综合医院门诊抑郁障碍和焦虑障碍患者处方变化分析

目的 调查某大型三甲综合医院门诊抑郁障碍和焦虑障碍的处方5年前后变化情况,分析临床药物治疗演变规律。方法 以2010年及2015年全年作为2个调查时段,根据相关诊断导出相对应的处方,分析比较其中的精神类药物的使用情况。结果 2015年抑郁障碍和焦虑障碍门诊治疗上使用占比高的药物分别为选择性5-HT再摄取抑制剂(SSRI,27%)、第二代抗精神病药(SGA,19.9%)、苯二氮卓类(BDZ,18.5%)及选择性5-HT/NE再摄取抑制剂(SNRI,15.5%),单药治疗中SSRI(51.7%)及SNRI(40%)占有相当大的比例,联合治疗中占比高的为SSRI(31.8%)、SGA(26%)及SNRI(17.4%);2015年较2010年相比,β受体阻断剂及三环类占比明显下降,联用药物数量较之前明显减少,从3药联合变为以双药联合治疗为主。结论 综合医院抑郁障碍和焦虑障碍门诊治疗药物选择较5年前更加规范和个体化;选择疗效良好、不良反应轻微的药物及联合用药已成为主要趋势。     

Efficacy of levomilnacipran extended release in treating major depressive disorder

Introduction: Major depressive disorder (MDD) is the leading cause of disability worldwide with a heterogeneous symptom profile. Levomilnacipran extended release (ER) (Fetzima), a SNRI, has been approved by the Food and Drug Administration for treatment of MDD. While categorized as a SNRI, in contradistinction to other approved SNRIs, levomilnacipran exhibits differential affinity for the norepinephrine reuptake transporter when compared to the serotonin reuptake transporter.

Areas covered: Completed clinical trials which focused on levomilnacipran ER administered in those with MDD were included in this drug evaluation.

Expert opinion: Levomilnacipran ER, like all other first-line antidepressants exhibits significant efficacy in reducing total symptom severity. Levomilnacipran ER is particularly effective at improving measures of motivation, energy, and interest. Head to head comparative trials are not available with other antidepressants, and consequently, there are no claims of superior efficacy when compared to alternative antidepressants. Notwithstanding, it would be a viable and testable hypothesis that differential efficacy in favor of levomilnacipran may be obtained across select dimensions of depressive symptoms (e.g., fatigue and lack of motivation). Unfortunately, rigorous studies evaluating levomilnacipran for cognitive function in MDD have not been conducted. Levomilnacipran ER is generally well tolerated with minimal propensity for metabolic and weight disturbance.     

Vortioxetine: a review of efficacy,safety and tolerability with a focus on cognitive symptoms in major depressive disorder

Introduction: Vortioxetine is a pharmacodynamically novel antidepressant that exerts effects on various neurotransmitters including serotonin, noradrenaline, dopamine, glutamate, histamine and acetylcholine. Its efficacy in the symptomatic management of major depressive disorder (MDD) has been established in several short- and long-term trials. Vortioxetine has also demonstrated independent pro-cognitive effects in adults with MDD.

Areas covered: This report provides a concise review of the pharmacology, efficacy and safety of vortioxetine as they pertain to cognition.

Expert opinion: The significant impact of cognitive dysfunction in MDD has achieved increased consideration among researchers over the past decade. Vortioxetine is the first antidepressant agent to demonstrate meaningful clinical efficacy in the improvement of cognition in adults with MDD, independent of improvement in affective symptomatology. These results provide the impetus for further study into the potential pro-cognitive effects of vortioxetine in other conditions wherein cognitive dysfunction is prominent.     

Animal models of major depressive disorder and the implications for drug discovery and development

Introduction: Depression is a highly debilitating psychiatric disorder that affects the global population and causes severe disabilities and suicide. Depression pathogenesis remains poorly understood, and the disorder is often treatment-resistant and recurrent, necessitating the development of novel therapies, models and concepts in this field.

Areas covered: Animal models are indispensable for translational biological psychiatry, and markedly advance the study of depression. Novel approaches continuously emerge that may help untangle the disorder heterogeneity and unclear categories of disease classification systems. Some of these approaches include widening the spectrum of model species used for translational research, using a broader range of test paradigms, exploring new pathogenic pathways and biomarkers, and focusing more closely on processes beyond neural cells (e.g. glial, inflammatory and metabolic deficits).

Expert opinion: Dividing the core symptoms into easily translatable, evolutionarily conserved phenotypes is an effective way to reevaluate current depression modeling. Conceptually novel approaches based on the endophenotype paradigm, cross-species trait genetics and ‘domain interplay concept’, as well as using a wider spectrum of model organisms and target systems will enhance experimental modeling of depression and antidepressant drug discovery.     

Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of four short-term studies

ABSTRACT

Background: There is a need for effective, safe and well-tolerated pharmacotherapies for patients with major depressive disorder (MDD) who have inadequate response to antidepressant treatments (ADTs). This analysis aimed to summarize the short-term efficacy and safety of adjunctive brexpiprazole in adults with MDD.

Research design and methods: A pooled analysis of data from the 6-week, randomized, double-blind treatment phases of four studies of adjunctive brexpiprazole 1–3 mg/day versus placebo in outpatients with MDD and inadequate response to ADTs (n = 1,853). Efficacy was measured by Montgomery–Åsberg Depression Rating Scale (MADRS) scores, and safety by treatment-emergent adverse events (TEAEs).

Results: ADT + brexpiprazole 2–3 mg/day showed greater improvement in MADRS Total score from baseline to Week 6 than ADT + placebo (least squares mean difference: ?2.15; confidence limits: ?2.82, ?1.48; p < 0.0001; Cohen’s d effect size: 0.33). TEAEs with incidence ≥5% with ADT + brexpiprazole 1–3 mg/day were akathisia (8.0% versus 2.6% with ADT + placebo), headache (5.8% versus 6.0%), and weight increased (5.8% versus 1.6%).

Conclusions: Adjunctive brexpiprazole is an efficacious and well-tolerated treatment option for adult patients with MDD and inadequate response to ADTs. Study limitations included a lack of active comparator.     

SOD2 genetic polymorphism (rs4880) has no impact on 6‐month response to antidepressant treatment and inflammatory biomarkers in depressed patients

Two thirds of patients suffering from a major depressive episode (MDE) do not reach a complete response with antidepressant drugs. This lack of response is due to several factors, including genetic determinants. Since major depressive disorder is associated with inflammatory and oxidative stress abnormalities, the metabolism of superoxide anions might be involved in non‐response to antidepressant drugs. Superoxide anions are metabolized by manganese‐dependent superoxide dismutase (SOD2) in the mitochondria. A functional genetic polymorphism (SOD2, rs4880), responsible of a 40% reduction in enzyme activity, is associated with anti‐inflammatory response of rosuvastatin. We investigated the association of ala‐allele of SOD2 rs4880 and both antidepressant efficacy and inflammatory parameters in patients treated for a MDE with antidepressant drugs. The Hamilton Depression Rating Scale (HDRS) score and levels of plasma CRP and inflammatory cytokines were assessed at baseline, one month (M1), 3 months (M3) and 6 months (M6) after antidepressant treatment. They were compared according to SOD2 genetic polymorphism. Of the 484 patients studied, 361 (74.6%) carried the ala‐allele (Ala group), 123 (25.4%) of them had Val/Val genotype (Val/Val group). No significant difference was observed between the Ala and Val/Val groups neither for baseline clinical characteristics, nor for HDRS scores, response/remission rates, plasma CRP and cytokine levels throughout the study. The rs4880 SOD2 genetic polymorphism was not associated with the clinical response and cytokines levels after antidepressant treatment. These data suggest that SOD2 is not a major genetic determinant of antidepressant response. Other genes of the oxidative stress pathways should be explored in further studies.     

Milnacipran plasma levels and antidepressant response in Japanese major depressive patients

The relationship between antidepressant effects and plasma levels of milnacipran was studied in 49 cases of major depression without psychotic features during 6 weeks of milnacipran treatment. The daily dose of milnacipran was 50 mg/day for the first week, and up to 100 mg/day thereafter. Depressive symptoms were evaluated by the Montgomery and Asberg depression rating scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of this study. Thirty-four patients (69.4%) were responders (defined as a 50% or greater decrease in the baseline MADRS score). Significant differences of MADRS scores were seen from 1 week after the beginning of this study (p=0.004, unpaired t-test) between responders and nonresponders. The mean plasma milnacipran level of responders, 82.0 +/- 29.4 ng/ml, was similar to that of non-responders, 78.6+/-23.1 ng/ml; there was no significant difference between responders and nonresponders. Neither a significant linear nor a curvilinear relationship was obtained between the final MADRS score and the plasma levels of milnacipran. Although there was no significant relationship between the plasma levels of milnacipran and the antidepressant response, milnacipran should be considered an efficacious agent in the treatment of major depressive patients.     

Novel routes to bipolar disorder drug discovery

Introduction: Bipolar disorder (BD) is a severe and chronic medical condition typified by episodic recurrent mania (or hypomania) in addition to major depression. BD is associated with a number of negative outcomes including premature death, reduced quality of life and can also lead to other complications including impaired cognitive function. Unfortunately, the currently available pharmacological treatments for BD are insufficient for many with the condition.

Areas covered: This review focuses on known therapeutic targets of mood stabilizing drugs including: the glycogen synthase kinase-3 (GSK-3), the phosphoinositide pathway and protein kinase C (PKC), the brain-derived neurotrophic factor (BDNF), and histone deacetylases (HDACs). This article also presents new promising therapeutic targets including: the glutamatergic pathway, mitochondrial modulators, neuropeptide-converting endopeptidases, the insulin transduction pathway, the purinergic system and the melatoninergic system.

Expert opinion: Challenges in improving methods and tools to generate, integrate and analyze high-dimensional data are required to allow opening novel routes to BD drug discovery. Through the application of systems biology approaches and the use of bioinformatical tools to integrate all omics data, it will be possible in the near future to gain deeper insights into pathophysiology of BD. This will in turn lead to the identification and exploitation of new potential therapeutic approaches.     

Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM

Background:

Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants.

Methods:

We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[¹⁸F]fluorophenylthio)benzylamine (4-[¹⁸F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more.

Results:

Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders.

Conclusions:

The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD.     

Pharmacological management of depression in patients with multiple sclerosis

ABSTRACT

Introduction: The pharmacotherapeutic management of depression in patients with multiple sclerosis (MS) is a matter of debate that cannot be decided from the evidence available in the current literature. Therefore, its management essentially relies on the clinical experience of the prescribing clinician rather than on evidence-based approaches.

Areas covered: This review provides a clinically oriented critical perspective on the connection between MS and major depressive disorder (MDD) or depression associated with bipolar disorder (BD), focusing on its optimal pharmacotherapy. Both clinical and pharmacological considerations are accounted in order to promote rational pharmacotherapy, both in terms of efficacy and tolerability.

Expert opinion: Despite its clinical burden and relatively frequent occurrence, the interplay of MS and depression still requires further controlled trials to better clarify the appropriate pharmacotherapy across varying ‘diseases categories’ of MS itself, as well as discriminating between depressive symptoms that do not necessarily reach the threshold of either MDD or BD. Additional insight into new mood-tolerated neurological pharmacotherapy for MS is likewise warranted toward a more effective, immune- and patient-tailored pharmacotherapy, while promoting innovation in drug design, with the ultimate goal of enhancing the overall quality life of the affected individual, his/her caregivers, and to reduce the associated economic and social burden.     

Agomelatine in depression

Introduction: Agomelatine is a relatively new antidepressant with a mechanism of action that is different from other antidepressants: it is a melatonergic agonist and a 5-HT2C antagonist. It is an effective treatment for depression, with relatively mild side effects. It may be a valuable pharmacological alternative in the clinical approach on depression.

Areas covered: The literature about agomelatine has been comprehensively reviewed. Agomelatine's efficacy, safety and tolerability are reviewed based on the studies undertaken in patients with major depressive disorder (MDD) and bipolar disorder (BPD).

Expert opinion: Agomelatine has shown an antidepressant effect in preclinical models, and the results of a large-scale clinical trial program, conducted in MDD, indicate both an antidepressant activity and a favorable tolerability profile. Agomelatine has no discontinuation syndrome, sexual discomfort is rare, and it is generally weigh neutral. The drug appears to be relatively safe in case of overdose. However, some cases of elevated hepatic transaminases are reported during treatment. As agomelatine has a mechanism of action that differs from other agents, it may represent a valuable additional treatment option in those patients who do not respond fully or who do not tolerate the side effects of other antidepressants.     

Resting Glutamate Levels and Rapid Glutamate Transients in the Prefrontal Cortex of the Flinders Sensitive Line Rat: A Genetic Rodent Model of Depression

Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression), the search for novel therapeutics continues because of their poor response rates (∼30%) and slow onset of action (2–4 weeks). To better understand role of glutamate in depression, we used an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 × 333 μm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3- to 6-month-old and 12- to 15-month-old Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. Although no changes in glutamate dynamics were observed between 3 and 6 months FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12- to 15-month-old FSL rats compared with the 3- to 6-month-old FSL and age-matched FRL rats on days 3–5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all the four rat groups of fluctuations in resting glutamate, which we have termed glutamate transients. Although these events lasted only for seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate-burst events was significantly increased in the 12- to 15-month-old FSL rats compared with 3- to 6-month-old FSL and age-matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression.     

Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems

OBJECTIVE: The aim of the present study was to investigate the oxidative-antioxidative systems and effects of different antidepressants on these systems in patients with major depressive disorder (MDD). METHOD: Ninety-six patients with a Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) diagnosis of MDD and 54 healthy controls were included in the study. Plasma malondialdehyde (MDA) levels and susceptibility of red blood cells (RBCs) to oxidation were determined to investigate the oxidative status, plasma vitamin E, vitamin C, serum total carotenoid levels, total antioxidant capacity (TAOC), RBC superoxide dismutase (SOD) and whole blood glutathione peroxidase (GPx) activities were measured to investigate the antioxidative defence before and after 6 weeks of antidepressant treatment. RESULTS: Plasma MDA levels and susceptibility of RBCs to oxidation were significantly higher in the MDD group compared with the control group. RBC SOD activity was significantly increased in patients with MDD, and furthermore there was a significant positive correlation between the severity of the disease and SOD activity. CONCLUSION: MDD is accompanied with oxidative stress; however, oxidative-antioxidative systems do not seem to be affected by 6 weeks of antidepressant treatment.     

Fluoxetine and olanzapine combination therapy in treatment-resistant major depression: review of efficacy and safety data

Background: There has been growing evidence supporting the use of atypical antipsychotic drugs as adjunctive treatments in patients with major depression who fail to respond adequately to antidepressants. Objective: To review the efficacy and safety data for one such combination, fluoxetine (FLX) + olanzapine (OLZ) in treatment-resistant depression (TRD). Methods: We reviewed published randomized, controlled acute-phase studies, as well as available long-term clinical studies. Results/conclusions: In each acute-phase study (n = 5), FLX/OLZ group experienced rapid antidepressant effects and, in two of these studies, resulted in significantly greater improvement at study end point compared with antidepressant monotherapy. These effects were strongest when TRD was defined as having failed at least two antidepressant trials during the current depressive episode. FLX + OLZ was generally well tolerated; however, increases in body weight and prolactin levels with FLX + OLZ were greater than that of antidepressant monotherapy groups and were similar to OLZ monotherapy. However, changes in random total cholesterol were also greatest for FLX + OLZ and were greater in magnitude than that of OLZ or FLX monotherapy. Long-term effectiveness/safety data are sparse, and comparison trials and sequential treatment studies involving FLX + OLZ and other antidepressant-atypical antipsychotic combinations are lacking. Thus, the exact place of FLX + OLZ among other available options for TRD is difficult to determine.     

Tianeptine and paroxetine in major depressive disorder,with a special focus on the anxious component in depression: an international, 6-week double-blind study dagger

Tianeptine (37.5 mg/day) and paroxetine (20 mg/day) were compared in a population of depressive patients without past or current history of co-morbid anxiety and/or important anxiolytic treatment. In a 6-week, double blind trial, the special focus was on anxious symptoms.Both drugs showed good efficacy on depressive symptomatology, assessed with MADRS and HDRS, but no difference was detected between tianeptine and paroxetine, for any assessment criterion. Despite the choice of selected depressive patients, without any co-morbid anxious disorder, anxiety scale scores at inclusion (HAMA and BAS) were appreciable but correlated poorly with depressive scores. Both tianeptine and paroxetine improved the apparent anxious component in depression. Tolerability of both drugs was good, although significantly better with tianeptine.Thus tianeptine and paroxetine are effective and safe treatments for major depression and may also act directly on the anxious component of the psychopathology. Copyright 2001 John Wiley & Sons, Ltd.