As one of the most prevalent and debilitating psychiatric disorders worldwide, major depressive disorder (MDD) causes huge harm to both families and societies (Zhdanava et al., 2021). In clinical practice, patients with MDD usually have impairments in cognition, memory, emotional regulation, appetite, sleep, feeling of pleasure, motivation, and sociality (Dean and Keshavan, 2017). In addition, MDD also promotes secondary disability, as patients with MDD are more likely to develop chronic medical illnesses such as hypertension and diabetes, and these patients are less likely to comply with medical treatment (Dean and Keshavan, 2017). The combination of the primary clinical symptoms and the secondary disability of chronic medical illness induced by MDD make it one of the most costly medical burdens in the world. A study in 2021 showed that in the United States, the number of adults with MDD increased by 12.9 %, from 15.5 to 17.5 million, between 2010 and 2018, whereas the proportion of adults with MDD aged 18–34 years increased from 34.6 to 47.5 % (Greenberg et al., 2021). Moreover, over this period, the incremental economic burden of adults with MDD increased by 37.9 %, from 236.6 to 326.2 billion dollars (Greenberg et al., 2021).

Despite tremendous progress in neuroscience research over the past few decades, the pathophysiology of MDD has not been fully elucidated. Up to date, MDD research has implicated several biological mechanisms including altered serotonergic, noradrenergic, dopaminergic, and glutamatergic systems, increased inflammation, hypothalamic-pituitary-adrenal (HPA) axis abnormalities, vascular changes, and decreased neurogenesis and neuroplasticity (Krishnan and Nestler, 2008; Palazidou, 2012; Blier, 2016; Wohleb et al., 2016; Dean and Keshavan, 2017). Among these biological mechanisms, abnormalities in the HPA axis are present in a lot of MDD patients, as MDD is mainly precipitated by stressful life events, interacting with genetic and other predisposing factors (Klengel and Binder, 2013; Herbison et al., 2017; Ding and Dai, 2019). Moreover, the HPA axis has been well documented to be the major component of the neuroendocrine network responding to both acute and chronic stress (Herman et al., 2016; van Bodegom et al., 2017; Leistner and Menke, 2020). The biological function of the HPA axis involves the hypothalamus, pituitary gland, adrenal gland, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (human)/corticosterone (rodents), among which the biological synthesis and release of CRH is critical (Smith and Vale, 2006). It is well-known that CRH is mainly secreted from neurons in the paraventricular nucleus (PVN) of the hypothalamus (Smith and Vale, 2006). In 2022, we published a report in Molecular Psychiatry demonstrating that the salt-inducible kinase 1 (SIK1)-cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) signaling in the PVN plays a role in depression by regulating the expression of CRH and the activity of the HPA axis (Wang et al., 2022). In this report, we have found that chronic stress significantly decreased the expression of SIK1 but not SIK2 or SIK3 in the PVN, leading to fully enhanced CRTC1 nuclear translocation and CRTC1-CREB binding in PVN neurons (Wang et al., 2022). Both genetic knockdown of SIK1 and genetic overexpression of CRTC1 in the PVN simulated chronic stress, producing a depression-like phenotype in naive mice, and the CRTC1-CREB-CRH pathway mediates the pro-depressant actions induced by SIK1 knockdown in the PVN (Wang et al., 2022). In contrast, both genetic overexpression of SIK1 and genetic knockdown of CRTC1 in the PVN protected against chronic stress, leading to antidepressant-like effects in mice (Wang et al., 2022). Moreover, stereotactic infusion of TAT-SIK1 into the PVN also produced beneficial effects against chronic stress (Wang et al., 2022). Furthermore, the SIK1-CRTC1 system in the PVN played a role in the antidepressant-like effects of fluoxetine, paroxetine, venlafaxine, and duloxetine in mice (Wang et al., 2022). All these findings reveal that SIK1 and CRTC1 in PVN neurons are closely involved in depression neurobiology, and they could be viable targets for novel antidepressants.

Escitalopram is the S-enantiomer of the selective serotonin (5-HT) reuptake inhibitor (SSRI) citalopram, which contains equal amounts of the S- and R-forms in a racemic mixture (Höschl and Svestka, 2008). It has been demonstrated that it is escitalopram that carries the therapeutic potential of citalopram, and has statistically superior and clinically relevant properties compared with citalopram (Höschl and Svestka, 2008). Escitalopram is at least as effective in the treatment of depression and anxiety as other SSRIs (fluoxetine and paroxetine), venlafaxine, bupropion, and duloxetine (Höschl and Svestka, 2008). Moreover, compared with other antidepressants, escitalopram possesses a relatively faster onset of action and is generally better tolerated (Höschl and Svestka, 2008). Therefore, escitalopram is an effective first-line option in the management of patients with MDD or various anxiety disorders (Höschl and Svestka, 2008). Although thought to aim at the 5-HT system, recently it has been found that escitalopram affects several other targets (Wang et al., 2014; Abdo et al., 2019; Farahbakhsh and Radahmadi, 2022; Gołyszny et al., 2022a; Gołyszny et al., 2022b). Here, we speculated that like fluoxetine, paroxetine, venlafaxine, and duloxetine, the SIK1-CRTC1 system in the PVN may also underlie the pharmacological effects of escitalopram. In the present study, this assumption was thoroughly investigated using mouse models of depression.