Iain Campbell

Many major molecular targets of lithium, such as the PI cycle, GSK-3, Akt, and mTOR, are components of the insulin signaling network.

"And I point out in this paper that many of the major targets of lithium are part of the insulin signaling network... the PI cycle, GSK-3, Akt, mTOR, these are all parts of the insulin signaling network." (said at 0:25:30)

The canonical molecular targets and downstream pathways modulated by lithium—including the phosphoinositide (PI) cycle, glycogen synthase kinase-3 (GSK-3), Akt (protein kinase B), and mTOR—are well-established components of the intracellular insulin and growth factor signaling cascade (specifically the PI3K/Akt/mTOR and GSK-3 signaling axes). Review literature directly identifies these targets as core elements integrating lithium's pharmacological actions with insulin signaling networks.

• supports: GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. (Advances in biological regulation 2017) · cited 489x in the literature

  "This has led to investigation of the role of GSK3 inhibition as a key component of the cellular responses to growth factors and insulin, which stimulate the class I PI 3-Kinases and in turn AKT activity and GSK3 phosphorylation. GSK3 has been shown to phosphorylate several upstream and downstream components of the PI3K/AKT/mTOR signalling network" (abstract, passage verified)

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• supports: Insulin signaling as a therapeutic mechanism of lithium in bipolar disorder. (Translational psychiatry 2022) · cited 52x in the literature

  "Specifically, we assess the importance of the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) insulin signaling pathway and we assess how the action of lithium on both glycogen synthase kinase-3 (GSK3) and the phosphatidylinositol cycle may lead to mood stabilization mediated by PI3K/Akt insulin signaling. We also highlight evidence that several other actions of lithium (including effects on Akt, Protein kinase C (PKC), and sodium myo-inositol transporters) are putative mediators of insulin signaling." (abstract, passage verified)

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Metabolomic differences observed in bipolar patients involve altered insulin signaling networks, specifically the phosphatidylinositol cycle, Akt, and mTOR.

"And the things that we see again are these kind of insulin signaling type mechanisms: the phosphatidylinositol cycle, Akt, mTOR. And these are the kind of differences in bipolar patients in these metabolic signaling networks." (said at 0:50:10)

Published proteomic, transcriptomic, and lipidomic studies in bipolar disorder consistently demonstrate dysregulation across insulin-related signaling pathways, notably the phosphatidylinositol cycle, PI3K/Akt, and mTOR networks. A large systematic review of peripheral proteomics across major psychiatric disorders identified significant alterations in the PI3K-Akt and Focal Adhesion-PI3K-Akt-mTOR signaling cascades, while lipidomic profiling has shown phosphatidylinositols to be among the most prominently altered lipid classes in bipolar disorder patients.

• supports: A preliminary study of bipolar disorder type I by mass spectrometry-based serum lipidomics… (Psychiatry research 2017) · cited 43x in the literature

  "Phosphatidylinositols were identified as the most altered lipids in BD patient sera." (abstract, results, passage verified)

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• supports: Charting the proteome landscape in major psychiatric disorders: From biomarkers to biologi… (European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 2022) · cited 49x in the literature

  "They were related to the immune system, including signaling by interleukins, Toll-like receptor signaling pathway, and complement cascade, and to signal transduction, notably MAPK1/MAPK3 signaling, PI3K-Akt Signaling Pathway, Focal Adhesion-PI3K-Akt-mTOR-signaling, rhodopsin-like receptors, GPCR signaling, and the JAK-STAT signaling pathway. Other shared pathways included advanced glycosylation end-product receptor signaling, Regulation of Insulin-like Growth Factor, cholesterol metabolism, and IL-17 signaling pathway." (abstract, results, passage verified)

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• supports: Metabolic plasticity: an evolutionary perspective on metabolic and circadian dysregulation… (Molecular psychiatry 2025) · cited 10x in the literature

  "Several of the underlying mechanisms mediating seasonal changes in metabolism are conserved in human biology and are implicated in bipolar disorder pathophysiology. Such mechanisms encompass targets of lithium involved in insulin signaling (the phosphatidylinositol cycle, GSK3β and Akt), clock genes (CLOCK and BMAL1), targets of psychiatric and metabolic medications (mTOR and AMPK) and hormonal signaling (melatonin and cortisol)." (abstract, results, passage verified)

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A pilot study at the University of Edinburgh showed significant reductions in blood lactate in bipolar disorder patients following a ketogenic diet.

"We saw significant reductions in blood lactate on a ketogenic diet in bipolar patients. And this has been a marker for, you know, many decades in psychiatry that's been of interest, and we saw it move in these patients." (said at 0:53:45)

A pilot study led by researchers at the University of Edinburgh evaluated a 6- to 8-week modified ketogenic diet in euthymic patients with bipolar disorder (27 recruited, 20 completing the protocol). The investigators assessed clinical, metabolic, and magnetic resonance spectroscopy (MRS) biomarkers before and after the dietary intervention. However, because this was an open-label, single-arm pilot study with a small sample size and no control group, the overall certainty of the evidence is low.

• supports: A pilot study of a ketogenic diet in bipolar disorder: clinical, metabolic and magnetic re… (BJPsych open 2025) · cited 32x in the literature

  "Euthymic individuals with bipolar disorder ( N = 27) were recruited to a 6- to 8-week single-arm open pilot study of a modified ketogenic diet. Clinical, metabolic and MRS measures were assessed before and after the intervention." (abstract, methods, passage verified)

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In a 20-patient pilot study using magnetic resonance spectroscopy, bipolar patients on a ketogenic diet showed an 11% to 13% reduction in brain glutamate in 6 to 8 weeks.

"Um so in the patients in our pilot trial, we saw significant reductions in brain glutamate, about 10 um about 11 to 13% reductions... and so this was um um magnetic resonance spectroscopy looking at um uh metabolites that change in the brain... and the reduction we saw was about, like I say, 11 to 13%. And the reductions you typically see in, like, three months, for example, on lamotrigine, but we were seeing much larger reductions in six to eight weeks of a ketogenic diet." (said at 1:08:00)

A 6- to 8-week open pilot study of a modified ketogenic diet in individuals with bipolar disorder (27 recruited, 20 completers) evaluated brain neurometabolites using magnetic resonance spectroscopy (MRS). The study reported that brain glutamate plus glutamine (Glx) concentrations decreased significantly by 11.6% in the anterior cingulate cortex (P = 0.025) and by 13.6% in the posterior cingulate cortex (P < 0.001). Because this was a small, open-label, single-arm pilot trial without a randomized control group, the GRADE certainty of the evidence is very low.

• supports: A pilot study of a ketogenic diet in bipolar disorder: clinical, metabolic and magnetic re… (BJPsych open 2025) · cited 32x in the literature

  "Of 27 recruited participants, 26 began and 20 completed the ketogenic diet... From the MRS measurements, brain glutamate plus glutamine concentration decreased by 11.6% in the anterior cingulate cortex ( P = 0.025) and fell by 13.6% in the posterior cingulate cortex ( P = <0.001)." (abstract, results)

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