Ventral tegmental area and substantia nigra neuromelanin sensitive MR in patients with difficult-to-treat depression during esketamine treatment

Abstract

Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide, with a lifetime prevalence of 5–17%. MDD significantly impairs quality of life through social withdrawal, emotional distress, and cognitive dysfunction (Culpepper, 2015; Elmer and Stadtfeld, 2020). Even when guideline treatments for MDD are provided, a critical challenge exists with about 30% of patients remaining symptomatic despite multiple therapeutic approaches (McIntyre et al., 2023). These patients are classified as having difficult to treat depression (DTD) (Gastaldon et al., 2020; Vasiliu, 2023). One emerging novel treatment for DTD is intranasal esketamine, a glutamatergic neuromodulator that blocks NMDA receptors (Rizzo et al., 2025). Approximately 50% of DTD patients respond positively to esketamine after four weeks of treatment (Popova et al., 2019). While this shows a significant improvement, there is still room for enhancing response rates and tailoring treatments to individual patients. Personalization of treatments like esketamine might be leveraged by advancing our understanding of the specific neurotransmitter systems targeted by pharmacological interventions and their relevance to MDD pathophysiology. Dysregulation of monoamine neurotransmitter systems (involving dopamine, serotonin, and norepinephrine) has long been associated with MDD (Fries et al., 2023). Evidence suggests that downregulation of the dopaminergic system is a core feature of MDD pathophysiology, contributing to key symptoms like anhedonia (Pare et al., 1969; D’haenen and Bossuyt, 1994; Meyer et al., 2001; Sarchiapone et al., 2006; Der-Avakian and Markou, 2012). Dopamine neurons are found primarily in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) (Trutti et al., 2019), regions essential for reward prediction, motivational arousal, and assigning motivational salience to stimuli, all functions that are disrupted in MDD (Wise, 2009; Liu et al., 2024). Recent research has also highlighted glutamatergic dysfunction in MDD, revealing imbalances in excitatory/inhibitory neurotransmitter signaling and reduced levels of glutamate metabolites (Sanacora et al., 2004; Moriguchi et al., 2019). Although esketamine primarily targets glutamatergic systems, one prominent hypothesis about its mode of action in MDD is that it engages dopaminergic pathways, especially those involved in reward processing and motivation of behaviour, by disinhibiting midbrain dopamine neurons via lateral habenula (LHb) suppression. The habenula is hypothesized to be hyperactive in MDD and to exert inhibitory GABAergic control over the SNc and VTA (Christoph et al., 1986; Matsumoto and Hikosaka, 2007; Yang et al., 2018; Pulcu et al., 2022). This interplay suggests that esketamine’s efficacy may partially depend on the functional integrity of dopaminergic systems. Here we will use neuromelanin-sensitive magnetic resonance imaging (NM-MRI) to detect neuromelanin (NM), a pigment that accumulates in catecholamine-producing neurons such as dopamine neurons, providing insight into catecholaminergic function (Trujillo et al., 2024). Regions rich in NM, including the SN and VTA, appear hyperintense on NM-MRI scans (Cassidy et al., 2019; Horga et al., 2021). Thus, NM-MRI could potentially be used as a proxy of the integrity of the dopaminergic system. Only limited data have been published on VTA/SN NM-MRI in depressed patients. Moreover, the published studies on SN NM contrast ratios (CRs, i.e., (NM contrast of region of interest + NM contrast of control region)/ NM contrast of control region) have yielded mixed results, with reductions in contrast (Kuai et al., 2024), while others report no significant changes (Shibata et al., 2008; Sasaki et al., 2010). Regarding symptom severity, one study reported lower VTA signal in MDD patients which was linked to reduced extrinsic motivation, but not to self-reported depression symptom severity or anhedonia (Morris et al., 2022). We hypothesize that patients with more intact dopamine systems, indexed by higher NM-MRI signal in the SNc and VTA, will respond more favorably in terms of depression symptom severity and specifically anhedonia reduction to esketamine treatment. Furthermore, we hypothesize that treatment resistance will be accompanied by lower NM CRs in VTA and SNc.

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