Relaxin polymorphisms associated with metabolic disturbance in patients treated with antipsychotics.

People with schizophrenia have an increased risk of metabolic syndrome, with consequent elevated morbidity and mortality, largely due to cardiovascular disease. Metabolic disorders comprise obesity, dyslipidemia and elevated levels of triglycerides, hypertension, and disturbed insulin and glucose metabolism. The elevated risk of metabolic syndrome in individuals suffering from schizophrenia is believed to be multifactorial, related to a genetic predisposition, lifestyle characteristics and treatment with antipsychotic medications. Relaxin 3 (RLN3, also known as INSL7) is a recently identified member of the insulin/relaxin superfamily that plays a role in the regulation of appetite and body weight control. RLN3 stimulates relaxin-3 receptor 1 (relaxin/insulin-like family peptide receptor 3, RXFP3) and relaxin receptor 2 (relaxin/insulin-like family peptide receptor 4, RXFP4). We have investigated the role of ten polymorphisms in these genes (RLN3 rs12327666, rs1982632, and rs7249702, RLN3R1 rs42868, rs6861957, rs7702361, and rs35399, and RLN3R2 rs11264422, rs1018730 and rs12124383) in the occurrence of metabolic syndrome phenotypes (obesity, diabetes, hypercholesterolemia, hypertrigyceridemia, and hypertension) in a cross-sectional cohort of 419 US Caucasian patients treated with antipsychotic drugs. We found several associations between relaxin polymorphisms and hypecholesterolemia, obesity and diabetes, suggesting a role for the relaxin/insulin pathway in the development of metabolic disturbance observed in patients treated with antipsychotics.

Validation of candidate genes associated with cardiovascular risk factors in psychiatric patients.

The purpose of this study was to identify genetic variants predictive of cardiovascular risk factors in a psychiatric population treated with second generation antipsychotics (SGA). 924 patients undergoing treatment for severe mental illness at four US hospitals were genotyped at 1.2 million single nucleotide polymorphisms. Patients were assessed for fasting serum lipid (low density lipoprotein cholesterol [LDLc], high density lipoprotein cholesterol [HDLc], and triglycerides) and obesity phenotypes (body mass index, BMI). Thirteen candidate genes from previous studies of the same phenotypes in non-psychiatric populations were tested for association. We confirmed 8 of the 13 candidate genes at the 95% confidence level. An increased genetic effect size was observed for triglycerides in the psychiatric population compared to that in the cardiovascular population.

Lack of replication of the association of low serum cholesterol and attempted suicide in another country raises more questions.

BACKGROUND: In 2 Spanish case-control studies, low cholesterol levels in males were consistently associated with suicide attempts. METHODS: This US study tried to replicate the association between low cholesterol levels and suicide attempts, using a case-control design to study all patients admitted to Eastern State Hospital in Lexington, Kentucky, during a 1-year period. Psychiatric patients who had currently attempted suicide were studied as cases, and psychiatric patients who had not currently attempted suicide served as controls. A fasting serum total cholesterol <160 mg/dL was considered a possible risk factor for suicide. Logistic regression provided an adjusted estimate of the univariate odds ratios (ORs) for confounding factors. RESULTS: There were 193 current suicide attempters (cases) and 1091 non-current suicide attempters (controls). In the total sample logistic regression model, low cholesterol levels were significantly associated with lower risk of current suicide attempt (OR, 0.60; confidence interval (CI), 0.39 to 0.92) after adjusting for confounding variables. After sex stratification, low cholesterol levels were significant only among men (OR, 0.47; CI, 0.26 to 0.86). This US study did not replicate our prior Spanish findings; to the contrary, low cholesterol levels were not associated with increased suicide risk but with a decreased risk in US men. CONCLUSIONS: It is possible cholesterol abnormalities and low body mass index may be markers of suicide risk, particularly in some male patients.

Association study of serotonergic gene variants with antipsychotic-induced adverse reactions.

INTRODUCTION: The products of the serotonin receptor genes are important targets for conventional and atypical antipsychotics, and may be relevant for antipsychotic activity and associated adverse reactions. It has been shown that the high potency at 5-HT2 receptors may also be associated with the production of moderate extrapyramidal side effects (EPS). In addition, serotonin neurotransmitter systems in the central nervous system play an important role in eating behaviours, and are involved in the symptomatology related to the metabolic syndrome, including obesity, diabetes and hyperlipidemia. MATERIALS AND METHODS: This study was designed to investigate the hypothesis that serotonin pathway genes play a part in mediating antipsychotic-induced adverse reactions, including EPS, tardive dyskinesia, obesity and diabetes. Polymorphisms in the 5-HT2A (102 (T/C), His452Tyr), 5-HT2C (Cys23Ser, -759 (C/T), -995 (G/A), TPH2 (-366 (C/T), -8933 (A/G) and 5-HTT (LPR, -15370 (A/G)) genes were investigated in a cohort of 427 US Caucasian patients undergoing antipsychotic treatment, using automated genotyping techniques. RESULTS: 5-HTT (LPR) and 5-HT2A (102 (T/C) polymorphisms were found to be associated with BMI (P=0.05 and 0.005, respectively). The genotype distribution of the TPH2-366 (T/C) polymorphism was found to be significantly associated with the presence of diabetes (P=0.01). A trend towards an association (P=0.07) between the 5-HT2C Cys23Ser polymorphism and tardive dyskinesia was found when age, duration of treatment, dose and sex were considered. Genotype distributions of the 5-HT2C -995 (G/A), 5-HT2C -759 (C/T) and 5-HT2A His452Tyr polymorphisms differed among patients presenting EPS and those without (P=0.08, 0.06 and 0.08, respectively). No other statistically significant associations were observed. CONCLUSION: Serotonergic polymorphism may play a moderate role in the development of side effects associated with antipsychotic treatment.

Tobacco smoking behaviors in bipolar disorder: a comparison of the general population, schizophrenia, and major depression.

OBJECTIVES: This study compared the prevalence of tobacco smoking behaviors in patients with bipolar disorder with normal and psychiatric (schizophrenia and major depression) controls. The main goal was to establish that bipolar patients smoke more than normal controls. Differences with psychiatric controls were explored. METHODS: Samples of 424 patients (99 bipolar, 258 schizophrenia and 67 major depression) and 402 volunteer controls were collected in Central Kentucky. Smoking data for Kentucky's general population were available. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to establish the strength of associations. Logistic regression was used to adjust ORs for confounding variables. RESULTS: Using epidemiological definitions of smoking behaviors and the general population as controls provided bipolar disorder unadjusted ORs of 5.0 (95% CI: 3.3-7.8) for current cigarette smoking, 2.6 (95% CI: 1.7-4.4) for ever cigarette smoking, and 0.13 (95% CI: 0.03-0.24) for smoking cessation. Using a clinical definition and volunteers as controls provided respective bipolar disorder adjusted ORs of 7.3 (95% CI: 4.3-12.4), 4.0 (95% CI: 2.4-6.7), and 0.15 (95% CI: 0.06-0.36). Prevalences of current daily smoking for patients with major depression, bipolar disorder, and schizophrenia were 57%, 66%, and 74%, respectively. CONCLUSIONS: Bipolar disorder was associated with significantly higher prevalences of tobacco smoking behaviors compared with the general population or volunteer controls, independently of the definition used. It is possible that smoking behaviors in bipolar disorder may have intermediate prevalences between major depression and schizophrenia, but larger samples or a combination of multiple studies (meta-analysis) will be needed to establish whether this hypothesis is correct.

DNA microarray technology in the clinical environment: the AmpliChip CYP450 test for CYP2D6 and CYP2C19 genotyping.

INTRODUCTION: An important technological advance in genetic testing is the DNA microarray, which allows for the simultaneous testing of thousands of DNA sequences. The AmpliChip CYP450 Test employs this microarray technology for cytochrome P450 (CYP) 2D6 and CYP2C19 genotyping. Isoenzymes encoded by these genes are responsible for the metabolism of many widely prescribed drugs. The objectives of this study were to identify CYP2D6 and CYP2C19 alleles and phenotypes in a psychiatric patient population in Kentucky, and to describe practical issues associated with DNA microarray technology. METHODS: A total of 4,532 psychiatric patients were recruited from three state hospitals in Kentucky. Whole blood, buccal swabs, or saliva samples were genotyped with the AmpliChip CYP450 Test to derive a predicted phenotype. RESULTS: In this cohort, the overall prevalence of CYP2D6 poor metabolizers was 7.6% (95% CI 7%, 8.3%), 8.2% in the Caucasians (95% CI 7.4%, 9.%) and 1.8% in the African Americans (95% CI 0.9%, 3.5%). The overall prevalence of CYP2D6 ultrarapid metabolizers was 1.5% (95% CI 1.2%, 1.9%), 1.5% in the Caucasians (95% CI 1.1%, 1.9%) and 2.0% in the African Americans (95% CI 1.1%, 3.7%). The overall prevalence of CYP2C19 poor metabolizers was 2.0% (95% CI 1.8%, 2.7%), 2.2% in Caucasians (95% CI 1.6%, 2.5%) and 4.0% in African Americans (95% CI 2.6%, 6.1%). CONCLUSION: We also propose a numeric system for expression of CYP2D6 and CYP2C19 enzyme activity to aid clinicians in determining treatment strategy for patients receiving therapeutics that are metabolized by the CYP2D6 or CYP2C19 gene products.

The association between schizophrenia and smoking: unexplained by either the illness or the prodromal period.

Age at onset of daily smoking (AODS) was compared in schizophrenia (N=258), mood disorders (N=166) and controls (N=381) to replicate a different AODS in schizophrenia patients, and to confirm that this is not necessarily explained by the prodromal period. The cumulative hazard curves for schizophrenia, mood disorders and controls were significantly different (p<0.001), even after controlling for gender and education (p<0.001). After excluding the patients who started smoking within 5 years of starting psychiatric medication, the cumulative hazard curve for schizophrenia patients was significantly different from that for ever-smoker controls (p=0.002), even after adjusting for gender and education (p=0.03).

An investigation of the alpha1A-adrenergic receptor gene and antipsychotic-induced side-effects.

Antipsychotic treatment is hampered by the induction of side-effects such as tardive dyskinesia (TD), weight gain, sedation and extrapyramidal side-effects (EPS). Identification of the factors related to their development would facilitate their avoidance and the improvement of antipsychotic treatment. It has been hypothesised that genetic variants in drug targeted receptors may contribute to the development of side-effects. In this study, we have investigated the possible influence of genetic variants (-563-C/T, -4155-G/C and -4884-A/G) of the alpha(1A)-adrenergic receptor, an important target of atypical antipsychotic drugs, and development of side-effects after antipsychotic medication in a sample of N = 427 US Caucasian patients. We found several marginal associations (p < 0.05) between alpha(1A)-adrenergic genetic variants and antipsychotic-induced side-effects which did not reach statistical significance after corrections for multiple analyses. These results do not support a major role of alpha(1A)-adrenergic genetic variants in obesity and other side-effects observed after prolonged treatment with antipsychotic medications.

A clinical study of the association of antipsychotics with hyperlipidemia.

Following a prior Kentucky clinical practice study on metabolic syndrome, serum glucose and lipid levels were used in a new sample to determine whether after correcting for confounding factors, olanzapine hyperlipidemia risk may be higher under naturalistic non-randomized treatment. Serum glucose, total cholesterol, HDL cholesterol and triglyceride levels were assessed in 360 patients with severe mental illnesses. The initial goal was to focus on olanzapine lipid profiles, but visual data inspection indicated that quetiapine needed attention as well. Patients were divided into 3 groups: 57 (16%) on olanzapine, 105 (29%) on quetiapine, and 198 (55%) on other antipsychotics (risperidone, ziprasidone, aripiprazole or typicals). HDL and glucose levels were not significantly different across the three antipsychotic groups. When compared with other antipsychotics, olanzapine patients had a borderline significantly higher mean total serum cholesterol level (178 vs. 192 mg/dl, p=0.06) and mean triglyceride level (172 vs. 202 mg/dl, p=0.06). These differences became significant (p=0.006 and 0.03) after correcting for confounders. Quetiapine appeared overprescribed in patients with metabolic syndrome complications. When compared with other antipsychotics, quetiapine patients had a significantly higher mean total serum cholesterol level (178 vs. 194 mg/dl, p=0.004) and mean triglyceride level (172 vs. 225 mg/dl, p<0.001). These differences were significant (p=0.02 and <0.001) after correcting for confounders. This study is consistent with emerging literature that suggests that some antipsychotics may have direct and immediate effects on lipid levels beyond obesity effects. The effect sizes of olanzapine and quetiapine on hyperlipidemia were about 0.40 in this naturalistic study.

A poor metabolizer for cytochromes P450 2D6 and 2C19: a case report on antidepressant treatment.

Scientific literature has never described a poor metabolizer for both the cytochrome P450 (CYP) 2D6 and the CYP 2C19. They are expected to be rare (<1% in different ethnic groups) and prone to adverse drug reactions with many antidepressants. In an ongoing pharmacogenetic study, after genotyping 1,576 subjects in three Kentucky state hospitals we have found one poor metabolizer for both CYP 2D6 and CYP 2C19, which corresponds to a prevalence of 0.06% (95% CI 0.01 to 0.36). The naturalistic antidepressant treatment of this poor metabolizer for both enzymes is described in this article. As genotyping reaches clinical practice, it will be interesting to prospectively establish whether mirtazapine is a reasonable choice as an antidepressant for these patients, as the data and this case suggest.

The AmpliChip CYP450 genotyping test: Integrating a new clinical tool.

The AmpliChip CYP450 Test, which analyzes patient genotypes for cytochrome P450 (CYP) genes CYP2D6 and CYP2C19, is a major step toward introducing personalized prescribing into the clinical environment. Interest in adverse drug reactions (ADRs), the genetic revolution, and pharmacogenetics have converged with the introduction of this tool, which is anticipated to be the first of a new wave of such tools to follow over the next 5-10 years. The AmpliChip CYP450 Test is based on microarray technology, which combines hybridization in precise locations on a glass microarray and a fluorescent labeling system. It classifies individuals into two CYP2C19 phenotypes (extensive metabolizers [EMs] and poor metabolizers [PMs]) by testing three alleles, and into four CYP2D6 phenotypes (ultrarapid metabolizers [UMs], EMs, intermediate metabolizers [IMs], and PMs) by testing 27 alleles, including seven duplications. CYP2D6 is a metabolic enzyme with four activity levels (or phenotypes): UMs with unusually high activity; normal subjects, known as EMs; IMs with low activity; and PMs with no CYP2D6 activity (7% of Caucasians and 1-3% in other ethnic groups). Levels of evidence for the association between CYP2D6 PMs and ADRs are relatively reasonable and include systematic reviews of case-control studies of some typical antipsychotics and tricyclic antidepressants (TCAs). Evidence for other phenotypes is considerably more limited. The CYP2D6 PM phenotype may be associated with risperidone ADRs and discontinuation due to ADRs. Venlafaxine, aripiprazole, duloxetine, and atomoxetine are newer drugs metabolized by CYP2D6 but studies of the clinical relevance of CYP2D6 genotypes are needed. Non-psychiatric drugs metabolized by CYP2D6 include metoprolol, tamoxifen, and codeine-like drugs. CYP2C19 PMs (3-4% of Caucasians and African Americans, and 14-21% of Asians) may require dose adjustment for some TCAs, moclobemide, and citalopram. Other drugs metabolized by CYP2C19 are diazepam and omeprazole. The future of pharmacogenetics depends on the ability to overcome serious obstacles, including the difficulties of conducting and publishing studies in light of resistance from grant agencies, pharmaceutical companies, and some scientific reviewers. Assuming more studies are published, pharmacogenetic clinical applications may be compromised by economic factors and the lack of physician education. The combination of a US FDA-approved test, such as the AmpliChip CYP450 Test, and an FDA definition of CYP2D6 as a 'valid biomarker' makes CYP2D6 genotyping a prime candidate to be the first successful pharmacogenetic test in the clinical environment. One can use microarray technology to test for hundreds of single nucleotide polymorphisms (SNPs) but, taking into account the difficulties for single gene approaches such as CYP2D6, it is unlikely that very complex pharmacogenetic approaches will reach the clinical market in the next 5-10 years.

Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer.

Codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. Codeine is a much weaker agonist at mu opioid receptors than morphine. Therefore, codeine analgesia is highly dependent on CYP2D6 activity. Large prospective studies in the clinical environment do not exist, but it appears reasonable to avoid codeine use in CYP2D6 poor metabolizers (PMs). CYP2D6 metabolizes other opioid analgesics, including tramadol, dihydrocodeine, oxycodone and hydrocodone, although they have been less systematically studied. It is unclear whether these other pro-drugs may be as completely dependent on CYP2D6 for their analgesia as codeine. We describe a patient identified as a CYP2D6 PM with a history of problems with opioid analgesics. The patient was an 85-year-old female Caucasian who had hip surgery. The patient had a long-standing intolerance to codeine. In her first admission, she couldn't tolerate the regimen of oxycodone combined with tramadol prns (as needed). She was genotyped as a CYP2D6 PM and after the information was provided to the treating physician in her second admission, she seemed to have a better response to hydrocodone. Large case-control naturalistic studies followed by randomized trials in patients taking opioid analgesics may be needed to definitively establish that CYP2D6 genotyping has clinical relevance in the use of several opioid analgesics.

Polymorphic variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 receptors and their association with tardive dyskinesia in severe mental illness.

This study tested the association between tardive dyskinesia (TD) and polymorphic variations in (a) 2 cytochrome P450 (CYP) genes (CYP2D6 or CYP3A5), (b) 2 DRD2 variants (Ser311Cys and -141C Ins/del) and the Ser9Gly DRD3 variants, (c) 2 glutathione S-transferases (GSTT1 and GSTM1), and (d) variations in the PgP gene, MDR1. The study sample included 516 severely mentally ill patients from Central Kentucky facilities. Logistic regression models that included clinical variables associated with TD were developed. Gene variants were added to these clinical models. The total sample included 31% (162/516) with TD where 30% (49/162) of those had severe TD. Polymorphisms in DRD2, MDR1, and GSTT1 were never significant. Two gene variants appeared to be significant after adding them to the clinical regression models: (1) Ser9Gly DRD3 polymorphism was associated with severe TD (odds ratio for patients with 1 mutant allele when compared with individuals with 2 wild types was 2.5, 95% confidence interval 1.1-5.6, whereas the odds ratio for patients with 2 mutant alleles when compared with individuals with 1 mutant was 2.8, 95% confidence interval 1.0-7.4), and (2) GSTM1 absence was associated with TD (odds ratio 1.7, 95% confidence interval 1.2-2.4) particularly in white women. The CYP2D6 and CYP3A5 absence showed potential for significant associations in larger samples, particularly in white men. New studies need to replicate whether these or other genes could be used conjointly with clinical variables to identify subjects at risk for TD in clinical settings.

Obesity and associated complications in patients with severe mental illnesses: a cross-sectional survey.

BACKGROUND: This naturalistic cross-sectional survey of patients with severe mental illnesses explores the association between important variables and obesity, extreme obesity, diabetes mellitus type 2, hypertension, and hyperlipidemia in the clinical environment. METHOD: Weight and height were obtained from 560 patients with severe mental illnesses (including DSM-IV schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder) at central Kentucky inpatient and outpatient facilities to estimate their body mass index (BMI). Chart diagnoses of diabetes mellitus, hypertension, and hyperlipidemia were obtained. RESULTS: When comparing the patients with severe mental illnesses with Kentucky adults from the general population, the odds ratio (OR) of obesity (BMI > or = 30 kg/m(2)) was 2.6 (95% confidence interval [CI] = 2.2 to 3.0), and the OR of diabetes mellitus was 2.9 (95% CI = 2.3 to 3.6). Female gender, African American race, early start of psychiatric medication, and long psychiatric medication duration were significantly associated with obesity. Current alcohol and nicotine use exhibited significant ORs of obesity lower than 1, particularly in males. Obesity was closely associated with hypertension, type 2 diabetes mellitus, and hyperlipidemia. These complications were closely associated with each other and may indicate a further progression of obesity after aging. CONCLUSIONS: These results suggest a complex pattern of variables that may influence the development of obesity and its complications in patients with severe mental illnesses, but they need replication. The major factors associated with obesity appear to be a long-term illness or treatment duration and substance use. The former may be more important in females, while the latter may be more important in males. Clinical diagnoses (schizophrenic or mood disorders) or current treatment did not appear to be fundamental factors.

The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation.

OBJECTIVE: The cytochrome P450 2D6 (CYP2D6) enzyme metabolizes risperidone. CYP2D6 poor metabolizers have no CYP2D6 activity (7% of whites and 1%-2% of other races). This study tested whether the CYP2D6 poor metabolizer phenotype was associated with adverse drug reactions (ADRs) and discontinuation due to ADRs. METHOD: Adult inpatients and outpatients were recruited from July 2000 to March 2003 including (1) 325 who were stabilized on risperidone therapy and classified as either expressing moderate-to-marked ADRs (22%, 73/325) or not (78%, 252/325) and (2) 212 who discontinued risperidone and were classified as discontinued due to ADRs (38%, 81/212) or for other reasons (62%, 131/212). Genetic tests were performed by allele-specific polymerase chain reaction and/or by the AmpliChip CYP450 microarray system for up to 34 separate CYP2D6 alleles. Two logistic regression models with dependent variables (moderate-to-marked ADRs while taking risperidone and risperidone discontinuation due to ADRs) were evaluated with respect to the CYP2D6 phenotype. RESULTS: The odds ratios (ORs) and 95% confidence intervals (CIs) for the CYP2D6 poor metabolizer phenotype in the univariate analyses and after correcting for clinical variables were (1) OR = 3.1 (CI = 1.4 to 7.0) and 3.4 (CI = 1.5 to 8.0) for moderate-to-marked ADRs on risperidone and (2) OR = 3.0 (CI = 0.85 to 10.6) and 6.0 (CI = 1.4 to 25.4) for discontinuation due to ADRs. CONCLUSIONS: The CYP2D6 poor metabolizer phenotype appears to be associated with risperidone ADRs and discontinuation due to ADRs; however, this finding requires further study in larger patient populations. The CYP3A5 and p-glycoprotein exon 21 and 26 genotypes were not significantly associated with risperidone response.

Variables associated with alcohol, drug, and daily smoking cessation in patients with severe mental illnesses.

BACKGROUND: Co-occurrence of substance use disorders and severe mental illnesses (SMIs) is a major U.S. public health issue, although the role of tobacco is usually neglected. This study explored variables associated with alcohol, drug, and smoking cessation in a naturalistic setting. METHOD: Logistic regression was used to study variables associated with cessation of alcohol and drug use disorder and daily smoking in 560 SMI inpatients and outpatients from central Kentucky facilities. Patients with a lifetime history of alcohol or drug use disorder were considered to be in cessation if they had not suffered from abuse or dependence during the last year. Alcohol and drug use disorder diagnoses were determined using the Clinician Rating of Alcohol and Drug Use Disorder. Patients were recruited from July 2000 to March 2003. RESULTS: The cessation rates for alcohol and drug use disorders were, respectively, 44% (95% CI = 39% to 49%) and 46% (CI = 40% to 51%); these were higher than the daily cigarette smoking cessation rate of 10% (CI = 7% to 13%). Drug use disorders (p < or = .02), outpatient status (p < .001), and having a medical complication of obesity (diabetes mellitus, hypertension, or hyperlipidemia; p < .001) were significantly associated with alcohol cessation. Alcohol use disorder (p < .001), starting treatment with psychiatric medications after 33 years of age (p < .001), taking these medications for 14 years or more (p = .02), schizophrenia diagnosis (p < .001), outpatient status (p = .03), and obesity (p = .04) were significantly associated with drug cessation. Cessation of daily smoking was associated with hypertension (p = .02), late start of treatment with psychiatric medications (> 33 years old; p = .01), and lack of lifetime drug abuse (p < .001). CONCLUSIONS: These results are limited by the cross-sectional and naturalistic design but suggest that public health experts, researchers, and clinicians need to mindfully address smoking cessation in patients with SMIs. Clinicians may want to consider that medical illnesses may motivate patients with SMIs to stop substance abuse and that patients with SMIs who abuse both alcohol and drugs rarely stop abusing just one of them.