-term periods. Olanzapine is an atypical antipsychotic reported to be effective without producing many of the disabling extrapyramidal adverse effects associated with older, typical antipsychotic drugs. Despite the fact that olanzapine is still associated with a known risk of metabolic side effects, including weight gain, many clinicians continue to prescribe olanzapine for the treatment of schizophrenia with the expectation of additional therapeutic antipsychotic efficacy relative to other first-line atypical antipsychotics. This review focuses on the epidemiology, pathogenesis, and treatment of schizophrenia with special emphasis on the role of olanzapine in the treatment of schizophrenia. Genetic variants associated with the therapeutic efficacy and adverse effects of olanzapine are reviewed and those with the potential to act as a clinical predictor of therapeutic response and/or adverse effects are discussed. Recommendations are made for the use of some of these genetic variants in clinical medicine.

Drugs Affecting Body Weight, Body Fat Distribution, and Metabolic Function-Mechanisms and Possible Therapeutic or Preventive Measures: an Update.

Weight gain and body fat redistribution are common side effects of many widely used drugs. We summarize recent literature on prevalence data and mechanisms associated with drug-induced body fat changes and mechanisms to prevent or treat metabolic side effects. The highest prevalence of metabolic complications is seen with antipsychotics and antiretroviral drugs used in the treatment of HIV and may, at least partly, be responsible for the increased risk for co-morbid diseases such as diabetes, steatosis of the liver, and cardiovascular disease. The pathogenetic mechanisms leading to weight gain from antipsychotics are increasingly known and help to unravel the complex interaction that exists between psychopathology and metabolic complications. Although the classic lipodystrophy mainly occurred with older HIV drugs, also with the newer HIV treatment, weight gain seems to be a major side effect. Early detection of the metabolic consequences of drugs can lead to an early diagnosis of the complications and their treatment. Different medications, including the newer antidiabetics, are being studied in the therapy of drug-induced obesity. Future research should focus on identifying individuals at risk for metabolic side effects and on early markers to identify individuals with side effects so that timely treatment of metabolic complications can be initiated.

Association of clozapine-related metabolic disturbances with CYP3A4 expression in patients with schizophrenia

Clozapine is effective in treatment-resistant schizophrenia; however, adverse effects often result in discontinuation of clozapine therapy. Many of the side-effects are associated with pharmacokinetic variations; therefore, the expression of major clozapine-metabolizing enzymes (CYP1A2, CYP3A4) in patients may predict development of adverse effects. In patients with schizophrenia (N = 96), development of clozapine concentration-dependent metabolic side-effects was found to be associated with pharmacokinetic variability related to CYP3A4 but not to CYP1A2 expression. In low CYP3A4 expressers, significant correlation was detected between fasting glucose level and clozapine concentration; moreover, the incidence of abnormal glucose level was associated with exaggerated clozapine concentrations (> 600 ng/ml). In low CYP3A4 expressers, exaggerated concentrations were more frequently observed than in normal/high expressers. Moderate/high risk obesity (BMI ≥ 35) more frequently occurred in low CYP3A4 expresser patients than in normal/high expressers. In patients with normal/high CYP3A4 expression and consequently with extensive clozapine-metabolizing capacity, norclozapine/clozapine ratio correlated with fasting glucose levels, triglyceride concentrations and BMI. Low CYP3A4 expression often resulting in exaggerated clozapine concentrations was considered to be as an important risk factor for some concentration-dependent adverse effects as normal/high CYP3A4 expression evoking high norclozapine/clozapine ratios. CYP3A4-status can identify patients with increased risk for metabolic side-effects and prevent their development by careful therapeutic strategy.

Aripiprazole Cytotoxicity Coincides with Activation of the Unfolded Protein Response in Human Hepatic Cells.

Schizophrenia is a mental disease that results in decreased life expectancy and well-being by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. Although the second-generation antipsychotics (SGA), Olanzapine and Aripiprazole, are more effective in treating schizophrenia, they display a higher risk of metabolic side effects, mostly by development of diabetes and insulin resistance, weight gain, and dyslipidemia. Endoplasmic reticulum (ER) stress is induced when ER homeostasis of lipid biosynthesis and protein folding is impaired. This leads to the activation of the unfolded protein response (UPR), a signaling cascade that aims to restore ER homeostasis or initiate cell death. Chronic conditions of ER stress in the liver are associated with diabetes and perturbed lipid metabolism. These metabolic dysfunctions resemble the pharmacological side effects of SGAs. We therefore investigated whether SGAs promote the UPR in human and mouse hepatocytes. We observed full-fledged activation of ER stress by Aripiprazole not by Olanzapine. This occurred at low micromolar concentrations and to variable intensities in different cell types, such as hepatocellular carcinoma, melanoma, and glioblastoma. Mechanistically, Aripiprazole caused depletion of ER calcium, leading to activation of inositol-requiring enzyme 1 (IRE1)and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), two major transducers of the UPR. Cells underwent apoptosis with Aripiprazole treatment, which coincided with UPR induction, and this effect was reduced by adding glutathione without affecting UPR itself. Deletion of IRE1 from HepG2, a human liver cancer cell line, protected cells from Aripiprazole toxicity. Our study reveals for the first time a cytotoxic effect of Aripiprazole that involves the induction of ER stress. SIGNIFICANCE STATEMENT: The antischizophrenic drug Aripiprazole exerts cytotoxic properties at high concentrations. This study shows that this cytotoxicity is associated with the induction of endoplasmic reticulum (ER) stress and IRE1 activation, mechanisms involved in diet-induced obesity. Aripiprazole induced ER stress and calcium mobilization from the ER in human and mouse hepatocytes. Our study highlights a new mechanism of Aripiprazole that is not related to its effect on dopamine signaling.

<p>A commentary on the efficacy of olanzapine for the treatment of schizophrenia: the past, present, and future</p>

Olanzapine is a second-generation atypical antipsychotic with proven efficacy for the treatment of schizophrenia. Approved in 1996, olanzapine is one of the most studied antipsychotics, resulting in a considerable amount of clinical data across diverse patient populations. Despite the fact that olanzapine is associated with a known risk of metabolic side effects, including weight gain, many clinicians continue to prescribe olanzapine for the treatment of schizophrenia with the expectation of additional therapeutic antipsychotic efficacy relative to other first-line atypical antipsychotics. The goal of this narrative is to revisit the role of oral olanzapine in the management of patients with schizophrenia, including those with recently diagnosed schizophrenia (“first-episode”), those with an established schizophrenia diagnosis who experience acute exacerbations, those receiving long-term antipsychotic treatment as a maintenance intervention, and those with suboptimal response to antipsychotic treatment, including treatment resistance. Collectively, data from published literature support the favorable efficacy of olanzapine compared with other first- and second-generation antipsychotics, including lower rates of treatment discontinuation and clinically meaningful improvements in the symptoms of schizophrenia. The development of antipsychotic medications with the favorable efficacy of olanzapine, but with reduced weight gain, could address a major unmet need in the treatment of schizophrenia.

Long-Term Antipsychotic Use and Major Cardiovascular Events: A Retrospective Cohort Study.

Chronic treatment with antipsychotics may result in both metabolic side effects and cardiovascular disease. Our aim was to evaluate the effect of antipsychotic medications categorized by their metabolic side effect profiles as low, intermediate, or high risk on major cardiovascular events. A retrospective cohort study was conducted in adult outpatients aged 30 years or older initiating antipsychotic treatment from 2002 to 2007. Antipsychotic medications were divided into 3 groups (low-, intermediate-, and high-risk) according to the severity of their side-effect profiles in developing metabolic abnormalities associated with cardiovascular disease. The primary outcome measure was the time to the composite of acute myocardial infarction, acute coronary syndrome, ischemic stroke, peripheral artery disease, or a new revascularization procedure. Inverse probability weighting of a marginal structural Cox model was used to adjust for confounding. A total of 1,008 patients were included (mean age = 72.4 years, median follow-up = 36.5 months), and 19.6% of patients experienced the primary outcome. The adjusted hazard ratios of a major cardiovascular event for patients in the high- or intermediate-risk medication groups compared to the low-risk group were 2.82 (95% CI, 1.57-5.05) and 2.57 (95% CI, 1.43-4.63), respectively. Older adult patients under antipsychotic regimens with high or intermediate risk of metabolic side effects may face a higher incidence of major cardiovascular events than those under a low-risk regimen during long-term follow-up.

Clinical vignette – Aripiprazol long acting injection monotherapy as long-term treatment for bipolar disease

IntroductionOver the last decade a number of effective maintenance treatments for bipolar disorder (BPD) have been developed. Lithium remains the best-established option, but valproic acid, lamotrigine, olanzapine, and quetiapine are also effective maintenance drugs. However, oral administration contributes to lower adherence rates with these drugs. In the United States and Europe, aripiprazole is approved for the acute management of manic and mixed episodes and maintenance in BPD. It presents the advantage of a low risk of metabolic side effects, sexual dysfunction, and sedation, which can facilitate treatment adherence and help improve clinical outcomes.ObjectivesThe authors present an illustrative case on which aripiprazol long acting injection monotherapy was effective as maintenance treatment in a patient with long history of BPD with several hospital inpatient admissions and very poor therapeutic adherence.MethodsCase report based on the patient's file. Narrative review of articles available in PubMed about the use of aripiprazol in BPD.ResultsFor this patient, aripiprazol long acting injection has proved to be an excellent choice for long-term treatment of BPD. The once-a-month injection promotes therapeutic adherence, which in this case was combined with involuntary outpatient treatment, ensuring therapeutic compliance.ConclusionsAripiprazol has been shown to be safe and effective in the maintenance treatment in BPD. It shows similar efficacy and a superior tolerability profile when compared with other well-established treatments. Further studies are needed, warranted by its potential advantages, particularly on patients with poor insight and adherence.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Clinical Practice Guidelines for Management of Schizophrenia.

Clinical Practice Guidelines for Management of Schizophrenia.

Olanzapine and aripiprazole differentially affect glucose uptake and energy metabolism in human mononuclear blood cells

The use of antipsychotics carries the risk of metabolic side effects, such as weight gain and new onset type-2 diabetes mellitus. The mechanisms of the observed metabolic alterations are not fully understood. We compared the effects of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (aripiprazole), on glucose metabolism. Primary human peripheral blood mononuclear cells (PBMC) were isolated and stimulated with olanzapine or aripiprazole for 72 h. Cellular glucose uptake was analyzed in vitro by 18F-FDG uptake. Further measurements comprised mRNA expression of glucose transporter (GLUT) 1 and 3, GLUT1 protein expression, DNA methylation of GLUT1 promoter region, and proteins involved in downstream glucometabolic processes. We observed a 2-fold increase in glucose uptake after stimulation with aripiprazole. In contrast, olanzapine stimulation decreased glucose uptake by 40%, accompanied by downregulation of the cellular energy sensor AMP activated protein kinase (AMPK). GLUT1 protein expression increased, GLUT1 mRNA expression decreased, and GLUT1 promoter was hypermethylated with both antipsychotics. Pyruvat-dehydrogenase (PDH) complex activity decreased with olanzapine only.Our findings suggest that the atypical antipsychotics olanzapine and aripiprazole differentially affect energy metabolism in PBMC. The observed decrease in glucose uptake in olanzapine stimulated PBMC, accompanied by decreased PDH point to a worsening in cellular energy metabolism not compensated by AMKP upregulation. In contrast, aripiprazole stimulation lead to increased glucose uptake, while not affecting PDH complex expression. The observed differences may be involved in the different metabolic profiles observed in aripiprazole and olanzapine treated patients.

НЕЙРОЛЕПТИКИ В ЛЕЧЕНИИ ШИЗОФРЕНИИ (ОБЗОР ЛИТЕРАТУРЫ)

Aim. To analyze the administration of antipsychotics as main pharmaceuticals in treatment of schizophrenia as chronic mental disease involving several positive, negative, cognitive, and affective symptoms resulting in disorganization of mental activity and mental disadaptation in patients. Results. We have found the data on the absence of significant differences in efficacy of antipsychotics relative to positive symptoms and mental disorganization symptoms except for advantages of clozapine in the treatment of resistant cases. It shown that the therapy efficacy from the position of treatment of negative, depressive, and cognitive symptoms is determined depending on: (1) how the reduction of positive symptoms (delirium and hallucinations) improves the secondary symptoms of disease, and (2) how side extrapyramidal effects (EPSE) and side anticholinergic effects are corrected by drugs administered to influence EPSE aggravating the mentioned symptoms. There is a reasonable opinion that strong antipsychotics that do not have accompanying extrapyramidal actions and do not require the combined anticholinergic therapy have huge therapeutic advantages. Conclusion. It is found that having much in common in efficacy all antipsychotics greatly differ in rate and intensity of side effects. Contrary to belief that second-generation antipsychotics (so called atypical antipsychotics) are normally considered the drugs with less risk of extrapyramidal actions and higher risk of metabolic side effects in comparison with traditional antipsychotics; the significant variability of frequency of these and other side effects of these two types of drugs indicates that such categorical distinguishing of pharmaceuticals is not clinically justified. The choice of antipsychotic should be based on individual preferences of patients, their therapeutic response to the previous treatment, history of presence and specifics of antipsychotic side effects, medical data on risk factors, level of compliance to the prescribed treatment, and, especially, the profile of side effects of various antipsychotics.

Clinical vignette – aripiprazol long acting injection monotherapy as long-term treatment for bipolar disease

Introduction Over the last decade a number of effective maintenance treatments for bipolar disorder (BPD) have been developed. Lithium remains the best-established option, but valproic acid, lamotrigine, olanzapine, and quetiapine are also effective maintenance drugs. However, oral administration contributes to lower adherence rates with these drugs. In the United States and Europe, aripiprazole is approved for the acute management of manic and mixed episodes and maintenance in BPD. It presents the advantage of a low risk of metabolic side effects, sexual dysfunction, and sedation, which can facilitate treatment adherence and help improve clinical outcomes. Objectives/aims The authors present an illustrative case on which aripiprazol long acting injection monotherapy was effective as maintenance treatment in a patient with long history of BPD with several hospital inpatient admissions and very poor therapeutic adherence. Methods Case report based on the patient's file. Narrative review of articles available in PubMed about the use of aripiprazol in BPD. Results For this patient, aripiprazol long acting injection has proved to be an excellent choice for long-term treatment of BPD. The once-a-month injection promotes therapeutic adherence, which in this case was combined with involuntary outpatient treatment, ensuring therapeutic compliance. Conclusions Aripiprazol has been shown to be safe and effective in the maintenance treatment in BPD. It shows similar efficacy and a superior tolerability profile when compared with other well-established treatments. Further studies are needed, warranted by its potential advantages, particularly on patients with poor insight and adherence.

All diuretics used in the treatment of hypertension are not the same

Diuretics have been used for years to treat hypertension as both a monotherapy and in combination. Hydrochlorothiazide, indapamide, and chlorthalidone have frequently been considered in the same category as thiazide diuretics, but there is no evidence that their activities are similar. Studies have shown that chlorthalidone and indapamide reduce cardiovascular morbidity and mortality; however, there is no study indicating that hydrochlorothiazide has beneficial effects on cardiovascular outcomes such as myocardial infarction, renal failure, stroke, or death. Hydrochlorothiazide has less effect on blood pressure, a high risk of metabolic side effects, and may not have pleiotropic effects. As a result, it is not accurate to evaluate chlorthalidone and indapamide as similar to thiazide diuretics. Indapamide or chlorthalidone is a better choice of diuretic for use in the treatment of hypertension.

Gender differences in antipsychotics prescribed to veterans with serious mental illness

ObjectiveTo examine gender differences in prescribing of antipsychotic medications (APMs) according to their liability for weight gain and other metabolic side effects. MethodWe identified 4510 patients with schizophrenia or bipolar disorders receiving usual care in a Veterans Affairs (VA) health care network in the U.S. mid-Atlantic region who initiated treatment with an APM between October 2006 and September 2011. We used multivariable logistic regression to examine gender differences in the likelihood of incident prescription of APMs with low versus medium/high metabolic risk, adjusting for fiscal year of prescribing and selected Veteran demographic, mental health and physical health characteristics. ResultsOverall, 58% of women were prescribed an APM with a low risk of metabolic side effects compared to 45% of men (P<.001). In multivariable analysis, women Veterans were 1.47 times as likely as men to be prescribed a low-metabolic-risk APM (95% confidence interval: 1.26–1.73, P<.001). Several demographic and clinical covariates were also independently related to prescribing of APMs by level of metabolic risk. ConclusionsThe results may suggest that prescribing choices for APMs by VA mental health prescribers and female Veterans reflect a growing awareness of the potential adverse health consequences of these treatments in women.

Towards a framework for treatment effectiveness in schizophrenia.

IntroductionPrompt administration of antipsychotic treatment that is adhered to is essential for the optimal treatment of schizophrenia. Many patients have benefited from the advent of second-generation antipsychotics, which can offer good symptomatic control with reduced incidence of extrapyramidal symptoms, although with higher risk of metabolic side effects. It is unsurprising that accounts as to whether first- and second-generation antipsychotics differ in their efficacy vary, since treatment effectiveness is a broad notion and difficult to define.ObjectivesNumerous factors may be used to gauge treatment effectiveness and, while it has largely been defined in terms of improvements in four domains (symptoms of disease, treatment burden, disease burden, and health and wellness), the real-world clinical utility of this consensus is unclear. Therefore, this article aims to provide a framework that can aid psychiatrists in making assessments about treatment effectiveness.Methods and resultsA panel of 12 psychiatrists and psychopharmacologists convened to develop and propose an accessible and globally-applicable framework for assessing the effectiveness of antipsychotic treatments in patients with schizophrenia. Following presentation of a preliminary proposal to a wider group of psychiatrists from across Europe, it was refined into a framework comprising five domains: symptomatic remission and retention of treatment; affective symptoms; cognitive functioning; treatment satisfaction; and personal and social functioning – each of which is discussed in this article.ConclusionsThis article provides a framework that can aid psychiatrists in making assessments about treatment effectiveness. It is anticipated that the framework outlined here may contribute to improving clinical practice through the promotion of a patient-centered approach to the assessment of treatment effectiveness, using five specified domains, in patients with schizophrenia.

Fatty Acid Desaturase Gene Polymorphisms and Metabolic Measures in Schizophrenia and Bipolar Patients Taking Antipsychotics

Atypical antipsychotics have become a common therapeutic option in both schizophrenia and bipolar disorder. However, these medications come with a high risk of metabolic side effects, particularly dyslipidemia and insulin resistance. Therefore, identification of patients who are at increased risk for metabolic side effects is of great importance. The genetics of fatty acid metabolism is one area of research that may help identify such patients. Therefore, in this present study, we aimed to determine the effect of one commonly studied genetic polymorphism from both fatty acid desaturase 1 (FADS1) and FADS2 gene on a surrogate measure of insulin resistance and lipid levels in a metabolically high-risk population of patients largely exposed to atypical antipsychotics. This study used a cross-sectional design, fasting blood draws, and genetic analysis to investigate associations between polymorphisms, haplotypes, and metabolic measures. A total of 320 subjects with schizophrenia (n = 226) or bipolar disorder (n = 94) were included in this study. The mean age of the population was 42.5 years and 45% were male. A significant association between FADS1 and FADS2 haplotypes was found with insulin resistance while controlling for confounders. Further investigation is required to replicate this finding.

Org 214007-0: A Novel Non-Steroidal Selective Glucocorticoid Receptor Modulator with Full Anti-Inflammatory Properties and Improved Therapeutic Index

Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.

Abstract 2719: MM-141, a novel bispecific antibody co-targeting IGF-1R and ErbB3, blocks ligand-induced signaling and demonstrates antitumor activity

Abstract Monoclonal antibodies have significantly advanced our ability to treat cancer, but most patients do not show durable responses to therapy. This, in part, can be explained by the tumor cells responding to two or more growth factors in a redundant fashion. We show that cancer cell lines frequently rely on Insulin-like growth factor 1 (IGF-1) and Heregulin (HRG) signaling to support their survival and proliferation. Using a Network Biology approach, we have designed, constructed and optimized a novel bispecific antibody, MM-141, for co-targeting of ErbB3 and IGF-1R. MM-141 blocks IGF-1, IGF-2, and HRG binding to IGF1R and ErbB3, and causes downregulation of these receptors. MM-141 inhibits phosphorylation of IGF1R and ErbB3 as well as downstream activation of the PI3K/Akt pathway. In our in vitro and in vivo testing, MM-141 displays potency in the presence of single or multiple ligands, over a broad range of receptor profiles. Inhibition of growth by MM-141 has been observed in vitro as well as in vivo in multiple xenograft models including human pancreatic cancer (BxPC-3) and human prostate cancer (DU145). MM-141 does not bind the insulin receptor, thus reducing the risk of metabolic side effects. Our in vivo and in vitro studies reveal that MM-141 has favorable pharmaceutical properties and pharmacokinetic profiles. We are advancing MM-141 into preclinical development. Taken together, these results suggest that MM-141 has the potential to be an effective therapeutic for treatment of patients with solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2719. doi:1538-7445.AM2012-2719

Clozapine is underutilized.

I read the piece by Wang and Li[1] with great interest. The issues surrounding the use of clozapine in China and the United States provide an interesting contrast. Wang and Li suggest that clozapine is over-utilized in China both as a first-line treatment and (in low doses) to augment other antipsychotic agents. The situation in the United States is that clozapine is grossly underutilized as a treatment for patients with refractory schizophrenia and clinically significant suicidality. Despite the evidence that 25-40% of patients with schizophrenia would be candidates for clozapine based on labeled indications, approximately 5% of patients with schizophrenia are receiving it. Clozapine was approved by the Food and Drug Administration in the United States in 1989 following a large-scale clinical trial we conducted in 1988[2] demonstrating clozapine's superiority over chlorpromazine in carefully selected treatment refractory patients who had undergone a prospective trial of high dose haloperidol in order to confirm their lack of response. Over the subsequent two decades clozapine's superiority has been confirmed in several government-funded studies.[3]–[5] Despite the introduction of other so called ‘atypical’ or second generation antipsychotics, no other compound—even those with similar chemical structures—has consistently replicated clozapine's effects. Although clozapine has been shown to be superior in patients who have failed on other medications, there is no evidence that clozapine is superior as a first-line medication. At the same time, however, it is possible that waiting until a patient fails adequate trials of three different medications is too conservative an approach; these patients may be waiting too long to try an effective treatment. Unfortunately, there is insufficient research to establish the optimum point in an individual's treatment history to introduce clozapine. It is certainly possible that the introduction of clozapine after one fully adequate failed trial of an antipsychotic medication (with confirmed adherence and therapeutic blood levels) would be sufficient. If this proved true it would be particularly valuable in the first episode of illness or in the first years after onset of illness as it would increase the likelihood of a timely treatment response. Clozapine's use has been somewhat constrained by the requirement for weekly blood monitoring in order to detect the presence of agranulocytosis. The risk of true agranulocytosis appears to have declined since the early years of clozapine use, and new methods for managing this condition has reduced fatality rates enormously. Nevertheless, the management of clozapine's side effects continues to be a challenge. Though progress is being made in identifying individuals at high risk for agranulocytosis[6] this still remains an obstacle for some physicians and patients. The risk of metabolic side effects is also very real and needs to be considered in any management plan. The appropriate or optimum dosing of clozapine also remains a challenge. Dosage patterns vary considerably from country to country. Though some studies provide guidance regarding therapeutic blood levels it is likely that there are ethnic differences in these relationships as well. Clearly, as suggested by Wang and Li,[1] more research is necessary to achieve the goals of personalized medicine in the use of a drug like clozapine, where both the potential rewards and risks are higher than usual. Some clinicians and policy makers attribute the underutilization of clozapine to its side effect profile and, therefore, patient resistance to its use. However, it is often the case that physicians project their own concerns about the possible serious side effects of clozapine onto patients and make assumptions about patients' desires without an appropriate process of shared decision-making. Moreover, many physicians in the United States and in China appear more comfortable with antipsychotic drug polypharmacy than with clozapine monotherapy, despite the fact that polypharmacy has not been adequately established as an appropriate strategy for the treatment of refractory patients. The fact that clozapine utilization varies as much as it does from country to country underscores the variety of factors that contribute to its use. Many clinicians are inadequately informed about the evidence base for the use of clozapine and about the strategies necessary for managing its potential adverse effects. Further training about clozapine is necessary. But there is also a need for research on implementation. How can the field of psychiatry better succeed at promulgating the use of evidence-based practices?

Dopamine: A Marker of Psychosis and Final Common Driver of Schizophrenia Psychosis

Our attempt to understand schizophrenia in neurochemical terms began with the landmark studies of Carlsson and Lindqvist (1) in the 1960s. The results of these studies, based on the action of chlorpromazine, were strengthened by the binding studies carried out in both Seeman's (2) and Synder's (3) laboratories, which showed that antipsychotic potency was correlated with dopamine D2 receptor binding. The one major exception to this correlation is clozapine, which appears to be the most effective available drug for treating schizophrenia symptoms. The most recent version of the resulting dopamine hypothesis suggests that genetic, environmental, and developmental variables play major etiological roles in schizophrenia, but that striatal dopamine presynaptic overactivity remains the final trigger resulting in psychosis......