Background: Between 30 and 50% of patients with major depressive disorder (MDD) do not respond sufficiently to antidepressant regimens. The conventional pharmacological treatments predominantly target serotonergic brain signaling but better tools to predict treatment response and identify relevant subgroups of MDD are needed to support individualized and mechanistically targeted treatment strategies. The aim of this study is to investigate antidepressant-free patients with MDD using neuroimaging, electrophysiological, molecular, cognitive, and clinical examinations and evaluate their ability to predict clinical response to SSRI treatment as individual or combined predictors.

Background Cognitive disturbances are common and disabling features of major depressive disorder (MDD). Previous studies provide limited insight into the co-occurrence of hot (emotion-dependent) and cold (emotion-independent) cognitive disturbances in MDD. Therefore, we here map both hot and cold cognition in depressed patients compared to healthy individuals. Methods We collected neuropsychological data from 92 antidepressant-free MDD patients and 103 healthy controls. All participants completed a comprehensive neuropsychological test battery assessing hot cognition including emotion processing, affective verbal memory and social cognition as well as cold cognition including verbal and working memory and reaction time. Results The depressed patients showed small to moderate negative affective biases on emotion processing outcomes, moderate increases in ratings of guilt and shame and moderate deficits in verbal and working memory as well as moderately slowed reaction time compared to healthy controls. We observed no correlations between individual cognitive tasks and depression severity in the depressed patients. Lastly, an exploratory cluster analysis suggested the presence of three cognitive profiles in MDD: one characterised predominantly by disturbed hot cognitive functions, one characterised predominantly by disturbed cold cognitive functions and one characterised by global impairment across all cognitive domains. Notably, the three cognitive profiles differed in depression severity. Conclusion We identified a pattern of small to moderate disturbances in both hot and cold cognition in MDD. While none of the individual cognitive outcomes mapped onto depression severity, cognitive profile clusters did. Overall cognition-based stratification tools may be useful in precision medicine approaches to MDD.

VG. Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women. Objective: Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent registerbased studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin 4 receptor (5-HT4R) brain imaging. Methods: [ 11 C]SB207145-PET imaging data on 53 healthy women, of whom 16 used OCs, were available from the Cimbi database. We evaluated global effects of OC use on 5-HT4R binding in a latent variable model based on 5-HT4R binding across cortical and subcortical regions. Results: We demonstrate that OC users have 9-12% lower global brain 5-HT4R binding potential compared to non-users. Univariate regionbased analyses (pallidostriatum, caudate, hippocampus, amygdala, anterior cingulate cortex, and neocortex) supported the global effect of OC use with the largest difference present in the hippocampus (À12.8% (95% CI [À21.0; À3.9], P corrected = 0.03). Conclusion: We show that women who use OCs have markedly lower brain 5-HT4R binding relative to non-users, which constitutes a plausible molecular link between OC use and increased risk of depressive episodes. We propose that this reflects a reduced 5-HT4R gene expression, possibly related to a blunted ovarian hormone state among OC users.

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Disruptions in hot cognition, i.e., the processing of emotionally salient information, are prevalent in most neuropsychiatric disorders and constitute a potential treatment target. EMOTICOM is the first comprehensive neuropsychological test battery developed specifically to assess hot cognition. The aim of the study was to validate and establish a Danish language version and reference data for the EMOTICOM test battery. To evaluate the psychometric properties of 11 EMOTICOM tasks, we collected data from 100 healthy Danish participants (50 males, 50 females) including retest data from 49 participants. We assessed test–retest reliability, floor and ceiling effects, task-intercorrelations, and correlations between task performance and relevant demographic and descriptive factors. We found that test–retest reliability varied from poor to excellent while some tasks exhibited floor or ceiling effects. Intercorrelations among EMOTICOM task outcomes were low, indicating that the tasks capture different cognitive constructs. EMOTICOM task performance was largely independent of age, sex, education, and IQ as well as current mood, personality, and self-reported motivation and diligence during task completion. Overall, many of the EMOTICOM tasks were found to be useful and objective measures of hot cognition although select tasks may benefit from modifications to avoid floor and ceiling effects in healthy individuals.

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Concurrent anxiety is frequent in major depressive disorder and a shared pathophysiological mechanism between anxiety and other depressive symptoms is plausible. The serotonin 4 receptor (5-HT4R) has been implicated in both depression and anxiety. This is the first study to investigate the association between the cerebral 5-HT4R binding and anxiety in patients with depression before and after antidepressant treatment and the association to treatment response. Ninety-one drug-free patients with depression were positron emission tomography scanned with the 5-HT4R ligand [11C]-SB207145. Depression severity and concurrent anxiety was measured at baseline and throughout 8 weeks of antidepressant treatment. Anxiety measures included four domains: anxiety/somatization factor score; Generalized Anxiety Disorder 10-items (GAD-10) score; anxiety/somatization factor score ≥7 (anxious depression) and syndromal anxious depression. Forty patients were rescanned at week 8. At baseline, we found a negative association between global 5-HT4R binding and both GAD-10 score (p < 0.01) and anxiety/somatization factor score (p = 0.06). Further, remitters had a higher baseline anxiety/somatization factor score compared with non-responders (p = 0.04). At rescan, patients with syndromal anxious depression had a greater change in binding relative to patients with non-syndromal depression (p = 0.04). Concurrent anxiety in patients with depression measured by GAD-10 score and anxiety/somatization factor score is negatively associated with cerebral 5-HT4R binding. A lower binding may represent a subtype with reduced natural resilience against anxiety in a depressed state, and concurrent anxiety may influence the effect on the 5-HT4R from serotonergic antidepressants. The 5-HT4R is a promising neuroreceptor for further understanding the underpinnings of concurrent anxiety in patients with depression.