Advances in the Treatment of Cognitive Impairment in Major Depressive Disorder: Innovations and Research Challenges

Why the body matters in major depressive disorder: neuroimaging findings of somatic symptoms and ongoing challenges.

With growing recognition that somatic symptoms constitute a clinically significant yet underexplored dimension of major depressive disorder (MDD), symptoms including sleep disturbances, gastrointestinal discomfort, pain, appetite changes, and fatigue have attracted increasing research attention. These symptoms are not only highly prevalent but are also closely associated with poor prognosis, treatment resistance, and elevated suicide risk. In this context, neuroimaging studies of the somatic manifestations of MDD have provided critical insights to advance precision diagnosis and individualized intervention. This review comprehensively integrates functional and structural neuroimaging findings on discrete somatic symptoms and somatic symptom clusters in MDD. It identifies the specific neural circuit abnormalities associated with individual symptom domains while elucidating shared pathophysiological mechanisms across symptom types, including disrupted interoceptive processing, pathological default mode network activity, and impaired sensory gating. On this basis, the review discusses the therapeutic and predictive implications of these findings and proposes future research directions oriented toward network-based brain-symptom mapping, transdiagnostic and longitudinal designs, and multimodal multilevel integration. By synthesizing existing evidence, this review provides a framework for understanding the neural substrates of somatic symptoms in MDD, developing somatic phenotype-based biomarkers and targeted neuromodulation therapies, and integrating systems-level neuroimaging into precision psychiatry to advance biologically informed diagnosis/treatment.

Cognitive Reserve as a Stratification Factor for Cognitive Impairment and Disease Progression in Major Depressive Disorder.

674. Cognitive and neurobiological indicators of risk and prognosis in mood disorders

Abstract Background Mood disorders are major contributors to the global burden of disease. There is a critical need for reliable markers that can identify individuals at elevated risk for developing mood disorders and predict poor prognosis among those already affected, in order to guide personalized interventions. Aims & Objectives This presentation summarizes findings from a series of studies examining: (1) risk markers for the future development of a first episode of major depressive disorder (MDD) in initially healthy individuals; and (2) markers of adverse outcomes, including treatment non-response and psychiatric hospitalization, in individuals with MDD and bipolar disorder (BD). Method Longitudinal data on depression diagnoses, treatment resistance, and psychiatric hospitalizations were obtained from Danish national health registers across multiple cohorts: (1) 372 individuals without prior psychiatric diagnoses who completed cognitive and personality assessments, and positron emission tomography (PET); (2) 518 individuals diagnosed with BD or MDD who completed cognitive assessments, with a subset also undergoing structural (sMRI) and functional MRI (fMRI); (3) 98 unmedicated individuals with MDD enrolled in an antidepressant treatment trial who underwent PET, sMRI, fMRI, and cognitive assessments. All analyses were conducted using Cox proportional hazards regression models, adjusting for relevant demographic and clinical covariates. Results Cognitive impairments, as well as serotonin system dysfunction in combination with high personality trait neuroticism, were associated with increased risk of subsequent MDD onset in initially healthy individuals (HR=1.14 CI [1.02-1.25], p=0.018). In individuals with mood disorders, cognitive impairments were associated with a higher risk of psychiatric hospitalization (HR = 1.84, [CI:1.05–3.25], p = 0.034), alongside alterations in neurocircuitry supporting cognitive control and emotional processing. Within the antidepressant treatment trial, approximately 20% of participants met criteria for treatment-resistant depression within 3 years, although 50% of these individuals had initially responded or remitted within 12 weeks of SSRI treatment initiation. Multimodal biomarker analyses suggested the presence of early clinical and cognitive profiles associated with long-term treatment non-response. Discussion & Conclusions These findings indicate that serotonin neurotransmission, emotional neural processing, cognition, and personality traits contribute to both risk for the onset of mood episodes and risk for adverse clinical events. The results reinforce that early markers can track future risk and therefore potentially guide identifying high-risk individuals and possibly treatment selection.

How Does Exercise Improve Executive Function During Recovery from Major Depressive Disorder? A Narrative Review

Major Depressive Disorder (MDD) is frequently associated with persistent cognitive deficits that often remain despite remission of depressive symptoms. Executive dysfunction, including impairments in working memory, inhibitory control, cognitive flexibility, planning, and decision-making, contributes to poorer psychosocial functioning and increased relapse risk. Although exercise is an established treatment for depression, its role in restoring executive functioning remains less well understood.This narrative review evaluated current evidence on the effects of exercise on executive function recovery in individuals with MDD, identified exercise characteristics associated with the greatest cognitive benefits, and summarized the underlying neurobiological mechanisms.A structured narrative review was conducted using PubMed, Scopus, and Web of Science. Priority was given to systematic reviews, meta-analyses, randomized controlled trials, and mechanistic studies investigating exercise, executive functioning, and neurobiological adaptations relevant to MDD.Structured exercise consistently improved executive functioning in individuals recovering from MDD. The greatest benefits were observed following moderate-to-vigorous aerobic exercise performed approximately three times per week, with sessions lasting 45–60 minutes for at least 13 weeks. Improvements were associated with enhanced neuroplasticity, reduced neuroinflammation, improved cerebral perfusion, neurotransmitter modulation, mitochondrial adaptations, and functional brain network reorganization.Structured exercise should be regarded as a mechanism-based intervention that extends beyond symptom reduction by promoting executive function recovery and long-term functional rehabilitation. We propose an Integrated Exercise–Neurobiology Model linking exercise prescription with coordinated physiological and neurobiological adaptations that may guide future mechanistic research and precision exercise interventions.

Treatment-Resistant Depression: A Literature Review of Innovative and Emerging Treatment Strategies

Introduction and objective: Major depressive disorder (MDD) is a heterogeneous psychiatric condition characterized by affective, cognitive and somatic symptoms that considerably impair daily functioning. It is defined clinically by prolonged low mood, diminished interest or pleasure, and a range of associated disturbances, including changes in cognitive skills, appetite, and sleep patterns. Although many treatment strategies are well-established and available, not all patients achieve satisfactory improvement. Treatment-resistant depression (TRD), often defined as insufficient response to at least two antidepressant trials of proper dose and duration, represents a major therapeutic challenge. This review aims to present and assess emerging treatment strategies for TRD, focusing on their mechanisms, effectiveness and safety. Brief description of the state of knowledge: Recent advances in the understanding of depression pathophysiology have initiated the development of new therapeutic approaches targeting various systems thought to be involved in mood regulation. Glutamatergic modulators, such as ketamine and esketamine, have demonstrated prompt antidepressant effects, particularly in patients with severe or refractory symptoms. Neuromodulatory techniques, including repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), remain important treatment options with growing research interest. Simultaneously, heightened attention has been directed toward psychedelic-assisted therapies, especially psilocybin, which may produce sustained antidepressant effects through modulation of various neural networks. Additionally, invasive interventions such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are being studied for resistant cases, although their use remains limited. Summary: Emerging therapies for TRD offer promising alternatives to conventional treatment strategies, particularly for patients not responding to routine interventions.  Further research is crucial for the optimization of therapeutic outcomes and integration of those novel approaches into clinical practice.

Baseline cortical structural features are associated with depressive and cognitive improvement in major depressive disorder

Major depressive disorder (MDD) exhibits substantial clinical and neurobiological heterogeneity, along with marked variability in treatment response, underscoring the need for objective neuroimaging markers to inform personalized interventions. Twenty-two patients with MDD and twenty-one age- and sex-matched healthy controls (HCs) were enrolled. Depressive symptoms were assessed using the 17-item Hamilton Rating Scale for Depression (HAMD17), and the Hamilton Rating Scale for Anxiety (HAMA), while cognitive function was evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Structural magnetic resonance imaging (sMRI) was performed to assess cortical features in MDD patients and HCs. Cortical morphological features [fractal dimension (FD), gyrification index (GI), sulcus depth (SD), and cortical thickness (CT)] were quantified using the automated Computational Anatomy Toolbox (CAT12). Multiple regression analyses were conducted to identify cortical regions in which baseline morphology was associated with subsequent depressive and cognitive changes, controlling for age and sex (voxel-wise p  < 0.001, family wise error corrected cluster-level p  < 0.05). To further assess the stability and potential out-of-sample consistency of these associations, exploratory leave-one-out cross-validation (LOOCV) analyses with permutation testing were performed. Baseline FD in the left superior frontal cortex (SFC), left cuneus, right rostral middle frontal cortex and right lateral occipital cortex (LOC), GI in the left LOC, and CT in the bilateral insula and pericalcarine cortex were significantly associated with greater improvement in depressive symptoms following antidepressant treatment. In addition, lower baseline SD in the left LOC was associated with greater improvement in delayed memory. Single-ROI models (adjusted for age and sex) revealed that baseline left cuneus FD and left SFC FD was significantly correlated with changes in HAMD17 and HAMA, respectively, and the baseline left LOC/lingual SD showed a moderate cross-validated correlation with delayed memory change. These associations were supported by permutation testing, whereas the model for memory improvement showed only exploratory, non-significant cross-validated performance. Baseline cortical morphometric features were associated with clinical and cognitive changes following antidepressant treatment in MDD. Single-ROI LOOCV models based on left cuneus and left SFC FD showed cross-validated associations with symptom improvement. These findings are preliminary and should be interpreted with caution, pending replication in independent cohorts.