Ignite Creation Date:
2024-05-06 @ 5:18 PM
Last Modification Date:
2024-10-26 @ 2:26 PM
Study NCT ID:
NCT05268809
Status:
RECRUITING
Last Update Posted:
2024-04-23
First Post:
2022-01-06
Brief Title:
Can Neural Network Instability in Schizophrenia Be Improved with a Very Low Carbohydrate Ketogenic Diet
Sponsor:
Northern California Institute of Research and Education
Organization:
Northern California Institute of Research and Education
Study Overview
Official Title:
Can Neural Network Instability in Schizophrenia Be Improved with a Very Low Carbohydrate Ketogenic Diet
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Wide ranging cognitive deficits are major drivers of functional decline and poor outcomes in people with schizophrenia SZ and bipolar disorder BD Medications do not target pathophysiological mechanisms thought to underlie these deficits In the search for interventions targeting underlying cognitive impairment in SZ and BD we look comprehensively beyond just the brain and to the potential role of dysfunctional systemic metabolism
Disrupted insulin and glucose metabolism are seen in medication-naïve first-episode SZ suggesting that SZ itself and not just the medications used to treat it is associated with risk of Type 2 diabetes cardiovascular morbidity and mortality and more generally accelerated aging Even young people with SZ have increased risk of metabolic disease and cognitive deficits Sadly their life span is shortened by 15-20 years BD is associated with similar but less severe disruptions in glucose and insulin metabolism and life expectancy
Although the human brain is 2 of the bodys volume it consumes over 20 of its energy and accordingly the brain is particularly vulnerable to the dysregulation of glucose metabolism seen in SZ and BD While glucose is considered to be the brains default fuel ketones provide 27 more free energy and are a major source of energy for the brain Ketones prevent or improve various age-associated diseases and a ketogenic diet 70 fat 20 protein 10 carbohydrates has been posited as an anti-aging and dementia antidote
The premise of the work is based on recent evidence that ketogenic diets improve dynamic neural network instability related to cognitive deficits aging and Type 2 diabetes Mujica-Parodi et al Proc Natl Acad Sci U S A 2020117116170-7 The rigor of the work rests on findings of 1 poor cerebral glucose homeostasis in SZ and BD 2 neural network instability in SZ and BD and 3 direct effects of ketosis on network instability Unknown is whether ketogenic diets can improve network instability in people with SZ and BD
Disrupted insulin and glucose metabolism are seen in medication-naïve first-episode SZ suggesting that SZ itself and not just the medications used to treat it is associated with risk of Type 2 diabetes cardiovascular morbidity and mortality and more generally accelerated aging Even young people with SZ have increased risk of metabolic disease and cognitive deficits Sadly their life span is shortened by 15-20 years BD is associated with similar but less severe disruptions in glucose and insulin metabolism and life expectancy
Although the human brain is 2 of the bodys volume it consumes over 20 of its energy and accordingly the brain is particularly vulnerable to the dysregulation of glucose metabolism seen in SZ and BD While glucose is considered to be the brains default fuel ketones provide 27 more free energy and are a major source of energy for the brain Ketones prevent or improve various age-associated diseases and a ketogenic diet 70 fat 20 protein 10 carbohydrates has been posited as an anti-aging and dementia antidote
The premise of the work is based on recent evidence that ketogenic diets improve dynamic neural network instability related to cognitive deficits aging and Type 2 diabetes Mujica-Parodi et al Proc Natl Acad Sci U S A 2020117116170-7 The rigor of the work rests on findings of 1 poor cerebral glucose homeostasis in SZ and BD 2 neural network instability in SZ and BD and 3 direct effects of ketosis on network instability Unknown is whether ketogenic diets can improve network instability in people with SZ and BD
Detailed Description:
The diagnosis of schizophrenia SZ and bipolar disorder BPD as traditionally been based on positive symptoms such as delusions and hallucinations and negative symptoms such as anhedonia and amotivation Although not part of the diagnostic criteria wide ranging cognitive deficits are common and they are major drivers of functional decline as well as poor social and occupational outcomes experienced as illness chronicity sets in While antipsychotic medications treat positive symptoms they do not improve cognitive deficits nor do they target pathophysiological mechanisms thought to underlie these deficits Accordingly in the search for interventions targeting brain dysfunction underlying cognitive impairment in SZ the investigators will look comprehensively beyond the brain to the potential role of dysfunctional systemic metabolism given that obesity insulin resistance and associated systemic inflammation are co-morbidities Modern anti-psychotic medications disrupt metabolic homeostasis which may contribute to the brain dysconnectivity thought to underlie cognitive deficits However both SZ and BPD have been associated with disrupted insulin and glucose metabolism reported appearing well before the advent of antipsychotic treatment and consistent with a recent meta-analysis indicating these metabolic disturbances In fact insulin resistance and both SZ and BPD have been genetically linked Thus SZ and BPD themselves are associated with metabolic disease while the anti-psychotic medications acutely induce insulin resistance independent of food intake and weight gain compounding the associated metabolic susceptibilities The cause-and-consequence relationship of these disorders and insulin resistance is unknown and whether re-establishing metabolic homeostasis improves the underlying neural substrates of cognition is also unknown
The brain is an obligate glucovore and is particularly vulnerable to changes in glucose metabolism Robust energy demands of the brain cannot be met by lipid transformation and during times of glucose deprivation they must be satisfied by ketone bodies Disrupted central glucose metabolism as observed in SZ and BPD patients modulates peripheral metabolism by re-allocation of nutrients towards a brain-centric focus to maintain critical central functions Low-carbohydrate high fat or ketogenic diets are an emerging therapy for insulin resistance Type 2 diabetes and associated co-morbidities Increased ketones prevent or improve the symptoms of various age-associated diseases reduce inflammation and the production of reactive oxygen species and upregulate mitochondria in the brain In addition ketogenic diets have shown promise but without the needed controls
The premise of this proposal is based on a recent paper showing a ketogenic diet reduced 7T resting state fMRI neural network dynamic instability a measure of how long a network of independent nodes maintains a stable connection Instability is related to cognitive deficits aging and Type 2 diabetes in neurotypical adults The investigators fMRI data show similar network dynamic instability in SZ and BPD adding to a larger literature showing static brain network dysconnectivity underlying neurocognitive deficits Unknown is whether network instability can be rescued with a ketogenic diet and whether improvements are mediated by ketogenic diet-induced increases in available ketone bodies as brain fuel andor with reductions in systemic inflammation and indices of metabolic syndrome
The rigor of the proposed work rests on findings of a poor glucose homeostasis in SZ and BPD b neural network instability in SZ and BPD and c direct effects of ketosis on network instability in neurotypical adults Unknown is how ketogenic diets might improve network instability in overweightobese SZ and BPD with risk of insulin resistance The investigators propose a mechanistic prospective pilot clinical study comparing 4-weeks of ketogenic diet KETO vs diet as usual DAU on neural network instability in SZ and BPD They will randomize 70 SZ and BPD 40-65 years old balanced for sex to KETO n35 or DAU n35 KETO meals will be delivered to participants by Metabolic Meals Metabolic inflammatory and 7T MRI data will be acquired before and after the 4-week diet
Aim 1 Assess changes in network instability with KETO and DAU in SZ and BD over the 4-week period Hypothesis 1 KETO relative to DAU will improve network stability
Aim 2 Establish metabolic and inflammatory indices as correlates of change in network instability with the KETO diet Hypothesis 2 Improvements in network stability will be correlated with increased circulating ketone levels and improved insulin sensitivity reduced visceral fat weight loss and reduced systemic inflammation
Aim 3 Assess neuropsychological function at baseline to determine whether it is correlated with baseline network instability in SZ and BD similar to what has been reported in neurotypical adults Hypothesis 3 Cognitive deficits will be related to network instability in SZ and BD at baseline The over-arching hypothesis is Disrupted metabolic homeostasis contributes to neural network instability in SZ and BD and that induction of ketosis restores it
The brain is an obligate glucovore and is particularly vulnerable to changes in glucose metabolism Robust energy demands of the brain cannot be met by lipid transformation and during times of glucose deprivation they must be satisfied by ketone bodies Disrupted central glucose metabolism as observed in SZ and BPD patients modulates peripheral metabolism by re-allocation of nutrients towards a brain-centric focus to maintain critical central functions Low-carbohydrate high fat or ketogenic diets are an emerging therapy for insulin resistance Type 2 diabetes and associated co-morbidities Increased ketones prevent or improve the symptoms of various age-associated diseases reduce inflammation and the production of reactive oxygen species and upregulate mitochondria in the brain In addition ketogenic diets have shown promise but without the needed controls
The premise of this proposal is based on a recent paper showing a ketogenic diet reduced 7T resting state fMRI neural network dynamic instability a measure of how long a network of independent nodes maintains a stable connection Instability is related to cognitive deficits aging and Type 2 diabetes in neurotypical adults The investigators fMRI data show similar network dynamic instability in SZ and BPD adding to a larger literature showing static brain network dysconnectivity underlying neurocognitive deficits Unknown is whether network instability can be rescued with a ketogenic diet and whether improvements are mediated by ketogenic diet-induced increases in available ketone bodies as brain fuel andor with reductions in systemic inflammation and indices of metabolic syndrome
The rigor of the proposed work rests on findings of a poor glucose homeostasis in SZ and BPD b neural network instability in SZ and BPD and c direct effects of ketosis on network instability in neurotypical adults Unknown is how ketogenic diets might improve network instability in overweightobese SZ and BPD with risk of insulin resistance The investigators propose a mechanistic prospective pilot clinical study comparing 4-weeks of ketogenic diet KETO vs diet as usual DAU on neural network instability in SZ and BPD They will randomize 70 SZ and BPD 40-65 years old balanced for sex to KETO n35 or DAU n35 KETO meals will be delivered to participants by Metabolic Meals Metabolic inflammatory and 7T MRI data will be acquired before and after the 4-week diet
Aim 1 Assess changes in network instability with KETO and DAU in SZ and BD over the 4-week period Hypothesis 1 KETO relative to DAU will improve network stability
Aim 2 Establish metabolic and inflammatory indices as correlates of change in network instability with the KETO diet Hypothesis 2 Improvements in network stability will be correlated with increased circulating ketone levels and improved insulin sensitivity reduced visceral fat weight loss and reduced systemic inflammation
Aim 3 Assess neuropsychological function at baseline to determine whether it is correlated with baseline network instability in SZ and BD similar to what has been reported in neurotypical adults Hypothesis 3 Cognitive deficits will be related to network instability in SZ and BD at baseline The over-arching hypothesis is Disrupted metabolic homeostasis contributes to neural network instability in SZ and BD and that induction of ketosis restores it
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None