There is new evidence that a blood pressure medicine that has been around for 50 years could be used to treat the life-changing effects of post-traumatic stress disorder (PTSD), which is becoming more common.
Clonidine is frequently prescribed to treat hypertension and ADHD. Because clonidine works on adrenergic receptors in the brain, which are probably best known for their role in “fight or flight,” a heightened state of response that helps keep us safe, it’s application to PTSD has also been investigated.
These receptors are thought to be activated in PTSD and to play a role in traumatic memory consolidation. Clonidine’s sister drug, guanfacine, which also activates these receptors, has been studied in the treatment of PTSD. Due to conflicting clinical trial results, clonidine, which has shown promise in PTSD, has been set aside, along with guanfacine, which has not.
Pandemic PTSD Treatment
According to Qin Wang, MD, Ph.D., neuropharmacologist and founding director of the Program for Alzheimer’s Therapeutics Discovery at Medical College of Georgia at Augusta University, while the two drugs bind to the same receptors, they do different things there.
The findings of their study suggest that clonidine could provide immediate treatment to the significant number of people suffering from PTSD due to the current pandemic, as well as longer-established causes such as wars and other forms of violence.
The researchers believe that large-scale clinical trials of clonidine in PTSD are justified. Their findings also suggest that other new therapies could be discovered by studying the effect of existing drugs on activating a key protein called cofilin.
Cofilin And Spinophilin
The new research looked at genetically modified mice as well as neurons derived from human stem cells, which have the ability to produce a wide range of cell types.
They discovered that a unique axis on an adrenergic receptor called 2A is essential to maintaining fear memories, in which you associate a place or situation, such as the scene of a horrific car accident or school shooting, with the fear or other distressing emotions that are hallmarks of PTSD.
They found that the protein spinophilin interacts with cofilin, which is known to control protrusions on dendritic spines of neurons, where memories are consolidated and stored. A single neuron may feature hundreds of these spines, each of which changes shape in response to brain activity and influences the strength of the synapse between them.
Normally, whenever there is a stimulus — positive or negative — the brain has to go through a process where the spines store the information and enlarge, changing from a slender profile to a more mushroom-like shape.
“The mushroom spine is very important for your memory formation,”
said corresponding author Wang, Georgia Research Alliance Eminent Scholar in Neuropharmacology. Cofilin levels need to be significantly lowered in the synapse where the spines are located for these mushroom shapes to occur. In this situation, clonidine is useful.
Polar Opposite Effects
The researchers discovered that clonidine prevents cofilin from leaving by enticing it to interact with the receptor, which subsequently prevents the dendritic spine from resuming a mushroom shape and retaining the memory. On the other hand, guanfacine had no impact on cofilin, a crucial player.
According to Wang, the findings help explain the discrepant outcomes in the clinical trials of these two related drugs. In fact, when mice received both medications, the guanfacine seemed to mitigate the effects of clonidine in the critical phase of reconsolidating, and thereby maintaining, a traumatic memory, indicating at least on this biological function that they had polar-opposite effects.
Live evidence was also present. Mice were given a mild shock in their studies, which mimicked the symptoms of PTSD, and then immediately treated with clonidine after being brought back to the scene of the shock and expected to be remembering what happened earlier.
When brought back to the scene, mice treated with clonidine had a significantly reduced response, such as stopping in their tracks, compared to untreated mice. In fact, their behaviour resembled that of mice that were never shocked. There was no effect of Guanfacine on freezing behaviour.
Memory Reconsolidation Intervention
Wang pointed out that it is not possible to know with certainty how much the mice remember of previous events, but it is evident that mice treated with clonidine did not exhibit the same overt reaction as untreated or guanfacine-treated mice.
She noted that the interpretation is that they have a weaker memory. The objective is not to eliminate memories of war, but rather to lessen their impact on a soldier’s life.
When a memory is recalled, such as when a person returns to an intersection where he or she was involved in a terrible car accident, the synapses that hold the memory of what occurred there become temporarily unstable, or labile, before the memory becomes stable again, or reconsolidates.
Wang stated that this natural dynamic presents an opportunity to intervene in reconsolidation and thereby weaken the strength of a poor memory. Clonidine appears to be one method for achieving this objective.
Clonidine and other similar adrenergic drugs bind to receptors in the central nervous system to decrease blood levels of stress hormones such as epinephrine (adrenaline) and norepinephrine, which increase blood pressure and heart rate.
Off-Label Use
Studies like the one published in 2006 that only examined guanfacine showed it had no therapeutic value for PTSD. However, a retrospective analysis of 79 PTSD-affected veterans treated with clonidine in 2021 revealed that 72% of them showed improvement, and 49% showed significant or very significant improvement with few side effects.
Adrenergic receptor manipulation may affect how fear memories are formed and retained, according to earlier studies in basic science, but the exact mechanism is still unknown.
According to Wang, PTSD has now emerged as a major neuropsychiatric component of the COVID-19 pandemic. It affects approximately 30% of survivors, a similar percentage of healthcare workers who care for them, and an estimated 20% of the total population, implying that the impact on human health and healthcare systems could be “profound.”
Psychotherapy is widely regarded as the most effective treatment for PTSD, and some medications, such as antidepressants, can also be used, but there are few drug options, she says, with only two drugs approved by the Food and Drug Administration specifically for the condition. Due to a lack of approved drugs, drugs such as clonidine are being used off-label.
References:
- Saggu, S., Chen, Y., Cottingham, C. et al. Activation of a novel α2AAR-spinophilin-cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidation. Mol Psychiatry (2022).
- Neylan TC, Lenoci M, Samuelson KW, Metzler TJ, Henn-Haase C, Hierholzer RW, Lindley SE, Otte C, Schoenfeld FB, Yesavage JA, Marmar CR. No improvement of posttraumatic stress disorder symptoms with guanfacine treatment. Am J Psychiatry. 2006 Dec;163(12):2186-8. doi: 10.1176/appi.ajp.163.12.2186.