Metabolic Psychiatry – A new paradigm in the management of Mental Health disorder?

Metabolic or Nutritional Psychiatry is a relatively new term for a topic that's been studied for many decades. Recently more formalised as a psychiatric subspecialty, it focusses on identifying and treating metabolic dysfunction in order to improve mental health outcomes. Growing evidence strongly suggests an association between metabolic dysfunction in the brain and mental illness and there is a rapidly expanding field of research that examines how nutritional intervention can reduce or alleviate symptoms.  

Many mental illnesses have a higher than general population incidence of cardiovascular diagnoses/death and this was traditionally thought to be driven by factors including a higher incidence of smokers in the cohort and greater propensity for recreational drug use, as well as secondary weight gain associated with many of the anti-depressant or anti-psychotic medications and the consequence of less physical activity due to reduced energy of many mental health conditions.

Research has however demonstrated that metabolic dysfunction is present at greater than general population incidence prior to diagnosis and treatment¹, supporting the theory that metabolic dysfunction may be a driver rather than a consequence. Findings from the Swiss Re UK Disability Income Protection Claims Audit provide some evidence of this in the insured cohort, where 94% of claimants with a BMI exceeding 35 (who had been off work for 12 months or more) had either declared mood disorder or depressive symptoms at claim stage, or a pre-existing mental health diagnosis was contained within their health records.

Insulin is released from the pancreas when our blood glucose levels rise. When we eat, we release insulin to lower blood glucose levels by stimulating glucose uptake into muscle and fat cells.

Many modern diets provide a majority of daily calories from "convenience foods" containing highly processed carbohydrate³, and the increase over the years in the percentage of these in the diet is strongly associated with the rising levels of obesity globally. Processed carbohydrates release glucose more rapidly, triggering the release of more insulin to deal with the rapid spike. Eating behaviours that include regular processed carbohydrate-based snacks provide repetitive stimulation and insulin release.

Over time insulin resistance develops as a response to repeated stimulation, and higher insulin levels are needed to keep blood glucose within a normal range. Eventually, unless the diet changes, this leads to the development of insulin resistance or metabolic syndrome, and Type 2 diabetes. It's important to emphasise that hyperinsulinaemia exists in advance of hyperglycaemia, and Professor Ben Bikman, of Brigham Young University in the US, cites that "insulin resistance can be present long before a person develops Type 2 diabetes".⁴

From a medical underwriting perspective you can conclude then that finding an abnormal fasting glucose or HbA1c result from a blood panel demonstrates (outside of the rare occurrence of finding a new T1 diabetic) that the hyperinsulinaemia has been present chronically for some years. How this drives future mortality risk, through the development of diabetes or heart disease for example, is the subject of much research. Including insulin testing in an underwriting blood panel is not easy however, due to costs and lab processes, though it might well be the future test of choice when you consider the wide-spread effects of hyperinsulinaemia and insulin resistance over time, as you can see from the graphic below.

Most clinicians would agree that the root of mental health disorder is multifactorial, including genetic, chemical or environmental triggers, or indeed a combination. Chemical theories have historically focused on imbalances of neurotransmitters, leading to pharmaceutical developments for drugs to "correct the imbalance". But is this the whole story? Meta-analyses⁵ have found no categorical evidence that low serotonin, for instance, leads to depression despite this having been a long-accepted target for antidepressant medications (e.g. Prozac/Fluoxetine).

In Figure 2 below you can see the delicate balance between neurotransmitters, resulting in either neuroprotection or inflammation.

Imbalances between Gamma-aminobutyric acid (GABA) and Glutamate (2 key brain neurotransmitters) caused by inflammation and oxidative stress can have significant consequences. Glutamate has been described as a neurotoxin or excitotoxic⁶. We can see in Figure 3 the detrimental effects increased glutamate has on the brain. Does this lead to mental health disorder per se, or is it the downstream effect of a poorly functioning metabolism?

While insulin is not critical for getting glucose into the brain, it is critical for efficient metabolism of that glucose once it is in the brain cells.  However, in those that are insulin resistant, which is now the majority of adults, it becomes harder for insulin itself to cross the blood brain barrier and carry out its functions. The consequence of this is a paradoxical situation where although blood glucose and blood insulin levels are both high in metabolic dysfunction, and brain levels of glucose are high, the brain insulin level is low (see Fig 4). And as insulin is needed in the brain to efficiently metabolize glucose, this brain insulin "deficiency" leads to sluggish brain glucose metabolism (cerebral glucose hypometabolism).

Many conditions (see Table 1) are now known to be associated with insulin resistance and/or cerebral glucose hypometabolism. The research of mitochondrial health points not just to impacts in terms of cognitive functioning and mental health, but also to processes leading to the development of neurodegenerative disorders, such as Alzheimer's disease. Is it also possible that the relatively new term of "brain fog" that accompanies many mental health consultations could be explained by this?

The growth in research heralds the arrival of changes to the mainstream treatment paradigms in the field of psychiatry. The global epidemic of obesity and poor metabolic health, and its proven associations with mental health disorders, suggests that treatment of the root cause is likely to reap greater rewards than solely the pharmaceutical options currently available. Professor Shebani Sethi of Stanford University, where they've established the first specialist Metabolic Psychiatry centre globally, is researching the impact of a very low carbohydrate, or ketogenic, diet on patients with schizophrenia or bipolar disorder⁹. Small patient numbers but the early success has resulted in funding for larger scale research.

Across the water the University of Cambridge's Professor Marazziti published on the associations of metabolic syndrome with major depression¹⁰. In June 2024 the UK's Royal College of Psychiatry ran a national training event to educate psychiatrists on the clinical and research interface between metabolism and mental illness¹¹. Evidence is growing that mental ill health is very much a mitochondrial brain energy dysfunction, and that by following strategies that address this energy dysfunction and improve mitochondrial health, significant improvement may be possible. A seminal book¹² by leading Harvard psychiatrist Dr Christopher Palmer puts forward the case that mental disorders are metabolic disorders of the brain, and how many current treatments likely work by affecting brain metabolism.

For over 100 years¹³ medical specialists have managed to help young children with intractable and treatment resistant epilepsy by changing their diet. By putting them on a strict ketogenic diet, increased levels of beta hydroxybutyrate (major ketone body) used for fuel stabilized the neurons and significantly reduced the excitability and seizure activity of the brain. Somehow psychiatry was separated from neurology, but it’s the same brain with the same metabolic pathways and consequences, and considering psychiatry and mental health more biologically, and more akin to neurology in its pathophysiology is leading to many of these new breakthrough paradigms like metabolic psychiatry.

It would be remiss to talk about Metabolic Psychiatry without commenting on the support given to this field by the Baszucki Foundation¹⁴. In 2016, the founders experienced the challenges of a mental health crisis firsthand when the eldest of their four children, their son Matt, was diagnosed with bipolar disorder at age 19. After battling bipolar illness for five years, Matt achieved a full recovery from his condition using a metabolic ketogenic therapy. This heralded multimillion dollar support by way of research grants¹⁵ and the establishment of Metabolic Mind¹⁶. More than a dozen clinical trials of ketogenic therapy for serious mental illness are now completed or underway for conditions that include major depression, schizophrenia spectrum disorder, bipolar disorder, and anorexia. An example is the randomized control trial¹⁷ that involved 100 participants with schizophrenia and bipolar disorder in Queensland, Australia which will compare the outcome of a 12-week dietician led medically supervised ketogenic diet with a control following dietitian-led and medically supervised nutrition regime, aligning with the principles outlined in the Australian Guide to Healthy Eating (AGHE). A similar randomized control trial¹⁸ is being conducted at the University of Basel in Switzerland for patients suffering from major depressive disorder or bipolar depression.

Researcher and author of "Change your Diet; Change your Mind" Harvard trained psychiatrist Georgia Ede cited "The most powerful way to change brain chemistry is with food, because that's where brain chemicals come from in the first place"¹⁹. Undoubtedly brain chemistry plays a significant part in the maintenance of positive mental health. What we eat and how we eat makes a difference. As does physical activity and sufficient sleep. All these have direct effects on insulin sensitivity. The potential to reverse the rising incidence of metabolic dysfunction related mental health disorder is one that can play a significant part both for individuals but also insurers. Having the means to reverse a trend, to stay healthy, perhaps to stave off early dementia. Perhaps this read offered some contemplation as to how metabolic health interventions might support both your business and your personal health?