The association of kynurenine pathway metabolites with symptom severity and clinical features of bipolar disorder: An overview

Bartoli, Francesco; Cioni, Riccardo; Cavaleri, Daniele; Callovini, Tommaso; Crocamo, Cristina; Misiak, Błażej; Savitz, Jonathan; Carrà, Giuseppe

doi:10.1192/j.eurpsy.2022.2340

Cited by 12 publications

(6 citation statements)

References 56 publications

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“…depression and mania, than by the disease itself. [68][69][70] Potential neurobiological underpinnings of predominant polarity in bipolar disorder are also a matter for future research.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and correlates of manic/hypomanic and depressive predominant polarity in bipolar disorder: systematic review and meta-analysis

Bartoli,

Bassetti,

Gazzola

et al. 2024

BJPsych open

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Background Identification of the predominant polarity, i.e. hypomanic/manic (mPP) or depressive predominant polarity (dPP), might help clinicians to improve personalised management of bipolar disorder. Aims We performed a systematic review and meta-analysis to estimate prevalence and correlates of mPP and dPP in bipolar disorder. Method The protocol was registered in the Open Science Framework Registries (https://doi.org/10.17605/OSF.IO/8S2HU). We searched main electronic databases up to December 2023 and performed random-effects meta-analyses of weighted prevalence of mPP and dPP. Odds ratios and weighted mean differences (WMDs) were used for relevant correlates. Results We included 28 studies, providing information on rates and/or correlates of mPP and dPP. We estimated similar rates of mPP (weighted prevalence = 30.0%, 95% CI: 23.1 to 37.4%) and dPP (weighted prevalence = 28.5%, 95% CI: 23.7 to 33.7%) in bipolar disorder. Younger age (WMD = −3.19, 95% CI: −5.30 to −1.08 years), male gender (odds ratio = 1.39, 95% CI: 1.10 to 1.76), bipolar-I disorder (odds ratio = 4.82, 95% CI: 2.27 to 10.24), psychotic features (odds ratio = 1.56, 95% CI: 1.01 to 2.41), earlier onset (WMD = −1.57, 95% CI: −2.88 to −0.26 years) and manic onset (odds ratio = 13.54, 95% CI: 5.83 to 31.46) were associated with mPP (P < 0.05). Depressive onset (odds ratio = 12.09, 95% CI: 6.38 to 22.90), number of mood episodes (WMD = 0.99, 95% CI: 0.28 to 1.70 episodes), history of suicide attempts (odds ratio = 2.09, 95% CI: 1.49 to 2.93) and being in a relationship (odds ratio = 1.98, 95% CI: 1.22 to 3.22) were associated with dPP (P < 0.05). No differences were estimated for other variables. Conclusions Despite some limitations, our findings support the hypothesis that predominant polarity might be a useful specifier of bipolar disorder. Evidence quality was mixed, considering effects magnitude, consistency, precision and publication bias. Different predominant polarities may identify subgroups of patients with specific clinical characteristics.

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“…depression and mania, than by the disease itself. [68][69][70] Potential neurobiological underpinnings of predominant polarity in bipolar disorder are also a matter for future research.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and correlates of manic/hypomanic and depressive predominant polarity in bipolar disorder: systematic review and meta-analysis

Bartoli,

Bassetti,

Gazzola

et al. 2024

BJPsych open

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“…Instead, a non-linear relationship was detected where deviation from midline kynurenine concentrations in either direction was associated with more extreme neurological and dementia symptoms [ 149 ]. Kynurenine metabolites have also been linked to bipolar disorder, which is a complex neurological disorder that affects approximately 2% of the population [ 150 , 151 ]. Notably, recent meta-analyses have shown there is a connection between metabolites of the kynurenine pathway and bipolar disorder, but the mechanistic and possibly causative relationship remains less well understood [ 150 , 151 ].…”

Section: The Tryptophan Pathway: Microbial-derived Metabolic Mind Con...mentioning

confidence: 99%

“…Kynurenine metabolites have also been linked to bipolar disorder, which is a complex neurological disorder that affects approximately 2% of the population [ 150 , 151 ]. Notably, recent meta-analyses have shown there is a connection between metabolites of the kynurenine pathway and bipolar disorder, but the mechanistic and possibly causative relationship remains less well understood [ 150 , 151 ]. Though the causative relationship may not yet be fully elucidated, it is nevertheless clear that metabolites stemming from the kynurenine pathway play key roles as markers of disease or perhaps even causative agents.…”

Section: The Tryptophan Pathway: Microbial-derived Metabolic Mind Con...mentioning

confidence: 99%

Microbial-Derived Tryptophan Metabolites and Their Role in Neurological Disease: Anthranilic Acid and Anthranilic Acid Derivatives

2023

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The gut microbiome provides the host access to otherwise indigestible nutrients, which are often further metabolized by the microbiome into bioactive components. The gut microbiome can also shift the balance of host-produced compounds, which may alter host health. One precursor to bioactive metabolites is the essential aromatic amino acid tryptophan. Tryptophan is mostly shunted into the kynurenine pathway but is also the primary metabolite for serotonin production and the bacterial indole pathway. Balance between tryptophan-derived bioactive metabolites is crucial for neurological homeostasis and metabolic imbalance can trigger or exacerbate neurological diseases. Alzheimer’s, depression, and schizophrenia have been linked to diverging levels of tryptophan-derived anthranilic, kynurenic, and quinolinic acid. Anthranilic acid from collective microbiome metabolism plays a complex but important role in systemic host health. Although anthranilic acid and its metabolic products are of great importance for host–microbe interaction in neurological health, literature examining the mechanistic relationships between microbial production, host regulation, and neurological diseases is scarce and at times conflicting. This narrative review provides an overview of the current understanding of anthranilic acid’s role in neurological health and disease, with particular focus on the contribution of the gut microbiome, the gut–brain axis, and the involvement of the three major tryptophan pathways.

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“…However, some of this evidence has been mixed. For instance, a more recent review found that some features of BD, such as psychotic episodes and suicide attempts, may also be associated with an imbalance in kynurenine pathway metabolism, though this finding requires replication ( Bartoli et al, 2022 ). In addition, another recent meta-analysis of eight CSF studies found no evidence of increased KA levels or differences in TRP levels associated with BD ( Inam et al, 2023 ).…”

Section: The Immune-inflammatory Systemmentioning

confidence: 99%

Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

Machado-Vieira,

Courtes,

Zarate

et al. 2023

Front. Neurosci.

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Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these episodes can vary widely between individuals, significantly impacting quality of life. Individuals with BD spend almost half their lives experiencing mood symptoms, especially depression, as well as associated clinical dimensions such as anhedonia, fatigue, suicidality, anxiety, and neurovegetative symptoms. Persistent mood symptoms have been associated with premature mortality, accelerated aging, and elevated prevalence of treatment-resistant depression. Recent efforts have expanded our understanding of the neurobiology of BD and the downstream targets that may help track clinical outcomes and drug development. However, as a polygenic disorder, the neurobiology of BD is complex and involves biological changes in several organelles and downstream targets (pre-, post-, and extra-synaptic), including mitochondrial dysfunction, oxidative stress, altered monoaminergic and glutamatergic systems, lower neurotrophic factor levels, and changes in immune-inflammatory systems. The field has thus moved toward identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction. Diverse pharmacological and non-pharmacological approaches targeting neurobiological pathways other than neurotransmission have also been tested in mood disorders. This article reviews different neurobiological targets and pathophysiological findings in non-canonical pathways in BD that may offer opportunities to support drug development and identify new, clinically relevant biological mechanisms. These include: neuroinflammation; mitochondrial function; calcium channels; oxidative stress; the glycogen synthase kinase-3 (GSK3) pathway; protein kinase C (PKC); brain-derived neurotrophic factor (BDNF); histone deacetylase (HDAC); and the purinergic signaling pathway.

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The association of kynurenine pathway metabolites with symptom severity and clinical features of bipolar disorder: An overview

Abstract: This peer-reviewed article has been accepted for publication but not yet copyedited or typeset, and so may be subject to change during the production process. The article is considered published and may be cited using its DOI.

Cited by 12 publications

References 56 publications

Prevalence and correlates of manic/hypomanic and depressive predominant polarity in bipolar disorder: systematic review and meta-analysis

Prevalence and correlates of manic/hypomanic and depressive predominant polarity in bipolar disorder: systematic review and meta-analysis

Microbial-Derived Tryptophan Metabolites and Their Role in Neurological Disease: Anthranilic Acid and Anthranilic Acid Derivatives

Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

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