Tag: schizophrenia

Probiotics plus Vitamin D may Boost Cognition in Schizophrenia

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Previous studies have questioned whether gut microbe imbalances and vitamin D deficiency may be linked to schizophrenia. New research published in Neuropsychopharmacology Reports now indicates that taking probiotics plus vitamin D supplements may improve cognitive function in individuals with the disease.

For the study, 70 adults with schizophrenia were randomised to take a placebo or probiotic supplements plus 400 IU vitamin D daily for 12 weeks. Severity of the disease and cognitive function were evaluated by tests called the Positive and Negative Syndrome Scale (PANSS) and the 30-point Montreal Cognitive Assessment (MoCA), respectively.

A total of 69 patients completed the study. The MoCA score increased by 1.96 units in the probiotic-containing supplement group compared with the placebo group. Also, the percentage of patients with MoCA scores of 26 or higher (indicating normal cognition) rose significantly in the intervention group. Between-group differences in PANSS scores were not significant.

“Probiotics may be a novel way to treat mental disorders by regulating gut microbiota,” said corresponding author Gita Sadighi, MD, of the University of Social Welfare and Rehabilitation Sciences, in Iran.

Source: Wiley

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

Magnetic Stimulation may Ameliorate Memory Deficits in Schizophrenia

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Schizophrenia is often accompanied by extensive impairment of memory, including prospective memory, which is the ability to remember to perform future activities. In a randomised clinical trial published in Neuropsychopharmacology Reports, researchers found that repetitive transcranial magnetic stimulation (rTMS), a non-invasive method that uses alternating magnetic fields to induce an electric current in the underlying brain tissue, may help ameliorate certain aspects of prospective memory in individuals with schizophrenia.

The trial included 50 patients with schizophrenia and 18 healthy controls. Of the 50 patients, 26 completed active rTMS and 24 completed a sham rTMS. Healthy controls received no treatment.

Investigators assessed event-based prospective memory, which is remembering to perform an action when an external event occurs, such as remembering to give a message to a friend when you next see them and also time-based prospective memory, which is remembering to perform an action at a certain time, such as remembering to attend a scheduled meeting.

Both event-based prospective memory and time-based prospective memory scores at the baseline of the trial were significantly lower in patients with schizophrenia than in controls. After rTMS treatments, the scores of event-based prospective memories in patients were significantly improved and were similar to those in controls, while patients’ scores of time-based prospective memory did not improve.

“The findings of this study may provide one therapeutic option for prospective memory in patients with schizophrenia,” said co–corresponding author Su-Xia Li, MD, PhD, of Peking University, in China.

Source: Wiley

Schizophrenia Might Stem From Genetic Mutations In Utero

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As an adult-onset psychiatric disorder, schizophrenia is thought to be triggered by some combination of environmental factors and genetics, although the exact cause remains unclear. In a study published in the journal Cell Genomics, researchers find a correlation between schizophrenia and somatic copy-number variants, a type of mutation that occurs early in development but after genetic material is inherited. This study is one of the first to rigorously describe the relationship between somatic genetic mutations and schizophrenia risk.

“We originally thought of genetics as the study of inheritance. But now we know that genetic mechanisms go way beyond that,” says senior author Chris Walsh, an investigator at the Howard Hughes Medical Institute and chief of genetics and genomics at Boston Children’s Hospital. “We’re looking at mutations that are not inherited from the parents.”

The researchers analysed genotype-marker data from over 20,000 blood samples of people with or without schizophrenia from the Psychiatric Genomics Consortium. They ultimately identified two genes, NRXN1 and ABCB11, that correlated with schizophrenia cases when disrupted in uteroNRXN1, a gene that helps transmit signals throughout the brain, has been associated with schizophrenia before. However, this is the first study to associate somatic, not inherited, NRXN1 mutations with schizophrenia.

Unlike inherited mutations, which are present in all the cells of the body, somatic mutations are only present in a fraction of cells based on when and where a mutation occurred. If a mutation occurs early in development, it is expected that the variant is present throughout the body in a mosaic pattern. On the basis of this principle, researchers can identify somatic mutations that occurred early in development and are present not only in the brain but also in a fraction of cells in the blood.

“If a mutation occurs after fertilisation when there are only two cells, the mutation will be present in half of the cells of the body,” says Walsh. “If it occurs in one of the first four cells, it will be present in about a quarter of the cells of the body, and so on.”

The second gene the researchers identified, ABCB11, is most known to encode a liver protein. “That one came out of nowhere for us,” says Eduardo Maury, a student in Harvard-MIT’s MD-PhD program. “There have been some studies associating mutations in this gene with treatment-resistant schizophrenia, but it hasn’t been strongly implicated in schizophrenia per se.”

When the team investigated further, they found that ABCB11 is also expressed in very specific subsets of neurons that carry dopamine from the brainstem to the cerebral cortex. Most schizophrenia drugs are thought to act on these cells to decrease an individual’s dopamine levels, so this might explain why the gene is associated with treatment resistance.

Next, the team is working towards identifying other acquired mutations that might be associated with schizophrenia. Given that the study analysed blood samples, it will be important to look at more brain-specific mutations that might have been too subtle or recent in a patient’s life for this analysis to detect. In addition, somatic deletions or duplications might be an under-investigated risk factor associated with other disorders.

“With this study, we show that it is possible to find somatic variants in a psychiatric disorder that develops in adulthood,” says Maury. “This opens up questions about what other disorders might be regulated by these kinds of mutations.”

Source: Cell Press via ScienceDaily

Scientists Strengthen Evidence Linking Autoimmunity and Schizophrenia

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Links have been reported between schizophrenia and autoimmunity. In a study published in Brain Behavior and Immunity, Japanese researchers identified autoantibodies that target a ‘synaptic adhesion protein’, neurexin 1α, in a subset of patients with schizophrenia. When injected into mice, the autoantibodies caused many schizophrenia-related changes.

What is a synaptic protein, and why might it be linked to schizophrenia? Synaptic adhesion proteins are specialised proteins that bind to create physical connections between brain cells. These connections, called synapses, allow the cells to communicate by passing molecules back and forth. Both synapses and autoimmunity are known to be associated with schizophrenia, so the research team from Tokyo Medical and Dental University (TMDU) decided to investigate autoantibodies that target synaptic proteins in patients with schizophrenia.

“In around 2% of our patient population, we identified autoantibodies against the synaptic protein neurexin 1α, which is expressed by one cell in the synapse and binds to proteins known as neuroligins on the other cell in the synapse,” says lead author of the study Hiroki Shiwaku. “Once we had identified these autoantibodies, we wanted to see if they were able to cause schizophrenia-related changes.”

To do this, the researchers isolated autoantibodies from some of the patients with schizophrenia and injected them into the cerebrospinal fluid of mice, so that the autoantibodies would travel into the brain. In these mice, the autoantibodies blocked neurexin 1α and neuroligin binding and altered some related synaptic properties. The administration of these autoantibodies also resulted in fewer synapses in the brains of mice and schizophrenia-related behaviours, such as reduced social behaviour toward unfamiliar mice and reduced cognitive function.

“Together, our results strongly suggest that autoantibodies against neurexin 1α can cause schizophrenia-related changes, at least in mice,” explains Hiroki Shiwaku. “These autoantibodies may therefore represent a therapeutic target for a subset of patients with schizophrenia.”

Schizophrenia has a wide variety of both symptoms and treatment responses, and many patients have symptoms that are resistant to currently available treatment options. Therefore, the identification of possible disease-causing autoantibodies is important for improving symptom control in patients with schizophrenia. It is hoped that the results of this investigation will allow patients with autoantibodies that target neurexin 1α – all of whom were resistant to antipsychotic treatment in the present study — to better control their symptoms in the future.

Source: Tokyo Medical and Dental University

Low Maternal Vitamin D Levels may Increase Schizophrenia Risk of Offspring

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Neuroscientists published in the Journal of Neurochemistry, shows that maternal levels of vitamin D are key in the development of dopaminergic neurons, which are thought to be involved in schizophrenia.

Professor Darryl Eyles has built on past research out of his laboratory at the Queensland Brain Institute linking maternal vitamin D deficiency and brain development disorders, such as schizophrenia, to understand the functional changes taking place in the brain.

Schizophrenia is associated with many developmental risk factors, both genetic and environmental. While the precise neurological causes of the disorder are unknown, what is known is that schizophrenia is associated with a pronounced change in the way the brain uses dopamine, the neurotransmitter often referred to as the brain’s ‘reward molecule’.

Professor Eyles has followed the mechanisms that might relate to abnormal dopamine release and discovered that maternal vitamin D deficiency affects the early development and later differentiation of dopaminergic neurons.

The team at the Queensland Brain Institute developed dopamine-like cells to replicate the process of differentiation into early dopaminergic neurons that usually takes place during embryonic development.

They cultured the neurons both in the presence and absence of the active vitamin D hormone. In three different model systems they showed dopamine neurite outgrowth was markedly increased. They then showed alterations in the distribution of presynaptic proteins responsible for dopamine release within these neurites.

“What we found was the altered differentiation process in the presence of vitamin D not only makes the cells grow differently, but recruits machinery to release dopamine differently,” Professor Eyles said.

Using a new visualisation tool known as false fluorescent neurotransmitters, the team could then analyse the functional changes in presynaptic dopamine uptake and release in the presence and absence of vitamin D.

They showed that dopamine release was enhanced in cells grown in the presence of the hormone compared to a control.

“This is conclusive evidence that vitamin D affects the structural differentiation of dopaminergic neurons.”

Leveraging advances in targeting and visualising single molecules within presynaptic nerve terminals has enabled Professor Eyles and his team to further explore their long-standing belief that maternal vitamin D deficiency changes how early dopaminergic circuits are formed.

The team is now exploring whether other environmental risk factors for schizophrenia such as maternal hypoxia or infection similarly alter the trajectory of dopamine neuron differentiation.

Eyles and his team believe such early alterations to dopamine neuron differentiation and function may be the neurodevelopmental origin of dopamine dysfunction later in adults who develop schizophrenia.

Source: University of Queensland

Young Males Most at Risk of Developing Schizophrenia from Cannabis Use

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A registry-based study on cannabis users in Denmark spanning 39 years found that young males were more than twice as likely to develop schizophrenia as young females. The researchers, who published their findings in Psychological Medicine, estimated that about 15% of schizophrenia in this population group is due to cannabis use.

Previous research suggests an increase in schizophrenia population attributable risk fraction (PARF) for cannabis use disorder (CUD). However, sex and age variations in CUD and schizophrenia suggest the importance of examining differences in PARFs in sex and age subgroups.

Moreover, cannabis potency measured by the percentage of delta-9-tetrahydrocannabinol (THC) (main psychoactive component of cannabis) has increased dramatically, eg from 13% in 2006 to 30% in 2016 in Denmark. CUD has also increased markedly – past-year CUD rose significantly from 4.9% in 2014 to 5.9% in 2018 among US 18–25-year-olds.

A growing body of evidence suggests that the relationship between CUD and schizophrenia may differ by sex. Male sex and early heavy or frequent cannabis use are associated with earlier onset of psychosis.

The researchers conducted a nationwide Danish register-based cohort study including all individuals aged 16–49 at some point during 1972–2021, identifying CUD and schizophrenia status.

The researchers examined 6 907 859 individuals, with 45 327 cases of incident schizophrenia during follow-up. Males had slightly higher risk for schizophrenia with CUD (142%) than females (102%). But among 16–20-year-olds, the risk for males (284%) was more than twice that for females (81%). They also found that during the 39-year study period, the annual average increase in PARF for CUD in schizophrenia incidence was 4.8% among males and 3.2% among females. In 2021, among males, this risk fraction was 15%; among females, it was around 4%.


The researchers concluded that “Young males might be particularly susceptible to the effects of cannabis on schizophrenia. At a population level, assuming causality, one-fifth of cases of schizophrenia among young males might be prevented by averting CUD. Results highlight the importance of early detection and treatment of CUD and policy decisions regarding cannabis use and access, particularly for 16–25-year-olds.”

Schizophrenia Associated with 12-hour Gene Cycles in the Brain

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In the open-access journal PLOS Biology, researchers present the first evidence of 12-hour cycles of gene activity in the human brain. Led by Madeline R. Scott, the study also reveals that some of those 12-hour rhythms are missing or altered in the postmortem brains of patients with schizophrenia.

Schizophrenia patients are known to have disturbances in several types of 24-hour bodily rhythms, including sleep/wake cycles, hormone levels, and gene activity in the prefrontal cortex of the brain. However, virtually nothing is known about gene activity in the brain for cycles that are shorter than the usual 24-hour circadian rhythm. A few years ago, researchers discovered that certain genes in the body were associated with 12-hour bodily rhythms, which may have an origin in the 12-hour cycle of ocean tides.

As it is not possible to measure gene transcript levels in living brains, the new study instead used a time-of-death analysis to search for 12-hour rhythms in gene activity within postmortem brains. They focused on the dorsolateral prefrontal cortex as it is associated with cognitive symptoms and other abnormalities in gene expression rhythms that have been observed in schizophrenia.

Numerous genes in the normal dorsolateral prefrontal cortex were found to have 12-hour rhythms in activity. Among them, gene activity levels related to building connections between neurons peaked in the afternoon/night, while those related to mitochondrial function (and therefore cellular energy supply) peaked in the morning/evening.

In contrast, postmortem brains from patients with schizophrenia contained fewer genes with 12-hour activity cycles, and those related to neural connections were missing entirely. Additionally, although the mitochondria-related genes did maintain a 12-hour rhythm, their activity did not peak at the normal times. Whether these abnormal rhythms underlie the behavioural abnormalities in schizophrenia, or whether they result from medications, nicotine use, or sleep disturbances should be examined in future studies.

Co-author Colleen A. McClung adds: “We find that the human brain has not only circadian (24 hour) rhythms in gene expression but also 12-hour rhythms in a number of genes that are important for cellular function and neuronal maintenance. Many of these gene expression rhythms are lost in people with schizophrenia, and there is a dramatic shift in the timing of rhythms in mitochondrial-related transcripts which could lead to suboptimal mitochondrial function at the times of day when cellular energy is needed the most.”

Source: ScienceDaily

Autoimmune Clue in Some Schizophrenia Cases

Mirror symbolising schizophrenia
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Schizophrenia, which affects how people interact with reality, is difficult to treat because it has many possible causes. In a study published in Cell Reports Medicine, Japanese researchers have identified an autoantibody – an antibody which attacks the body’s own tissues – in some patients with schizophrenia.

Notably, they also found that this autoantibody caused schizophrenia-like behaviours and changes in the brain when they injected it into mice.

When considering possible autoantibodies that might cause schizophrenia, researchers from Tokyo Medical and Dental University (TMDU) had a specific protein in mind. Previous research has suggested that neural cell adhesion molecule (NCAM1), which helps facilitate synaptic connections, may have a role in the development of schizophrenia.

“We decided to look for autoantibodies against NCAM1 in around 200 healthy controls and 200 patients with schizophrenia,” explained lead author of the study Hiroki Shiwaku. “We only found these autoantibodies in 12 patients, suggesting that they may be associated with the disorder in just a small subset of schizophrenia cases.”

The research went on to find out whether these autoantibodies could cause any changes that commonly occur in schizophrenia, so they purified autoantibodies from some of the patients and injected them into the brains of mice.

“The results were impressive,” said the study’s senior author, Hidehiko Takahashi. “Even though the mice only had these autoantibodies in their brains for a short time, they had changes in their behaviour and synapses that were similar to what is seen in humans with schizophrenia.”

The mice given the patient autoantibodies had cognitive impairment and changes in their regulation of the startle reflex, which are both seen in other animal models of schizophrenia. They also had fewer synapses and dendritic spines, which are structures that are important for the connections between brain cells, and are also affected in schizophrenia.

The study findings hold promise for the diagnosis and treatment of schizophrenia can present very differently among patients and is often resistant to treatment. If schizophrenia is indeed caused by autoantibodies against NCAM1 in some patients, this will lead to important improvements in their diagnosis and treatment.

Source: Tokyo Medical and Dental University