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Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

Background: There is limited knowledge on the prevalence of disease in total populations. Such studies have historically been difficult to conduct but the development of health data registers has facilitated large-scale studies on recorded diagnoses in entire regions. The aim of this study was to analyze the prevalence of diagnosis of six common diseases in the Swedish capital region.Methods: The study population included all living persons who resided in Stockholm County, Sweden, on December 31st 2011 (N=2 093 717). Information on all consultations between 2007 and 2011 was obtained from primary health care, specialist outpatient care and inpatient care. Prevalence was defined as the proportion of individuals with a recorded diagnosis of diabetes, depression, anxiety disorders, hypertension, asthma and chronic obstructive pulmonary disease during the five year period, respectively. Analyses were done by age and gender.Results: Hypertension had the highest five-year prevalence (12.2%), followed by depression (6.6%), diabetes mellitus (6.2%), asthma (5.9%), anxiety disorders/phobia (4.8%), and COPD (1.8%). Diabetes was more common in men (5.3% of women and 7.1% of men) while depression (8.7% in women and 4.4% in men) and anxiety (6.3% in women and 3.4% in men) were considerably more common in women. Smaller gender differences were also found for hypertension (13.0% in women and 11.4% in men), asthma (6.4% in women and 5.4% in men) and COPD (2.1% in women and 1.6% in men). Diabetes, hypertension and COPD increased markedly with age, whereas anxiety, depression and asthma were fairly constant in individuals above 18 years. During one year of observation, more than half of all patients had only been diagnosed in primary health care, with hypertension being the diagnosis with the largest proportion of patients only identified in primary health care (70.6%).Conclusion: The prevalence of common diseases in the population can be estimated by combining data gathered during consecutive years from primary care, specialist outpatient care and inpatient care. However, accuracy of disease prevalence is highly dependent on the quality of the data. The high prevalence of the six diagnoses analysed in this study calls for preventive action to minimize suffering and costs to society. [ABSTRACT FROM AUTHOR]

Background: Mortality among patients with mental disorders is higher than in general population. By using national longitudinal registers, we studied mortality changes and excess mortality across birth cohorts among people with severe mental disorders in Denmark and Finland.Methods: A cohort of all patients admitted with a psychiatric disorder in 1982-2006 was followed until death or 31 December 2006. Total mortality rates were calculated for five-year birth cohorts from 1918-1922 until 1983-1987 for people with mental disorder and compared to the mortality rates among the general population.Results: Mortality among patients with severe mental disorders declined, but patients with mental disorders had a higher mortality than general population in all birth cohorts in both countries. We observed two exceptions to the declining mortality differences. First, the excess mortality stagnated among Finnish men born in 1963-1987, and remained five to six times higher than at ages 15-24 years in general. Second, the excess mortality stagnated for Danish and Finnish women born in 1933-1957, and remained six-fold in Denmark and Finland at ages 45-49 years and seven-fold in Denmark at ages 40-44 years compared to general population.Conclusions: The mortality gap between people with severe mental disorders and the general population decreased, but there was no improvement for young Finnish men with mental disorders. The Finnish recession in the early 1990s may have adversely affected mortality of adolescent and young adult men with mental disorders. Among women born 1933-1957, the lack of improvement may reflect adverse effects of the era of extensive hospitalisation of people with mental disorders in both countries. [ABSTRACT FROM AUTHOR]

Introduction: Patients with schizophrenia are at increased risk of suicide, but data from controlled studies of pharmacotherapy in relation to suicide risk is limited.Aim: To explore suicide risk in schizophrenia in relation to medication with antipsychotics, antidepressants, and lithium.Methods: Of all patients with a first clinical discharge diagnosis of schizophrenia or schizoaffective disorder in Stockholm County between 1984 and 2000 (n=4000), patients who died by suicide within five years from diagnosis were defined as cases (n=84; 54% male). Individually matched controls were identified from the same population. Information on prescribed medication was retrieved from psychiatric records in a blinded way. Adjusted odds ratios [OR] of the association between medication and suicide were calculated by conditional logistic regression.Results: Lower suicide risk was found in patients who had been prescribed a second generation antipsychotic (clozapine, olanzapine, risperidone, or ziprasidone; 12 cases and 20 controls): OR 0.29 (95% confidence interval [CI], 0.09-0.97). When the 6 cases and 8 controls who had been prescribed clozapine were excluded, the OR was 0.23 (95% CI 0.06-0.89). No significant association was observed between suicide and prescription of any antipsychotic, depot injection antipsychotics, antidepressants, SSRI, or lithium.Conclusions: Lower suicide risk for patients who had been prescribed second generation antipsychotics may be related to a pharmacological effect of these drugs, to differences in adherence, or to differences in other patient characteristics associated with lower suicide risk. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present study was to investigate the predictive value of the risperidone metabolic ratio for the individual CYP2D6 genotype., Methods: The determination of risperidone, 9-hydroxyrisperidone, and CYP2D6 genotype was performed in 89 schizophrenic patients. The receiver operator characteristic (ROC) method and the area under the ROC curve (AUC) were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. The area under the ROC curve (AUC) was used as a global measure of this predictive value. To evaluate the proposed cutoff levels of >1 and <0.1 to identify individuals with a poor or ultrarapid CYP2D6 genotype the sensitivity, specificity, positive predictive value and negative predictive were calculated., Results: The area under the ROC curve (AUC) for poor and ultrarapid metabolisers was 0.85 and 0.86, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of a risperidone/9-OH-risperidone ratio >1 to CYP2D6 poor metaboliser genotype were 75 %, 95 %, 60 % and 97 %, respectively. The corresponding measures for a metabolic ratio < 0.1 to predict ultrarapid metabolisers were 80 %, 77 %, 18 % and 98 %., Conclusions: A metabolic ratio > 1 or < 0.1 may be a useful therapeutic biomarker to recommend CYP2D6 genetic testing to guide the present or future treatment of patients in need of psychotropic drugs.

Background: Psychosis is associated with excess cardiovascular morbidity and mortality., Aims: To determine the prevalence of cardiovascular risk factors in patients with psychotic disorders compared with the population., Methods: 731 consecutive patients with psychosis recruited from psychiatric outpatient clinics in Stockholm County, Sweden, were compared with 5580 individuals from a population study performed in the same area. The main outcome measures were waist circumference, body mass index (BMI) and fasting glucose., Results: Mean waist circumference in patients vs. controls was for males 106 and 94 cm, respectively, and for females 97 and 85 cm, respectively (P < 0.001); mean fasting glucose in patients vs. controls was for males 5.8 and 5.2 mmol/l, respectively, and for females 5.6 and 4.8 mmol/l, respectively (P < 0.001). Comparisons were controlled for differences in age and family history of diabetes. Increased waist circumference was more common in psychotic patients compared with controls (OR = 3.99; 95% CI 3.09-5.15), controlling for fasting insulin, differences in gender, blood pressure, fasting glucose, family history of diabetes, age and tobacco use. Increased fasting blood glucose was also more common in psychotic patients (OR = 2.41; 95% CI 1.84-3.14) controlling for the same factors with the exception of fasting glucose and with the addition of increased waist circumference., Conclusion: Our study shows that the psychosis illness per se can be considered as a cardiovascular risk factor, independent of the traditional risk factors such as age and smoking.

Unlabelled: Improved Health-related quality of life (HRQoL) is an alternative treatment goal for individuals with psychosis, who have up to two times greater prevalence of type 2 diabetes, hypertension and obesity than the general population., Aim: to compare HRQoL in patients with psychosis, especially schizophrenia, with a reference sample and explore the relationship between HRQoL and metabolic risk factors in these patients., Methods: a prospective cohort study was carried out in specialized psychiatric outpatient departments in Sweden. The patients were invited consecutively. A prospective population-based study of public health in the south-east of Sweden served as reference group. Patients were assessed with psychiatric questionnaires that included Global Assessment of Functioning (GAF). Health-related quality of life was assessed using the questionnaire EQ5D, both for patients and the population, and several other health status outcomes were used., Results: At 73%, schizophrenia and schizoaffective disorder were the most common diagnoses in the patient group. The results in patients (n=903) and population (n=7238) showed significant differences in lower EQ5D among patients. According to the definition by the International Diabetes Federation (IDF), elevated blood pressure was the only metabolic risk associated with lower HRQoL in patients. Raised LDL-cholesterol levels were also significantly related to lower HRQoL., Conclusion: patients suffering from psychosis had significantly lower HRQoL regarding all components in EQ5D, except for the pain/discomfort component. Almost half of the patient group met the criteria for metabolic syndrome. According to the IDF criteria, elevated blood pressure was the only metabolic risk factor that had an impact on HRQoL., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: To undertake a multi-country study to investigate the risk of acute hyperglycaemia with antipsychotic use., Methods: Using a distributed network model with a common minimal data set, we performed a prescription sequence symmetry analysis (PSSA) to investigate the risk of acute hyperglycaemia associated with antipsychotic initiation. Incident insulin prescriptions were used as a proxy indicator of acute hyperglycaemia. Participating countries and population datasets included Australia (300,000 persons), Japan I (300,000 persons), Japan II (200,000 persons), Korea (53 million persons) Taiwan (1 million persons), Sweden (9 million persons), USA-Public (87 million persons) and USA-Private (47 million persons)., Results: Olanzapine showed a trend towards increased risk in most databases, with a significant association observed in the USA-Public database (Adjusted sequence ratio (ASR) = 1.14; 95% Confidence Interval (CI) 1.10-1.17) and Sweden (ASR = 1.53; 95% CI 1.13-2.06). Null or negative associations were observed for haloperidol, quetiapine and risperidone., Conclusion: Acute hyperglycaemia appears to be associated with olanzapine use, however, this effect was only observed in two large databases. Despite different patterns of utilization of both antipsychotics and insulin, PSSA analysis results for individual antipsychotic medicines were qualitatively similar across most countries. PSSA, used in conjunction with existing methods, may provide a simple and timely method further supporting multi-national drug safety monitoring., (Copyright © 2013 John Wiley & Sons, Ltd.)

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study., Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling., Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders)., Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Objective: To estimate the cardiovascular mortality among persons with bipolar disorder in Sweden compared to the general population., Design: Population register-based cohort study with a 20-year follow-up., Setting: Sweden., Participants: The entire population of Sweden (n=10.6 million) of whom 17 101 persons were diagnosed with bipolar disorder between 1987 and 2006., Main Outcome Measures: Mortality rate ratios (MRR), excess mortality (excess deaths), cardiovascular disorder (CVD) and specifically cerebrovascular disease, coronary heart disease, acute myocardial infarction, sudden cardiac deaths and hospital admission rate ratio (ARR)., Results: Persons with bipolar disorder died of CVD approximately 10 years earlier than the general population. One third (38%) of all deaths in persons with bipolar disorder were caused by CVD and almost half (44%) by other somatic diseases, whereas suicide and other external causes accounted for less than a fifth of all deaths (18%). Excess mortality of both CVD (n=824) and other somatic diseases (n=988) was higher than that of suicide and other external causes (n=675 deaths). MRRs for cerebrovascular disease, coronary heart disease and acute myocardial infarction were twice as high in persons with bipolar disorder compared to the general population. Despite the increased mortality of CVD, hospital admissions (ARR) for CVD treatment were only slightly increased in persons with bipolar disorder when compared to the general population., Conclusions: The increased cardiovascular mortality in persons with bipolar disorder calls for renewed efforts to prevent and treat somatic diseases in this group. Specifically, our findings further imply that it would be critical to ensure that persons with bipolar disorder receive the same quality care for CVD as persons without bipolar disorder.

Background: Excess mortality among patients with severe mental disorders has not previously been investigated in detail in large complete national populations., Objective: To investigate the excess mortality in different diagnostic categories due to suicide and other external causes of death, and due to specific causes in connection with diseases and medical conditions., Methods: In longitudinal national psychiatric case registers from Denmark, Finland, and Sweden, a cohort of 270,770 recent-onset patients, who at least once during the period 2000 to 2006 were admitted due to a psychiatric disorder, were followed until death or the end of 2006. They were followed for 912,279 person years, and 28,088 deaths were analyzed. Life expectancy and standardized cause-specific mortality rates were estimated in each diagnostic group in all three countries., Results: The life expectancy was generally approximately 15 years shorter for women and 20 years shorter for men, compared to the general population. Mortality due to diseases and medical conditions was increased two- to three-fold, while excess mortality from external causes ranged from three- to 77-fold. Mortality due to diseases and medical conditions was generally lowest in patients with affective disorders and highest in patients with substance abuse and personality disorders, while mortality due to suicide was highest in patients with affective disorders and personality disorders, and mortality due to other external causes was highest in patients with substance abuse., Conclusions: These alarming figures call for action in order to prevent the high mortality.

It is well known that abdominal obesity, dyslipidemia, and insulin resistance are highly prevalent in patients receiving maintenance treatment with antipsychotics, but there is limited knowledge about the association between cardiovascular risk factors and treatment with antipsychotic drugs. In this naturalistic study we investigated a sample of 809 antipsychotic-treated patients from Swedish psychosis outpatient teams. Cardiovascular risk factors (eg, metabolic syndrome, homeostasis model assessment of insulin resistance, and low-density lipoprotein values) were measured, and their associations to current antipsychotic pharmacotherapy were studied. Ten antipsychotic drugs were compared in a stepwise logistic regression model. For the patients, the presence of the components of metabolic syndrome ranged from 35% for hyperglycemia to 64% for elevated waist circumference. Hypertriglyceridemia was associated with clozapine (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.08-3.04), reduced high-density lipoprotein with both clozapine and olanzapine (OR = 1.73, 95% CI 1.01-2.97; and OR = 2.03, 95% CI 1.32-3.13), hypertension with perphenazine (OR = 2.00, 95% CI 1.21-3.59), and hyperglycemia inversely with ziprasidone (OR = 0.21, 95% CI 0.05-0.89) and positively with haloperidol (OR = 2.02, 95% CI 1.18-3.48). There were no significant relationships between any of the antipsychotic drugs and increased waist circumference, homeostasis model assessment of insulin resistance, or low-density lipoprotein levels. In conclusion, treatment with antipsychotic drugs is differentially associated with cardiovascular risk factors, even after adjusting for waist circumference, sex, age, and smoking.

Objective:   Several genetic loci have been suggested to be associated with bipolar disorder but results have been inconsistent. Studying associations between bipolar symptoms and candidate genes may better expose this relationship. Here we investigate the association between bipolar key symptoms and the P2RX7 gene., Methods:   Key symptoms of mania were rated in two sets of medicated bipolar disorder patients (n=171 and n=475) at two specialized outpatient clinics for affective disorders and three regular psychiatric outpatient units in Sweden. The relationships between all manic symptoms according to DSM-IV were entered in a principal component analysis. We used a case-case model to reduce the genetic heterogeneity and tested associations between four factors related to manic symptoms and their association to four single nucleotide polymorphisms in the P2RX7 gene., Results:   The combination of the cognitive symptoms, distractibility, talkativeness, and thought disorder was significantly associated with rs1718119 in the P2RX7 gene in Set 1 [odds ratio (OR) = 1.78; p=0.011]. The association was re-tested in the second set (OR = 1.42; p=0.009). In the total sample, the association was even stronger (OR = 1.49; p<0.001). None of the other factors was associated with the P2RX7 gene. Within the first factor, the distractibility symptom accounted for a significant portion of the association to rs1718119 (p=0.016)., Conclusion:   There is an association between specific symptoms of bipolar disorder and the P2RX7 gene. This finding may open up new approaches to elucidating the neurobiology behind bipolar symptoms., (© 2011 John Wiley and Sons A/S.)

Excessive level of radicals and/or dysfunctional antioxidant response, oxidative stress, is implicated in the pathogenesis of schizophrenia. A condition of oxidative stress has been detected in the brain, peripheral tissues and fluids including plasma. Plasma thioredoxin-1 (Trx1) is well characterized and a putative marker for oxidative stress and recently shown to be increased in plasma at the onset of schizophrenia. The present study aimed to explore whether Trx1 can be used as a marker to identify schizophrenic patients at the time-point when patients have their first episode of psychosis as compared to patients with long-term schizophrenia and mentally healthy patients, respectively. Plasma samples obtained from 18 patients at first episode of psychosis, from 49 long-term schizophrenic patients and from 20 mentally healthy controls (admitted with minor physical injury to the general ward) where analyzed by ELISA for Trx1. The patients with first episode of psychosis were diagnosed at least 6 months later and shown to constitute various psychotic syndromes, including schizophrenia, or affective disorder. The concentration of Trx1 in the patients with first episode of psychosis was 1.5 ± 1.0 ng/ml and 0.8 ± 0.6 ng/ml in controls. In the long-term schizophrenic patients the plasma concentration was 1.5 ± 0.7. The differences between the groups of acute psychotic or long-term schizophrenia patients to controls were significant (p < 0.016 and p < 0.001, respectively). Our data indicate that Trx1 may not be used as an early marker to identify schizophrenic patients in a mixed population of first episode psychotic patients. Further, Trx1 did not discriminate with reliable accuracy patients with psychotic disorder from mentally healthy controls on an individual basis due to overlap in levels of Trx1. However, our observations show that psychotic patients in general are in a significant long-term condition of oxidative stress, with possible implications for the profound morbidity and mortality found in this patient population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Individuals with severe psychiatric disorders are more likely than the population at large to develop metabolic derangements such as overweight and diabetes. Cardiovascular disease is also more frequently seen in this group. Contributing factors may include inappropriate diet or lack of physical activity, but antipsychotic medication may also play a role. Seven Swedish specialist medical societies have collaborated in formulating a set of concise clinically applicable guidelines-reproduced here in modified form-for the prevention and management of metabolic risk in this patient group. The importance of implementation is emphasized.

Background: Bipolar disorder patients often display abnormalities in circadian rhythm, and they are sensitive to irregular diurnal rhythms. CRY2 participates in the core clock that generates circadian rhythms. CRY2 mRNA expression in blood mononuclear cells was recently shown to display a marked diurnal variation and to respond to total sleep deprivation in healthy human volunteers. It was also shown that bipolar patients in a depressive state had lower CRY2 mRNA levels, nonresponsive to total sleep deprivation, compared to healthy controls, and that CRY2 gene variation was associated with winter depression in both Swedish and Finnish cohorts., Principal Findings: Four CRY2 SNPs spanning from intron 2 to downstream 3'UTR were analyzed for association to bipolar disorder type 1 (n = 497), bipolar disorder type 2 (n = 60) and bipolar disorder with the feature rapid cycling (n = 155) versus blood donors (n = 1044) in Sweden. Also, the rapid cycling cases were compared with bipolar disorder cases without rapid cycling (n = 422). The haplotype GGAC was underrepresented among rapid cycling cases versus controls and versus bipolar disorder cases without rapid cycling (OR = 0.7, P = 0.006-0.02), whereas overrepresentation among rapid cycling cases was seen for AAAC (OR = 1.3-1.4, P = 0.03-0.04) and AGGA (OR = 1.5, P = 0.05). The risk and protective CRY2 haplotypes and their effect sizes were similar to those recently suggested to be associated with winter depression in Swedes., Conclusions: We propose that the circadian gene CRY2 is associated with rapid cycling in bipolar disorder. This is the first time a clock gene is implicated in rapid cycling, and one of few findings showing a molecular discrimination between rapid cycling and other forms of bipolar disorder.

The aim of this study was to estimate suicide risk during hospitalization and in the year following discharge for patients with mental disorders. All suicide cases in Sweden 18 years and older, between 1991 and 2003 (N=20,675; 70% male), were individually matched to 10 controls from the general Swedish population. Discharge diagnoses in the year before suicide of any mental disorder, mood disorder, schizophrenia spectrum disorder, and alcohol use disorder were identified from the Swedish Patient Register. Highest suicide risk during hospitalization and in the year following discharge was found for mood disorder [odds ratio (OR) 55 (95% CI, 47-65) for men and 86 (95% CI, 70-107) for women], with the risk peaking in the first week following discharge [OR 177 (95% CI, 78-401) for men and OR 268 (95% CI, 85-846) for women]. Compared to that for mood disorder, the suicide risk for schizophrenia spectrum disorder and alcohol use disorder was about half and more constant over time. The majority of suicide victims with a psychiatric diagnosis had been discharged from psychiatric treatment more than a month before the suicide. Over time, a constant proportion of 25% of the suicide victims had been hospitalized with a mental disorder in the year before suicide (23% of males and 31% of females), despite a significant decrease in psychiatric hospitalizations in the population. In conclusion, suicide risk was found to vary by type of mental disorder, time since discharge, and sex. This should be taken into account when planning suicide preventive efforts., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Purpose: The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia., Methods: A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine., Results: In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact., Conclusions: At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established.

Background: Little is known as to whether suicide seasonality is related to psychiatric disorders affecting suicide risk/incidence. The present study aims to assess suicide seasonality patterns with regard to the history of psychiatric morbidity among suicide victims., Methods: The history of psychiatric inpatient diagnoses in the five years prior to suicide was identified among all suicides in Sweden from 1992 to 2003. Suicide seasonality was estimated as the relative risk of suicide during the month of highest to that in the month of lowest suicide incidence. Analyses were performed with respect to sex, suicide method and history of inpatient treatment of psychiatric disorder., Results: Among both male (n=9,902) and female (n=4,128) suicide victims, there were peaks in suicide incidence in the spring/early summer. This seasonal variation was more evident in suicide victims with a psychiatric inpatient diagnosis than in those without such a diagnosis. A seasonal variation was found in most diagnostic groups, with significant peaks in males with a history of depression and in females with a history of a neurotic, stress-related, or somatoform disorder. Overall, suicide seasonality was more evident in violent than in non-violent suicide methods., Limitation: Only psychiatric disorders severe enough to require hospital admission were studied., Conclusion: A history of inpatient-treated psychiatric disorder appears to be associated with an increase in suicide seasonality, especially in violent suicide methods. This increase is found in several psychiatric disorders.

Previous reports regarding risk factors for suicide in schizophrenia have been inconclusive. We performed a matched case-control study of in-patient-treated schizophrenia patients in order to assess the suicide risk associated with socioeconomic, demographic, and psychiatric factors. The cases were 84 patients who died by suicide within five years after diagnosis in a cohort of all patients discharged for the first time from psychiatric hospitals in Stockholm County, Sweden, with a diagnosis of schizophrenia, schizophreniform disorder or schizoaffective disorder between the years 1984 and 2000. One control was individually and randomly matched with each case from the same cohort by date (+/-1 year) and age (+/-5 years) at index diagnosis. Data were retrieved from clinical records of the case-control pairs in a blind fashion. Of the suicides, 54% were men and 46% were women. In multivariate analyses, higher educational attainment (odds ratio [OR] 3.0, 95% confidence interval [CI] 1.03-8.0), age >or=30 years at onset of symptoms (OR 4.8, CI 1.1-21.2), and a history of a suicide attempt requiring non-psychiatric medical treatment (OR 5.0, CI 1.6-15.4) were found to be significantly associated with an increased suicide risk. Gender did not significantly affect the suicide risk, nor did a history of self-discharge, compulsory in-patient treatment, substance-use disorder or a family history of mental disorders or suicide. In schizophrenia, certain suicide risk factors may differ from those in the general population. Clinical suicide risk assessment for schizophrenia patients should be performed taking this into account.

Background: Experimental evidence indicates that the endogenous opioid system influences stress responses as well as reinforces effects of addictive drugs. Because stress is an important factor contributing to drug dependence and relapse, we have now studied ethanol preference in enkephalin- and beta-endorphin-deficient mice under baseline conditions and after stress exposure., Methods: In the present study we used a two-bottle choice paradigm to study ethanol consumption and stress-induced ethanol preference. To examine alcohol withdrawal symptoms the forced drinking procedure was employed. We performed an association analysis in two case-control samples of alcohol addicts to determine whether these opioid peptides also contribute to ethanol dependence in humans., Results: Ethanol consumption was significantly reduced in the absence of beta-endorphins, particularly in female knockout animals. Stress exposure results in an increased ethanol consumption in wild-type mice but did not influence ethanol-drinking in beta-endorphin knockouts. Enkephalin-deficient mice showed no difference from wild-type mice in baseline ethanol preference but also showed no stress-induced elevation of ethanol consumption. Interestingly, we found a two-marker haplotype in the POMC gene that was associated with alcohol dependence in females in both cohorts., Conclusions: Together these results indicate a contribution of beta-endorphin to ethanol consumption and dependence.

Background: Earlier research has indicated a positive association between coeliac disease (CD) and some mental disorders. Studies on CD and depression have inconsistent findings and we know of no study of CD and the risk of bipolar disorder (BD)., Methods: We used Cox regression to investigate the risk of subsequent mood disorders (MD); depression and BD in 13,776 individuals with CD and 66,815 age- and sex-matched reference individuals in a general population-based cohort study in Sweden. We also studied the association between prior MD and CD through conditional logistic regression., Results: CD was associated with an increased risk of subsequent depression (Hazard ratio (HR)=1.8; 95% CI=1.6-2.2; p<0.001, based on 181 positive events in individuals with CD and 529 positive events in reference individuals). CD was not associated with subsequent BD (HR=1.1; 95% CI=0.7-1.7; p=0.779, based on 22 and 99 positive events). Individuals with prior depression (OR=2.3; 95% CI=2.0-2.8; p<0.001) or prior BD (OR=1.7; 95% CI=1.2-2.3; p=0.001) were at increased risk of a subsequent diagnosis of CD., Limitations: Study participants with CD and MD may have more severe disease than the average patient with these disorders since they were identified through a hospital-based register., Conclusions: CD is positively associated with subsequent depression. The risk increase for CD in individuals with prior depression and BD may be due to screening for CD among those with MD.