Summary: Two new studies reveal that Ezogabine, a drug originally approved for epilepsy, can alleviate depression symptoms by targeting potassium channels in the brain. The researchers discovered that the drug improves the function in the brain regions linked to the reward such as the Ventral Tegmental Zone (VTA), which is the key to motivation and pleasure.
Ezogabine has also reduced abnormal connectivity between reward centers and regions associated with negative thoughts, such as the posterior cingular cortex. These results suggest that the openers of potassium channels could offer a new processing strategy based on biology for depression and anhedonia.
Key facts:
- New mechanism: The ezogabine targets KCNQ potassium channels to adjust brain activity.
- Reward circuits: It normalizes hyperactive brain areas linked to dopamine in depressed patients.
- Cognitive shift: Reduces connectivity between reward and negative emotional networks, softening symptoms.
Source: Mount Sinai Hospital
A mechanism involving potassium channels in the brain that control the activity of brain cells could provide a new fundamentally different way of treating depression symptoms in adults suffering from major depressive disorders, according to two additional articles published recently by researchers from the Icahn School of Medicine at Mount Sinai.
In two new research articles, published in Biological psychiatry And Molecular psychiatryResearchers provide new information on how a drug called Ézogabine may have an impact on the brain to improve depression.
“Depression is a devastating problem of public health, and our understanding of changes in the brain that cause disease are still very limited,” explains James Murrough, MD, PHD, Director of Depression and the Center of Anxiety for Discovery and Treatment at Mount Sinai and the main author of the two studies.
“Our work represents a major step in the detangling of the potential role of a specific protein complex in the brain – the KCNQ channel – and how it could possibly offer an important new modality to treat depression.”
The ezogabine was approved by the Food and Drug Administration of the United States in 2011 as an anticonvulsant drug for partial appearance crises in adults with epilepsy.
Previous research on neuroscience in mice, led by researchers from the Friedman Brain Institute of Mount Sinai, suggested that the increase in the activity of the KCNQ channels could also represent a new approach to the treatment of depression.
Based on these results, Dr. Murrough’s research team became the first to test the hypothesis in humans suffering from depression.
This study, published in the American Journal of Psychiatry In 2021, the revelation of the ezogabine was associated with significant improvements in the symptoms of depression and the ability to feel pleasure (anhedonia) in patients treated with the drug compared to patients who received a placebo.
The two new articles provide details from new analyzes of the human brain imaging data collected from this initial clinical trial.
The first of the two articles, published in Molecular psychiatryLight on the effects of ezogabine on a specific cerebral track.
This study examined the impact of the ezogabine in the Ventral Tegmental Zone (VTA) of the brain, which is involved in the release of dopamine, an essential neurotransmitter for motivation, pleasure and strengthening of behavior.
The results, based on functional magnetic resonance imaging, have shown an important role for KCNQ channel operators such as ezogabine in the normalization of hyperactivity of VTA in people with depression and anhedonia.
“Until half of people suffering from depression do not respond to first-line treatment, which may be due to the lack of interventions that directly affect the underlying symptoms of neurobiology such as anhedonia,” explains Laurel S. Morris, PHD, deputy professor of psychiatry at Icahn School of Medicine and first author of the newspaper.
“By specifically targeting VTA activity and connectivity, ezogabine could open the door to resolutely improved results for people who fight daily with depression and anhedonia.”
In a second article, published in Biological psychiatryResearch revealed that ezogabine was able to normalize connectivity between the main brain reward regions and brain networks on a larger scale, including the posterior cingular cortex, which plays a key role in internal directed thought and negative emotions.
Patients who have experienced greater improvement in their depression and their anhedonia when treated with ezogabine have shown a decrease in connectivity between brain reward regions and cingular cortex.
Together, these two complementary studies suggest that KCNQ channel operators can potentially mitigate specific known neurobiological changes that occur in animal depression models and change the function of larger brain networks that could be used in a single manner in humans to regulate thought processes such as rumination.
“These results have suggested that the drugs targeting the KCNQ canal can trigger antidepressant effects by reducing interactions between the reward centers in the brain and those linked to negative thinking and emotion,” said Dr. Murrough.
“This hypothesis will require confirmation in larger clinical trials.”
Dr. Murrough is an inventor appointed to a patent request for the use of ezogabine and other KCNQ channels to treat depression and related disorders.
About this news of the research of psychopharmacology and depression
Author: Elizabeth Dowling
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mont Sinai Hospital
Picture: The image is credited with Neuroscience News
Original search: Closed access.
“Effects of the modulation of the KCNQ potassium channel on the activity and connectivity of the ventral tegmentary area in individuals with depression and anhedonia” by James Murrough et al. Molecular psychiatry
Closed access.
“The effects of the Ezogabine of the opening of the KCNQ channel (KV7) on functional connectivity to the rest state of the regions of reward of the striatal brain, depression and anhedonia in the major depressive disorder: results of a randomized” trial of “James Murrough et al. Biological psychiatry
Abstract
Effects of modulation of the KCNQ potassium channel on the activity and connectivity of the ventral tegmental zone in individuals with depression and anhedonia
Up to half of people with depression do not respond to first-line treatments, perhaps due to a lack of treatment interventions informed by neurobiology.
A new therapeutic approach for depression is recently emerged from the translation work targeting the aberrant activity of dopamine neurons in the Ventral Tegmental Zone (VTA) via the modulation of potassium channels of KCNQ tension.
In this study, individuals with major depressive disorders (TDM) with a high anhedonia were randomized at five weeks before the KCNQ channel, the ezogabine (up to 900 mg / day) or the placebo. The participants finished the functional MRI during a monetary anticipation task and the state of rest at the start and at the end of treatment.
The clinical results were reported above.
Here, we examined the activity of VTA during monetary anticipation and functional connectivity to the rest state between VTA and the Ventromedial Prefrontal Cortex (Mesocortical Way) and the ventral striatum (mesolimbic route) at the start and end of treatment.
The results indicated significant drug interaction in activation of VTA during anticipation (F(1.34)= 4.36, p = 0.044), where the activation of VTA has been reduced by the pre-post ezogabine, compared to the placebo.
Mesocortical functional connectivity was also higher among participants depressed at the start compared to a healthy control group (t(56)= 2.68, p = 0.01) and associated with hyper-activity VTA during functional MRI based on tasks at the start (R = 0.352, p= 0.033). Mesocortical connectivity has also been reduced by pre-post ezogabine(1.33)= 4.317, p= 0.046).
Together, this translation work is consistent with the preclinical results highlighting the hyper-activity VTA in depression, and suggesting an action mechanism for KCNQ channel operators to normalize this hyper-activity in people with depression and anhedonia.
Abstract
Effects of the Ezogabine of the opening of the KCNQ channel (KV7) on functional connectivity to the state of rest of the regions of reward of the striatal brain, depression and anhedonia in major depressive disorder: results from a controlled trial randomized randomized
Background
Major depressive disorder (MDD) is an invalid cause worldwide, available treatments often showing limited efficiency. Recent research suggests that targeting specific depression subtypes and understanding underlying brain mechanisms can improve treatment results.
This study examines the potential of opening the KCNQ channel (KV7) to modulate functional connectivity (RSFC) of the brain of brain reward circuits and alleviate depressive symptoms, including anhedonia, a central characteristic of the MDD.
Methods
A double -blind clinical trial, randomized randomized and controlled by placebo in people with CT 18 to 65 years, compared the daily dosage with the ezogabine (n=19) with a placebo (n =21) for 5 weeks. Functional magnetic resonance imaging evaluated RSFC of the main regions of brain reward (ventral caudé, core accumbens) at the start and after treatment. Clinical symptoms have been measured using the Snaiteh -Hamilton (RON) pleasure scale, the Montgomery – Åsberg (MADR) depression and other clinical symptoms.
Results
The ezogabine has considerably reduced the RSFC between the reward seeds and the posterior cingular cortex (CCC) / pre -cord compared to the placebo, which was associated with a reduction in the severity of the depression. Improvements of the anhedonia (RON) and depressive symptoms (MADR) with ezogabine compared to placebo have also been associated with a decrease in connectivity between the reward seeds and the medium / posterior cms (Midceluller Cortex, PCC, Pre -Cunus).
Conclusions
The results suggest that the antidepressant effects of the ezogabine are mediated by the modulation of the STRIATAL-MID / posterior cingular connectivity, indicating a potential therapeutic mechanism for the targeted drugs for KCNQ for the MDD and the anhedonia. Future studies should validate these results in greater trials.
