Metabolic Insights into Neuropsychiatric Illnesses and Ketogenic Therapies: A Transcriptomic View.

The disruption of brain energy metabolism, leading to alterations in synaptic signaling, neural circuitry, and neuroplasticity, has been implicated in severe mental illnesses such as schizophrenia, bipolar disorder, and major depressive disorder. The therapeutic potential of ketogenic interventions in these disorders suggests a link between metabolic disturbances and disease pathology; however, the precise mechanisms underlying these metabolic disturbances, and the therapeutic effects of metabolic ketogenic therapy, remain poorly understood. In this study, we conducted an in silico analysis of transcriptomic data to investigate perturbations in metabolic pathways in the brain across severe mental illnesses via gene expression profiling. We also examined dysregulation of the same pathways in rodent or cell culture models of ketosis, comparing these expression profiles to those observed in the disease states. Our analysis revealed significant perturbations across all metabolic pathways, with the greatest perturbations in glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC) across all three disorders. Additionally, we observed some discordant gene expression patterns between disease states and ketogenic intervention studies, suggesting a potential role for ketone bodies in modulating pathogenic metabolic changes. Our findings highlight the importance of understanding metabolic dysregulation in severe mental illnesses and the potential therapeutic benefits of ketogenic interventions in restoring metabolic homeostasis. This study provides insights into the complex relationship between metabolism and neuropsychiatric disorders and lays the foundation for further experimental investigations aimed at appreciating the implications of the present transcriptomic findings as well as developing targeted therapeutic strategies.

The Potential Effects of the Ketogenic Diet in the Prevention and Co-Treatment of Stress, Anxiety, Depression, Schizophrenia, and Bipolar Disorder: From the Basic Research to the Clinical Practice.

BACKGROUND: The ketogenic diet (KD) has been highly developed in the past for the treatment of epileptic pathological states in children and adults. Recently, the current re-emergence in its popularity mainly focuses on the therapy of cardiometabolic diseases. The KD can also have anti-inflammatory and neuroprotective activities which may be applied to the prevention and/or co-treatment of a diverse range of psychiatric disorders. PURPOSE: This is a comprehensive literature review that intends to critically collect and scrutinize the pre-existing research basis and clinical data of the potential advantageous impacts of a KD on stress, anxiety, depression, schizophrenia and bipolar disorder. METHODS: This literature review was performed to thoroughly represent the existing research in this topic, as well as to find gaps in the international scientific community. In this aspect, we carefully investigated the ultimate scientific web databases, e.g., PubMed, Scopus, and Web of Science, to derive the currently available animal and clinical human surveys by using efficient and representative keywords. RESULTS: Just in recent years, an increasing amount of animal and clinical human surveys have focused on investigating the possible impacts of the KD in the prevention and co-treatment of depression, anxiety, stress, schizophrenia, and bipolar disorder. Pre-existing basic research with animal studies has consistently demonstrated promising results of the KD, showing a propensity to ameliorate symptoms of depression, anxiety, stress, schizophrenia, and bipolar disorder. However, the translation of these findings to clinical settings presents a more complex issue. The majority of the currently available clinical surveys seem to be moderate, usually not controlled, and have mainly assessed the short-term effects of a KD. In addition, some clinical surveys appear to be characterized by enormous dropout rates and significant absence of compliance measurement, as well as an elevated amount of heterogeneity in their methodological design. CONCLUSIONS: Although the currently available evidence seems promising, it is highly recommended to accomplish larger, long-term, randomized, double-blind, controlled clinical trials with a prospective design, in order to derive conclusive results as to whether KD could act as a potential preventative factor or even a co-treatment agent against stress, anxiety, depression, schizophrenia, and bipolar disorder. Basic research with animal studies is also recommended to examine the molecular mechanisms of KD against the above psychiatric diseases.

A randomized controlled trial to compare the effects of time-restricted eating versus Mediterranean diet on symptoms and quality of life in bipolar disorder.

BACKGROUND: The primary objective of this randomized controlled trial (RCT) is to establish the effectiveness of time-restricted eating (TRE) compared with the Mediterranean diet for people with bipolar disorder (BD) who have symptoms of sleep disorders or circadian rhythm sleep-wake disruption. This work builds on the growing evidence that TRE has benefits for improving circadian rhythms. TRE and Mediterranean diet guidance will be offered remotely using self-help materials and an app, with coaching support. METHODS: This study is an international RCT to compare the effectiveness of TRE and the Mediterranean diet. Three hundred participants will be recruited primarily via social media. Main inclusion criteria are: receiving treatment for a diagnosis of BD I or II (confirmed via DIAMOND structured diagnostic interview), endorsement of sleep or circadian problems, self-reported eating window of ≥ 12 h, and no current mood episode, acute suicidality, eating disorder, psychosis, alcohol or substance use disorder, or other health conditions that would interfere with or limit the safety of following the dietary guidance. Participants will be asked to complete baseline daily food logging for two weeks and then will be randomly allocated to follow TRE or the Mediterranean diet for 8 weeks, during which time, they will continue to complete daily food logging. Intervention content will be delivered via an app. Symptom severity interviews will be conducted at baseline; mid-intervention (4 weeks after the intervention begins); end of intervention; and at 6, 9, and 15 months post-baseline by phone or videoconference. Self-rated symptom severity and quality of life data will be gathered at those timepoints, as well as at 16 weeks post baseline. To provide a more refined index of whether TRE successfully decreases emotional lability and improves sleep, participants will be asked to complete a sleep diary (core CSD) each morning and complete six mood assessments per day for eight days at baseline and again at mid-intervention. DISCUSSION: The planned research will provide novel and important information on whether TRE is more beneficial than the Mediterranean diet for reducing mood symptoms and improving quality of life in individuals with BD who also experience sleep or circadian problems. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06188754.

Ketogenic-Mimicking Diet as a Therapeutic Modality for Bipolar Disorder: Biomechanistic Rationale and Protocol for a Pilot Clinical Trial.

There is growing interest in the investigation of ketogenic diets as a potential therapy for bipolar disorder. The overlapping pharmacotherapies utilized for both bipolar disorder and seizures suggest that a mechanistic overlap may exist between these conditions, with fasting and the ketogenic diet representing the most time-proven therapies for seizure control. Recently, preliminary evidence has begun to emerge supporting a potential role for ketogenic diets in treating bipolar disorder. Notably, some patients may struggle to initiate a strict diet in the midst of a mood episode or significant life stressors. The key question addressed by this pilot clinical trial protocol is if benefits can be achieved with a less restrictive diet, as this would allow such an intervention to be accessible for more patients. Recent development of so-called ketone esters, that once ingested is converted to natural ketone bodies, combined with low glycemic index dietary changes has the potential to mimic two foundational components of therapeutic ketosis: high levels of ketones and minimal spiking of glucose/insulin. This pilot clinical trial protocol thus aims to investigate the effect of a 'ketogenic-mimicking diet' (combining supplementation of ketone esters with a low glycemic index dietary intervention) on neural network stability, mood, and biomarker outcomes in the setting of bipolar disorder. Positive findings obtained via this pilot clinical trial protocol may support future target engagement studies of ketogenic-mimicking diets or related ketogenic interventions. A lack of positive findings, in contrast, may justify a focus on more strict dietary interventions for future research.

Probiotic Treatment in Individuals with Euthymic Bipolar Disorder: A Pilot-Study on Clinical Changes and Compliance.

The importance of the microbiome for psychological well-being has gained rising interest in the last decade. A strategy to examine the role of the microbiome in different diseases is the intake of supplements that modulate the gut microbiome. Despite promising results in animal studies, research in humans is sparse to date and especially in individuals with psychiatric disorders almost missing. The current report of the ProbioBIP-one pilot study aims at describing general effects of the intake of the probiotic OMNi-BiOTiC Stress repair® on psychological parameters as well as gastrointestinal symptoms and general compliance in a cohort of euthymic individuals with bipolar disorder (BD), receiving daily probiotic treatment over a time period of 3 months. Twenty-seven individuals with BD took part in the present study (mean age = 50.7 years, SD = 12.2; females 40.7%). In sum, there was a high compliance rate with 81.5% of the study participants completing all 3 study visits and 85% of planned probiotic ingestions taken. Gastrointestinal problems were prevalent in more than half of the patients at the time of inclusion (t1). Expectedly, in the whole cohort, a high proportion of study participants experienced changes concerning digestion during probiotic treatment, around one third reported positive changes (reduced flatulence and easier and more frequent bowel movements) after 1 month (t2) and further after 3 months (t3). In contrast, a smaller part of study participants reported gastrointestinal discomfort after 1 and after 3 months (mainly flatulence and obstipation). We found a significantly reduced cognitive reactivity to sad mood between t2 and t3 indicating that participants under probiotic supplementation perceived themselves to be less distracted by ruminative thoughts. Further changes in psychiatric symptoms were small due to the euthymic state and already low scoring at the time of inclusion. Nevertheless, we found a significant symptom reduction in the rating scales measuring manic symptoms. From a clinical point of view, probiotic supplementation might provide a well-tolerated tool to positively influence gastrointestinal quality of life as well as mental and somatic health, cognition and immune response and potentially have effects on psychiatric symptoms.

Diet quality, dietary inflammatory index and body mass index as predictors of response to adjunctive N-acetylcysteine and mitochondrial agents in adults with bipolar disorder: A sub-study of a randomised placebo-controlled trial.

AIMS: We aimed to explore the relationships between diet quality, dietary inflammatory potential or body mass index and outcomes of a clinical trial of nutraceutical treatment for bipolar depression. METHODS: This is a sub-study of a randomised controlled trial of participants with bipolar depression who provided dietary intake data (n = 133). Participants received 16 weeks adjunctive treatment of either placebo or N-acetylcysteine-alone or a combination of mitochondrial-enhancing nutraceuticals including N-acetylcysteine (combination treatment). Participants were followed up 4 weeks post-treatment discontinuation (Week 20). Diet was assessed by the Cancer Council Victoria Dietary Questionnaire for Epidemiological Studies, Version 2, converted into an Australian Recommended Food Score to measure diet quality, and energy-adjusted dietary inflammatory index score to measure inflammatory potential of diet. Body mass index was also measured. Generalised estimating equation models were used to assess whether diet quality, energy-adjusted dietary inflammatory index score and/or body mass index were predictors of response to significant outcomes of the primary trial: depression symptoms, clinician-rated improvement and functioning measures. RESULTS: In participants taking combination treatment compared to placebo, change in depression scores was not predicted by Australian Recommended Food Score, dietary inflammatory index or body mass index scores. However, participants with better diet quality (Australian Recommended Food Score) reported reduced general depression and bipolar depression symptoms (p = 0.01 and p = 0.03, respectively) and greater clinician-rated improvement (p = 0.02) irrespective of treatment and time. Participants who had a more anti-inflammatory dietary inflammatory index had less impairment in functioning (p = 0.01). Combination treatment may attenuate the adverse effects of pro-inflammatory diet (p = 0.03) on functioning. Participants with lower body mass index who received combination treatment (p = 0.02) or N-acetylcysteine (p = 0.02) showed greater clinician-rated improvement. CONCLUSION: These data support a possible association between diet (quality and inflammatory potential), body mass index and response to treatment for bipolar depression in the context of a nutraceutical trial. The results should be interpreted cautiously because of limitations, including numerous null findings, modest sample size and being secondary analyses.

Gut microbiota and bipolar disorder: a review of mechanisms and potential targets for adjunctive therapy.

There is increasing evidence that connections formed between microbiome, the gut, and the brain play a role in health and well-being. Non-pharmaceutical targets for management of mood disorders, such as bipolar disorder, are relatively under-researched. At the same time, it is clear that there is an intimate connection between psychiatry and gastrointestinal health. Here, we have discussed various comorbid conditions associated with bipolar disorders such as inflammation, irritable bowel disease and antibiotic induced mania with importance to demonstrate possible involvement of the gut microbiota. Gut microbiota-targeted preclinical and clinical interventions have demonstrated enhancement in various psychological conditions. Further in this review, we explore links between bipolar disorder, inflammation and gut microbiome with a focus on dietary, pro- and pre-biotic interventions as potential adjuvant therapies for use in the management of mood disorders such as bipolar disorder.

Microbiota abnormalities and the therapeutic potential of probiotics in the treatment of mood disorders.

Major depressive disorder (MDD) and bipolar disorder (BD) are among the leading causes of burden and disability worldwide. Despite intensified research efforts to improve the treatment options and remission rates in mood disorders, no disease modifying treatment exists for these disorders. Accumulating evidence implicates the involvement of the gut microbiota in processes relevant to etiopathology of central nervous system-based disorders. The objective of this article was to critically evaluate the evidence supporting the link between gastrointestinal microbiota and mood disorders and to discuss the potential benefits of using probiotics in the treatment of MDD and BD. The concept of psychobiotics, which is bacterial-based interventions with mental health benefit, is emerging in the field. On the other hand, while probiotics might potentially represent a significant advance, specific roles of microbiota in the pathophysiology of mood disorders still need further investigation along with intervention studies.

Remote Healing of Bipolar Disorder, Eating Disorder Not Otherwise Specified, Posttraumatic Stress Disorder, Fibromyalgia, and Irritable Bowel Syndrome Through Lifestyle Change.

This case report illustrates the relationship between gut, hormonal, and brain function in that dietary change, mindfulness interventions, and detoxification led to resolution of disabling psychiatric symptoms. In this case, a single Caucasian female resolved her symptoms of bipolar disorder (BD) including psychotic features and suicidality, posttraumatic stress disorder symptoms from childhood torture, disordered eating, fibromyalgia, and irritable bowel syndrome through lifestyle interventions. This patient survived a severe trauma history only to develop alcohol dependence, disordered eating, and depressive symptoms, which were treated with a polypharmaceutical psychiatric approach. She was formally diagnosed with BD after being treated with antidepressants and went on to be treated with up to 15 medications in the ensuing years. Disabled by the side effects of her treatment, she worked with her treating psychiatrist to taper off of 4 medications before she learned of nutritional change through a book authored by the author. After completing 1 mo of these recommendations including dietary change, detox, and meditation, she enrolled in the author's online program and went on to resolve her symptoms, physical and psychiatric, to the extent that BD has been removed from her medical record. She has been symptom free for 1 y. This case is evidence of the potential for self-directed healing and resolution of chronic illness.

Pharmacotherapy in Children and Adolescents at Clinical-High Risk for Psychosis and Bipolar Disorder.

This review aims to describe the importance of i) detecting individuals at clinical high-risk for psychosis (schizophrenia) or bipolar disorder, especially in children and adolescents, in order to enable early intervention, and ii) evaluating different intervention strategies, especially pharmacotherapy, during the subsyndromal or "prodromal" stages of these severe and often debilitating disorders. The different approaches regarding the psychotic and bipolar clinical high-risk state are discussed, including reasons and evidence for early (pharmacological) intervention and risks of treatment vs. non-treatment. Only 10 prospective studies of antipsychotics (randomized=4) and 6 prospective studies of non-antipsychotic pharmacologic agents (randomized=3, i. e., omega-3 fatty acids=2, glycine=1) for the psychotic clinical high-risk state and only 4 prospective studies of mood stabilizing medications for the bipolar clinical high-risk state (randomized=2, i. e., lithium=1, valproate=1) were detected. Based on the minimal efficacy data, adverse effect risks, especially in pediatric populations, nonspecific psychopathology, and unknown true risk for the development of either psychosis or bipolar disorder or of chronically disabling symptoms and disability, medication treatment currently remains second choice after psychosocial intervention. Additional research in this area is clearly needed in order to shed more light on the relevance and predictive value of potentially prodromal symptoms, their identification and most appropriate management options.

Tracking medication changes to assess outcomes in comparative effectiveness research: A bipolar CHOICE study.

BACKGROUND: Comparative effectiveness research uses multiple tools, but lacks outcome measures to assess large electronic medical records and claims data. Aggregate changes in medications in response to clinical need may serve as a surrogate outcome measure. We developed the Medication Recommendation Tracking Form (MRTF) to record the frequency, types, and reasons for medication adjustments in order to calculate Necessary Clinical Adjustments (NCAs), medication adjustments to reduce symptoms, maximize treatment response, or address problematic side effects. METHODS: The MRTF was completed at every visit for 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. RESULTS: Responders had significantly fewer NCAs compared to non-responders. NCAs predicted subsequent response status such that every additional NCA during the previous visit decreased a patient's odds of response by approximately 30%. Patients with more severe symptoms had a greater number of NCAs at the subsequent visit. Patients with a comorbid anxiety disorder demonstrated a significantly higher rate of NCAs per month than those without a comorbid anxiety disorder. Patients with greater frequency, intensity, and interference of side effects had higher rates of NCAs. Participants with fewer NCAs reported a higher quality of life and decreased functional impairment. LIMITATIONS: The MRTF has not been examined in community clinic settings and did not predict response more efficiently than the Clinical Global Impression-Bipolar Version (CGI-BP). CONCLUSIONS: The MRTF is a feasible proxy of clinical outcome, with implications for clinical training and decision-making. Analyses of big data could use changes in medications as a surrogate outcome measure.

Nutrition and Bipolar Depression.

As with physical conditions, bipolar disorder is likely to be impacted by diet and nutrition. Patients with bipolar disorder have been noted to have relatively unhealthy diets, which may in part be the reason they also have an elevated risk of metabolic syndrome and obesity. An improvement in the quality of the diet should improve a bipolar patient's overall health risk profile, but it may also improve their psychiatric outcomes. New insights into biological dysfunctions that may be present in bipolar disorder have presented new theoretic frameworks for understanding the relationship between diet and bipolar disorder.

Diet and Bipolar Disorder: A Review of Its Relationship and Potential Therapeutic Mechanisms of Action.

OBJECTIVES: It is well accepted that diet quality has an important role in the prevention and treatment of several physical diseases. However, its influence on mental health has received far less attention, although there is increasing evidence to support a relationship with depression. In this narrative review, investigations into the relationship between diet and bipolar disorder are examined and the potential implications in the management and treatment of bipolar disorder are reviewed. METHODS: The authors provide a narrative review of the relevant information. RESULTS: Research is limited, although there are preliminary findings to suggest a relationship between diet and bipolar disorder. Findings from cross-sectional research suggest that people with bipolar disorder consume an unhealthier dietary pattern. This has significant treatment implications as bipolar disorder has a high comorbidity with several physical diseases. In addition, diet also influences several biological processes that are dysregulated in bipolar disorder, namely monoaminergic activity, immune/inflammatory processes, oxidative stress, mitochondrial activity, and neuroprogression. CONCLUSIONS: The role of diet in bipolar disorder requires further attention in research as it presents as a factor that may contribute to the worsening course of this condition and may potentially enhance current treatment outcomes.

Novel nutritional treatment for manic and psychotic disorders: a review of tryptophan and tyrosine depletion studies and the potential of protein-based formulations using glycomacropeptide.

RATIONALE: Current amino acid (AA) mixtures used in acute tryptophan (Trp) and tyrosine (Tyr) plus phenylalanine (Phe) depletion and loading tests are unpalatable and lack specificity. Specificity is improved by reducing content of branched-chain amino acids (BCAA) and palatability to a certain extent by dose reduction. OBJECTIVES: This study aims to identify a palatable naturally occurring alternative(s) to amino acids with the desired BCAA content for use in the above tests. METHODS: A palatable alternative lacking in Trp, Tyr and Phe has been identified in the whey protein fraction caseino-glycomacropeptide (c-GMP). The absence of these three aromatic amino acids renders GMP suitable as a template for seven formulations for separate and combined depletion or loading and a placebo control. The absence of Phe and Tyr enables GMP to provide a unique nutritional therapy of manic and psychotic disorders by inhibition of cerebral dopamine synthesis and release and possibly also by enhancing glutamatergic function, in general, and in patients resistant to anti-psychotic medication, in particular. RESULTS: Seven GMP-based formulations for the above tests are proposed, two of which can be used in the above nutritional therapy and a third formulation as a placebo control in clinical trials. CONCLUSIONS: Development of these formulations should advance the above research and diagnostic tests, open new avenues for neuroscience research on monoamine function, and improve the therapy of bipolar and psychotic disorders and enhance the quality of life of sufferers.

Influence of lifelong dietary fats on the brain fatty acids and amphetamine-induced behavioral responses in adult rat.

The influence of dietary fatty acids (FA) on mania-like behavior and brain oxidative damage were evaluated in rats. First generation of rats born and maintained under supplementation with soybean-oil (SO), fish-oil (FO) or hydrogenated-vegetable-fat (HVF), which are rich in n-6, n-3 and trans (TFA) FA, respectively, until adulthood, were exposed to an amphetamine (AMPH)-induced mania animal model to behavioral and biochemical evaluations. While AMPH caused hyperlocomotion in HVF and, to a less extent, in SO- and FO-groups, a better memory performance was observed in FO group. Among vehicle-groups, HVF increased reactive species (RS) generation and protein-carbonyl (PC) levels in cortex; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. Among AMPH-treated animals, HVF exacerbated RS generation in all evaluated brain areas and increased PC levels in cortex and striatum; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. FO was related to higher percentage of polyunsaturated fatty acids (PUFA) and docosahexaenoic acid (DHA) in cortex and striatum, while HVF was associated to higher incorporation of TFA in cortex, hippocampus and striatum, besides increased n-6/n-3 FA ratio in striatum. While a continuous exposure to TFA may intensify oxidative events in brain, a prolonged FO consumption may prevent mania-like-behavior; enhance memory besides decreasing brain oxidative markers. A substantial inclusion of processed foods, instead of foods rich in omega-3, in the long term is able to influence the functionality of brain structures related to behavioral disturbances and weaker neuroprotection, whose impact should be considered by food safety authorities and psychiatry experts.

The ketogenic diet for type II bipolar disorder.

Successful mood stabilizing treatments reduce intracellular sodium in an activity-dependent manner. This can also be achieved with acidification of the blood, as is the case with the ketogenic diet. Two women with type II bipolar disorder were able to maintain ketosis for prolonged periods of time (2 and 3 years, respectively). Both experienced mood stabilization that exceeded that achieved with medication; experienced a significant subjective improvement that was distinctly related to ketosis; and tolerated the diet well. There were no significant adverse effects in either case. These cases demonstrate that the ketogenic diet is a potentially sustainable option for mood stabilization in type II bipolar illness. They also support the hypothesis that acidic plasma may stabilize mood, perhaps by reducing intracellular sodium and calcium.