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 PublicationIMAGE: 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.
JOURNAL
Journal of Clinical Investigation
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 PublicationSome 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.
JOURNAL
The BMJ
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 PublicationMany 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.
JOURNAL
The BMJ
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
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