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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Selective serotonin reuptake inhibitors (SSRIs) are the first line pharmacological treatment of Major Depressive Disorder (MDD), but only about half of patients benefit from it. Cerebral serotonin 4 receptor (5-HT4R) binding measured with positron emission tomography (PET) is inversely related to serotonin levels and can serve as a proxy for brain serotonin levels. We here determine if 5-HT4R differs between healthy and MDD individuals and if it is associated with successful outcomes of serotonergic treatment of MDD. We [11C]-SB207145 PET-scanned 100 (71 F) untreated patients with moderate to severe MDD and 91 (55 F) healthy controls; 40 patients were re-scanned after 8 weeks treatment. All patients started treatment with the SSRI escitalopram and were followed clinically after 1, 2, 4, 8 and 12 weeks. Treatment response was measured as change from baseline. Before treatment, patients with MDD had 8% lower global 5-HT4R binding than controls (95%CI[-13.1%;-2.5%], p<0.001). Non-responders did not differ from controls, whereas remitters had 9% lower binding than controls ([-16.1%;-2.7%], p=0.004). Independent of treatment outcomes, patients reduced their neostriatal 5-HT4R binding (-9%, [-12.8%;-5.0%], p<0.001) after serotonergic intervention. Overall, patients with MDD have lower cerebral 5-HT4R binding than controls, suggesting that 5-HT4R is a biomarker for MDD. The observation that SSRI treatment leads to reduced neostriatal 5-HT4R binding supports that the treatment does indeed increase brain 5-HT levels. Patients who remit to SSRIs have lower cerebral 5-HT4R prior to treatment than controls whereas non-responders do not differ. We propose that non-responders to SSRI's constitute a subgroup with non-serotonergic depression.

Previous studies have indicated that antidepressants that inhibit the serotonin transporter reduces oxidative stress. DNA and RNA damage from oxidation is involved in aging and a range of age-related pathophysiological processes. Here, we studied the urinary excretion of markers of DNA and RNA damage from oxidation, 8-oxodG and 8-oxoGuo, respectively, in the NeuroPharm cohort of 100 drug-free patients with unipolar depression and in 856 non-psychiatric community controls. Patients were subsequently treated for 8 weeks with escitalopram in flexible doses of 5–20 mg; seven of these switched to duloxetine by week 4, as allowed by the protocol. At week 8, 82 patients were followed up clinically and with measurements of 8-oxodG/8-oxoGuo. Contextual data were collected in patients, including markers of cortisol excretion and low-grade inflammation. The intervention was associated with a substantial reduction in both 8-oxodG/8-oxoGuo excretion (25% and 10%, respectively). The change was not significantly correlated to measures of clinical improvement. Both markers were strongly and negatively correlated to cortisol, as measured by the area under the curve for the full-day salivary cortisol excretion. Surprisingly, patients had similar levels of 8-oxodG excretion and lower levels of 8-oxoGuo excretion at baseline compared to the controls. We conclude that intervention with serotonin reuptake inhibitors in unipolar depression is associated with a reduction in systemic DNA and RNA damage from oxidation. To our knowledge, this to date the largest intervention study to characterize this phenomenon, and the first to include a marker of RNA oxidation.