Tolerability of High-Dose Venlafaxine After Switch From Escitalopram in Nonresponding Patients With Major Depressive Disorder.

BACKGROUND: Within a single depressive episode, most patients receive different antidepressants because of an inadequate response to the first-line antidepressant. A commonly used strategy is to switch from a selective serotonin reuptake inhibitor to a selective serotonin-norepinephrine reuptake inhibitor. However, little is known about the tolerability of this switch with consideration of dose and drug concentration in blood. METHODS: After 4 weeks of inadequate response to escitalopram (10-20 mg/d), medication was switched to another 4 weeks of venlafaxine (VF, 150-375 mg/d) in 234 depressed patients. Serum concentrations, depression severity, and adverse drug reactions (ADRs) were assessed weekly. RESULTS: The switch of medication led to an increase of ADRs such as reduced salivation (+11%), orthostatic dizziness (+11%), and sweating (+9.8%). The most frequent ADRs during treatment with VF were reduced salivation (28.6%), sweating (24.6%), and orthostatic dizziness (15.8%). In patients receiving high-dose VF, a significant improvement of depressive symptomatology was observed, and most ADRs decreased during the course of treatment, even in patients above the therapeutic reference range. LIMITATIONS: Patients and physicians were aware of medication, and there was no direct comparison with the herein presented switch of medication. IMPLICATIONS: This study provides important information about the tolerability of a commonly used antidepressant treatment strategy. More detailed information about putative ADRs may help clinicians increase compliance through effective patient education. Because ADRs of VF were associated with the plasma concentration, therapeutic drug monitoring is recommended to guide the therapy and manage problems of tolerability.

Teaching Conflicts of Interest and Shared Decision-Making to Improve Risk Communication: a Randomized Controlled Trial.

BACKGROUND: Risk communication is a core aspect of a physician's work and a fundamental prerequisite for successful shared decision-making. However, many physicians are not able to adequately communicate risks to patients due to a lack of understanding of statistics as well as inadequate management of conflicts of interest (COI). OBJECTIVE: To evaluate the effects of an integrated curriculum encompassing COI and shared decision-making on the participants' risk communication competence, that is, their competence to advise patients on the benefits and harms of diagnostic or therapeutic interventions. DESIGN: A rater-blind randomized controlled trial with a 30 (± 1)-week follow-up conducted from October 2016 to June 2017 at two German academic medical centers. PARTICIPANTS: Sixty-three medical students in their fourth or fifth year. INTERVENTIONS: Participants received either a newly developed 15-h curriculum or a course manual adapted from teaching as usual. MAIN MEASURES: Primary outcome: change in risk communication performance in a video-observed structured clinical examination (VOSCE). KEY RESULTS: Participants were 25.7 years old on average (SD 3.6); 73% (46/63) were female. Increase in risk communication performance was significantly higher in the intervention group with post-intervention Cohen's d of 2.35 (95% confidence interval (CI) 1.62 to 3.01, p < 0.01) and of 1.83 (CI 1.13 to 2.47, p < 0.01) 30 (± 1) weeks later. Secondary outcomes with the exception of frequency of interactions with the pharmaceutical industry also showed relevant improvements in the intervention as compared with the control group (d between 0.91 and 2.04 (p < 0.001)). CONCLUSIONS: Our results show that an integrated curriculum encompassing COI and risk communication leads to a large and sustainable increase in risk communication performance. We interpret the large effect sizes to be a result of the integration of topics that are usually taught separately, leading to a more effective organization of knowledge. TRIAL REGISTRATION: The trial is registered in the International Clinical Trials Registry with the trial number DRKS00010890.

Higher BDNF plasma levels are associated with a normalization of memory dysfunctions during an antidepressant treatment.

One important symptom of patients with major depressive disorder (MDD) is memory dysfunction. However, little is known about the relationship between memory performance and depression severity, about the course of memory performance during antidepressant treatment as well as about the relationship between memory performance and brain-derived neurotrophic factor (BDNF). Memory function [learning and delayed recall) was assessed in 173 MDD patients (mean age 39.7 ± 11.3 years] treated by a pre-defined treatment algorithm within the early medication change (EMC) study at baseline, days 28 and 56. Depression severity was assessed in weekly intervals, BDNF plasma levels were measured at baseline, days 14 and 56, BDNF exon IV and p11 methylation status at baseline. Linear mixed regression models revealed that the course of depression severity was not associated with the course of learning or delayed recall in the total group. 63 (36%) of the investigated patients showed memory deficits (percent range ≤ 16) at baseline. Of those, 26(41%) patients experienced a normalization of their memory deficits during treatment. Patients with a normalization of their delayed recall performance had significantly higher plasma BDNF levels (p = 0.040) from baseline to day 56 than patients with persistent deficits. Baseline BDNF exon IV promoter and p11 gene methylation status were not associated with memory performance. Our results corroborate a concomitant amelioration of learning and delayed recall dysfunctions with successful antidepressant therapy in a subgroup of patients and support a role of BDNF in the neural mechanisms underlying the normalization of memory dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

Effects of age on depressive symptomatology and response to antidepressant treatment in patients with major depressive disorder aged 18 to 65 years.

BACKGROUND: There is evidence that symptomatology in patients with major depressive disorder (MDD) changes with age. However, studies comparing depressive symptomatology between different age groups during antidepressant therapy are rare. We compared demographic and clinical characteristics in depressed patients of different age groups at baseline and during treatment. METHODS: 889 MDD inpatients were divided into four age groups (18-29, 30-39, 40-49, 50-65 yrs.). Demographic and clinical characteristics including depressive symptomatology (assessed by the Inventory of Depressive Symptoms) were assessed at baseline and weekly during treatment. RESULTS: At baseline, young patients (18-29 years) significantly more often reported cognitive symptoms like irritability, suicidality, negative self-concept and interpersonal sensitivity and more often suffered from drug abuse and comorbid personality disorders. Late middle aged patients (50-65 years) significantly more often suffered from neuro-vegetative symptoms such as reduced general interest, sexual interest and sleep disturbances and more often showed a recurrent MDD and comorbid physical disorders. During therapy, symptoms such as interpersonal sensitivity in young patients and low interest in sex in late middle aged patients persisted until the end of treatment while all other symptoms declined until day 56. LIMITATIONS: The herein presented age differences in depressive symptomatology only hold true for the study medication and are not generalizable to other antidepressants agents. CONCLUSION: There are substantial differences in the clinical presentation of depression between age groups. Whereas many of these differences disappear during treatment, some differences persisted until the end of treatment. These findings my help to more specifically tailor the treatment of depressed patients.

Predictors of the effectiveness of an early medication change strategy in patients with major depressive disorder.

BACKGROUND: Patients with Major Depressive Disorder (MDD) who are non-improvers after two weeks of antidepressant treatment have a high risk of treatment failure. Recently, we did not find differences in outcomes in non-improvers randomized to an early medication change (EMC) strategy compared to treatment as usual (TAU). This secondary analysis investigated possible predictors of higher remission rates in the EMC strategy. METHODS: Of 192 non-improvers (i.e. decrease of ≤20% on the HAMD-17 depression scale) after a two-week treatment with escitalopram, n = 97 were randomized to EMC (immediate switch to high doses of venlafaxine XR) and n = 95 to TAU (continued escitalopram until day 28 with non-responders switched to venlafaxine XR). We first analyzed patient characteristics, psychopathological features and subtypes of MDD by logistic regression analyses as possible predictors of remission rates. In a second investigation, we analyzed the predictors, which showed a significant association in the first analysis before Bonferroni-Holm correction by chi-squared tests separated for treatment groups. All analyses were corrected by Bonferroni-Holm method. RESULTS: The first analyses yielded no statistically significant results after correction for multiple testing. In the second analyses, however, patients with prior medication at study entry showed higher remission rates in EMC than in TAU (24.2% versus 8.6%, p = 0.017; Bonferroni-Holm corrected significance level: p = 0.025.). Furthermore, patients with a recurrent course of MDD benefited less from treatment as usual (p = 0.009; Bonferroni-Holm corrected significance level: p = 0.025). Age, sex, age of onset, psychiatric or somatic comorbidities, and other subtypes of MDD did not predict remission rates. CONCLUSIONS: Although in our first analysis we found statistically non-significant results, the second analysis showed significant differences in remission rates between patients with or without previous medication and in patients with recurrent MDD or the first depressive episode. It would therefore be valuable to examine in larger and prospective studies whether remission rates can be increased by quick escalation of treatment in certain subgroups of patients. Promising subgroups to be tested are patients who were previously medicated, and who show a recurrent course of MDD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00974155 . Registered at the 10th of September 2009. Retrospectively registered.

Development of a checklist for evaluating psychiatric reports.

BACKGROUND: Performing a psychiatric interview and documenting the recorded findings in the form of a brief psychiatric report is one of the main learning goals in the psychiatric curriculum for medical students. However, observing and assessing students' reports is time consuming and there are no objective assessment tools at hand. Thus, we applied an integrative approach for designing a checklist that evaluates clinical performance, as a tool for the assessment of a psychiatric report. METHODS: A systematic review of the literature yielded no objective instrument for assessing the quality of written reports of psychiatric interviews. We used a 4-step mixed-methods approach to design a checklist as an assessment tool for psychiatric reports: 1. Development of a draft checklist, using literature research and focus group interviews; 2. Pilot testing and subsequent group discussion about modifications resulting from the pilot testing; 3. Creating a scoring system; 4. Testing for interrater-reliability, internal consistency and validity. RESULTS: The final checklist consisted of 36 items with a Cronbach's alpha of 0.833. Selectivity of items ranged between 0.080 and 0.796. After rater-training, an interrater-reliability of 0.96 (ICC) was achieved. CONCLUSIONS: Our approach, which integrated published evidence and the knowledge of domain experts, resulted in a reliable and valid checklist. It offers an objective instrument to measure the ability to document psychiatric interviews. It facilitates a transparent assessment of students' learning goals with the goal of structural alignment of learning goals and assessment. We discuss ways it may additionally be used to measure the ability to perform a psychiatric interview and supplement other assessment formats.

Detectability of cannabinoids in the serum samples of cannabis users: Indicators of recent cannabis use? A follow-up study.

Forensic toxicologists are frequently required to predict the time of last cannabis consumption. Several studies suggested the utility of minor cannabinoids as indicators of recent cannabis use. Because several factors influence blood cannabinoid concentrations, the interpretation of serum cannabinoid concentrations remains challenging. To assess the informative value of serum cannabinoid levels in cannabis users (in total N = 117 patients, including 56 patients who stated an exact time of last cannabis use within 24 h before blood sampling), the detectability of cannabinoids, namely, delta-9-tetrahydrocannabinol (delta-9-THC), 11-hydroxy-delta-9-THC, 11-nor-9-carboxy-delta-9-THC, cannabichromene (CBC), cannabidiol (CBD), cannabinol (CBN), cannabidivarin, tetrahydrocannabivarin, cannabigerol (CBG), cannabicyclol, delta-8-THC, tetrahydrocannabinolic acid A, cannabichromenic acid, cannabidiolic acid (CBDA), cannabigerolic acid, cannabicyclolic acid (CBLA), 11-nor-9-carboxy-THCV (THCVCOOH), and 11-nor-CBN-9-COOH, was investigated. Excluding CBDA and CBLA, all investigated cannabinoids were detected in at least one analyzed sample. The interval between cannabis consumption and sample collection (reported by the patients) was not correlated with cannabinoid concentrations. Minor cannabinoids tended to be more easily detected in samples obtained shortly after consumption. However, some samples tested positive for minor cannabinoids despite an interval of several hours or even days between consumption and sampling (according to patients' statements). For instance, CBC, CBG, THCVCOOH, CBD, and CBN in certain cases could be detected more than 24 h after the last consumption of cannabis. Thus, findings of minor cannabinoids should always be interpreted with caution.

Early onset of depression and treatment outcome in patients with major depressive disorder.

Major depressive disorder (MDD) is a highly heterogeneous disorder, which may partly explain why treatment outcome using antidepressants is unsatisfactory. We investigated the onset of depression as a possible clinical marker for therapy response prediction in the context of somatic biomarkers blood pressure and plasma electrolyte concentration. 889 MDD patients were divided into early (EO, n = 226), intermediate (IO, n = 493), and late onset (LO, n = 169) patients and were analyzed for differences in socio-demographic and clinical parameters, comorbidities and treatment outcome as well as systolic blood pressure and electrolytes. EO patients more often suffered from a recurrent depression, had more previous depressive episodes, a higher rate of comorbid axis I and II disorders, and more often reported of suicidality (p < 0.001) compared to IO and LO patients. Treatment outcome was not different from IO and LO patients, although LO patients responded faster. EO patients who showed an early non-improvement of depression after 2 weeks of therapy (<20% improvement) had a 4.3-fold higher likelihood to become non-remitter as compared to LO patients with an early improvement. EO patients had significantly lower systolic blood pressure than patients with IO or LO and electrolytes in EO patients were significantly correlated with depression severity. Our results confirm other studies showing an association of an early onset of depression with a slower treatment response. The worse treatment outcome in patients with an additional early non-improvement to antidepressant therapy opens perspectives to develop and test individualized treatment approaches for EO and LO patients in the future, which may be based on differences in autonomic regulation.

Development, implementation, and evaluation of a curriculum for medical students on conflicts of interest and communicating risk.

Background: Insufficient risk competence of physicians, conflicts of interests from interactions with pharmaceutical companies, and the often distorted presentation of benefits and risks of therapies compromise the advising of patients by physicians in the framework of shared decision-making. An important cause of this is that teaching on this subject is mostly lacking, or fragmented when it does take place [1], [2], [3], [4]. Even though the German National Competence-Based Catalog of Learning Goals in Medicine defines learning goals on the topics of conflicts of interest and communication of risk, there are no classes that integrate both topics. Our goal was to develop a model curriculum to teach conflicts of interest and communication of risk that would integrate statistical know-how, communicational competency on the presentation of benefits and risks, and the meaning and management of conflicts of interest. Project Description: The development of the curriculum took place according to the six-step cycle of Kern et al [5]. An integrated curriculum was conceptualized, piloted, and adapted with the support of experts for the topics of shared decision-making, conflicts of interest, and communication of risk. The final version of the curriculum was implemented at the medical schools of Mainz and Heidelberg and evaluated by the students. Results: The final curriculum consists of 19 lesson units. The contents are the fundamentals of statistics, theory of risk communication, practical exercises on communication of risk, and the fundamentals of the mechanisms of effect of conflicts of interest, recognition of distortions in data, and introductions to professional management of conflicts of interest. The course was implemented three times at two different medical schools with a total of 32 students, and it was positively rated by most of the 27 participating students who evaluated it on the 1-6 German school grading scale (mean: 1.4; SD: 0.49; range: 1-2). Discussion: The curriculum we developed fills a gap in the current medical education. The innovative concept, which sensibly connects the transmission of theory and practice, was positively received by the students. The next steps are an evaluation of the curriculum by means of a two-center randomized study and the implementation at German and international medical schools. The process should be accompanied by continuous evaluation and further improvement.

Discrepancies from registered protocols and spin occurred frequently in randomized psychotherapy trials-A meta-epidemiologic study.

OBJECTIVES: This study aimed to investigate the relationship between trial registration, trial discrepancy from registered protocol, and spin in nonpharmacological trials. STUDY DESIGN AND SETTING: Recent psychotherapy trials on depression (2015-2018) were analyzed regarding their registration status and its relationship to discrepancies between registered and published primary outcomes and to spin (discrepancy between the nonsignificant finding in a study and an overly beneficial interpretation of the effect of the treatment). RESULTS: A total of 196 trials were identified, of which 78 (40%) had been registered prospectively and 56 (29%) had been registered retrospectively. In 102 (76%) of 134 registered trials, discrepancies between trial and protocol were present. Of 72 trials with a nonsignificant difference between treatments for the primary outcome, 68 trials (94%) showed spin. Discrepancies from protocol were less frequent in prospectively than in retrospectively registered trials (odds ratio= 0.19; 95% confidence interval [CI]: 0.07-0.52), but regarding the amount of spin, there was no difference between prospectively and retrospectively registered trials (rb = -0.12; 95% CI: -0.41 to 0.19) or between registered and unregistered trials (rb = -0.22, 95% CI -0.49 to 0.08). CONCLUSION: Protocol discrepancies and spin have a high prevalence in psychotherapy outcome research. The results show no relation between registration and spin, but prospective registration may prevent discrepancies from protocol.

Body mass index (BMI) in major depressive disorder and its effects on depressive symptomatology and antidepressant response.

BACKGROUND: Obesity is one of the most prevalent somatic comorbidities of Major Depressive Disorder (MDD). We aimed to investigate the relationship between body mass index (BMI) and MDD, the symptomatology of the disorder as well as the outcome of antidepressant treatment. METHODS: Early medication change (EMC) trial participants with BMI measurement (n = 811) were categorized according to WHO-criteria in normal or low weight (BMI < 25), overweight (25-< 30), and obese (≥30). Depression severity and BMI was assessed in weekly intervals up to 8 weeks. BMI at baseline and course of BMI during the study were investigated in linear regression models as possible moderators of therapy response. Possible moderators such as plasma concentrations of applied drugs, sex, comorbidities or age were controlled. RESULTS: 388 (48%) patients showed normal weight, 251 (31%) were overweight and 172 (21%) obese. Linear regression analyses revealed an association between BMI and antidepressant therapy outcome: Overweight patients showed the best response to antidepressant treatment. BMI at baseline was significantly correlated with improvement in neurovegetative and cognitive symptoms of depression. Furthermore, weight gain during the study was associated with better therapy response, independent of symptom complex. Other moderators including serum concentrations of drugs were not able to explain the differences between the BMI groups. LIMITATIONS: Secondary exploratory analysis. No investigation of visceral fat. CONCLUSION: We showed for the first time that patients with higher initial increase in BMI showed larger decrease in depression severity during study. The underlying mechanisms are unclear and require further investigation.

Plasma brain-derived neurotrophic factor (pBDNF) and executive dysfunctions in patients with major depressive disorder.

Objectives: Executive dysfunctions are frequently seen in patients with major depressive disorder (MDD) and normalise in many cases during effective antidepressant therapy. This study investigated whether a normalisation of executive dysfunctions during antidepressant treatment correlates with or can be predicted by clinical parameters or levels of brain-derived neurotrophic factor (BDNF).Methods: In 110 MDD patients with executive dysfunctions (percentile <16), executive functions and plasma BDNF levels were analysed at baseline, and days 14 and 56 of an antidepressant treatment. BDNF exon IV and P11 methylation status was studied at baseline.Results: Eighty patients (73%) experienced a normalisation of executive dysfunctions, while 30 (27%) suffered from persistent dysfunctions until day 56. Patients with persistent dysfunctions had significantly higher HAMD scores at days 14 and 56, and lower plasma BDNF levels at each time point than patients with a normalisation of dysfunctions (F1= 10.18; P = 0.002). This was seen for verbal fluency, but not processing speed. BDNF exon IV and p11 promoter methylation was not associated with test performance.Conclusions: Our results corroborate a concomitant amelioration of executive dysfunctions with successful antidepressant therapy and support a role of BDNF in the neural mechanisms underlying the normalisation of executive dysfunctions in MDD.ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome.

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) plays a pivotal role in alkylating drug resistance. Here, we determined MGMT activity in primary and recurrent glioblastomas (GBM, WHO grade IV) of patients who received radiation therapy (RT) or RT plus chemotherapy with alkylating agents (temozolomide, chloroethylnitrosoureas). The mean MGMT activity of untreated GBM was 37 +/- 45 (range 0-205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 +/- 50 (13-194) to 68 +/- 44 (14-143) and 182 +/- 163 (64-423) fmol/mg protein, respectively. Comparing patients who received RT only with RT plus chemotherapy, a significant increase of MGMT in 1st recurrences was only found after treatment with RT plus chemotherapy, indicating either selection of MGMT expressing cells or induction of the MGMT gene by alkylating agents. The p53 status was not significantly related to the MGMT expression level, although a trend for lower MGMT activity in p53 positively stained tumors was observed. Patients expressing MGMT activity of

BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant Treatment Response.

Major problems of current antidepressant pharmacotherapy are insufficient response rates and difficulties in response prediction. We recently provided preliminary evidence in a small study that patients with major depressive disorder (MDD) with a hypomethylation of the CpG-87 site of the promoter IV region of the brain-derived neurotrophic factor (BDNF) gene are less likely to benefit from antidepressants. Here, we aimed at replicating this finding in a secondary analysis of 561 MDD patients (mean age 40.0 ± 11.9 years, 56% female) included into the Early Medication Change study (EMC). We measured BDNF exon IV promoter and p11 gene methylation at Baseline (BL) as well as BDNF-plasma-levels (pBDNF) at BL and day 14 and related them to treatment outcome. Although we were not able to replicate the predictor function of hypomethylation of the BDNF exon IV promoter, a subgroup of patients with severe depression (Hamilton Depression Rating Scale [HAMD-17] ≥ 25) (n = 199) and hypermethylation at CpG-87 of the BDNF exon IV promoter had significantly higher remission rates than patients without a methylation (p = 0.032). We also found that 421 (75%) of 561 patients showed an early improvement (≥ 20% HAMD-17 reduction after 2 weeks), which was associated with a 4.24-fold increased likelihood to remit at study end compared to the 140 patients without early improvement. However, specificity of response prediction of early improvement was low (34%) and false positive rate high (66%). The combination of early improvement with a pBDNF increase between BL and day 14, however, increased the specificity of response prediction from 34 to 76%, and the combination with methylation of the CpG-87 site of the BDNF exon IV promoter from 34 to 62%. Thus, the combined markers reduced false positives rates from 66 to 24% and 38%, respectively. Methylation at other sites or p11 promoter methylation failed to increase specificity of early improvement prediction. In sum, the results add to previous findings that BDNF, BDNF promoter methylation and the combination of clinical and biological markers may be interesting candidates for therapy response prediction which has to be confirmed in further studies. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00974155, identifier: NCT00974155.

Conflicts of Interest in Medicine. A Systematic Review of Published and Scientifically evaluated Curricula.

Objective: Conflicts of interests resulting from interactions with pharmaceutical companies are pervasive in medicine and can result in an undue influence on physicians' decision-making. The objective of this systematic review is to analyze published and scientifically evaluated curricula for medical students and residents regarding such conflicts of interest. We begin by describing the covered topics and teaching methods; afterwards we analyze the quality of the curricula using the published data on their evaluations and comparing the content with content recommended for such curricula. Methods: We searched Pubmed, PsycInfo, EMBASE, OECD, WISO, SOWI and googlescholar up to and including the 5th of September 2016. Publications describing curricula for residents or medical students on the topic of conflicts of interest in medicine and evaluating them for their effects on the participants' learning were included. We analyzed the covered topics and the teaching methods used and compared them with recommendations by the American Medical Students' Association (AMSA) and Health Action International (HAI). Results: The literature search resulted in 20 publications that fulfilled our search criteria. In five trials, a control group was used, in no trial the participants were randomized to intervention or control group. 16/20 published curricula primarily covered marketing strategies by pharmaceutical companies, especially the interaction with pharmaceutical sales representatives (PSRs). Most curricula only covered a limited number of topics recommended by AMSA/HAI. The most frequent teaching method was a group discussion, which was used in 18/20 curricula; all curricula used at least one interactive teaching method. The evaluation of the curricula was heterogeneous in results as well as design. Some publications described a change of attitudes toward a stronger skepticism regarding interactions with pharmaceutical companies. Four publications described improved knowledge, one publication described a change in behavior toward a reduction of the acceptance of gifts. Conclusion: The trials conducted to this date regarding curricula on conflicts of interests are methodologically flawed and the described curricula lack important topics beyond marketing strategies of pharmaceutical companies. In addition, there are no data so far on the sustainability of the courses' effects on participants' behavior. It is therefore necessary to develop a model curriculum that covers a broader variety of topics and to evaluate it using a well thought-out methodology to create a foundation for the further improvement of teaching conflicts of interest in medicine.

Early improvement as a resilience signal predicting later remission to antidepressant treatment in patients with Major Depressive Disorder: Systematic review and meta-analysis.

Early improvement of depressive symptoms during the first two weeks of antidepressant treatment has been discussed to be a resilience signal predicting a later positive treatment outcome in patients with Major Depressive Disorder (MDD). However, the predictive value of early improvement varies between studies, and the use of different antidepressants may explain heterogeneous results. The objective of this review was to assess the predictive value of early improvement on later response and remission and to identify antidepressants with the highest chance of early improvement. We included 17 randomized controlled trials investigating early improvement in 14,779 adult patients with MDD comparing monotherapy with an antidepressant against placebo or another antidepressant drug. 62% (range: 35-85%) of patients treated with an antidepressant and 47% (range: 21-69%) with placebo were early improver, defined as a >20%/25% symptom reduction after two weeks of treatment. Early improvement predicted response and remission after 5-12 weeks of treatment with high sensitivity (85%; 95%-CI: 84.3 to 85.7) and low to moderate specificity (54%; 95%-CI: 53.1 to 54.9). Early improver had a 8.37 fold (6.97-10.05) higher likelihood to become responder and a 6.38 fold (5.07-8.02) higher likelihood to be remitter at endpoint than non-improver. The highest early improver rates were achieved in patients treated with mirtazapine or a tricyclic antidepressant. This finding of a high predictive value of early improvement on treatment outcome may be important for treatment decisions in the early course of antidepressant treatment. Further studies should test the efficacy of such early treatment decisions.

A combined marker of early non-improvement and the occurrence of melancholic features improve the treatment prediction in patients with Major Depressive Disorders.

BACKGROUND: Early Improvement of depressive symptoms within two weeks of antidepressant treatment is a highly sensitive but less specific predictor of later treatment outcome. The aim of this study was to identify clinical features at treatment initiation which are associated with early improvement and non-improvement as well as to identify variables predicting non-remission in patients showing an early improvement. METHODS: 889 patients with a major depressive episode according to DSM-IV who had participated in an antidepressant treatment trial served as study sample. Clinical predictors (demographic variables, psychopathology, comorbid disorders) were analysed in 698 (79%) early improver (Hamilton Depression Rating Scale reduction > 20% after 14 days of treatment) compared to 191 (21%) non-improver. Furthermore, clinical predictors for later remission and non-remission were analysed in the 698 patients showing an early improvement. RESULTS: Patients with more severe depression and suicidality were more likely to become non-improver, and also non-remitter after 8 weeks of treatment in case of early improvement. Early improver with melancholic, anxious or atypical depression as well as with comorbid social phobia or avoidant personality disorder had an increased risk for non-remission at study end. The combined marker of early non-improvement and the occurrence of melancholic features increased the specificity of treatment prediction from 30% to 90%. LIMITATIONS: Comorbid disorders were only assessed at baseline. CONCLUSIONS: Patients with early non-improvement and melancholic features at treatment initiation have a particularly high risk of later non-remission. This group of patients should be considered more attention in treatment decisions.

Randomized controlled study of early medication change for non-improvers to antidepressant therapy in major depression--The EMC trial.

Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram. Of those, 192 patients had no improvement, defined as a reduction of < 20% on the Hamilton Depression Rating Scale (HAMD-17) after 14 days of treatment, and were randomly assigned to open treatment with the EMC strategy (n = 97; venlafaxine XR for study days 15-56; in case of sustained non-improvement on day 28, lithium augmentation for days 29-56) or TAU (n = 95; escitalopram continuation; non-responders on day 28 were switched to venlafaxine XR for four weeks, i.e. days 29-56). The primary outcome was remission (HAMD-17 ≤ 7) after 8 weeks of treatment as assessed by blinded raters. Remission rates were 24% for EMC and 16% for TAU, which was not significantly different (p = 0.2056). Sensitivity analyses for the primary and secondary effectiveness endpoints consistently showed favorable results for patients randomized to EMC. The results confirm data from post-hoc analyses of clinical trials showing that early non-improvement identifies patients who likely need alternate interventions. However, the herein used two-step switch/augmentation strategy for this risk group was not more effective than the control intervention. Alternate strategies and other design aspects are discussed in order to support researchers addressing the same research question.

Early reactions of brain-derived neurotrophic factor in plasma (pBDNF) and outcome to acute antidepressant treatment in patients with Major Depression.

In Major Depressive Disorder, a growing data base suggests that the onset of antidepressants' action can be detected by improvement of depressive symptoms in the first 10-14 days of treatment. Previous studies showed that the mean concentration of the brain-derived neurotrophic factor (BDNF) in blood increases during antidepressant treatment and positively correlates with amelioration of MDD symptoms. We previously showed an association between very early changes of the serum BDNF concentration and treatment outcome (Tadic et al., 2011. Prog Neuropsychopharmacol Biol Psychiatry 35, 415-420). However, no study has yet investigated whether BDNF concentration in plasma increases in the early course of treatment and enables the prediction of final treatment outcome. The goal of this study was to investigate in MDD patients, whether the change of pBDNF in the early course of treatment is a specific and sensitive marker for final treatment outcome. For this purpose, we performed a naturalistic pilot study with 39 inpatients with MDD according to DSM-IV. Depression severity and pBDNF were measured in weekly intervals from baseline (EP) to endpoint (EP, max. week six) with the 21-item Hamilton Depression Rating Scale (HAMD-21) and enzyme-linked immunosorbent assay (ELISA), respectively. According to ROC-analysis, the best cut-off value for the prediction of response at EP is an increase of 338 pg/ml or 126%, respectively, of pBDNF between BL and day 7. The single markers pBDNF change and HAMD-21 improvement from BL-d7 predicted later treatment outcome with moderate to high sensitivity and specificity (pBDNF: 42% and 96%, resp.; HAMD improvement: 83% and 65%, resp.). The combined marker early pBDNF change plus HAMD-21 improvement at day 7 increased the specificity for response to 100%. Our data provide first preliminary evidence that an early change of pBDNF in conjunction with early improvement might be a peripheral marker predictive for treatment outcome in patients with MDD. This has to be confirmed in further investigations. This article is part of a Special Issue entitled 'Anxiety and Depression'.

The early non-increase of serum BDNF predicts failure of antidepressant treatment in patients with major depression: a pilot study.

In the treatment of patients with major depressive disorder (MDD), early non-improvement of symptoms after initiation of antidepressant treatment is a highly sensitive and specific marker for final treatment failure. On the other hand, meta-analyses of clinical studies investigating serum BDNF (sBDNF) concentration before and after antidepressant treatment showed an increase of sBDNF during treatment, which was correlated with amelioration of depressive symptoms. No study has yet investigated the predictive value of early changes of sBDNF for final treatment outcome of the individual patient. The aim of this study was to investigate in patients with MDD, whether i) the non-increase of sBDNF in the early course of treatment is a specific and sensitive marker for final treatment failure, ii) whether the sensitivity and specificity of early non-improvement for treatment failure can be increased by combining it with the marker "early non-increase of sBDNF". For this purpose, we performed a pilot study with 41 inpatients with MDD according to DSM-IV, who were treated in a naturalistic setting. Depression severity and sBDNF were measured in weekly intervals from baseline to week six with the 21-item Hamilton Depression Rating Scale (HAMD-21) and ELISA, respectively. The individual markers sBDNF non-increase and HAMD-21 non-improvement from baseline to day 7 or 14 predicted later non-response and non-remission with moderate to high specificity. The combined marker sBDNF non-increase plus HAMD-21 non-improvement at day 14 increased the specificity for non-response and non-remission to 100%. Our data provide the first evidence that the absence of an early increase of sBDNF in conjunction with early non-improvement might be a highly specific peripheral marker predictive for treatment failure in patients with MDD. If replicated, this combined marker could be considered useful for prospective confirmatory trials in patients with MDD.