Jul 2026· Current Neuropharmacology· Vol 24· 0 citations
Medicine
TL;DR
The dual roles of antidepressants and antiepileptic drugs (AEDs) in the treatment of depression in epilepsy are explored and the importance of timely depression screening, long-term management, and personalized therapy for patients with epilepsy and comorbid depression is highlighted.
Abstract
Depression is a common comorbidity in patients with epilepsy, significantly impacting their quality of life. However, the precise mechanisms underlying depression in epilepsy remain unclear. This review synthesizes the latest research on the pathogenesis of depression in epilepsy, focusing on abnormalities in monoamine neurotransmitters, neuroinflammation, HypothalamicPituitary-Adrenal (HPA) axis dysfunction, neurotrophic factors, mitochondrial dysfunction, and oxidative stress. The article explores the dual roles of antidepressants and antiepileptic drugs (AEDs) in the treatment of depression in epilepsy, highlighting drugs that may exacerbate either depression or seizure activity. The need for more nuanced treatment strategies, including the careful selection of antidepressants and AEDs, is emphasized. Additionally, non-drug interventions, such as Cognitive-Behavioral Therapy (CBT), neuromodulation techniques, and dietary modifications (anti-inflammatory and antioxidant foods), are reviewed as vital adjuncts to pharmacological treatments. This article aims to guide clinicians in choosing optimal treatment strategies and underscores the importance of timely depression screening, long-term management, and personalized therapy for patients with epilepsy and comorbid depression.
Treatment-resistant depression (TRD) represents one of the most complex forms of major depressive disorder, characterized by the persistence of clinically significant symptoms despite the performance of appropriate therapeutic interventions. This condition is associated with a worse prognosis, higher risk of recurrence, functional impairment, increased morbidity and mortality, and high socioeconomic impact. The objective of this article was to review the main aspects related to ESRD, addressing its definition, diagnostic criteria, epidemiology, pathophysiological mechanisms, and currently available therapeutic strategies. A narrative review of the literature was carried out, including national and international studies that discuss advances in the management of resistant depression. It is observed that the pathophysiology of ESRD involves alterations in mon oaminergic and glutamatergic neurotransmission, reduced neuroplasticity, inflammatory processes, neuroendocrine dysfunctions, and genetic factors, justifying the limited efficacy of conventional antidepressants in some patients. Current therapeutic strategies include optimization and combination of antidepressants, pharmacological potentiation, use of atypical antipsychotics, lithium, and thyroid hormones, as well as innovative therapies such as ketamine and esketamine, which demonstrate rapid antidepressant response in selected cases. It is concluded that the management of ESRD should be individualized, based on up-to-date scientific evidence, and integrated with multidisciplinary approaches, aiming at symptom remission, functional recovery, and improvement of patients' quality of life.
Samuel Cândido Freres, M. A. F. Cançado, Aline Ferreira Catrolio et al.· International Health Science...· 0 citations
BACKGROUND
Major depressive disorder (MDD) is one of the leading causes of disability globally, and conventional monoaminergic antidepressants often have a slow onset and limited efficacy. About onethird of patients suffer from treatment-resistant depression (TRD), which emphasizes the urgent need for alternative therapies. This review aims to systematically evaluate the available data about ketamine's involvement in depression, with particular attention to its pharmacological properties, modes of action, clinical effectiveness, safety profile, and potential as a next-generation antidepressant treatment.
METHODS
The databases ScienceDirect and PubMed/MEDLINE were searched extensively for relevant literature. Ketamine's pharmacodynamics, clinical results, safety, and mechanistic insights in Major depressive disorder (MDD) and treatment-resistant depression (TRD) were all investigated in eligible studies. Particular focus was given to its reported side effects and molecular mechanisms.
RESULTS
The FDA's 2019 clearance of intranasal esketamine further cemented the paradigm shift in treatment for treatment-resistant depression (TRD), which has been revolutionized by ketamine's ability to provide quick and long-lasting symptom relief. A strong neurobiological cascade underlies its therapeutic impact: NMDA receptor antagonistic action causes glutamate-AMPA activation to spike, which in turn activates the BDNF-mTORC1 signalling pathway, promoting fast synaptogenesis and reversing neuronal atrophy in the prefrontal cortex. Although dissociative side effects and cardiovascular risks now limit clinical use, the field is moving toward next-generation drugs like (2R,6R)-hydroxynorketamine. In order to create safer and more easily accessible rapid-acting antidepressants, these metabolites seek to eliminate the negative psychoactive character of ketamine while using its transformative neuroplasticity.
CONCLUSION
When conventional treatments are ineffective for treating treatment-resistant depression, ketamine offers quick and strong results, marking a paradigm change in psychiatric care. To optimise longitudinal dosage regimens, assess long-term safety profiles, and develop next-generation analogues that maintain neuroplastic benefits while reducing side effects, further investigation is necessary.
Prachi Tayal, Rina Das, M. Khan et al.· Current pharmaceutical desig...· 0 citations
Background: Managing comorbid depression and epilepsy is challenging due to complex drug-drug interactions (DDIs). Objective: This systematic review evaluates clinically significant pharmacokinetic and pharmacodynamic interactions between antidepressants and antiepileptic drugs (AEDs). Methods: A systematic search was conducted across PubMed, ScienceDirect, and Google Scholar (2010–2025) following PRISMA guidelines. Results: Of 377 identified records, 24 studies met the inclusion criteria. Pharmacokinetic interactions (n=18; 75%) primarily involve the CYP450 enzyme system, notably CYP2D6 inhibition by fluoxetine and induction by carbamazepine. Significant pharmacodynamic risks include serotonin syndrome (n=3) and lowered seizure thresholds. Conclusion: While modern therapies offer better safety profiles, specific combinations like valproate-lamotrigine or SSRI-tramadol require rigorous monitoring. Clinical Implications: Pharmacists must prioritize screening for enzyme-inducing AEDs to prevent therapeutic failure or toxicity in neuropsychiatric care.
Unknown authors· Journal of Pharmaceuticals a...· 0 citations
Graves’ disease (GD), an autoimmune thyroid disorder, is a common cause of hyperthyroidism and is frequently associated with neuropsychiatric symptoms such as depression and cognitive impairment. Despite this, mental health concerns remain overlooked in GD management guidelines. This review evaluates the neuropsychiatric effects of GD, highlighting the need for integrated treatment approaches, underlying processes, and its link to depression. A literature-based analysis was conducted, focusing on the pathophysiological links between GD and psychiatric manifestations, particularly depression. GD alters inflammatory cytokines, affects neurotransmitter metabolism, increases blood-brain barrier permeability, and causes hormonal dysregulation, all of which contribute to the development of depression. Gut microbiota imbalance also influences the gut-brain axis, playing a role in cognitive and mood disturbances. GD-related eating disorders further impact patient outcomes. Conventional treatments, including antithyroid drugs, selective serotonin reuptake inhibitors (SSRIs), β-blockers, and in some cases, electroconvulsive therapy (ECT), have shown efficacy in managing both thyroid and psychiatric symptoms. Psychological interventions and probiotics offer additional support. Graves’ disease has a significant neuropsychiatric aspect that requires routine mental health evaluation and integrated treatment. Addressing psychological symptoms alongside endocrine therapy improves patient quality of life and outcomes. Future research should further elucidate the mechanisms connecting GD and mental illness to enhance patient-centered care.
Sandli Jain, B. Chaturvedi, H. Bareth et al.· Discover Public Health· 0 citations
INTRODUCTION
Depression is a heterogeneous and multifactorial condition with substantial unmet therapeutic need. Despite significant research, current pharmacotherapies remain limited in efficacy and onset, reflecting an incomplete understanding of underlying pathophysiology. Animal models have therefore been central to dissecting biological mechanisms and enabling antidepressant drug discovery.
AREA COVERED
This review provides a synthesis of animal models of depression, including stress paradigms, developmental and genetic models, neuroendocrine manipulations, immune-based, metabolic and hormone-related models. PubMed was searched from database inception to March 2026 using depression-, species-, and model-specific terms. Each paradigm is evaluated in terms of face, construct, and predictive validity, with emphasis on relevance to drug discovery. Converging evidence across models highlights shared pathophysiological domains, including HPA axis dysregulation, neuroinflammation, monoaminergic and glutamatergic imbalance, and impaired neuroplasticity.
EXPERT OPINION
No single model captures the complexity of depression; thus, reliance on isolated paradigms may contribute to translational failure. Future progress will depend on multimodal and endophenotype-driven approaches that align biological mechanisms with defined subtypes (e.g. inflammation-associated, hormone-sensitive, or stress-related depression). Integration of animal models with human-relevant data and sex-informed experimental design will advance precision psychiatry, improving predictive validity of preclinical antidepressant discovery.
Pavlina Pavlidi, Dimitrios Kalampokis, Ifigeneia Ioannidi et al.· Expert Opinion on Drug Disco...· 0 citations
Depression is a frequent and clinically significant comorbidity in schizophrenia, contributing to poorer functional outcomes, reduced quality of life, increased relapse rates, and elevated suicide risk. Despite its substantial impact, depressive symptomatology in schizophrenia remains underrecognized and undertreated due to diagnostic overlap with negative symptoms, demoralization, and medication-related effects. This narrative review examines the epidemiology, phenomenology, and underlying neurobiological and psychosocial mechanisms of depression in schizophrenia, with a particular focus on integrated management strategies. Current evidence on pharmacological optimization, adjunctive antidepressant use, and psychosocial and psychological interventions is discussed alongside multidisciplinary and recovery-oriented care models. Emerging paradigms, including precision psychiatry, biomarker-guided approaches, neurostimulation techniques, and lifestyle-based interventions, are highlighted as promising directions for future care. The review underscores the need for longitudinal research, refined diagnostic frameworks, and context-sensitive implementation strategies to advance holistic, patient-centered management of depression in schizophrenia.
Oshi Malik, Priyanka Yadav· Indian Journal of Medical Sp...· 0 citations