Jose de Leon

A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors.

A meta-analysis of worldwide studies, found by a 10-year literature follow-up and/or by searching PubMed, was performed. Forty-two studies across 20 nations consistently demonstrated an association between schizophrenia and current smoking (weighted average odds ratio, OR=5.9; 95% confidence interval, CI 4.9--5.7). In 32 male studies across 18 nations, the weighted average OR was 7.2 (CI, 6.1--8.3). In 25 female studies across 15 nations, the weighted average OR was 3.3 (CI, 3.0--3.6). The association between schizophrenia and current smoking remained after using severe mentally ill controls (18 studies across 9 countries, weighted average OR was 1.9, CI 1.7--2.1) and controlling for other variables (3 studies, adjusted ORs ranged 2-3). Heavy smoking (6 studies across 4 countries, ORs ranged 1.9--6.4) and high nicotine dependence were more frequent in smokers with schizophrenia versus the general population. There was no consistent evidence that heavy smoking or high nicotine dependence was more frequent in smokers with schizophrenia versus severe mentally ill controls. Cessation rates were lower in schizophrenia smokers versus the general population. Schizophrenia patients had a higher prevalence of ever smoking than the general population (9 studies across 6 countries, weighted average OR=3.1, CI 2.4--3.8) and than severe mentally ill patients (5 studies across 5 countries, OR=2.0, CI 1.6--2.4). Moreover, in two studies adjusting for confounders schizophrenia patients had an increased risk of starting daily smoking than controls. Thus, people who are going to develop schizophrenia have risk factors that make them more vulnerable to start smoking.

Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature.

Polydipsia among chronic psychiatric patients is poorly understood and underdiagnosed. It may have three stages: simple polydipsia, polydipsia with water intoxication, and physical complications. Epidemiological surveys have used staff reports and polyuria measures to identify polydipsic patients. Water intoxication has been screened by chart review, weight, or serum sodium data. According to these surveys, polydipsia, not explained by medically induced polyuria, may be present in more than 20% of chronic inpatients. Up to 5% of chronic inpatients had episodes of water intoxication although mild cases may have been missed. Single time point surveys show that 29% of polydipsic patients had presented water intoxication. Methodologically limited clinical studies suggest that polydipsia with water intoxication rather than simple polydipsia may be associated with poor prognosis in schizophrenia. Epidemiological surveys found polydipsia with water intoxication to be associated with chronicity, schizophrenia, smoking, some medications, male gender, and white race. New pathophysiological models need to elucidate these findings.

Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness.

The influence of cytochrome P450 2D6 (CYP2D6) genetic variability was examined in psychiatric inpatients by evaluating adverse drug events (ADEs), hospital stays, and total costs over a 1-year period in an extension of a previously published brief report. One hundred consecutive psychiatric patients from Eastern State Hospital in Lexington, Kentucky, were genotyped for CYP2D6 expression. ADEs were evaluated by a neurologic rating scale, modified Udvalg for Kliniske Undersogelser Side Effect Rating Scale, or chart review. Information on total hospitalization days and total costs were gathered for a 1-year period. Forty-five percent of the patients received medications that were primarily dependent on the CYP2D6 enzyme for their elimination. When the analysis was restricted to just those patients in each group receiving medication heavily dependent on the CYP2D6 enzyme, the following were observed: (1) a trend toward greater numbers of ADEs from medications as one moved from the group with ultrarapid CYP2D6 activity (UM) to the group with absent CYP2D6 activity (PM); (2) the cost of treating patients with extremes in CYP2D6 activity (UM and PM) was on average

The AmpliChip™ CYP450 Genotyping Test

4,000 to

Initiation of daily smoking and nicotine dependence in schizophrenia and mood disorders

6,000 per year greater than the cost of treating patients in the efficient metabolizer (EM) and intermediate metabolizer (IM) groups; and (3) total duration of hospital stay was more pronounced for those in CYP2D6 PM group. Variance of hospital stays and costs calculated from these preliminary data suggests that 1,500 to 2,000 patients must be evaluated over at least a 1-year period to determine whether the CYP2D6 genetic variation significantly alters the duration of hospital stay and costs.

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

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.

Comparison of Two CYP2D6 Genotyping Methods and Assessment of Genotype-Phenotype Relationships

This study replicates, using more refined methodology, the indications of prior studies that patients with schizophrenia show a greater frequency of tobacco smoking than patients with mood disorders. The sample included 66 patients with schizophrenia and 51 patients with a mood disorder who were admitted at a state hospital in Kentucky. The control group included 404 community subjects. Ever daily smoking was studied using logistic regression. Survival analyses of age of onset of daily smoking (AODS) were performed controlling for several variables including education level. Nicotine dependence was measured with a scale. The prevalence of ever and current daily smoking was respectively 92 and 83% for patients with schizophrenia, 78 and 65% for patients with mood disorders, and 47 and 26% for controls. Before the age of 20, the three populations appear to have a similar risk of smoking initiation. However, after the age of 20, the initiation rate of daily smoking for patients with schizophrenia was higher than in patients with a mood disorder, or controls. Among daily smokers, there were no differences in nicotine dependence between patients with schizophrenia and those with a mood disorder. Schizophrenia was associated with a greater probability of ever daily smoking than mood disorders and with higher rates of initiation of daily smoking after 20 years old.

AmpliChip CYP450 test: personalized medicine has arrived in psychiatry.

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 Kentuckys 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.

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

BACKGROUND There have been no published reports comparing the CYP450 GeneChip microarray assay with more standard methods of genetic testing. METHODS We collected 20-mL blood samples from 236 volunteers for DNA isolation and testing before each individual ingested 60 mg of dextromethorphan, and collected their urine. CYP2D6 alleles *3 to *7, *9, *17, and *41, and multiple CYP2D6 gene copies were tested by allele-specific PCR (AS-PCR), whereas alleles *2 to *4 and *6 to *11 were tested by the Affymetrix CYP450 GeneChip assay. Five of the CYP2D6 alleles (*3, *4, *6, *7, and *9) were tested by both AS-PCR and the CYP450 GeneChip assay in an independent and blinded fashion in 232 of the 236 healthy volunteers. The combined CYP2D6 genotype from both methods was used to divide the population into four subgroups, poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs), based on their relative function and ability to express the CYP2D6 gene. The urinary elimination of dextromethorphan was assessed in each of these CYP2D6 subgroups. RESULTS The CYP2D6*3, *4, *6, *7, and *9 alleles showed a high degree of concordance between the CYP450 GeneChip and AS-PCR methods (>99% concordance). The mean (SD) of the log[dextromethorphan metabolic ratio (MR)] in the four CYP2D6 subgroups was PM = 0.49 (0.38); IM = -1.24 (0.53); EM = -2.35 (0.61); and UM = -2.43 (0.38). CONCLUSIONS Oligonucleotide microarray technology is an efficient and reliable way to test for CYP2D6 gene variation based on five alleles compared by separate methods. The methodology is influenced by the quality and amount of DNA present. The log(dextromethorphan MR) is a highly variable index that appears to reflect the crude nature of the dextromethorphan MR as an indicator of CYP2D6 in vivo enzyme activity.

Schizophrenia and tobacco smoking: a replication study in another US psychiatric hospital

The US FDA has granted market approval for the first pharmacogenetic test using a DNA microarray, the AmpliChip CYP450, which genotypes cytochrome P450 (CYP)2D6 and CYP2C19. The test uses software to predict phenotypes and tests for 27 CYP2D6 alleles, including the deletions and duplications, and three CYP2C19 alleles. Other DNA microarray platforms are being developed for CYP testing, but none have been completely developed or approved by the FDA to date. The differences between an implementation of pharmacogenetic tests centered on the individual and implementation using a public health approach are discussed. In this review, the major obstacles to the wide implementation of pharmacogenetic testing in the clinical environment are summarized.The US FDA has granted market approval for the first pharmacogenetic test using a DNA microarray, the AmpliChip CYP450, which genotypes cytochrome P450 (CYP)2D6 and CYP2C19. The test uses software to predict phenotypes and tests for 27 CYP2D6 alleles, including the deletions and duplications, and three CYP2C19 alleles. Other DNA microarray platforms are being developed for CYP testing, but none have been completely developed or approved by the FDA to date. The differences between an implementation of pharmacogenetic tests centered on the individual and implementation using a public health approach are discussed. In this review, the major obstacles to the wide implementation of pharmacogenetic testing in the clinical environment are summarized.