Loots et al (2021) note that psychiatric disorders comprise 13% of the total global disease burden, with non-adherence to medication ranging from 63–74% in patients with schizophrenia and some 50% in patients with bipolar disorder (BD). And whereas around one third of those with BD respond to mood stabilisers, almost half of those for whom medication interventions provide relief initially, ‘continue to experience recurrent mood episodes despite continuing treatment’, with Ede (2024) asking whether such patients are failing treatment, or whether treatment is failing them.
In addressing this question, one element worth considering is the role of metabolism in individuals with BD. In a Cochrane Review, Tully et al (2018) reported that, compared with the general population, individuals with BD are more often overweight or obese. Obesity can contribute to diabetes, hypertension, metabolic syndrome, cardiovascular disease and coronary heart disease; and ‘cardiovascular disease is the leading cause of premature death in BD, occurring a decade or more earlier, on average, than in the general population.’
One outcome of considering mental health disorders as disorders of metabolism is an increasing focus on the benefits conferred by a ketogenic diet (KD). KDs are very-low-carbohydrate, moderate-protein, high-fat diets, which were originally devised in 1921 to treat children with epilepsy, and which stimulate the body to burn fat, turning some of the fat into ketones, which provide energy for the brain (Ede, 2024).
In a recent review, Yu et al (2023) cite evidence supporting the idea ‘that BD may have roots of metabolic dysfunction: cerebral glucose hypometabolism, oxidative stress, as well as mitochondrial and neurotransmitter dysfunction … [and] … Preliminary data support further testing of a low carbohydrate KD as a potential therapeutic tool in repairing energy metabolism in bipolar illness.’
Evidence of the value of further testing of a KD in BD was adduced by Needham et al (2023), whose elegant pilot study is one of the first to explore the feasibility and safety of a KD in people with BD.' Of 27 recruited euthymic individuals with BD, 26 began and 20 completed a modified KD for 6-8 weeks, and the pilot study results indicate that the ‘intervention was feasible, with high completion rates for outcome measures’ (Needham et al, 2023).
As to the possible metabolic mechanisms involved in BD, Campbell and Campbell (2024) suggest a metabolic overdrive hypothesis in bipolar mania. Noting that metabolic dysfunction is characterised by abnormal glucose metabolism, mitochondrial dysfunction, and insulin resistance - all important features in the pathophysiology of BD - they suggest that in BD, impaired insulin signalling may be a contributing factor to a chronic form of disrupted energy production culminating in mitochondrial dysfunction. Such metabolic disruptions, Campbell and Campbell (2024) suggest, ‘act as a form of mild but persistent brain trauma occurring over long periods of time.’
The authors further note that epilepsy research has focused on glutamate metabolism, and that the altered dynamics of glutamate metabolism and glycolysis – the release of energy by the breakdown of glucose into two three-carbon molecules called pyruvates – in both epilepsy and BD ‘display cyclic or episodic occurrence and may provide insight into mechanisms relevant to BD’ (Campbell and Campbell, 2024).
In BD, glycolysis is induced by an energy deficit arising from a chronic impairment of oxidative glucose metabolism, with Campbell and Campbell (2024) proposing that this state leads to an oscillation between brain hypometabolism and hyperglycolysis over a long timescale. Further, they ‘have noted that mania is a secondary outcome in both traumatic brain injury and epilepsy and that it appears to occur during periods of energy crisis characterised by increased brain glutamate and glycolysis.’
Finally, it is significant that under ‘competing interests’ the first author states: ‘Dr Iain H Campbell has a diagnosis of Bipolar Disorder Type 2 and follows a seizure control type Ketogenic Diet’ (Campbell and Campbell, 2024). Given the medication-related challenges of non-adherence and inconsistency of effectiveness cited by Loots et al (2021) it warrants attention when Dr Campbell – a leading researcher in metabolic psychiatry – states that he has been in ketosis for some 7 years, and that ketosis ‘promotes stable energy in the brain while reducing hyperexcitability and protecting neurons from damage.
‘If you were to design a treatment for BD it would be hard to think of a better combination of effects’ (Ede, 2024: 150).