New findings reverse hypothesis of GABA neurodevelopment in schizophrenia

New research by scientists at the University of Pittsburgh provides an unprecedented level of resolution and insight into disturbances in cortical GABAergic microcircuits, which are thought to underlie cognitive impairments in schizophrenia. Published in Biological Psychiatry, the study led by Dr. Kenneth Fish reveals new detailed understanding about alterations in neurocircuitry that point to abnormal neurodevelopment in the disorder.

A recent generation of studies of postmortem brain tissue from people with schizophrenia, particularly from the laboratory of Professor David Lewis and his colleagues at the University of Pittsburgh, have shed light on schizophrenia-related abnormalities in the interplay of the main excitatory neurons, pyramidal neurons, and a specific class of inhibitory nerve cells, called chandelier cells, in the prefrontal cortex. Chandelier cells tune the activity of pyramidal neurons by releasing the inhibitory transmitter GABA through complex arrays of connections called cartridges. Prior postmortem studies have led to the hypothesis that most cartridges across cortical layers 2-5 have a decreased level of GABA reuptake, presumably a compensatory mechanism for lower GABA signaling associated with the disorder. However, the new postmortem study from the same group found evidence suggesting that the ability of chandelier cells to synthesize and release GABA within the prefrontal cortex is unaltered in schizophrenia. The study also demonstrates that the density of a specific subclass of chandelier cell cartridges is higher exclusively in layer 2 in the disease.

In the study, first author Brad Rocco, a graduate student in Fish’s laboratory, and colleagues compared GABA synthesizing and packaging proteins within chandelier cell cartridges, as well as the density of these cartridges in the prefrontal cortex of 20 schizophrenia subjects and 20 comparison subjects. In layer 2, the density of cartridges arising from a transcriptionally-unique subset of chandelier cells containing calbindin was nearly 3-fold higher in the schizophrenia group. This subset only comprises a small fraction of neurons in the prefrontal cortex. In contrast, there was no difference in the density of chandelier cell cartridges lacking calbindin in layer 2 or in either type of cartridge across layers 3-6.

“These findings challenge prior studies that suggested that GABA deficits were a relatively universal feature of schizophrenia,” said Dr. John Krystal, Editor of Biological Psychiatry.

The study was unable to determine the cause of this increased cartridge density, but the researchers suspect a developmental origin based on the layer specificity of the findings. Chandelier cell cartridges undergo dramatic pruning during development, and layer 2 matures much later than the deeper cortical layers, which had normal cartridge densities. “This finding suggests that the normal developmental pruning of these cartridges might be blunted in schizophrenia,” said Fish.

According to Fish, substantial resources are being invested in the identification of transcriptionally-unique subtypes of human brain cells, an essential element in understanding the human brain, and the new findings highlight the importance of studying these types of cells in psychiatric disease. “The long-term goal of these efforts is to identify new ways to treat, cure, and even prevent brain disorders,” said Fish.

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Disappointing outcome of bitopertin treatment for negative symptoms in schizophrenia

Two new phase III clinical trials investigating the efficacy and safety of bitopertin, a glycine uptake inhibitor considered to be a promising new add-on therapy for treating negative symptoms in schizophrenia, failed to show a benefit of the drug over placebo. The findings throw a wrench in the hopeful efforts to find a treatment for negative symptoms of schizophrenia, which account for some of the most debilitating aspects of the disorder and are associated with poorer outcomes in patients.

The outcomes of the trials were published in a paper in Biological Psychiatry by Dr. Dragana Bugarski-Kirola of Roche Pharmaceuticals in Basal, Switzerland. The randomized, double-blind, parallel-group, placebo-controlled studies were a collaboration between Roche and several research institutions around the world.

“We are back to the drawing board,” said Dr. John Krystal, Editor of Biological Psychiatry.

Previous attempts to treat negative symptoms have employed drugs, hormones, and brain stimulation, but none have provided the desired clinical benefit. Research fingering glutamate signaling in negative symptoms has spurred the idea of targeting glutamate receptors, but this approach has failed in large trials. Glycine reuptake inhibitors have been considered a promising alterative to enhance glutamatergic signaling, and a small proof-of-concept study showed that bitopertin, which selectively inhibits glycine transporter type 1 (GlyT-1), reduced negative symptoms in stable patients with schizophrenia.

“GlyT-1 inhibition was one of the most promising approaches to the treatment of schizophrenia,” said Krystal. “While it still may be possible to optimize GlyT-1 inhibition as a treatment, these negative results suggest GlyT-1 inhibition is not a broadly effective or optimal therapeutic strategy to enhance NMDA glutamate receptor function in schizophrenia.”

The trials were carried out over 201 sites, with each trial including about 600 patients with persistent, predominant negative symptoms of schizophrenia. Patients treated with antipsychotics were administered placebo or bitopertin (5, 10, or 20 mg) for 24 weeks. The doses were chosen to test the minimal effective dose (5 mg) and the dose with a predicted maximal effect (20 mg).

All participants showed some improvement in the negative symptom factor score, but there were no differences between placebo or bitopertin treatment at 24 weeks. No differences were observed in other symptom domains of schizophrenia either. All three doses of bitopertin were well-tolerated and generally safe over the course of the study.

According to Bugarski-Kirola, tackling complex clinical, regulatory and commercial development processes, reliability and quality control was a daunting task when dealing with over 200 study sites across different cultures. “We demonstrated that quality can be accomplished across the sites, but consider a different approach to the design,” she said, explaining that rather than treating negative symptom patients as one homogenous target, priority should be given to exploring the usefulness of novel mechanisms in separate negative symptom domains to better define the target population and maximize the chance of success before launching large phase III trials.

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Effectiveness of antipsychotic treatments in patients with schizophrenia

A new study published by JAMA Psychiatry examines the comparative effectiveness of antipsychotic treatments for the prevention of psychiatric rehospitalization and treatment failure among a nationwide group of patients with schizophrenia in Sweden.

Jari Tiihonen, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden, and coauthors used nationwide register-based data in their study. Nationwide databases were linked to study the risk of rehospitalization and treatment failure from 2006 to 2013 among all patients in Sweden with a schizophrenia diagnosis who were 16 to 64 years old in 2006. There were 29,823 patients in the total prevalent cohort (people who have had the condition) and 4,603 in the incident cohort of newly diagnosed patients.

“Our results suggest that there are substantial differences between specific antipsychotic agents and between routes of administration concerning the risk of rehospitalization and treatment failure among patients with schizophrenia,” the article concludes.

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Study could help explain link between seizures and psychiatric disorders

In a new study published in Cell Reports, scientists at the Gladstone Institutes identified different types of neurons in a brain region called the reticular thalamus. A better understanding of these cells could eventually help explain how both seizures and certain psychiatric disorders can occur at the same time.

Most sensory information from the outside world — including sight, touch and sound — is collected in a region of the brain called the thalamus. The thalamus then relays signals to the cerebral cortex, the brain’s outermost layer responsible for higher processes like decision-making.

“The reticular thalamus acts like a gate that filters information from the thalamus and dispatches signals to the cortex,” explained Jeanne Paz, PhD, assistant investigator at Gladstone and senior author of the new study. “You can think of it as a switchboard operator from the 1950s, who would transfer incoming calls to the correct parties.”

The reticular thalamus is involved in several functions, including attention, perception, and consciousness. Disruptions in this region can lead to seizures and psychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder (ADHD). However, little is known about how neurons in this brain region function as gatekeepers.

“Before our study, the reticular thalamus was thought to be composed of one type of neuron,” said Alexandra Clemente, graduate student in the Paz laboratory and first author of the study. “We did not have a firm grasp on how cells in the reticular thalamus could execute the different functions of this brain region. We have now shown in mice that the reticular thalamus contains at least two different types of neurons, each with distinctive properties, roles, and locations.”

The two main types of neurons can be differentiated, because they produce distinct proteins, either parvalbumin (PV) or somatostatin (SOM). These cell types have been extensively studied in other regions of the brain, but not in the reticular thalamus.

“Importantly, we discovered that the two types of cells control different brain functions,” said Paz, who is also an assistant professor of neurology at the University of California, San Francisco. “We found that PV cells are involved in sensation and can be targeted to control seizures. In contrast, SOM cells are involved in cognition and emotion, and dysfunctions in these cells may contribute to ADHD and schizophrenia.”

Thanks to optogenetics tools, a technology that uses light to control the activity of cells, Paz’s team was able to specifically target and study each of the different cell types in mouse models.

“Along with my lab colleagues Stefanie Makinson and Bryan Higashikubo, we designed studies to examine seizures,” added Clemente. “Our results showed that targeting PV cells could disrupt seizures, whereas targeting SOM cells had no effect. This finding reinforced the notion that, in addition to their distinct physiological functions, the two cell types have very different roles in disease.”

Through collaborative efforts, the scientists also validated, for the first time, that both PV and SOM cells exist in the human reticular thalamus.

“Now that we’ve confirmed the human relevance of our findings, our future goal is to better understand the roles of the different cell types in psychiatric and neurological disorders, and to determine if targeting these cells can actually help treat seizures,” concluded Paz. “The interaction between the two types of neurons could also help explain the presence of seizures in patients with schizophrenia, dementia and some forms of autism.”

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New genetic roots for intelligence discovered

Intelligence is one of the most investigated traits in humans and higher intelligence is associated with important economic and health-related life outcomes. Despite high heritability estimates of 45% in childhood and 80% in adulthood, only a handful of genes had previously been associated with intelligence and for most of these genes the findings were not reliable. The study, published in the journal Nature Genetics, uncovered 52 genes for intelligence, of which 40 were completely new discoveries. Most of these genes are predominantly expressed in brain tissue.

“These results are very exciting as they provide very robust associations with intelligence. The genes we detect are involved in the regulation of cell development, and are specifically important in synapse formation, axon guidance and neuronal differentiation. These findings for the first time provide clear clues towards the underlying biological mechanisms of intelligence,” says Danielle Posthuma, Principal Investigator of the study.

The study also showed that the genetic influences on intelligence are highly correlated with genetic influences on educational attainment, and also, albeit less strongly, with smoking cessation, intracranial volume, head circumference in infancy, autism spectrum disorder and height. Inverse genetic correlations were reported with Alzheimer’s disease, depressive symptoms, smoking history, schizophrenia, waist-to-hip ratio, body mass index, and waist circumference.

“These genetic correlations shed light on common biological pathways for intelligence and other traits. Seven genes for intelligence are also associated with schizophrenia; nine genes also with body mass index, and four genes were also associated with obesity. These three traits show a negative correlation with intelligence,” says Suzanne Sniekers, first author of the study and postdoc in the lab of Posthuma. “So, a variant of gene with a positive effect on intelligence, has a negative effect on schizophrenia, body mass index or obesity.”

Future studies will need to clarify the exact role of these genes in intelligence in order to obtain a more complete picture of how genetic differences lead to differences in intelligence. “The current genetic results explain up to 5% of the total variance in intelligence. Although this is quite a large amount of variance for a trait as intelligence, there is still a long road to go: given the high heritability of intelligence, many more genetic effects are expected to be important, and these can only be detected in even larger samples,” says Danielle Posthuma.

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City life could present psychosis risk for adolescents

Living in a city could significantly increase young people’s vulnerability to psychotic experiences, according to a new study from King’s College London and Duke University.

Published in Schizophrenia Bulletin, the study found that British adolescents raised in major cities in England and Wales were over 40 per cent more likely to report psychotic experiences (e.g. hearing voices and feeling extremely paranoid) than their rural counterparts.

Neighbourhood conditions and crime were strong contributing factors. Among adolescents who had grown up in the most adverse neighbourhoods and been victim of a violent crime, 62 per cent reported psychotic experiences. This high rate of psychotic experiences was almost three times greater than among adolescents living in more favourable neighbourhood conditions who had not experienced violent crime (21 per cent).

Adolescence is a particularly vulnerable time for the development of mental health difficulties -around 70 per cent of adults with mental health problems are thought to become unwell for the first time during adolescence. Up to one in three young people at some point have psychotic experiences, and these individuals have an elevated risk for schizophrenia and other mental health problems in adulthood as well as increased rates of suicide. Yet little is known about the potential impact of social surroundings — such as living in a city — on adolescent expressions of psychosis.

Previous research from the team at King’s College London and Duke University reported higher rates of psychotic symptoms among children living in cities, but this new study is the first to examine the effects of city life on psychotic experiences during adolescence.

The researchers from King’s interviewed more than 2,000 British 18-year-olds about psychotic experiences since the age of 12. The authors note that they were only looking for subclinical experiences of psychosis, rather than evidence of a diagnosable, clinical disorder. Adolescents were considered to have psychotic experiences if they reported at least one out of thirteen potential experiences including, for example, that they heard voices that others could not, believed they were being spied on, or their food was being poisoned.

Levels of ‘urbanicity’were assigned to each participant via their postcode, using data from the Office of National Statistics. Neighbourhood social factors, such as trust, support and cooperation between neighbours, and signs of threat like muggings, assaults and vandalism were measured through surveys of over 5,000 immediate neighbours of the participants. Finally, personal victimisation by violent crime was assessed through interviews with the participants themselves.

Adolescents raised in urban versus rural neighbourhoods were significantly more likely to have psychotic experiences, and this association remained significant after considering a range of other factors, including family socioeconomic status, family psychiatric history, and adolescent cannabis use.

Among those who lived in the largest, most densely populated cities, 34 per cent subsequently reported psychotic experiences between age 12 and 18, compared to 24 per cent of adolescents in rural settings.

Almost half of the association between city life and psychotic experiences was explained by adverse and threatening social characteristics of urban neighbourhoods, including lack of trust and support between neighbours, and high levels of threat in the neighbourhood.

The study authors suggest a number of reasons why living in a city could pose a risk for psychotic experiences, including a heightened biological response to stress, which can in turn disrupt the activity of dopamine in the brain. Excess dopamine is the best biological explanation researchers currently have for psychotic illnesses such as schizophrenia.

They also propose that adolescents growing up in threatening neighbourhoods could develop maladaptive cognitive responses, such as hypervigilance (e.g. becoming excessively aware of potential threats) and attributing negative intentions to people, which might lead them to become paranoid about those around them.

Jo Newbury, first author of the study, from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, said: ‘Our study suggests that the effects of city life on psychotic experiences are not limited to childhood but continue into late adolescence, which is one of the peak ages at which clinical psychotic disorders are typically diagnosed.’

Dr Helen Fisher, senior author from IoPPN at King’s College London, said: ‘These findings highlight the importance of early, preventative strategies for reducing psychosis risk and suggests that adolescents living in threatening neighbourhoods within cities should be made a priority. If we intervene early enough, for example by offering psychological therapies and support to help them cope better with stressful experiences, we could reduce young people’s risk for developing psychosis and other mental health problems further down the line.’

Professor Candice Odgers, senior author from Duke University, said: ‘As increasing numbers of young people around the world are living in cities, there is a growing need to improve our understanding of how both built and social features of urban settings are supporting and challenging young people’s mental health.’

Benefits of antipsychotics outweigh risks, find experts

An international group of experts has concluded that, for patients with schizophrenia and related psychotic disorders, antipsychotic medications do not have negative long-term effects on patients’ outcomes or the brain. In addition, the benefits of these medications are much greater than their potential side effects.

These findings, by Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chairman of Psychiatry at Columbia University College of Physicians and Surgeon and Director of the New York State Psychiatric Institute, and colleagues from institutions in the United States, Germany, The Netherlands, Austria, Japan, and China, were published today in the American Journal of Psychiatry.

Nearly seven million Americans take antipsychotic medications for the treatment of schizophrenia and related conditions. The medications are prescribed to alleviate the symptoms of psychosis and longer-term, to prevent relapse. In recent years, however, concerns have been raised that these medications could have toxic effects and negatively impact long-term outcomes. This view, if not justified by data, has the potential mislead some patients (and their families) to refuse or discontinue antipsychotic treatment.

For this reason, the researchers undertook a comprehensive examination of clinical and basic research studies that examined the effects of antipsychotic drug treatment on the clinical outcomes of patients and changes in brain structure.

“The evidence from randomized clinical trials and neuroimaging studies overwhelmingly suggests that the majority of patients with schizophrenia benefit from antipsychotic treatment, both in the initial presentation of the disease and for longer-term maintenance to prevent relapse,” said Dr. Lieberman. Moreover, whatever side effects that these medications might cause are greatly outweighed by their therapeutic benefits.

“Anyone who doubts this conclusion should talk with people whose symptoms have been relieved by treatment and literally given back their lives,” Lieberman added.

The studies also revealed that delaying or withholding treatment has been associated with poorer long-term outcomes. “While a minority of patients who recover from an initial psychotic episode may maintain their remission without antipsychotic treatment, there is currently no clinical biomarker to identify them, and it is a very small number of patients who may fall into this subgroup,” said Dr. Lieberman. “Consequently, withholding treatment could be detrimental for most patients with schizophrenia.” And while preclinical studies in rodents suggested that antipsychotic medications can sensitize dopamine receptors, there is no evidence that antipsychotic treatment increases the risk of relapse. While antipsychotic medications can increase the risk for metabolic syndrome, which is linked to heart disease, diabetes, and stroke, the study did not include a risk-benefit analysis.

“While more research is needed to address these questions, the strong evidence supporting the benefits of antipsychotic medications should be made clear to patients and their families, while at the same time they should be used judiciously” said Dr. Lieberman.

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Cannabis use in adolescence linked to schizophrenia

Scientists believe that schizophrenia, a disorder caused by an imbalance in the brain’s chemical reactions, is triggered by a genetic interaction with environmental factors. A new Tel Aviv University study published in Human Molecular Genetics now points to cannabis as a trigger for schizophrenia.

The research, conducted by Dr. Ran Barzilay and led by Prof. Dani Offen, both of TAU’s Sackler School of Medicine, finds that smoking pot or using cannabis in other ways during adolescence may serve as a catalyst for schizophrenia in individuals already susceptible to the disorder.

“Our research demonstrates that cannabis has a differential risk on susceptible versus non-susceptible individuals,” said Dr. Barzilay, principal investigator of the study. “In other words, young people with a genetic susceptibility to schizophrenia — those who have psychiatric disorders in their families — should bear in mind that they’re playing with fire if they smoke pot during adolescence.”

The research team included Prof. Inna Slutsky and Hadar Segal-Gavish, both of TAU’s Sackler School of Medicine, and Prof. Abraham Weizman of Geha Medical Health Center and Prof. Akira Sawa of Johns Hopkins Medical Center.

Clinical picture of mouse models mimics human adolescence

Researchers exposed mouse models with a genetic susceptibility to schizophrenia — the mutant DISC-1 gene — to THC, the psychoactive compound in cannabis. During a time period similar to that of human adolescence, the susceptible mice were found to be at a far higher risk for lasting brain defects associated with the onset of schizophrenia.

Four categories of mice were used in the experiment: Genetically susceptible and exposed to cannabis; genetically susceptible and not exposed to cannabis; genetically intact and exposed to cannabis; and, finally, genetically intact and not exposed to cannabis. Only the genetically susceptible mice developed behavioral and biochemical brain pathologies related to schizophrenia after being exposed to cannabis, behavioral tests and neurological biochemical analyses revealed.

“The study was conducted on mice but it mimics a clinical picture of ‘first episode’ schizophrenia, which presents during adolescence in proximity to robust cannabis use,” said Dr. Barzilay, a child and adolescent psychiatrist.

The researchers also discovered the mechanism through which the cannabis and the specific gene interact.

“A protective mechanism was observed in the non-susceptible mice,” said Prof. Offen. “This mechanism involves the upregulation of a protective neurotrophic factor, BDNF, in the hippocampus. We showed in the study that if we artificially deliver BDNF to the genetically susceptible mice, they could be protected from the deleterious effect of THC during adolescence.

“This research clearly has implications in terms of public health,” Prof. Offen concluded. “The novel protective mechanism identified in the study may serve as a basis for the future development of compounds capable of attenuating the deleterious effect of cannabis on brain development. However, until that time, it is important that young people at risk for psychiatric disorders (i.e., have psychiatric disorders in their family or have reacted strongly to drugs in the past) should be particularly cautious with cannabis use during adolescence.”

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A pilot study of deep brain stimulation in treatment-resistant schizophrenia

Deep brain stimulation (DBS) has proven its effectiveness in different types of psychiatric disorders, neuropathic pain and neurodegenerative diseases. Schizophrenia remains one of the leading causes of disability worldwide, with 30 percent of the patients’ refractory to the treatment. Study authors hypothesized that DBS may be an effective treatment in patients with refractory schizophrenia. This study’s purpose is to describe the protocol and the preliminary results of the first seven cases of schizophrenia treated with DBS.

This is a prospective, randomized, double-blind clinical trial in patients with treatment-resistant, chronic paranoid schizophrenia. Patients were randomized into DBS of either of two areas, based on two different physiological hypothesis. After clinical stabilization, the authors also performed a cross-type sequence randomization (generator on/off) every three months. The primary outcome was the changes from baseline score to 12 months scores in the Positive and Negative Syndrome Scale for Schizophrenia (PANSS).

From December 2014, seven patients (57 percent women) underwent surgery (in four cases the target was the nucleus accumbens and in three the subgenual area). The most remarkable changes included a progressive improvement in all patients of the social isolation type symptoms and auditory hallucinations. Two patients were dropped off the randomization phase because they presented a noticeable worsening of the symptoms when the generator was switched off. One patient presented complications related to the surgery. The study is currently under analysis and collection of patient outcomes and will be finished in 2017 after one more case is recruited.

Preliminary results support the hypothesis that DBS can be an effective therapy to treat refractory schizophrenia, though it is necessary to complete the ongoing study, do a comprehensive analysis of the data and expand the trials to obtain definitive answers.

Winner of the Best International Abstract Award, Laura Salgado Lopez, MD, presented her research, A Pilot Study of Deep Brain Stimulation in Treatment-resistant Schizophrenia, during the 2017 American Association of Neurological Surgeons (AANS) Annual Scientific Meeting.

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Risk of psychosis from cannabis use lower than originally thought, say scientists

The research, published in the journal, Addiction, also showed for the first time that there is sufficient evidence to demonstrate that for patients who already have schizophrenia, cannabis makes their symptoms worse.

More than two million people in England and Wales used cannabis in the past 12 months, but the latest research shows that banning the drug would have low impact on mental health.

In order to prevent just one case of psychosis, more than 20,000 people would have to stop using cannabis, as shown by a previous study led by the University of Bristol.

This means that at a population level, an increased risk of psychosis from cannabis use is low, and those vulnerable to developing serious mental health problems is relatively rare. The research highlights, however, that more reviews on the impact of high potency cannabis is needed in order to make a full assessment of the risks.

Ian Hamilton, lecturer in mental health at the University of York, said: “The link between cannabis and psychosis has been an ongoing research topic since the drug became popular in the 1960s. Most of the high profile studies that we have access to, however, are from a time when low potency cannabis was the norm, but today high potency is more common.

“High potency cannabis contains less of a chemical that is believed to protect against negative side-effects, such as psychosis, and a higher level of a chemical that can trigger psychosis. In this new study, we looked at both low and high potency, but it is clear that we need more evidence from high potency-related health cases to further investigate this link in modern-day users.”

Despite this, the research was clear that the more high potency cannabis used, the higher the risk of developing mental health problems, even if they are relatively low in number. For those who already had schizophrenia cannabis exacerbated the symptoms.

The greatest risk to health, however, comes from cannabis users who combine the drug with tobacco. This exposes young people in particular to tobacco dependency at an early age, increasing the chances of cancers, infections, and other health-related issues.

Previous research at York showed that regulating cannabis use could result in more effective strategies aimed at helping drug users to access the right support and guidance. The policy report illustrated, however, that there is too much uncertainly around treatment regimes in an unregulated market to target the appropriate level of care.

Mr Hamilton said: “Regulation could help reduce the risks to health that cannabis use poses, as a regulated cannabis market would introduce some quality control.

“This would provide users with information about the strength of cannabis on offer, something they usually only discover after exposure in the current unregulated market.

“The public health message about the link between cannabis and psychosis has been a difficult one to communicate, but the evidence still points to the benefits of regulations that seek to advise on the greatest potential health risks, which currently arise due to tobacco use.”

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Schizophrenia signs in mice linked to uncoordinated firing of brain cells

Researchers at Columbia University have discovered that a small group of neurons fired haphazardly in mice with signs of schizophrenia. The findings suggest that a breakdown in the synchronized behavior of these brain cells could produce the classic disordered thinking and perceptions associated with the disease.

The study, which may be the first to test the idea that schizophrenia arises from disruptions in small networks of neurons, was published in Neuron.

Affecting about one percent of the population, schizophrenia is marked by a range of distinct symptoms, from hallucinations and delusions, to memory problems and social withdrawal. It also comes in a variety of forms, which has hindered researchers in finding a unifying explanation for the disease that could improve diagnosis and treatment.

“If you think of the neurons in the schizophrenic mice as pixels on a TV screen, it’s as if most of the pixels have been scrambled,” said the study’s lead author, Jordan Hamm, a postdoctoral researcher at Columbia University. “Each pixel no longer relates to its neighbor to form a coherent, stable picture.”

The researchers chose to focus on the visual cortex because impaired visual processing is one of schizophrenia’s defining traits. Using calcium-imaging techniques, they recorded flashes of light emitted by individual neurons as each fired off an electric signal. In healthy mice, they found that groups of 60 to 120 neurons flashed in a consistent pattern, as if following a choreographed arrangement. The neurons in the mice with signs of schizophrenia, by contrast, fired more randomly as if working in isolation.

The researchers tested two mouse models of the disease, genetic and chemical, and found similar results. Mice given regular doses of ketamine, an anesthetic that acts on glutamate receptors and can produce psychotic behavior, showed erratic neural activity, as did mice bred with a genetic mutation associated with a high risk of developing schizophrenia in humans.

“The pattern emerging from this analysis is one of profound disorganization, as though neurons were acting on their own rather than as a coherent group,” said study coauthor Dr. Joseph Gogos, a neuroscientist at Columbia University Medical Center and Columbia’s Zuckerman Institute who studies underlying mechanisms of schizophrenia in genetic models of the disorder.

In a related study published in Science last year, the researchers showed that repeatedly stimulating a small group of neurons in the same region of the mouse brain, the visual cortex, caused the neurons to fire together, as if their respective connections had been strengthened by use. Dr. Rafael Yuste, the study’s senior author and a neuroscientist at Columbia, has suggested that this process could explain how memories and thoughts form, and how neural circuits might be reprogrammed through artificial manipulation.

Both studies suggest new avenues for treating schizophrenia, the researchers say, through the manipulation of genes, genetic pathways, and even individual neurons, to restore disrupted neural units to their normal functioning.

“I’ve experienced deep frustration in trying to treat schizophrenic patients without understanding how this disease works,” said Yuste. “I’m excited by the possibility of reversing some of schizophrenia’s symptoms by reprogramming neurons to fire in a more coordinated fashion.”

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Balance test improves insight into illness in schizophrenia

A common symptom of schizophrenia — not knowing that you’re ill — can be temporarily alleviated using a balance test that stimulates part of the brain with cold water, an exploratory study at the Centre for Addiction and Mental Health (CAMH) has shown. The study was published in Psychiatry Research.

More than 50 per cent of people with schizophrenia experience impaired insight into their illness, which is a key reason they refuse medication or don’t seek treatment, says Dr. Philip Gerretsen, Clinician-Scientist in the Campbell Family Mental Health Research Institute at CAMH. Lack of insight is extremely difficult to treat because it doesn’t respond to psychological therapies or medication. The result is poorer health, as well as a higher likelihood of being hospitalized or experiencing housing instability.

Dr. Gerretsen devised the idea of using this test for schizophrenia based on research in paralyzed patients with stroke damage who lacked awareness of their paralysis. The test, caloric vestibular stimulation, involves irrigating the ear canal with water at varying temperatures and is commonly used in tests of the body’s vestibular or balance system. The procedure can stimulate different areas of the brain, including areas associated with a lack of insight, which has been confirmed by brain imaging studies. In stroke patients with right hemisphere damage, cold water temporarily led to awareness of their paralysis.

The results among people with schizophrenia were promising.

“Cold water in the left ear significantly increased patients’ insight and awareness of their schizophrenia, which we measured 30 minutes after the test, compared with the sham or placebo treatment using room temperature water,” says Dr. Gerretsen. Shortly afterward this insight had diminished. In the right ear, however, the cold water treatments appeared to worsen insight.

Dr. Gerretsen and his colleagues tested the water procedure with 16 patients with schizophrenia spectrum disorder, who had moderate to severe lack of insight into their illness. The study participants were given, in a random order, one of three conditions: cold water at 4°C in their left ear, cold in their right ear, and sham procedure, in which the water was at body temperature. Patients’ insight into their illness was assessed at 30 minutes after the test, using the VAGUS Insight into Psychosis Scale. This scale is designed to capture subtle changes in insight over a short period of time.

“With these promising results, we’re embarking on new research aiming to make the period of awareness last longer, using a new device that makes the procedure much more convenient,” says Dr. Gerretsen.

To this end, he’s testing a new device, a vestibular stimulation headset with temperature-controlled earpieces. The device was developed by Scion Neurostim. Unlike the water test, this device was designed for home use and doesn’t require water or a trained specialist to administer. Study participants will receive this form of thermal stimulation over several consecutive days, to see if it leads to a sustained improvement in illness awareness.

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Alcohol use in veterans with schizophrenia less common than thought; no level safe

U.S. military veterans who are being treated for schizophrenia are much less likely to drink any alcohol than the general population. However, they are equally likely to misuse alcohol. And when they do misuse alcohol, it leads to worsening of their symptoms, according to a new study led by Dr. Alexander Young, a psychiatry professor at UCLA.

Alcohol and drug use disorders are believed to have substantial negative effects on outcomes in people with schizophrenia. However, it has not been possible to know the extent of this problem, because diagnoses and details regarding substance use are typically not documented in people’s medical records, previous research shows.

Prior studies of veterans with serious mental illness have found that heavy drinking prevents them from sticking to prescribed medication regimens. Efforts to reduce alcohol misuse and better ensure that veterans with schizophrenia take their medications would improve outcomes for them and could reduce the incidence of hospitalization.

Researchers randomly selected 801 veterans undergoing treatment for schizophrenia at Veterans Health Administration medical centers in California, New York, Louisiana and Texas. Trained assessors conducted confidential interviews to collect information about their psychiatric symptoms, how well they followed their prescription regimens, alcohol and illicit drug use, quality of life, and use of treatment services.

At these clinics, only 23 percent of those interviewed said that they drank any alcohol in the previous 30 days. Fifteen percent reported some use and 7 percent reported drinking alcohol to intoxication, or “misuse.” In contrast, 56 percent of the general population report drinking in the past month, according to the National Institute on Alcohol Abuse and Alcoholism.

The veterans in the study who misused alcohol were less likely to take their medications as prescribed, more likely to use other drugs and had worse quality of life. Both alcohol users and misusers, compared with those who didn’t drink at all, reported less use of general medical, mental health and housing services. Less use of services correlates with worse outcomes.

The findings indicate there is no safe level of alcohol use for people with schizophrenia, suggesting that clinicians should ask patients with schizophrenia about alcohol use or misuse and advise them about risks.

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Shared genetic origin for ALS/MND and schizophrenia

Researchers have shown for the first time that Amyotrophic Lateral Sclerosis (ALS), also known as Motor Neurone Disease (MND) and schizophrenia have a shared genetic origin, indicating that the causes of these diverse conditions are biologically linked. The work has just been published in the prestigious journal Nature Communications.

By analyzing the genetic profiles of almost 13,000 ALS/MND cases and over 30,000 schizophrenia cases, the research led by scientists from Trinity College Dublin in Ireland confirms that many of the genes that are associated with these two very different conditions are the same.

In fact, the research which involved collaborators from the University of Utrecht, Kings College London and members of the Project MinE and Psychiatric Genome Consortia has shown an overlap of 14% in genetic susceptibility to the adult onset neuro-degeneration condition ALS/MND and the developmental neuropsychiatric disorder schizophrenia.

While overlaps between schizophrenia and other neuropsychiatric conditions including bipolar affective disorder and autism have been shown in the past, this is the first time that an overlap in genetic susceptibility between ALS/MND and psychiatric conditions has been shown.

Dr Russell McLaughlin, Ussher Assistant Professor in Genome Analysis at Trinity College Dublin, and lead author of the paper said: “This study demonstrates the power of genetics in understanding the causes of diseases. While neurological and psychiatric conditions may have very different characteristics and clinical presentations, our work has shown that the biological pathways that lead to these diverse conditions have much in common.”

Professor of Neurology in Trinity and Consultant Neurologist at the National Neuroscience Centre, Orla Hardiman, who is the senior author and lead investigator on the project said: “Our work over the years has shown us that ALS/MND is a much more complex disease than we originally thought. Our recent observations of links with psychiatric conditions in some families have made us think differently about how we should study ALS/MND. When combined with our clinical work and our studies using MRI and EEG, it becomes clear that ALS/MND is not just a disorder of individual nerve cells, but a disorder of the way these nerve cells talk to one another as part of a larger network.”

She continued: “So instead of thinking of ALS/MND as a degeneration of one cell at a time, and looking for a ‘magic bullet’ treatment that works, we should think about ALS/MND in the same way that we think about schizophrenia, which is a problem of disruptions in connectivity between different regions of the brain, and we should look for drugs that help to stabilize the failing brain networks”.

“The other significant issue that this research brings up is that the divide between psychiatry and neurology is a false one. We need to recognise that brain disease has many different manifestations, and the best way to develop new treatments is to understand the biology of what is happening. This will have major implications for how we classify diseases going forward, and in turn how we train our future doctors in both psychiatry and neurology. That in itself will have knock on consequences for how society understands, approaches and treats people with psychiatric and neurological conditions,” Professor Hardiman added.

The new research was prompted by earlier epidemiological studies by researchers at Trinity, led by Professor Hardiman. These studies showed that people with ALS/MND were more likely than expected to have other family members with schizophrenia, and to have had another family member who had committed suicide. This was first noted as family histories were ascertained from people with ALS/MND in the Irish National ALS Clinic and was subsequently investigated as part of case control studies in Ireland in which over 192 families with ALS/MND and 200 controls participated. Details of over 12,000 relatives were analysed and the rates of various neurological and psychiatric conditions calculated in family member of those with ALS/MND and controls. This work was subsequently published in the prestigious American journal the Annals of Neurology in 2013.

This led the Trinity group to team up with European collaborators in ALS/MND to see if these epidemiological observations could be due to a genetic overlap between ALS/MND and schizophrenia.

The Trinity group, along with their partners in the University of Utrecht, will continue to study the links between ALS/MND and psychiatric conditions using modern genetics, epidemiology and neuroimaging, and in this way will develop new and more effective treatments that are based on stabilizing disrupted brain networks.

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Major research project provides new clues to schizophrenia

Researchers at Karolinska Institutet collaborating in the large-scale Karolinska Schizophrenia Project are taking an integrative approach to unravel the disease mechanisms of schizophrenia. In the very first results now presented in the scientific journal Molecular Psychiatry, the researchers show that patients with schizophrenia have lower levels of the vital neurotransmitter GABA as well as changes in the brain’s immune cells.

Schizophrenia is one of the most disabling psychiatric diseases and affects approximately one per cent of the population. It commonly onsets in late adolescence and is often a life-long condition with symptoms such as delusions, hallucinations, and anxiety. The disease mechanisms are largely unknown, which has hampered the development of new drugs. The drugs currently available are designed to alleviate the symptoms, but are only partly successful, as only 20 per cent of the patients become symptom-free.

The Karolinska Schizophrenia Project (KaSP) brings together researchers from a number of different scientific disciplines to build up a comprehensive picture of the disease mechanisms and to discover new targets for drug therapy. Patients with an acute first-episode psychosis are recruited and undergo extensive tests and investigations. Cognitive function, genetic variation, biochemical anomalies as well as brain structure and function are analysed using the latest techniques and then compared with healthy peers.

The first results from the project are now presented in two studies published in the journal Molecular Psychiatry. One of the studies shows that patients with newly debuted schizophrenia have lower levels of the neurotransmitter GABA in their cerebrospinal fluid than healthy people and that the lower the concentration of GABA the more serious their symptoms are.

GABA is involved in most brain functions and along with glutamate it accounts for almost 90 per cent of all signal transmission. While glutamate stimulates brain activity, GABA inhibits it, and the two neurotransmitters interact with each other.

“Over the years, animal studies have suggested a link between decreased levels of GABA and schizophrenia,” says Professor Göran Engberg at Karolinska Institutet’s Department of Physiology and Pharmacology. “Our results are important because they clinically substantiate this hypothesis.”

The other study used the imaging technique of positron emission tomography (PET) to show that patients with untreated schizophrenia have lower levels of TSPO (translocator protein), which is expressed on immune cells such as microglia and astrocytes.

“Our interpretation of the results is an altered function of immune cells in the brain in early-stage schizophrenia,” says Senior lecturer Simon Cervenka at Karolinska Institutet’s Department of Clinical Neuroscience.

The results of the two studies provide new clues to the pathological mechanisms of schizophrenia, but it is unclear if the changes are the cause or the result of the disease. Follow-up studies are now underway to examine what causes the anomalies and how these biological processes can be influenced to change the progression of the disease.

KaSP is a collaboration between clinical and preclinical research groups at Karolinska Institutet and four psychiatric clinics under Stockholm County Council.

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