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Background: Cognitive symptoms are a core feature of depressive disorders, interfere with full functional recovery and are prominent in patients with treatment-resistant depression (TRD), particularly in severe chronic cases. Intranasal (IN) esketamine was recently approved for the treatment of TRD; however, its effects on cognitive symptoms are unclear. In this article, we describe cognitive changes in 8 patients with chronic TRD who were treated with IN administration of esketamine., Methods: Eight outpatients with chronic TRD received IN esketamine over 3 months and were assessed at baseline and after 4, 8, and 12 weeks of treatment using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Digit Symbol Substitution Test (DSST), the Trail Making Test-B (TMT-B), the Patient Deficits Questionnaire for Depression 5-item (PDQ-D5), the Hamilton Anxiety Rating Scale (HARS), and the Clinical Global Impressions Scale (CGI)., Findings: We observed reductions in cognitive symptoms according to DSST, TMT-B, and PDQ-D5 scores within the first 2 months of treatment with IN esketamine. These improvements were observed before patients achieved clinical response (≥50% decrease in baseline MADRS scores), and they also occurred earlier than reductions in HARS scores., Conclusions: A clinical response to IN esketamine was detected in severely ill patients with chronic TRD after 3 months of treatment. Interestingly, improvements on measures of cognitive symptoms were observed before patients achieved antidepressant response. These preliminary observations suggest an additional value to the antidepressant properties of IN esketamine. Clinical studies specifically investigating cognition as a primary outcome measure of IN esketamine in TRD are warranted., Competing Interests: M.D.N. is/has been a consultant and/or a speaker for and/or has received research grants from: Angelini, Idorsia Pharmaceuticals, Janssen, Lundbeck, Neuraxpharma, Otsuka. G.S. is/has been a consultant and/or a speaker for and/or has received research grants from: Angelini, Janssen, Lundbeck, Neuraxpharma, and Otsuka. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We review the conflicting results from imaging studies of dopamine transporter availability in depressed patients and also discuss the heterogeneity of the variables involved. Major depression includes diverse clinical manifestations and in recent years there has been an increasing interest in the identification of homogeneous phenotypes and different clinical subtypes of depression, e.g. anhedonic depression, retarded depression, etc. In addition, the use of different radioligands and imaging techniques, diverse rating scales, together with the lack of control of clinical variables (clinical course, recent or past use of substances of abuse, etc.) make it difficult to clearly identify neuronal regions or networks with consistently abnormal structures or functions in major depressive disorder. It is probably necessary to build a shared approach between clinicians and researchers in order to identify standardized procedures to better understand the role of the dopamine transporter in depression. We outline a list of major issues and also suggest some standardized procedures in collecting clinical and imaging data on major depressed patients. Our aim is to delineate a possible "modus operandi" that would be a proposal for neuroreceptor studies on major depression., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

It is now well established that major depression is accompanied and characterized by altered responses of the immune-inflammatory system. In this study we investigated the pro-inflammatory activation of monocytes isolated from depressed patients as a parameter not influenced by such confounds as the time of day, the nutritional and exercise status or the age and gender of patients. Monocytes from depressed patients and from healthy controls were isolated in vitro; after 24-h incubation under basal conditions, cells were exposed for 24-h to 100 ng/ml of endotoxin (bacterial lipopolysaccharide, LPS). We found that monocytes from drug-free depressed patients and controls release the same amounts of prostaglandin E2 (PGE2) under basal conditions, whereas monocytes from patients are dramatically less reactive to LPS (8.62-fold increase vs previous 24 hrs) compared to healthy controls (123.3-fold increase vs previous 24 hrs). Such blunted prostanoid production was paralleled by a reduction in COX-2 gene expression, whereas other pro-inflammatory mediators, namely interleukin-1β (IL-1 β) and -6 (IL-6) showed a trend to increased gene expression. The above changes were not associated to increased levels of circulating glucocorticoids. After 8 months of antidepressive drug treatment, the increase in PGE2 production after the endotoxin challenge was partially restored, whereas the increase in IL-1 β and -6 levels observed at baseline was completely abolished. In conclusion, our findings show that the reactivity of monocytes from depressed patients might be considered as a marker of the immune-inflammatory disorders associated to depression, although the lack of paired healthy controls at follow-up does not allow to conclude that monocyte reactivity to endotoxin is also a marker of treatment outcome.

Objectives: High, normal, or low plasma magnesium (Mg) levels have been observed in depressed patients. The aim of our study was to investigate the relationship of Mg levels with depression severity, specific psychopathological dimensions, and treatment outcome., Methods: A total of 123 outpatients during a major depressive episode were recruited. All patients showed at least two major depressive episodes and did not achieve remission in the former treatment trial. A blood sample was collected to determine total plasma Mg levels. The psychopathological status was assessed using Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Depression Retardation Rating Scale for psychomotor retardation, and Snaith-Hamilton Pleasure Scale for anhedonia. Hamilton Depression Rating Scale was repeated at 3 months after treatment., Results: All patients showed Mg levels mostly within the normal range. No association between Mg levels and psychopathological severity was reported. Patients who responded to antidepressant treatment showed higher Mg levels and higher retardation scores at basal evaluation in comparison with non-responders., Discussion: Although further studies investigating the relationship between hypomagnesaemia, depression, and treatment outcome are certainly necessary, we have hypothesized that hypomagnesaemia could be an epiphenomenic biochemical trait in less drug-responsive depressed patients. It is also plausible that lower Mg levels and hyperactive traits identify a biological subtype of patients with increased catecholaminergic functioning and a poorer response to aminergic drugs. Moreover, Mg depletion could partly account for the correlation between low Mg levels and poor outcome and this raises the question of Mg's possible therapeutic role in depression.