Elunetirom, a brain-targeted TRβ prodrug, promotes neuronal plasticity and mitochondrial biogenesis-related signaling in primary neuronal cultures

PT320, a GLP-1 receptor agonist, mitigates nucleus accumbens–associated depression- and anxiety-like behaviors in MitoPark mice of Parkinson's disease

By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression by restoring neurotrophic signaling and dopaminergic function in the nucleus accumbens.

Reprogramming brain bioenergetics in depression: an integrative framework linking creatine, branched-chain amino acids, and exercise to neuroplasticity, cognitive function, and depression-related outcomes

Depression represents a multifaceted neuropsychiatric disorder distinguished by disruptions in cerebral energy metabolism, neurotransmitter communication, neuroplasticity, and cognitive processes. An increasing body of literature indicates that integrative non-pharmacological interventions aimed at metabolic and neurochemical pathways may present promising adjunctive strategies for ameliorating depressive manifestations and concomitant cognitive impairments. This review explores the prospective combined effects of creatine supplementation, branched-chain amino acids (BCAAs), and physical exercise as a multimodal bioenergetic intervention for the management of depression. Creatine is pivotal in maintaining neuronal energy equilibrium via the phosphocreatine system, thereby facilitating mitochondrial functionality and adenosine triphosphate availability within neural cells. BCAAs may influence central fatigue and exercise performance through competitive inhibition of tryptophan transport across the blood-brain barrier. Importantly, this mechanism primarily reflects acute exercise-related serotonergic responses associated with central fatigue and should not be considered mechanistically equivalent to the chronic serotonergic dysfunction observed in major depressive disorder. Accordingly, within the context of depression, BCAAs are discussed as indirect modulators of mental health outcomes through their effects on fatigue perception, exercise tolerance, and adherence to physical activity, rather than as direct serotonergic antidepressant interventions. Concurrently, consistent engagement in physical exercise activates critical neuroplasticity-associated signaling pathways, which are instrumental in promoting hippocampal neurogenesis and enhancing stress resilience. Emerging empirical evidence derived from both experimental and clinical investigations suggests that the combined application of these interventions may exert complementary influences on brain bioenergetics, neuroplasticity, exercise capacity, and cognitive function. Collectively, this integrative paradigm highlights the potential of creatine supplementation, BCAAs, and physical exercise to support depression-related outcomes through distinct yet complementary mechanisms involving bioenergetic regulation, enhanced exercise capacity, neuroplastic adaptations, and improved cognitive and emotional functioning.

Neuroinflammation in major depressive disorder: Mechanisms, biomarkers, and emerging therapeutic targets

Major depressive disorder (MDD) affects an estimated 280 million people worldwide and remains a leading cause of disability. The monoamine hypothesis, and later the neuroplasticity hypothesis, transformed treatment but leave a substantial share of patients with delayed response, partial remission, or outright treatment resistance. Over the past two decades, evidence has accumulated that a subset of MDD is driven by chronic, low-grade neuroinflammation rather than, or in addition to, monoaminergic deficits. This review synthesizes current evidence on the neuroimmune mechanisms involved in MDD microglial activation, pro-inflammatory cytokine signaling, blood–brain barrier disruption, oxidative stress, kynurenine pathway dysregulation, and impaired neuroplasticity and examines how these mechanisms are captured by peripheral, central, neuroimaging, and emerging molecular biomarkers. It then reviews therapeutic strategies that target inflammation directly (minocycline, celecoxib, TNF-α antagonists), indirectly (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), ketamine), or through lifestyle modification (exercise, diet, sleep), with attention to why inflammation-stratified trials have outperformed unstratified ones. Across mechanisms, biomarkers, and treatment response, a consistent pattern emerges: neuroinflammation does not simply co-occur with depression, it may mark a biologically distinct, identifiable subtype roughly a quarter to a third of patients with elevated high-sensitivity C-reactive protein (hsCRP) or IL-6 for whom anti-inflammatory or immune-modulating strategies produce disproportionate benefit. Overall, the findings suggest that neuroinflammation represents a promising and increasingly actionable target for biomarker-guided, personalized psychiatric care.

Trace Amine-Associated Receptors (TAARs) as Emerging Targets in Neuropsychiatric Disorders

Trace amines (TAs) are endogenous biogenic amines present at low concentrations in the brain and were historically considered byproducts of monoamine metabolism. The discovery of trace amine-associated receptors (TAARs), a family of G protein-coupled receptors, has redefined their physiological and pharmacological relevance. TAAR1 regulates dopaminergic, serotonergic, and glutamatergic signaling and is increasingly implicated in neuropsychiatric disorders. Preclinical studies show that TAAR1 agonists normalize dopaminergic function and improve cognitive deficits in schizophrenia models. Early clinical evidence suggests potential antipsychotic efficacy with a favorable extrapyramidal and metabolic safety profile. However, the failure of subsequent phase III trials to meet their primary efficacy endpoints highlights the need to identify responsive patient subgroups, optimize trial design, and clarify the clinical settings in which TAAR1 agonism may provide the greatest therapeutic benefit. In depression, TAAR1 activation produces antidepressant-like effects in preclinical models, whereas findings in anxiety are variable and context-dependent. TAAR1 may also modulate reward-driven feeding and metabolic parameters. Mechanistically, TAAR1 agonists differ in their effects on dopamine transporter function and monoaminergic neuron activity, indicating that their pharmacological effects are compound-specific rather than class-wide. These properties distinguish TAAR1-targeting compounds from classical D2 receptor antagonists and may underlie their clinical profile. Further translational studies are required to confirm their efficacy across symptom domains and establish long-term clinical benefit.

From Structural Resolution to Functional Elucidation: Research Progress of GPR158 as a Target for Antidepressant Drug Development.

G Protein-Coupled Receptors (GPCRs) are the most widely used drug targets in neuropsychiatric disorders. GPR158, an orphan class C GPCR, is highly enriched in the central nervous system and has emerged as a critical regulator of stress-related depression. However, its precise mechanisms in depression remain incompletely understood. This review aims to establish a systematic framework spanning the molecular structure to physiological function, highlighting the role of GPR158 in the onset and progression of depression. We summarize the expression pattern, unique structural features, novel ligands, and downstream signaling pathways of GPR158, with a focused discussion on its multiple regulatory mechanisms in depression, including Cyclic Adeno-sine Monophosphate (cAMP) signaling, neuronal excitability, Brain-derived Neurotrophic Factor (BDNF) translation, glutamatergic transmission, and mitophagy. Abnormally upregulated GPR158 in the prefrontal cortex and hippocampus promotes depressive-like behaviours, whereas knockout or inhibition of GPR158 exerts antidepressant-like effects. These findings not only reveal the potential regulatory function of GPR158 in the pathological process of depression but also provide a solid theoretical basis for the development of antidepressant drugs targeting GPCRs, facilitating the subsequent development of more accurate and efficient antidepressant candidate drugs.

Medicinal-Edible Plants in Depression Therapy: Mechanistic Basis, Bioactive Compounds, and Translational Perspectives