European Group for the Study of Resistant Depression (GSRD) - Where have we gone so far: Review of clinical and genetic findings
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.
Available from: Ulrich Rabl
- "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.
Available from: Wenhua Zhou
- "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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ABSTRACT: Background: VGF (non-acryonimic) and PI3K/AKT/mTOR signaling play pivotal role in depression. However, whether the PI3K/AKT/mTOR signaling-mediated VGF participates in the rapid-acting antidepressant-like actions of GLYX-13 is unclear. Methods: Herein, we evaluated the effects of acute treatment of GLYX-13 (0.5, 5 and 10 mg/kg, i.p.) in the forced swim test (FST). In addition, we assessed whether the acute treatment with GLYX-13 reverses the depressive-like behaviors induced by chronic unpredictable mild stress (CUMS). Furthermore, we determined whether the Vgf knock-down in hippocampus of mice blocks the effects of GLYX-13. Moreover, we also demonstrated the effects of intra-hippocampus (i.h.) infusion of LY294002 (10 nmol/side), a specific PI3K inhibitor prior to the treatment of GLYX-13 in FST. Lastly, whether AMPA receptor and mTOR activation involves in the antidepressant-like effects of GLYX-13 were examined.
Results: Our results shown that GLYX-13 dose-dependently reversed the depressive-like behaviors in FST. Additionally, GLYX-13 significantly reversed the down-regulation of phosphorylation of AKT (pAKT), mTOR (pmTOR) and eukaryotic elongation factor 2 (peEF2) and VGF induced by CUMS in hippocampus. Further, Vgf knock-down in hippocampus of mice significantly blocked the rapid-acting antidepressant-like effects and up-regulation on PI3K/AKT/mTOR/VGF signaling of GLYX-13. Moreover, i.h. infusion of LY294002 significantly abolished the antidepressant-like effects and up-regulation on PI3K/AKT/mTOR/VGF signaling of GLYX-13. Finally, antidepressant-like effects of GLYX-13 required AMPA receptor and mTOR activation, as evidenced by the ability of NBQX and rapamycin to block the effects of GLYX-13 respectively.
Conclusions: Our results suggest that PI3K/AKT/mTOR signaling-mediated VGF in hippocampus may involve in the antidepressant-like effects of GLYX-13.
Available from: Cristina Benatti
- "Major depression (MD) is one of the most prevalent and disabling of all medical disorders and is estimated to rank second among the major causes of disability worldwide by 2030 . Despite its increasing incidence the currently available treatments have major clinical drawbacks: (i) latency of therapeutic action while undesirable side-effects appear earlier; (ii) only 60–65% of depressed patients benefit from the first antidepressant drug (AD) administered, while the remaining 35–40% fail to achieve a sufficient remission  . Moreover, the development of faster and more effective compounds is a slow and often unsuccessful process . "
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ABSTRACT: The study of depression is facing major challenges: firstly, the need to develop new drugs with a faster onset of action and secondly, fulfilling the unmet needs of treatment resistant patients with more effective compounds. The chronic escape deficit (CED) is a valid and useful model of depression and is based on the induction of an escape deficit after exposure of rats to unavoidable stress. This behavioural model provides a method for evaluating the capacity of a treatment to revert the escape deficit. The majority of antidepressant drugs need to be administered for at least 3-4 weeks in order to revert the escape deficit. A 7-day treatment with escitalopram reverted the stress-induced escape deficit in approximately 50% of the animals. Escitalopram treatment decreased anxiety-related behaviours in stressed animals, by increasing the time spent in the central part of the arena with respect to saline treated stressed animals, without affecting exploratory related behaviours. Gene expression profiling was carried out in the hippocampus to identify new targets associated with the effects of stress or with the different response to escitalopram. By combining a well-validated animal model with gene expression analysis we demonstrated that the CED model may represent a perfect tool for studying treatment-resistant depression.
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