Endophenotypes Of Depression Research Articles

Emotional, inflammatory, and genetic factors of resilience and vulnerability to depression in patients with premenopausal breast cancer: A longitudinal study protocol.

Psychosocial stress and depressive disorder have been associated with cancer as putative contributors to worse prognosis. On the other hand, cancer diagnosis is a recognised life event that can contribute to distress and depressive states. Humoral and cellular inflammation can promote depressive disorder by means of decreased monoamine synthesis, glutamate neurotoxicity, neurogenesis and neuroplasticity, dysregulated hypothalamic-pituitary-adrenal axis, and glucocorticoid resistance. This protocol objectives are to observe the interactions between psychosocial variables and biochemical and immunological biomarkers in a longitudinal, prospective design; to identify inflammation-related depression endophenotypes in breast cancer patients and to understand if early diagnosed and treated depression in this population will translate in better inflammation status and better global prognosis. Prospective observational cohort, composed by 100 consecutive premenopausal patients, diagnosed with non-distant metastatic breast carcinoma and with no history of major psychopathology or other organic illness. The participants will have an in-person assessment in three different moments, along illness treatment and follow-up, with respect to cytometric, immunologic, and psychosocial parameters and will be tested for depression vulnerability and resilience inflammation-related functional genetic polymorphisms. Additionally, at years 5 and 10 post enrollment, patients`medical records will be assessed. As a control cohort, all patients excluded due to psychiatric history or past psychiatric treatments will have their clinical records assessed at years 5 and 10 after admission. All the data will be managed with the SPSS® software. This study is an original longitudinal cohort of breast cancer premenopausal patients, with a comprehensive approach to psychosocial, clinical, inflammatory, and genetic variables. It expects to provide evidence regarding the links between genetic, cytometric, immunologic, and psychosocial factors, their potential contribution to the pathophysiology of depressive disorder, breast cancer course, progression, and prognosis. It may further contribute with data to better efficacy of the psycho-oncological interventions. National Commission of Data Protection (CNPD) 13413/2017; Ethics Committee of IPOP project code CI-IPOP81/2017.

Efficacy of eicosapentaenoic acid in inflammatory depression: study protocol for a match-mismatch trial

BackgroundMost antidepressant treatment studies have included patients strictly based on the Diagnostic and Statistical Manual of Mental Disorders definition of Major Depressive Disorder (MDD). Given the heterogeneity of MDD, this approach may have obscured inter-patient differences and hampered the development of novel and targeted treatment strategies. An alternative strategy is ​​to use biomarkers to delineate endophenotypes of depression and test if these can be targeted via mechanism-based interventions. Several lines of evidence suggest that “inflammatory depression” is a clinically meaningful subtype of depression. Preliminary data indicate that omega-3 fatty acids, with their anti-inflammatory and neuroprotective properties, may be efficacious in this subtype of depression, and this study aims to test this hypothesis.MethodWe conduct a match-mismatch-trial to test if add-on omega-3 fatty acid eicosapentaenoic acid (EPA) reduces depressive symptoms in patients with MDD and systemic low-grade inflammation. MDD patients on a stable antidepressant treatment are stratified at baseline on high sensitivity-C-reactive protein (hs-CRP) levels to a high-inflammation group (hs-CRP ≥ 3 mg/L) or a low-inflammation group (hs-CRP < 3 mg/L). Both groups receive add-on EPA (2 g per day) for 8 weeks with three study visits, all including blood draws. Patients and raters are blind to inflammation status. Primary outcome measure is change in Hamilton Depression Rating Scale score between baseline and week 8. We hypothesize that the inflammation group has a superior antidepressant response to EPA compared to the non-inflammation group. Secondary outcomes include a composite score of “inflammatory depressive symptoms”, quality of life, anxiety, anhedonia, sleep disturbances, fatigue, cognitive performance and change in biomarkers relating to inflammation, oxidative stress, metabolomics and cellular aging.DiscussionIn this study we will, for the first time using a match-mismatch trial design, test if omega-3 is an efficacious treatment for inflammatory depression. If our study is successful, it could add to the field of precision psychiatry.Trial registrationThis trial was registered May 8, 2017 on clinicaltrials.gov under the reference number NCT03143075

Family history of diabetes moderates metabolic depression endophenotypes in overweight/obese adults

ObjectiveInsulin resistance (IR) is linked to depressive disorders, and there is growing evidence that targeting IR may be beneficial in treating them. We examine the association between depressive symptoms and a direct measure of IR, and whether family history of type 2 diabetes (FHx-T2DM) or major depressive disorder (FHx-MDD) moderate this relationship. MethodsCross-sectional data were collected from 96 primarily overweight/obese adults ages 25–50 without diabetes or clinical depression. Multiple regression and correlation analyses were used to assess the association between depressive symptoms and a direct measure of IR (steady-state plasma glucose) as well as moderating effects of FHx-T2DM or FHx-MDD. ResultsIn the total sample, elevated depressive symptoms were positively associated with IR (p = 0.005). IR was associated with depressive symptoms in subjects with FHx-T2DM (p = 0.002) or FHx-MDD (p = 0.009) whereas BMI was associated with depressive symptoms in subjects without FHx-T2DM (p = 0.049) or FHx-MDD (p = 0.029). The odds of being in the top tertile of IR increased with elevated depressive symptoms alone (OR, 4.22; 95%CI, 1.15 to 17.33), presence of FHx-T2DM alone (OR, 3.42; 95%CI, 1.26 to 10.00), and presence of both FHx-T2DM and elevated depressive symptoms (OR, 10.08; 95%CI, 1.94 to 96.96). ConclusionsOur findings indicate that depressive symptoms are positively associated with a direct measure of IR in overweight/obese individuals without diabetes or clinical depression. This association is moderated by FHx-T2DM. Early identification of groups vulnerable to IR related to depressive symptomatology may be useful for determining personalized interventions that have the potential to reduce morbidity in later years.

Molecular Endophenotypes of Depression: From Computational Approaches to Exosome Biology

Depression is an heterogenous and highly prevalent mental disorder worldwide. At present, objective tools for detecting depressive disorders and monitoring treatment responses are not available. Exosomes are nanovesicles carrying functional proteins that regulate synaptic plasticity among other physiological functions. Here, we used computational psychiatry approaches to study the role of specific brain molecular signatures together with peripheral markers of mitochondrial metabolism in the pathophysiology of depression.

P261. Using Computational Approaches for Predictive Models of Antidepressant Response: Integrating Biological Networks With Clinical Outcomes

There is a need for new mechanistic models to develop objective tools that can aid the diagnosis of depression and monitor antidepressant responses. We and others showed that, in rodent models, administration of acetylcarnitine (LAC) leads to rapid and sustained antidepressant response by epigenetic regulation of glutamatergic function in key brain areas, such as the ventral dentate gyrus. Using exosomes, our group also showed decreased levels of the pivotal mitochondrial metabolite LAC in clinical endophenotypes of depression characterized by brain insulin resistance.

Sex Differences in Depression-Like Behaviors in Adult Mice Depend on Endophenotype and Strain.

Depression affects women nearly twice as frequently as men. In contrast, rodent models of depression have shown inconsistent results regarding sex bias, often reporting more depression-like behaviors in males. This sex discrepancy in rodents modeling depression may rely on differences in the baseline activity of males and females in depression-related behavioral tests. We previously showed that the baseline despair and anhedonia behaviors, major endophenotypes of depression, are not sex biased in young adolescent wild-type mice of C57BL/6N, DBA/2, and FVB/N strains. Since the prevalence of depression in women peaks in their reproductive years, we here investigated sex differences of the baseline depression-like behaviors in adult mice using these three strains. Similar to the results in young mice, no difference was found between adult male and female mice in behavioral tests measuring despair in both tail suspension and forced swim tests, and anhedonia in the sucrose preference test. We then extended our study and tested apathy, another endophenotype of depression, using the splash test. Adult male and female mice showed significantly different results in the baseline apathy-like behaviors depending on the investigated strain. This study dissects the complex sex effects of different depression endophenotypes, stresses the importance of considering strain, and puts forward a hypothesis of the inconsistency of results between different laboratories investigating rodent models of depression.

“A melancholy…compounded of many simples, extracted from many objects”: heritability of affective temperaments suggests their role as endophenotypes for depression

“A melancholy…compounded of many simples, extracted from many objects”: heritability of affective temperaments suggests their role as endophenotypes for depression

Machine Learning-Based Definition of Symptom Clusters and Selection of Antidepressants for Depressive Syndrome.

The current polythetic and operational criteria for major depression inevitably contribute to the heterogeneity of depressive syndromes. The heterogeneity of depressive syndrome has been criticized using the concept of language game in Wittgensteinian philosophy. Moreover, “a symptom- or endophenotype-based approach, rather than a diagnosis-based approach, has been proposed” as the “next-generation treatment for mental disorders” by Thomas Insel. Understanding the heterogeneity renders promise for personalized medicine to treat cases of depressive syndrome, in terms of both defining symptom clusters and selecting antidepressants. Machine learning algorithms have emerged as a tool for personalized medicine by handling clinical big data that can be used as predictors for subtype classification and treatment outcome prediction. The large clinical cohort data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), Combining Medications to Enhance Depression Outcome (CO-MED), and the German Research Network on Depression (GRND) have recently began to be acknowledged as useful sources for machine learning-based depression research with regard to cost effectiveness and generalizability. In addition, noninvasive biological tools such as functional and resting state magnetic resonance imaging techniques are widely combined with machine learning methods to detect intrinsic endophenotypes of depression. This review highlights recent studies that have used clinical cohort or brain imaging data and have addressed machine learning-based approaches to defining symptom clusters and selecting antidepressants. Potentially applicable suggestions to realize machine learning-based personalized medicine for depressive syndrome are also provided herein.

Set Shifting and Inhibition Deficits as Potential Endophenotypes for Depression

The etiology of Major Depressive Disorder (MDD) is poorly understood, and identifying endophenotypes, or intermediate processes implicated in pathophysiology, for MDD may inform treatment and identification/prevention efforts. Impaired set-shifting and inhibition are commonly observed in MDD; however, few studies have examined they are endophenotypes for MDD. Thus, the present study tested whether set-shifting and/or inhibition satisfy several endophenotype criteria: specifically, whether they were (1) impaired in current MDD, (2) impaired in remitted MDD, and (3) familial (i.e., correlated within sibling pairs). Set-shifting and inhibition were assessed using subtests from the Delis-Kaplan Executive Function System. Psychopathology was assessed using the Structured Clinical Interview for DSM-5. Results indicated set-shifting deficits were familial and present in both current MDD and in remitted MDD individuals who had no current disorders, suggesting they may be state-independent. Inhibition was familial, but was generally not impaired in current nor remitted MDD (although the remitted MDD group with no current disorders exhibited impairments on one of the two inhibition tasks). These findings indicate that impaired set-shifting is a promising endophenotype candidate for MDD. Findings are limited to young adults, and further research is needed to test generalizability to other populations, evaluate longitudinal relationships, and examine other endophenotype criteria.

Effects of high fat diet-induced obesity and pregnancy on prepartum and postpartum maternal mouse behavior

Obesity before and during pregnancy negatively affects the mental and physical health of the mother. A diet high in fat also increases the risk for anxiety, depression and cognitive dysfunction. We examined the effects of high fat diet (HFD) -induced obesity and pregnancy on maternal behavior, cognitive function and anxiety- and depression-like behaviors in mice. Four-week-old female CD-1 mice were placed on a HFD or regular chow diet (RCD) for 5 weeks. Mice were maintained on either diet as non-pregnant HFD and RCD groups, or allowed to breed, and then fed these diets throughout gestation, lactation and after weaning, as pregnant HFD and RCD groups. Mice on HFD but not on RCD for 5 weeks pre-pregnancy significantly gained weight and had impaired glucose clearance. Maternal behavior was assessed by nest building prepartum and pup-retrieval postpartum. Anxiety-like behavior was evaluated both prepartum and postpartum by elevated plus maze and cognitive function was assessed by the novel object recognition test postpartum. Anhedonia, a measure of impaired reward function, is an endophenotype of depression and was assessed by sucrose preference test pre- and post-weaning in dams. Mice on HFD in pregnancy exhibited both impaired maternal behavior and cognitive function in the postpartum period. We did not detect measurable differences between the HFD and RCD groups in anxiety-like behavior in the prepartum period. In contrast, HFD was also associated with anhedonia in pregnant mice pre-weaning, and anxiety-like behavior post-weaning. Thus, HFD has a negative effect on maternal behavior in the outbred CD-1 mouse, which provides a model to study associated outcomes and related mechanisms.

REM density is associated with treatment response in major depression: Antidepressant pharmacotherapy vs. psychotherapy

Major depression is one of the most common psychiatric illnesses. Interestingly, a few studies have indicated the existence of depression subgroups, which respond differently to the available treatment options. Previously, sleep abnormalities have been suggested to indicate amenability to different treatment regimens. Thereby, especially REM-sleep parameters seem to play a prominent role, and REM-sleep dysregulation has been repeatedly discussed as a potential endophenotype of depression. With that said, estimating therapy outcome in order to choose the best line of treatment is of utmost importance to patients suffering from depression.The present study looks deeper into these clues by investigating the capability of polysomnographic sleep parameters to predict treatment response in depressed patients to either pharmacotherapy or psychotherapy. Moderately to severely depressed patients (n = 38) were randomly assigned to either psychotherapy (i.e. interpersonal psychotherapy) or pharmacotherapy (i.e., monotherapy with selective serotonin reuptake inhibitors, SSRI, or selective serotonin noradrenalin reuptake inhibitors, SSNRI). Prior to treatment, all patients underwent polysomnography in the sleep laboratory. After treatment, responders and non-responders of both treatment groups were compared regarding their baseline sleep parameters.Higher baseline REM density, i.e. the amount of rapid eye movements during REM sleep, predicted better response to antidepressant pharmacotherapy. In the psychotherapy group, the effect seemed reversed but was not statistically significant. No other sleep parameter predicted treatment response.Our findings support the notion that REM-sleep dysregulation is indeed indicative of a distinct endophenotype of depression and that pharmacotherapy with SSRI/SSNRI might be superior to psychotherapy in these patients.

Hopelessness, Dissociative Symptoms, and Suicide Risk in Major Depressive Disorder: Clinical and Biological Correlates.

Background: Major depressive disorder (MDD) has different clinical presentations and is associated with neurobiological alterations. Hopelessness, anhedonia, and dissociation represent some of the most pervasive psychopathological symptoms that often lead to suicidal thoughts, attempts, and actions. To further research on the concept of depression endophenotypes, this study aimed to assess the possible relationships between hopelessness and other clinical and biological correlates (i.e., striatal dopaminergic dysfunction) in depressed patients. Methods: We recruited 51 subjects with MDD. All subjects underwent 123I-FP-CIT SPECT to assess striatal dopamine transporter (DAT) availability and a psychometric evaluation using the psychometric scale to assess depressive, anxious, dissociative, and hopelessness symptoms aside from suicidal ideation. Result: An inverse correlation between the hopelessness score and dopamine transporter availability in all basal ganglia was bilaterally found. (Right Putamen, r = −0.445, p < 0.01; Left Putamen, r = −0.454, p < 0.01; Right Caudate, r = −0.398, p < 0.01; Left Caudate, r = −0.467, p < 0.01) Moreover, a positive correlation was also found between hopelessness and dissociative symptoms. Conclusions: These results provide important evidence on the neurobiological and clinical correlates of different psychopathological symptoms of depression with potential implications in terms of devising more effective treatment programs.

Early Life Sensitizes Individuals to the Effects of Inflammation on Depression Endophenotypes

Early Life Sensitizes Individuals to the Effects of Inflammation on Depression Endophenotypes

Decreased Density of Perineuronal Net in Prelimbic Cortex Is Linked to Depressive-Like Behavior in Young-Aged Rats.

Perineuronal nets (PNNs) are condensed extracellular matrix (ECM) structures regulating developmental plasticity and protecting neurons against oxidative stress. PNN abnormalities have been observed in various psychiatric disorders such as schizophrenia and bipolar disorder, but the relationship between PNN density and depression still remains unclear. In the present study, we examined the density and components of PNNs including aggrecan, neurocan and Tenascin-R in the prelimbic cortex (PrL) after chronic unpredictable mild stress (CUMS). We found that depressive-like behaviors were induced after 30 days of CUMS accompanied by decreases in PNN+ cell density and aggrecan expression in the PrL. In addition, rats subjected to 20 days of CUMS were separated into vulnerable and resilient subpopulations that differ along several behavioral domains. Consistently, the density of PNNs and the expression level of neurocan in the vulnerable group were decreased compared to control and resilient groups. Finally, we examined individual differences based on locomotion in a novel context and classified rats as high responding (HR) and low responding (LR) phenotypes. The density of PNNs and the expression level of neurocan in the LR group were lower than the HR group. Moreover, the LR rats were more susceptible to depressive-like behaviors compared with HR rats. Altogether, these results suggest that the density of PNNs in the PrL is associated with depressive-like behaviors in young-aged rats, and it may serve as a potential endophenotype or therapeutic target for depression.

Polygenic risk score models based on anxiety-related traits as endophenotypes to predict unipolar depression and suicidal behavior

The present study included the construction of polygenic risk score (PRS) models of individual differences in anxiety level, which increased values represent the endophenotype of depression and suicidal behavior, to predict these psychopathologies based on genotyping of 63 SNPs of serotoninergic, hypothalamicpituitary-adrenal and neurotrophic factors systems together with the relative leukocyte telomere length. According to logistic regression analysis, PRS models of individual differences in Neuroticism (EPI) level (P&lt;0,2) predicted decreased risk of unipolar depression (P0.2=0,033, β=-5,24, r2=0,78) in women, which points to the necessity to consider sex during polygenic risk score analysis.

Impaired reward-related learning signals in remitted unmedicated patients with recurrent depression.

One of the core symptoms of major depressive disorder is anhedonia, an inability to experience pleasure. In patients with major depressive disorder, a dysfunctional reward-system may exist, with blunted temporal difference reward-related learning signals in the ventral striatum and increased temporal difference-related (dopaminergic) activation in the ventral tegmental area. Anhedonia often remains as residual symptom during remission; however, it remains largely unknown whether the abovementioned reward systems are still dysfunctional when patients are in remission. We used a Pavlovian classical conditioning functional MRI task to explore the relationship between anhedonia and the temporal difference-related response of the ventral tegmental area and ventral striatum in medication-free remitted recurrent depression patients (n = 36) versus healthy control subjects (n = 27). Computational modelling was used to obtain the expected temporal difference errors during this task. Patients, compared to healthy controls, showed significantly increased temporal difference reward learning activation in the ventral tegmental area (PFWE,SVC = 0.028). No differences were observed between groups for ventral striatum activity. A group × anhedonia interaction [t(57) = -2.29, P = 0.026] indicated that in patients, higher anhedonia was associated with lower temporal difference activation in the ventral tegmental area, while in healthy controls higher anhedonia was associated with higher ventral tegmental area activation. These findings suggest impaired reward-related learning signals in the ventral tegmental area during remission in patients with depression. This merits further investigation to identify impaired reward-related learning as an endophenotype for recurrent depression. Moreover, the inverse association between reinforcement learning and anhedonia in patients implies an additional disturbing influence of anhedonia on reward-related learning or vice versa, suggesting that the level of anhedonia should be considered in behavioural treatments.

The role of family studies in research of neurobiological basis of depressive disorders

Depression belongs to a large class of multifactorial diseases and genetic factors play a significant role in its formation, development and clinical manifestations. The authors present an overview of current studies of recurrent depressive disorder (RDD), a heterogeneous group of disorders with phenotypically similar psychopathological symptoms. A study of families with a high risk for RDD using clinical and biological (including genetic) approaches can greatly help in understanding of the neurobiological basis of depressive disorders, as well as in the identification of endophenotypes of depression. The most important criterion of the endophenotype is its heritability, which can be proved only within the framework of family design research. Comprehensive clinical and molecular genetic studies based on family design have the best prospects.

Social anhedonia in major depressive disorder: a symptom-specific neuroimaging approach.

While research concerning brain structural biomarkers of major depressive disorder (MDD) is continuously progressing, our state of knowledge regarding biomarkers of specific clinical profiles of MDD is still limited. The aim of the present study was to investigate brain structural correlates of social anhedonia as a cardinal symptom of MDD. In a cross-sectional study, we investigated n = 166 patients with MDD and n = 166 matched healthy controls (HC) using structural magnetic resonance imaging (MRI). Social anhedonia was assessed using the Chapman Scales for Social Anhedonia (SAS). An anhedonia x group ANCOVA was performed in a region of interest approach of the dorsal and ventral striatum (bilateral caudate nucleus, putamen, nucleus accumbens respectively) as well as on whole-brain level. The analyses revealed a significant main effect for social anhedonia: higher SAS-scores were associated with reduced gray matter volume in the bilateral caudate nucleus in both the MDD-group (pFWE = 0.002) and the HC-group (pFWE = 0.032). The whole-brain analysis confirmed this association (left: pFWE = 0.036, right: pFWE = 0.047). There was no significant main effect of group and no significant anhedonia x group interaction effect. This is the first study providing evidence for volumetric aberrations in the reward system related to social anhedonia independently of diagnosis, depression severity, medication status, and former course of disease. These results support the hypothesis that social anhedonia has a brain biomarker serving as a possible endophenotype of depression and possibly providing an alternative approach for a more precise and effective treatment.

Altered Expression Profile of IgLON Family of Neural Cell Adhesion Molecules in the Dorsolateral Prefrontal Cortex of Schizophrenic Patients.

Neural adhesion proteins are crucial in the development and maintenance of functional neural connectivity. Growing evidence suggests that the IgLON family of neural adhesion molecules LSAMP, NTM, NEGR1, and OPCML are important candidates in forming the susceptibility to schizophrenia (SCZ). IgLON proteins have been shown to be involved in neurite outgrowth, synaptic plasticity and neuronal connectivity, all of which have been shown to be altered in the brains of patients with the diagnosis of schizophrenia. Here we optimized custom 5′-isoform-specific TaqMan gene-expression analysis for the transcripts of human IgLON genes to study the expression of IgLONs in the dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients (n = 36) and control subjects (n = 36). Uniform 5′-region and a single promoter was confirmed for the human NEGR1 gene by in silico analysis. IgLON5, a recently described family member, was also included in the study. We detected significantly elevated levels of the NEGR1 transcript (1.33-fold increase) and the NTM 1b isoform transcript (1.47-fold increase) in the DLPFC of schizophrenia patients compared to healthy controls. Consequent protein analysis performed in male subjects confirmed the increase in NEGR1 protein content both in patients with the paranoid subtype and in patients with other subtypes. In-group analysis of patients revealed that lower expression of certain IgLON transcripts, mostly LSAMP 1a and 1b, could be related with concurrent depressive endophenotype in schizophrenic patients. Additionally, our study cohort provides further evidence that cannabis use may be a relevant risk factor associated with suicidal behaviors in psychotic patients. In conclusion, we provide clinical evidence of increased expression levels of particular IgLON family members in the DLPFC of schizophrenic patients. We propose that alterations in the expression profile of IgLON neural adhesion molecules are associated with brain circuit disorganization in neuropsychiatric disorders, such as schizophrenia. In the light of previously published data, we suggest that increased level of NEGR1 in the frontal cortex may serve as molecular marker for a wider spectrum of psychiatric conditions.

Fluoxetine, not donepezil, reverses anhedonia, cognitive dysfunctions and hippocampal proteome changes during repeated social defeat exposure

While anhedonia is considered a core symptom of major depressive disorder (MDD), less attention has been paid to cognitive dysfunctions. We evaluated the behavioural and molecular effects of a selective serotonin re-uptake inhibitor (SSRI, fluoxetine) and an acetylcholinesterase inhibitor (AChEI, donepezil) on emotional-cognitive endophenotypes of depression and the hippocampal proteome. A chronic social defeat (SD) procedure was followed up by “reminder” sessions of direct and indirect SD. Anhedonia-related behaviour was assessed longitudinally by intracranial self-stimulation (ICSS). Cognitive dysfunction was analysed by an object recognition test (ORT) and extinction of fear memory. Tandem mass spectrometry (MSE) and protein-protein-interaction (PPI) network modelling were used to characterise the underlying biological processes of SD and SSRI/AChEI treatment. Independent selected reaction monitoring (SRM) was conducted for molecular validation. Repeated SD resulted in a stable increase of anhedonia-like behaviour as measured by ICSS. Fluoxetine treatment reversed this phenotype, whereas donepezil showed no effect. Fluoxetine improved recognition memory and inhibitory learning in a stressor-related context, whereas donepezil only improved fear extinction. MSE and PPI network analysis highlighted functional SD stress-related hippocampal proteome changes including reduced glutamatergic neurotransmission and learning processes, which were reversed by fluoxetine, but not by donepezil. SRM validation of molecular key players involved in these pathways confirmed the hypothesis that fluoxetine acts via increased AMPA receptor signalling and Ca2+-mediated neuroplasticity in the amelioration of stress-impaired reward processing and memory consolidation. Our study highlights molecular mediators of SD stress reversed by SSRI treatment, identifying potential viable future targets to improve cognitive dysfunctions in MDD patients.