Treatment expectation in acute major depressive disorder: an fMRI study on the effects of esketamine on emotion processing in patients with major depression
Abstract
Major depressive disorder (MDD) has a lifetime prevalence of around 8-15%, affecting about 300 million people worldwide. MDD is the leading global cause of disability in terms of total years lost due to disability and is associated with excess mortality (Vos et al., 2012). About one third of patients with MDD fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (Fava, 2003). Treatment algorithms suggest that an antidepressant medication be started initially at lower doses and that adjustment of the medication may be considered if at least a moderate improvement is not observed after 4-6 weeks. This means that even in patients who do respond to antidepressants the time to onset of effect can be several weeks. During this time patients may remain symptomatic and at risk of suicidal behaviour. An unresolved issue in antidepressant trials is high and possibly increasing placebo responses across the last 3 decades (Walsh et al., 2002). Patients’ expectation about treatment benefits is thought to play a major role in the placebo response (Petrie and Rief, 2018). Most patients with MDD present with low mood and anhedonia (i.e. loss of pleasure and blunted responsiveness to reward). The severity of these cardinal symptoms of MDD is related to emotion dysregulation (low mood) and deficits in reward value processing (anhedonia) (Pulcu and Elliott, 2015). Structural and functional Magnetic Resonance Imaging (MRI) studies in MDD (irrespective of treatment) vs healthy subjects have identified distinctive morphological and functional brain changes in MDD mainly in cortico-limbic networks (Fu et al., 2004; Surguladze et al., 2005). Brain regions involved in these networks, in particular the dorsolateral prefrontal cortex (DLPFC), insula, rACC, and amygdala, are crucial for the processing of information with emotional (e.g. emotional faces) significance. Functional imaging data acquired while patients with MDD process emotional stimuli have widely demonstrated altered physiological responses in the amygdala as well as in anatomically related areas (Drevets, 2003), with negative emotional stimuli (e.g. fearful faces) eliciting enhanced amygdala responses in patients (Fu et al., 2004), while amygdala hypo-activity has been found in relation to positive facial expressions (Fu et al., 2004; Surguladze et al., 2005). Functional MRI (fMRI) studies have helped to identify brain regions responding to antidepressant treatments in healthy people and patients with MDD. Generally, these regions are part of emotion-processing networks, i.e. DLPFC, insula, ACC and amygdala (Wessa and Lois, 2015). More specifically, antidepressant treatment (mainly SSRI and SNRI) has been found to normalize abnormally elevated responses to mainly negative emotional stimuli particularly in the amygdala but also other limbic areas (e.g. ACC), to enhance prefrontal cortex (PFC) activity and to enhance the coupling between subcortical (amygdala, thalamus, striatum) and cortical (ACC, PFC) regions in patients with MDD (see Wessa and Lois, 2015 for a review). Knowledge of the differential neurobiological mechanisms underlying the response to pharmacological treatments vs the effects of positive expectation in MDD is almost completely lacking. It is also unclear how neurofunctional alterations in brain regions involved in emotion processing are related to treatment expectation in MDD, and also how drug-specific effects separate from other non-specific elements of the treatment response, such as the placebo effect (Meister et al., 2017). This is important, as placebo response rates in antidepressant clinical trials average 30-40% compared with response rates to antidepressants of around 50% (Furukawa et al., 2016) and there is some evidence that the placebo response rate increases with increasing publication year (Walsh et al., 2002), although this is subject to debate (Furukawa et al., 2016). A better knowledge of such mechanisms would significantly improve the understanding of antidepressant effects and ultimately help to provide more effective relief of depressive symptoms for patients. Therefore the current study aims to investigate the differential effect of esketamine and expectation on the neural correlates of emotion processing in MDD. The brain activation in the network implicated in emotion processing, placebo and antidepressant treatment response in MDD and the pathophysiology of MDD (consisting of the ventromedial prefrontal cortex [VMPFC], rACC, amygdala, hippocampus) is investigated. This is operationalized as change in BOLD-signal as measured using fMRI in the one network of four interconnected brain structures. The data acquisition is constructed by employing a balanced randomization procedure, resulting in four experimental conditions in a balanced block design with manipulation of medication (esketamine vs placebo) and outcome expectation (high vs low). Patients with MDD are randomly allocated to one of the four conditions. After receiving the treatment and the instruction about outcome expectation, participants complete an implicit emotion processing task during fMRI examination. Neuronal activity is analyzed using a general linear model (GLM) approach in line with the medication and expectation manipulations.
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