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01.
arXiv (CS.AI) 2026-06-18

Compute Efficiency and Serial Runtime Tradeoffs for Stochastic Momentum Methods

arXiv:2606.19179v1 Announce Type: cross Abstract: Stochastic momentum methods such as heavy ball (HB), Nesterov momentum, and variants of Accelerated SGD (ASGD) [Kidambi et al., 2018] are widely used in modern training, but their stochastic benefits depend on two distinct quantities: serial runtime, the number of iterations needed to reach a target accuracy, and compute efficiency (CE), the inverse total gradient-query or FLOP cost. Larger batches reduce serial runtime without hurting CE only when the contraction gap grows linearly with batch size. We study stochastic HB and ASGD for consistent linear regression with Gaussian covariates and prove finite-dimensional, discrete-time lower bounds on their batch-size tradeoffs. Our first result shows that HB does not improve the CE frontier over SGD for arbitrary spectra; rather, it preserves SGD-level CE over a larger batch-size window, allowing larger batches to reduce serial runtime until HB reaches its deterministic accelerated scale. This window can be a factor $\sqrt{\kappa}$ larger than the SGD critical batch size. For ASGD, the picture is more spectrum-dependent: for rapidly decaying power-law spectra, ASGD improves small-batch CE over HB/SGD, but as batch size grows it trades this CE advantage for improved serial runtime. Synthetic linear-regression experiments verify these qualitative regimes, including near-overlap of ASGD and HB for slowly decaying spectra and the predicted CE–serial tradeoff for rapidly decaying spectra.

02.
arXiv (quant-ph) 2026-06-16

Optimal learning of quantum channels in diamond distance

arXiv:2512.10214v3 Announce Type: replace Abstract: Quantum process tomography, the task of estimating an unknown quantum channel, is a central problem in quantum information theory. A long-standing open question is how many uses of an unknown channel are required to learn it in diamond distance, the standard metric for distinguishing quantum processes. While quantum state tomography is well understood, for general channels the problem remained open beyond the unitary case. Here we establish the query complexity of channel tomography with optimal dependence on the dimension parameters, at any fixed constant accuracy. We design an algorithm showing that any channel with input/output dimensions $d_{\mathrm{in}},d_{\mathrm{out}}$ and Kraus rank at most $k$ can be learned to accuracy $\varepsilon$ using $O(d_{\mathrm{in}}d_{\mathrm{out}}k/\varepsilon^{2})$ channel uses. Conversely, we prove that $\Omega(d_{\mathrm{in}}d_{\mathrm{out}}k)$ uses are necessary at constant accuracy and that, for non-minimal Kraus rank, a separate $\Omega(1/\varepsilon^{2})$ contribution is unavoidable. Since channels subsume states, unitaries, isometries, and measurements as special cases, our protocol provides a unified framework for these tomography tasks, yielding new guarantees for isometry and measurement tomography while recovering known optimal scalings for state and unitary tomography. Our algorithm follows the natural strategy of performing optimal tomography on the Choi state. The main technical contribution is to show that this suffices to control the induced diamond-distance error, avoiding the dimension loss incurred by a naive conversion from Choi-state trace distance to channel diamond distance. The protocol uses the channel non-adaptively to prepare Choi-state copies, purifies them in parallel, and performs optimal pure-state tomography on the resulting purifications. Hence, we reduce channel tomography to pure-state tomography.

03.
arXiv (CS.CL) 2026-06-16

ttda704 at SemEval-2026 Task 4: Modeling Narrative Structures via Pseudonymization and Multi-View Sentence Alignment

We present our approach to SemEval 2026 Task 4: Narrative Story Similarity and Narrative Representation Learning. Our solution uses contrastive learning with fine-tuned sentence transformers to capture narrative similarity across abstract themes, course of action, and outcomes. We develop two pipelines: (Track A) a single-view method that encodes full narratives with smart layer freezing to reduce overfitting, and (Track B) a multi-view method that models theme, plot, and outcome with view-specific projection heads and self-supervised alignment. Both pipelines build on sentence-transformers models and are trained with contrastive loss on synthetic data. The code is available at the following GitHub repository: https://github.com/dinhthienan33/SemEval2026-Task4-ttda704.

04.
arXiv (CS.CV) 2026-06-11

From Prompts to Tokens: Internalizing Causal Supervision in Vision-Language Model for Multi-Image Causal Reasoning

Visual causal reasoning is essential for understanding and intervening in the physical world, requiring identification of causal variables from visual inputs and reasoning over intervention effects. Despite recent progress, large vision–language models (VLMs) remain brittle at such tasks, especially for interventional and counterfactual queries over multi-image inputs. Most existing explorations inject causal knowledge via textual prompts, leaving causal mechanisms external to model execution and limiting reliable control during inference. To address this problem, we propose BridgeVLM, which internalizes visual causal reasoning by inducing a causal graph from multi-image inputs and converting it into structured Causal Tokens executed by RAMP layers injected into the LLM decoder for causal message passing. We further introduce a unified training interface M3S for fine-grained causal supervision from different granularities (local/global level). BridgeVLM achieves 54.4% accuracy on intervention tasks on CausalVLBench (vs. 33.2% with prompt-level supervision), improves results on Causal3D from 43.6% to 49.0%, and substantially improves causal structure learning on CausalVLBench ($F_1$: 33.4% $\rightarrow$ 75.1%).

05.
arXiv (CS.CL) 2026-06-19

Characterizing Narrative Content in Web-scale LLM Pretraining Data

The narrative composition of web-scale LLM pretraining corpora remains largely unexplored even though narrative is a fundamental mode of human communication. We present the first fine-grained study of narrative features in Dolma, a 3-trillion-token open pretraining corpus. Drawing on narrative theory, we design a framework spanning three core narrative elements (agency, setting, and events) operationalized as 11 interpretable dimensions. After sampling and annotating a diverse set of 400 passages, we finetune and validate NarraBERT, a RoBERTa-based model for fine-grained narrative prediction. We apply NarraBERT to 3M passages, resulting in a new dataset, NarraDolma. We find (i) narrative structure is measurable at scale across extremely heterogeneous data, (ii) we uncover a continuous, multidimensional narrative structure underlying web text, and (iii) narrative qualities are unequally distributed across pretraining sources and topics in ways that current curation practices neither measure nor account for. Our framework, dataset, and analyses provide a foundation for understanding how narrative qualities are distributed in LLM pretraining data and for studying how data composition affects narrative reasoning tasks. We publicly release NarraDolma and NarraBERT.

06.
arXiv (CS.AI) 2026-06-16

FasterPy: An LLM-based Code Execution Efficiency Optimization Framework

arXiv:2512.22827v2 Announce Type: replace-cross Abstract: Code often suffers from performance bugs. These bugs necessitate the research and practice of code optimization. Traditional rule-based methods rely on manually designing and maintaining rules for specific performance bugs (e.g., redundant loops, repeated computations), making them labor-intensive and limited in applicability. In recent years, machine learning and deep learning-based methods have emerged as promising alternatives by learning optimization heuristics from annotated code corpora and performance measurements. However, these approaches usually depend on specific program representations and meticulously crafted training datasets, making them costly to develop and difficult to scale. With the booming of Large Language Models (LLMs), their remarkable capabilities in code generation have opened new avenues for automated code optimization. In this work, we proposed FasterPy, a low-cost and efficient framework that adapts LLMs to optimize the execution efficiency of Python code. FasterPy combines Retrieval-Augmented Generation (RAG), supported by a knowledge base constructed from existing performance-improving code pairs and corresponding performance measurements, with Low-Rank Adaptation (LoRA) to enhance code optimization performance. Our experimental results on the Performance Improving Code Edits (PIE) benchmark demonstrate that our method outperforms existing models on multiple metrics. The FasterPy tool and the experimental results are available at https://github.com/WuYue22/fasterpy.

07.
arXiv (CS.CV) 2026-06-12

Transformer-Guided Graph Attention for Direct Cardiac Mesh Reconstruction: A Structural Digital Twin Framework

Building patient-specific cardiac models sits at the heart of precision cardiology, yet getting those models into clinical use keeps running into the same wall: mesh generation is slow, messy, and frustrating. The standard workflow – segmenting the image, running Marching Cubes, and then manually cleaning up the result – is time-consuming, inconsistent across operators, and demands specialist knowledge most clinical teams do not have. We take a fundamentally different approach. Instead of treating segmentation and mesh generation as two separate problems, we train a single end-to-end network that goes directly from a raw 3D medical image to a smooth, simulation-ready cardiac surface mesh. The core is a 3D Swin Transformer encoder-decoder that extracts volumetric features from CT or MRI volumes, paired with a Graph Attention Network (GAT) head that iteratively deforms a template mesh to fit the patient's cardiac boundary. We tested on the MM-WHS 2017 benchmark using both CT and MRI. Segmentation scores were competitive (Dice of 0.84 on CT, 0.83 on MRI), but the primary focus is mesh quality: mean Chamfer distance of 1.8 mm, with 95th-percentile surface distance below 5 mm. Every mesh is produced in a single forward pass – no Marching Cubes, no smoothing filters, no manual cleanup. We argue that for cardiac digital twin pipelines, geometric fidelity and topological correctness matter more than pixel-level Dice scores. By removing the post-processing bottleneck, this approach makes patient-specific cardiac simulation substantially more accessible for clinical use.

08.
arXiv (CS.LG) 2026-06-19

Multi-Modal Contrastive Learning for Implicit Earth Embeddings via Location Tying

arXiv:2606.20167v1 Announce Type: new Abstract: Spatial prediction tasks are often limited by a lack of high-quality labelled ground-truth observations. To overcome this challenge, self-supervised pre-training is a possible solution, with contrastive learning dominant for location encoders. Those approaches usually align geographic coordinates with just one additional modality. We propose two multimodal contrastive learning architectures: Multimodal Embedding via Location Tying (MELT) and Sequential Alternating Location Training (SALT). These architectures expand this framework beyond two modalities by utilising unpaired geospatial data. Both methods are technically viable and match the performance of the strongest two-modality baseline (SATCLIP) across four downstream tasks. However, increasing the number of modalities does not consistently improve performance, suggesting that the chosen location encoder is the main limitation - the contrastive objective reaches its peak early, regardless of modality diversity or pre-training volume. MELT provides more stable training than SALT and presents a stronger foundation for future scaling.

09.
arXiv (CS.LG) 2026-06-11

What Uncertainties Do We Need for Dynamical Systems?

arXiv:2606.11988v1 Announce Type: new Abstract: The distinction between aleatoric and epistemic uncertainty has received considerable attention in machine learning research, mainly in the context of supervised learning but also in other settings such as generative modeling. In this paper, we offer a machine learning perspective on uncertainty modeling for dynamical systems, which has been studied much less so far. In particular, we ask: what uncertainties do we need for dynamical systems? We discuss sources of uncertainty, clarify their nature (aleatoric or epistemic), and consider how the objectives of representing and quantifying uncertainty vary across different tasks.

10.
arXiv (CS.AI) 2026-06-18

Bounded Context Management for Tabular Foundation Models on Stream Learning

arXiv:2606.18677v1 Announce Type: cross Abstract: Tabular stream learning requires predictions on sequentially arriving examples under distribution shift. While standard methods adapt by updating model states, tabular foundation models (TFMs) make predictions conditioned on a labeled context in an in-context manner, making them a natural alternative for stream learning. This shifts the challenge from how to update the model to how to manage the context. We propose a future information view that yields three practical requirements for context management: preserve recent examples, retain uncertain examples, and remove redundant examples. We instantiate these requirements as CURE (Context management via Uncertainty-aware admission and Redundancy aware Eviction), a context-managing policy with entropy-gated admission and redundancy-aware eviction. Across seven streams, CURE shows up to 27.0% relative improvement over classical stream learners, remains robust across multiple TFM backbones, and ranks first among other policy variants. Code and datasets are available at https://github.com/morcellinus/CURE-ICML-FMSD.

12.
arXiv (CS.CL) 2026-06-15

OLaPh: Optimal Language Phonemizer

Phonemization is a critical component in text-to-speech synthesis. Traditional approaches rely on deterministic transformations and lexica, while neural methods offer potential for higher generalization on out-of-vocabulary (OOV) terms. We introduce OLaPh (Optimal Language Phonemizer), a hybrid framework that integrates extensive multilingual lexica with advanced NLP techniques and a statistical subword segmentation function. Evaluations on the WikiPron benchmark show OLaPh significantly outperforms established baselines in overall accuracy and maintains robustness on OOV data through advanced fallback mechanisms. To further explore neural generalization, we utilize the framework to synthesize a high-consistency training corpus for an instruction-tuned Large Language Model (LLM). While the deterministic framework remains more accurate overall, the LLM demonstrates strong generalization, matching or partly exceeding the framework's performance. This suggests that the LLM successfully internalized phonetic intuitions from the synthetic data that transcend the framework's capabilities. Together, these tools provide a comprehensive, open-source resource for multilingual grapheme-to-phoneme conversion (G2P) research.

13.
arXiv (CS.LG) 2026-06-15

Hybrid Uncertainty Sensitivity Analysis Based on the HSIC for High-Dimensional Responses with Aleatory–Epistemic Separation

arXiv:2606.14053v1 Announce Type: cross Abstract: Quantifying the influence of hybrid aleatory and epistemic uncertainties on high-dimensional system responses remains a major challenge in global sensitivity analysis (GSA). Existing Hilbert–Schmidt Independence Criterion (HSIC)-based approaches are primarily restricted to single-output settings and lack a rigorous decomposition of heterogeneous uncertainty sources and their interactions. To address this limitation, a novel double-space tensor-product RKHS framework is proposed for sensitivity analysis under hybrid uncertainty. By constructing factorized kernels over both the latent input space and the multidimensional output space, a concurrent double Möbius inversion is derived to orthogonally decompose the global dependence measure into pure aleatory effects, pure epistemic effects, and their interaction contributions. The resulting dimension-wise sensitivity indices preserve the uncertainty attribution structure across all output dimensions. To satisfy the independence assumptions required by the decomposition, an auxiliary-variable representation based on the inverse probability integral transform is introduced, enabling the treatment of hierarchical uncertainties and Copula-induced correlations within a unified latent space. A fully vectorized single-loop implementation is further developed to avoid the computational burden of nested Monte Carlo simulation. Statistical significance and estimation uncertainty are quantified through permutation testing and Bootstrap confidence intervals. Numerical studies on a modified multi-output Ishigami function and an aerodynamic pressure-field problem demonstrate the accuracy, scalability, and practical applicability of the proposed framework.

14.
arXiv (CS.CV) 2026-06-16

Interpolation between Convolution and Attention via K-Nearest Neighbors

作者:

The shift from Convolutional Neural Networks to Transformers has reshaped computer vision, yet these two architectural families are typically viewed as fundamentally distinct. Convolutional Neural Networks are defined by spatially local convolution operations, while Transformers rely on global self-attention. We argue that convolution and self-attention, despite their apparent differences, can be unified within a single k-nearest neighbor aggregation framework. The critical insight is that both operations are special cases of neighbor selection and weighted aggregation. Convolution selects neighbors by spatial proximity while self-attention selects by feature similarity, revealing that they lie on a continuous spectrum rather than representing categorically different computations. We introduce Convolutional Nearest Neighbors (ConvNN), a unified framework that formalizes this connection. ConvNN exactly recovers standard and depthwise convolution by restricting neighbor selection to normalized spatial coordinates, and exactly recovers self-attention and its sparse variants, including KVT-attention, by replacing spatial proximity with scaled dot-product similarity. Beyond these special cases, ConvNN serves as a drop-in replacement for both convolution and attention layers, enabling systematic exploration of the intermediate spectrum between local and global aggregation through configurable similarity functions, neighbor selection strategies, positional encodings, and aggregation kernels.

15.
arXiv (CS.LG) 2026-06-19

Convex training of Lipschitz-regularized shallow neural networks

arXiv:2606.19652v1 Announce Type: new Abstract: In this work, we introduce a training procedure for shallow neural networks that promotes robustness against adversarial attacks. We solve a non-convex Lipschitz-regularized training program by introducing a convex restriction that can be efficiently solved to global optimality. Our approach can be employed as a post-processing step by taking a pre-trained network as an initial solution to then solving the convex program whose optimal network is guaranteed to be no worse than the initial one. We illustrate the improvements of our training procedure with experiments using real world datasets for regression tasks under an adversarial setting. We show numerically that solving our proposed convex program yields networks with lower objective values on the Lipschitz-regularized program compared to existing methods. Additionally, we show that on certain datasets, networks obtained using our convex training program are both more accurate and robust with respect to adversarial attacks.

16.
arXiv (CS.CL) 2026-06-16

QK-Normed MLA: QK normalization without full key caching

Query-key (QK) normalization stabilizes attention by controlling the scale of queries and keys before the dot product, but is not immediately compatible with Multi-head Latent Attention (MLA). MLA achieves efficient decoding by caching low-dimensional latent states instead of full keys, whereas post-projection QK RMSNorm appears to require the fully projected key for every cached token. We show this apparent incompatibility is an implementation artifact, not an architectural constraint. RMSNorm decomposes into a static affine weight and a dynamic scalar RMS statistic. The static key-side weight can be absorbed into the MLA query-side projection; the dynamic key statistic reduces to one inverse-RMS scalar per token and KV group. The resulting formulation is exactly equivalent to explicit post-projection QK RMSNorm in exact arithmetic and preserves MLA's latent decode path. In our 400M runs trained for up to 100B tokens, QK-Normed MLA achieves lower training loss and better downstream accuracy than QK clipping, while H800 decode benchmarks show less than 2% latency overhead up to 256k context. These results make QK normalization a practical stabilization option for MLA models without requiring full-key caching.

17.
arXiv (CS.LG) 2026-06-16

Semantic DLM+: Improving Diffusion Language Models through Bias-variance Trade-off in Transition Kernel Design

arXiv:2606.15327v1 Announce Type: new Abstract: Diffusion Language Models (DLMs) have demonstrated strong scaling capacity as alternatives to autoregressive language models. However, their performance is highly sensitive to the choice of transition kernels, and poorly designed kernels can lead to issues like training instability, slow convergence, and biased sampling. In this paper, we study this sensitivity through a principled analysis of generalization error and identify three critical factors: asymptotic bias (difficulty in approximating the posterior distribution), exposure bias (error propagation during sampling), and optimization variance induced by kernel dispersion. We further compare different transition kernels: masking diffusion yields sparse and easier posterior-approximation targets, while uniform diffusion provides stronger sampling-side repair but induces harder approximation. Motivated by this trade-off, we revisit a previously overlooked variant, semantic DLM (SemDLM), where the transition kernel corrupts tokens to neighborhoods that are semantically similar. Our theory suggests that SemDLM can serve as a plausible middle ground by reducing the posterior approximation difficulty of uniform diffusion while retaining repair ability. However, we find that SemDLM suffers from a semantic basin problem, where sampling repeatedly stays within a semantic region and produces low-diversity text. To address this, we propose SemDLM+, which adds a global transition and a semantic-frequency penalty during sampling. Experiments on LM1B and OpenWebText show that SemDLM+ improves training dynamics and achieves competitive language modeling and generation quality with satisfactory diversity.

18.
arXiv (CS.CV) 2026-06-16

GridVQA-X: A Framework for Evaluating Multimodal Explainability Methods

With the increasing development of Vision-Language Models, it becomes imperative that their predictions are readily explainable to relevant stakeholders. However, the field of explainability has not kept pace with the multimodal surge. While recent Multimodal Explainable AI (MxAI) methods generate explanations to attribute the interaction between different modalities, current evaluation protocols lack the ground truth required to distinguish between true cross-modal reasoning (e.g., spatial composition) and shallow cross-modal shortcuts (e.g., Bag-of-Words attribute matching). It remains unknown whether MxAI methods faithfully capture synergistic interactions or merely hallucinate reasoning on models acting as simple feature detectors. In this paper, we introduce GridVQA-X, the first diagnostic framework specifically designed to evaluate cross-modal explainability. Unlike natural datasets, GridVQA-X leverages a closed-world synthesis logic to generate unique, mathematically guaranteed explanations. We utilize this controlled environment to train paired ground-truth models on identical architectures: $M_{pure}$, which learns robust spatial-relational reasoning and $M_{spur}$, which is structurally forced to rely on cross-modal shortcuts. This behavioral divergence creates a rigorous testbed: a faithful explainer must report distinct reasoning pathways for each model. Our findings reveal that widely used methods fail to distinguish between models relying on genuine spatial-relational reasoning and those exploiting cross-modal shortcuts, highlighting a critical gap in capturing true cross-modal synergy and misrepresenting how multimodal models actually make decisions.

19.
arXiv (CS.LG) 2026-06-16

Circuit Tracing in Autoregressive Protein Language Models

arXiv:2606.16044v1 Announce Type: new Abstract: Protein language models (pLMs) can generate novel protein sequences with properties beyond those observed in nature, yet the mechanisms underlying protein generation remain poorly understood. Existing mechanistic interpretability methods based on sparse autoencoders and transcoders primarily focus on protein representation learning models and do not capture the computation required for autoregressive generation. Here, we introduce ProGenMech, a mechanistic interpretability framework for generative protein language models that extends cross-layer transcoders (CLTs) to ProGen3, a sparse Mixture-of-Experts model trained for both causal generation and span infilling. Unlike per-layer approaches, CLTs reconstruct each layer using sparse latent variables from all preceding layers, enabling faithful recovery of inter-layer generative computation. We further develop a zero-shot circuit discovery framework to identify sparse latent circuits responsible for protein generation and fitness prediction. In causal generation and zero-shot fitness estimation tasks, ProGenMech outperforms local transcoder baselines in recovering ProGen3's probability distribution and functional scoring behavior, while matching the original model's generative distribution in span infilling tasks. Moreover, the recovered circuits reveal biologically meaningful motifs and functional regions associated with conserved sequence patterns and protein fitness landscapes, establishing a foundation for interpretable and steerable protein generation.

20.
Science (Express) 2026-06-11

Laser phase plate improves structure determination of small proteins by cryo-EM | Science

作者: 未知作者

Phase plates can in principle overcome the poor image contrast in electron cryo–microscopy (cryo-EM) and the resulting limits on the structural reconstruction of small proteins. However, previous designs have been unstable and compromised the high-resolution signal. They have thus been unable to surpass results achieved by standard cryo-EM. Here, we show that the laser phase plate (LPP), installed in a custom, modern Titan Krios microscope, enhances the resolution in single-particle reconstruction of small proteins by improving specimen-motion correction, recovery of information from the early frames, as well as particle visualization, 3D classification, and alignment. These advances use standard defocus ranges and reconstruction procedures, but open the door to LPP-tailored protocols offering further improvements by leveraging the LPP demonstrated here.

21.
arXiv (CS.LG) 2026-06-16

Peak-Based Nuclide Identification in HPGe $\gamma$-Spectrometry with Machine Learning and SHAP

arXiv:2606.14874v1 Announce Type: cross Abstract: High-purity germanium gamma spectra often require time-consuming analyses from subject matter experts. Photopeaks within these spectra are carefully fitted and numerical methods are employed to assist with nuclide identification (NID) and quantification. Amending the list of nuclides identified by analysis software can be nontrivial. When many samples need to be analyzed, it is therefore challenging to make timely and correct decisions. Supervised machine-learning-based NID can serve as an expert-informed, automated tool to improve the initial set of radionuclides suggested to an analyst and more effectively drive subsequent quantification. To that end, we implemented machine learning models that map photopeaks carefully fitted by analysts to NID results for experimental spectra containing various isotopic combinations drawn from a set of 65 isotopes. The best model achieved an F1 score of 0.97, markedly surpassing the F1 score of 0.84 achieved by traditional software when compared using a nuclide library comprising the same 65 isotopes assessed by the models. Finally, we illustrated the most important input features for model predictions using Shapley Additive Explanations. These explanations revealed that the models use physically relevant photopeaks when making predictions for the isotopes in our nuclide library.

23.
arXiv (CS.CV) 2026-06-11

Understanding Cross-Sensor Feature Variations for Generalizable 3D Perception

Radar-camera BEV perception often suffers from degraded performance when evaluated across datasets, as changes in driving scenes, sensor configurations, and environmental conditions can alter both the input observations and the internal fused representations. This work studies this issue from the perspective of source-domain variation modeling, aiming to improve the robustness of BEV-based 3D detectors without relying on target-domain samples. We introduce a framework that characterizes visual scene variations in the frequency domain and uses them to synthesize diverse source-domain views. By comparing the resulting fused BEV representations, the framework further captures how image-level variations influence multi-modal BEV features. These variation patterns are then used to regularize the detector, encouraging the learned fusion space to remain stable under latent scene changes. The proposed method is applied only during training and leaves the inference pipeline unchanged. Experiments on cross-dataset radar-camera 3D detection between View-of-Delft and TJ4DRadSet demonstrate consistent improvements over multiple BEV fusion backbones, and the gains remain effective when a small amount of target-domain data is available.

24.
Nature Medicine 2026-06-12

Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression: a randomized placebo-controlled trial

Anhedonia is a core and disabling symptom of mood disorders with limited treatment options. We evaluated the efficacy and safety of the dopamine agonist pramipexole in patients with mood disorders characterized by clinically significant anhedonia. In this single-center, randomized, double-blind, placebo-controlled trial, adults with major depressive disorder, dysthymia or bipolar depression and elevated Snaith−Hamilton Pleasure Scale (SHAPS) scores were assigned (1:1) to flexible dose, once-daily oral pramipexole as add-on treatment or placebo for 9 weeks. The primary outcome was change in SHAPS score from baseline to week 9. Analyses were conducted in the modified intention-to-treat population. Eighty-five participants were randomized, and 82 were included in the analysis. The primary outcome was met: pramipexole was associated with a greater reduction in SHAPS scores compared to placebo (mean difference: −4.04, 95% confidence interval: −6.89 to −1.18, P = 0.006, Hedges’ g = 0.62). Exploratory analyses indicated that pramipexole was associated with increased light physical activity and relative preservation of reward-related ventral striatal activation. Improvements in anhedonia were sustained during a 6-month open-label extension. Pramipexole was generally well tolerated compared to placebo. Pramipexole significantly improved anhedonia and showed a favorable safety profile, supporting its potential as an augmentation strategy in mood disorders. ClinicalTrials.gov identifiers: NCT05355337 and NCT05825235 . Pramipexole, in patients with major depressive disorder, dysthymia or bipolar depression, reduced Snaith−Hamilton Pleasure Scale scores significantly compared to placebo.