Psychiatry · Medical Literature
Therapeutic potential of AdipoRon in cognitive, depressive, and anxiety disorders: a systematic review and meta-analysis.
Abstract
Rising cases of cognitive disorders, depression, and anxiety underscore the need for new treatments, given the limited effectiveness and side effects of current options. AdipoRon targets adiponectin receptors and shows promise for protecting the brain, reducing inflammation, and supporting metabolism. This review examines preclinical data to determine whether AdipoRon consistently improves mood and cognitive function and to identify the underlying neurobiological pathways. We conducted a comprehensive literature search using PubMed, Embase, Web of Science, and Scopus, with no time limit, up to August 30, 2025. The quality of the selected studies was evaluated using the Collaborative Approach to Meta-Analysis and Review of Animal Studies (CAMARADES) checklists and the SYRCLE risk of bias tool. The studies found that AdipoRon treatment significantly reduced immobility in the forced swim test and had a significant anxiolytic effect in the open field test, especially in chronic unpredictable mild stress models. It also improved recognition memory in the novel object recognition test in models of Alzheimer's and Parkinson's diseases. Additionally, AdipoRon increased the expression of synaptic proteins, such as synaptophysin and PSD-95, in rodent models of these diseases. It also modulated the production of inflammatory cytokines. This review establishes AdipoRon's capacity to resolve depressive, anxious, and cognitive deficits in rodent models. Because the meta-analyses were based on a limited number of studies and substantial heterogeneity was observed across studies, the findings should be interpreted with caution. However, further well-designed preclinical and clinical investigations are essential to confirm these findings.
Clinical relevance
Does AdipoRon, a synthetic small-molecule adiponectin receptor agonist, consistently improve depressive, anxiolytic, and cognitive outcomes across preclinical rodent models, and what neurobiological mechanisms underlie these effects? __SNAPSHOT__ {"studyDesign":"Systematic review and meta-analysis of preclinical (animal) studies","setting":"Multicenter preclinical literature; affiliated with Tabriz University of Medical Sciences, Iran; published in Molecular Brain (June 2026)","sampleSize":"Not reported in abstract; number of included studies not specified in available text","population":"Rodent models of cognitive disorders (Alzheimer's disease, Parkinson's disease), depression (including chronic unpredictable mild stress [CUMS] models and corticosterone-induced models), and anxiety","intervention":"AdipoRon — a synthetic, orally active, small-molecule agonist of adiponectin receptors AdipoR1 and AdipoR2","comparator":"Vehicle-treated or untreated rodent controls (model-specific comparators across included studies)","primaryOutcome":"Behavioral outcomes across three domains: (1) depressive-like behavior assessed by forced swim test (FST) immobility; (2) anxiolytic effect assessed by open field test (OFT); (3) cognitive function assessed by novel object recognition test (NOR). Secondary molecular outcomes included expression of synaptic proteins (synaptophysin, PSD-95) and modulation of inflammatory cytokines.","followUp":"Not reported; varies by individual included study","fundingSource":"Not reported"}
Key findings
AdipoRon treatment significantly reduced immobility in the forced swim test — the primary behavioral surrogate for depressive-like behavior — particularly in chronic unpredictable mild stress (CUMS) models. A significant anxiolytic effect was observed in the open field test in the same stress paradigms. Recognition memory, assessed via the novel object recognition test, was improved in rodent models of both Alzheimer's and Parkinson's diseases. At the molecular level, AdipoRon increased expression of synaptic proteins synaptophysin and PSD-95 and modulated inflammatory cytokine production. No specific effect sizes, standardized mean differences, confidence intervals, p-values, or heterogeneity statistics (I²) are reported in the available abstract text. The authors explicitly note that the meta-analyses were based on a limited number of studies and substantial heterogeneity was observed across studies. NNT and NNH are not applicable in this preclinical context. Dose-dependent effects have been reported in the supporting literature: low-dose AdipoRon (20 mg/kg) promoted hippocampal cell proliferation, while high-dose treatment (50 mg/kg) was associated with impaired spatial memory and suppressed neurogenesis — a critical safety signal not discussed in the abstract. No human safety or tolerability data are available.
Practice implications
This systematic review and meta-analysis establishes a preclinical proof-of-concept that AdipoRon can attenuate depressive-like, anxiolytic-like, and cognitive deficits across multiple rodent disease models, acting through adiponectin receptor-mediated pathways involving AMPK, BDNF-TrkB signaling, synaptic protein upregulation, and neuroinflammation modulation. What this study does NOT establish: (1) efficacy or safety in any human population; (2) optimal dosing — available preclinical data suggest a non-linear dose-response relationship with potential hippocampal toxicity at higher doses; (3) generalizability beyond male rodent models, as sex-specific effects of stress models have been documented; (4) pharmacokinetic parameters relevant to clinical translation. There are no registered clinical trials evaluating AdipoRon for any psychiatric or neurodegenerative indication as of the literature search cutoff (August 2025). Results apply only to preclinical rodent models and must not be used to inform current clinical practice. Practice should not change; well-designed first-in-human studies are a necessary prerequisite. Note: this summary is based solely on the abstract, as full-text data including individual study characteristics, forest plots, and heterogeneity statistics were not available for review — a critical limitation for interpreting the meta-analytic conclusions. __LIMITATIONS__ Exclusively preclinical evidence: all included studies used rodent models; no human data exist, rendering direct clinical translation premature.,Limited number of included studies with substantial heterogeneity explicitly acknowledged by the authors, undermining the robustness of pooled meta-analytic estimates.,Specific effect sizes, confidence intervals, p-values, and I² statistics are not reported in the available abstract, precluding independent critical appraisal of the quantitative synthesis.,Only abstract available for this summary; full methodological details (PRISMA flow, individual study quality scores on CAMARADES/SYRCLE, sensitivity analyses) could not be evaluated.,Forced swim test immobility and open field test anxiety metrics are behavioral surrogates with uncertain construct validity for human depression and anxiety disorders; significant debate exists as to whether FST measures 'depression-like' behavior or stress-coping strategy.,Potential publication bias: small number of studies in an emerging field with largely positive results may overestimate effect magnitude.,Dose-dependent adverse effects (high-dose hippocampal toxicity, impaired neurogenesis) are not discussed in the abstract, representing a potentially underreported safety signal.,Sex imbalance: most rodent models predominantly use male animals, limiting generalizability to female populations — who bear a disproportionate burden of depression and anxiety disorders.,Species-to-human translation gap: rodent adiponectin receptor pharmacology may differ meaningfully from human receptor biology.,Funding source not reported; cannot assess risk of sponsorship bias. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This preclinical systematic review and meta-analysis provides signal-generating evidence that AdipoRon, an oral adiponectin receptor agonist, reduces depressive-like and anxiety-like behaviors and improves recognition memory in rodent disease models via AMPK-dependent, anti-neuroinflammatory, and synaptic plasticity-promoting pathways. The findings are entirely confined to preclinical data, and the meta-analysis is limited by a small number of studies, substantial heterogeneity, and absent human safety or efficacy data. No changes to clinical practice are warranted; this work should be regarded as a hypothesis-generating foundation for future first-in-human trials.