Category Archives: Psychiatry

A New Way To Treat PTSD? (Psychiatry)

Exposure to a traumatic experience can lead to post-traumatic stress disorder (PTSD), an incapacitating disorder in susceptible persons with no reliable therapy. Particularly puzzling is understanding how transient exposure to trauma creates persistent long- term suffering from PTSD and why some people are susceptible to PTSD while others that were exposed to the same trauma remain resilient.

Epigenetic modifications are chemical marks on genes that program their activity. These marks are written into DNA during fetal development to correctly program how our genes function in different organs. However, research in the last two decades has suggested that these marks could also be modulated by experiences and exposures at different point of time in life. Studies in humans have suggested that perhaps the initial trauma exposure results in “epigenetic alterations” that in turn mediate and embed the PTSD disorder. These ideas were based on analysis of blood DNA of humans with PTSD, but it was not known whether epigenetic changes play a causal role in the brain regions that are considered important for PTSD.

A team of scientists from Bar-Ilan University, led by Prof. Gal Yadid, of the Mina and Everard Goodman Faculty of Life Sciences and Gonda (Goldschmied) Multidisciplinary Brain Research Center, examined this question using an animal PTSD model and discovered a new way for treating PTSD that might be applied to humans. Their findings were recently published in the Nature journal Molecular Psychiatry.

The researchers first mapped ‘epigenetic DNA methylation marks’ in a brain region which is important for PTSD. They found distinct epigenetic differences between animals that were exposed to trauma and were resilient, and those animals that were exposed to trauma and were susceptible and developed PTSD-like behavior. The researchers found that an important ‘epigenetic’ enzyme that transfers methyl groups onto DNA, DNMT3A, is reduced in animals that are susceptible to PTSD. The researchers also searched for groups of genes whose methylation is altered in the PTSD susceptible animals and found that one group of genes is controlled by the retinoic acid receptor which is activated by vitamin A. Indeed, delivering DNMT3A or retinoic acid orphan receptor gene into the animal brains reverses the PTSD-like phenotypes, suggesting that these genes that are differentially methylated are responsible for PTSD behavior.

Injecting brains with genes is still not a feasible therapeutic option. Therefore, the authors tested whether nutritional supplements that mimic the activity of these genes could treat and reverse PTSD in susceptible animals. Since DNMT3A increases DNA methylation, the researchers used a natural product that donates methyl groups S-adenosylmethionine (SAMe) and to activate the retinoic acid receptor they treated the animals with vitamin A.  They found that combined treatment with the methyl donor SAM and retinoic acid reversed PTSD-like behaviors.

The data suggest a novel approach to treatment of PTSD, which involves combining two natural products that modulate the epigenome. Importantly, epigenetic treatments reverse the underlying causes of the disorder on DNA and thus serve as a “cure” rather than temporary relief of symptoms. “Since these nutritional supplements are relatively nontoxic, they offer hope for a nontoxic treatment of PTSD that reverses the underlying genomic cause of the disease,” said Prof. Yadid.


Reference: Gal Warhaftig et al, Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy, Molecular Psychiatry (2021). DOI: 10.1038/s41380-021-01178-y


Provided by Bar-Ilan University

Discovery Points To Ketamine’s Long-term Antidepressant Effects (Psychiatry)

THE IDEA

Building on recent research confirming how ketamine induces rapid antidepressant action, Professor of Pharmacology Lisa Monteggia and her collaborators show how the molecular mechanism of the gene MeCP2 and associated synaptic adaptability are critical to the long-term antidepressant effects of ketamine.

While MeCP2 has been shown to be important for typical antidepressants, this research indicates that, in cooperation with ketamine’s initial target, the gene is important for long-term antidepressant action, Monteggia said. The researchers discovered that MeCP2 influences ketamine’s behavioral effect as well as potentiation—the strengthening of synapses—improving its antidepressant effects over time. This work also shows that the long-term effects of ketamine involve synaptic adaptability, or plasticity—not simply structural changes. Monteggia and her team went on to show that repeated exposure to ketamine further strengthened synaptic plasticity—eliciting more plasticity of plasticity—which the team termed “metaplasticity.” This may explain why repeated doses of ketamine produce a cumulative and prolonged effect.

Lisa Monteggia
Lisa Monteggia © Vanderbilt University

WHY IT MATTERS

“We think we have the pathway in the brain to engage these long-term effects,” said Monteggia, also director of the Vanderbilt Brain Institute. “To have an impact on treatment or clinical drug development, you must know the processes in the brain that are involved. This is the first research that gives us an explanation for how ketamine produces long-term effects involving synaptic plasticity in the brain and why ketamine has cumulative antidepressant effects—a huge step forward.”

This discovery will allow researchers to target the neural pathway that prolongs ketamine’s antidepressant effects without the drug itself. While ketamine has significant promise, it also carries abuse liabilities, as the drug can trigger psychomedical effects. At low doses the drug is not harmful, but no one knows the outcome of sustained use of ketamine to date. This discovery may be a way to circumvent the unintended and still unknown negative effects of ketamine exposure.

WHAT’S NEXT

With the knowledge that MeCP2 can regulate gene expression, researchers are now looking to understand the neural pathway of the gene more fully, and to find commonalities with common antidepressants to extend their effects.

FUNDING

This work was supported by National Institutes of Health grants MH070727, MH081060 and MH066198, the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education grant 2016R1A6A3A03008533, and the Swedish Pharmaceutical Society and the Swedish Society for Medical Research.

GO DEEPER

The article “Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation” was published in the journal Nature Neuroscience on June 28.

Collaborators on this research include Ege Kavalali, professor of pharmacology and William Stokes Chair in Experimental Therapeutics, and Vanderbilt postdoctoral researcher Ji-Woon Kim, as well as Anita Autry of Albert Einstein College of Medicine, Elisa Na of Texas Woman’s University, Megumi Adachi of Astellas Pharma, and Carl Bjorkholm of University of Texas Southwestern Medical Center.


Provided by Vanderbilt University

Study Strengthens Argument Postpartum Depression Different To Major Depression (Psychiatry)

Women with postpartum depression experience smell differently to other women, a University of Otago study has found.

Mei Peng image
Dr Mei Peng. © University of Otago

Lead author Dr Mei Peng, of the Department of Food Science, says the findings add further evidence to the growing argument postpartum depression is different to major depression, and requires separate research and medical attention.

“Postpartum depression has been long regarded as a sub-category of major depressive disorder. This condition has a very poor diagnostic rate, with many women suffering from it without being properly diagnosed or treated.

“Recently, the scientific community has been questioning whether postpartum depression should be studied and treated separately from major depression following insights into the different effect each disorder has on neurobiology,” she says.

Pregnancy-related depression is very common, with 6–12 per cent of women being affected during pregnancy, and more than 20 per cent being affected after having a baby. Resolving the status of postpartum depression may have important implications for diagnosis, treatment, policy and research of the disorder.

“Our world-first study helps show the sensory symptoms related to postpartum depression are very different from those of major depression. Specifically, patients with postpartum depression show normal olfactory sensitivity whereas generic depressed patients would show substantially declined olfactory sensitivity.”

The multi-disciplinary study, published in Scientific Reports, assessed the olfactory abilities of 39 depressed mothers, who were pregnant and up to one-year post pregnancy, comparing them against a healthy cohort.

The researchers found no difference between the two groups in terms of their ability to detect smells, but postpartum depressed women experienced different intensity and hedonic perception of some smells.

“These findings imply that postpartum depression is associated with alterations in higher-order olfactory perception, but not early-processing of odours.”

The researchers are currently seeking funding to further study the effects of pregnancy on women’s long-term quality of life.


Publication details:

Olfactory shifts linked to postpartum depression
Mei Peng, Hazel Potterton, JoannaTing Wai Chu and PaulGlue
Scientific Reports


Provided by University of Otago

Researchers Discovered How Levels Of A Protein Could be Used in the Future To Diagnose Schizophrenia (Psychiatry)

Scientists at Sanford Burnham Prebys have discovered how levels of a protein could be used in the future as a blood-based diagnostic aid for schizophrenia. The activity of the protein, which is found in both the brain and blood, affects neural connections in human brains and is uniquely imbalanced in people diagnosed with the condition. The research also provides guidance for future analyses into the molecular basis of this serious, disabling mental disorder.

The study, an international collaboration among groups at Yokohama City University Graduate School of Medicine in Japan and the Department of Psychiatry at Harvard Medical School in Belmont, Massachusetts, was recently published in PNAS.

“This study examined the activity of CRMP2, a protein found in the brain (called a ‘cytoskeletal protein’) that regulates how neurons make connections with each other,” says Evan Y. Snyder, M.D., Ph.D., director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys and co-senior author of the study. “CRMP2 also happens to be expressed in lymphocytes in the blood and can therefore be readily sampled in people by doing nothing more than a simple venipuncture.

“There was an abundance of CRMP2 levels in samples from people with schizophrenia compared to people without the disorder. We also saw structural abnormalities in the dendrites of neurons that could potentially be disabling because dendrites play an important role in receiving impulses from other nerve cells in the brain.”

Previous research has shown that most people maintain an even balance between the two forms of CRMP2: its active, non-phosphorylated form and its inactive, phosphorylated form. The new research first examined postmortem brain tissue and then blood samples from people with schizophrenia. The research team compared these levels to those in people without the disorder.

The findings indicated that the amount of active CRMP2 was too high in people with schizophrenia and, at least in young people with schizophrenia, was not balanced by an appropriate amount of increased inactive CRMP2. That imbalance between active and inactive CRMP2 could account for some dysfunctions in neural connections.

Measuring an abundance of active CRMP2, particularly if its ratio with inactive CRMP2 is too low, could become a format for a rapid, minimally invasive blood test to support the diagnosis of schizophrenia.

“Schizophrenia can be challenging to diagnose early on or in young patients for a number of reasons,” says Snyder. “Pairing a blood test with psychiatric and neurobehavioral exams could help doctors distinguish schizophrenia from other conditions that have somewhat similar symptomologies, such as the manic phase of bipolar disorder or other behavioral, personality, or thought disorders.

“Our results were most striking in people under the age of 40, and even more so in people under the age of 30. An early diagnosis could improve the clinical management of affected individuals as well as accelerate the development of new therapeutic options,” Snyder adds.

The researchers now want to dig deeper into the molecular biology of the disease to discover the “regulator” that keeps most people’s CRMP2 levels on an even keel. They also want to conduct a larger, multi-center clinical study that compares schizophrenia with other psychiatric disorders. Future research will aim to include a wider range of ethnicities and age groups.

Featured image: Functional magnetic resonance imaging (fMRI) and other brain imaging technologies allow for the study of differences in brain activity in people diagnosed with schizophrenia. The image shows two levels of the brain, with areas that were more active in healthy controls than in schizophrenia patients shown in orange, during an fMRI study of working memory. Credit: Kim J, Matthews NL, Park S./PLoS One.


Reference: Munetaka Nomoto el al., “Clinical evidence that a dysregulated neural network modulator may aid in diagnosing schizophrenia,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2100032118


Provided by Sanford Burnham Prebys Medical Discovery Institute

Scientists Reverse Age-related Memory Loss in Mice (Psychiatry)

Scientists at Cambridge and Leeds have successfully reversed age-related memory loss in mice and say their discovery could lead to the development of treatments to prevent memory loss in people as they age.

“Although our study was only in mice, the same mechanism should operate in humans – the molecules and structures in the human brain are the same as those in rodents. This suggests that it may be possible to prevent humans from developing memory loss in old age.”

— James Fawcett

In a study published in Molecular Psychiatry, the team show that changes in the extracellular matrix of the brain – ‘scaffolding’ around nerve cells – lead to loss of memory with ageing, but that it is possible to reverse these using genetic treatments.

Recent evidence has emerged of the role of perineuronal nets (PNNs) in neuroplasticity – the ability of the brain to learn and adapt – and to make memories. PNNs are cartilage-like structures that mostly surround inhibitory neurons in the brain. Their main function is to control the level of plasticity in the brain. They appear at around five years old in humans, and turn off the period of enhanced plasticity during which the connections in the brain are optimised. Then, plasticity is partially turned off, making the brain more efficient but less plastic.

PNNs contain compounds known as chondroitin sulphates. Some of these, such as chondroitin 4-sulphate, inhibit the action of the networks, inhibiting neuroplasticity; others, such as chondroitin 6-sulphate, promote neuroplasticity. As we age, the balance of these compounds changes, and as levels of chondroitin 6-sulphate decrease, so our ability to learn and form new memories changes, leading to age-related memory decline.

Researchers at the University of Cambridge and University of Leeds investigated whether manipulating the chondroitin sulphate composition of the PNNs might restore neuroplasticity and alleviate age-related memory deficits.

To do this, the team looked at 20-month old mice – considered very old – and using a suite of tests showed that the mice exhibited deficits in their memory compared to six-month old mice.

For example, one test involved seeing whether mice recognised an object. The mouse was placed at the start of a Y-shaped maze and left to explore two identical objects at the end of the two arms. After a short while, the mouse was once again placed in the maze, but this time one arm contained a new object, while the other contained a copy of the repeated object. The researchers measured the amount of time the mouse spent exploring each object to see whether it had remembered the object from the previous task. The older mice were much less likely to remember the object.

The team treated the ageing mice using a ‘viral vector’, a virus capable of reconstituting the amount of 6-sulphate chondroitin sulphates to the PNNs and found that this completely restored memory in the older mice, to a level similar to that seen in the younger mice.

Dr Jessica Kwok from the School of Biomedical Sciences at the University of Leeds said: “We saw remarkable results when we treated the ageing mice with this treatment. The memory and ability to learn were restored to levels they would not have seen since they were much younger.”

To explore the role of chondroitin 6-sulphate in memory loss, the researchers bred mice that had been genetically-manipulated such that they were only able to produce low levels of the compound to mimic the changes of ageing. Even at 11 weeks, these mice showed signs of premature memory loss. However, increasing levels of chondroitin 6-sulphate using the viral vector restored their memory and plasticity to levels similar to healthy mice.

Professor James Fawcett from the John van Geest Centre for Brain Repair at the University of Cambridge said: “What is exciting about this is that although our study was only in mice, the same mechanism should operate in humans – the molecules and structures in the human brain are the same as those in rodents. This suggests that it may be possible to prevent humans from developing memory loss in old age.”

The team have already identified a potential drug, licensed for human use, that can be taken by mouth and inhibits the formation of PNNs. When this compound is given to mice and rats it can restore memory in ageing and also improves recovery in spinal cord injury. The researchers are investigating whether it might help alleviate memory loss in animal models of Alzheimer’s disease.

The approach taken by Professor Fawcett’s team – using viral vectors to deliver the treatment – is increasingly being used to treat human neurological conditions. A second team at the Centre recently published research showing their use for repairing damage caused by glaucoma and dementia.

The study was funded by Alzheimer’s Research UK, the Medical Research Council, European Research Council and the Czech Science Foundation.

Featured image: Spatially oriented model (mouse brain) © University of Cambridge


Reference
Yang, S et al. Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing. Molecular Psychiatry; 16 July 2021; DOI: doi.org/10.1038/s41380-021-01208-9


Provided by University of Cambridge

Researchers Found First Direct Genetic Link Between The SUV39H2 Gene and ASD (Psychiatry)

New research from the RIKEN Center for Brain Science (CBS) in Japan shows that a deficit in histone methylation could lead to the development of autism spectrum disorders (ASD). A human variant of the SUV39H2 gene led researchers to examine its absence in mice. Published in Molecular Psychiatry, the study found that when absent, adult mice exhibited cognitive inflexibility similar to what occurs in autism, and embryonic mice showed misregulated expression of genes related to brain development. These findings represent the first direct link between the SUV39H2 gene and ASD.

Genes are turned on and off throughout our development. But genetic variation means that what is turned off in some people remains turned on in others. This is why, for example, some adults can digest dairy products and others are lactose intolerant; the gene for making the enzyme lactase is turned off when some people become adults, but not others. One way that genes can be turned on and off is through a process called histone methylation in which special enzymes transfer methyl groups to histone proteins that are wrapped around DNA.

Variations in genes related to methylation during brain development can lead to serious problems. One such variation occurs in a rare disorder called Kleefstra Syndrome, in which a mutation prevents methylation of H3K9–a specific location on histone H3. Because Kleefstra Syndrome resembles autism in some ways, RIKEN CBS researchers led by Takeo Yoshikawa looked for autism-specific variations in genes that can modify H3K9. Among nine such genes, they found one variant in an H3K9 methyltransferase gene–SUV39H2–that was present in autism, and the mutated SUV39H2 prevented methylation when tested in the lab. Similar loss-of-function results were found for the mouse version of the variant.

Behavioral sequencing task for self-paced learning and flexibility, showing opposite rewarded corners where the mouse has to go back and forth. In one task, the diagonally opposite rewarded corners are alternated sequentially with the other, upon achieving the successful visit-rate criterion at one diagonal. In the other task only one of the two previously rewarded corners is switched. When these two tasks were mixed together (serial reversal-learning), the Suv39h2-deficient mice had difficulty adapting to changes in rules. © RIKEN

The next step was to see what happens in mice that lack the Suv39h2 gene. Behaviorally, the researchers found that the mice could learn a simple cognitive task, but had difficultly when the task required cognitive flexibility. In the simple task, mice learned to get a reward by poking a door at alternating diagonal corners of a cage. After they could do this well, the possible reward locations switched to the other two diagonal corners. The genetically modified mice did this as well as wild-type mice. In another task, after learning to alternate between the two diagonal corners, only the location of one reward was switched. When the mice were challenged to alternate randomly between these two tasks, wild-type mice could adapt quickly, but the Suv39h2-deficient mice took much longer. “This serial reversal-learning task was essential,” says first author Shabeesh Balan. “Cognitive inflexibility is a core symptom of ASD, and our new task was able to address this behavioral feature in ways that previous mouse studies could not.”

When the researchers examined what happened in the mouse brain when H3K9 methylation failed to occur, they found that important genes that are usually silenced in early development were turned on in the experimental mice. “Suv39h2 is known to be expressed in early neurodevelopment and to methylate H3K9,” explains Yoshikawa. “This keeps a check on genes that should be switched-off. But without it, genes in the protocadherin β cluster were abnormally expressed at high levels in embryonic mice.” Because protocadherins are critical for the formation of neural circuits, the researchers believe they have found an important biological pathway that could be central to several neurodevelopmental disorders.

The team then verified the importance of SUV39H2 in human ASD by finding that its expression was lower in the postmortem brains of people with ASD than of controls. “What began with a loss-of-function mutation in only one person with ASD,” says Yoshikawa, “has led to a general causal landscape for ASD that culminates in brain circuit abnormality.”

Protocadherins have already been proposed to be related to a broad range of mental disorders. This study shows that activating the SUV39H2 gene is a potential therapy for mental disorders–including ASD–that should be investigated more thoroughly in future studies.

Featured image: H3K9 methylation levels in the cerebellum were lower in the Suv39h2-deficient mice than in control mice controls. © RIKEN


Reference: Balan et al. (2021) A loss of function variant in SUV39H2 identified in autism spectrum disorder causes altered H3K9-trimethylation and dysregulation of protocadherin β cluster genes in the developing brain. Molecular Psychiatry. doi: 10.1038/s41380-021-01199-7


Provided by RIKEN

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

Scientists Show How Light Therapy Treats Depression In Mice Model (Psychiatry)

Light activates the circadian clock gene Period1 in a brain region that affects the mood

Light therapy can help improve the mood of people with seasonal affective disorder (SAD) during short winter days, but exactly how this therapy works is not well understood. A new study by Urs Albrecht at the University of Fribourg, published July 8th in the journal PLOS Genetics, finds that light therapy’s beneficial effects come from activating the circadian clock gene Period1 in a part of the brain involved in mood and sleep-wake cycles.

Nighttime light has strong effects on the physiology and behavior of mammals. It can reset an animal’s circadian rhythms, and in the form of light therapy, affect mood in humans. Albrecht and his colleagues investigated how nighttime light impacts mood using mice as a model. They exposed mice to a pulse of light at different points during the night and then tested them for depressive behavior. The researchers discovered that light exposure at the end of the dark period–two hours before daytime–had an antidepressant effect on the animals. The pulse of light activated the Period1 gene in a brain region called the lateral habenula, which plays a role in mood. Light at other times, however, had no effect. When they deleted the Period1 gene, the mice no longer experienced the light’s beneficial effects.

The new results provide evidence that turning on Period1 in the lateral habenula is the key to light’s mood-boosting powers. The discovery that mice appeared to be less depressed when exposed to light at the end of the dark period than the beginning is similar to findings in humans. Light therapy is more efficient in the early morning than in the evening for patients with SAD. However, the researchers caution against making too many direct comparisons to humans since mice are nocturnal animals.

The researchers add, “Light perceived in the late part of the night induces expression of the clock gene Per1, which is related to improvement of depression like behavior in mice.”

In your coverage please use this URL to provide access to the freely available article in PLOS Geneticshttp://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009625

Funding: This work was supported by the Velux Foundation (https://veluxstiftung.ch) Projects 995 and 772 to U.A. and the Swiss National Science Foundation (http://www.snf.ch) project number 310030_184667/1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Featured image: Per1 gene expression (yellow color) before (left panel) and after a 15 minute light pulse (right panel) given in the dark at zeitgeber time 22 in the lateral habenula (area visualized by hatched lines). The blue color depicts cell nuclei. The white line bottom left indicates the scale and corresponds to 200 μm © Iwona Olejniczak, 2021, PLOS Genetics, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)


Reference: Olejniczak I, Ripperger JA, Sandrelli F, Schnell A, Mansencal-Strittmatter L, Wendrich K, et al. (2021) Light affects behavioral despair involving the clock gene Period 1. PLoS Genet 17(7): e1009625. https://doi.org/10.1371/journal.pgen.1009625


Provided by PLOS

New Anticholinergic Drug Keeps PTSD Flashbacks and Nightmares Away (Psychiatry)

Researchers find that central anticholinergic drug trihexyphenidyl can potentially keep away post-traumatic stress disorder-related flashbacks and nightmares

Post-traumatic stress disorder (PTSD) rings a bell for many, due to its rampant references in pop culture, and more, importantly, its prevalence in today’s society. It is only probable that this disorder, which develops after shocking or dangerous events, would unfortunately affect the lives of many people. Medical researchers have been hard at work trying to come up with solutions to combat this condition and its manifestations effectively. Unfortunately, the neurological mechanisms of PTSD aren’t clear, and without knowing this exactly, trying to find a cure is a shot in the dark.

Fortunately, a group of Japanese researchers from the Sogo PTSD Institute, Medical Corporation Sogokai, Japan led by Dr. Masanobu Sogo appear to have made a breakthrough in PTSD treatment! They have identified a drug called trihexyphenidyl, that can significantly reduce the flashbacks and nightmares experienced by patients with PTSD, according to a study published in Brain and Behavior, a sister open access journal to ACTA J.

Trihexyphenidyl is a central anticholinergic drug used to manage disorders like parkinsonism, and alleviate several side-effects induced by drugs acting on the central nervous system (CNS). It acts by blocking the activity of a neurotransmitter, acetylcholine, in the CNS. Interestingly, it has been available for therapeutic use for around 66 years.

So, what inspired the researchers to pick up this drug? In 2009, they encountered a patient who suffered severe PTSD-related flashbacks and nightmares for 9 years, was diagnosed with bacterial diarrhea at another hospital, and administered a drip infusion containing antibiotics and scopolamine butyl bromide (SB), which is a peripheral anticholinergic that doesn’t cross the blood-brain barrier (BBB, penetration rate 0.01%). Twenty minutes after the infusion, the patient’s flashbacks completely disappeared!

Since SB is a “peripheral” anticholinergic agent, it shouldn’t be able to cross the BBB, but it is probable that the patient’s brain was in a state of severe brain excitement due to PTSD. There are eight acetylcholine basal ganglia in the brain, of which the largest, the Meynert nucleus, is closely associated with BBB permeability. The researchers hypothesized that due to abnormal excitement of the Meynert basal ganglia, SB enters the brain and activates anticholinergic action to suppress abnormal acetylcholine secretion of acetylcholine-memory-related circuits centered on the Meynert basal ganglia, eliminating the flashbacks.

From this valuable clinical experience, they figured that PTSD is generated through an acetylcholine-memory-related-circuit centered on Meynert. Based on this, Dr. Sogo and his team considered the use of a central anticholinergic agent: trihexyphenidyl.

Excited at the discovery, the researchers went on to devise an exploratory study, to check if trihexyphenidyl is effective against similar symptoms in other patients with PTSD. They administered trihexyphenidyl in 34 patients with PTSD, who had previously received psychiatric treatment for several years without therapeutic benefits, and determined its effect through interviews.

A significant 88% of the analyzed patients reported mild to no PTSD-related nightmares. Similarly, 79% of the analyzed patients reported similar responses for PTSD-related flashbacks. Notably, the researchers found that trihexyphenidyl has efficacy and a rapid onset (1-2 days) in the treatment of PTSD-related nightmares and flashbacks. Clearly, trihexyphenidyl is the elusive silver bullet against PTSD!

Dr. Sogo states, “To the best of our knowledge, this is the first pharmacological report describing the novel use of trihexyphenidyl for PTSD-related nightmares, which doesn’t respond to conventional psychiatric treatment.” While further studies are needed to prove the mechanism of PTSD, repurposing trihexyphenidyl to treat PTSD would be a promising turn of events, since the drug is inexpensive, and has no adverse effects. Here’s to hope for patients suffering from PTSD, with the discovery of trihexyphenidyl!


Reference

  • Authors: Katsumasa Sogo, Masanobu Sogo, Yoshie Okawa
  • Title of original paper: Centrally acting anticholinergic drug trihexyphenidyl is highly effective in reducing nightmares associated with post-traumatic stress disorder
  • JournalBrain and Behavior
  • DOIhttps://doi.org/10.1002/brb3.2147
  • Affiliations: Sogo PTSD Institute, Medical Corporation, Sogokai, Hiroshima-city, Japan

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