Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients

BackgroundTherapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients.MethodsOne hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA (rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone givenasmonotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2.ResultsThe three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment.ConclusionsThe present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients.     

A phase II/III trial of bitopertin monotherapy compared with placebo in patients with an acute exacerbation of schizophrenia – Results from the CandleLyte study

Bitopertin is a glycine reuptake inhibitor postulated to improve N-methyl-d-aspartate receptor hypofunction by increasing synaptic glycine concentrations. This randomised, double-blind, placebo- and active-controlled phase II/III trial evaluated the efficacy and safety of bitopertin monotherapy over 4 weeks in patients with acute exacerbation of schizophrenia. Of 301 patients randomised, 299 received placebo (n=80), bitopertin 10 mg (n=80) or 30 mg (n=77), or olanzapine 15 mg (n=62). The primary endpoint, change from baseline in mean Positive and Negative Syndrome Scale (PANSS) total score, showed non-statistically significant improvements with bitopertin 30 mg and olanzapine vs. placebo: bitopertin 10 mg (–11.7; standard error [SE], 1.89; p=0.945), bitopertin 30 mg (–15.3; SE, 1.87; p=0.211), olanzapine (–14.9; SE, 2.13; p=0.295) and placebo (–11.9; SE, 1.90). The PANSS positive subscale score, a secondary endpoint, also showed improvement with bitopertin 30 mg (p=0.030) whereas a trend was observed with olanzapine (p=0.072) vs. placebo. Although not statistically significant, bitopertin 30 mg and olanzapine reduced overall illness severity (Clinical Global Impression–Severity Scale; p=0.098 and p=0.126, respectively). More patients receiving bitopertin 30 mg (51.3%) or olanzapine (52.5%) than placebo (32.9%) were ready for hospital discharge at Week 4 (bitopertin, p=0.014; olanzapine, p=0.024). In summary, this study failed due to lack of statistical separation of either bitopertin or olanzapine (active control) from placebo on the primary endpoint. Of interest, improved positive symptoms and readiness for hospital discharge were associated with both bitopertin and olanzapine treatment. Bitopertin was safe and well tolerated in this study.     

Association between corneal temperature and mental status of treatment-resistant schizophrenia inpatients

IntroductionPreliminary point-prevalent data suggest that drug-free schizophrenia patients may exhibit increased body/corneal temperature, that antipsychotic drugs (APDs) may decrease body/core temperature and that patients' mental status might be associated with their body/corneal temperature. Hence, we hypothesized that treatment-resistant psychotic APD-treated schizophrenia patients' mental status may correlate with their corneal temperature during a continuous 6-week period.MethodsCorneal temperature of 12 treatment-resistant schizophrenia inpatients and 16 healthy volunteers was evaluated 2–3 times a week during 6 consecutive weeks using a flir thermal imaging camera.ResultsA significant and substantial correlation was found between inpatients' mean weekly Positive and Negative Syndrome Scale (PANSS)'s total scores and their mean weekly corneal temperature during the 6-week study period (r = 0.82; n = 6 weeks; p = 0.043). There was no significant difference in mean 6-week corneal temperature between the patient group and the healthy subjects (34.25 ± 0.64 °C vs. 34.39 ± 0.69 °C, respectively; t = 1.127, df = 131, p = 0.26).ConclusionsThis study indicates that treatment-resistant overtly psychotic schizophrenia inpatients' mental status (as assessed by the PANSS) correlates with their corneal temperature. The relevance of these phenomena to the pathophysiology of schizophrenia, the biological mechanism underlying corneal temperature alterations and the possible role of temperature-modulating drugs (neuroleptics or non-neuroleptics) on schizophrenic psychosis merits further large-scale investigation in both medicated- and drug-free schizophrenia patients compared to matched controls.     

Effect on lipid profiles of switching from olanzapine to another secondgeneration antipsychotic agent in veterans with schizophrenia

ObjectiveTo compare (1) mean low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride differences after switching from olanzapine to quetiapine, risperidone, or ziprasidone and (2) the mean lipid change between switch patterns.DesignRetrospective, naturalistic, nonequivalent control group design.SettingUnited States between April 1, 2002, and September 30, 2002.Patients1,826 U.S. Veterans Healthcare System enrollees with diagnoses of schizophrenia or schizoaffective disorders and receiving a second-generation antipsychotic (SGA) medication.InterventionsAnalysis of data from the Veterans Information Systems and Technology Architecture.Main outcome measuresDifferences in LDL-C, HDL-C, and triglycerides and mean differences between switch patterns. Predictors were the type of switch (e.g., olanzapine to quetiapine) and switch patterns (e.g., olanzapine to quetiapine versus olanzapine to risperidone). Data were analyzed using Pearson’s χ2 and multivariate analysis of covariance with planned comparisons.ResultsAfter adjusting for age, gender, and race/ethnicity, LDL-C decreased significantly among patients switched from olanzapine to ziprasidone (–16.9 mg/dL, P <0.01) and olanzapine to quetiapine (–7.6 mg/dL, P = 0.04) and trended upward in patients switched from olanzapine to risperidone (+6.6 mg/dL, P = 0.12). Triglyceride levels decreased among those switched from olanzapine to ziprasidone (–62.9 mg/dL, P <0.01) and olanzapine to risperidone (–48.5 mg/dL, P <0.01) but not among veterans switched from olanzapine to quetiapine (+7.8 mg/dL, P = 0.54). HDL-C levels did not change significantly when veterans were switched from olanzapine to quetiapine, risperidone, or ziprasidone.ConclusionSwitching SGAs can increase or decrease cardiovascular risk depending on the clinician’s follow-on SGA choice. LDL-C and triglyceride levels decreased significantly among veterans switched from olanzapine to ziprasidone. Switching to quetiapine was associated with a reduction in LDL-C, while switching to risperidone resulted in lower triglyceride levels. Clinicians should use these results when building a patient care plan that includes switching of SGAs.     

Pulmonary function in cannabis users: Support for a clinical trial of the vaporizer

BackgroundDebates about cannabis policy often mention respiratory symptoms as a negative consequence of use. The cannabis vaporizer, a machine that heats the plant to release cannabinoids in a mist without smoke and other respiratory irritants, appears to have the potential to minimize respiratory complaints.MethodsTwenty frequent cannabis users (uninterested in treatment) reporting at least two respiratory symptoms completed subjective ratings of respiratory symptoms and spirometry measures prior to and following 1 month's use of a cannabis vaporizer in a pre/post-design. Outcome measures included self-reported severity of nine respiratory symptoms as well as spirometry measures, including the maximum amount of air exhaled in 1 s (forced expiratory volume; FEV1) and maximum total lung volume (forced vital capacity; FVC).ResultsThe 12 participants who did not develop a respiratory illness during the trial significantly improved respiratory symptoms (t(11) = 6.22, p = 0.000065, d = 3.75) and FVC, t(11) = 2.90, p = 0.007, d = 1.75. FEV1 improved but not significantly t(11) = 1.77, p = 0.053, d = 1.07.ConclusionsThese preliminary data reveal meaningful improvements in respiratory function, suggesting that a randomized clinical trial of the cannabis vaporizer is warranted. The vaporizer has potential for the administration of medical cannabis and as a harm reduction technique.     

Treatment of depression in first episode of schizophrenia: Results from EUFEST

Depressive symptomatology is an important target of treatment in first episode schizophrenia. This reanalysis of the European First Episode Schizophrenia Trial (EUFEST) describes the depressive symptomatology and the effect of antipsychotic treatment in patients suffering from first episode schizophrenia and schizophreniform disorder randomized to treatment with low dose haloperidol (n=103), amisulpride (n=104), olanzapine (n=105), quetiapine (n=104) or ziprasidone (n=82) for one year. At baseline, the mean score on the Calgary Depression Scale for Schizophrenia (CDSS) was 5.1 (±4.9) with 38.3% of patients having a CDSS score≥6, i.e. clinically relevant depressive symptom severity. During treatment depression scores decreased, the mean CDSS score being 1.1 (±2.1) and 3.0% of patients having a CDSS≥6 at 52 weeks. The proportion of patients using antidepressants during the complete trial was 18.5% in the haloperidol group, 28.6% in the olanzapine group compared to 5.8% in the quetiapine group, 12.5% in the amisulpride group, and 9.8% in the ziprasidone group. There were no differences over time in the probability of being depressed (CDSS≥6) between the 5 treatment groups after adjustment for antidepressant use, nor in a sub analysis of patients who did not take any antidepressant. Depression scores at baseline or during the trial had no effect on treatment discontinuation or on the reduction of positive symptoms. In summary, the results of EUFEST did not demonstrate a differential effect of the antipsychotics studied on depressive symptomatology in patients with first episode schizophrenia.     

The effectiveness of outreach case management in re-enrolling discharged methadone patients

BackgroundHeroin dependence is a chronic relapsing disease often requiring multiple treatment experiences. Despite this knowledge, few methadone programs follow-up with discharged patients who frequently continue to engage in risky behaviors. The aim of this project was to evaluate the effectiveness of outreach case management for post-discharged methadone patients.MethodsAt 90 days post-discharge 128 active out of treatment heroin users were randomly assigned to receive either a passive referral (PR) for drug treatment (n = 52) or were provided with 6 weeks of outreach case management (OCM), an intervention designed to help motivate and coach patients to re-enter treatment (n = 76).ResultsAt 6 months post-baseline 29% of the OCM participants had successfully re-enrolled in drug treatment compared to 8% of the PR participants (χ² = 7.6, d.f. = 1, p = 0.006). A logistic regression analysis showed that OCM participants were nearly six times more likely than PR participants to re-engage in MMT (OR = 5.8, CI = 1.6–20.8, p = 0.008). Moreover, OCM subjects had fewer opiate and cocaine positive urines at the 6-month follow-up compared to PR subjects.ConclusionsThe findings highlight the importance of engaging former patients in treatment and actively assisting in treatment re-entry. OCM is a simple approach to reduce the number of out-of-treatment drug users, although availability of treatment funding limits enrollment opportunities.     

Childhood hyperactivity-inattention symptoms and smoking in adolescence

Background:The objective of the study was to examine in both genders the link between childhood hyperactivity-inattention symptoms (HI-s) and smoking in adolescence, controlling for psychopathology, temperament and environmental risk factors.Methods:Subjects (421 males, 495 females), aged 7 to 18, were recruited in the GAZEL cohort representative of the general population and surveyed in 1991 and 1999. Parent and adolescent self-report measures were used to assess child psychopathology and smoking patterns. Logistic regression was used to assess the effects of childhood hyperactivity-inattention symptoms and other predictors on adolescent smoking.Results:In females, hyperactivity-inattention symptoms contributed independently to subsequent daily smoking (OR = 1.98, p = 0.04). In males, hyperactivity-inattention symptoms alone did not increase the risk for smoking. Conduct disorder symptoms was an important predictor in males (OR = 2.95, p < 0.01) and females (OR = 1.75, p = 0.09). The risk of adolescent smoking was significantly increased in boys with high activity level (OR = 1.70, p = 0.03) and decreased in shy girls (OR = 0.60, p = 0.02). Parental smoking increased the liability to smoking in their offspring (males: OR = 1.96, p < 0.01; females: OR = 1.63, p = 0.02).Conclusions:If replicated, these findings suggest a role for smoking prevention in girls with hyperactivity-inattention symptoms and in boys with high activity level.     

Cluster randomised trial of the effectiveness of motivational interviewing for universal prevention

AimsTo investigate whether variation may exist in betel nut- and ecstasy-involved adolescents in terms of sociobehavioral characteristics, the experience of psychoactive substance use, and behavioral/emotional problems.MethodsStudents (n = 53,528) aged 12–18 sampled via stratified, multistage, random cluster sampling in 2004, 2005, and 2006 throughout Taiwan were categorized into four groups: betel nut- and ecstasy-naïve (n = 51,009), betel nut use only (n = 1965), ecstasy use only (n = 196), and use of both (n = 152). Participants completed a questionnaire with information on sociodemographic features, substance-use experiences, and the Chinese adaptation of the Youth Self Report.ResultsHaving a job, a larger weekly allowance, truancy, sexual experience, and externalizing behaviors were all in strong association with the involvement of either betel nut or ecstasy use. Compared with ecstasy-only users, betel nut-only users were more likely to be male, from the Eastern region of Taiwan, with initiation motivated by family members or friends, and having excess risks for Anxiety/Depression, Thought Problems, and Attention Problems. In contrast, ecstasy-only users were more likely to be female and involved in using other illegal drugs, with their initiation motivated by entertainment and with the drug use taking place in such settings.ConclusionsThe variation in the experience of psychoactive substance use and behavioral problems for betel nut and ecstasy users suggests the existence of subgroups of drug-using adolescents in Taiwan. The identification of such heterogeneity may guide the efforts to reduce substance use and develop subgroup-tailored preventive programs.     

Correlates of extramedical use of OxyContin versus other analgesic opioids among the US general population

BackgroundThere has been substantial public and media attention regarding extramedical use of OxyContin^®, but few studies focus on the characteristics of extramedical OxyContin^® users and whether they differ from extramedical other opioid users.MethodsWe used data from 8218 respondents who were past-year extramedical opioid analgesic users in the 2005 and 2006 National Survey of Drug Use and Health (NSDUH). We investigated differences in socio-demographic and psychiatric characteristics associated with past-year extramedical OxyContin^® use (n = 1144) versus extramedical other opioid analgesics use (n = 7074). Data on opioid sources was compared among past-month users. We also compared extramedical opioid users (n = 8218) versus other drug users (n = 16,214), and individuals with an analgesic disorder who had past-year extramedical OxyContin^® use (n = 339) versus those with other opioid use (n = 820).ResultsPast-year opioid users were more likely than users of other illegal drugs to be more educated and have a past-year major depressive episode. Past-year OxyContin^® users were more likely than other opioid users to be 18–25 years old (aOR = 1.9[1.1,3.2]), and have mental health and deviant behavior problems. Those with past-year analgesic disorder who used OxyContin^® were more likely to be younger, sell illegal drugs (aOR = 2.5[1.5,4.2]), and use illegal drugs than those who used other opioids. Past-month OxyContin^® users were more likely than past-month other opioid users to buy analgesics from drug dealers/other strangers and obtain opioid analgesics from multiple sources.ConclusionOur findings point out differences between OxyContin^® and other opioid users that might help prevention specialists and assist efforts to curb opioid analgesics diversion.     

Effects of pantoprazole on dual antiplatelet therapy in stable angina pectoris patients after percutaneous coronary intervention

BackgroundOur aim was to prospectively assess the potential influence of pantoprazole therapy on the antiplatelet effects of acetylsalicylic acid (ASA) and clopidogrel (CLO) in stable angina pectoris (SAP) patients after percutaneous coronary intervention (PCI).MethodsForty-four patients with SAP (CCS I-III) and successful PCI with stent implantation were enrolled into the study. The patients were divided into group proton pump inhibitors (PPI): 23 patients with indications for PPI (F/M = 9/14; age = 64 ±  9; standard therapy + 20 mg pantoprazole) and the control group (group C): 21 patients (F/M = 6/15; age = 64 ±  8; standard therapy). The platelet function analysis in whole blood based on impedance aggregometry (ASPI, COL, ADP, TRAP tests) using Multiplate – V2.02.11 was performed 18–24 h after the PCI + CLO loading dose (600 mg) and 30 days after PCI.ResultsBoth baseline patient characteristics and clinical outcomes were comparable between the study groups. There were no differences in the mean values of the platelets (PTL) tests measured at the 30^th day after PCI between both groups (PPI vs. C: ASPI: 24.6 ±  10.0 vs. 42.1 ±  14.8U, COL: 32.9 ±  8.6 vs. 34.0 ±  7.7U, ADP: 26.8 ±  12.4 vs. 30.4 ±  8.1U, TRAP: 78.7 ±  16.6 vs. 78.1 ±  22.6U, p = ns). The mean delta values of the PTL tests (18–24 h post-PCI/30 days post-PCI) were also comparable between the groups. The PTL aggregometry results were related to time (ADP, ASPI, TRAP vs. time, p = 0.001; COL vs. time, p = 0.03) – the baseline values of ADP, ASPI, COL and TRAP tests were smaller than those measured after the one-month observation.ConclusionsPantoprazole treatment does not impair the efficacy of dual antiplatelet therapy in patients with SAP after PCI.     

The association of race, comorbid anxiety, and antidepressant adherence among Medicaid enrollees with major depressive disorder

BackgroundDepressed patients often have comorbid anxiety. African-Americans with depression are less likely to adhere to antidepressant treatment. Knowledge of the association between race, comorbid anxiety, and adherence among Medicaid enrollees with depression is limited.ObjectiveThe objective of this study was to evaluate the association of race, comorbid anxiety, and antidepressant adherence, and persistence among Medicaid enrollees with major depressive disorder (MDD).MethodsThe MarketScan^® Multi-State Medicaid Database (Thomson Reuters, Ann Arbor, MI) was used in this retrospective cross-sectional study. Medicaid enrollees aged between 18 and 64 years, with MDD but without bipolar disorders, and with a newly initiated antidepressant between January 1, 2004 and December 31, 2006 were identified. An index date was assigned corresponding to the newly initiated antidepressant. Patients having claims for any antidepressant refills during the 12 months before the index date were excluded. Eligible patients were then followed-up for 12 months after the index date. Adherence was measured by a modified medication possession ratio. Adherence was evaluated using multivariate logistic regression. Persistence was assessed based on treatment discontinuation and examined by Kaplan-Meier survival curves and Cox-propositional hazard regression models.ResultsA total of 3083 Medicaid patients with MDD were included. Approximately, 25% of patients had comorbid anxiety. The odds of adhering to antidepressants were 40% lower among African-Americans than Caucasians, adjusting for covariates (AOR [adjust odds ratio] = 0.60; 95% confidence interval [CI] = 0.51-0.72, P < .001). MDD patients with comorbid anxiety were more likely to adhere to antidepressants than patients with MDD alone (AOR = 1.55, 95% CI = 1.27-1.90, P < .001). African-Americans had a higher hazard of not persistently taking antidepressants (hazard ratio = 1.47, 95% CI = 1.30-1.65, P < .001). The interaction between race and comorbid anxiety was not associated with adherence or persistence.ConclusionsAmong Medicaid enrollees with MDD, race and comorbid anxiety disorders are significantly associated with antidepressant adherence and persistence. Physicians need to recognize comorbid anxiety and race as 2 important determinants of antidepressant use behaviors when they encounter Medicaid patients with MDD.     

Effect of total and partial nephrectomy on the elimination of ciprofloxacin in humans

BackgroundRenal cell carcinoma (RCC) is the most common form of kidney cancer. Surgery is a standard procedure to resect the tumor during total (TN) or partial (nephron-sparing) nephrectomy (PN). Ciprofloxacin is most often administered at the usual intravenous dose of 100–400 mg/12 h. The application of such low doses of ciprofloxacin as 200 mg/24 h carries the risk of achieving subtherapeutic concentrations even in patients with limited renal function. The aim of the study was a comparison of concentrations and pharmacokinetics for ciprofloxacin at steady-state in patients after total and partial nephrectomy and evaluation of the effectiveness of the iv dose 200 mg/24 h against the theoretical value of MIC, 0.5 μg/ml.MethodsThe research was carried out on two groups of patients after nephrectomy: total (group 1, n = 21; mean [SD], age, 62.9 [14.4] years; weight, 76.0 [14.6] kg; creatinine clearance, clcr, 90.7 [22.2] ml/min) and partial (group 2, n = 15; 61.7 [9.3] years; 87.8 [16.4] kg; CL_CR, 107.8 [36.4] ml/min). The patients were treated with ciprofloxacin in the dose of 200 mg/24 h (iv). Plasma concentrations of ciprofloxacin at steady state were measured with validated HPLC method with UV detection.ResultsThe mean values of plasma concentrations of ciprofloxacin at steady state in group 1 and 2 were: C^ss_max, 2.012 and 1.345; C^ss_min, 0.437 and 0.244 μg/ml, respectively. The main pharmacokinetic parameters for ciprofloxacin in group 1 and 2 were as follows: AUC_(0–last), 30.9 [17.9] and 19.5 [8.7] μg h/ml; AUMC_(0–last), 177.91 [11.1] and 91.9 [66.5] μg h²/ ml; _t1/2β, 13.9 [7.7] and 9.8 [3.3] h; MRT, 16.5 [12.1] and 9.77 [5.4] h; V_d, 115.0 [67.2] and 142.2 [78.7] l; CL, 6.2 [3.3] and 10.8 [5.7] l/h, respectively. With the assumed MIC = 0.5 μg/ml, the values of C^ss_max/MIC < 10 and AUC/MIC < 125 were obtained in all the patients.ConclusionIn our patients we observed significant differences in some pharmacokinetic parameters of ciprofloxacin after two types of nephrectomy.     

Memory performance in polyvalent MDMA (ecstasy) users who continue or discontinue MDMA use

Background:The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine = MDMA) is a serotonergic neurotoxin in animal studies. Several cross-sectional investigations reported low memory and learning performance in ecstasy users, particularly in those reporting heavy patterns of drug use. Since, serotonin has a recognized role in memory processes, these findings were mostly interpreted as evidence for ecstasy-related neurotoxicity in humans. However, studies with user populations and controls suffer from many inherent methodological problems. Moreover, longitudinal data on memory performance after continued or discontinued ecstasy use are scarce.Methods:In the present longitudinal study, we examined memory performance in 38 MDMA users over the course of 18 months.Results:Subjects who stopped MDMA use after the baseline examination (n = 17) did not improve, and subjects who continued MDMA use (n = 21) did not deteriorate in terms of test performance.Conclusions:Our data do not support, but they also do not rule out memory decline following use of the serotonergic neurotoxin MDMA. In light of the popularity of ecstasy among young people, further investigations are needed. In our view, research strategies should now move to prospective designs in order to shed more light on the course of possible adverse cognitive effects of ecstasy use.     

Atomoxetine hydrochloride in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: A placebo-controlled Italian study

ObjectiveThe primary aim of this study was to assess the efficacy of atomoxetine in improving ADHD and ODD symptoms in paediatric patients with ADHD and comorbid oppositional defiant disorder (ODD), non-responders to previous psychological intervention with parent support.MethodsThis was a multicentre, randomised, placebo-controlled trial conducted in patients aged 6–15 years, with ADHD and ODD diagnosed according to the DSM-IV criteria by a structured clinical interview (K-SADS-PL). Only subjects who are non-responders to a 6-week standardized parent training were randomised to atomoxetine (up to 1.2 mg/kg/day) or placebo (in a 3:1 ratio) for the following 8-week double blind phase.ResultsOnly 2 of the 156 patients enrolled for the parent support phase (92.9% of males; mean age: 9.9 years), improved after the parent training program; 139 patients were randomised for entering in the study and 137 were eligible for efficacy analysis. At the end of the randomised double blind phase, the mean changes in the Swanson, Nolan and Pelham Rating Scale-Revised (SNAP-IV) ADHD subscale were − 8.1 ± 9.2 and − 2.0 ± 4.7, respectively in the atomoxetine and in the placebo group (p < 0.001 between groups); changes in the ODD subscale were − 2.7 ± 4.1 and − 0.3 ± 2.6, respectively in the two groups (p = 0.001 between groups). The CGI-ADHD-S score decreased in the atomoxetine group (median change at endpoint: − 1.0) compared to no changes in the placebo group (p < 0.001 between groups). Statistically significant differences between groups, in favour of atomoxetine, were found in the CHIP-CE scores for risk avoidance domain, emotional comfort and individual risk avoidance subdomains. An improvement in all the subscales of Conners Parents (CPRS-R:S) and Teacher (CTRS-R:S) subscales was observed with atomoxetine, except in the cognitive problems subscale in the CTRS-R:S. Only 3 patients treated with atomoxetine discontinued the study due to adverse events. No clinically significant changes of body weight, height and vital signs were observed in both groups.ConclusionsTreatment with atomoxetine of children and adolescents with ADHD and ODD, who did not initially respond to parental support, was associated with improvements in symptoms of ADHD and ODD, and general health status. Atomoxetine was well tolerated.     

Low prefrontal perfusion linked to depression symptoms in methadone-maintained opiate-dependent patients

BackgroundClinically depressed patients without substance use disorders, compared to controls, exhibit significantly lower resting regional cerebral blood flow (rCBF) in the prefrontal cortex (PFC). In this study, we examined the link between resting rCBF in the PFC and current depressive symptoms in methadone-maintained opiate-dependent (MM) patients with or without major depression.MethodsArterial spin labeled perfusion fMRI at 3 Tesla was used to measure resting rCBF in 21 MM patients. Perfusion data were analyzed using SPM2. The relationship between Beck Depression Inventory (BDI) score and resting rCBF was examined in a single regression analysis.ResultsThe BDI scores ranged between 0 and 18 (m = 7.0, S.D. = 4.8), and 30% of the sample had mild to moderate depression symptoms according to BDI scores. A negative correlation was observed between BDI scores and relative rCBF in the bilateral ventrolateral prefrontal cortex, and middle frontal gyri.ConclusionsThe inverse relationship between prefrontal paralimbic rCBF and depression scores suggests a link between reduced fronto-limbic activity and depressive symptoms in MM patients. A significant subgroup of opiate-dependent patients has clinical or sub-clinical depression that is often undetected; our data identify brain substrates of depression symptoms that may also be a potential marker of relapse in this population. Treatment strategies targeting these brain regions may improve outcomes in depressed substance abusers.     

Deposition of ethyl glucuronide in WHP rat hair after chronic ethanol intake

BackgroundThis study investigated the relationship between ethanol intake in rats and the resulting level of ethyl glucuronide (EtG) in rat hair.MethodsRats (n = 50) consumed a 10% ethanol solution for 4 weeks, then EtG was extracted from samples of their hair using a novel extraction procedure involving freezing and thawing. The EtG concentration was measured using gas chromatography and mass spectrometry. The animals voluntarily drank ethanol, with daily consumption in most rats exceeding 5 g/kg b.w. The silylated EtG was stable for at least 28 h. The limit of detection was 0.03 ng/mg, and the limit of quantification was 0.1 ng/mg.ResultsHair samples from rats that consumed ethanol had EtG levels ranging from 0.17–20.72 ng/mg in female rats and 0.15–13.72 ng/mg in males. There was a correlation between the amount of alcohol consumed and the EtG levels in hair from female (p < 0.01), but not male, rats.ConclusionThe method presented allows detection and quantification of EtG in rat hair. We also observed differences in EtG deposition in male and female rats.     

Ziprasidone with adjunctive mood stabilizer in the maintenance treatment of bipolar I disorder: Long-term changes in weight and metabolic profiles

This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5–4 months of open label ziprasidone (80–160 mg/d) plus lithium or valproic acid (ZIP + MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP + MS (n = 127) vs. placebo + MS (n = 113).At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p < 0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP + MS group had similar weight and metabolic profiles compared to the placebo + MS group across visits.These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes.     

A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD)

The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n = 766) had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥ 26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10 mg Lu AA21004, placebo, or 60 mg duloxetine. The 5 mg and 10 mg doses of Lu AA21004 were tested separately versus placebo at p ≤ 0.025 in a pre-specified order. In the pre-defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n = 145) of ? 1.7 (Lu AA21004 5 mg, n = 155) and ? 1.5 points (Lu AA21004 10 mg, n = 151) were not statistically significant; nor were those for Lu AA21004 2.5 mg (? 1.4 points, n = 155) or duloxetine (? 2.0 points, n = 149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5 mg, 5 mg and 10 mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5 mg and 10 mg and duloxetine. Lu AA21004 (2.5, 5 and 10 mg) was well tolerated.     

Emergency department visits and admissions due to drug related problems at Riyadh military hospital (RMH), Saudi Arabia

ObjectivesAim of this study was to prospectively determine the incidence and types of emergency department (ED) visits and admissions due to drug related problems (DRPs) at Riyadh Military Hospital (RMH), to assess the severity and preventability of these drug related admissions or visits, and to identify the drugs and patient groups that are most commonly involved.MethodPatients (n = 300) were selected randomly from patients presented to the ED during the study period (one month). Computerized randomization program was used to select ten beds daily on different areas and times. Patient was eligible to be included if either visited ED or admitted through it due to DRPs.ResultsDuring the study period, 300 patients presented to ED were randomly selected with a mean age of 47.8 ± 27.7 years. One hundred and forty of them were females (46.67%) and 160 were male patients (53.33%). Of these 300 patients, 56 (18.7%) were presented to ED due to DRPs, and 244 (81.3%) patients were presented to ED due to non-drug related problems (NDRPs). About ninety-three percent (n = 52) of the DRP group were exposed to hospital admission while only 7.1% (n = 4) were ED visits (Fig. 2). Male to female ratio in ED visits was 3:1 while it was 9.7:8.9 in the ED admission group.ConclusionThe prospective design of this study, sample size, and randomization increases the likelihood that our estimates are accurate and increase the generalizability of our findings. Most DRPs attributed to hospital admissions or visits were avoidable. Direct patient contact with pharmacist and family physician was beneficial in providing a safe and effective therapy. Corrective, preventive and educational strategies should concentrate on the most frequently reported populations, diseases and medications. The study addresses the proper use of medications to ensure the best outcomes of pharmacological interventions. Finally, more studies with longer duration focusing on DRPs in Saudi Arabia are needed.