Tag: bipolar disorder

Wide-ranging Animal Studies Link pH Changes to Cognitive and Psychiatric Disorders

Source: CC0

A global collaborative research group has identified brain energy metabolism dysfunction leading to altered pH and lactate levels as common hallmarks in numerous animal models of neuropsychiatric and neurodegenerative disorders. These include models of intellectual disability, autism spectrum disorders, schizophrenia, bipolar disorder, depressive disorders, and Alzheimer’s disease. The findings were published in eLife.

The research group, comprising 131 researchers from 105 laboratories across seven countries, sheds light on altered energy metabolism as a key factor in various neuropsychiatric and neurodegenerative disorders. While considered controversial, an elevated lactate level and the resulting decrease in pH is now also proposed as a potential primary component of these diseases. Unlike previous assumptions associating these changes with external factors like medicationa, the research group’s previous findings suggest that they may be intrinsic to the disorders. This conclusion was drawn from five animal models of schizophrenia/developmental disorders, bipolar disorder, and autism, which are exempt from such confounding factorsb. However, research on brain pH and lactate levels in animal models of other neuropsychiatric and neurological disorders has been limited. Until now, it was unclear whether such changes in the brain were a common phenomenon. Additionally, the relationship between alterations in brain pH and lactate levels and specific behavioural abnormalities had not been clearly established.

This study, encompassing 109 strains/conditions of mice, rats, and chicks, including animal models related to neuropsychiatric conditions, reveals that changes in brain pH and lactate levels are a common feature in a diverse range of animal models of conditions, including schizophrenia/developmental disorders, bipolar disorder, autism, as well as models of depression, epilepsy, and Alzheimer’s disease. This study’s significant insights include:

I. Common Phenomenon Across Disorders: About 30% of the 109 types of animal models exhibited significant changes in brain pH and lactate levels, emphasising the widespread occurrence of energy metabolism changes in the brain across various neuropsychiatric conditions.

II. Environmental Factors as a Cause: Models simulating depression through psychological stress, and those induced to develop diabetes or colitis, which have a high comorbidity risk for depression, showed decreased brain pH and increased lactate levels. Various acquired environmental factors could contribute to these changes.

III. Cognitive Impairment Link: A comprehensive analysis integrating behavioural test data revealed a predominant association between increased brain lactate levels and impaired working memory, illuminating an aspect of cognitive dysfunction.

IV. Confirmation in Independent Cohort: These associations, particularly between higher brain lactate levels and poor working memory performance, were validated in an independent cohort of animal models, reinforcing the initial findings.

V. Autism Spectrum Complexity: Variable responses were noted in autism models, with some showing increased pH and decreased lactate levels, suggesting subpopulations within the autism spectrum with diverse metabolic patterns.

“This is the first and largest systematic study evaluating brain pH and lactate levels across a range of animal models for neuropsychiatric and neurodegenerative disorders. Our findings may lay the groundwork for new approaches to develop the transdiagnostic characterisation of different disorders involving cognitive impairment,” states Dr Hideo Hagihara, the study’s lead author.

Professor Tsuyoshi Miyakawa, the corresponding author, explains, “This research could be a stepping stone towards identifying shared therapeutic targets in various neuropsychiatric disorders. Future studies will centre on uncovering treatment strategies that are effective across diverse animal models with brain pH changes. This could significantly contribute to developing tailored treatments for patient subgroups characterized by specific alterations in brain energy metabolism.”

The exact mechanism behind the reduction in pH and the increase in lactate levels remains elusive. But the authors suggest that, since lactate production increases in response to neural hyperactivity to meet the energy demand, this might be the underlying reason.

Source: Fujita Health University

Can a Ketogenic Diet Treat Serious Mental Illnesses?

Photo by Inzmam Khan: https://www.pexels.com/photo/man-in-black-shirt-and-gray-denim-pants-sitting-on-gray-padded-bench-1134204/

Antipsychotic medications for serious mental illness like schizophrenia or bipolar disorder often causes metabolic side effects such as insulin resistance and obesity, leading some patients to discontinue the treatment.

Now, a pilot study led by Stanford Medicine researchers has found that a ketogenic diet not only restores metabolic health in these patients as they continue their medications, but it further improves their psychiatric conditions. The results, published in Psychiatry Research, suggest that a dietary intervention can be a powerful aid in treating mental illness.

“It’s very promising and very encouraging that you can take back control of your illness in some way, aside from the usual standard of care,” said Shebani Sethi, MD, associate professor of psychiatry and behavioral sciences and the first author of the new paper.

The senior author of the paper is Laura Saslow, PhD, associate professor of health behavior and biological sciences at the University of Michigan.

Making the connection

Sethi, who is board certified in obesity and psychiatry, remembers when she first noticed the connection. As a medical student working in an obesity clinic, she saw a patient with treatment-resistant schizophrenia whose auditory hallucinations quieted on a ketogenic diet.

That prompted her to dig into the medical literature. There were only a few, decades-old case reports on using the ketogenic diet to treat schizophrenia, but there was a long track record of success in using ketogenic diets to treat epileptic seizures.

“The ketogenic diet has been proven to be effective for treatment-resistant epileptic seizures by reducing the excitability of neurons in the brain,” Sethi said. “We thought it would be worth exploring this treatment in psychiatric conditions.”

A few years later, Sethi coined the term metabolic psychiatry, a new field that approaches mental health from an energy conversion perspective.

Meat and vegetables

In the four-month pilot trial, Sethi’s team followed 21 adult participants who were diagnosed with schizophrenia or bipolar disorder, taking antipsychotic medications, and had a metabolic abnormality – such as weight gain, insulin resistance, hypertriglyceridaemia, dyslipidaemia or impaired glucose tolerance. The participants were instructed to follow a ketogenic diet, with approximately 10% of the calories from carbohydrates, 30% from protein and 60% from fat. They were not told to count calories.

“The focus of eating is on whole non-processed foods including protein and non-starchy vegetables, and not restricting fats,” said Sethi, who shared keto-friendly meal ideas with the participants. They were also given keto cookbooks and access to a health coach.

The research team tracked how well the participants followed the diet through weekly measures of blood ketone levels, which are produced when the body breaks down fat instead of glucose for energy. By the end of the trial, 14 patients had been fully adherent, six were semi-adherent and only one was non-adherent.

Physical and mental improvement

The participants underwent a variety of psychiatric and metabolic assessments throughout the trial.

Before the trial, 29% of the participants met the criteria for metabolic syndrome, defined as having at least three of five conditions: abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure and elevated fasting glucose levels. After four months on a ketogenic diet, none of the participants had metabolic syndrome.

On average, the participants lost 10% of their body weight; reduced their waist circumference by 11% percent; and had lower blood pressure, body mass index, triglycerides, blood sugar levels and insulin resistance.

“We’re seeing huge changes,” Sethi said. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, the insulin resistance. I think that’s very encouraging for patients.”

The psychiatric benefits were also striking. On average, the participants improved 31% on a psychiatrist rating of mental illness known as the clinical global impressions scale, with three-quarters of the group showing clinically meaningful improvement. Overall, the participants also reported better sleep and greater life satisfaction.

“The participants reported improvements in their energy, sleep, mood and quality of life,” Sethi said. “They feel healthier and more hopeful.”

The researchers were impressed that most of the participants stuck with the diet. “We saw more benefit with the adherent group compared with the semi-adherent group, indicating a potential dose-response relationship,” Sethi said.

Alternative fuel for the brain

There is increasing evidence that psychiatric diseases such as schizophrenia and bipolar disorder stem from metabolic deficits in the brain, which affect the excitability of neurons, Sethi said. The researchers hypothesise that just as a ketogenic diet improves the rest of the body’s metabolism, it also improves the brain’s metabolism.

“Anything that improves metabolic health in general is probably going to improve brain health anyway,” Sethi said. “But the ketogenic diet can provide ketones as an alternative fuel to glucose for a brain with energy dysfunction.”

Likely there are multiple mechanisms at work, she added, and the main purpose of the small pilot trial is to help researchers detect signals that will guide the design of larger, more robust studies.

As a physician, Sethi cares for many patients with both serious mental illness and obesity or metabolic syndrome, but few studies have focused on this undertreated population. She is founder and director of the metabolic psychiatry clinic at Stanford Medicine.

“Many of my patients suffer from both illnesses, so my desire was to see if metabolic interventions could help them,” she said. “They are seeking more help. They are looking to just feel better.”

Source: Stanford Medicine

Wearable Device may Detect Skin Electrical Impulses Associated with Mood Changes in Bipolar Disorder

Researchers have used wearable technology to measure electrical impulses in the skin and other physiological biomarkers possibly linked to mood changes in bipolar disorder. Though at an early stage, they hope their work will be able to build on these patterns to detect mood swings in bipolar disorder sufferers, so helping in diagnosis and potentially offering more rapid and personalised treatments. They presented their research at the 36th ECNP Congress in Barcelona, and more information is available on GitHub.

Bipolar disorder (formerly called manic-depressive illness or manic depression) is a mental illness that causes swings in a person’s mood, energy, activity levels, and concentration. These shifts can make it difficult to carry out day-to-day tasks and can make interactions with other people difficult. The degree of mood swing can vary from person to person, from feeling manic (very “up”) to feeling depressed. At present, these mood swings are mostly diagnosed subjectively, through interview with doctors or by questionnaires. This takes time, and requires an immediate medical presence.

Now a group of Barcelona-based psychiatrists, in collaboration with data scientist in Edinburgh, have used a research grade wearable device to continuously collect several physiological biomarkers during the diverse phases and episodes of bipolar disorder. Among the collected physiological biomarkers is electrodermal activity which uses changes in the skin’s electrical conductivity to indicate the level of stress through the reactivity of the nervous system. This is a potential immediate indicator of whether someone is in a manic, depressive or in a normal mood state.

They recruited 38 patients with bipolar disorder, and 19 healthy controls, all from the Barcelona area.

Researcher Diego Hidalgo-Mazzei said “Each participant was fitted with a commercially available Empatica E4 bracelet, which they were asked to wear for around 48 hours. This can measure a variety of physiological changes, but we were most interested in measuring small electrophysiological changes in the skin of the wearer. We found that bipolar disorder patients in their depressed phase had on average a significantly lower skin electrical activity than the rest of the bipolar group or the healthy control group. We also found that as an individual moved from manic to depressive state (or vice versa), this was detectable by a change in skin surface electrical activity.

“It is important for the patient and doctor to know how and when these mood fluctuations take place. It is important also to highlight that the treatment is different for manic or depressive states. This can help with a prompt diagnosis and early personalized treatment, but it can also help in preventing adverse outcomes, for example in alerting to an increased risk of suicide, or of mood swings which may lead to dangers with activities such as driving. It is also easier to treat patients if we know if they are in a manic phase or a depressed phase. Until now, these mood swings have mostly been diagnosed subjectively, through interview with doctors or by questionnaires, and this had led to real difficulties. Arriving at the correct drug is difficult, with only around 30 to 40% of treated individuals having the expected response. We hope that the additional information these systems can provide will give us greater certainty in treating patients.

“We are still some way from that though. This is an exploratory observational study, so we need to look at a larger sample and use machine learning to analyse all the biomarkers collected by the wearers to confirm the findings to determine patterns which might indicate a specific episode. This may not be ideal for every bipolar disorder sufferer, in every circumstance, but a potential pattern may help in the future the people hardest hit by the mood changes which affect their lives”.

For information on the wearable device see https://e4.empatica.com/e4-wristband

Source: EurekAlert!

Aripiprazole Improves Sleep in Psychiatric Disorders by Entrainment to Light/Dark Cycles

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Researchers in Japan have shown that the commonly prescribed antipsychotic drug aripiprazole helps reduce sleep disruptions in patients with certain psychiatric disorders by improving their natural entrainment to light and dark cycles. Their findings are published in Frontiers in Neuroscience.

Many patients with psychiatric conditions, such as bipolar disorder and major depressive disorder, frequently experience disruptions in their sleep–wake cycles. Research has shown that the administration of aripiprazole, a commonly prescribed antipsychotic drug, alleviates the symptoms of circadian sleep disorders in these patients. This improvement may be attributed to the effects of aripiprazole on the circadian central clock, specifically the hypothalamic suprachiasmatic nucleus (SCN), which regulates various circadian physiological rhythms, including the sleep–wake cycle, in mammals. However, the precise mechanism through which aripiprazole addresses these sleep disorder symptoms remains elusive.

Researchers from the University of Tsukuba have discovered that aripiprazole can directly affect the mammalian central circadian clock; specifically, it can modulate the photic entrainment in mice. Located in the hypothalamic suprachiasmatic nucleus (SCN), the central circadian clock comprises clock neurons that synchronize with each other, maintaining a roughly 24-hour rhythm. Simultaneously, SCN is receptive to external inputs like light, aligning itself with the environmental light-dark cycle. The researchers have found that aripiprazole disrupts the synchronization among the clock neurons in the SCN, heightening the responsiveness of these neurons to light stimuli in mice. Additionally, aripiprazole influences intracellular signalling within the SCN by targeting the serotonin 1A receptor, a prominent receptor in the SCN.

These findings suggest that the efficacy of aripiprazole in alleviating circadian rhythm sleep disorder symptoms in psychiatric patients might be attributed to the modulation of the circadian clock by the drug. This study expands the potential clinical usage of aripiprazole as a treatment for circadian rhythm sleep disorders.

Source: University of Tsukuba

Modern Antidepressants may Reduce Risk of Bipolar Relapse

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Treatment with modern antidepressants may help prevent patients with bipolar disorder from relapsing into a depressive episode, according to an international clinical trial published in the New England Journal of Medicine. The findings challenge current clinical practice guidelines and could change how bipolar depression is managed around the world.

“Treating depression in bipolar disorder is challenging and the depressive episodes can be quite devastating for patients and their families,” said Dr Lakshmi Yatham, professor and head of the department of psychiatry at UBC, and the study’s lead author. “Reducing the risk of relapse is important because it can provide patients with a great deal of stability that ultimately lets them get back to the activities they enjoy and can greatly improve their quality of life.”

Patients with bipolar disorder experience extreme changes in their emotional state that cycle through periods of intense highs (mania or hypomania) and lows (depression). During depressive episodes, patients can experience feelings of sadness, hopelessness and loss of interest or pleasure in activities, in addition to trouble sleeping, changes in appetite and suicidal thoughts.

Antidepressant adjunctive therapy, in which antidepressants are prescribed alongside mood stabilisers and/or second-generation antipsychotic medications, is a commonly used strategy by clinicians to treat depressive episodes. However, the duration of this therapy is hotly debated due to a lack of evidence and concerns that antidepressants may induce mania, mixed states or rapid cycling between mania and depression.

Practice guidelines for the management of bipolar disorder published by the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) currently recommend discontinuing antidepressant treatment eight weeks after remission of depression.

“It’s an area that hasn’t been widely studied and there is not a lot of consensus among experts,” said Dr Yatham. “Some studies have shown that up to 80 percent of patients continue receiving antidepressants for six months or longer.”

Now, results from the world’s first randomised clinical trial assessing the duration of adjunctive antidepressant therapy suggest that extending the treatment period beyond current guidelines may help prevent depressive relapses.

The clinical trial, conducted at sites in Canada, South Korea and India, involved 178 patients with bipolar I disorder who were in remission from a depressive episode following treatment with modern antidepressant drugs (escitalopram or bupropion XL). The patients were randomly assigned to either continue antidepressant treatment for 52 weeks, or begin tapering off antidepressants at six weeks and switch to a placebo at eight weeks.

Over the year-long study, 46% of patients in the placebo group experienced a relapse of a mood event, compared to only 31% in the group that continued antidepressant treatment. While this primary outcome was not found to be statistically significant, the comparison included relapses that occurred during the first six weeks of the study when both groups were receiving the same treatment.

However, in an analysis from week six onward, when treatment between the two groups differed, patients that continued antidepressant treatment were 40% less likely to experience a relapse of any mood event, and 59% less likely to experience a depressive episode relative to the placebo group. There was no significant difference in the rate of manic episodes or the rate of adverse events between groups.

“From the point where the two groups began receiving different treatments, we see a significant benefit for patients who continued treatment with antidepressants,” said Dr Yatham.

Patients with bipolar I disorder experience depressive symptoms three times more frequently than manic symptoms. Previous studies have shown that suicide attempts and suicide deaths are at least 18 times more common during depressive episodes compared to during manic episodes.

“Stabilizing patients and keeping them stable by preventing relapse is critical and can quite literally be lifesaving,” said Dr Yatham. “Future revisions of bipolar guidelines will incorporate the evidence from this study and contribute to changes in clinical practice on how antidepressants will be used to manage patients with bipolar disorder.”

Source: University of British Columbia