Mechanisms of antidepressant resistance

Abstract

Depression is one of the most frequent and severe mental disorder. Since the discovery of antidepressant (AD) properties of the imipramine and then after of other tricyclic compounds, several classes of psychotropic drugs have shown be effective in treating major depressive disorder (MDD). However, there is a wide range of variability in response to ADs that might lead to non response or partial response or in increased rate of relapse or recurrence. The mechanisms of response to AD therapy are poorly understood, and few biomarkers are available than can predict response to pharmacotherapy. Here, we will first review markers that can be used to predict response to pharmacotherapy, such as markers of drug metabolism or blood-brain barrier (BBB) function, the activity of specific brain areas or neurotransmitter systems, hormonal dysregulations or plasticity, and related molecular targets. We will describe both clinical and preclinical studies and describe factors that might affect the expression of these markers, including environmental or genetic factors and comorbidities. This information will permit us to suggest practical recommendations and innovative treatment strategies to improve therapeutic outcomes.

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder

“…Indeed, there is little information to date regarding possible associations of gene polymorphisms with a clinical response to different SSRIs. Candidate genes for these association analyses included polymorphisms affecting the serotonin transporter, serotonin receptors, intracellular transduction, noradrenergic and other neurotransmitter systems, the hypothalamic-pituitary adrenal (HPA) axis, the brain-derived neurotrophic factor (BDNF), and related alteration in adult hippocampal neurogenesis [33][34][35][36]53]. We selected the KL locus because Klotho protein is involved in the dysregulation of the stress system response related to depression [20,26] and in the aging processes [25].…”

“…Several clinical trials, however, reported a variable response rate to SSRI up to 65 %, particularly in older patients [31,32]. While major evidences suggested an important contribution of pharmacogenetics in SSRI response in younger subjects, the role of genetics in SSRI response in LLD is still under debate [33][34][35][36]. The aim of the present study was to investigate the KL gene polymorphisms to evaluate a potential involvement of this gene in the response to SSRI treatment in patients with late-life MDD.…”

Treatment-resistant depression: are animal models of depression fit for purpose?

“…The utility of these models remains to be determined (as, indeed, is the case for the majority of the models reviewed). There are also some known causes of antidepressant resistance that we have described as 'theoretically trivial' (Willner et al 2013), including, for example, pharmacokinetic factors such as polymorphisms of liver cytochrome 450 enzymes or failure to penetrate the blood-brain barrier (El-Hage et al 2013), which, if modelled in animals, would likely not be associated with increased stress sensitivity. And as we have pointed out, the greater propensity to depression in women relative to men is not associated with antidepressant resistance.…”

Chronic selective serotonin reuptake inhibition modulates endothelial dysfunction and oxidative state in rat chronic mild stress model of depression

“…Although drug resistance and treatment failures are frequent during antidepressant therapy (54,62), the reason for this is unknown. Several factors important for antidepressant responsiveness/resistance have been suggested (16). In humans, these factors can be both acquired throughout life and be inherited in the form of mutations of key transporters and enzymes involved in the drug metabolism.…”