Table 1.

Evidence for a model of metabolic dysregulation-mediated progression of bipolar disorder and need for future research.

Argument	Supporting Evidence		Need for Future Research
	Description of Evidence	Level of Evidence
IR/T2DM is a key underlying process affecting course of bipolar illness	Calkin et al., 2015 (reference 5): Compared to euglycemic patients, BD patients with IR or T2DM had higher odds of chronic course and rapid cycling.	Cross-sectional study, N = 121	Certain results have been inconsistent between cross-sectional studies, such as rapid cycling and lifetime number of mood episodes. There is currently a paucity of longitudinal evidence to demonstrate that the onset of IR precedes a change in the course of bipolar illness from episodic/treatment-responsive to chronic/treatment-refractory.
	Steardo et al., 2019 (reference 6): Compared to euglycemic patients, BD patients with IR or T2DM had a greater lifetime number of mood episodes and a younger onset of illness.	Cross-sectional study, N = 91
	Mansur et al., 2016 (reference 7): Compared to euglycemic patients, BD patients with IR or T2DM had a greater lifetime number of (hypo)manic episodes, a younger onset of illness and longer illness duration.	Cross-sectional study, N = 55
	Ruzickova et al., 2003 (reference 8): Compared to euglycemic patients, BD patients with T2DM had higher rates of chronic course and rapid cycling, poorer quality of life and overall functioning.	Cross-sectional study, N = 222
	Cairns et al., 2018 (reference 13): Psychiatric morbidity increased 12-fold following the onset of impaired glucose metabolism in BD patients.	Longitudinal case series, N = 6
IR/T2DM is associated with poor mood stabilizing treatment response	Calkin et al., 2015 (reference 5): Compared to euglycemic patients, BD patients with IR or T2DM were less likely to respond to lithium treatment. As IR increases, response to lithium decreases.	Cross-sectional study, N = 121	There is currently no longitudinal evidence to demonstrate a change in treatment responsiveness in BD patients who develop IR/T2DM.
	Steardo et al., 2019 (reference 6): Compared to euglycemic patients, BD patients with IR or T2DM were less likely to respond to any mood stabilizing treatment.	Cross-sectional study, N = 91
IR/T2DM is associated with brain abnormalities	Hajek et al., 2015 (reference 17): BD patients with IR or T2DM showed lower prefrontal NAA levels compared to euglycemic BD patients, who had comparable NAA levels to euglycemic, non-psychiatric controls.	Cross-sectional study, N = 59	Additional research is required in the BD population to support the suggestion that brain abnormalities found in BD may be moderated by metabolic dysregulation.
	Hajek et al., 2014 (reference 18): BD patients with IR or T2DM had significantly smaller hippocampal and regional cortical volumes compared to euglycemic BD patients, who had comparable volumes to euglycemic, non-psychiatric controls.	Cross-sectional study, N = 59
	Wu et al., 2017 (reference 19): In the general T2DM population, NAA-to-creatine ratio was found to be lower in several brain regions, including the frontal, occipital and parietal lobes, as well as the thalamus and the lenticular nucleus. In the general T2DM population, NAA levels were found to be normal in frontal lobe white matter; NAA levels in other regions were not reported.	Meta-analysis of cross-sectional studies, N = 467
	Jones et al., 2014 (reference 20); Lee et al., 2014 (reference 21): Structural neuroimaging studies have provided evidence for global brain atrophy, as well as region-specific atrophy in the hippocampus and cortex.	Reviews of neuroimaging evidence
IR/T2DM is associated with cognitive impairment	Tsai et al., 2007 (reference 22): Patients with BD and T2DM had significantly lower scores than euglycemic patients on a measure of global cognitive functioning.	Cross-sectional study, N = 82	Conflicting results have been found in studies focusing on BD patients (references 22, 23, and 24), as only one of three has identified a significant relationship between T2DM and cognitive impairment. Methodological differences may be contributing to inconsistencies between studies.
	Cheng et al., 2012 (reference 28): T2DM in the general population was associated with significantly increased relative risk for cognitive impairment (all-cause dementia or Mild Cognitive Impairment).	Meta-analysis of longitudinal studies, N = 44,714
IR is a potentially modifiable marker of progression of bipolar illness	Zeinoddini et al., 2015 (reference 84): Pioglitazone was associated with a significantly greater decrease in depressive symptoms compared to placebo during a 6-week trial in BD patients. Potential patients were excluded if they met criteria for T2DM or metabolic syndrome. Glucose levels and A1C were tested at study entry; however, insulin levels were not.	Randomized, double-blinded control trial, N = 44	Inconsistent results have been found in randomized, double-blinded control trials in BD patients. Additional high-quality trials are needed in this population.
	Kemp et al., 2014 (reference 85), NCT00835120: Pioglitazone was associated with a significant decrease in depressive symptoms during an 8-week trial in BD patients.	Open-label trial, N = 34
	Aftab et al., 2019 (reference 87), NCT01717040: Pioglitazone was not superior to placebo in reducing depressive symptoms during an 8-week trial in BD patients. Not all patients had IR at study entry (IR was defined as HOMA-IR ≥ 2.5).	Randomized, double-blinded control trial, N = 37
	Colle et al., 2017 (reference 86): In patients with either major depressive disorder or BD, pioglitazone was found to be 3.3 times more likely than placebo to lead to remission of depressive symptoms.	Meta-analysis of randomized, double-blinded control trials, N = 161

BD: bipolar disorder; HOMA-IR: Homeostatic Model Assessment – Insulin Resistance; IR: insulin resistance; NAA: N-acetyl aspartate; T2DM: type 2 diabetes mellitus..