Electroconvulsive Therapy (ECT) has long been a controversial yet profoundly effective treatment modality in psychiatry, particularly for severe mood disorders resistant to pharmacological intervention. Despite its clinical efficacy, the underlying biological mechanisms and reliable predictive markers for treatment response have remained elusive. A recent narrative review by Zilles-Wegner, von Mücke-Heim, Yrondi, and colleagues, published in Translational Psychiatry in 2026, offers an exhaustive synthesis of current clinical and biological markers that may predict and explain ECT’s therapeutic effects. This comprehensive review sheds new light on the mechanistic underpinnings of ECT and proposes a pathway toward precision psychiatry by integrating neurobiological data with clinical phenotyping.
The hallmark of ECT’s efficacy lies in its ability to induce controlled seizures under general anesthesia, which paradoxically leads to marked improvements in psychiatric symptoms, especially in major depressive disorder (MDD) and certain psychotic illnesses. Early clinical observations documented its rapid mood-enhancing effects, but the variability in patient outcomes necessitated a deeper search for biomarkers. These markers are critical not only for improving patient selection and reducing cognitive side effects but also for unraveling the complex pathophysiology of treatment-resistant depression.
A key clinical challenge addressed by the review is the heterogeneity of patient responses. While some patients exhibit dramatic remission, others derive minimal benefit. This variability suggests underlying neurobiological differences. Hence, the authors emphasize the role of clinical parameters such as symptom clusters, illness duration, and comorbidities as initial predictors. More granular clinical features, including baseline cognitive function and psychomotor retardation, are correlated with differential outcomes, hinting at distinct neural circuit involvement and neuroplasticity potential.
Venturing beyond clinical descriptors, the review meticulously catalogues neuroimaging findings as promising biological markers. Structural and functional MRI studies highlight the normalization of aberrant connectivity patterns in the prefrontal cortex, hippocampus, and limbic system post-ECT. Changes in cortical thickness and hippocampal volume appear as reliable correlates of clinical improvement, implicating ECT-triggered neurogenesis and synaptic remodeling. Importantly, resting-state functional connectivity analyses reveal shifts in the default mode network and salience network activity, which may underpin symptom alleviation mechanisms.
Electroencephalography (EEG) has also emerged as an invaluable tool in the biomarker landscape. Alterations in spectral power, particularly increased theta and delta rhythms during seizures, are associated with positive treatment response. Pre-ECT EEG patterns also serve predictive functions; patients exhibiting specific baseline slow-wave activity tend to respond more favorably. This electrophysiological data not only enhances treatment customization but also provides real-time markers to optimize ECT parameters such as stimulus intensity and seizure duration.
At the molecular and cellular biology level, the review synthesizes evidence implicating neurotrophic factors as central mediators of ECT effectiveness. Brain-derived neurotrophic factor (BDNF), known for its role in neuronal survival and synaptic plasticity, increases significantly following therapy. Parallel changes in inflammatory markers suggest an interplay between immune modulation and neuroplastic processes. The authors highlight that ECT’s capacity to modulate neuroinflammation and promote neurogenesis could represent the biological substrate for sustained symptom remission.
Genetic and epigenetic investigations further deepen insight into ECT response variability. Polymorphisms in genes regulating neurotransmitter systems, neurotrophic signaling, and stress response pathways may predict both efficacy and side effect susceptibility. Epigenetic modifications, such as DNA methylation changes in key regulatory genes, are emerging as dynamic biomarkers that could reflect the biological imprint of treatment. These molecular markers pave the way for personalized medicine approaches where genetic profiling informs individualized ECT protocols.
One of the most intriguing advances discussed is the potential for integrating multimodal biomarker data into predictive algorithms. Machine learning techniques applied to clinical scores, neuroimaging metrics, EEG parameters, and molecular profiles demonstrate enhanced accuracy in forecasting ECT outcomes. This multidimensional biomarker strategy marks a pivotal step toward clinical decision support systems, allowing psychiatrists to strike a balance between maximal therapeutic effect and minimal cognitive risk.
Cognitive side effects remain a clinical concern, particularly with bilateral electrode placement. The review outlines how emerging biomarkers could predict cognitive trajectories post-ECT, enabling optimized electrode positioning and dosage tailoring. Functional imaging studies indicate that selective modulation of hippocampal circuits is crucial to preserving memory function, a finding that could guide future technical refinements in ECT administration.
Importantly, the authors advocate for longitudinal biomarker assessments throughout the treatment course, emphasizing the dynamic nature of biological response. Real-time biomarker monitoring could inform adaptive therapy protocols, identifying early responders and non-responders to modify treatment plans in real time. This approach aligns with the evolving paradigm of precision psychiatry that transcends static diagnosis-based frameworks.
The review also discusses the ethical and methodological challenges in biomarker research, including cohort heterogeneity, small sample sizes, and technical variability across centers. Standardization of protocols and international consortia for data sharing are proposed as solutions to accelerate biomarker validation and ultimately clinical translation. Moreover, integrating patient-reported outcomes and functional measures complements biological markers for a holistic picture of treatment impact.
Looking ahead, the synthesis provided in this narrative review sets the stage for innovative clinical trials that incorporate biomarker-guided stratification. The emerging biomarker profiles could identify novel therapeutic targets and facilitate combination strategies, such as augmenting ECT with pharmacotherapy or brain stimulation techniques tailored to individual biological profiles. Such synergistic approaches promise to enhance clinical efficacy while mitigating adverse effects.
In conclusion, the comprehensive evaluation of clinical and biological markers reviewed by Zilles-Wegner and colleagues represents a major milestone in understanding ECT’s intricate mechanisms. By bridging clinical phenomenology with cutting-edge neuroscience, this work propels the field toward predictive and personalized psychiatry. As technological and computational advancements converge with deeper biological insights, the vision of tailored, efficient, and safe ECT treatments moves within reach, offering hope for millions afflicted by treatment-resistant psychiatric disorders.
Subject of Research: Clinical and biological markers predicting the effectiveness of electroconvulsive therapy in treatment-resistant psychiatric disorders
Article Title: Clinical and biological markers of electroconvulsive therapy effectiveness: a narrative review
Article References:
Zilles-Wegner, D., von Mücke-Heim, IA., Yrondi, A. et al. Clinical and biological markers of electroconvulsive therapy effectiveness: a narrative review. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03900-2
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