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Background: Given the great interest in identifying reliable predictors of the response to antidepressant drugs, the present study investigated whether polygenic scores (PGS) for Major Depressive Disorder (MDD) and antidepressant treatment response (ADR) were related to the complex trait of antidepressant response in the Early Medication Change (EMC) cohort., Methods: In this secondary analysis of the EMC trial (N = 889), 481 MDD patients were included and compared to controls from a population-based cohort. Patients were treated over eight weeks within a pre-defined treatment-algorithm. We investigated patients' genetic variation associated with MDD and ADR, using PGS and examined the association of PGS with treatment outcomes (early improvement, response, remission). Additionally, the influence of two cytochrome P450 drug-metabolizing enzymes (CYP2C19, CYP2D6) was determined., Results: PGS for MDD was significantly associated with disorder status (NkR 2  = 2.48 %, p < 1*10 -12 ), with higher genetic burden in EMC patients compared to controls. The PGS for ADR did not explain remission status. The PGS for MDD and ADR were also not associated with treatment outcomes. In addition, there were no effects of common CYP450 gene variants on ADR., Limitations: The study was limited by variability in the outcome parameters due to differences in treatment and insufficient sample size in the used ADR genome-wide association study (GWAS)., Conclusions: The present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes., Competing Interests: Declaration of competing interest A Tadic is designated as inventor of the European patent number 12171541.1–2404 ‘Method for predicting response or non-response to a mono-aminergic antidepressant’. He has received during the last five years consultancy fees from Janssen and ROVI. K Lieb is designated as inventor of the European patent number 12171541.1–2404 ‘Method for predicting response or non-response to a mono-aminergic antidepressant’. S Heilmann-Heimbach and P Hoffmann are employees at Life&Brain GmbH, Bonn. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Stopping antidepressants can cause withdrawal (discontinuation) symptoms, the return of the original illness, and rebound. The latter means that the disease will return stronger, faster, or with greater likelihood than if it had not been treated with medication. The Psychiatry Working Group of the Drug Commission of the German Medical Association (AkdÄ) presents the scientific findings and provides practical recommendations for action. Withdrawal symptoms are multiform; unspecific physical symptoms are predominant. Distinguishing them from the recurrence of depressive symptoms can be difficult. Most of them are mild and self-limiting. There is insufficient evidence on the extent and frequency of rebound depression. The rebound risk implies that when establishing the medication, the short-term benefit must be weighed against the possible long-term risk of chronic depression or the possible need for long-term medication. Patients should be informed about the risk of withdrawal both as early as the joint decision-making process about treatment initiation and regularly during the course of treatment. Withdrawal should take place gradually, except in emergency situations, whereby small steps should be taken, especially in the low-dose range., (© 2021. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest AT has received consultancy fees from Janssen and Novartis. All other authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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 ( F 1 = 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.

Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response.

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.

Executive dysfunctions frequently occur in patients with Major Depressive Disorder and have been shown to improve during effective antidepressant treatment. However, the time course of improvement and its relationship to treatment outcome is unknown. The aim of the study was to assess the test performance and clinical outcome by repetitive assessments of executive test procedures during antidepressant treatment. Executive test performance was assessed in 209 -patients with Major Depressive Disorder (mean age 39.3 ± 11.4 years) and 84 healthy controls five times in biweekly intervals from baseline to week 8. Patients were treated by a defined treatment algorithm within the early medication change study (EMC trial; ClinicalTrials.gov NCT00974155), controls did not receive any intervention. Cognitive domains were processing speed, cognitive flexibility, phonemic and semantic verbal fluency. Intelligence was assessed at baseline. Depression severity was tested once a week by the Hamilton Depression Rating Scale (HAMD17). 130 patients (62%) showed executive dysfunctions in at least one of four tests at baseline. Linear mixed regression models revealed that the course of depression severity was associated to the course of cognitive flexibility (p = 0.004) and semantic verbal fluency (p = 0.020). Cognitive flexibility and semantic verbal fluency may be candidates easily to apply for therapy response prediction in clinical routine, which should be tested in further prospective studies., Trial Registration: ClinicalTrials.gov NCT00974155 EudraCT: 2008-008280-96.

Little is known about guideline adherence of naturalistic antidepressant drug therapy in outpatients with major depressive disorder (MDD). The aim of the study was to analyze guideline adherence, especially regarding treatment length, treatment evaluation and medication change strategies. We investigated 889 patients with MDD who had been admitted for inpatient treatment and were enrolled in the early medication change trial (ClinicalTrials.gov NCT00974155). We investigated all patients at screening visit regarding previous outpatient drug treatment in the index episode, which was assessed by structured interviews. Demographic variables were obtained from patients and patients' records. 51.0% of the patients had received previous drug treatment in the index episode, 56.6% were females, and their mean age was 40.0 years. In the 153 patients who were pharmacologically treated at least 8 weeks, medication was not changed in 129 (84.3%) patients. Patients who had a medication change in their index episode (n = 24, 15.7%) waited 71.1 weeks (±110.4) for their treatment optimization. Only 5 of those 153 patients (3.3%) had a dose increase, whereas 132 patients (86.3%) had no dose adaption at all. Antidepressant blood levels were measured in 46 patients (30.1%). We conclude that a large proportion of patients with MDD is not treated in adherence to treatment guidelines recommending treatment evaluation (e.g. therapeutic drug monitoring) and treatment change after 4 to 8 weeks in non-responders. Earlier treatment optimization may prevent long-term suffering of patients and may avoid inpatient treatment.

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Drug treatment of patients with borderline personality disorder (BPD) is common but mostly not supported by evidence from high-quality research. This review summarises the current evidence up to August 2014 and also aims to identify research trends in terms of ongoing randomised controlled trials (RCTs) as well as research gaps. There is some evidence for beneficial effects by second-generation antipsychotics, mood stabilisers and omega-3 fatty acids, while the overall evidence base is still unsatisfying. The dominating role SSRI antidepressants usually play within the medical treatment of BPD patients is neither reflected nor supported by corresponding evidence. Any drug treatment of BPD patients should be planned and regularly evaluated against this background of evidence. Research trends indicate increasing attention to alternative treatments such as dietary supplementation by omega-3 fatty acids or oxytocin.

Introduction: Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations., Methods: 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly., Results: Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L(A) allele carriers (r² = 34.3 %; p = 0.001), but not in S/L(G)-allele carriers (p = 0.31)., Discussion: In the group of L(A) allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Empirical evidence supports the existence of significant executive deficits in patients with major depressive disorder (MDD) as compared to non-depressed controls. Nevertheless, the effect size of executive dysfunctions in unipolar, non-psychotic MDD as well as their relationship to antidepressant treatment is ambiguous., Method: Meta-analytic methods were used to assess the severity of executive dysfunctions in unipolar, non-psychotic MDD as compared to healthy controls and to investigate their course during antidepressant treatment., Results: Fifteen studies comparing the executive functions of 375 patients with DSM-IV MDD and 481 healthy controls were analysed. Furthermore, in three studies, including 122 patients with MDD, the Stroop test performance was examined before and after antidepressant treatment. Patients with MDD performed 0.439 up to 1.18 (P < 0.0001) standard mean differences worse than healthy controls. The Stroop performance improved during the course of treatment (P = 0.0001)., Conclusion: We revealed significant executive dysfunctions in patients with unipolar, non-psychotic MDD compared with healthy controls and an improvement of the Stroop performance during the course of treatment. Future studies with different test procedures are needed to further investigate the influence of antidepressant treatment on executive functions., (© 2011 John Wiley & Sons A/S.)

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 (Tadić 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'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: In Major Depressive Disorder (MDD), treatment outcomes with currently available strategies are often disappointing. Therefore, it is sensible to develop new strategies to increase remission rates in acutely depressed patients. Many studies reported that true drug response can be observed within 14 days (early improvement) of antidepressant treatment. The identical time course of symptom amelioration after early improvement in patients treated with antidepressants of all classes or with placebo strongly suggests a common biological mechanism, which is not specific for a particular antidepressant medication. However, the biology underlying early improvement and final treatment response is not understood and there is no established biological marker as yet, which can predict treatment response for the individual patient before initiation or during the course of antidepressant treatment. Peripheral blood markers and executive functions are particularly promising candidates as markers for the onset of action and thus the prediction of final treatment outcome in MDD., Methods/design: The present paper presents the rationales, objectives and methods of a multi-centre study applying close-meshed repetitive measurements of peripheral blood and neuropsychological parameters in patients with MDD and healthy controls during a study period of eight weeks for the identification of biomarkers for the onset of antidepressants' action in patients with MDD. Peripheral blood parameters and depression severity are assessed in weekly intervals from baseline to week 8, executive performance in bi-weekly intervals. Patients are participating in a randomized controlled multi-level clinical trial, healthy controls are matched according to mean age, sex and general intelligence., Discussion: This investigation will help to identify a biomarker or a set of biomarkers with decision-making quality in the treatment of MDD in order to increase the currently disappointing remission rates of antidepressant treatment.

Background: In major depressive disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease >or=20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome., Methods/design: The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17

Background: The full response to antidepressant pharmacotherapy is evident only after several weeks, but considerable improvements may already be visible within the first two weeks. Little is known about the potential influence of additional psychotherapy on the speed of response to antidepressant treatment. We have analysed in more severely depressed inpatients treated with antidepressants i) the predictive value of early improvement for later response and ii) the impact of additional psychotherapy on the time course of response., Methods: 124 patients with a major depression referred for hospitalized care were randomized to 5 weeks of sertraline (or amitriptyline as a second choice) plus either additional Interpersonal Psychotherapy modified for inpatients (IPT) or Clinical Management (CM). "Improvement" was defined as a decrease of > or = 20% on the 17-item Hamilton Rating Scale for Depression (HAMD). "Onset of response" was defined as sustained improvement (without any subsequent increase in the HAMD) culminating in 50% decrease on the HAMD by week 5., Results: Early improvement within two weeks was highly predictive of later stable response (> or = 50% decrease on the HAMD at weeks 4 and 5) or stable remission (HAMD score of < or = 7 at weeks 4 and 5), irrespective of the type of medication or additional IPT or CM. Survival analysis of the ITT sample revealed that patients of the IPT group had a shorter time to "onset of response" than patients in the CM group (median: 12 vs. 30 days; p=0.041, Log Rank). However, there was no significant difference in the time to onset of response, when more stringent conditions were used., Limitations: Due to ethical restrictions a comparison with an untreated placebo group could not be performed., Conclusions: Early improvement is highly predictive for later stable response or remission in more severely depressed inpatients. In combination therapy, the additional benefit of psychotherapy occurs at least as rapid as the response to antidepressants.

Remission, i.e. the complete absence of symptoms, is the major goal in the treatment of major depressive disorders because residual symptoms cause less functioning and a worse outcome. Despite several treatment steps, numerous patients do not reach complete remission of symptoms. In these patients, it is necessary to rule out several possible causes, including inadequate pharmacotherapy, to confirm the diagnosis of treatment-resistant depression (TRD). In the treatment of TRD, pharmacotherapy plays a central role. Nonpharmacological treatment strategies such as psychotherapy, electroconvulsive therapy, and other brain stimulation methods are also used for TRD treatment and are discussed elsewhere in this issue. Regarding complex pharmacotherapy of TRD, only a limited number of randomized-controlled trials have been done. In consequence, treatment decisions are often based on clinical experience, case series, and uncontrolled studies. Nevertheless, there are some interesting new developments, which are summarized and assessed on the basis of existing evidence in this article. Afore, we present an overview of the most important definitions, epidemiologic data, diagnostic needs and methods for treatment optimization. We end with a critical view on the present and future development of antidepressant drugs.

Objective: The purpose of this article was to determine the relative efficacy of a psychotherapy program when combined with pharmacotherapy versus medication and clinical management in more severely depressed patients., Method: A randomized controlled trial was conducted in 124 hospitalized patients with DSM-IV major depressive disorder that compared 5 weeks of interpersonal psychotherapy modified for depressed inpatients (15 individual and eight group sessions) plus pharmacotherapy with a regimen that involved medication plus intensive clinical management. The study included a prospective, naturalistic follow-up 3 and 12 months after acute treatment in 97 of 105 treatment completers. The 17-item version of the Hamilton Depression Rating Scale (HAM-D) was the primary outcome measure., Results: For the intent-to-treat cohort (N=124), analysis of covariance (ANCOVA) showed that patients treated with interpersonal psychotherapy had a significantly greater reduction of depressive symptoms at week 5. Response rates differed significantly between the two treatment conditions, favoring the group that received adjuvant interpersonal psychotherapy (70%) versus clinical management (51%). Remission rates also tended to be higher for patients in the interpersonal psychotherapy group (49% versus 34%). Patients who initially responded to interpersonal psychotherapy exhibited greater treatment gains at the 3-month follow-up evaluation, since only 3% of these subjects relapsed, compared with 25% of the clinical management subjects. Nine months later, this difference lost statistical significance., Conclusions: An inpatient treatment program with both brief and intensive psychotherapy plus pharmacotherapy is superior to standard treatment. The results, which add to a growing body of evidence, suggest that this combination treatment may offer an advantage over treatment with medication and clinical management for more severely depressed patients.

The neuropeptide substance P (SP) and its receptor, the neurokinin receptor-1 (NK-1), have been associated with some aspects of the pathophysiology of depression. There is limited information available about the effects of antidepressant treatment on serum and cerebrospinal fluid (CSF) concentrations of SP. We measured serum levels of SP in 78 depressed patients after a 6-day medication washout period, as well as after 14 and 35 days of antidepressant treatment with either paroxetine or amitriptyline. In 11 patients, SP was determined in CSF both before and after treatment. Eleven healthy male subjects served as controls. Baseline SP concentrations were independent of age, gender and severity of depression. Neither the total group nor subgroups showed significant differences in SP serum concentrations. SP concentrations in CSF did not change significantly in the patients during treatment, but there was a trend for an increase in paroxetine-treated patients. Serum SP concentrations were not related to treatment response or the class of antidepressant administered. Our data do not support the hypothesis that changes in SP levels in serum or CSF are related to antidepressant response.

Increasing evidence suggests that substance P (SP) and its receptor (neurokinin [NK]-1 receptor [NK1R]) might play an important role in the modulation of stress-related, affective and/or anxious behaviour. First, SP and NK1R are expressed in brain regions that are involved in stress, fear and affective response (e.g. amygdala, hippocampus, hypothalamus and frontal cortex). Second, the SP content in these areas changes upon application of stressful stimuli. Third, the central administration of SP produces a range of fear-related behaviours. In addition, the SP/NK1R system shows significant spatial overlap with neurotransmitters such as serotonin and noradrenaline (norepinephrine), which are known to be involved in the regulation of stress, mood and anxiety. Therefore, it was hypothesised that blockade of the NK1R might have anxiolytic as well as antidepressant effects. Preclinical studies investigating the effects of genetic or pharmacological NK1R inactivation on animal behaviour in assays relevant to depression and anxiety revealed that the behavioural changes resemble those seen with reference antidepressant or anxiolytic drugs. Furthermore, antagonism or genetic inactivation of the NK1R causes alterations in serotonin and norepinephrine neuronal transmission that are likely to contribute to the antidepressant/anxiolytic activity of NK1R antagonists but that are--at least partially--distinct from those produced by established antidepressant drugs. This underlines the conceivable unique mechanism of action of this new class of compounds. In three independent clinical trials with three different compounds (aprepitant [MK-869], L-759274 and CP-122721), an antidepressant effect of NK1R antagonists could be demonstrated. These results, however, have been challenged by recent failed studies with aprepitant. There are numerous indications from preclinical studies that, in addition to SP and NK1R, other neurokinins and/or neurokinin receptors might also be involved in the modulation of stress-related behaviour and that exclusive blockade of the NK1R might not be sufficient to produce consistent anxiolytic and antidepressant effects. One such candidate is the neurokinin-2 receptor (NK2R), and clinical trials to assess the antidepressant effects of NK2R antagonists are currently underway. Of special interest might also be substances that block more than one receptor type such as NK1/2R antagonists or NK1/2/3R antagonists. These compounds may be more efficacious in antagonising the effects of SP than compounds that only block the NK1R.

Substance P (SP) is a neuropeptide which is widely distributed in the periphery and the central nervous system (CNS), where it is co-localised with other neurotransmitters such as serotonin or dopamine and where it acts as a neuromodulator. SP has been proposed to play a role in the aetiopathology of asthma, inflammatory bowel disease, emesis, psoriasis, as well as neuropsychiatric disorders including pain syndromes (e.g. migraine and fibromyalgia) and affective disorders, anxiety disorders, schizophrenia and Alzheimer's disease. This review focuses on the role of SP in the pathogenesis of affective disorders. It summarises the current knowledge on measurements of SP in the CSF and serum in patients with depressive disorders or fibromyalgia, effects of SP-application in humans, SP-receptor expression in postmortem brains and the modulation of SP levels in the course of antidepressant treatment. It also discusses the promise of substance P-receptor antagonists (SPA) for the treatment of affective disorders and their proposed mechanism of action. In summary, much more research is needed to elucidate the role of SP in the pathogenesis of depression. SPA are promising as future drugs for the treatment of affective disorders, but current clinical trials have yet to be completed to draw a firm conclusion. Key words: substance P, neurokinin1-receptor, affective disorders, depression, review.

We tested the hypothesis that extracts from St. John's wort interfere with protein synthesis induced by substance P (SP), a neuropeptide which has been implicated in the etiopathology of depression and anxiety. Using human astrocytoma cells, which express functional neurokinin (NK)-1-receptors, we investigated whether extracts from St. John's wort are able to inhibit SP-induced synthesis of the cytokine interleukin-6 (IL-6). We found a potent and dose-dependent inhibition of SP-induced IL-6 synthesis by various extracts from St. John's wort. These results do not only give further evidence of the anti-inflammatory effects of St. John's wort, but also lend support to the hypothesis that the antidepressant effect of St. John's wort is, at least in part, a result of its inhibitory effects on SP-induced protein synthesis.