The potential effect of metformin on cognitive and other symptom dimensions in patients with schizophrenia and antipsychotic-induced weight gain: a systematic review, meta-analysis, and meta-regression

Battini, Vera; Cirnigliaro, Giovanna; Leuzzi, Rodolfo; Rissotto, Eleonora; Mosini, Giulia; Benatti, Beatrice; Pozzi, Marco; Nobile, Maria; Radice, Sonia; Carnovale, Carla; Dell’Osso, Bernardo; Clementi, Emilio

doi:10.3389/fpsyt.2023.1215807

Cited by 9 publications

(6 citation statements)

References 85 publications

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“…This implies a potential overlap in therapeutic targets between schizophrenia and T2DM, which could lead to a reassessment of treatment strategies for these patients. Previous randomised-controlled trials (RCTs) confirmed the efficacy of metformin in contrasting antipsychotic-induced metabolic side effects in individuals with psychoses (Agarwal et al, 2021;de Silva et al, 2016), while improving psychiatric and cognitive symptoms in the same population (Battini et al, 2023). Another finding of this study was the identification of significant colocalisation signals.…”

Section: Discussionsupporting

confidence: 67%

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions

Fanelli,

Franke,

Fabbri

et al. 2024

Preprint

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The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such asSLC39A8andHLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

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Section: Discussionsupporting

confidence: 67%

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions

Fanelli,

Franke,

Fabbri

et al. 2024

Preprint

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“…This study once again provided compelling clinical evidence for the efficacy of metformin in reducing prolactin. Additionally, clinical evidence suggests that metformin, while improving antipsychotic-induced metabolic syndrome in patients with schizophrenia, also has a role in improving psychiatric and cognitive symptoms ( 38 ). This indicates that the benefits of metformin for patients may be multidimensional and worth exploring further.…”

Section: Discussionmentioning

confidence: 99%

Treatment of antipsychotic-induced hyperprolactinemia: an umbrella review of systematic reviews and meta-analyses

Jiang,

Li,

Zhao

et al. 2024

Front. Psychiatry

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BackgroundHyperprolactinemia is a common antipsychotic-induced adverse event in psychiatric patients, and the quality of clinical studies investigating the best treatments has varied. Thus, to better summarize the clinical evidence, we performed an umbrella review of overlapping systematic reviews and meta-analyses for the treatment of antipsychotic-induced hyperprolactinemia.MethodsThe PubMed, Cochrane Library, PsycINFO, Scopus and EMBASE were searched, and reviews and meta-analyses meeting our inclusion criteria were selected. Relevant data were extracted, and an umbrella review was conducted of all included meta-analyses. The quality of included meta-analyses was assessed by using PRISMA scores and AMSTAR 2 quality evaluation. Finally, the clinical evidence for appropriate treatments was summarized and discussed.ResultsFive meta-analyses published between 2013 and 2020 met the requirements for inclusion in this umbrella review. The PRISMA scores of the included meta-analyses ranged from 19.5–26. AMSTAR 2 quality evaluation showed that 2 of the 5 included meta-analyses were of low quality and 3 were of very low quality. The included meta-analyses provide clinical evidence that adding aripiprazole or a dopamine agonist can effectively and safely improve antipsychotic-induced hyperprolactinemia. Two meta-analyses also showed that adjunctive metformin can reduce serum prolactin level, but more clinical trials are needed to confirm this finding.ConclusionAdjunctive dopamine agonists have been proven to be effective and safe for the treatment of antipsychotic-induced hyperprolactinemia. Among the researched treatments, adding aripiprazole may be the most appropriate.

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“…Another meta-analysis suggests that metformin may enhance cognitive function in diabetic patients, potentially treating mild cognitive impairment and Alzheimer's disease, although its use for dementia prevention in older non-diabetic adults is not currently recommended, according to the study [193].…”

Section: The Winding Path From Neuroprotective Mechanisms To Proving ...mentioning

confidence: 99%

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

Isop,

Neculau,

Necula

et al. 2023

Pharmaceuticals

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Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer’s, Parkinson’s, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin’s mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as “metformin”, “neuroprotection”, and “neurodegenerative diseases”, with data up to September 2023. Recent research on metformin’s glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1–AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions.

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The potential effect of metformin on cognitive and other symptom dimensions in patients with schizophrenia and antipsychotic-induced weight gain: a systematic review, meta-analysis, and meta-regression

Cited by 9 publications

References 85 publications

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions

Treatment of antipsychotic-induced hyperprolactinemia: an umbrella review of systematic reviews and meta-analyses

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

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