Pharmacogenetic Profiling of Antipsychotics-Induced X-Syndrome and Diabetes (PAXD)
Pharmacogenetic Profiling of Antipsychotics-Induced X-Syndrome and Diabetes (PAXD)
Diabetes is prevalent in schizophrenics and may be induced by antipsychotic treatments.
 Several retrospective studies have suggested that psychiatric patients exposed to atypical
 antipsychotics may be at a higher risk for developing diabetes and ketoacidosis. The
 association between these atypical antipsychotics and the onset of diabetes is further
 strengthened by observations of:

 1. the time sequence between the initiation of antipsychotic treatment and the onset of
 diabetes;

 2. remission after the discontinuation of medications; and

 3. re-emergence of diabetes following the re-introduction of atypical antipsychotics.

 The treatment emergent diabetes, along with other metabolic disturbances, represents a
 serious issue in the use of atypical antipsychotics. Major current debates and unresolved
 research issues which are also the focus of this proposal, are:

 1. schizophrenia per se, versus the use of antipsychotics, in triggering diabetes;

 2. whether there are differences between "typicals" and "atypicals" in such an effect;

 3. whether there are differences among different "atypicals";

 4. whether, and to what extent, treatment emergent diabetes may be associated with, or
 independent of, weight gain, which also often is associated with the use of
 antipsychotics; and

 5. genetic and environmental risks in association with treatment emergent diabetes.

 The policy of some hospitals in Taiwan that discourages the use of atypical antipsychotics
 for new onset schizophrenia directs the investigators to a study design looking at the
 associated diabetes of both types of antipsychotics. Such a design may provide some hints to
 the unresolved research issues mentioned above.

 Meanwhile, a broader defined term, X-syndrome, or metabolic syndrome, is being used to
 describe the diabetic condition associated with antipsychotics. X-syndrome is a risky
 condition leading to cardiovascular diseases and diabetes, with insulin resistance as the
 major outcome, associated with two of the following conditions: truncal obesity (deposited in
 the thorax and abdomen, instead of the hips and thighs), high triglycerides, high low-density
 lipoprotein (LDL) cholesterol or hypertension. The proposed study will combine the phenotypes
 of diabetes and X-syndrome to explore the abnormal metabolism caused by antipsychotics,
 bridge important information gaps, and provide data contributing towards a better
 understanding of the risk and management of diabetes and X-syndrome associated with the use
 of antipsychotics. Three assessment tools, namely the Clinical Global Severity (Clinical
 Global Impressions - Severity) or the Positive and Negative Symptom Scale (PANNS), the
 Diabetes Risk Assessment (ADA) and the Life Style Survey, together with physical
 measurements, collect additional information for this study. Diabetes related biochemistry,
 including glucose, insulin, leptin, lipids and glycohemoglobin, will be measured to form a
 composite phenotype for further pharmacogenetic studies. Candidate genes involved in
 pancreatic beta cell insulin secretion will be examined in priority to see if they play a
 role in the development of the antipsychotics-induced diabetes.
Specific Aims

 Although our original interests were condensed in atypicals, the fact that some hospitals
 discourage the use of atypical antipsychotics for new onset schizophrenia for policy reasons
 directs us to a study design looking at both types of therapeutics. Coincidently, such a
 design may provide some hints to the unresolved research issues mentioned above. The proposed
 study will bridge these important information gaps, and provide data contributing towards a
 better understanding of the risk and management of diabetes associated with the use of both
 types of antipsychotics. As some researchers in this field have described the diabetic
 related conditions in a broader term called "metabolic X-syndrome", a risky condition leading
 to cardiovascular diseases and diabetes, with insulin resistance as the major outcome,
 associated with two of the following conditions: truncal obesity (deposited in the thorax and
 abdomen, instead of the hips and thighs), high triglycerides, high LDL cholesterol or
 hypertension,3 we therefore extend our study to both diabetes and metabolic X-syndrome as a
 phenotype for further genetic study.

 This proposal aims to study:

 1. the prevalence of diabetes/metabolic X-syndrome associated with the use of
 antipsychotics in Taiwanese Han Chinese populations;

 2. clinical and sociodemographic correlation of diabetes/metabolic X-syndrome associated
 with the use of antipsychotics; and

 3. the putative role of genes in the development of treatment emergent diabetes/metabolic
 X-syndrome secondary to the administration of antipsychotics.

 Background

 Affecting approximately 1% of any population worldwide, schizophrenia represents a major
 cause for morbidity and dysfunction for the afflicted and their loved ones, as well as a
 significant burden for the health care system and the society in general. Although
 antipsychotics are often remarkably effective in ameliorating schizophrenic symptoms and in
 enhancing social functioning, their use often is limited by their propensity to cause serious
 side effects that could further compromise patients' health conditions. One such side effect
 is diabetes. Research publications from 1919, long before the advent of psychotropic
 medication, had showed schizophrenia might predispose individuals to diabetes.1 Following the
 introduction of chlorpromazine, the first antipsychotic in the modern era, a large number of
 case reports of antipsychotics-induced diabetes were reported. This complication seems more
 serious in the new type of antipsychotic, which is generally regarded as an atypical
 antipsychotic due to the lack of extrapyramidal reactions seen in schizophrenics treated with
 antipsychotics discovered previously. Several retrospective studies based on health services
 claim databases, strongly suggested that psychiatric patients exposed to atypical
 antipsychotics may be at a higher risk for developing diabetes. In addition, patients treated
 with these medications also appear to be at a higher risk for developing ketoacidosis. Risk
 factors included ethnicity (African Americans, Asians, Hispanics and Native Americans),
 family history of diabetes and overweight or obesity. The association between these atypical
 antipsychotics and the onset of diabetes is further strengthened by observations of:

 1. the time sequence between the initiation of antipsychotic treatment and the onset of
 diabetes;

 2. remission after the discontinuation of medications; and

 3. re-emergence of diabetes following the re-introduction of atypical antipsychotics.

 Together, these data indicate that treatment emergent diabetes, along with other metabolic
 disturbances (e.g., dyslipidemia and obesity), represents a serious issue in the use of
 atypical antipsychotics. This notwithstanding, many questions of crucial clinical and
 theoretical interest remain un-clarified. Major current debates and unresolved research
 issues include:

 (1) schizophrenia per se, versus the use of antipsychotics, in triggering diabetes; (2)
 whether there are differences between "typicals" and "atypicals" in such an effect; (3)
 whether there are differences among different "atypicals;" (4) whether, and to what extent,
 treatment emergent diabetes may be associated with, or independent of, weight gain, which
 also often is associated with the use of antipsychotics; and (5) genetic and environmental
 risks in association with treatment emergent diabetes.

 This application aims at addressing some of these important issues, as well as establishing a
 platform for future studies that may be more comprehensive and in-depth in nature.

 In contrast to the plethora of case reports and reports based on secondary data analyses,
 there is a dearth of information deriving from studies that might be more useful for
 providing definitive answers to some of these questions. Our review of the extant literature
 led to two studies that are worth noting in this regard:

 1. A five-year longitudinal study conducted by Henderson et al in Boston, reporting that
 patients treated with clozapine experienced significant weight gain and lipid
 abnormality and appear to be at an increased risk for developing diabetes.2 Overall,
 36.6% (30/82) of the patients developed newly diagnosed diabetes during the 5-year
 period.

 2. In a sizeable cross-sectional study conducted in northern Sweden, prevalence of diabetes
 in patients receiving clozapine was approximately 12% versus 6% in controls.3 It is of
 note that both studies focused only on clozapine, and neither of them provide
 information specifically on populations of Oriental or Asian backgrounds.

 Obesity and overweight are known risk factors for insulin resistance, which could eventually
 lead to the development of type 2 diabetes. Since most atypicals (as well as schizophrenia
 itself) are likely to induce significant weight gain, it is reasonable to speculate that
 diabetes associated with atypicals might be secondary to weight changes. However, a number of
 reasons suggest that factors in addition to/or other than weight gain may also be important:

 (1) diabetes also occurs in patients who do not gain weight;2 (2) in many cases, improvement
 in diabetes occurred within 2 weeks, too fast for this to be an effect of a reversal in
 weight changes; and (3) the relatively high rate of ketoacidosis, as well as the rapidity of
 the recovery following the discontinuation of the treatment, suggests that the putative
 diabetogenic effects of the atypicals might be secondary to the inhibition of insulin
 secretion, rather than insulin resistance. Very little is known about the mechanisms of
 typical antipsychotics in obesity and overweight, however, there should be some shared
 pathways in both types of antipsychotics, and specific pathways used by only typicals or
 atypicals.

 The possible role of insulin secretion in mediating atypicals' diabetogenic effects is
 further supported by the abundance of serotonin receptors in pancreatic beta cells. In
 addition to the mechanisms involving the production and function of insulin, factors
 affecting the pharmacokinetics and pharmacodynamics of atypicals might also significantly
 determine whether individuals and/or populations would be more or less likely to develop
 diabetes, as well as the severity of such an unintended effect.

 Putting these considerations together, we propose a multi-factorial working model which,
 while emphasizing the central role of the function of the pancreatic beta cells, also will
 include factors mediating insulin resistance, as well as those controlling the metabolism of
 the atypicals, and their effects on the central nervous system. Such a model concurrently
 considers genetic and other factors that might determine the effects of the atypicals and
 factors altering glucose homeostasis in target tissues, as well as the interactions among
 these factors.

 Previous achievements

 Dr. Loh has been engaged in studies of psychiatric genetics since 1993. These studies mainly
 emphasized the genetic susceptibility of alcoholism and illicit drug abuse. The research
 extended from thesis work to an international collaboration and is still being conducted
 using both family and case control designs.

 Methods

 Subject Recruitments:

 Research subjects will be recruited from three collaborative sites: Taipei City Hospital
 Songde Branch, Mackay Memorial Hospital and Yu-Li Hospital. The Institutional Review Boards
 of the National Health Research Institutes, the Yu-Li Hospital and the Mackay Memorial
 Hospital have approved this study, while a permit from the Institutional Review Board of the
 Taipei City Hospital Songde Branch is still being applied.

 Inpatients and outpatients diagnosed with schizophrenia according to DSM-IV criteria, treated
 either with typical or atypical antipsychotics, either male or female, age between 18 to 65
 years old, are eligible for this study. Exclusion criteria include:

 1. Illegal drug use/abuse/dependence;

 2. alcoholism;

 3. pregnancy; and

 4. clinical diagnosis of type I or type II diabetes before the onset of schizophrenia or
 treatment of schizophrenia (via chart review).

 According to empirical experience, around 150 new onset schizophrenics may be collected
 each year from our three collaborative sites. For chronic schizophrenics, clinicians
 must be aware that the eligible patients are those who can be suitably grouped in
 statistics (e.g., poor responder to typical psychotics). Eligible subjects will be
 invited to participate in this study, after the signing of written informed consent.

 Possible Impediments: The patients may complain of too many biochemical measurements
 conducted in the study period. We can reduce the total number of biochemical
 measurements to 3~4 times a year for all research subjects or for those who complain. We
 will lose some information but the data should be able to reveal the trend of
 biochemical changes.

 Clinical and Laboratory Procedures

 -  Clinical Assessments for New cases

 Clinical information of subjects who come for the treatment of schizophrenia for the
 first time will be collected by using the following assessment tools in the Chinese
 version:

 (I) Clinical Global Severity (Clinical Global Impressions - Severity) or Positive and
 Negative Symptom Scale (PANNS): CGI Severity or PANNS is used by the clinician to record
 the severity of schizophrenic illness at the time of assessment. The score ranges for
 CGI are from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).
 One of these scales will be chosen to access the psychiatric conditions of the patients.

 (II) Diabetes Risk Assessment: The Diabetes Risk Assessment (ADA, 2000) is a 7-item
 self-report scale designed to determine the presence of known risk factors for the
 development of Type 2 diabetes. Each item is assigned a point value and points are then
 totaled to achieve an overall risk rating.

 (III) Life Style Survey: The Life Style Survey is a self-report scale specifically
 designed for this study to ascertain certain aspects of daily health habits of the study
 participants. Behaviors related to smoking, alcohol use, substance use, diet, exercise,
 and family history are evaluated.

 The CGI, ADA and assessment tools in the Chinese version were translated and validated
 by Dr. Tsuo-Hung Lan, and have been used in his clinical studies of metabolic X-syndrome
 (YLH93001 and B20030902).

 ---Data collection for Old cases: While new cases provide the information we are
 interested in, patients who have been treated for schizophrenia previously and with well
 documented records warrant a retrospective study. Although the psychiatric and physical
 conditions may not consist of all the variables we are interested in, they nevertheless
 point out a direction for the study of new cases. In brief, psychiatric and physical
 information of old cases are assessed by chart review and valued variables (e.g., Brief
 Psychiatric Rating Scale [BPRS], triglyceride levels, glucose levels, etc.) and DNA will
 be collected and used in further pharmacogenetic studies. If possible, the variables of
 necessity described below will be collected by following a simplified guideline derived
 from the current protocol.

 -  Physical Assessments:

 Weight, height, hip and waist circumference and blood pressure, will be collected by
 standard methods.

 ---Biochemistry: The following biochemical values are measured in a fasting state every
 two months, for 6 times: glucose, insulin, leptin, lipid panel (Total cholesterol, HDL
 cholesterol, LDL cholesterol and triglycerides) and glycohemoglobin (HBA1C or A1C).

 For exploratory purposes, the data will be processed and examined in two ways. First, we
 adopt diagnostic guidelines suggested by The Expert Committee On The Diagnosis And
 Classification Of Diabetes Mellitus, and The American Diabetes Association,5 to define
 and classify subjects' glucose metabolism status. However, because these criteria change
 from time to time and because we are interested to see how these biochemical values may
 form a new index, a second option to manipulate all these variables has been planned.

 We use the measurement of HbA1C as an additional index for diabetes. The Expert
 Committee On The Diagnosis And Classification Of Diabetes Mellitus did not include HbA1C
 as one of the criteria of diabetes because of difficulties in standardizing reference
 ranges of such a measurement across laboratories. This is much less a concern in this
 study since all procedures will be performed in the same laboratory, and the results are
 used for research rather than clinical purposes. The addition of the HbA1C affords us
 with information on glycemic levels in a time scale of weeks, whereas plasma glucose
 varies greatly within any given day and from day to day. Thus, an elevated HbA1C
 indicates a chronic state of hyperglycemia while hyperglycemia as measured by the FPG or
 2-h PG may be transitory.

 -  Pharmacogenetics:

 Current suggestions include candidate genes involved in pancreatic beta cell insulin
 secretion (e.g., HNF-1a, HNF-4a), insulin action (e.g., calpain 10, TNFα),
 serotonin/dopamine functions (e.g., 5-HT2A, 2C, D2, COMT) and pharmacokinetic (e.g.,
 CYP1A2, CYP2D6,) pathways. SNPs with a population frequency of 0.1~0.15 will be
 concerned as priority.

 ---Data Analysis: Clinical Data: The primary outcome is the diagnosis of diabetes based
 on American Diabetes Association criteria. Estimates of insulin secretion (fasting
 glucose/insulin ratios) and insulin sensitivity as well as demographic variables and
 evidence of over-weight/obesity will be evaluated as risk factors for the development of
 diabetes.

 Pharmacogenetic Data: The approach to analysis will be a case-control association study:
 SNPs within a gene will be combined to form haplotypes to provide more informative
 genotypes. Association studies of haplotypes will be done first, comparing the diabetic
 with the non-diabetic group. Modeling of contributions of multiple genes will also be
 conducted. When SNPs associated with antipsychotics induced diabetes are identified,
 their interactive effects will be analyzed by multiple logistic regression.

 ---Sample Size and Power Considerations: Based on current available data of the CATIE
 (Clinical Antipsychotic Trials of Intervention Effectiveness) conducted in the U.S.A, a
 9.5% incidence rate of diabetes in schizophrenics treated with atypical antipsychotics
 is predicted. In addition, Hagg reported a 12% incidence rate of confirmed type II
 diabetes among patients treated with clozapine in their cross sectional study.4 We used
 the Genetic Power Calculator6 to estimate the sample size needed. We defined a power of
 0.8, type I error rate of 0.05, with simple and common acceptable parameters, i.e.,

 (1) risk ratio of susceptible homozygous genotypes set at 3, (2) risk ratio of heterozygous
 genotypes set at 1.5, (3) prevalence of phenotypes of interest set at 10%. When SNPs with
 allele frequency of 0.15 are used in such conditions, approximately 135 cases and 270
 controls are needed to reach this desired power. Expectedly, to obtain 135 subjects with
 atypical antipsychotics-induced diabetes, we need to examine about 1350 new schizophrenic
 patients treated with antipsychotics. Such an expectation implies that the pharmacogenetic
 study of atypical antipsychotics-induced diabetes is not feasible, however, in reality, the
 prevalence of hyperglycemia (one of the components of X-syndrome) among patients treated with
 antipsychotics may be higher than 10% in a Han Chinese population. In addition, the
 susceptible genotype may have a higher risk ratio. Thus, posterior power estimations may give
 even higher power than the conservative estimation even at a smaller sample size. Moreover,
 our samples will merge from samples from other medical centers. Thus, the task to examine
 1350 schizophrenic patients treated with antipsychotics, is feasible.

 ---A Sample for Preliminary Pharmacogenetic Studies: We plan to examine a collection of DNAs
 in which 292 samples were from the Tao-Yuan Psychiatric Hospital and 393 samples were from
 the Yu-Li hospital. The samples were evaluated with the same clinical procedures and physical
 measurements described above. However, leptin was not measured and the HbA1C was only
 evaluated once. Furthermore, the rest of the biochemistries were only measured twice at the
 1st month and 6th month. Nevertheless, this sample collection is worth being explored in a
 preliminary study.

 Anticipated Results and Discussions

 Years 1 and 2: Collect clinical information, biochemical data and DNA samples, carry out
 preliminary statistical analysis and examine the 292 and 393 samples from the Tao-Yuan
 Psychiatric Hospital and Yu-Li hospital, respectively. Years 3, 4 and 5: Form composite index
 from preliminary statistical analysis, continue collecting DNAs and conduct pharmacogenetic
 studies using the DNA samples collected in this study.

 A better understanding of the nature and correlates of diabetic complications is crucial in
 the field's ongoing efforts in improving the care and welfare of schizophrenic patients. In
 addition, diabetes and X-syndrome associated with antipsychotics and/or schizophrenia also
 may represent a unique opportunity for understanding the pathogenesis and management of
 diabetes in general. It also could be potentially a particularly effective model for studying
 gene-environment interactions that are crucial for understanding most common human diseases.
 Ultimately, our goal is to develop genetic tests to predict therapeutic responses. As such,
 from the view of a national health economy, this study may prove that personalized medicine
 saves money.

 This study provides an opportunity for the researchers to be trained to extend statistical
 skills in estimating the putative role of genes in therapeutic responses. In addition, an
 understanding of the HbA1C, an interesting but debatable laboratory diagnostic test for
 diabetes, will be gained.

 References

 1. Kohen D. Diabetes mellitus and schizophrenia: historical perspective. Br.J.Psychiatry
 Suppl 2004; 47: S64-S66.

 2. Henderson DC, Cagliero E, Gray C et al. Clozapine, diabetes mellitus, weight gain, and
 lipid abnormalities: A five-year naturalistic study. Am.J.Psychiatry 2000; 157: 975-981.

 3. Timar, O., Sestier, F. and Levy, E. (2000). Metabolic Syndrome X: A Review. Canadian
 Journal of Cardiology, 16:779-789.

 4. Hagg S, Joelsson L, Mjorndal T, Spigset O, Oja G, Dahlqvist R. Prevalence of diabetes
 and impaired glucose tolerance in patients treated with clozapine compared with patients
 treated with conventional depot neuroleptic medications. J.Clin.Psychiatry 1998; 59:
 294-299.

 5. Genuth S, Alberti KG, Bennett P et al. Follow-up report on the diagnosis of diabetes
 mellitus. Diabetes Care 2003; 26: 3160-3167.

 6. Purcell S, Cherny SS, Sham PC. Genetic Power Calculator: design of linkage and
 association genetic mapping studies of complex traits. Bioinformatics. 2003; 19:
 149-150.
Inclusion Criteria:

 -  Inpatients and outpatients diagnosed with schizophrenia according to Diagnostic and
 Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria

 -  Treated either with typical or atypical antipsychotics

 Exclusion Criteria:

 -  Illegal drug use/abuse/dependence

 -  Alcoholism

 -  Pregnancy

 -  Clinical diagnosis of type I or type II diabetes before the onset of schizophrenia or
 treatment of schizophrenia (via chart review).