Mortality rate trends in patients diagnosed with schizophrenia or bipolar disorder: a nationwide study with 20 years of follow-up.

BACKGROUND: Patients with severe mental illness (SMI) have a reduced life expectancy of one to two decades as compared to the general population, with most years of life lost due to somatic diseases. Most previous studies on disorders constituting SMI, e.g. schizophrenia and bipolar disorder, have investigated the disorders separately and hence not compared the disorders in terms of mortality rates relative to the background population. METHODS: A register-based cohort study including the entire Danish population comparing mortality rates relative to the background population, controlling for age and sex, i.e. standardized mortality ratios (SMRs) in patients diagnosed with schizophrenia with those in patients diagnosed with bipolar disorder, during the study period from 1995 to 2014. RESULTS: The SMR of patients with SMI was significantly higher than one for each calendar year in the study period with an overall SMR of 4.58, 95% CI (4.48-4.69) in patients diagnosed with schizophrenia (n = 38,500) and of 2.57 (95% CI 2.49-2.65) in patients diagnosed with bipolar disorder (n = 23,092). When investigating time trends in SMR for schizophrenia and for bipolar disorder, respectively, an increase in SMR over time was shown with a mean increase of 0.03 per year for schizophrenia and 0.02 for bipolar disorder (p < 0.01 for both disorders). The ratio between SMR for schizophrenia and SMR for bipolar disorder for each calendar year over the study period was constant (p = 0.756). CONCLUSIONS: Increasing SMRs over the last 20 years were found for both patients diagnosed with bipolar disorder and patients diagnosed with schizophrenia. Despite clear differences between the two disorders regarding SMRs, the increases in SMR over time were similar, which could suggest similar underlying factors influencing mortality rates in both disorders.

High prevalence of prediabetes and metabolic abnormalities in overweight or obese schizophrenia patients treated with clozapine or olanzapine.

OBJECTIVE: To assess the prevalence of prediabetes and metabolic abnormalities among overweight or obese clozapine- or olanzapine-treated schizophrenia patients, and to identify characteristics of the schizophrenia group with prediabetes. METHODS: A cross-sectional study assessing the presence of prediabetes and metabolic abnormalities in schizophrenia clozapine- or olanzapine-treated patients with a body mass index (BMI) ≥27 kg/m2. Procedures were part of the screening process for a randomized, placebo-controlled trial evaluating liraglutide vs placebo for improving glucose tolerance. For comparison, an age-, sex-, and BMI-matched healthy control group without psychiatric illness and prediabetes was included. Prediabetes was defined as elevated fasting plasma glucose and/or impaired glucose tolerance and/or elevated glycated hemoglobin A1c. RESULTS: Among 145 schizophrenia patients (age = 42.1 years; males = 59.3%) on clozapine or olanzapine (clozapine/olanzapine/both: 73.8%/24.1%/2.1%), prediabetes was present in 69.7% (101 out of 145). While schizophrenia patients with and without prediabetes did not differ regarding demographic, illness, or antipsychotic treatment variables, metabolic abnormalities (waist circumference: 116.7±13.7 vs 110.1±13.6 cm, P = 0.007; triglycerides: 2.3±1.4 vs 1.6±0.9 mmol/L, P = 0.0004) and metabolic syndrome (76.2% vs 40.9%, P<0.0001) were significantly more pronounced in schizophrenia patients with vs without prediabetes. The age-, sex-, and BMI-matched healthy controls had significantly better glucose tolerance compared to both groups of patients with schizophrenia. The healthy controls also had higher levels of high-density lipoprotein compared to patients with schizophrenia and prediabetes. CONCLUSION: Prediabetes and metabolic abnormalities were highly prevalent among the clozapine- and olanzapine-treated patients with schizophrenia, putting these patients at great risk for later type 2 diabetes and cardiovascular disease. These results stress the importance of identifying and adequately treating prediabetes and metabolic abnormalities among clozapine- and olanzapine-treated patients with schizophrenia.

Pregabalin for anxiety in patients with schizophrenia - A randomized, double-blind placebo-controlled study.

INTRODUCTION: Anxiety is frequent in patients with schizophrenia and poses a major impact on patients perceived quality of life, daily functioning and risk of suicide. Pregabalin has shown effective in the treatment of generalized anxiety disorder and has been suggested for the treatment of anxiety in patients with schizophrenia. As evidence is sparse regarding treatment of anxiety in this patient group, we aimed to investigate the use of pregabalin for anxiety in patients with schizophrenia. METHODS: A randomized, double-blind placebo controlled study was used. Patients were randomized to either placebo or pregabalin (≤600mg/d) as add-on treatment. Primary analyses were intention-to-treat based with change in Hamilton Anxiety Scale after 4 and 8weeks of treatment as primary outcome. Secondary outcomes were change in psychopathology, quality-of-life, cognitive functioning and sleep. The study used centralized raters to increase accuracy and minimize baseline inflation. RESULTS: A total of 54 patients were included with 46 completing the study. Pregabalin reduced the HAM-A6 score significantly compared to placebo and with a medium effect size 0.72 (p=0.01). No significant between-group difference was found for the overall HAM-A14. Most common side-effects were weight gain, dizziness, sedation and increased duration of sleep. CONCLUSIONS: Although no effect was found on overall HAM-A14, pregabalin might be effective in the treatment of psychic anxiety symptoms in patients with schizophrenia with a medium effect size.

Antipsychotic-associated psoriatic rash - a case report.

BACKGROUND: Antipsychotics are a heterogeneous group of drugs. Although, antipsychotics have been used for years, unexpected side effects may still occur. With this case report we focus on a possible association between psoriasis and antipsychotics. Data on the patient's course of psychiatric disease, onset of psoriasis and its evolution were extracted from the patient's medical files. CASE PRESENTATION: We present a case of a 21-year-old female diagnosed with schizophrenia. She was initially treated with quetiapine, and later switched to aripiprazole due to weight gain. After initiation of antipsychotic treatment, the patient suffered from severe psoriasis lesions. CONCLUSIONS: Antipsychotics may possess immunological properties that may be involved in immune-mediated conditions, such as psoriatic rash. Further studies are warranted to determine causality and mechanism.

Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial.

Importance: Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects. Objectives: To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders. Design, Setting, and Participants: This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016. Interventions: Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study. Main Outcomes and Measures: The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters. Results: Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (-5.3 kg; 95% CI, -7.0 to -3.7 kg). Reductions in waist circumference (-4.1 cm; 95% CI, -6.0 to -2.3 cm), systolic blood pressure (-4.9 mm Hg; 95% CI, -9.5 to -0.3 mm Hg), visceral fat (-250.19 g; 95% CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4 mg/dL; 95% CI, -23.2 to -7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract. Conclusions and Relevance: Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine. Trial Registration: clinicaltrials.gov Identifier: NCT01845259.

Antipsychotic treatment of schizotypy and schizotypal personality disorder: a systematic review.

Schizotypal personality disorder (SPD) is characterised by thought disorders, experiences of illusions, obsessive ruminations, bizarre or eccentric behaviour, cognitive problems and deficits in social functioning - symptoms that SPD shares with schizophrenia. Efforts have been undertaken to investigate the relationship between these conditions regarding genetics, pathophysiology, and phenomenology. However, treatment of SPD with antipsychotics has received less scientific attention. Embase and PubMed databases were searched using all known generic names of antipsychotics as search terms in combination with the following diagnostic terms: latent schizophrenia, schizotypal disorder, latent type schizophrenia, or SPD. Studies were categorised according to evidence level on the basis of their methodology from A, being the best, to E, being the worst. Five hundred and nine studies were retrieved and scrutinised. Sixteen studies, from the period 1972 to 2012, on antipsychotic treatment of SPD were extracted. Four studies were categorised as evidence level A, two as level B, six as level C and three as level D, with one study level E. Only four randomised, double-blind, placebo-controlled trials, on subjects with well-defined diagnoses, exists. Only amisulpride, risperidone and thiothixene have been studied according to evidence level A. This result warrants further high quality studies of the effects of antipsychotic treatment of SPD.

Cardiovascular safety of antipsychotics: a clinical overview.

INTRODUCTION: Although antipsychotics have been associated with sudden cardiac death (SCD), they still remain a cornerstone in the treatment of psychiatric patients. Most antipsychotics have an unfavorable cardiovascular adverse effect profile, and SCD may occur even in patients with no cardiovascular risk factors. AREAS COVERED: This clinical overview summarizes the cardiovascular safety of antipsychotics by focusing on the wide range of associated adverse effects. In addition, we also discuss current guidelines regarding routine electrocardiogram (ECG) monitoring. EXPERT OPINION: As SCD in psychiatric patients is multifactorial, the contribution from antipsychotic treatment remains largely unknown. Cardiovascular adverse effects of antipsychotics vary substantially, even when used in therapeutic doses. Currently, most clinical concern focuses on antipsychotic-induced corrected QT prolongation, as this may increase risk of Torsades de Pointes and eventually SCD. However, other serious cardiovascular adverse effects of antipsychotics also include Brugada syndrome phenotype, myocardial infarction, and myocarditis. Increased awareness of the cardiovascular safety of antipsychotics can allow physicians to better manage and monitor high-risk patients. In this patient group, ECG monitoring may be warranted and other examinations symptom driven. Prescription of antipsychotics should always be a balance between the perceived clinical effect and the burden of adverse effects.

Abuse Potential of Pregabalin: A Systematic Review.

BACKGROUND: Several case reports and epidemiological studies have raised concern about the abuse potential of pregabalin, the use of which has increased substantially over the last decade. Pregabalin is, in some cases, used for recreational purposes and it has incurred attention among drug abusers for causing euphoric and dissociative effects when taken in doses exceeding normal therapeutic dosages or used by alternative routes of administration, such as nasal insufflation or venous injection. The magnitude of the abuse potential and the mechanism behind it are not fully known. OBJECTIVE: The aim of this study was to present a systematic review of the data concerning the abuse potential of pregabalin. METHODS: We performed a systematic literature search and reviewed the preclinical, clinical and epidemiological data on the abuse potential of pregabalin. RESULTS: We included preclinical (n = 17), clinical (n = 19) and epidemiological (n = 13) studies addressing the abuse potential of pregabalin. We also reviewed case reports (n = 9) concerning abuse of pregabalin. The preclinical studies indicated that pregabalin possesses modulatory effects on the GABA and glutamate systems, leaving room for an abuse potential. Further, clinical studies reported euphoria as a frequent side effect in patients treated with pregabalin. The majority of case reports concerning abuse of pregabalin involved patients with a history of substance abuse and, similarly, epidemiological studies found evidence of abuse, especially among opiate abusers. CONCLUSIONS: Overall, the available literature suggests an important clinical abuse potential of pregabalin and prescribers should pay attention to signs of abuse, especially in patients with a history of substance abuse.

Geographical and temporal variations in clozapine prescription for schizophrenia.

Despite its unsurpassed efficacy in treatment-resistant schizophrenia, clozapine remains underutilized. Trends in the prescription of clozapine in patients with ICD-10 F20.x schizophrenia were assessed using data from Danish national registers. Three substudies were carried out: (i) an assessment of differences in national prescription patterns between 1996 and 2007 using a cross-sectional design; (ii) a comparison of time from first schizophrenia diagnosis to first prescription of clozapine in a five-year cohort study, using the Cox regression model, of two patient groups who were first diagnosed in 1996 and in 2003; (iii) an assessment of differences in the general psychiatric hospitals' use of clozapine in 2009. The results are as follows: (i) The percentage of schizophrenia patients receiving clozapine rose from 9.0% in 1996 to 10.1% in 2007 (p<0.001). In the same period, the percentage of patients having clozapine treatment augmented with another antipsychotic increased from 43.1% to 64.2%, p<0.001. (ii) Time from diagnosis with schizophrenia until first clozapine prescription was longer for patients diagnosed in 2003 compared to those diagnosed in 1996 (HR: 0.28 CI: 0.16-0.49). (iii) In 2009 there was significant variation in clozapine administration from one hospital to the other, with percentages of patients receiving the drug ranging from 5.7% to 16.8%, with 10.2% as the national mean. Although, the percentage of schizophrenia patients receiving clozapine increased from 1996 to 2007, the time from diagnosis of schizophrenia until first prescription of clozapine increased.

The impact of selective and non-selective non-steroid anti-inflammatory drugs on secondary hemostasis in healthy volunteers.

BACKGROUND: Clinical and epidemiological studies have associated selective COX-2 inhibitors with an increased risk of cardiovascular events. There are no clinical studies on the possible effects of these drugs on secondary hemostasis. The hypothesis for this study is that the use of selective COX-2 inhibitors could affect the secondary hemostasis and by that increase the risk of cardiovascular events in a population at high risk. METHODS: An open-label randomized cross-over study was performed in 20 healthy male volunteers. The study consisted of two periods of each 21 days with medication, either celecoxib 100 mg b.i.d. or naproxen 250 mg b.i.d. Treatment periods were separated by a washout period of 28 days. Blood samples were obtained before the first medication period, and at the end of each medication period. Primary effect parameter was FXII level. Secondary effect parameters included a wide range of coagulation factors involved in secondary hemostasis. RESULTS: There was no statistically significant effect of celecoxib or naproxen on the primary effect parameter. Protein C activity was significantly decreased after treatment with naproxen (P<0.01), compared to baseline. Platelet function, demonstrated as closure time (CT), was at baseline 118+/-24 sec. (mean+/-SD). Naproxen prolonged CT to 171+/-50 sec. (P<0.001). Celecoxib did not change CT significantly (119+/-24 sec.). CONCLUSIONS: Neither the selective COX-2 inhibitor celecoxib, nor the non-selective NSAID naproxen caused any change in the primary effect parameter from the secondary hemostasis.