Clinical and metabolic response to vitamin D plus probiotic in schizophrenia patients
Ghaderi and colleagues in 2019 analysed the effects of a novel combination of vitamin D and probiotics on metabolic and clinical symptoms of chronic schizophrenia. A total of sixty patients with schizophrenia took part in this study, of which half received a dose of either vitamin D3 (50,000 IU) every two weeks as well as 8 of 10^9 CFU/day probiotic and the other half receive placebo for 12 weeks. The supplementation with vitamin D and probiotics correlated to a significant improvement in both general and total PANSS scores (PANSS assesses negative, positive and general psychopathological signs of schizophrenia). Compared with the placebo group, those who received the intervention showed significantly greater total antioxidant capacity, significantly reduced malondialdehyde and high sensitivity C-reactive protein levels. Furthermore, the following were also significantly reduced after taking vitamin D plus probiotics: fasting plasma glucose; insulin concentrations; homeostasis model of assessment-estimated insulin resistance; triglycerides; total cholesterol levels; and total-/HDL-cholesterol ratio. To conclude, the supplementation of vitamin D plus probiotics in patients with chronic schizophrenia had beneficial effects on the general and total PANSS score, and metabolic profiles.
Healthy eating, physical activity, and sleep hygiene (HEPAS) as the winning triad for sustaining physical and mental health in patients at risk for or with neuropsychiatric disorders: considerations for clinical practice
Briguglio and colleagues (2020) provide us with an overview of the current evidence for Healthy Eating education, Physical Activity programs, and Sleep hygiene promotion (HEPAS) in the prevention and management of neuropsychiatric disorders and come up with suggestions for clinical practice. There are plenty of determinants that contribute to the worsening of neuropsychiatric disorders, including unhealthy lifestyles which is a significant contributor in the interplay between genetic, epigenetic (non-genetic influences on gene expression), and environmental factors that ultimately represent the pathophysiological basis of this impairing condition. HEPAS has the potential to become one of the most suitable interventions to lower the risk of developing neuropsychiatric disorders but the writers believe that in the overall management of these disorders it is essential for HEPAS to be paired with pharmacological and psychological therapies with the aim to reduce disability and enhance quality of life.
Diet quality and eating patterns in euthymic bipolar patients
This study published in 2019 aimed to determine the diet quality of bipolar disorder (BP) patients while investigating diet’s association with clinical features of BD, co-morbid obesity and disorders of carbohydrate metabolism. Through a food frequency questionnaire this study assessed the eating patterns of 113 euthymic BD patients (without mood disturbances) and 160 healthy control subjects. Findings included BD patients scored lower in Mediterranean Diet score than controls, and significant associations between diet quality indices and the clinical course of BD could not be found. Principal analysis revealed 4 types of dietary patterns in the BD group: Western-type; pro-healthy carbohydrates; unhealthy snacks and meats and potatoes. In addition, over 70% of patients with BD had Body Mass Index (BMI) above 25kg/m2, and significantly higher values of Fasting Triglycerides Glucose Index and waist circumference were observed in BD patients compared to the control group. Due to the increased values of insulin resistance indicators in the BD group, Lojko and co. (2019) believe it may be necessary to monitor glucose and triglyceride levels and measurement of waist circumference in bipolar patients routinely, alluding to the necessity of psychiatrists, dieticians and other medical professionals to work together to develop dietary recommendations for BD sufferers.
High-dose omega-3 polyunsaturated fatty acid supplementation might be more superior than low-dose for major depressive disorder in early therapy period: a network meta-analysis
Luo et. al (2020) conducted a network meta-analysis comparing the efficacy of different dosages of n-3 polyunsaturated fatty acids (PUFAs) on patients with Major Depressive Disorder (MDD) from an early period. The researchers extracted randomised controlled trials (RCTs) from the PubMed, Embase and Cochrane databases that explored the efficacy of n-3 PUFA supplementation for adult (>18 years old) MDD patients with no comorbidities. A total of 910 MDD patients in 10 trials with 3 adjuvant therapy strategies (high-dose n-3 PUFAs, low-dose n-3 PUFAs and placebo) were included. Pairwise meta-analysis revealed that n-3 PUFAs were superior to placebo while network meta-analysis demonstrated that both the high and low dose of n-3 PUFAs were better than placebo, and the efficacy of high-dose n-3 PUFAs is superior compared to low-dose. Although additional head-to-head clinical trials need to be carried out to enhance the evidence, this meta-analysis discovered that high dose n-3 PUFA supplementation may be superior to the low-dose in the early therapy period of MDD patients.
Ketogenic diet for schizophrenia: clinical implication
While this 2019 review aimed to review the recent findings on the efficacy of ketogenic diet in preclinical models and in schizophrenic patients, it also highlights emerging evidence for compromised glucose and energy metabolism in schizophrenia, which provides a strong rationale and a potential mechanism of action for ketogenic diet. Sarnyai et. al (2019) state that recent postmortem prefrontal cortical samples and in-vivo NMR spectroscopy results support the idea that there is impaired synaptic communication in the brain of people with schizophrenia which is the result of abnormal sugar handling and dysfunctions of the mitochondria. In some pharmacological and genetic mouse models, the ketogenic diet - which provides alternative fuel to glucose for bioenergetic processes in the brain - normalises schizophrenia-like behaviors, while in recent case studies adoption of the ketogenic diet improved psychiatric symptoms, metabolic dysfunctions, and body composition in schizophrenic patients. Randomised controlled clinical trials are warranted to confirm the efficacy of the ketogenic diet as a co-treatment in the management of both clinical symptoms and metabolic abnormalities inherent to the disease and resulting from antipsychotic treatment.
Ketogenic diet prevents impaired prepulse inhibition of startle in an acute NMDA receptor hypofunction model of schizophrenia
After Kraeuter, van den Buuse & Sarnyai (2019) observed that a low carbohydrate, high fat therapeutic ketogenic diet (KD) prevented a variety of behavioural abnormalities induced by pharmacological inhibition of NMDA glutamate receptors, the researchers hypothesised in this study whether the beneficial effects of KD can be generalised to impaired prepulse inhibition of startle (PPI) - a translationally validated endophenotype of schizophrenia - in a pharmacological mice model. The possibility that a metabolically -based intervention might have therapeutic value in the management of schizophrenia came to light after studies highlighted an abnormal cerebral glucose and energy metabolism as one of the potential pathophysiological mechanisms of schizophrenia. This study also addressed the issue of whether the effect of KD is linked to the calorie-restricted state typical of the initial phase of KD. Male C57BL/6 mice with schizophrenia induced by acute injection of dizocilpine (MK-801) were fed a KD for 7 weeks and tested for PPI at 3 and 7 weeks (in the presence and absence of a significant digestible energy deficit, respectively). It was shown that KD effectively prevented MK-801-induced PPI impairments at both 3 and 7 weeks, irrespective of the presence or absence of digestible energy deficit. These results support the efficacy of the therapeutic KD in a translational model of schizophrenia and provide evidence against the role of calorie restriction in its mechanism of action.
Polyunsaturated fatty acids: what is their role in treatment of psychiatric disorders?
Bozzatello and her team in 2019 searched for all randomised controlled trials (RCTs), systematic reviews and meta-analyses on omega-3 fatty acids and psychiatric disorders to provide an update of a previous systematic review and to conduct a complete report of data published between 1980 and 2019 on efficacy and tolerability of omega-3 fatty acids in psychiatric disorders. Of the 126 total records included in this review, 102 were RCTs while 24 were reviews and meta-analyses. The role of omega-3 fatty acids was studied in schizophrenia, major depression, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, eating disorders, substance use disorder and borderline personality disorder. Small beneficial effects of omega-3 fatty acids were observed in ADHD and positive results were reported in a few trials on core symptoms of borderline personality disorder; some efficacy was found in the early stages of schizophrenia in addition to antipsychotic treatment, but not in the chronic phases of psychosis. The main evidence for the efficacy of omega-3 fatty acids was obtained when treating depressive symptoms in patients and to a lesser degree, bipolar depression.
Antidepressive mechanisms of probiotics and their therapeutic potential
This 2020 review looks at the available literature to outline antidepressant mechanisms of probiotics and discusses their therapeutic potential in treating/managing depression. The use of probiotics gained attention in recent years according to Yong et. al (2020), backed up by human and animal studies, some of which have implicated the involvement of a maladaptive microbiota-gut-brain (MGB) axis in the pathophysiology of depression. The physiological changes observed in some studies have led to the strategy of using probiotics to restore proper functioning of the MGB axis but certain challenges have been identified such as the heterogeneous nature of both the gut microbiota composition and depressive symptoms in the clinical setting. Despite this, the reviewers believe probiotics offer a number of advantages over standard pharmaceutical antidepressants, with regards to residual symptoms, side effects, and stigma involved.
The gut microbiota links dietary polyphenols with management of psychiatric mood disorders
This 2019 review explores several potential therapeutic mechanisms in which dietary polyphenols is able to establish cognitive resilience in neuropsychiatric disorders and looks at how synbiotics (combination of probiotics and dietary polyphenols) may provide a novel therapeutic strategy for depression. Westfall and Pasinetti (2019) state that the multifactorial pathophysiology of depression would require a broad acting strategy, as suggestions are that gut-brain-axis signaling may play a crucial role in promoting resilience to several stress-induced changes and that the interaction of the gut microbiota with dietary polyphenols can synergistically alleviate the biological signatures of depression. The phenolic metabolites of dietary polyphenols are known to have multiple beneficial properties and therapeutic efficacy against depression while symbiotics have the potential to alleviate neuroinflammation by modulating a number of factors such as reducing oxidative stress and balance serotonin metabolism, effectively they are capable of simultaneously targeting several of the major pathological risk factors of depression. Overall, synbiotics may act as a novel therapeutic paradigm for neuropsychiatric disorders and further understanding the fundamental mechanisms of gut-brain-axis signaling will allow full utilization of the gut microbiota as a therapeutic tool.
The relationship between serum concentration of vitamin D, total intracranial volume, and severity of depressive symptoms in patients with major depressive disorder
Zhu et al. (2019) studied the total intracranial volume (TIV) of fifty patients with major depressive disorder (MDD) through the use of high-resolution structural magnetic resonance imaging to explore the neural substrate that underlies the link between depression and vitamin D deficiency. As well as collecting peripheral venous blood samples (to measure serum vitamin D concentrations), the study employed the Hamilton Rating Scale for Depression (HAMD) to assess depression symptom severity. In patients with MDD, HAMD score was negatively correlated with TIV and serum vitamin D concentration, and TIV was positively correlated with serum vitamin D concentration. TIV and serum vitamin D levels were observed to significantly predict HAMD score in the linear regression analyses, while mediation analysis discovered also that TIV significantly mediated the relationship between serum vitamin D concentration and HAMD score. One of the findings the researchers conclude with is that TIV may serve as a potential neural biomarker for monitoring responses to adjuvant therapy of vitamin D in patients with MDD.
Serum vitamin D concentrations are associated with depressive symptoms in men: the sixth Korea National Health and Nutrition Examination Survey 2014
The aim of this 2020 study was to investigate the correlation between serum vitamin D concentrations and specific domains of depressive symptoms by each sex in the Korean general population. Rhee, Lee & Ahn (2020) retrieved data from the Korea National Health and Nutrition Examination Survey of 2014 to gather a sample size of 820 men and 916 women (aged 19-76) who had completed health interviews and health examinations thereby providing results for serum 25-hydroxyvitamin [25(OH)D] concentrations, the Patient Health Questionnaire-9 (PHQ-9), and certain covariates. A statistically significant association between log-transformed serum 25(OH)D concentrations and total PHQ-9 scores in men (incidence rate ratio [IRR] = 0.74) was identified after multiple covariate adjustments. In men, log-transformed serum 25(OH)D concentrations were significantly associated with the PHQ-9 cognitive/affective subscore (IRR = 0.56). The findings show serum vitamin D levels were inversely associated with cognitive/affective depressive symptoms in men.
The food-specific serum IgG reactivity in Major Depressive Disorder patients, Irritable Bowel Syndrome patients and healthy controls
This 2018 study compared levels of serum IgG against 39 selected food antigens in patients with MDD, those with IBD and healthy controls (HC group). The sample size was 65, with 22 in the MDD group, 22 in the IBS group, and 21 healthy controls. IgG food hyperreactivity (interpreted as an average of levels of IgG antibodies above 7.5 µg/mL) was detected in 28 (43%) participants, including 14 (64%) from the MDD group, ten (46%) from the IBS group and four (19%) from the HC group. Patients with MDD had significantly higher serum levels of total IgG antibodies and IgG against celery, garlic and gluten compared with healthy controls. In comparison to the IBS group, the MDD group also had higher serum IgG levels against gluten. The final data suggests dissimilarity in immune responses against food proteins between the examined groups, with the highest immunoreactivity in the MDD group. More robust studies and those that examine the clinical utility of IgG-based elimination diet in patients with MDD and IBS are warranted.
The study evaluating the effect of probiotic supplementation on the mental status, inflammation, and intestinal barrier in major depressive disorder patients using gluten-free or gluten-containing diet (SANGUT study): a 12-week, randomized, double-blind, and placebo-controlled clinical study protocol
Karakula-Juchnowicz et. al (2019) planned this 12-week, randomised, double-blind and placebo-controlled study (SANGUT) to evaluate the effect of probiotic supplementation on the mental status, inflammation, and intestinal barrier in major depressive disorder patients using gluten-free or gluten-containing diet and in order to determine the impact of interventions focused on the gut-brain-microbiota axis - which is backed by evidence to be a promising approach - in a group of MDD patients. A total of 120 outpatients will be equally assigned into one of four groups: probiotic supplementation plus gluten-free diet group (PRO-GFD); placebo supplementation and gluten-free diet group (PLA-GFD); probiotic supplementation and gluten containing diet group (PRO-GD); or placebo supplementation with gluten containing diet group (PLA-GD). PRO groups will receive a mixture of psychobiotics (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175), and GFD groups will follow a gluten-free diet. The idea behind this study is that microbiota and its metabolites have the potential to influence CNS function and probiotics may restore the eubiosis (homeostasis) within the gut while a gluten-free diet may alter the activity of microbiota-gut-brain axis previously found to be associated with the pathophysiology of depression. With the suggestion that microbiota may also be digest the gluten and play a role in the formation of peptides with different immunogenic capacities, the combination of the gluten-free diet with probiotic supplementation may inhibit the immune-inflammatory cascade in MDD course and improve both psychiatric and gut barrier-associated traits.
The Microbiota-Inflammasome hypothesis of major depression
This review by Inserra and colleagues (2018) hypothesised that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro-inflammatory pathways mediated by the Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes), which then leads to the exacerbation of depressive symptomatology and further worsens gut dysbiosis. Novel therapeutic strategies could emerge for MDD and co-morbid conditions, with a number of promising approaches arising that modulate gut microbiota composition via inflammasome modulation, fecal microbiota implantation, psychobiotics supplementation, or diet change. This review describes MDD/chronic stress-induced changes in NLRP3 inflammasome, gut microbiota, metabolic pathways, and explains how inflammasome signaling may affect depressive-like behavior and gut microbiota composition.
Ketogenic therapy in serious mental illness: emerging evidence
This 2020 online article provides us with a brief overview of preclinical and clinical evidence supporting the progress of ketogenic therapies in a variety of psychiatric disorders, especially in psychosis. This comes after Morris et. al (2020) published a review recognising the exciting potential of the ketogenic diet and other ketogenic therapies in the treatment of serious mental disorders. This present article aimed to further strengthen the case for induced ketosis in psychiatry brought up by Morris et. al.
Therapeutic potential of exogenous ketone supplement induced ketosis in the treatment of psychiatric disorders: review of current literature
Based on several studies suggesting taking ketone supplements, such as ketone salts or ketone esters, can generate rapid and sustained nutritional ketosis and metabolic changes (which may evoke potential therapeutic effects in psychiatric diseases), Kovács and others (2019) summarised the current literature on ketone supplementation as a potential therapeutic tool for psychiatric disorders. Ketone supplementation elevates the levels of ketone bodies in the blood such as D-β-hydroxybutyrate (βHB), acetoacetate (AcAc), and acetone. It is said that these compounds, exert positive effects on the mitochondria, glycolysis, neurotransmitter levels, activity of free fatty acid receptor 3 (FFAR3), hydroxycarboxylic acid receptor 2 (HCAR2), and histone deacetylase, as well as functioning of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and mitochondrial uncoupling protein (UCP) expression. Kovács et. al (2019) here also states that the result is reduction in pathophysiology associated with various psychiatric disorders. The conclusion was that supplement-induced nutritional ketosis leads to metabolic changes and improvements, and that there is a strong case for the development of specific adjunctive ketogenic protocols for psychiatric diseases to be pursued.
Induced Ketosis as a treatment for neuroprogressive disorders: food for thought?
Morris et. al (2020) explains the mechanisms by which induced ketosis might reduce mitochondrial dysfunction, inflammation, and oxidative stress in neuropsychiatric disorders, and may be able to ameliorate abnormal levels of molecules and signaling pathways that appear to contribute to the pathophysiology of disorders such as schizophrenia, bipolar disorder, and major depressive disorder. The researchers in addition examined the safety data relating to induced ketosis over the long term and discussed future study design.
Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders.
This 2020 article outlines in detail possible mechanisms in which nutritional ketosis may be capable of mitigating changes observed in several neurodegenerative and neuroprogressive disorders. Detrimental effects of oxidative stress, mitochondrial dysfunction and neuroinflammation on neuronal function have been observed in disorders such as cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, autistic spectrum disorder, and all of which can be potentially ameliorated by the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation. The detailed mechanisms led Morris et. al (2020) to hypothesize that nutritional ketosis may have therapeutic applications in the aforementioned disorders.
A pyruvate dehydrogenase complex disorder hypothesis for bipolar disorder
Campbell and Campbell (2019) proposes a hypothesis on how the ketogenic diet (KD) induces the subjective mood stabilization it is associated with affecting. Mitochondrial dysfunction has been consistently linked to playing a causal role in bipolar disorder, and this article hypothesizes it is due to a disorder of the Pyruvate Dehydrogenase Complex (PDC) and/or Mitochondrial Carrier Protein (MCP) shuttle which moves intracellular pyruvate into mitochondria. This theory could explain mood instability and cycling in bipolar disorder as the result of ATP reduction (since this can lead to inhibition of neurotransmitter release or increased hyperexcitability). If this proposed novel causal pathway is true, the Campbells claim there should be increased research attention to PDC as potential therapeutic targets and additional studies on the possible role of the ketogenic diet in bipolar disorder. Experimental approaches, such as through a clinical trial of KD on mood stabilization in BD, are called for to further investigate this hypothesis.
Ketogenic diet as a metabolic therapy for mood disorders: Evidence and developments
(2018) This study investigated the possible role of ketogenic diets in treating mood disorders. These disorders often lead to reduced cognitive and emotional ability. With high incidence of treatment resistance, there is an ever growing demand for novel interventions. The ketogenic diet, which is a low-carbohydrate diet, has been confirmed as an effective anticonvulsant, and this review takes a look at the more recent studies analysing its function in treating mood disorders. This specific diet has been found to hold promise in stabilising mood, as it acts on several targets linked with the pathophysiology of mood disorders including glutamate/GABA transmission, monoamine levels, inflammation and neurotrophism. Preclinical studies on the ketogenic diet as an antidepressant and mood stabiliser have been successful, but clinical trials have yet to be undertaken. This review could spark the use of the ketogenic diet as an intervention in mood disorders.