Core Discrete Event Simulation Model for the Evaluation of Health Care Technologies in Major Depressive Disorder

ObjectiveA review of existing economic models in major depressive disorder (MDD) highlighted the need for models with longer time horizons that also account for heterogeneity in treatment pathways between patients. A core discrete event simulation model was developed to estimate health and cost outcomes associated with alternative treatment strategies.MethodsThis model simulated short- and long-term clinical events (partial response, remission, relapse, recovery, and recurrence), adverse events, and treatment changes (titration, switch, addition, and discontinuation) over up to 5 years. Several treatment pathways were defined on the basis of fictitious antidepressants with three levels of efficacy, tolerability, and price (low, medium, and high) from first line to third line. The model was populated with input data from the literature for the UK setting. Model outputs include time in different health states, quality-adjusted life-years (QALYs), and costs from National Health Service and societal perspectives. The codes are open source.ResultsPredicted costs and QALYs from this model are within the range of results from previous economic evaluations. The largest cost components from the payer perspective were physician visits and hospitalizations. Key parameters driving the predicted costs and QALYs were utility values, effectiveness, and frequency of physician visits. Differences in QALYs and costs between two strategies with different effectiveness increased approximately twofold when the time horizon increased from 1 to 5 years.ConclusionThe discrete event simulation model can provide a more comprehensive evaluation of different therapeutic options in MDD, compared with existing Markov models, and can be used to compare a wide range of health care technologies in various groups of patients with MDD.     

Disparities in antidepressant treatment in Medicaid elderly diagnosed with depression

OBJECTIVES: To determine whether there were racial or ethnic disparities in the use of antidepressants in low-income elderly patients insured by Medicaid. DESIGN: Examination of 1998 Medicaid claims data. SETTING: Centers for Medicare and Medicaid Services Medicaid claims data for five U.S. states. PARTICIPANTS: All Medicaid recipients aged 65 to 84 with a diagnosis of depression. MEASUREMENTS: Treatment versus no treatment; in those treated, treatment with drugs was classified as old- or new-generation antidepressants. RESULTS: In 1998, 7,339 unique individuals aged 65 to 84 had at least one outpatient encounter with depression as the primary diagnosis. Nearly one in four (24.2%) received no antidepressant drug therapy, and 22% received neither psychotherapy nor an antidepressant. African-American individuals were substantially more likely to be untreated (37.1%) than Hispanic (23.6%), white (22.4%), or Asian (13.8%) individuals. In logistic regression models adjusting for sex, state, long-term care status, and age group, African Americans with a primary diagnosis of depression were almost twice as likely as whites not to receive an antidepressant within the study period (odds ratio=1.91, 95% confidence interval=1.62-2.24). Patients in long-term care facilities and those aged 65 to 74 were less likely to receive treatment. CONCLUSION: Substantial numbers of elderly Medicaid enrollees with a primary diagnosis of depression did not receive antidepressants or behavioral therapy. This gap in care disproportionately affected African-American patients.     

抗幽门螺杆菌联合抗抑郁药治疗功能性消化不良疗效观察

目的观察抗幽门螺杆菌联合抗抑郁药、心理疏导辅助治疗伴有焦虑抑郁状态且幽门螺杆菌H.pylori（＋）功能性消化不良（FD）的疗效。方法采用Zung焦虑自评量表（SAS 5.0）和抑郁自评量表（SDS 5.0）筛选出符合罗马Ⅲ诊断标准伴有焦虑抑郁状态的H.pylori（＋）FD患者60例,随即分为A、B两组,A组（n=30）抗幽门螺杆菌联合抗抑郁药黛力新及心理疏导辅助治疗,B组（n=30）仅使用抗幽门螺杆菌治疗,两组患者于停药4周后复查14C-尿素呼气试验以评估H.pylori根除率,比较两组治疗前后症状改善情况、SDS评分。结果 A、B两组临床症状均改善,A组较明显,两组H.p根除率分别为82.5%8,0%,差异无统计学意义（P〉0.05）,A组抑郁量表评分较治疗前提高（P〈0.05）,且与B组比较,差异有统计学意义（P〈0.05）。结论抗幽门螺杆菌联合抗抑郁药、心理疏导辅助治疗伴有焦虑抑郁状态的FD,疗效优于单一使用抗幽门螺杆菌治疗。     

新型抗抑郁剂单用与合用氟哌噻吨美利曲辛片治疗躯体形式障碍对照研究

目的:探讨分析新型抗抑郁剂单用与合用氟哌噻吨美利曲辛片(黛力新)治疗躯体形式障碍患者的临床疗效。方法:收集我院2007年5月～2010年7月,门诊治疗的80例躯体形式障碍患者临床资料,随机分为治疗组和对照组,每组患者40例。对照组20例患者应用新型抗抑郁剂五羟色胺再摄取抑制剂-"帕罗西汀"(赛乐特)单药进行治疗,另20例患者应用新型抗抑郁剂五羟色胺和去甲肾上腺素再摄取抑制剂-"文拉法辛"(怡诺思)单药进行治疗:治疗组20例患者应用赛乐特合用黛力新进行治疗,另20例患者应用怡诺思合用黛力新进行治疗。两组均连续治疗8周应用SDS(抑郁自评量表)、SAS(焦虑自评表)量表观察两组治疗8周后的疗效。结果:治疗组40例患者经应用新型抗抑郁剂合用黛力新治疗8周后,痊愈患者22例,显效患者4例,好转患者8例,无效患者6例(有效率85%)。对照组40例患者经应用新型抗抑郁剂单药治疗8周后,痊愈患者18例,显效患者6例,好转患者6例,无效患者I0例(有效率75%)。两组患者有效率差异显著(P<0.05)。应用SDS(抑郁自评量表)、SAS(焦虑自评表)量表观察两组治疗8周后的疗效,两组评分差异显著(P<0.05)。结论:应用新型抗抑郁剂合用黛力新治疗躯体形式障碍患者,临床疗效佳,值得临床推广。     

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

In the search for antidepressants'' (ADs'') mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different ADs on autophagic processes in rat primary astrocytes and neurons. Autophagy has a significant role in controlling protein turnover and energy supply. Both, the tricyclic AD amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced upregulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II-positive structures indicative of autophagosomes, which associated with AVs in a time-dependent manner. Deletion of Atg5, representing a central mediator of autophagy in MEFs, led to abrogation of AMI-induced LC3B-I/II conversion. By contrast, VEN, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class-III PI3 kinase-dependent pathways as 3-methyladenine slightly diminished the effects of AMI. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI- and CIT-mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct ADs promote autophagy in neural cells, with important implications on energy homeostasis.     

Hair analysis of antidepressants and antipsychotics—Overview of quantitative data

Antidepressant and antipsychotic drugs are regularly encountered in different aspects of forensic toxicology, and some cases require the examination of hair samples. In this study, common antidepressant and antipsychotic drugs regarding hair concentrations over the past decades were reviewed. Although numerous publications around method validations, case reports, or controlled dose studies were found, apparently there is a lack of comprehensive data for many substances. Information on the hair length and dosage across the publications varied largely, and case numbers were generally low except for several retrospective controlled dose studies. Many substances were described only in method validations or case reports, and data were obtained from small case numbers. On the contrary, clozapine, haloperidol, amitriptyline, nortriptyline, risperidone and its metabolite, methylphenidate, citalopram, chlorpromazine, chlorprothixene, and quetiapine had a well‐founded database as these substances were investigated in controlled dose studies with higher case numbers. Given the advancements made in analytical techniques over the past years, gas chromatography–mass spectrometry and liquid chromatography with tandem mass spectrometry techniques were the methods of choice and allowed the detection of chemical compounds at low concentrations. The controversy around a potential use of hair analysis to estimate the dosage remains as dose‐concentration studies provided divergent results. A harmonization on the investigated hair length as well as on the extraction protocol would be of favor to achieve better comparability. Although hair analysis research focused mainly on drug abuse, availability of more data on antidepressants and antipsychotics would help to gain better knowledge and assist other forensic investigators.     

Segmental analysis of antidepressant and antipsychotic drugs in the hair of schizophrenic patients

Hair analysis is useful for documenting long‐term exposure to drugs. The potential of hair analysis for therapeutic drug monitoring within the forensic field has been studied, but reference values for some antidepressants and antipsychotics in the hair of individuals undergoing chronic therapy are still lacking. In the present study, a method was developed and validated for the determination of 23 analytes, including antidepressants, antipsychotics, and related metabolites, in human hair by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Hair samples (10 mg) were extracted with a 25:25:50 (v/v/v) mixture of methanol/acetonitrile/2 mM ammonium formate (8% acetonitrile, pH 5.3) utilizing cryogenic grinding. The present method demonstrated sufficient selectivity, robustness, and accuracy. Sixteen analytes in hair were reported in 46 psychiatric patients receiving fixed drug dosages. To the best of our knowledge, the hair concentrations of perphenazine and norolanzapine, as well as the concentrations of amisulpride, aripiprazole and its metabolite dehydroaripiprazole, olanzapine, and sulpiride, in hair from individuals receiving fixed dosages is reported for the first time. A significant relationship between the administered dose and the concentration in the proximal hair segment was found only for clozapine, norclozapine, and chlorpromazine. The results confirmed that the idea of using hair concentrations to monitor a daily dose is inapplicable.     

Polypharmacy in schizophrenia

Schizophrenia is a severe mental disorder characterized by a heterogeneous symptom profile which comprises a clinical platform for widespread use of polypharmacy even though antipsychotic monotherapy is the recommended treatment regimen. This narrative review provides a summary of the current gap between evidence and practice for use of antipsychotic combination therapy in patients with schizophrenia. Antipsychotic polypharmacy is frequently prescribed instead of following international consensus of clozapine monotherapy in treatment‐resistant patients. Antipsychotic‐benzodiazepine combination therapy clearly has a role in the treatment of acute agitation whereas there is no evidence to support an effect on core schizophrenia symptoms when chronically prescribed. Antidepressants are typically added to antipsychotic treatment in case of persistent negative symptoms. Available evidence suggests that antidepressants may improve negative symptom control in schizophrenia. Combining an antipsychotic with an antiepileptic is not supported by any firm evidence, but individual mood stabilizers have come out positively in single trials. Generally, the evidence base for polypharmacy in schizophrenia maintenance treatment is sparse but may be warranted in certain clinical situations. Therapeutic benefits and side effects should be carefully monitored and considered to ensure a beneficial risk‐benefit ratio if prescribing polypharmacy for specific clinical indications.     

cGMP Signaling, Phosphodiesterases and Major Depressive Disorder

Deficits in neuroplasticity are hypothesized to underlie the pathophysiology of major depressive disorder (MDD): the effectiveness of antidepressants is thought to be related to the normalization of disrupted synaptic transmission and neurogenesis. The cyclic adenosine monophosphate (cAMP) signaling cascade has received considerable attention for its role in neuroplasticity and MDD. However components of a closely related pathway, the cyclic guanosine monophosphate (cGMP) have been studied with much lower intensity, even though this signaling transduction cascade is also expressed in the brain and the activity of this pathway has been implicated in learning and memory processes. Cyclic GMP acts as a second messenger; it amplifies signals received at postsynaptic receptors and activates downstream effector molecules resulting in gene expression changes and neuronal responses. Phosphodiesterase (PDE) enzymes degrade cGMP into 5’GMP and therefore they are involved in the regulation of intracellular levels of cGMP. Here we review a growing body of evidence suggesting that the cGMP signaling cascade warrants further investigation for its involvement in MDD and antidepressant action.