Karin Hedenmalm

Glucose intolerance with atypical antipsychotics

AbstractBackground: Previous studies have suggested that the atypical antipsychotics clozapine and olanzapine may be associated with an increased risk of glucose intolerance and diabetes mellitus. Early studies have also suggested an association between use of conventional antipsychotics and the development of glucose intolerance. Objective: To examine quantitatively the association between glucose intolerance including diabetes mellitus and the use of the atypical antipsychotics clozapine, olanzapine or risperidone, and to identify possible risk factors for the development of glucose intolerance during treatment with these drugs. Methods: All reports suggestive of glucose intolerance for clozapine, olanzapine and risperidone were identified in the WHO database for adverse drug reactions. In the analyses of possible risk factors for glucose intolerance all other reports of adverse drug reactions for clozapine, olanzapine and risperidone were used as reference. Using the Bayesian Confidence Propagation Neural Network method, the strengths of the associations over time between glucose intolerance and the use of these drugs were analysed. For comparison, the strengths of the associations between glucose intolerance and the use of the conventional antipsychotics haloperidol and chlorpromazine were also analysed. Results: Clozapine, olanzapine and risperidone were significantly associated with glucose intolerance. In contrast, chlorpromazine and haloperidol were not associated with glucose intolerance. For clozapine, olanzapine and risperidone grouped together, the following potential risk factors for glucose intolerance were identified: an underlying diabetic condition (odds ratio [OR] 10.22, 95% CI 8.20–12.73), an increase in weight (OR 2.36, 95% CI 1.76–3.17), male gender (OR 1.27, 95% CI 1.11–1.47), and concomitant use of valproic acid (OR 1.97, 95% CI 1.61–2.40), selective serotonin reuptake inhibitors (OR 1.63, 95% CI 1.33–1.99) or buspirone (OR 2.24, 95% CI 1.33–3.77). Conclusion: Treatment with clozapine, olanzapine or risperidone appears to be associated with an increased risk of glucose intolerance.

Hyponatraemia and the Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Induced by Psychotropic Drugs

SummaryThe use of psychotropic drugs has been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a number of case reports. SIADH is characterised by the sustained release of antidiuretic hormone (ADH) from the posterior pituitary. The patients have a reduced ability to excrete diluted urine, ingested fluid is retained, and the extracellular fluid expands and becomes hypo-osmolar. The cardinal signs are hyponatraemia, serum hypoosmolality and a less than maximally diluted urine. Common symptoms include weakness, lethargy, headache, anorexia and weight gain. These symptoms may be followed by confusion, convulsions, coma and death. The early symptoms are vague and nonspecific, and they may even mimic the symptoms of the psychiatric disorder itself.For antidepressants, the risk of SIADH seems to be highest during the first weeks of treatment. For antipsychotics, the risk seems to be more spread out in time. The causative role of the drug may sometimes be difficult to estimate, as even drug-free psychiatric patients, mostly those with schizophrenia, develop SIADH on the basis of psychogenic polydipsia. Smoking is another factor associated with the development of SIADH, and the risk may also increase with age.The acute treatment of SIADH induced by a psychotropic drug includes discontinuation of the drug as well as restriction of fluid intake. In cases with significant clinical symptoms, infusion of sodium chloride is recommended. After the acute management, it is useful to evaluate the causative role of the drug by performing a water loading test and/or drug rechallenge. If continued treatment with an antidepressant or antipsychotic is indicated, a drug with a different pharmacological profile should be chosen, and the serum sodium levels should be monitored closely. If treatment with the drug that caused SIADH must be continued, concomitant treatment with demeclocycline may reduce the tendency of hyponatraemia.

Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme, and serotonin and dopamine transporter and receptor polymorphisms.

Introduction: Extrapyramidal symptoms (EPS) are rare adverse drug reactions to selective serotonin reuptake inhibitors (SSRIs). This study aimed to investigate the potential risk factors for EPS associated with SSRIs including polymorphisms of cytochrome P-450 isoenzymes, and serotonin and dopamine transporters and receptors. Methods: All spontaneous adverse drug reaction reports received by the Swedish Medical Products Agency until December 1999 that were coded with EPS and judged to be at least possibly related to SSRI treatment were included in the study. Reporting physicians received a form for collection of relevant information including current and previous use of SSRIs and antipsychotics, alcohol or substance abuse, central nervous system damage, a history of epilepsy or EPS, and a family history of Parkinson disease. A blood sample was also requested for genotyping of selected cytochrome P-450, and serotonin and dopamine transporter and receptor mutations. Results: A total of 64 cases of EPS were reported. Twenty-eight forms (46%) were returned, and 20 blood samples were obtained. Identified potential risk factors included age of 65 years or older and the presence of the A1 allele of the D2 dopamine receptor gene (DRD2) Taq1A polymorphism (relative risk, 2.4; 95% confidence interval, 1.2-4.5 vs literature controls). No relationship was apparent for sex, drug dose, or other genetic polymorphisms. At least 1 additional potential risk factor for EPS, such as a history of central nervous system damage, alcohol or substance abuse, epilepsy, Parkinson disease, previous or current exposure to antipsychotic drugs, concomitant treatment with other antidopaminergic or serotonergic agents, or a history of EPS, was found in 93% of the cases. Conclusion: The risk of EPS with SSRIs seems to increase with advanced age and with the presence of the A1 allele of DRD2 Taq1A polymorphism. Because of the small sample size of our study and the use of historical controls rather than patients who did not experience EPS during SSRIs treatment, the DRD2 finding is preliminary and needs to be replicated in other studies before firm conclusions can be drawn. At least 1 additional potential risk factor was found in almost all cases.

Muscle toxicity with statins.

Statins rarely cause serious muscle toxicity and rhabdomyolysis. The aim of our investigation was to identify and quantify potential risk factors for statin‐induced rhabdomyolysis.

Risk factors for venous thromboembolism in pre-and postmenopausal women

INTRODUCTION Hemostasis in women is affected by changes of estrogen levels. The role of endogenous estrogens on risk of venous thromboembolism (VTE) remains unclear. The aim of this study was to investigate the importance of acquired and genetic risk factors for VTE in pre-and postmenopausal women. METHOD In a nationwide case-control study we included as cases 1470 women, 18 to 64years of age with a first time VTE. The 1590 controls were randomly selected and matched by age to the cases. Information on risk factors was obtained by interviews and DNA-analyses. We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS The ORs were generally of similar magnitude in pre- and postmenopausal women. The highest risk was for the combination of surgery and cast (adjusted OR 54.12, 95% CI 16.62-176.19) in postmenopausal women. The adjusted OR for use of menopausal hormone therapy was 3.73 (95% CI 1.86-7.50) in premenopausal and 2.22 (95% CI 1.54-3.19) in postmenopausal women. Overweight was linked to an increased risk and exercise to a decreased risk, regardless of menopausal status. CONCLUSION Menopausal status had only minor influence on the risk levels. Acquired transient risk factors conveyed the highest risks for VTE.

Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome P450 2D6 gene.

AbstractObjectiveThis study aimed to investigate the importance of cytochrome P450 enzymes for the reported interaction between tramadol and warfarin.Materials and methodsCases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19.ResultsSeven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition.ConclusionThe liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity.

Mortality from venous thromboembolism in young Swedish women and its relation to pregnancy and use of oral contraceptives - : an approach to specifying rates

AbstractBackground: Pregnancy and use of combined oral contraceptives (COCs) are major risk factors for venous thromboembolism (VTE) in young women and we wanted to obtain accurate VTE mortality data overall, by age, associated with the use of COCs and pregnancy. Methods: From the Swedish Cause of Death Register (CDR) we identified women aged 15–44 with VTE as underlying or contributory cause of death during the period 1990–1999. We scrutinized medical records and included verified VTE cases without active cancer or terminal disease. Pregnancy statistics and COC utilization data were obtained from national databases. Results: Of the 120 cases included, 9 (8%) were associated with pregnancy and 28 (23%) with current COC use. The overall refined VTE mortality rate in current COC users was 7.5[4.7; 10.3] per million user-years and the corresponding pregnancy-related rate was 8.9[4.1;17.0] per million pregnancy years, rates increasing with age. For ages 15–24, the rate was significantly higher in current COC users than in non-pregnant women not using COCs: 6.0[3.1; 10.5] per million user-years vs. 0.3[0.0; 1.2] per million woman years. Underlying cause mortality data included 82% of VTE deaths associated with COCs, and 56% of maternal deaths had a pregnancy-related code. Conclusion: Mortality figures from VTE associated with the use of COCs and pregnancy were similar. COC use had an important impact on the total VTE mortality in the youngest age group. Standard mortality statistics do not allow accurate monitoring of VTE mortality in young women due to missing data, misdiagnoses and coding rules.

Antipsychotics associated with pulmonary embolism in a Swedish medicolegal autopsy series.

To determine the association between fatal pulmonary embolism and use of antipsychotic drugs in a Swedish medicolegal autopsy series. Persons aged 18–65 years and subjected to a medicolegal autopsy in 1992–2005 were selected. On the basis of external cause of death, determined by the forensic pathologist, unnatural deaths (including fatal intoxications) were excluded and participants in whom pulmonary embolism was the cause of death were identified. Use of antipsychotics was based on the results of the postmortem analyses and categorized as use of high-potency first-generation antipsychotics, low-potency first-generation antipsychotics, second-generation antipsychotics or no use of antipsychotics. Logistic regression analyses were performed. Use of antipsychotics was verified in 538 of the 14 439 included participants. Pulmonary embolism was recorded as the cause of death in 279 participants and 33 of these used antipsychotics. Use of low-potency first-generation antipsychotics and second-generation antipsychotics was significantly associated with fatal pulmonary embolism (adjusted odds ratio: 2.39; 95% confidence interval: 1.46–3.92 and 6.91; 95% confidence interval: 3.95–12.10, respectively). Out of 26 participants classified as high-potency first-generation antipsychotic drug users, none had pulmonary embolism as the cause of death. Pulmonary embolism was overrepresented among medicolegal autopsy cases identified as users of low-potency first-generation and second-generation antipsychotics.

Pulmonary embolism associated with combined oral contraceptives : reporting incidences and potential risk factors for a fatal outcome.

Background.  It is established that combined oral contraceptive (COC) treatment increases the risk of a pulmonary embolism (PE), but specific risk factors for a fatal outcome from a PE remain to be determined. This study aimed to identify such risk factors, and to calculate the reporting rates of fatal and non‐fatal PE.

Urinary excretion of codeine, ethylmorphine, and their metabolites : Relation to the CYP2D6 activity

The formation of morphine from codeine and ethylmorphine is mainly mediated by the polymorphic enzyme CYP2D6. The objective of this study was to investigate whether CYP2D6 poor metabolizers (PM) and CYP2D6 extensive metabolizers (EM) would respond differently during testing for opiate drugs of abuse in urine after intake of these drugs. Five PM and five EM of dextromethorphan were administered single oral doses of codeine (25 mg) and ethylmorphine (25 mg), and the urinary excretion of parent compounds and selected metabolites was observed for 72 hours. Analysis was performed with GC-MS after hydrolysis of the glucuronide conjugates. Selected urine samples were screened for the presence of opiates by the Abbott ADx immunoassay method. The results from one PM and one EM were excluded because of technical analytical problems. EM excreted significantly more morphine than PM after intake of both codeine (6.5% vs. 1.1% of the dose; p < 0.05) and ethylmorphine (11.0% vs. 3.0% of the dose; p < 0.05). Screening results were positive significantly longer for EM than for PM after codeine intake (mean, 33 hours vs. 17 hours; p < 0.05), and the same trend, albeit nonsignificantly, was noted for ethylmorphine (mean, 33 hours vs. 24 hours). Regardless of CYP2D6 phenotype, significantly more morphine was formed after intake of ethylmorphine than after intake of codeine (7.0% vs. 3.8% of the dose; p < 0.05). There were high correlations between dextromethorphan metabolic ratios and the ratios of codeine to morphine, ethylmorphine to morphine, norcodeine to normorphine, and norethylmorphine to normorphine (r = 0.80 to 0.92; p = 0.030 to 0.001). Although this study should be interpreted with caution because of the few subjects included and the single-dose design, it demonstrates that the CYP2D6 phenotype clearly affects the results when testing for opiates in urine after intake of codeine and ethylmorphine.