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This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: 1) To determine the efficacy of reboxetine in comparison with other antidepressive agents in alleviating the acute symptoms of depression. 2) To investigate acceptability of treatment with reboxetine in comparison with other antidepressive agents. 3) To investigate the adverse effects of reboxetine in comparison with other antidepressive agents.

According to our model, the motivation for appetitive-searching vs. distress-avoiding behaviors is regulated by two parallel cortico-striato-thalamo-cortical (CSTC) re-entry circuits that include the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side to the centromedial amygdala on the other side, control the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure); while, hyperactive motivation to exhibit behavior related to avoidance of aversive states results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. We hypothesized that the mechanism inducing the switch from bipolar depression to mania is the most essential characteristic of bipolar disorder. This switch is attributed to a dysfunction of the lateral habenula, which regulates the activity of midbrain centers, including the dopaminergic ventral tegmental area (VTA). Froman evolutionary perspective, the activity of the lateral habenula should be regulated by the human homolog of the habenula-projecting globus pallidus, which in turn might be directed by the amygdaloid complex and the phylogenetically old part of the limbic cortex. In bipolar disorder, it is possible that the system regulating the activity of this reward-driven behavior is damaged or the interaction between the medial and lateral habenula may be dysfunctional. This may lead to an adverse coupling between the activities of the misery-fleeing and reward-seeking circuits, which results in independently varying activities.

Purpose: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases. Methods: Annual prevalence per 10,000 person-years (PYs) was calculated for 2001-2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications. Results: The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15-57 % and 39-69 % for depression respectively). Conclusion: Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations. © 2014 Springer-Verlag.

Introduction: Antidepressant drug consumption in 18 European countries doubled between 2000 and 2012. Increase in the use of antidepressant drugs includes indications other than depression, some studies showed that prevalence of prescription is higher in the elder. Objectives: To describe the indications related to new antidepressant drug prescriptions in two primary care databases from The Netherlands and Catalonia 2010-2015. Methods: A retrospective descriptive study was conducted, including new antidepressant users (excluding IMAO inhibitors) aged ≥65 years. Data was retrieved from the Dutch NIVEL Primary Care Database and SIDIAP (Information System for Research in Primary Care from Catalan Institute ofHealth) databases. Primary outcome was concurrent diagnoses for antidepressant prescribing as a proxy of indication, including: depression, anxiety, sleep disorders, migraine/headache, neuropathic pain, fibromyalgia, other mental and behavioral disorders or other diagnoses. Results were stratified by age and gender. Results: A total of 16 537 and 199 168 new antidepressant users were identified in NIVEL-PCD and SIDIAP, respectively during the study period. Women 65-69 years old prevailed in both databases (22% and 26.5%, respectively). Depression was the most frequent active diagnosis in both databases during the study period (24% and 31%, respectively). Tricyclic antidepressants were the most commonly prescribed (48.7%) in NIVELPCD mainly for neuropathic pain and selective serotonin reuptake inhibitors in SIDIAP (63.1%) mainly for depression. More details result below: Summary / Conclusions: Depression is the most common diagnosis related to antidepressant prescribing in both countries. Anxiety and Sleep disorders are other associated diagnoses which should be prescribed with caution in the elder.

OBJECTIVE: To compare the use of drugs for pulmonary diseases in children who were exposed to antidepressants in utero with non-exposed children. Some studies suggest an association between in utero exposure to antidepressants and the occurrence of pulmonary diseases later in life. Antidepressants are thought to be involved in the development of the respiratory rhythm generator and the maturation of surfactant formation. DESIGN AND METHODS: The pharmacy prescription database IADB.nl was used for a cohort study. The use of drugs for pulmonary diseases in children after in utero exposure to antidepressants was compared to children with no antidepressant exposure in utero. Drugs for pulmonary diseases were applied as a proxy for disturbed development of the respiratory tract. RESULTS: A small but significant increase in the incidence risk ratio (IRR) of the use of drugs for pulmonary diseases was found after anytime in utero exposure to serotonin reuptake inhibitors (SSRIs) (1.17; CI951.16-1.18). IRR also was increased for specific use of SSRIs in the first trimester (1.18; CI951.17-1.20). IRR increase for children who were exposed to tricyclic antidepressants was not statistically significant. As sample size was rather small in both groups, the effect size is modest and may also be confounded by maternal smoking. CONCLUSIONS: Children exposed to SSRIs in utero use significantly more drugs for pulmonary diseases, especially when exposure occurred during the first trimester of pregnancy. However, the increased use of such drugs may also be related to other factors.

PURPOSE: The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed. METHODS: Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age. RESULTS: Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs. CONCLUSION: Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association. Copyright © 2016 John Wiley & Sons, Ltd.

Purpose: To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases. Methods: The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases. Results: The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to >10years and different types of cancer. Conclusions: A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.

JUSTIFICATIVA E OBJETIVOS: O tratamento da dor envolve a utilização de analgésicos opioides, analgésicos comuns, anti-inflamatórios não hormonais (AINH's) e analgésicos adjuvantes. Tradicionalmente, estes fármacos são administrados por via sistêmica ou no neuroeixo. Entretanto, quando aplicados por estas vias, estão associados a efeitos colaterais importantes, os quais podem inviabilizar o seu uso. A administração tópica de analgésicos é uma alternativa. O objetivo deste trabalho é discutir os analgésicos tópicos, seus mecanismos de ação e eficácia clínica. CONTEÚDO: Trata-se de um trabalho de revisão que aborda a utilização tópica de anestésicos locais, capsaicina, clonidina, antidepressivos tricíclicos, cetamina, opioides e canabinoides, discutindo o seu mecanismo de ação e a sua eficácia. CONCLUSÕES: Os analgésicos tópicos são promissores como estratégia para o tratamento da dor, já que estão associados à menor incidência de efeitos colaterais. O benefício dos anestésicos locais, dos AINH's e da capsaicina está bem estabelecido, entretanto, a eficácia de clonidina, antidepressivos tricíclicos, cetamina, opioides e canabinoides ainda é questionável. Trabalhos demonstram que a abordagem multimodal é uma alternativa, porém estudos são necessários para confirmar esta hipótese. BACKGROUND AND OBJECTIVES: Pain treatment involves the usage of common and opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and adjuvant analgesics. Traditionally, these drugs are administered systemically or into the neuraxis. However, when analgesics are applied through these pathways, they are associated with significant side effects, which can hinder its use. Topical administration of analgesics is an alternative. The objective of this paper is to discuss topical analgesics, the mechanisms of action and clinical efficacy. CONTENT: This is a review paper addressing the usage of the topical local anesthetics: capsaicin, clonidine, tricyclic antidepressants, ketamine, opioids and cannabinoids, discussing mechanism of action and effectiveness. CONCLUSIONS: Topical analgesics are promising as a strategy for pain treatment, as they are associated with lower incidence of side effects. The benefit of local anesthetics, NSAID's and capsaicin is well established. However, the efficacy of clonidine, tricyclic antidepressants, ketamine, opioids and cannabinoids is still questionable. Studies have shown that the multimodal approach is an alternative, but studies are needed to confirm this hypothesis. JUSTIFICATIVA Y OBJETIVOS: El tratamiento del dolor involucra la utilización de analgésicos opioides, analgésicos comunes, antiinflamatorios no hormonales (AINH's) y analgésicos adyuvantes. Tradicionalmente, esos fármacos son administrados por vía sistémica o en el neuro eje. Sin embargo, cuando se aplican por esas vías, están asociados a los efectos colaterales importantes, los cuales pueden impedir su uso. La administración tópica de analgésicos es una alternativa. El objetivo de este trabajo es discutir los analgésicos tópicos, sus mecanismos de acción y la eficacia clínica. CONTENIDO: Se trata de un trabajo de revisión que aborda la utilización tópica de anestésicos locales, capsaicina, clonidina, antidepresivos tricíclicos, cetamina, opioides y canabinoides, discutiendo su mecanismo de acción y su eficacia. CONCLUSIONES: Los analgésicos tópicos son promisorios como una estrategia para el tratamiento del dolor, ya que están asociados con una menor incidencia de efectos colaterales. El beneficio de los anestésicos locales, de los AINH's y de la capsaicina está muy bien establecido, sin embargo, la eficacia de la clonidina, los antidepresivos tricíclicos, cetamina, opioides y canabinoides, todavía es cuestionable. Algunos trabajos demuestran que el abordaje multimodal es una alternativa, pero más estudios son necesarios para poder confirmar esa hipótesis.

The development of a new drug is characterized by distinct developmental stages, usually described as phases I to IV. Dose tolerance and dose response exploration studies are undertaken in phase II or III. Pharmacokinetic studies are often involved in these phases, but frequently only as an objective of minor importance. The usefulness of therapeutic drug monitoring (TDM) is not consequently investigated for new drugs. Usually the need for TDM is only discovered much later, when the drug is already on the market. TDM is particularly valuable under the following circumstances: (i) if there is a stronger relationship between the drug concentration and effect than between the dose and effect; (ii) if there is no simple and clear clinical parameter available to evaluate the clinical efficacy of the drug; (iii) if the therapeutic window is small; (iv) to document interactions; (v) to monitor drug compliance; and (vi) if there is large intra- and interindividual variability and unpredictability in pharmacokinetic parameters. Our recommendation is that randomized concentration controlled trials should be performed during the early stages of drug development and that it should be obligatory for drug licensing. © 2008 Adis Data Information BV. All rights reserved.

Background: In observational studies of time-varying treatment, conditioning on time-dependent confounders that are affected by previous treatment using conventional regression methods may adjust-away(indirect) treatment effects.In the presence of unmeasured common causes of confounders and outcome, it can also induce collider-stratification bias. Objectives: To compare time-dependent propensity scores, conventional Cox and marginal structural models (MSM) in a study of selective serotonin reuptake inhibitors (SSRI) and the risk of hip fracture (HF). Methods: A cohort of patients with a first prescription for antidepressants (AD, SSRI or tricyclic antidepressants, TCA) was extracted from the Dutch Mondriaan GP database in the period 2001-2009.Potential confounders were ascertained when antidepressant use changed over time or at six month intervals. Follow-up began with the first day of AD prescription and ended at the occurrence of HF, death, unregistration with the GP, or end of the study.Treatment effects were estimated using time-varying Cox regression, PS stratification, covariate adjustment, and inverse probability weighting (MSM) to control for confounding. In MSMs, censoring was accounted for by including inverse probability of censoring weights (IPCW). Results: The crude HR of HF in current SSRI users versus non-current SSRI users was 1.70 [95%CI 1.09-2.65]. Effects increased after confounder adjustment, PS stratification, and PS adjustment: HR 2.28 [1.45-3.59], 2.47 [1.54-3.95], and 2.51 [1.54-4.09], respectively.When MSMs with stabilized weights were used, the HR was 1.34 [0.65-2.76] and 1.53 [0.81-2.93] with and without accounting for censoring, respectively. After weight truncation, the HR became 2.09 [1.31-3.35] and 2.37 [1.49-3.78] with and without accounting for censoring, respectively. Conclusions: When treatment and confounders are time-varying, accounting for informative censoring can materially influence effect estimates in addition to the potential collider-stratification and confounding bias that arise due conditioning or stratification on time-dependent confounders.Hence, the use of methods such as MSMs is recommended.

Background: Pregnancy-induced hypertension (PIH) is possibly caused by an increased activity of the sympatic nervous system. Previous studies have suggested that inhibition of the re-uptake of serotonin and norepinephrine by selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) could contribute to this increased activity. Objectives: To assess the association between the use of antidepressants (ADs) and the development of pregnancyinduced hypertension. Methods: Using the prescription database IADB.nl we conducted a case-control study among pregnant women between 1995 and 2012. Cases were defined as>1 dispensed prescription of an antihypertensive drug (methyldopa, dihydralazine, ketanserin, labetalol, nifidepine) after 20weeks of gestation. Controls were matched for age at time of giving birth. Only first and singleton pregnancies of women not using any antihypertensive drug during 6months before pregnancy till 20weeks of gestation were included. Exposure was defined as>1 dispensed prescription of an antidepressant during pregnancy. Logistic regression analysis was used to estimate odds ratios (OR) and their corresponding 95% confidence intervals (95% CIs). Subanalyses were conducted for class of AD (TCA, SSRI, other) and duration of AD use (1-30, ≥ 31 Defined Daily Doses (DDDs)). As the exact duration of gestation was unknown, all analysis were conducted for 3 theoretical gestational ages (36, 38, 40weeks). Results: A total of 312 PIH cases and 12480 controls were included in the analysis (gestational age 36 weeks). The exposure rate among case and control pregnancies was 3.2% and 1.5% respectively. The use of AD increased the risk for developing PIH more than twice (OR [95% CI] 2.24 [1.17-4.27]). Significant associations (OR [95% CI]) were also found for the subgroups TCA (3.39 [1.04-11.08]), SSRI (2.23 [1.03-4.81]) and ≥ 31 DDDs (2.38 [1.16-4.90]). Increasing the theoretical gestational age showed comparable results. Conclusions: Prolonged use of ADs during pregnancy appeared to be associated with an increased risk of developing PIH. When balancing the benefit and risks of using these drugs during pregnancy, this should be taken into account.

Background: The use of antidepressants(AD,selective serotonin reuptake inhibitors,SSRI, or tricyclic antidepressants,TCA) has been associated with hip fractures(HF) in observational studies.However, it has been suggested that such results may be confounded by unmeasured patient characteristics. Objectives: To assess the effect of AD use on the risk of HF using self-controlled case series design. Methods: A self-controlled case series study was conducted in two primary care databases among patients with a first HF and a prescription for AD at any time during observation.Data were extracted from the UK THIN and the Dutch Mondriaan GP databases of the period 2001-2009.The incidence rate ratio(IRR) of HF for periods of AD use versus no AD use was estimated using conditional Poisson regression. Results: There were 6,632 and 136 HF patients for analysis in THIN and Mondriaan, respectively.After adjustment for age, an increased risk of HF was observed during the 30 day period after AD initiation: IRR 1.57 (95% CI, 1.39-1.78) in THIN and 3.22 (1.51-6.84) in Mondriaan.The increased risk was also observed during the next six months of AD use: IRR 1.52(1.39-1.65) in THIN and 2.76 (1.69-4.50) in Mondriaan.In the period after six months, the risk remained higher in THIN (IRR: 1.47; 1.31-1.65) but not significant in Mondriaan (IRR 1.94; 0.84-4.47). Furthermore, an increased risk of HF was observed during the 30 day period prior to AD initiation (IRR 1.22; 1.06-1.41) in THIN and (IRR 2.51; 1.00-6.33) in Mondriaan.In both THIN and Mondriaan, when cases were censored at the event times (HF) there appeared to be a substantial bias in IRR in all the periods: IRR during the 30 day period after AD initiation: 3.07 (2.66-3.54) in THIN and 12.34 (2.13-71.54) in Mondriaan.The risk of HF was higher in SSRI users than TCA users (4.39; 2.42-7.99 vs. 1.39; 0.58-2.41) in Mondriaan but was similar in THIN (1.49; 1.36- 1.63 vs. 1.49; 1.33-1.66). Conclusions: The incidence rate of hip fractures was higher in the periods both immediately after the start of AD use and during the first six months of AD use compared to periods of no use, although the magnitude of the risk varied between databases.

Background: Pregnancy-induced hypertension (PIH) is possibly caused by an increased activity of the sympatic nervous system. Previous studies have suggested that inhibition of the re-uptake of serotonin and norepinephrine by selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) could contribute to this increased activity. Objectives: To assess the association between the use of antidepressants (ADs) and the development of pregnancyinduced hypertension. Methods: Using the prescription database IADB.nl we conducted a case-control study among pregnant women between 1995 and 2012. Cases were defined as>1 dispensed prescription of an antihypertensive drug (methyldopa, dihydralazine, ketanserin, labetalol, nifidepine) after 20weeks of gestation. Controls were matched for age at time of giving birth. Only first and singleton pregnancies of women not using any antihypertensive drug during 6months before pregnancy till 20weeks of gestation were included. Exposure was defined as>1 dispensed prescription of an antidepressant during pregnancy. Logistic regression analysis was used to estimate odds ratios (OR) and their corresponding 95% confidence intervals (95% CIs). Subanalyses were conducted for class of AD (TCA, SSRI, other) and duration of AD use (1-30, ≥ 31 Defined Daily Doses (DDDs)). As the exact duration of gestation was unknown, all analysis were conducted for 3 theoretical gestational ages (36, 38, 40weeks). Results: A total of 312 PIH cases and 12480 controls were included in the analysis (gestational age 36 weeks). The exposure rate among case and control pregnancies was 3.2% and 1.5% respectively. The use of AD increased the risk for developing PIH more than twice (OR [95% CI] 2.24 [1.17-4.27]). Significant associations (OR [95% CI]) were also found for the subgroups TCA (3.39 [1.04-11.08]), SSRI (2.23 [1.03-4.81]) and ≥ 31 DDDs (2.38 [1.16-4.90]). Increasing the theoretical gestational age showed comparable results. Conclusions: Prolonged use of ADs during pregnancy appeared to be associated with an increased risk of developing PIH. When balancing the benefit and risks of using these drugs during pregnancy, this should be taken into account.

Objective: The rate of polypharmacy is increasing in patients with psychotic disorders. Polypharmacy is defined as the concomitant use of two or more drugs at a time. As most psychotropic medications are metabolized via the cytochrome enzyme system, it is easy to predict that polypharmacy will increase the risk of drug-drug interactions. This study was planned to evaluate the interaction risks of medications used by patients with a diagnosis of schizophrenia and schizoaffective disorder., Method: This study enrolled inpatients and outpatients of 18-65 years of age, diagnosed with schizophrenia or schizoaffective disorder according to the DSM-IV classification, who had been receiving antipsychotics for at least 12 weeks. Co-administration of antipsychotic and other psychotropic drugs for at least 4 weeks was recorded as polypharmacy. The risk of interaction was determined as follows: all medications one patient was using were sent to the internet site https://drugs.com as individual treatment regimens, and interaction information for healthcare specialists was used., Results: The study sample consisted of 240 patients (141 males; 58.8%; 99 females; 41.2%) in total, with the schizophrenia spectrum of diseases (schizophrenia, schizoaffective disorder). One hundred and thirty six (56.6%) patients used only one antipsychotic and 104 (43.4%) patients used 2 or more antipsychotics. The mean number of medications was 2.58±1.22 (min 1-max 6), the mean number of interactions was 1.90±2.04 (min 1-max 10). One hundred and seventy two (71.7%) patients were taking medications with a risk of interaction, with 417 total drug interaction risks. Of the interaction risks, 87.8% (total number 366) were at a moderate level. Approximately one quarter of the patients (n=42, 24.4%) were using medications with a major risk, and two patients (1.2%) were taking drugs with a minor risk of interaction. Among probable outcomes of drug interactions, the first 3 places were occupied by a risk of anticholinergic side effects, a risk of CNS or respiratory depression and a risk of QT prolongation., Conclusion: The present study reports that an important percentage of patients are exposed to drug-drug interactions with ever-increasing use of multiple medications in the schizophrenia spectrum of diseases, and among these interactions, most major risks were cardiovascular risks, especially QT prolongation. Prospective studies with larger numbers of patients are needed in this area. © 2014, Cukurova Univ Tip Fakultesi Psikiyatri Anabilim Dali. All rights reserved.

Recently, two importance articles about St. John's wort (Hypericum perforatum) appeared in the medical literature: a randomised clinical trial comparing St. John's wort with placebo and imipramine and a commentary about interactions between St. John's wort and registered medicines. These publications are discussed in the broader perspective of a benefit-risk assessment.

Objective: To collect data of toxicological cases for a 10-year period and to develop a database for comparing epidemiology of intoxications with data from the national poisoning information centre (NVIC) and national prescription data (GIP). Design: Retrospective database study. Methods: All drug intoxications between 1997 and 2006 were identified from the records of the Clinical Pharmaceutical and Toxicological Laboratory in The Hague, Netherlands. Patient demographics and details of drugs analysed were acquired. These data were compared with data from NVIC and GIP. Results and conclusion: Almost 6000 cases were reviewed. From 1997 to 2006 the number of toxicological cases in The Hague increased from 322 to 826 per year. From 2001-2005 >90% of toxicological cases comprised analgesics, antidepressants, antipsychotics and hypnotics. These drugs comprised 60-70% of cases reported to the PIC and 10-12% of prescriptions. Most drug intoxications in The Hague involved analgesics and psychopharmacologic drugs. Relative to prescription data, most intoxications occur with tricyclic antidepressants. There seems to be an imbalance between number of intoxications and prescriptions among SSRIs: citalopram is relatively more involved in intoxications than the other SSRIs, but more research is needed to confirm this.

Objective: To assess whether concerns and problems experienced with drug discontinuation occur more frequently in patients using antidepressants than in patients using benzodiazepines, antipsychotics or non-psychiatric medication. Clinical trials and epidemiological studies have shown that premature discontinuation is a major problem during antidepressant therapy. There is little information on how patients perceive treatment with antidepressants in clinical practice, and it is unclear whether patients perceive discontinuation as a problem. Design and methods: All calls to a Dutch national telephone medicines infotmation service received between 1990 and 2004 were examined retrospectively. Calls about discontinuation were identified and classified either as a genetal question about discontinuation, or as a problem experienced with discontinuation. These calls were grouped into four main classes: antidepressants, antipsychotics, benzodiazepines or non-psychiatric medicines. Results: Of all 39,786 registered phone calls, 6,159 (15-5%) related to antidepressants, 1,658 (4.2%) to antipsychotics and 3,916 (9.8%) to benzodiazepines. Patients calling about antidepressants called about discontinuation three times as often [odds ratio (OR) 2.8; 95% confidence interval (CI95) 2.6-3.0], and reported a problem with discontinuation five times more often (OR 5.4; CI95 4,6-6.3) than patients who called about non-psychiatric medicines. The proportion of questions about discontinuation and problems experienced with discontinuation was also higher in patients calling about benzodiazepines and antipsychotics than in patients calling about non-psychiatric medication. Conclusion: Patients perceive discontinuation of antidepressants, as well as discontinuation of antipsychotics and benzodiazepines, as a problem. Discontinuation seems a general problem for all psychiatric medicines, and needs more attention in the communication between patients and healthcare providers.

Background: Therapeutic Drug Monitoring (TDM) of Tricyclic Antidepressants (TADs) is considered useful in patients with major depressive disorders, since these drugs display large individual differences in clearance and therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (AMI), nortriptyline (NOR), imipramine (IMI) desipramine (DESI), clomipramine (CLOM) and desmethylclomipramine (DES-CLOM) in dried blood spots (DBS). Methods: A fast and robust LC-MS/MS method was developed and fully validated for simultaneous determination of AMI/NOR, IMI/DESI, or CLOM/ DES-CLOM in DBS. Nine millimetre circles were punched out from DBS collected on Whatman DMK-C paper and mixed with acetonitril:methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS Results: The assay was found to be linear in the range 20-500 mcg/L for all compounds. The Inter-assay variability (VC) and bias values are displayed below: The influence of punch position and blood volume per spot did not influence the results, but a low hematocrit (10% negative bias for all compounds. Comparison of venous blood samples with DBS samples revealed linear correlations and DBS/plasma ratio's ranging from 1.15 to 1.25. Conclusions: This fully validated method is suitable for determination of TADs in DBS and applicable for TDM. The method will be used to determine NOR in the Dutch CYSCE multicenter trial (ClincialTrail.gov Identifier NCT01778907) in which the effect of CYP2D6 genotyping combined with TDM on time to reach adequate blood drug levels will be investigated in depressed elderly patients.

OBJECTIVE: To compare the use of drugs for pulmonary diseases in children who were exposed to antidepressants in utero with non-exposed children. Some studies suggest an association between in utero exposure to antidepressants and the occurrence of pulmonary diseases later in life. Antidepressants are thought to be involved in the development of the respiratory rhythm generator and the maturation of surfactant formation. DESIGN AND METHODS: The pharmacy prescription database IADB.nl was used for a cohort study. The use of drugs for pulmonary diseases in children after in utero exposure to antidepressants was compared to children with no antidepressant exposure in utero. Drugs for pulmonary diseases were applied as a proxy for disturbed development of the respiratory tract. RESULTS: A small but significant increase in the incidence risk ratio (IRR) of the use of drugs for pulmonary diseases was found after anytime in utero exposure to serotonin reuptake inhibitors (SSRIs) (1.17; CI951.16-1.18). IRR also was increased for specific use of SSRIs in the first trimester (1.18; CI951.17-1.20). IRR increase for children who were exposed to tricyclic antidepressants was not statistically significant. As sample size was rather small in both groups, the effect size is modest and may also be confounded by maternal smoking. CONCLUSIONS: Children exposed to SSRIs in utero use significantly more drugs for pulmonary diseases, especially when exposure occurred during the first trimester of pregnancy. However, the increased use of such drugs may also be related to other factors.

Background Findings of brain structural changes in major depressive disorder are still inconsistent, partly because some crucial clinical variables have not been taken into account. Aims To investigate the effect of major depressive disorder on grey matter volumes. Method Voxel-based morphometry was used to compare 66 patients with depression at different illness stages (22 each with first-episode, remitted recurrent and treatment resistant/chronic depression) with 32 healthy controls. Brain volumes were correlated with clinical variables. Results Voxel-based morphometry showed a significant group effect in right superior frontal gyrus, left medial frontal gyrus and left cingulate gyrus (P

Data from 134 patients who were treated with clozapine are analysed in order to determine the influence of age, gender and comedication on the pharmacokinetics of clozapine. Serum concentration was corrected for the daily dose administered. Female patients had a statistically significant higher corrected serum concentration of clozapine than male patients. In female patients, corrected serum concentration tended to increase from

Purpose: The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed. Methods: Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age. Results: Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs. Conclusion: Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association.

Purpose: To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases. Methods: The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases. Results: The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to >10years and different types of cancer. Conclusions: A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.

Background Although pharmacological and psychological interventions are both effective for major depression, antidepressant drugs are frequently used as first-line treatment in primary and secondary care settings. Milnacipran, a dual serotonin-norepinephrine reuptake inhibitor (SNRI), is one of the antidepressant drugs that clinicians use for routine depression care. Objectives To assess the evidence for the efficacy, acceptability and tolerability of milnacipran in comparison with tricyclic antidepressants (TCAs), heterocyclics, SSRIs and other newer antidepressive agents in the acute-phase treatment of major depression. Search methods The Cochrane Collaboration Depression, Anxiety & Neurosis review group Controlled Trials Register (CCDANCTR-Studies and CCDANCTR-References) were electronically searched in August 2008. References of relevant trials and other reviews were also checked. Trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished trials were hand-searched in 2007. All relevant authors were contacted for supplemental data. No language restriction was applied. Selection criteria Randomised controlled trials comparing milnacipran with any other active antidepressive agents (including non-conventional agents such as herbal products like hypericum) as monotherapy in the acute phase of major depression were selected. Data collection and analysis Two reviewers independently checked eligibility, assessed methodological quality and extracted data from the eligible trials using a standardised data extraction form. The number of participants who responded to treatment or those who achieved remission were calculated on an intention-to-treat basis. Random-effects meta-analyses were conducted, combining data from the included trials. Main results A total of 16 randomised controlled trials (n=2277) were included in the meta-analysis.Despite the size of this sample, the pooled 95% confidence intervals were rather wide and there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressive agents. However, compared with TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse events (OR 0.55; 95%CI 0.35 to 0.85). There was also some weak evidence to suggest that patients taking milnacipran experienced fewer adverse events of sleepiness/ drowsiness, dry mouth or constipation compared with TCAs. Authors' conclusions Currently, there is inadequate evidence to conclude whether milnacipran is superior, inferior or the same as other antidepressive agents in terms of efficacy, acceptability and tolerability in the acute phase treatment of major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of dropouts due to adverse events (acceptability) and the rates of experiencing adverse events (tolerability). Information about other clinically meaningful outcomes such as cost-effectiveness and social functioning, including the ability to return to work, is lacking. Further study is needed to answer whether milnacipran would be the better choice of antidepressant for acute major depression.

These consensus guidelines have been developed by a group of Latin American experts in pain management, to point out patterns and make practical recommendations to guide the diagnosis, identify warning signs (yellow and red flags), and establish comprehensive medical management (pharmacologic and nonpharmacologic treatment) and monitoring plans for patients enduring neuropathic pain. From the viewpoint of pharmacologic management, drugs are classified into groups according to efficacy, availability/accessibility, and safety criteria. Drugs are recommended for use depending on the disease and particular circumstances of each patient, with an approach that favors multimodal treatment while taking into consideration the idiosyncrasies of medical practice in Latin America.

Objective: To assess whether concerns and problems experienced with drug discontinuation occur more frequently in patients using antidepressants than in patients using benzodiazepines, antipsychotics or non-psychiatric medication. Clinical trials and epidemiological studies have shown that premature discontinuation is a major problem during antidepressant therapy. There is little information on how patients perceive treatment with antidepressants in clinical practice, and it is unclear whether patients perceive discontinuation as a problem. Design and methods: All calls to a Dutch national telephone medicines infotmation service received between 1990 and 2004 were examined retrospectively. Calls about discontinuation were identified and classified either as a genetal question about discontinuation, or as a problem experienced with discontinuation. These calls were grouped into four main classes: antidepressants, antipsychotics, benzodiazepines or non-psychiatric medicines. Results: Of all 39,786 registered phone calls, 6,159 (15-5%) related to antidepressants, 1,658 (4.2%) to antipsychotics and 3,916 (9.8%) to benzodiazepines. Patients calling about antidepressants called about discontinuation three times as often [odds ratio (OR) 2.8; 95% confidence interval (CI95) 2.6-3.0], and reported a problem with discontinuation five times more often (OR 5.4; CI95 4,6-6.3) than patients who called about non-psychiatric medicines. The proportion of questions about discontinuation and problems experienced with discontinuation was also higher in patients calling about benzodiazepines and antipsychotics than in patients calling about non-psychiatric medication. Conclusion: Patients perceive discontinuation of antidepressants, as well as discontinuation of antipsychotics and benzodiazepines, as a problem. Discontinuation seems a general problem for all psychiatric medicines, and needs more attention in the communication between patients and healthcare providers.

Tricyclic antidepressant overdose is one of the most common causes of serious drug poisoning in children and adults. We report a 17-month-old girl with severe amitriptyline intoxication. She was admitted to hospital because of lethargy and seizures. It was estimated that she took approximately 75 mg/kg of amitriptyline 2 h before admission. On examination she was comatose, had ventricular tachycardia and multifocal clonic seizures. Intravenous fluid, per oral activated charcoal, diazepam, lidocaine, and sodium bicarbonate infusion were given. However, there was no response to this therapy, and the patient remained in a deep coma with cardiac arrhythmias and seizures. Hemoperfusion ( HP) was performed for 2 h. During this procedure, cardioversion was used six times due to ventricular fibrillation. She had a very good clinical response to HP and no complication was observed. We suggest that HP may be an effective treatment in children with severe amitriptyline intoxication.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:21:10Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:39:50Z : No. of bitstreams: 1 2-s2.0-10644263663.pdf: 71880 bytes, checksum: 5818b4d38d74a593babc54b276f5c71c (MD5) Made available in DSpace on 2014-05-27T11:21:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2004-11-01 BACKGROUND AND OBJECTIVES: Before epídural steroids were used in chronic lumbar pain, subarachnoid injection of these agents was the treatment of choice. Although still preconized by some authors, this technique may lead to severe complications with neurological sequelae. This report aimed at describing a case of accidental subarachnoid injection of steroid associated to local anesthetics during epidural puncture to treat lumbar pain. CASE REPORT: Male patient, 46 years old, followed byneuro-surgery for presenting right sciatic pain for 9 month, refractory to clinical treatment due to L 4-L 5 disk protrusion confirmed by CT scan, without neurological deficit. Epidural puncture for pain treatment was performed in L 4-L 5 with 17G needle and 10 mL solution were injected containing 4 mL of 0.25% bupivacaine, 80 mg methylprednisolone and 4 mL of 0.9% saline. Although there has not been CSF reflux, 5 minutes after injection there were sensory block in T 4 and motor block in T 6, associated to blood pressure and heart rate decrease. CONCLUSIONS: Accidental subarachnoid injections with the association of steroids for pain relief may cause adverse effects. There are several risks, varying from mild transient symptoms to nervous injuries, including spinal cord injuries. Our patient had no sequelae from the accidental subarachnoid injection, probably because it has been a single injection. CET/SBA Depto. de Anestesiol. da FM - UNESP Ctro. Paulista de Cir. Plast. de Jau , Rua Jamil Sarkis, 135, Jardim Alvorada 17210-39O Jau, SP CET/SBA Depto. de Anestesiol. da FM - UNESP

Flumazenil is a competitive inhibitor of the GABA receptor which effectively counteracts the effects of benzodiazepine overdose. It is considered to be safe, although infrequent adverse effects, including seizures, have been described. We present the case of a 30-year-old patient who was found in coma after taking an unknown amount of benzodiazepines and tricyclic antidepressants in an attempt to commit suicide After the administration of flumazenil, the patient suffered generalized tonic-clonic seizure. The patient was admitted to the ICU due to respiratory insufficiency secondary to broncoaspiration, with a satisfactory evolution after 48 hours. The risk factors for the development of seizure after flumazenil admisnistracion are discussed, recomendation for its safe use are suggested.

Repetitive transcranial magnetic stimulation (rTMS) has been found to exert modest to substantial antidepressant effects in the majority of prior clinical studies. As effect sizes and stimulation conditions have varied greatly, controversy persists regarding effective stimulation parameters (e.g. intensity, frequency, localization). In the present controlled study, we investigated whether the antidepressant efficacy of rTMS may be related to the stimulation intensity applied. Thirty-one patients suffering from a pharmacotherapy-resistant major depressive episode were randomly assigned to three treatment groups receiving rTMS at different stimulation intensities: (1) intensity at the individual motor threshold (MT); (2) 90% subthreshold intensity; and (3) low intensity of standard sham rTMS. Each patient underwent 10 sessions of 10 Hz rTMS with 1500 stimuli/day over the left dorsolateral prefrontal cortex. Improvement of depressive symptoms after rTMS significantly increased with stimulation intensity across the three groups. A 30% to 33% reduction of baseline depression scores was observed after rTMS at MT intensity. Similarly, groups differed significantly regarding the clinical course after rTMS with the lowest number of antidepressant interventions and the shortest hospital stay in the MT intensity group. These findings support the hypothesis of a relationship between stimulation intensity of rTMS and its antidepressant efficacy.

Background: Instrumental variable (IV) analysis can reduce bias due to unmeasured confounding, yet it has not been widely used in pharmacoepidemiologic studies. Objectives: To assess the performance of several IVs across multiple databases in a study of antidepressant use and risk of hip/femur fracture (HF). Methods: Information on adult patients with at least one prescription of a selective serotonin reuptake inhibitor (SSRI) or tricyclic antidepressant (TCA) during 2001-2009 was extracted from three European databases: THIN (UK, n = 570139), BIFAP (Spain, n = 250865), and Mondriaan (Netherlands, n = 22474). Conventional Cox model and two-stage IV analysis were applied to estimate the risk of HF associated to initiation of SSRI vs. TCA. IVs were created using the proportion of SSRI prescriptions per practice (PSP) or using the number, one (PPP1), five (PPP5) or ten (PPP10), of previous prescriptions by a physician. Quantitative methods (e.g. correlation (r), standardized difference (SDif)) were used to assess the validity of IVs. 95% confidence intervals (CI) in IV analysis were estimated using bootstrapping. Results: Conventional analysis showed that SSRI use was associated with an increased risk of HF in BIFAP and THIN, hazard ratio (HR) 1.35 [95%CI 1.18-1.56] and 1.35 [1.26-1.44], respectively and similarly in Mondriaan (though not significant), HR 1.36 [0.86-2.15]. The IVs PSP (THIN and BIFAP) and PPP10 (THIN and Mondriaan) were strongly associated (r>0.15) with SSRI prescribing and independent of confounders (SDif

Recently, two importance articles about St. John's wort (Hypericum perforatum) appeared in the medical literature: a randomised clinical trial comparing St. John's wort with placebo and imipramine and a commentary about interactions between St. John's wort and registered medicines. These publications are discussed in the broader perspective of a benefit-risk assessment.

Background: Therapeutic Drug Monitoring (TDM) of Tricyclic Antidepressants (TADs) is considered useful in patients with major depressive disorders, since these drugs display large individual differences in clearance and therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (AMI), nortriptyline (NOR), imipramine (IMI) desipramine (DESI), clomipramine (CLOM) and desmethylclomipramine (DES-CLOM) in dried blood spots (DBS). Methods: A fast and robust LC-MS/MS method was developed and fully validated for simultaneous determination of AMI/NOR, IMI/DESI, or CLOM/ DES-CLOM in DBS. Nine millimetre circles were punched out from DBS collected on Whatman DMK-C paper and mixed with acetonitril:methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS Results: The assay was found to be linear in the range 20-500 mcg/L for all compounds. The Inter-assay variability (VC) and bias values are displayed below: The influence of punch position and blood volume per spot did not influence the results, but a low hematocrit (10% negative bias for all compounds. Comparison of venous blood samples with DBS samples revealed linear correlations and DBS/plasma ratio's ranging from 1.15 to 1.25. Conclusions: This fully validated method is suitable for determination of TADs in DBS and applicable for TDM. The method will be used to determine NOR in the Dutch CYSCE multicenter trial (ClincialTrail.gov Identifier NCT01778907) in which the effect of CYP2D6 genotyping combined with TDM on time to reach adequate blood drug levels will be investigated in depressed elderly patients.

Data from 134 patients who were treated with clozapine are analysed in order to determine the influence of age, gender and comedication on the pharmacokinetics of clozapine. Serum concentration was corrected for the daily dose administered. Female patients had a statistically significant higher corrected serum concentration of clozapine than male patients. In female patients, corrected serum concentration tended to increase from