The metabolic overdrive hypothesis: hyperglycolysis and glutaminolysis in bipolar mania.

Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature of bipolar disorder pathophysiology. In this paper, we propose that mania represents a condition of heightened cerebral energy metabolism facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Glycolysis in astrocytes fuels the formation of denovo glutamate, which can be used as a mitochondrial fuel source in neurons via transamination to alpha-ketoglutarate and subsequent reductive carboxylation to replenish tricarboxylic acid cycle intermediates. Upregulation of glycolysis and glutaminolysis in this manner causes the brain to enter a state of heightened metabolism and excitatory activity which we propose to underlie the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, when recruited in the long term to counteract impaired oxidative metabolism it may become a pathological process. In this article, we develop these ideas in detail, present supporting evidence and propose this as a novel avenue of investigation to understand the biological basis for mania.

Investigating light sensitivity in bipolar disorder (HELIOS-BD).

Many people with bipolar disorder have disrupted circadian rhythms. This means that the timing of sleep and wake activities becomes out-of-sync with the standard 24-hour cycle. Circadian rhythms are strongly influenced by light levels and previous research suggests that people with bipolar disorder might have a heightened sensitivity to light, causing more circadian rhythm disruption, increasing the potential for triggering a mood switch into mania or depression. Lithium has been in clinical use for over 70 years and is acknowledged to be the most effective long-term treatment for bipolar disorder. Lithium has many reported actions in the body but the precise mechanism of action in bipolar disorder remains an active area of research. Central to this project is recent evidence that lithium may work by stabilising circadian rhythms of mood, cognition and rest/activity. Our primary hypothesis is that people with bipolar disorder have some pathophysiological change at the level of the retina which makes them hypersensitive to the visual and non-visual effects of light, and therefore more susceptible to circadian rhythm dysfunction. We additionally hypothesise that the mood-stabilising medication lithium is effective in bipolar disorder because it reduces this hypersensitivity, making individuals less vulnerable to light-induced circadian disruption. We will recruit 180 participants into the HELIOS-BD study. Over an 18-month period, we will assess visual and non-visual responses to light, as well as retinal microstructure, in people with bipolar disorder compared to healthy controls. Further, we will assess whether individuals with bipolar disorder who are being treated with lithium have less pronounced light responses and attenuated retinal changes compared to individuals with bipolar disorder not being treated with lithium. This study represents a comprehensive investigation of visual and non-visual light responses in a large bipolar disorder population, with great translational potential for patient stratification and treatment innovation.

Pilot study of a ketogenic diet in bipolar disorder.

BACKGROUND: Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. However, no clinical trials have been conducted to date. AIMS: To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder. METHOD: Euthymic individuals with bipolar disorder were recruited to a 6-8 week trial of a modified ketogenic diet, and a range of clinical, economic and functional outcome measures were assessed. Study registration number: ISRCTN61613198. RESULTS: Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet for 6-8 weeks. The outcomes data-set was 95% complete for daily ketone measures, 95% complete for daily glucose measures and 95% complete for daily ecological momentary assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (s.d. = 0.77, median = 1.1) during the intervention period, and 91% of all readings indicated ketosis, suggesting a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range, with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication). CONCLUSIONS: The recruitment and retention of euthymic individuals with bipolar disorder to a 6-8 week ketogenic diet intervention was feasible, with high completion rates for outcome measures. The majority of participants reached and maintained ketosis, and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.

Insulin signaling as a therapeutic mechanism of lithium in bipolar disorder.

In this paper, we propose that lithium may exert its therapeutic effect in bipolar disorder by acting on insulin signaling pathways. Specifically, we assess the importance of the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) insulin signaling pathway and we assess how the action of lithium on both glycogen synthase kinase-3 (GSK3) and the phosphatidylinositol cycle may lead to mood stabilization mediated by PI3K/Akt insulin signaling. We also highlight evidence that several other actions of lithium (including effects on Akt, Protein kinase C (PKC), and sodium myo-inositol transporters) are putative mediators of insulin signaling. This novel mode of action of lithium is consistent with an emerging consensus that energy dysregulation represents a core deficit in bipolar disorder. It may also provide context for the significant co-morbidity between bipolar disorder, type 2 diabetes, and other forms of metabolic illness characterized by impaired glucose metabolism. It is suggested that developments in assessing neuronal insulin signaling using extracellular vesicles would allow for this hypothesis to be tested in bipolar disorder patients.

Analysis of public engagement with ten major global health topics on a social network profile and a newspaper website.

BACKGROUND: Efforts in global health and development have broad political support and substantial financial commitment from most governments. However, this support could be greater if global health issues featured more prominently in the public debate. It has proven quite difficult to make global health issues attractive for viewing and engaging with, as compared to other forms of entertainment or public debates in the media. METHODS: Within the Massive Open Online Course "Survival: The Story of Global Health", we created 10 educational videos on major global health topics. Between August 1 and September 30, 2017, we posted each episode with a brief background text on the Facebook profile of the narrator, who had an average of 450 friends and further 800 followers throughout the period of study. We studied the interaction of Facebook friends and followers with each posted video, tracing the number of their "likes", "shares" and "comments". Moreover, a popular Croatian online newspaper portal with about 250 000 daily viewers shared three of these stories after they were posted on Facebook and views, shares and comments were monitored. We recorded the effect on the number of YouTube views of the featured videos. RESULTS: The 10 posts received between 65 and 274 "likes" on the Facebook profile and between 2 and 124 shares, receiving between 0 and 17 comments. The three episodes that were shared by the online newspaper portal were further shared between 164 and 2820 times, receiving between 8 and 111 comments from the general public. The effect of these two promotion channels on YouTube viewership resulted in between 107 and 9784 views of the 10 featured videos, with the number of "likes" received on YouTube ranging between 0 and 43. The video that raised the most attention and shares was the one on the history of pandemics, which also had the highest number of shares on YouTube (n=69), followed by the video on human evolution (n = 14). Topics of non-communicable diseases, ageing and dying, and the future of humanity were also popular, while the topics more specific to global health raised less interest - ie, maternal and child mortality, major infectious diseases, international organizations, inequality and equity, and the UN Millennium Development Goals. CONCLUSION: Our study showed that the interest in "core" global health topics was, as a rule, lower than in the topics which have a more general appeal - such as pandemic threat, human origins, ageing and dying. If we aim to increase public interest in global health topics, a feasible strategy would be to adjust the language and presentation used to be of more appeal to popular culture. Linking promotional materials to other popular topics that are dominating the public debate or capturing their interest could prove to be a successful strategy to achieve this.

A systematic analysis of online public engagement with 10 videos on major global health topics involving 229 459 global online viewers.

BACKGROUND: Online interest in issues specific to global health outside of times of pandemics or other crises is rather limited. To achieve long term global health goals, public support and engagement needs to be fostered on a continual basis. Strategies for capturing the attention of the general public online for the persisting problems outside of emergency situations are poorly defined. There are only a few isolated examples of success. In this study we explored the engagement of the viewers with different global health topics that were provided on public and privately advertised YouTube channels. METHODS: We developed the Massive Open Online Course "Survival: The Story of Global Health", consisting of 10 educational videos on major global health topics. We conducted two experiments in two separate samples of viewers. The first was based on posting videos on a YouTube channel between August 30 and September 30, 2017 and collecting analytics on the viewership. By June 30, 2019 this approach attracted 41 305 viewers. The second experiment was more controlled and conducted on a private YouTube channel and the videos were advertised to reach a high number of viewers. This attracted 188 154 viewers and we collected data on viewers' behaviour using YouTube Analytics. We investigated the nature of engagement, which was defined by 22 different parameters. RESULTS: In the first experiment, there were clear differences in all measured parameters of engagement based on the topic of the video. Episodes on pandemics (14 594 views) and human evolution (10 761 views) were clear outliers, while the remaining 8 episodes received between 1110 and 3197 views. In the second experiment, there were several clear differences between the 10 videos in the parameters analysed through YouTube Analytics. Episode 2 on maternal and child health had the highest view rate (18.90%), followed by Episode 7 on international organisations in global health (16.83%). At the bottom of the rank were Episode 6 on ageing and dying (view rate of 13.83%) and Episode 5 on non-communicable diseases (view rate 14.59%). CONCLUSIONS: We determined that 5 main interdependent factors contributed to the success or failure of our global health videos: Responsive content, timing, contribution to public debate, emotional valency and endorsement from an authentic scientific voice with a strong public profile. Several of these factors are also recognised as important in marketing research which may indicate the value of such techniques for use in a global health context. In order to communicate long term sustainable solutions to complex issues in a capricious media landscape focused on transient issues the global health community needs to embrace novel marketing approaches.

Effective approaches to public engagement with global health topics.

BACKGROUND: "Public engagement" in science is a term that covers a broad spectrum of activities undertaken by the scientific community. The precise definitions are constantly evolving to incorporate new means of engagement, facilitated by emerging technologies. Global health research is amenable to community engagement and popularization, but it is difficult to know which strategies work best to attract considerable attention from the public. METHODS: This is a review of the articles and documents that address the question of public engagement with topics in medical sciences, particularly in global health. Semantic searches were conducted using Google Scholar rather than indexed databases due to poor indexing of the topic. More than 1000 titles were screened and 48 articles were retained as most useful. It then moves to a more specific topic of the online public engagement in global health. RESULTS: The review presents the attempts to define public engagement in science and its general importance, particularly in the field of global health. Examples of the latter include tobacco use, vaccination, and maternal and child health. In reviewing effective approaches to public engagement in global health through online video campaigns, it studies the examples of crowdfunding, USAID's First Public Engagement Campaign, World Health Organization's Social Media Campaigns and the impact of Global Health Media Project. CONCLUSIONS: This review reveals three key gaps in the understanding of determinants of effective online public engagement in global health. The mixed results of traditional mass media campaigns in global health emphasise the calls for more research on message content. A framework for effective message content would help in both raising awareness of key issues and creating behaviour change in the general public. Moreover, it is surprising to find no formal research on what constitutes effective video content in global health. Finally, few studies considered important metrics to track in social media campaigns. There is a clear need to investigate which video features are effective in global health online public engagement. Success will be defined through key video marketing metrics and tracked in order to isolate effective content features.

Helping global health topics go viral online.

To maintain support for further investments into health research and prevent large groups of people from questioning modern science, researchers will increasingly need to master their communication of scientific progress in the 21st century to broad general population. The new generations, who inform and educate themselves online, prefer to make their own choices in what they view. This makes them vulnerable to many types of online misinformation, which is placed there mainly to attract their clicks. This evolving context could strongly undermine a consensus in the population over very important public health issues and gains. Therefore, we believe that it deserves to be recognised as a serious problem of our time that needs to be addressed. In addition to possible inaccuracies of the health information found online, the other component of the problem is how to make global public health topics and issues attractive for viewing online and engaging with. They need to compete with popular music, celebrity gossip, sports, movies and other forms of entertainment. In this issue, we bring a novel series aiming to explore effective strategies to promoting global health issues online and through other mass media, and reaching wide audiences.

Ketosis and bipolar disorder: controlled analytic study of online reports.

BACKGROUND: Members of online bipolar disorder forums often report experiences of mood-stabilisation on the ketogenic diet, which has traditionally been used in the treatment of epilepsy. We examined the nature and extent of such reports. AIMS: To investigate associations between a ketogenic diet and mood stabilisation among individuals with bipolar disorder. METHOD: We undertook an observational analytic study of free-text comments in online forums about mood effects of dietary interventions (ketogenic, omega-3 enriched or vegetarian) classified by a priori categories of change in mood stabilisation in 274 people with bipolar disorder. RESULTS: There were 141 (85.5%) free-text comments on ketogenic diets that reported a positive impact on mood stabilisation. Reports of significant mood stabilisation or remission of symptoms over a period were substantially higher for a ketogenic diet than for other diets (93/165, 56.4%, 95% CI 48.4-64.1) v. 14/94, 14.9%, 95% CI 8.4-23.7), odds ratio 7.4, 95% CI 3.8-14.1, P < 0.0001), many with detailed reports of the improvements experienced and several lasting for extended periods (months to years). Other reported associations included fewer episodes of depression (in 41.2%, 95% CI 30.6-52.4 of individuals); improved clarity of thought and speech (28.2%, 95% CI 19.0-39.0); increased energy (25.9, 95% CI 17.0-36.5); and weight loss (25.9%, 95% CI 17.0-36.5). CONCLUSIONS: Despite the inherent limitations of the observational data based on self-reports posted online, the association strength and reports of sustained benefit support a hypothesis of a ketogenic diet being associated with beneficial effects on mood stabilisation. Caution should be exercised in interpreting this data until a controlled trial can be carried out to examine this hypothesis. These preliminary observations are generally consistent with a mitochondrial dysfunction component to bipolar disorder aetiology with ketones bypassing a block between glycolysis and the tricarboxylic acid cycle. DECLARATION OF INTEREST: None.