This article examines the development of antipsychotic medications in the period following the discovery of chlorpromazine in the mid-1950s up to the early 21st century. This era is defined by the identification of dopamine modulation as the central mechanism for treating psychosis, and by the development of a diversity of treatments around this mechanism. This strategy yielded a broad range of effective treatments and transformed clinical care; however, with the notable exception of clozapine, it failed to produce substantial gains in overall efficacy. Newer agents primarily differed in tolerability rather than therapeutic impact. Partial dopamine agonists refined, rather than replaced, this approach. As a result, the dopaminergic era offers a cautionary lesson for psychiatric drug development and underscores the need to move beyond dopamine-based models per se.

Identifying reproducible brain-based stratifications across independent cohorts is critical for parsing heterogeneity in Major Depressive Disorder (MDD), yet robust profiles spanning micro- and macroscales remain poorly defined. We applied stability-based clustering to cortical thickness (CT) data from 1531 MDD individuals in UK Biobank (UKB), with replication in 144 inpatients from IRCCS San Raffaele Hospital (HSR). Two stable clusters emerged (normalized stability = 0.125) that generalized to a hold-out UKB sample with 96.5% accuracy (majority-cluster baseline = 59.5%). The clusters differed in widespread CT, largely reflected in global CT, with one showing cortical thinning, childhood trauma, and diabetes comorbidity. A two-cluster structure was independently replicated in HSR (normalized stability = 0.29), with a broadly similar cortical topography, although systematic CT differences between cohorts limited direct cross-cohort comparability. The clinical correlates identified in UKB did not replicate after correction for multiple comparisons. In UKB, mapping the CT differences between strata onto Neurosynth meta-analytic activation patterns revealed a ventral-dorsal gradient linked with emotion regulation, interoceptive, and motivational processes. Spatial correlations with 19 neurotransmitter receptors and transporters obtained from positron emission tomography identified the dopamine transporter as the dominant contributor in UKB, and the histamine H3 receptor in HSR. These findings provide a reproducible framework linking CT-based clusters in MDD to multiscale biological organization, although their clinical relevance warrants further investigation.

Dopaminergic signaling in the nucleus accumbens (NAc) is central to reward-based learning, but its relationship to brain-wide hemodynamics remains unclear. Using concurrent fMRI and dopamine photometry in awake, behaving mice, we reveal that associative learning induces a gradual temporal shift in NAc blood oxygenation responses that mirrors dopamine release dynamics. This shift emerges with cue-reward learning and extends across a distributed network encompassing the lateral septal complex, as well as prefrontal, insular, and hypothalamic regions. Further, dopamine transients tightly correspond with local blood oxygenation level dependent (BOLD) signals, and variations in reward value modulate delayed BOLD responses in both the NAc and additional subcortical structures. Regressing out the measured dopaminergic signal abolishes this reward-related modulation, suggesting that BOLD signals track dopaminergic reward prediction. These findings reveal a close relationship between dopamine signaling and widespread changes in brain activity during learning.

KCND3 encodes the voltage-gated potassium channel Kv4.3, and pathogenic variants in KCND3 are associated with spinocerebellar ataxia type 19/22 (SCA19/22) and related neurological phenotypes. Here, we report a Japanese patient harboring a novel KCND3 missense variant, classified as a variant of uncertain significance, who presented with a clinical phenotype compatible with SCA19/22, including slowly progressive cerebellar ataxia beginning in childhood, accompanied by asymmetric parkinsonism. Dopamine transporter single-photon emission computed tomography demonstrated reduced striatal uptake. Parkinsonian symptoms exhibited a partial response to dopaminergic therapy; however, the improvement was primarily based on clinical observation, with limited objective evidence supporting treatment efficacy. To our knowledge, abnormal dopamine transporter imaging has not been previously reported in patients with SCA19/22-related phenotypes. Although it was difficult to determine whether the parkinsonism was attributable to the KCND3 variant or to coexisting Lewy body disease, we reviewed the literature on parkinsonism associated with SCA19/22 and discussed the potential contributions of both pathologies in the present case.

A multifunctional supramolecular hydrogel (TF-MOD) through the synergistic integration of thioctic acid (TA), Fe3+, and MnO2@dopamine (DA) nanozymes was developed for diabetic wounds. The TA-based dynamic disulfide network offered remarkable injectability, tissue adhesion, and controllable degradation. The Fe3+ coordination significantly improved mechanical stability through metal-ligand interactions. The incorporated MnO2@DA nanozymes created a triple therapeutic synergy through cooperative antioxidant effects (MnO2's catalase-like activity, TA's redox activity achieving 92.3% H2O2 clearance), antimicrobial action (photothermal therapy with a 26.1°C temperature increase and TA's inherent antibacterial properties), and enhanced anti-inflammatory effects combined with pro-angiogenic effects mediated by the nanozymes. Through rheological analysis, lap-shear testing, and injectability assessments, the establishment of a stable yet dynamic network structure exhibited remarkable self-healing, injectability, and tissue adhesion. The TF-MOD hydrogel was designed to promote diabetic wound healing by providing sustained antibacterial efficacy (16.1% residual MRSA biofilm), anti-inflammatory activity, and pro-angiogenic effects, thereby enhancing collagen deposition (68.2%) and reducing wound area (15.2% remaining on day 10) significantly. Additionally, the TF-MOD hydrogel demonstrated dual therapeutic effects for both infected wounds (12.4% residual area, 67.8% collagen deposition) and incisional wounds (214.8 µm width). The TF-MOD hydrogel served as a novel and versatile platform for diabetic wound therapy.

Prolactinomas account for approximately 30% to 50% of pituitary adenomas. Dopamine agonists (DAs) are the first-line treatment and effectively induce tumor regression while normalizing prolactin levels. However, DA therapy not only inhibits tumor growth but also is associated with fibrosis within the tumor. This fibrotic transformation remodels the tumor microenvironment (TME), altering cellular interactions, vascular structures, and extracellular matrix (ECM) composition. We hypothesize that this fibrotic response may not be a mere side effect; emerging, though largely indirect, evidence suggests it could potentially protect residual tumor cells by impeding drug penetration and facilitating immune evasion. Despite extensive clinical use of DAs, the mechanisms underlying DA-associated fibrosis and its implications for tumor behavior as well as patient outcomes remain poorly understood. This review integrates current knowledge regarding the pathophysiological processes leading to DA-associated fibrosis in prolactinomas, explores alterations in the TME, and assesses the clinical implications of these alterations. By integrating recent experimental and clinical studies, we aim to provide a comprehensive overview that elucidates the challenges posed by this fibrotic change in DA therapy and to propose actionable avenues for future research aimed at overcoming these obstacles.

Rhodopsin-like G protein-coupled receptors (GPCRs) play a pivotal role in ophthalmic pathologies, and recent studies have substantially advanced our understanding of their underlying molecular mechanisms. Amine-responsive Rhodopsin-like GPCRs (ARh-GPCRs), encompassing adrenoceptors, dopamine receptors, muscarinic acetylcholine receptors, histamine receptors, serotonin receptors, melatonin receptors, and trace amine-associated receptors, are involved in a variety of ocular pathological processes and have emerged as key therapeutic targets. Elucidating their functional roles, alongside those of their ligands and downstream signaling macromolecules, holds considerable potential for the development of candidate biomarkers for early diagnosis, disease classification, prognostication, and predicting treatment response in specific ocular disorders. Despite significant progress, a comprehensive integration of their dual candidate biomarker-therapeutic roles across diverse ocular disorders remains largely unexplored. This narrative review summarizes and critically integrates current evidence on the regulatory roles and therapeutic potential of these receptors in ocular pathologies, with particular attention to their mechanistic involvement, candidate biomarker potential, and therapeutic relevance. Furthermore, we summarize the current research limitations and propose future directions to enhance the understanding of their molecular mechanisms, ultimately facilitating the development of precise diagnostic and therapeutic strategies.

Prolactinomas are the most common functioning pituitary tumors in women of reproductive age and can affect fertility, gonadal and skeletal health, and vision. Management becomes particularly complex when reproductive plans intersect with diagnostic uncertainty, tumor anatomy, pregnancy-related enlargement, and long-term treatment decisions. This focused narrative Mini Review synthesizes current guidelines, consensus statements, systematic reviews, and clinically informative cohort studies and proposes a reproductive-intent-based framework for organizing individualized care. Adequate diagnostic confidence is required before pathway assignment; patients may then enter one of three proposed dynamic management states: fertility-driven, endocrine-stabilization, or surveillance-dominant. Tumor-related risk-including optic-apparatus proximity, documented growth, apoplexy, and clinically important dopamine agonist resistance or intolerance-acts as a cross-cutting safety modifier. Dopamine agonists remain first-line therapy for most patients, with surgery considered for selected anatomically favorable tumors or when medical treatment is ineffective or poorly tolerated. Preconception care aims to restore ovulation and establish anatomical safety; pregnancy surveillance is predominantly symptom-driven; and postpartum reassessment should precede treatment resumption. Persistent hyperprolactinemia alone does not necessarily justify therapy without clinically meaningful hypogonadism, symptoms, or tumor progression. In women not seeking pregnancy, treatment intensity should reflect gonadal status, symptoms, skeletal consequences, and tumor risk. This framework does not replace guideline-based recommendations or constitute a validated clinical classification; rather, it makes management priorities and transitions explicit and requires prospective validation.