Tag Archives: #psychosis

Evidence Of Sustained Benefits of Pimavanserin For Dementia-related Psychosis (Medicine)

Evidence of the sustained benefits of an investigational antipsychotic treatment for people with dementia-related psychosis has been published.

Up to half of the 45 million people worldwide who are living with Alzheimer’s disease will experience psychotic episodes, a figure that is even higher in some other forms of dementia. Psychosis is linked to a faster deterioration in dementia.

Despite this, there is no approved safe and effective treatment for these particularly distressing symptoms. In people with dementia, widely-used antipsychotics lead to sedation, falls and increased risk of deaths.

Pimavanserin works by blocking serotonin 5HT2A receptors, and doesn’t interact with the dopamine receptors. It is licensed in the US to treat hallucinations and delusions in people with Parkinson’s disease psychosis.

A new paper published in the New England Journal of Medicine outlines a clinical trial, conducted in 392 people with psychosis associated with Alzheimer’s disease, Parkinson’s disease, Lewy body, frontotemporal, or vascular dementia. All participants were given pimavanserin for 12 weeks. Those who met a threshold of symptom improvement were then assigned to pimavanserin or placebo for up to 26 weeks.

The trial was stopped early for positive efficacy results. Of the 351 participants, 217 (61.8%) had a sustained initial treatment benefit, of whom 112 were assigned to placebo and 105 to pimavanserin. Relapse occurred in 28/99 (28.3%) of the placebo group, compared to 12/95 (12.6%) of the pimvanserin group, with pimvanserin more than halving the relapse rate and significantly improving the sustained benefit.

Professor Clive Ballard, Executive Dean of the University of Exeter Medical School, said: “Psychosis affects up to half of all people with dementia, and it’s a particularly distressing symptom – yet there’s currently no safe and effective treatment. Currently used antipsychotics are known to cause harms, and best practice guidelines recommend prescribing for no longer than 12 weeks for people with dementia as a result. We urgently need alternatives. It’s exciting that the relapse rate in the pimavanserin group was lower than the placebo group, indicating that the treatment benefits may be sustained over time. We now need longer and larger scale trials to explore this further.”

The trial found headache, urinary tract infection and constipation occurred more frequently in the pimavanserin group, but there was no increase in mortality or the other serious events, such as stroke, which are known to increase with other antipsychotics.

The full paper is entitled ‘Trial of Pimavanserin in Dementia-related psychosis‘, published in the New England Journal of Medicine.


Provided by University of Exeter

New Theory Suggests Blood Immune and Clotting Components Could Contribute To Psychosis (Psychiatry)

A scientific review has found evidence that a disruption in blood clotting and the first line immune system could be contributing factors in the development of psychosis.

The article, a joint collaborative effort by researchers at RCSI University of Medicine and Health Sciences, Cardiff University and the UCD Conway Institute, is published in Molecular Psychiatry.

Recent studies have identified blood proteins involved in the innate immune system and blood clotting networks as key players implicated in psychosis.

The researchers analysed these studies and developed a new theory that proposes the imbalance of both of these systems leads to inflammation, which in turn contributes to the development of psychosis.

The work proposes that alterations in immune defense mechanisms – including blood clotting – lead to an increased risk of inflammation, which is thought to contribute to the development of psychosis.

The new theory further refines the prevailing ‘two-hit’ hypothesis, where early genetic and/or environmental factors disrupt the developing central nervous system (the “first-hit”) and increases the vulnerability of the individual to subsequent, late environmental disruptions (the “second-hit”).

“Early identification and treatment significantly improves clinical outcomes of psychotic disorders. Our theory may provide a further step to biomarkers of psychosis and allow the identification of therapeutic targets for early and more effective treatment,” said Dr Melanie Föcking, joint first author on the paper and Lecturer in Psychiatric Neuroscience at RCSI Department of Psychiatry.

“While the idea of psychosis resulting from some form of inflammation and immune activation is not new, our data suggest a new understanding and change of focus towards a combined function of the innate immune complement system and coagulation pathways to the progression to psychotic disorder,” said Dr Meike Heurich, joint first author on the paper and lecturer at School of Pharmacy and Pharmaceutical Sciences, Cardiff University.

“The works builds on our recent studies which increasingly implicate dysregulation of the complement and coagulation pathways both in and preceding psychotic disorder,” said Professor David Cotter, senior author of the paper and Professor of Molecular Psychiatry at RCSI Department of Psychiatry.

The research was funded by the Health Research Board (HRB) in Ireland and Wellcome Trust.


Reference: Heurich, M., Föcking, M., Mongan, D. et al. Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01197-9


Provided by RCSI

Protecting the IQ Of People At Risk For Psychosis (Psychiatry)

A UNIGE team has found that a class of drugs can protect the development of intellectual abilities in people at risk of psychosis, if prescribed before adolescence.

One person in 2000 suffers from a microdeletion of chromosome 22 that can lead to the development of psychotic disorders, such as schizophrenia, in adolescence. In addition to symptoms such as hallucinations or delusions, psychotic disorders also comes with a progressive decline in intelligence quotient (IQ). If current drug treatments are successful in containing psychotic symptoms, nothing can be done to prevent the deterioration of intellectual skills that leads to loss of autonomy. Researchers at the University of Geneva (UNIGE), Switzerland, have discovered that prescription of selective serotonin reuptake inhibitors (SSRIs) – a class of drugs used to treat anxiety and depression –in late childhood can reduce the deterioration of intellectual abilities, and have a neuroprotective effect on some of the brain regions affected by the psychotic illness. This study, to be read in the journal Translational Psychiatry, opens up a new field of research and new hope for people affected by the microdeletion of chromosome 22.

The average IQ is around 100 points. However, for people who may develop a psychotic illness, such as those with a microdeletion of chromosome 22, the average drops to 70-80 points. “The problem is that when a psychotic disorder occurs, such as schizophrenia, the brain frontal lobe and the hippocampus are particularly affected, which leads to the gradual deterioration of already below-average intellectual capacities”, explains Valentina Mancini, a researcher in the Department of Psychiatry at UNIGE Faculty of Medicine and first author of the study. From then on, the average IQ drops to around 65-70 points, leading to a loss of autonomy that requires a protected environment. “At present, drug treatments manage to contain psychotic symptoms, such as hallucinations, anxiety or distortion of reality, but there is no treatment that can reduce the deterioration of affected people’s intellectual capacities”, notes the Geneva researcher.


200 patients followed over a 20 years period reveal a possible solution

The team of Stéphan Eliez, professor in the Department of Psychiatry at UNIGE Faculty of Medicine, has been following 200 patients affected by the microdeletion of chromosome 22 for the past 20 years. “30 to 40% of them developed schizophrenia psychotic disorder”, he explains. “Thanks to this cohort, we found that people suffering from this syndrome lost 7 to 8 IQ points from childhood to adulthood. This figure rises to 15 IQ points for those who developed psychotic disorders.”

Yet the physicians noted that two to three teenagers a year are exceptions, and even gained IQ points. Why? “We made a comprehensive analysis of these patients’ medical data to find out any common feature in the treatments prescribed to them by their GP”, explains Valentina Mancini. Two observations caught their attention.

The first is the prescription of small, regular doses of SSRIs –  a drug that increases the levels of serotonin, a neurotransmitter involved in the regulation of behaviour – in late childhood and throughout adolescence. “These drugs increase neurogenesis and act on synaptic plasticity. They are prescribed today to reduce anxiety and depressive symptoms”, explains the Geneva researcher. And the younger the patients received this treatment, at around 10-12 years of age, the more the frontal lobe and the hippocampus – and therefore the intellectual capacities – were preserved from deterioration caused by the psychotic illness. The second observation is that a neuroleptic drug – prescribed in small doses to control psychotic symptoms such as hallucinations or delusions – also seems to have a positive effect if added to SSRIs during adolescence. “These two medications, especially when combined, have thus preserved the anatomical structure of the brain affected by the degradation responsible for the decline in intellectual capacity”, remarks Stéphan Eliez.


A promising discovery for the future of people at risk of psychosis

This study provides for the first time an indication of a neuroprotective preventive treatment for the development and preservation of IQ. “It should be stressed that too great a deterioration of intellectual skills progressively leads to a very problematic psychosocial dependence. Here, we could succeed in protecting this population”, notes Stéphan Eliez.

Once the results of this study  are confirmed, the effect of SSRIs could be tested on other types of patients and possibly prescribed preventively to  people at risk of intellectual deterioration, such as individuals with other genetic syndromes like Fragile X or Down’s syndrome, or children of schizophrenic parents. “We also want to investigate whether the 3% to 4% of adolescents in the general population who develop psychotic symptoms would see this risk reduced by taking this drug”, continues Valentina Mancini.

The Geneva team will now compare the results obtained from their research cohort with international databases in order to confirm the neuroprotective role induced by these treatments prescribed at the end of childhood, adolescence being the critical phase for the onset of psychotic diseases.

Featured image: The frontal lobe and hippocampus (purple) are among the areas most affected by impairment due to psychotic illness. Treatment with selective serotonin reuptake inhibitors seems to have a neuroprotective effect on the maturation of these regions. © UNIGE


Reference: Mancini, V., Maeder, J., Bortolin, K. et al. Long-term effects of early treatment with SSRIs on cognition and brain development in individuals with 22q11.2 deletion syndrome. Transl Psychiatry 11, 336 (2021). https://doi.org/10.1038/s41398-021-01456-x


Provided by University of Geneve

New Findings Linking Brain Immune System to Psychosis (Psychiatry)

New research at Karolinska Institutet suggests a link between psychosis and a genetic change that affects the brain’s immune system. The study published in Molecular Psychiatry may impact the development of modern medicines for bipolar disorder or schizophrenia.

Göran Engberg. Photo: Stefan Zimmerman.

Psychosis affects approximately 2-3 per cent of the population and is characterized by a change in the perception of reality, often with elements of hallucinations and paranoid reactions.

Most of the people affected are patients with schizophrenia, but people with bipolar disorder may also experience psychotic symptoms.

The antipsychotics available today often have insufficient efficacy, and for patients, their life situation can be difficult.

The average life expectancy of people with schizophrenia is approximately 15 years shorter than that of the general population, according to Sweden’s National Board of Health and Welfare.

“It is not entirely known what biological mechanisms cause psychosis, but recent research suggests that immune activation in the brain’s glial cells may be the cause. People with psychosis have elevated levels of kynurenic acid in the brain, a messenger that transmits information from the brain’s immune system to the neurons,” says Göran Engberg, Professor at the Department of Physiology and Pharmacology, Karolinska Institutet, and the study’s corresponding author.

The critical role of the GRK3 protein

Portrait of Carl Sellgren, researcher at FyFa.
Carl Sellgren. Photo: Markus Marcetic.

Previous genome-wide association studies (GWAS) have shown that the protein GRK3 expresses itself via genetic changes in the immune system in patients with psychosis.

Now researchers at Karolinska Institutet, the University of California, San Diego, USA, and the Mayo Clinic, Rochester, USA, have studied more specifically which parts of the immune system impact psychotic disorders.

The study is based on extensive data from mice that lack the GRK3 protein in the brain, as well as an analysis of the genome from 70 people with bipolar disorder and 48 healthy control subjects.

Association with psychosis

Results show that the loss of the GRK3 protein appears to increase the sensitivity of the immune system and triggers a cascade of effects in the brain, involving an increased release of the cytokine IL-1beta and kynurenic acid.

“Our experimental data are confirmed through genetic studies where we see a link between psychosis in patients with bipolar disorder and decreased expression of GRK3, which leads to an increased amount of kynurenic acid in the brain,” says Carl Sellgren. He is a senior lecturer at the Department of Physiology and Pharmacology, Karolinska Institutet, and the study’s first author together with Sophie Imbeault, senior researcher at the same department.

Sophie Erhardt. Photo: Private.

The data in the study provide a connection between immune activation and psychosis and thus presents a starting point for further study of novel antipsychotic drugs possessing immune modulatory functions. The drugs currently used in psychosis treatment were developed in the 1960s.

“To develop effective, modern drugs, more knowledge is needed about the mechanisms in the brain that can trigger psychosis,” says Sophie Erhardt, professor at the Department of Physiology and Pharmacology, Karolinska Institutet, and the study’s last author.

The study was funded by the Swedish Research Council, The KI-AstraZeneca Translational Science Centre  Joint Research Program, the Torsten Söderberg Foundation, the Foundation for Strategic Research and the Brain Foundation, Petrus and Augusta Hedlund Foundation, Märta Lundqvist Foundation, Åhlén Foundation, National Institute of Mental Health, the Stanley Medical Research Institute, Region Stockholm-Karolinska Institutet’s ALF Agreement for Clinical Research and Medical Education, the Broad Institute, the Knut and Alice Wallenberg Foundation, the Mayo Clinic – Karolinska Institutet Collaborative Project Grant.

Carl Sellgren is a scientific advisor to Outermost Inc, USA. Doo-Sup Choi sits on the board of Peptron Inc, USA, and Maria Bhat is employed by AstraZeneca. There are no other reported conflicts of interest.

Featured image: Getty Images


Publication

“GRK3 deficiency elicits brain immune activation and psychosis.” Carl M. Sellgren, Sophie Imbeaul, Markus K. Larsson, Alfredo Oliveros, Ida A.K. Nilsson, Simone Codeluppi, Funda Orhan, Maria Bhat, Maximillian Tufvesson-Alm, Jessica Gracias, Magdalena E. Kegel, Yiran Zheng, Anthi Faka, Marie Svedberg, Susan B. Powell, Sorana Caldwell, Mary E. Kamenski, Marquis P. Vawter, Anton Schullman, Michel Goiny, Camilla I. Svensson, Tomas Hökfelt, Martin Schalling, Lilly Schwieler, Simon Cervenka, Doo-Sup Choi, Mikael Landén, Göran Engberg, Sophie Erhardt. Molecular Psychiatry, online 12 May 2021, doi: 10.1038/s41380-021-01106-0.


Provided by Karolinska Institute

Why Some People Report ‘Hearing the Dead’? (Spirituality)

Spiritualist mediums might be more prone to immersive mental activities and unusual auditory experiences early in life, durham researchers have found.

Their findings could explain why some people and not others say they receive communications from ‘the dead’ and eventually adopt spiritualist beliefs.

Spiritualism is a religious movement based on the idea that human souls continue to exist after death and communicate with the living through a medium or psychic.

Clairaudient communications

Mediums who “hear” spirits are said to be experiencing clairaudient communications, rather than clairvoyant (“seeing”) or clairsentient (“feeling” or “sensing”) communications.

Our researchers surveyed a mix of clairaudient spiritualist mediums from the Spiritualists’ National Union and members of the general population, in the largest scientific study into the experiences of clairaudient mediums to date.

They found that these spiritualists have a strong leaning towards absorption – a trait linked to immersion in mental or imaginative activities and altered states of consciousness.

Hearing spirits early and often

Mediums are also less concerned about the opinions of others and more prone to unusual visual and auditory experiences than members of the general public.

Eighteen per cent reported having clairaudient experiences ‘for as long as they could remember’, and seventy-one per cent had not encountered Spiritualism as a religious movement prior to their first experience.

Many who experience hearing voices, often early in life, encounter spiritualist beliefs when searching for the meaning behind, or supernatural significance of, their very personal and unusual experiences, our researchers found.

Improving understandings of psychosis

Spiritualists tend to report unusual auditory experiences which are positive, start early in life and which they are often then able to control.

Understanding how these develop is important in helping us learn more about distressing or non-controllable experiences of hearing voices, and how to support those whose voices are linked to psychosis or other mental health problems.


Reference: Adam J. Powell & Peter Moseley (2021) When spirits speak: absorption, attribution, and identity among spiritualists who report “clairaudient” voice experiences, Mental Health, Religion & Culture, DOI: 10.1080/13674676.2020.1793310 https://www.tandfonline.com/doi/full/10.1080/13674676.2020.1793310?tab=permissions&scroll=top


Provided by Durham University

Psychosis Symptoms Linked to Impaired Information Spread in the Brain (Neuroscience)

Altered white matter limits the brain’s conscious access to information, potentially contributing to delusions and other psychotic symptoms of mental health disorders, according to new research published in JNeurosci.

Altered white matter limits the brain’s conscious access to information, potentially contributing to delusions and other psychotic symptoms of mental health disorders. ©Berkovitch et al., JNeurosci 2020

Your brain is always active, but you are not always aware of it. Accepted theory holds you do not become consciously aware of something until non-conscious brain activity in sensory areas spreads to a larger network of neurons all over the brain via long-distance white matter tracts. Dysfunction in these tracts may explain the delusions characteristic of psychiatric disorders like bipolar disorder and schizophrenia.

Berkovitch et al. used MRI to compare the white matter structure and consciousness threshold of healthy adults, bipolar disorder patients with and without psychotic symptoms, and schizophrenia patients. The consciousness threshold corresponds to how long a visual stimulus must be presented on a screen to be broadcasted across the brain and become conscious – the shorter it is, the better the conscious access. Thresholds were significantly increased in patients with psychosis compared to those without. Across all participants, lower thresholds correlated with greater white matter connectivity in long distance tracts. These results mean altered white matter connectivity does not induce psychosis directly, but may through its effect on the consciousness threshold.

These results mean altered white matter connectivity does not induce psychosis directly, but may through its effect on the consciousness threshold.

References: Disruption of Conscious Access in Psychosis Is Associated With Altered Structural Brain Connectivity, JNeurosci, DOI: 10.1523/JNEUROSCI.0945-20.2020 http://dx.doi.org/10.1523/JNEUROSCI.0945-20.2020

Provided by Society for Neuroscience

Study Finds Evidence Of Neurobiological Mechanism For Hallucinations And Delusions (Neuroscience)

A new study from researchers at Columbia University Vagelos College of Physicians and Surgeons has found evidence of a potential neurobiological mechanism for hallucinations and delusions that fits within the hierarchical model of psychosis and can explain their clinical presentation.

The study was published in eLife.

Columbia researchers Kenneth Wengler, PhD, a Postdoctoral Research Fellow and Guillermo Horga, MD, PhD, Florence Irving Associate Professor of Psychiatry, investigated the neurobiological mechanisms of two symptoms of schizophrenia: hallucinations and delusions. These two symptoms form the syndrome of psychosis, an immensely disabling psychiatric condition where patients lose their ability for reality testing.

“Typically, patients with more severe hallucinations also have more severe delusions, and these two symptoms respond similarly to antipsychotic medications. But this is not always the case; some patients have very prominent hallucinations but less severe delusions and vice versa,” says Wengler. “This suggests that these symptoms may share a common neurobiological mechanism while simultaneously depending on symptom-specific pathways.”

Some experts in the field believe that a hierarchical perceptual-inference model can explain the mechanisms behind psychosis. Wengler explains, “In its simplest form, the hierarchical model has two levels to the hierarchy: low and high. The low level makes inferences about basic features of stimuli and the high level makes inferences about their causes. An intuitive example of this is inferring the weather. In this scenario, you must decide if you are going to take an umbrella with you when you leave the house. The stimulus in this scenario is what you see when you look out the window; let’s say it’s cloudy. The context in this scenario is what you expect the weather to be like on a given day in the city you are in; let’s say you are in Seattle. Although it is not currently raining, because it’s cloudy and you are in a city where it often rains, you may decide to take an umbrella with you. The hierarchical model of psychosis frames hallucinations as resulting from dysfunction at the lower levels of the hierarchy and delusions as resulting from dysfunction at the higher levels of the hierarchy. Critically, these levels of inference are distinct but interconnected, so a dysfunction at one level would likely propagate upwards or downwards to other levels, therefore explaining why these symptoms tend to co-occur.”

To investigate the neurobiological mechanisms of hallucinations and delusions within the framework of the hierarchical model, the researchers used functional magnetic resonance imaging to measure intrinsic neural timescales throughout the brain. These neural timescales reflect how long information is integrated in a given brain region. Most importantly, these neural timescales are organized hierarchically, making it a fitting measure to test the hierarchical model of psychosis.

The researchers collected data from 127 patients with schizophrenia from various online databases and determined how an individual’s neural timescales related to their hallucination and delusion severities together. They found that neural timescales in the lower levels of the hierarchy tended to be longer in patients with more severe hallucinations, while neural timescales in the higher levels tended to be longer in patients with more severe delusions. These results provide the first direct evidence of a potential neurobiological mechanism for hallucinations and delusions that fits within the hierarchical model of psychosis and can explain their clinical presentation. The common neurobiological mechanism for both symptoms could result in increased neural timescales, but the symptom-specific pathways are the level of the hierarchy at which the neural timescales are increased. “Our findings open the door for the development of treatments to target specific symptoms of psychosis depending on an individual subject’s symptom profile, in line with the current push for individualized medicine,” says Horga.

References: Kenneth Wengler , Andrew T Goldberg, George Chahine, Guillermo Horga, “Distinct hierarchical alterations of intrinsic neural timescales account for different manifestations of psychosis”, Neuroscience, 2020. DOI: 10.7554/eLife.56151 link: https://elifesciences.org/articles/56151

Provided by Columbia University Irving Medical Center

Folie A Duex Is The Psychosis You Share With The One You Love (Psychiatry)

When you live in close proximity to someone, it’s common for illness to spread from one person to another. But mental illness? It’s possible. The phenomenon is technically called shared psychotic disorder, but it’s most famously known as folie à deux.

The first case of the condition was documented in the 19th century and described a 30-something married couple, Margaret and Michael. The couple shared a delusion that people were sneaking into their house at night spreading dust, dropping pieces of fluff, and wearing down the soles of the couple’s shoes.

In another instance, not two, but three sisters experienced what could be called “folie à trois.” Two of the sisters moved into a house near a third sister to help her care for her children, and over time, all three became closer and more religious. At one point, the youngest began believing that there were troubling discrepancies between different versions of the Bible and became determined to make them right. For three days, the sisters prayed nonstop without sleeping until they believed that God wanted them to have a particular house in the town. Even though the house didn’t belong to them, the sisters went to the house and demanded to be let in, even breaking windows and attacking the occupant until police arrived.

According to a review published in the Canadian Journal of Psychiatry, shared psychotic disorder most often affects people in very close relationships, such as married couples, siblings, and parents and children. They’re also usually socially isolated, and often have pre-existing mental illness. The condition takes several forms, the most common and oldest known of which is “folie imposée,” or “imposed madness.” In that form, the more dominating person in the pair spreads his or her delusion to the more submissive, who doesn’t resist the ideas.

There’s also “folie simultanée”, or “simultaneous madness,” where two people with a deep connection both experience the delusion at once; “folie communiquée,” or “communicated madness,” which is like imposed madness except there’s a period of resistance from the second person; and “folie induite” or “induced madness,” which is like communicated madness except that extra delusions are spread from a second person.

Luckily, in most of these forms, the cure is simple: just separate the two people. When that doesn’t work — which, especially in cases of folie communiquée and folie induite, it may not — psychiatrists can resort to medication or electroconvulsive therapy. But, as Esther Inglis-Arkell of io9 points out, the tendency to share mental eccentricities isn’t always bad — and we all do it. “There are few old married [couples] who don’t share eccentricities. There are few families, or even close friendships, that don’t require both people to work with the various mental glitches of the other. We all go a little crazy for the other people in our lives.”