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New Paper: Keto for Mood Disorders

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Paper: https://link.springer.com/article/10.1007/s40501-024-00322-z

Notes:

  • It is estimated that 30% of people with major depressive disorder and bipolar depression are resistant to treatment

Intro Reel:

A new paper was published by Dr. Chris Palmer this week looking at the available evidence on keto for mood disorders. This paper proposes 4 primary biological mechanisms that are known to contribute to mood disorders:

  • Mitochondrial dysfunction
  • Inflammatory pathways
  • Oxidative stress
  • Insulin resistance

All of which we the paper provides evidence for keto being able to address.

The paper then goes on to highlights 6 case studies and 2 clinical trials for Bipolar disease and 2 case studies, 1 case report, and 3 clinical studies on major depression, all showing evidence that the low carb/keto dieting and being in ketosis can provide benefit.

All in all, the evidence presented in this paper is really compelling and definitely tells us that we should be at the very least considering keto as a piece in the holistic mental health care puzzle.

When I was reading this paper, one of the things I noticed is that the individual case studies showed much more impressive results than the clinical trials. I also noticed that in the clinical trials a lot of different appraoches were being taken. Some using keto, others using exogenous ketones, and some just simply focusing on carbohydrate restriction, each showing various degrees of success in the study participants. What this tells me is that: 1. its likely that using the keto diet for mental health disorders will require some personalization for each individual using it which is consistent with what see with keto in general

and 2. We should expect to see varying results in clinical trials that can’t always offer a personalized approach.

Other Content

There is converging evidence for energy dysregulation in mood disorders [19, 20]. Studies using brain 31P magnetic resonance spectroscopy have identified abnormalities related to redox regulation and bioenergetics, including NAD + /NADH imbalance [19] and decreased generation of ATP with energy demand

  • keto can enhance mitochondrial biogenesis and function by increasing the expression of genes involved in energy metabolism
  • Studies by Veech and colleagues have shown an improvement in mitochondrial function with the ketogenic diet [24, 25]. Furthermore, the ketogenic diet can reduce oxidative stress and inflammation, further supporting mitochondrial function and overall cellular resilience [22, 26, 27].

Inflammation & Mood Disorders

  • Inflammatory markers associaed with mood disorders
    • TNF-alpha
    • C-reactive protein
    • IL-1, 2,6,10
  • The ketogenic diet has been associated with significant reductions in inflammatory biomarkers. A meta-analysis by Masood et al. highlighted the diet's efficacy in reducing C-reactive protein, a key marker of inflammation, across several studies, suggesting a systemic anti-inflammatory effect. Another meta-analysis by Li et al. of 44 randomized, controlled trials found that adherence to a ketogenic diet can improve inflammatory biomarkers, including TNF-α and IL-6 [33, 34].

People with BD face a threefold higher risk of diabetes compared to the general population

Studies to Highlight:

Reports indicate improvements in mood, energy, sleep, mental clarity, and affective stability associated with the adoption of low-carbohydrate and ketogenic diets in individuals with type 2 diabetes and obesity [56].

Carousel: Keto For Bipolar Disorder Case Reports

Several case reports and case series suggest that the ketogenic diet may play a role in the treatment of bipolar disorder.

One was of a 27-year-old male diagnosed with bipolar affective disorder with rapid cycling who was treated with ketogenic diet therapy for 2 years in addition to pharmacotherapy after no response to depressive symptoms in 4 years of pharmacotherapy [57]. After the first year of treatment, the patient's mood improved and stabilized, cognitive functions and concentration improved and anxiety disappeared. In the second year of treatment, the beneficial effects continued. The patient experienced complete remission of his chronic depression, even with a reduction in pharmacologic treatment [57].

Another case report was a 69-year-old woman with bipolar II symptoms who started a ketogenic diet. After two years on the diet, the patient noticed a decrease in her anxiety, anger attacks and depressive symptoms [58]. Another patient in the same case report was a 30-year-old woman with type II bipolar illness. After experiencing the side effects of multiple medications, she started using the ketogenic diet. She reported experiencing mood-stabilizing effects after treatment [58].

In another case report, a 33-year-old single man diagnosed with schizoaffective disorder showed persistent positive and negative symptoms despite multiple drug trials. Over the course of a year, he predominantly adhered to a ketogenic diet and noted a decrease in both types of symptoms. Throughout the diet, his functionality notably improved [59]. The second case was of a 31-year-old woman with a psychiatric history encompassing major depression and anorexia nervosa, ultimately diagnosed with schizoaffective disorder. Despite undergoing electroconvulsive therapy and numerous drug trials, her positive and negative symptoms persisted. By the fourth month of adhering to the ketogenic diet, she experienced a reduction in both types of symptoms [59].

In another case study [60], a 60-year-old woman diagnosed with type 1 bipolar disorder started a ketogenic diet for treatment-resistant mood and psychotic symptoms. She experienced significant improvement in mood and anxiety symptoms [60].

In another case, a 49-year-old woman with a history of early-onset, treatment-resistant bipolar disorder had been managed with various mood stabilizers and neuroleptic medications. Alongside antipsychotic treatment, the patient followed two distinct ketogenic diets. However, there was no discernible clinical improvement, weight loss or urinary ketosis noted during this time. Although this case report suggested that the ketogenic diet failed to improve her symptoms, she never achieved urinary ketosis, implying that she never fully complied with the treatment [61].

A larger case series included 31 adults with treatment-resistant major depressive disorder, bipolar disorder, and schizoaffective disorder. They were prescribed a ketogenic diet [62]. Twenty-eight patients were able to adhere to the diet. Overall, all of the patients adherent to the diet experienced at least some improvement in symptoms, with 43% of the patients achieving clinical remission of illness [62]. In addition, 10 patients diagnosed with schizoaffective disorder reported improvement in positive and negative symptoms [62].

Carousel: Keto for Depression Case Studies

As detailed in a case study, a 65-year-old female diagnosed T2DM and major depressive disorder engaged in a 12-week ketogenic diet regimen [72]. Following the intervention, notable improvements were evident across both physiological and psychological realms. Alongside reductions in HbA1C and blood glucose levels, the patient reported amelioration of depressive symptoms and enhanced adherence to diabetes management. Notably, after the 12-week period, medication usage decreased by 75%. Moreover, the patient experienced heightened self-assurance, increased self-efficacy, elevated energy levels, enhanced sleep quality, and greater bodily stability [72].

In another case report, a 21-year-old female with obesity, a mood disorder, and comorbid conditions including emotion dysregulation, body dysmorphic disorder, and an eating disorder, underwent a 4-week ketogenic diet. Following the 4-week dietary regimen, notable improvements were observed, including stabilized mood, decreased anxiety, and normalization of the circadian rhythm. Additionally, the patient reported the absence of suicidal thoughts, alongside recorded weight loss [73].

In a study of individuals with chronic epilepsy, a retrospective survey was carried out among those who adhered to the Modified Atkins Diet (MAD) for a minimum of 1 month and up to 2 years. The MAD involves restricting net carbohydrates to 20 g per day while permitting high fat and unlimited protein intake [74]. Consequently, a reduction in depressive and anxiety symptoms was noted among the participants, with this decrease directly correlating with the duration of the diet. Additionally, it was observed that some individuals who did not experience a reduction in seizures opted to continue the diet due to the observed improvement in their mood and anxiety. Notably, changes in seizure frequency did not exhibit a significant correlation with alterations in measures of depression or anxiety severity. This implies that the noted improvement cannot solely be attributed to a decrease in seizures [74].

Can Exogenous Ketones help with Depression?

In another randomized, controlled trial, overweight or obese adults participated in a 6-week controlled feeding intervention involving hypocaloric diets, which comprised approximately 75% of their energy expenditure. The KD groups were divided into two: the first group received ketone salt (KD + KS; n = 12) twice daily, while the second group received a mineral-free, flavor-matched placebo (KD + PL; n = 13) [76]. Additionally, a third group of age- and BMI-matched adults was subsequently assigned to the isoenergetic low-fat diet (LFD; n = 12) for comparison with the KD. Mood assessments were conducted using the abbreviated Profile of Mood States and Visual Analog Mood Scale questionnaires. A noteworthy interaction between diet and time was observed regarding depression scores. Specifically, the results indicated that the KD + PL group exhibited higher depression scores compared to the KD + KS group at week 2. While there was a non-significant increase in depression scores for the LFD group at week 4, it's important to note that throughout the study, the KD + KS group consistently demonstrated lower depression scores compared to the other groups [76••].