Table 1 Biological Similarities of Hibernation/Torpor and Bipolar Disorder.

Metabolic

Glucose

Downregulation of glucose metabolism [130]. Downregulation of glycolytic enzymes [131]

Impaired peripheral glucose metabolism [132].

Altered cerebral glucose metabolism [133].

Metabolic Rate

Reduced, often exceeding 85% suppression [134].

Reduced cerebral metabolic rate in depression. Increased in mania [135].

Significantly reduced physical activity in depression and increased activity in mania [136].

PI3K/AKT Insulin Signalling

Downregulated PI3K/AKT pathway. Reduced phosphorylation of AKT [78] and GSK3 [137].

Impaired components of insulin signalling. Notably the phosphatidylinositol cycle [70], AKT [93] and GSK3 [138] which are targets of Lithium [70].

Insulin Resistance

Induced adaptively in peripheral tissues to direct glucose to essential biological functions [130].

More than 50% of bipolar patients have measurable insulin resistance (IR) [102].

IR is associated with rapid cycling and worse clinical outcomes and treatment response [57].

Indications of insulin sensitising medication metformin as therapeutic in bipolar disorder [102].

Ketone Bodies (e.g., β- hydroxybutyrate)

Increased lipid metabolism in hibernation as adipose tissue is utilised for fuel and glucose metabolism is supressed. Elevated levels of β-hydroxybutyrate [28].

Preliminary indications of a therapeutic effect of ketosis on metabolic and mental health outcomes bipolar disorder [114, 115, 117, 118].

AMPK

Downregulates metabolic processes in hibernation through interaction with AMPK/PGC-1α/PPAR-α axis [122].

AMPK activators rescue hyperexcitability in neurons from bipolar disorder patients [78].

Sirtuins

Associated with metabolic and cellular protective mechanisms in torpor [139].

Associated with mood disorders and regulation of circadian rhythm [140].

SIRT1, 2 and 6 mRNA levels reduced in bipolar depression [141].

mTOR

Supressed mTOR signalling during torpor [91].

mTOR hypoactivity associated with cognitive impairments in bipolar disorder [93].

Hormonal

Cortisol

Increased cortisol during hibernation/torpor contributing to reduced metabolic signalling via AMPK [122].

Increased level of cortisol and HPA axis dysfunction [142].

Dysregulated diurnal cortisol pattern [143].

Melatonin

Supressed plasma melatonin rhythm during hibernation [38, 39].

Supressed melatonin rhythm in bipolar disorder [144].

Insulin

Increased levels in hyperphagia in preparation for hibernation [145].

>50% of bipolar patients insulin resistant (IR) [102].

Thyroid Hormones (T3, T4)

Reduced levels to lower metabolic rate [146].

Altered thyroid hormone levels in bipolar disorder [147].

Immune System and Inflammation

Immune System

Suppressed immune function, reduction in all circulating leukocytes during hibernation.

Reactivation upon arousal [124].

Immune dysfunction. Reduction in circulating leukocytes [148].

IL-6

Elevated in arousal, reduced in hibernation/torpor [149].

Elevated in mania vs depression [150].

TNF-α

Elevated in arousal, reduced in hibernation/torpor [151].

Elevated in mania vs depression [152].

Circadian Rhythm

Circadian Rhythm

Suppression of circadian systems and extended periods of inactivity during hibernation [153].

Short periods of arousal from torpor later in the day.

Dysfunction of circadian systems and extended periods of inactivity during depression [154].

Eveningness chronotype and delayed sleep phase syndrome are common with waking hours later in the day [154, 155].

Clock Gene Expression

Altered expression of circadian clock genes to support extended inactivity [26].

Altered expression of clock genes [34, 156].

Activity

Psychomotor Activity

Complete or substantial reduction in activity to conserve energy [134].

Reduced activity and psychomotor retardation during depression [157, 158].