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European Group for the Study of Resistant Depression (GSRD) - Where have we gone so far: Review of clinical and genetic findings

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology (Impact Factor: 5.4). 03/2012; 22(7):453-68. DOI: 10.1016/j.euroneuro.2012.02.006
Source: PubMed

ABSTRACT The primary objective of this review is to give an overview of the main findings of the European multicenter project "Patterns of Treatment Resistance and Switching Strategies in Affective Disorder", performed by the Group for the Study of Resistant Depression (GSRD). The aim was to study methodological issues, operational criteria, clinical characteristics, and genetic variables associated with treatment resistant depression (TRD), that is failure to reach response after at least two consecutive adequate antidepressant trials. The primary findings of clinical variables associated with treatment resistance include comorbid anxiety disorders as well as non-response to the first antidepressant received lifetime. Although there is a plethora of hints in textbooks that switching the mechanism of action should be obtained in case of nonresponse to one medication, the results of the GSRD challenge this notion by demonstrating in retrospective and prospective evaluations that staying on the same antidepressant mechanism of action for a longer time is more beneficial than switching, however, when switching is an option there is no benefit to switch across class. The GSRD candidate gene studies found that metabolism status according to cytochrome P450 gene polymorphisms may not be helpful to predict response and remission rates to antidepressants. Significant associations with MDD and antidepressant treatment response were found for COMT SNPs. Investigating the impact of COMT on suicidal behaviour, we found a significant association with suicide risk in MDD patients not responding to antidepressant treatment, but not in responders. Further significant associations with treatment response phenotypes were found with BDNF, 5HTR2A and CREB1. Additional investigated candidate genes were DTNBP1, 5HT1A, PTGS2, GRIK4 and GNB3.

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    • "Please cite this article in press as: Bartova L, et al., Reduced default mode network suppression during a working memory task in remitted major depression, Journal of Psychiatric Research (2015), http://dx.doi.org/10.1016/j.jpsychires.2015.02.025 speculate that the dysfunctional DMN suppression present in nonsymptomatic MDD patients could also render the biological signature of increased relapse likelihood. This assumption is further supported by significantly pronounced DMN suppression deficits in adolescent-onset rMDD patients, who are prone to a more severe and chronic course compared to MDD patients with later onset, as repeatedly suggested in previous studies (Harrington et al., 1990; Klein et al., 1999; Weissman et al., 1999; Aalto-Setala et al., 2002; Zisook et al., 2007; Kendler et al., 2009; Pajer et al., 2012; Schosser et al., 2012; Ramirez et al., 2015). "
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    ABSTRACT: Insufficient default mode network (DMN) suppression was linked to increased rumination in symptomatic Major Depressive Disorder (MDD). Since rumination is known to predict relapse and a more severe course of MDD, we hypothesized that similar DMN alterations might also exist during full remission of MDD (rMDD), a condition known to be associated with increased relapse rates specifically in patients with adolescent onset. Within a cross-sectional functional magnetic resonance imaging study activation and functional connectivity (FC) were investigated in 120 adults comprising 78 drug-free rMDD patients with adolescent- (n = 42) and adult-onset (n = 36) as well as 42 healthy controls (HC), while performing the n-back task. Compared to HC, rMDD patients showed diminished DMN deactivation with strongest differences in the anterior-medial prefrontal cortex (amPFC), which was further linked to increased rumination response style. On a brain systems level, rMDD patients showed an increased FC between the amPFC and the dorsolateral prefrontal cortex, which constitutes a key region of the antagonistic working-memory network. Both whole-brain analyses revealed significant differences between adolescent-onset rMDD patients and HC, while adult-onset rMDD patients showed no significant effects. Results of this study demonstrate that reduced DMN suppression exists even after full recovery of depressive symptoms, which appears to be specifically pronounced in adolescent-onset MDD patients. Our results encourage the investigation of DMN suppression as a putative predictor of relapse in clinical trials, which might eventually lead to important implications for antidepressant maintenance treatment. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
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    • "Notably, to date, all drugs approved as antidepressant medications are either inhibitors of monoamine transporters or monoamine oxidase (Berton and Nestler, 2006) and take 3 to 8 weeks to exert their effects (Wong and Licinio, 2004). Patients that emerge as treatment resistant, defined as failing 2 or more trials of medication , are more severely ill with comorbid anxiety disorders and are at increased risk of suicide for an extended period of time (Schosser et al., 2012). Therefore, there is a pressing medical need to develop rapidly acting therapeutics that are capable of immediately relieving the depressive symptomology. "
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