Lost in translation. The quest for definitions of treatment-resistant depression with a focus on inflammation-related gene expression

Abstract

Approximately one third of individuals with major depressive disorder (MDD) do not respond to antidepressant treatments; but what does treatment-resistant depression (TRD) mean? With this article, I aim to provide an overview of the clinical and operational criteria currently used to define TRD, highlighting core gaps in knowledge and open questions to be addressed in order to drive future research in the field. Importantly, a better definition of TRD must include a better characterization of the biological and molecular correlates of non-response. Among these potential biomarkers, compelling evidence reveals a potential role of inflammation-related gene expression signatures. A more accurate clinical and etiopathological characterization of TRD subjects may help to identify biologically based MDD clinical phenotypes to be targeted in future research and finally achieve better outcomes.

Prognostic Significance of Blood-Based Baseline Biomarkers in Treatment-Resistant Depression: A Literature Review of Available Studies on Treatment Response

“…Also, taking into consideration the small number of participants in the majority of the reviewed studies, additional and larger prospective trials will be needed to explore the prognosis of treatment responses in TRD. Additionally, the investigation of specific blood-based, peripheral biomarkers should concurrently target factors from different pathophysiological pathways and be combined with (epi-)genetic, psychometric, and environmental factors, acknowledging also the individual medical histories of patients (e.g., immune/metabolic comorbidities and exposure to childhood trauma) in order to help establish sensitive and specific biomarkers for the different biological sub-phenotypes of the disorder [ 19 ].…”

“…The term TRD was first introduced 50 years ago [ 18 ]. However, there has been no unanimous consensus reached with respect to the exact definition of TRD [ 13 , 19 , 20 , 21 , 22 ]. For instance, a recent systematic review mentioned over 150 different definitions of TRD in the relevant literature [ 22 ].…”

“…Currently, several ongoing studies focus on the further clarification and formulation of an accurate, clinically relevant, and scientifically-sound definition of TRD [ 20 , 21 , 22 ]. Nevertheless, the most widely accepted clinical research definition to date classifies TRD as a poor response to two or more antidepressant treatments of adequate dose and duration during the current depressive episode [ 19 , 20 , 21 , 22 ]. In accordance with this, most real-world studies consider MDD patients resistant to treatment after having an insufficient response to at least two types of antidepressants [ 23 ].…”

“…However, apart from certain repeatedly confirmed clinical and psychosocial predictive factors of non-response [ 33 ], there is a clear lack of objective, personalized, and clinically applicable biomarkers that are potentially able to detect depressed patients with TRD and different responses to antidepressant treatment and/or predict the optimal treatment strategy in every day clinical practice [ 30 , 34 ]. This issue is also reflected in the fact that no biomarker has been included in any way in the definition of TRD to date [ 19 ].…”

Editorial commentary on the special issue emerging psychoneuroimmunology research: Future leaders in focus

“…For example, in the context of treatment resistant depression these genes may predict lack of response to particular treatments. It is suggested that instead of selecting genes a priori , that the entire transcriptome be analyzed based on whole-genome approaches, which may reveal gene candidates not previously associated with depressive disorders ( Sforzini, 2021 ) . Additionally, using an absolute, rather than a relative quantitative approach will better allow for the identification of defined thresholds of mRNA values of pro-inflammatory cytokines ( Mariani, 2021 ) .…”