Chronic pain-induced depression: Underlying mechanism revealed in mice, showing how ketamine acts as antidepressant in chronic pain

Chronic pain often leads to depression, which increases suffering and is clinically difficult to treat. Understanding the underlying mechanism identifies a potential therapeutic target for treatment

Peer-Reviewed Publication

UNIVERSITY OF ALABAMA AT BIRMINGHAM

 

IMAGE: LINGYONG LI view more 

CREDIT: UAB

BIRMINGHAM, Ala. – Chronic pain often leads to depression, which increases suffering and is clinically difficult to treat. Now, for the first time, researchers have uncovered the underlying mechanism that drives those depressive systems, according to a study published in The Journal of Clinical Investigation.

The mechanism acts to cause hypersensitivity in a part of the brain called the anterior cingulate cortex, or ACC, and knowledge of this mechanism identifies a potential therapeutic target for the treatment of chronic pain-induced depression, say Lingyong Li, Ph.D., and Kimberley Tolias, Ph.D., co-leaders of the research.

“Chronic pain is a major, unmet health issue that impacts the quality of life,” said Li, an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Unfortunately, patients suffering from chronic pain have limited effective treatment options.”

The research focused on a protein called Tiam1, which modulates the activity of other proteins that help build or unbuild the cytoskeletons of cells. Specifically, the research teams of Li and Tolias, a professor at Baylor College of Medicine, Houston, Texas, found that chronic pain in a mouse model leads to an activated Tiam1 in ACC pyramidal neurons, resulting in an increased number of spines on the neural dendrites. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons.

This higher spine density increased the number of connections, and the strength of those connections, between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with depression in the mouse model. Reversing the number and strength of connections in the model, by using an antagonist of Tiam1, relieved the mice of depression and diminished hypersensitivity of the neurons.

The ACC was already known as a critical hub for comorbid depressive symptoms in the brain. To investigate the mechanism for those symptoms, the team led by Li and Tolias first showed that Tiam1 in the ACC was activated in two mouse models of chronic pain with depressive or anxiety-like behaviors, as compared to controls.

To show that Tiam1 in the ACC modulates chronic pain-induced depressive-like behaviors, the researchers used molecular scissors to delete Tiam1 from the forebrain excitatory neurons of the mice. These mice were viable, and fertile, and displayed no gross alterations, and they still showed hypersensitivity to chronic pain. Strikingly, however, these Tiam1 conditional knockout mice did not display depressive- or anxiety-like behaviors in five different tests that gauge depression or anxiety.

When researchers specifically deleted Tiam1 from ACC neurons, they found the same results as the broader forebrain deletion. Thus, Tiam1 expressed in ACC neurons appears to specifically mediate chronic pain-induced depressive-like behaviors.

Other studies have established that an underlying cause of stress-induced depression and anxiety disorders is alterations in synaptic connections in brain regions involved in mood regulation, including the prefrontal cortex, the hippocampus and the amygdala. Li and Tolias found similar changes in dendritic neurons in the ACC for chronic pain-induced depressive-like behavior — they saw a significant increase in dendritic spine density and signs of increased cytoskeleton building. This was accompanied by increased NMDA receptor proteins and increased amplitudes of NMDA currents in the ACC neurons, both associated with hyperactivity.

These maladaptive changes were not seen in the Tiam1-knockout mice.

Researchers further showed that inhibiting Tiam1 signaling with a known inhibitor alleviated the chronic pain-induced depressive-like behaviors, without reducing the chronic pain hypersensitivity itself. The inhibition also normalized dendritic spine density, cytoskeleton building, NMDA receptor protein levels and NMDA current amplitudes.

Ketamine is a drug known to produce rapid and sustained antidepressant-like effects in chronic pain-induced depression, without decreasing sensory hypersensitivity. However, its mechanism is not fully understood. Li, Tolias and colleagues showed that ketamine’s sustained antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine’s blocking the Tiam1-dependent, maladaptive synaptic plasticity in the mouse ACC neurons.

“Our work demonstrates the critical role Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the sustained antidepressant-like effects of ketamine, revealing it as a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain,” Li said.

Co-first authors of the study, “TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain,” are Qin Ru and Yungang Lu, Baylor College of Medicine.

Co-authors with Li, Tolias, Ru and Lu are Ali Bin Saifullah, Francisco A. Blanco and Changqun Yao, Baylor College of Medicine; Juan P. Cata, MD Anderson Cancer Center, Houston, Texas; and De-Pei Li, University of Missouri School of Medicine, Columbia, Missouri.

Support came from United States Department of Defense grants W81XWH-20-10790 and W81XWH-21-10742, the Mission Connect/TIRR Foundation, and National Institutes of Health grant NS062829.

At UAB, Anesthesiology and Perioperative Medicine is a department in the Marnix E. Heersink School of Medicine.

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JOURNAL

Journal of Clinical Investigation

DOI

10.1172/JCI158545 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain

Most antidepressants ineffective for common pain conditions

Overview adds to mounting evidence challenging the use of medicines for pain

Peer-Reviewed Publication

BMJ

Some antidepressant drugs are effective for some pain conditions, but most are either ineffective or the evidence is inconclusive, despite being used for a range of pain conditions, finds an overview of the latest evidence published by The BMJ today.

Researchers call for a more nuanced approach when prescribing antidepressants for pain.

The use of antidepressants doubled in OECD countries from 2000 to 2015 and their off-label (unapproved) use to treat common pain conditions such as fibromyalgia, persistent headaches, and osteoarthritis is thought to be part of this increase.

To explore this further, a team of researchers led by Giovanni Ferreira at the University of Sydney carried out an overview of the effectiveness, safety, and tolerability of antidepressants for pain according to condition.

They searched databases for systematic reviews comparing any antidepressant with placebo for any pain condition in adults and found 26 eligible evidence reviews published between 2012 and 2022 involving 156 separate trials and over 25,000 participants.

These reviews reported on the effectiveness of eight classes of antidepressant covering 22 pain conditions (42 distinct antidepressant versus placebo comparisons). Almost half (45%) of the trials in these reviews had ties to industry.

Using data from each review, the researchers estimated relative risks of pain or average differences in pain between groups on a 0-100 point scale, taking account of dose, treatment duration, and number of trials and participants.

They also assessed safety and tolerability (withdrawals due to adverse events), certainty of evidence, and risk of bias. Findings were then classified from each comparison as effective, not effective, or inconclusive. 

No review provided high certainty evidence on the effectiveness of antidepressants for pain for any condition. 

Nine reviews provided evidence that some antidepressants were effective compared with placebo for nine conditions in 11 distinct comparisons. 

For example, moderate certainty evidence suggested that serotonin-norepinephrine reuptake inhibitors (SNRIs) were effective for back pain (average 5.3 points lower on the pain scale than placebo), postoperative pain, fibromyalgia, and neuropathic pain.

Low certainty evidence suggested that SNRIs were effective for pain linked to breast cancer treatment, depression, knee osteoarthritis, and pain related to other underlying conditions.

Low certainty evidence also suggested that selective serotonin reuptake inhibitors (SSRIs) were effective for people with depression and pain related to other conditions; and that tricyclic antidepressants (TCAs) were effective for irritable bowel syndrome, neuropathic pain, and chronic tension-type headache. 

For the other 31 comparisons, antidepressants were either not effective (five comparisons) or the evidence was inconclusive (26 comparisons).

Most safety and tolerability data were imprecise, indicating that the safety of antidepressants for several conditions is still uncertain.

This was a well designed review based on a thorough literature search and the researchers took steps to minimise the impact of issues such as differences in study design and quality, imprecision, and publication bias.

But they acknowledge that most comparisons had a limited number of trials, and results may not apply to antidepressants prescribed for symptoms linked to pain conditions, such as fatigue or sleep disturbance. Caution is also needed in interpreting these findings because 45% of the trials forming the evidence for this review had ties to industry, they add.

In conclusion, they say: “Some antidepressants were efficacious for some pain conditions; however, efficacy appears to depend on the condition and class of antidepressant. The findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain.”

These findings suggest that for most adults living with chronic pain, antidepressant treatment will be disappointing, say researchers in a linked editorial.

They acknowledge that clinicians continue to prescribe medicines for which the evidence is poor because they see that some people respond to them, albeit modestly, but say other less potentially harmful options, such as exercise and support with mobility and social isolation, can help people to live well with pain. 

For people with pain, compassionate and consistent relationships with clinicians remain the foundations of successful care, they write. 

Studies must also involve people living with pain to ensure, among many other things, that pain research is meaningful to those living with pain and helps them and their clinicians make better shared decisions about treatments, they conclude.

 

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JOURNAL

The BMJ

DOI

10.1136/bmj-2022-072415 

METHOD OF RESEARCH

Systematic review

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic review

ARTICLE PUBLICATION DATE

1-Feb-2023

Antidepressants use for chronic pain on the rise, but are they effective?

More thoughtful approach to prescribing for pain needed

Peer-Reviewed Publication

UNIVERSITY OF SYDNEY

Many people are unaware that some antidepressants (medications used to treat people living with depression) are also being prescribed to treat certain chronic pain conditions.

One in five people experience chronic pain in Australia and globally, and treatment of chronic pain is often suboptimal, with commonly used medicines having limited or unknown benefits. The use of antidepressants to help manage a person’s pain is on the rise, even when they do not have a mood disorder like depression.

An international team of researchers has found that some classes of antidepressants were effective in treating certain pain conditions in adults, but others were either not effective, or the effectiveness was unknown.

Published in The BMJ, the study reviewed the safety and effectiveness of antidepressants in the treatment of chronic pain.

The researchers say the results show that clinicians need to consider all the evidence before deciding to prescribe antidepressants for chronic pain management. 

“This review, for the first time, brings together all the existing evidence about the effectiveness of antidepressants to treat chronic pain in one comprehensive document,” said lead author Dr Giovanni Ferreira from The Institute for Musculoskeletal Health and Sydney Musculoskeletal Health at the University of Sydney.

The review examined 26 systematic reviews from 2012 to 2022 involving over 25,000 participants. This included data from 8 antidepressant classes and 22 pain conditions including back pain, fibromyalgia, headaches, postoperative pain, and irritable bowel syndrome.

Serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants such as duloxetine were found to be effective for the largest number of pain conditions, such as back pain, knee osteoarthritis, postoperative pain, fibromyalgia, and neuropathic pain (nerve pain).

By contrast tricyclic antidepressants, such as amitriptyline, are the most commonly used antidepressant to treat pain in clinical practice, but the review showed that it is unclear how well they work, or whether they work at all for most pain conditions.

The use of antidepressants as a treatment for pain has recently gained attention globally. A 2021 guideline for chronic primary pain management published by The National Institute for Health and Care Excellence (NICE) recommends against using pain medicines with the exception of antidepressants. The guideline recommends different types of antidepressants, such as amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine or sertraline for adults living with chronic primary pain.

Dr Ferreira said a more nuanced approach to prescribing antidepressants for pain is needed.

“Recommending a list of antidepressants without careful consideration of the evidence for each of those antidepressants for different pain conditions may mislead clinicians and patients into thinking that all antidepressants have the same effectiveness for pain conditions. We showed that is not the case.”

Co-author Dr Christina Abdel Shaheed from The School of Public Health and Sydney Musculoskeletal Health at the University of Sydney said:

“The findings from this review will support both clinicians and patients to weigh up the benefits and harms of antidepressants for various pain conditions so that they can make informed decisions about whether and when to use them.”

Dr Ferreira said that there are multiple treatment options for pain, and people should not rely solely on pain medicines for pain relief.

“Some pain medicines may have a role in pain management, but they need to be considered as only part of the solution. For some pain conditions, exercise, physiotherapy, and lifestyle changes may also help. Speak to your health professional to learn more about what alternatives might be appropriate for you,” Dr Ferreira said.

Professor Christopher Maher, Co-Director of Sydney Musculoskeletal Health at the University of Sydney, said, “This review distilled the evidence from over 150 clinical trials into an accessible summary that clinicians can use to help them make better decisions for their patients with chronic pain.”

The current status of antidepressants in Australia and globally

Most antidepressant prescriptions for pain are ‘off-label’, which is when antidepressants have not been approved to be prescribed for pain.

Many antidepressants are thought to help with pain by acting on chemicals in the brain that can assist with pain relief, such as serotonin. However, it is unknown exactly why some antidepressants improve pain. In Australia, the only antidepressant approved for treating pain is duloxetine, which is approved for diabetic neuropathic pain (nerve pain caused by diabetes).

Amitriptyline is approved in the United Kingdom for some pain conditions, such as neuropathic pain (nerve pain), tension-type headaches and migraines, but it is not approved for treating any pain conditions in Australia.

The use of antidepressants has doubled in OECD countries from 2000 to 2015, and the use of ‘off-label’ prescriptions of antidepressants for pain is considered a contributing factor to this increase. Data from Canada, the United States, the United Kingdom and Taiwan, suggest that among older people, chronic pain was the most common condition leading to an antidepressant prescription, even more so than depression.

Currently, no data from Australia shows how many antidepressant prescriptions are for pain.

-ENDS-

 

Note:  Antidepressants are prescription-only medicines. Do not use antidepressants unless advised by a doctor. It is very important not to abruptly cease treatment with antidepressant medicines. This can lead to withdrawal effects which can be distressing and sometimes present as serious health issues. These withdrawal effects include dizziness, nausea, anxiety, agitation, tremor, sweating, confusion, and sleep disturbance.

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JOURNAL

The BMJ

DOI

10.1136/bmj-2022-072415 

METHOD OF RESEARCH

Systematic review

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Efficacy, safety, and tolerability of antidepressants for pain: an overview of systematic reviews

ARTICLE PUBLICATION DATE

1-Feb-2023

Β-blocker use associated with lower rates of violence

Study assesses medicated vs. non-medicated behavioral health in 1.4 million individuals over an eight-year period

Peer-Reviewed Publication

PLOS

 

IMAGE: Β-BLOCKERS MAY REDUCE AGGRESSION IN PERSONS WITH MAJOR PSYCHIATRIC DISORDERS view more 

CREDIT: DAN BURTON, UNSPLASH (CC0, HTTPS://CREATIVECOMMONS.ORG/PUBLICDOMAIN/ZERO/1.0/)

Reductions in violence are seen in individuals using Beta adrenergic-blocking agents (β-blockers) compared with periods that they are not taking the medication, in a study published January 31st in the open access journal PLOS Medicine. If the findings are confirmed by other studies, β-blockers could be considered as a way to manage aggression and hostility in individuals with psychiatric conditions.

β-blockers are used to treat hypertension, angina and acute cardiovascular events, heart failure and arrhythmias as well as, migraine, symptoms of hyperthyroidism and glaucoma. They are often used for anxiety and have been suggested for clinical depression and aggression, but evidence is conflicting. They have been linked to an increased risk of suicidal behavior though evidence is inconclusive.

Seena Fazel of the University of Oxford, UK, and colleagues at the Karolinska Institute in Sweden investigated psychiatric and behavioral outcomes: hospitalizations for psychiatric disorders; suicidal behavior and deaths from suicide; and charges of violent crime. They compared 1.4 million β-blocker users in Sweden to themselves during medicated and non-medicated periods over an eight-year period from 2006-2013.

Periods on β-blocker treatment were associated with a 13% lower risk of being charged with a violent crime by the police, which remained consistent across the analyses. Additionally, an 8% lower risk of hospitalization due to a psychiatric disorder was reported as well as an 8% increased association of being treated for suicidal behavior. However, these associations varied depending on psychiatric diagnosis, past psychiatric problems, as well as the severity and type of the cardiac condition the β-blockers were being used to treat.

Previous research has linked severe cardiac events to an increased risk of depression and suicide, and these results might suggest that the psychological distress and other disabilities associated with serious cardiac problems, rather than the β-blocker treatment, increases the risk of serious psychiatric events. In secondary analyses, associations with hospitalization were lower for major depressive but not for anxiety disorders.

In order to understand the role of β-blockers in the management of aggression and violence, further studies including randomized controlled trials are needed. If these confirm the results of this study, β-blockers could be considered to manage aggression and violence in some individuals.

Fazel adds, “In a real-world study of 1.4 million persons, β-blockers were associated with reduced violent criminal charges in individuals with psychiatric disorders. Repurposing their use to manage aggression and violence could improve patient outcomes.”

#####

In your coverage, please use this URL to provide access to the freely available paper in PLOS Medicine:

http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004164

Citation: Molero Y, Kaddoura S, Kuja-Halkola R, Larsson H, Lichtenstein P, D’Onofrio BM, et al. (2023) Associations between β-blockers and psychiatric and behavioural outcomes: A population-based cohort study of 1.4 million individuals in Sweden. PLoS Med 20(1): e1004164. https://doi.org/10.1371/journal.pmed.1004164

Author Countries: Sweden, United Kingdom, United States of America

Funding: This study was supported by the Wellcome Trust (No 202836/Z/16/Z): https://wellcome.org/grant-funding (SF), the Swedish Research Council for Health Working Life and Welfare (2015-0028): https://forte.se/en/ (PL and HL), the American Foundation for Suicide Prevention (DIG-1-037-19): https://afsp.org/research-grant-information (BMD), and Karolinska Institutet Funds (2016fobi50581): https://staff.ki.se/ki-foundations-funds-list-of-grants (YM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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JOURNAL

PLoS Medicine

DOI

10.1371/journal.pmed.1004164 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

COI STATEMENT

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: HL reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; and sponsorship for a conference on attention-deficit/hyperactivity disorder from Shire/Takeda Pharmaceuticals and Evolan Pharma AB, all outside the submitted work. All other authors have declared that no competing interests exist.

Why reflecting on your values before opening your mouth makes for happier relationships

University of Bath Press Release

Peer-Reviewed Publication

UNIVERSITY OF BATH

Ever found yourself angry at a situation and in desperate need to tell the world about it by ranting to anyone who’ll listen? Maybe it’s time to pause; inhale and reflect on what values you hold dear.

A new interdisciplinary study, conducted by philosophers and linguists at Cardiff University and psychologists at the University of Bath has found that a process of reflecting on life values before a debate can enhance people’s willingness to listen to others and engage with them in a civil dialogue.

For the study, the research team recruited 303 participants. Participants were all put in small groups where they were asked to discuss the merits of charging tuition fees for education. Before the debate, half were first asked to write about the life values* they considered important. All discussions were recorded, coded, and analysed. 

The analysis revealed that the process of reflecting on values first helped to inspire individuals’ ‘intellectual humility’: their awareness of their own fallibility and openness to others’ views. 60.6% of participants who reflected on their values first showed more humility compared to the average person who was not given this task.

In a seemingly ever-distant world where opinions appear increasingly polarised, the researchers suggest their results show grounds for optimism. If people were to stop and reflect on the values which are important to them, debates in the online and offline world could be far more harmonious, they speculate.

Co-lead for the study, Dr Paul Hanel who conducted the research at the University of Bath but is now based at the University of Essex explained: “We are often told that we live in a polarised world where having the ‘wrong’ view about topics will get you shouted down before you have had a chance to finish.

“This research suggests that polarisation might be exaggerated and that by pausing to reflect on personal values before engaging in these kinds of conversations, our interactions could become more harmonious.”

Previous research from the University of Bath-based team in 2019 found that people are in fact much more united in their beliefs and values than media reporting often suggests. The work forms part of a wider project all about ‘Changing Attitudes in Public Discourse’, led by Cardiff University. 

Co-author, Professor Greg Maio, Head of the Department of Psychology at the University of Bath added: “The good news from this study is that the vitriol we often see perpetuated online does not have to be that way. By presenting participants with an opportunity to reflect on their values, we found a marked improvement in how they engaged with discussions.

“In the future, we would like to see if this kind of value reflection also works online, to encourage less arrogant dialogue among social media users. We would certainly be interested in sharing our findings with social media developers and others.”

Co-author, Professor Alessandra Tanesini, a philosopher at Cardiff University adds: “Our research shows that strategies promoting virtuous attitudes by means of value affirmation improve people’s ability to learn from each other. Ours is an intervention whose implementation in schools and universities can also make an important pedagogical contribution to students’ education”.

This research was funded by Templeton Foundation**.

Notes

* The most frequently chosen values by participants were ‘self-direction thought’, which is the freedom to cultivate one’s own ideas and abilities (chosen by 32 participants); ‘universalism-concern’, which represents commitment to equality, justice, and protection for all people (26 participants); ‘self-direction action’, which is the freedom to determine one’s own actions (19 participants); and ‘personal security’, which is safety in one’s immediate environment (16 participants).

**Research leading to the paper was partially funded by a subaward agreement from the University of Connecticut with funds provided by Grant No. 58942 from John Templeton Foundation. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of UConn or the John Templeton Foundation.

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JOURNAL

Royal Society Open Science

DOI

10.1098/rsos.220958 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Using self-affirmation to increase intellectual humility in debate

ARTICLE PUBLICATION DATE

1-Feb-2023

OR AS I LIKE TO SAY; 

'BEFORE SHOOTING YOURSELF IN THE FOOT 

BE SURE YOU HAVE REMOVED IT FROM YOUR MOUTH'

IQ changes over time may help track development, guide intervention in autistic youth

UC Davis MIND Institute study identifies three paths of intellectual development

Peer-Reviewed Publication

UNIVERSITY OF CALIFORNIA - DAVIS HEALTH

A long-term study by UC Davis MIND Institute researchers confirms that changes in the IQ level of autistic children may help predict their path of communication and behavioral development as adolescents.

The new work builds on a previous MIND Institute study of IQ trajectories in autistic children ages 2-8. It expands the findings to older youth.

The study, published in JCPP Advances, has identified three distinct paths of intellectual development in autistic children: persistent intellectual disability, an increase in IQ, or an IQ that remained average or above.

“Once more, we have shown that we can use IQ to identify a subtype of autism,” said lead author Marjorie Solomon. She is the MIND Institute’s associate director and a professor in the Department of Psychiatry and Behavioral Sciences. “Given that IQ is perhaps the strongest predicter of later outcomes in autistic children, we believe that studying IQ trajectories in childhood is very important. It provides clues about their potential different future paths and how we can help individuals to flourish.”

Study methods

The study’s participants were from the MIND Institute’s Autism Phenome Project, one of the world’s most comprehensive longitudinal studies of its kind. Researchers have been following a group of autistic children from about age 3 through adolescence

The study included 373 (115 females, 258 males) autistic participants ranging from age 2 to age 12. Importantly, individuals with all levels of intellectual ability were part of the sample.

Assessments of behavior and autistic characteristics were collected across childhood. IQ was evaluated at three timepoints: T1 (mean age of 3 years), T2 (mean age of 5.6 years) and T3 (mean age of 11.5 years).

Licensed clinical psychologists specializing in autism evaluated the participants using autism assessment tools. These included the ADOS (Autism Diagnostic Observation Schedule), ADOS-2, ADI-R (Autism Diagnostic Interview – Revised), and the Vineland Adaptive Behavior Scales (VABS).

Based on these assessments, the participants were divided into three subgroups:

• “Changers” described those who began with low IQs in early childhood, followed by a substantial increase that slowed as they entered middle childhood. “Changers” made up 39% of the participants.
• “Persistent Intellectual Disability” described the individuals who began with a below average IQ that persisted across childhood. Around 45% of the participants were in this group.
• “Persistently High IQ” described the individuals who began with an average or above average IQ and remained relatively stable throughout childhood. Sixteen percent belonged to this group.

Results

The researchers analyzed changes in autism traits and communication adaptive functioning. This is the ability to understand language, engage in meaningful verbal expression, and read and write, over time.

They also looked at internalizing behaviors, such as anxiety or depression, and externalizing behaviors, such as impulsivity or aggressiveness.

Of the 191 participants with assessments at two timepoints or more, 10 lost their autism diagnosis. This included about 5% of the “Changers,” 10% of the “Persistently High IQ” group and none of those in the “Persistent Intellectual Disability” group. Identifying what makes the “Changers” group different from those in the groups with more stable IQs is a major goal of the research.

Individuals with stronger early communication adaptive function and lower autism ‘severity’ scores were more likely to be in the “Persistently High IQ” group versus the “Persistent Intellectual Disability” group by adolescence.

Both the “Changers” and “Persistent Intellectual Disability” groups had lower IQ scores in early childhood. However, those that showed improved communication adaptive function and decreased externalizing behaviors into adolescence were more likely to be in the “Changers” group compared to the “Persistent Intellectual Disability” group.

“It is striking that we found so much overlap in individuals following different trajectories of intellectual development when assessed at the early childhood and adolescent time points,” Solomon said. “Of course, many other factors are involved in determining outcomes, but intellectual ability level is a core feature and an important starting point.”

Brain differences among the three autistic groups

Last year, a closely related MIND Institute study compared MRI scans of the three IQ subgroups at age 3. The researchers evaluated two brain networks associated with intellectual functioning: the frontoparietal network and the default mode network.

The frontoparietal network is involved in sustained attention, problem-solving and working memory. The default mode network contributes to remembering, thinking about the future and mind wandering.

The 2022 study was led by Joshua Lee, an assistant professional researcher in the Department of Psychiatry and Behavioral Sciences. The team found that the “Changers” and “Intellectual Disability” groups, which both had low IQs at age 3, differed from the group with average IQs in several regions of the frontoparietal network.

In contrast, the default mode network differed between the “Changers” group and the other two groups. This difference suggested that this network may be involved in mechanisms related to improving intellectual function.

“The findings of both studies provide clues about how brain differences between autistic individuals with and without intellectual disability during early childhood might predict future outcomes,” said Christine Wu Nordahl, director of the Autism Phenome Project, a professor in the Department of Psychiatry and Behavioral Sciences and a coauthor on both studies. “Future studies will evaluate brain structure and function development across childhood and how they differ across various subgroups of intellectual development in autism.”

Additional coauthors on the new study included Billy Cho, Ana-Maria Iosif, Brianna Heath, Apurv Srivastav, Emilio Ferrer and David G. Amaral, all of UC Davis.

This study received funding from the National Institute of Mental Health (R01MH106518, R01MH103284, R01MH103371 and R01MH104438); National Institutes of Health (R01MH104438); the T32 Ruth L. Kirchstein Institutional National Research Service Award (T32 MH073124); The MIND Institute Intellectual and Developmental Disabilities Research Center (P50 HD103526); and an Autism Center of Excellence grant from the National Institute of Child Health and Development (P50 HD093079).

Read the full study.

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JOURNAL

JCPP Advances

DOI

10.1002/jcv2.12127 

ARTICLE TITLE

IQ trajectories in autistic children through preadolescence

Suicide risk screening in high schools successfully identifies at-risk students

New research demonstrates the ability of in-school suicide risk screening to identify and facilitate adolescents to get the help they need

Peer-Reviewed Publication

PENN STATE

UNIVERSITY PARK, Pa. — Suicide death rates have increased significantly among adolescents in the U.S. in recent years, according to the Centers for Disease Control and Prevention. But while children are typically screened for scoliosis, body mass index, and vision and hearing problems in school, mental health screening has not been standardized in school settings. New research, led by the Penn State College of Medicine, evaluated the effectiveness of a school-based, adolescent suicide risk screening and found that it successfully identified at-risk adolescents and increased initiation of mental health services.

“Unfortunately, more than half of U.S. adolescents lack routine preventive health care, which limits the ability of primary care to address this worsening public health concern,” said Deepa Sekhar, associate professor of pediatrics and executive director of Penn State PRO Wellness. “Schools create a more equitable setting for screening given that most adolescents attend, regardless of race, ethnicity and socioeconomic status.”

In previous research, the team developed and tested Screening in High Schools to Identify, Evaluate and Lower Depression (SHIELD), a protocol to evaluate the effectiveness of school-based depression screening. The study used the Patient Health Questionnaire-9 (PHQ-9), a standard tool used by primary care providers to screen for symptoms of major depressive disorder. The team found that the universal depression screening approach in which everyone was screened was more effective than the existing process of targeted referral of students based on concerning behaviors such as acting out, failing classes or not showing up for classes.

“One of the challenging parts of the study was item 9 of the PHQ-9, which asks, ‘How often have you been bothered by … thoughts that you would be better off dead or of hurting yourself in some way?’” Sekhar said. “Students with a positive response to this question required same day follow-up, which can be difficult for resource- and staff-limited schools.”

While the PHQ-9 is not a suicide risk assessment tool, the team conducted a follow-up analysis to better understand the necessity of including suicide risk as part of screening.

The team worked with nearly 13,000 students in 14 Pennsylvania high schools. Half of the participating schools were randomized so that students in grades 9 and 11 received targeted screening and those in grades 10 and 12 received universal screening. The other half were randomized so that students in grades 10 and 12 received targeted screening and those in grades 9 and 11 received universal screening.

Students who were identified as at risk for suicide were referred to the Student Assistance Program, which is mandated in all Pennsylvania schools. Managers of this program then determined the follow-up procedure for these individuals.

The team found that adolescents in the universal screening arm had 7.1-fold greater odds of being identified as at risk for suicide, 7.8-fold greater odds of follow-up needs and 4.0-fold greater odds of initiating mental health treatment. The results were published in The Journal of Pediatrics.

“Although the PHQ-9 is a screening tool for major depressive disorder, we found that its use in universal screening increased identification and treatment initiation for adolescents at risk for suicide,” said Sekhar. “Our study confirms the value of universal screening and suggests that a suicide-specific risk assessment would have even greater impact on treatment initiation for identified youth.”

Other authors on the paper include Erich Batra, associate professor of family and community medicine and of pediatrics; Eric Schaefer, biostatistician, Penn State College of Medicine; Leslie Walker-Harding, chair, Department of Pediatrics, University of Washington; Krista Pattison, implementation coordinator, Crane Center for Early Childhood Research & Policy, Ohio State University; Alissa Molinari, registered nurse, St. Luke’s University Health Network; Perri Rosen, project director, Garrett Lee Smith Youth Suicide Prevention Grant; Jennifer Kraschnewski, director, Penn State Clinical and Translational Science Institute; James Waxmonsky, University Chair in Child Psychiatry, Penn State.

This research was supported by the Patient-Centered Outcomes Research Institute, the U.S. Department of Health and Human Services and the National Institutes of Health.  

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DOI

10.1016/j.jpeds.2022.07.036 

Mocktails or cocktails? Having a sense of purpose in life can keep binge drinking at bay

A new study reveals that having a sense of purpose in daily life can influence college students’ decisions on day-to-day alcohol consumption

Peer-Reviewed Publication

UNIVERSITY OF PENNSYLVANIA

Heavy alcohol use is common among college students—and as a consequence, it puts young adults at risk for a wide range of health issues, from cardiovascular disease to cancer. Day in and day out, college students are bombarded with cues to drink, whether that’s seeing a group of friends toast at a party or celebrating after an exam.

Using functional MRI (fMRI) scanning technology, researchers from the University of Pennsylvania, Columbia University, and Dartmouth College examined the relationship between these cues, alcohol craving, and alcohol consumption. They found that having a strong sense of purpose in life decreases the temptation to consume alcohol to excess among some social drinkers.

Why purpose in life?

Lead author Yoona Kang, a research director of the Communication Neuroscience Lab at the Penn’s Annenberg School for Communication, is deeply interested in the impact of purpose in life on health.

Her previous research has found that having a strong life purpose—the sense that your life is guided by personally meaningful values and goals—is associated with many health benefits, including easing the loneliness of COVID-19 isolation and reducing the effort it takes to make healthy choices.

“Values and purposes can have powerful effects on how people think and behave,” Kang says. “And what's interesting about this study is that we asked participants, ‘How much sense of purpose in life do you feel right now?’ Because your level of purpose can fluctuate day by day.”

Craving alcohol

For this study, Kang and colleagues charted the behavior and attitudes of 54 healthy college students, with daily surveys over the course of a month. Once a day, participants answered questions about their current level of purpose in life—and every morning and evening they reported how much they craved and consumed alcohol.

“We focused on craving because it is one of the strongest predictors of actual drinking. If you crave, then you’re more likely to drink,” Kang says. “But just because you crave alcohol doesn’t mean that you’re going to go out and drink, so we wanted to know what’s nudging these social drinkers into drinking when they crave alcohol.”

The student volunteers also received fMRI brain scans, which gave a real-time picture of their brain activity while they were exposed to alcohol cues, like photos of beer, wine, and liquor or photos of people toasting at a party. Researchers analyzed the participants’ brain activity within the ventral striatum, the area of the brain previously associated with reward and craving.

Individuals whose brains showed greater activity when they saw alcohol cues—people with higher neural alcohol cue reactivity—were more likely to drink after craving alcohol.

When this data was matched with life purpose data, Kang and colleagues found something interesting: These neurally sensitive drinkers did not necessarily drink more if they were feeling a strong life purpose when they craved alcohol. And if they felt less purposeful? They were more likely to drink heavily after a craving for alcohol.

Further implications

This finding opens the door to discovering new strategies to discourage binge drinking in college students, especially those with higher neural cue reactivity, not by talking about drinking specifically, but by helping students focus on their mission, purpose, and values. Kang suggests that future research could test interventions used in other purposes in life and related studies—strategies like reflecting on what matters to you or making positive wishes for other people.

While the researchers caution that further testing would be needed to determine whether the findings would generalize to non-college populations, they note that many studies point to the strong link between purpose in life and health behavior across diverse populations. 

And Kang underlines the importance of studying college populations. “College students are in a formative time in their lives where they are learning the norms around alcohol use and setting their own habits that will affect their health later in life,” she says. “So, I think there’s a lot of preventive values in studying alcohol use in college populations.”

The study, published in Addiction, is entitled “Purpose in life, neural alcohol cue reactivity and daily alcohol use in social drinkers.” In addition to Kang, authors include Emily Falk, Danielle Cosme, David Lydon-Staley, Jeesung Ahn, Mia Jovanova, Dani S. Bassett, Silicia Lomax, Faustine Corbani (Columbia University), Ovidia Stanoi (Columbia University), Kevin Ochsner (Columbia University), Victor Strecher (University of Michigan), and Peter J. Mucha (Dartmouth College).

Research was funded by the Army Research Office; Hopelab Foundation; and Mind and Life Institute.

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JOURNAL

Addiction

DOI

10.1111/add.16012 

ARTICLE TITLE

Purpose in life, neural alcohol cue reactivity and daily alcohol use in social drinkers

Silver nanoparticles show promise in fighting antibiotic-resistant bacteria

Peer-Reviewed Publication

UNIVERSITY OF FLORIDA

 

IMAGE: NEW RESEARCH INVESTIGATED WHETHER SILVER NANOPARTICLES COULD AMPLIFY THE EFFECTS OF ANTIBIOTICS ON ANTIBIOTIC-RESISTANT BACTERIA view more 

CREDIT: GARRETT ELLWARD

In a new study, scientists with the University of Florida found that a combination of silver nanoparticles and antibiotics was effective against antibiotic-resistant bacteria.

The researchers hope to turn this discovery into viable treatment for some types of antibiotic-resistant infections. Antibiotic-resistant infections kill more than a million people globally each year.

For centuries, silver has been known to have antimicrobial properties. However, silver nanoparticles — microscopic spheres of silver small enough to operate at the cellular level — represent a new frontier in using the precious metal to fight bacteria.

In this study, the research team tested whether commercially available silver nanoparticles boost the power of antibiotics and enable these drugs to counter the very bacteria that have evolved to withstand them. 

“We found that the silver nanoparticles and a common class of broad-spectrum antibiotics called aminoglycosides work together synergistically,” said Daniel Czyż, senior author of the study and an assistant professor in the UF/IFAS department of microbiology and cell science.

“When combined with a small amount of silver nanoparticles, the amount of antibiotic needed to inhibit the bacteria decreased 22-fold, which tells us that the nanoparticles make the drug much more potent,” Czyż explained. “In addition, aminoglycosides can have negative side effects, so using silver nanoparticles could allow for a lower dose of antibiotic, reducing those side effects.”

The findings were both surprising and exciting, said Autumn Dove, first author of the study and a doctoral candidate studying microbiology and cell science in the UF/IFAS College of Agricultural and Life Sciences.

“When I first saw the result, my first thoughts were, ‘Wow, this works!’” said Dove.

Over the last several decades, overuse of antibiotics had led to the emergence of antibiotic-resistant bacteria and a decline in the effectiveness of traditional antibiotic drugs, the researchers said. The study’s findings indicate that silver nanoparticles have the potential to renew the effectiveness of some of these drugs.  

“Let’s say you get a bad burn on your hand, and it gets infected with one of these resistant strains of bacteria,” Dove said. “It’s possible that dressing that burn with a combination of silver nanoparticles and antibiotics could both clear that infection and prevent those resistant bacteria from spreading elsewhere.”

Though antibiotics mainly target bacteria, they can also damage human and animal cells. Using a microscopic worm called C. elegans, the researchers confirmed that the silver nanoparticles did not also make the antibiotic more toxic to non-bacterial cells.

Building off the study’s promising findings, the scientists next plan to seek FDA authorization for clinical trials and work with UF Innovate to patent an antimicrobial product that uses silver nanoparticles.

The silver nanoparticles used in the study were manufactured by the Natural Immunogenics Corporation, which helped fund the study through the UF Industry Partnerships Matching Grant Program. This program pairs UF researchers with Florida-based technology and energy companies to research and develop new products.

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JOURNAL

Frontiers in Microbiology

DOI

10.3389/fmicb.2022.1064095 

METHOD OF RESEARCH

Data/statistical analysis

ARTICLE TITLE

Silver nanoparticles enhance the efficacy of aminoglycosides against antibiotic-resistant bacteria