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Brain Sciences
Special Issues
Novel Therapeutic Approaches for Treatment-Resistant Depression
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Novel Therapeutic Approaches for Treatment-Resistant Depression

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuropsychiatry".

Deadline for manuscript submissions: closed (30 November 2025) | Viewed by 1415

Special Issue Editor

Dr. Yuliya O. Knyahnytska

E-Mail Website
Guest Editor
Department of Psychiatry, Queen’s University, Kingston, ON, Canada
Interests: interventional psychiatry; treatment-resistant mood disorders; depression

Special Issue Information

Dear Colleagues,

Treatment-resistant/hard-to-treat depression poses a significant clinical challenge, affecting a substantial subset of individuals who fail to respond to conventional pharmacological and psychotherapeutic approaches. Despite the growing burden of depression on patients and healthcare systems, current interventions remain limited in efficacy and accessibility.

This Special Issue aims to highlight innovative and emerging therapeutic strategies, including but not limited to neuromodulation techniques (e.g., TMS, ECT, MST, tDCS, PBM, etc.), psychedelic-assisted therapy, digital therapeutics, precision medicine approaches, and novel pharmacological agents (ketamine, esketamine, etc.). We also welcome research exploring biomarkers, mechanisms of action, and personalized treatment frameworks through qualitative methodology.

We invite original research articles, clinical trials, reviews, and translational studies that advance our understanding or clinical management of hard-to-treat depression. Submissions that incorporate multidisciplinary approaches or examine real-world applications and long-term outcomes are especially encouraged.

Dr. Yuliya O. Knyahnytska
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • treatment resistant depression
  • hard-to-treat mood disorders
  • innovative interventions
  • therapeutic brain stimulation interventions
  • neuromodulation interventions
  • novel psychotropics

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Published Papers (1 paper)

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Research

11 pages, 419 KB  
Article
Short-Term Changes in Depressive Symptoms Among Patients with Alzheimer’s Disease Following a Precision Medicine Intervention
by Rammohan V. Rao, Alan Boyd, Sho Okada, William Lipa, Lance Kelly, Christine Coward, Aida L. Bredesen, Julie Gregory and Dale E. Bredesen
Brain Sci. 2026, 16(1), 2; https://doi.org/10.3390/brainsci16010002 - 19 Dec 2025
Viewed by 1157
Abstract
Background/Objectives: The ReCODE (Reversal of Cognitive Decline) protocol, a precision medicine program for patients with Alzheimer’s disease (AD), has demonstrated promising results in improving cognitive function. However, its impact on mood, specifically depressive symptoms, has been less explored. Depression is highly prevalent [...] Read more.
Background/Objectives: The ReCODE (Reversal of Cognitive Decline) protocol, a precision medicine program for patients with Alzheimer’s disease (AD), has demonstrated promising results in improving cognitive function. However, its impact on mood, specifically depressive symptoms, has been less explored. Depression is highly prevalent in individuals with mild cognitive impairment and AD, shares common risk factors (e.g., systemic inflammation), and negatively affects quality of life and disease trajectory. This study evaluated whether participation in the ReCODE program is associated with measurable improvement in depressive symptoms, as assessed by the Patient Health Questionnaire-9 (PHQ-9). Methods: This retrospective, observational analysis utilized de-identified data from 170 individuals diagnosed with mild to moderate AD enrolled in the ReCODE program. Participants received initial consultations and program orientation. Follow-up visits occurred 31 days post-enrollment, including further guidance on diet, lifestyle, medications, and supplements, along with mood assessment using the PHQ-9. Pre- and post-intervention PHQ-9 scores were analyzed using the non-parametric Wilcoxon signed-rank test. Results: Participants showed a statistically and clinically significant reduction in PHQ-9 scores. Improvement was observed across all baseline depression categories (mild, moderate, and severe). Critically, the proportion of participants scoring above the clinical threshold for depression decreased substantially following the intervention. Conclusions: These findings suggest that the ReCODE precision-medicine framework offers concurrent benefits for both mood and cognition. Extending prior work, our results indicate that the ReCODE program not only benefits cognitive and biological measures but also significantly alleviates depressive symptoms. While the results highlight ReCODE’s potential as a successful multifaceted therapeutic approach addressing both cognitive decline and mental health in Alzheimer’s disease, given the retrospective, uncontrolled design, the findings should be interpreted as associative and hypothesis-generating rather than causal. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches for Treatment-Resistant Depression)
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