A brief review of the neurobiology and psychopharmacology of PTSD

Authors: Mohamed Elmarasi, MD; Chadi G. Abdallah, MD; Lynnette A. Averill, Ph.D.

This post from Chronic Stress was written in commemoration of National Stress Awareness Month

Posttraumatic stress disorder (PTSD) is a debilitating mental disorder with limited treatment options. Historically, PTSD was associated with combat exposure and hence named “shell shock” in WWI and “combat stress reaction” in WWII. However, we came to realize that following severe trauma, both civilians and military personnel can develop PTSD. The lifetime prevalence of PTSD in the general population is about 10% in women and 4% in men, whereas it could be as high as 86% in certain refugee population. This variability suggests the presence of many factors that could affect PTSD prevalence-mainly the type and severity of trauma. Here, we present a summary of the current understanding of the neurobiology of PTSD and how this understanding contributes to the development of new treatment modalities.

Traumatic stress affects the brain via mechanisms that are not entirely understood. However, ample evidence from animal studies and human pilot studies points out that traumatic stress alters the connections between neurons. Neurons are the most critical information transmission cells in the brain. They communicate with each other, mainly through chemical connections known as synapses. Each neuron could have up to 10, 000 synapses, and the brain has approximately 86 billion neurons. Besides, life experiences alter theses synaptic connections by forming new or by removing existing synapses. This phenomenon is known as synaptic plasticity.

Although the brain functions in unison, neural circuits, which are densely connected brain regions, can perform specific functions. For example, the limbic circuit, which includes the prefrontal cortex, the amygdala, and the hippocampus is involved in emotions, motivation, and learning. Thus, connectivity between various brain regions is critical for maintaining these circuits and their function. Keeping in mind the importance of neuronal synapses and neural circuitry, now, let’s take a glance at the effects of stress on the brain. Acute stress could be beneficial to the brain as it might promote the formation of new synapses or consolidate existing ones. On the contrary, chronic stress (caused by traumatic experiences) is often damaging; it causes a reduction of synapses in various brain regions that are critical for adaptive behavior. Data from multiple animal and human studies-following traumatic chronic stress show reduced neuron connectivity in the hippocampus and the prefrontal cortex, a brain region involved in cognition control of behavior. In PTSD, Further worsening of these deficits often occurs: once PTSD symptoms develop, they lead to a vicious cycle of repeated arousal, re-experiencing symptoms, and reactivation of the stress response, all of which perpetuate the neuron connection deficits. The deficits exacerbate PTSD symptoms, and so forth.

Presently, only two medications are FDA approved for the treatment of PTSD: sertraline and paroxetine HCl, both of which are antidepressants. Antidepressants work by altering the levels of neurotransmitters, i.e., serotonin, noradrenaline, and dopamine. In addition to altering the levels of neurotransmitters, long-term treatment with antidepressants has shown to increase synaptic plasticity and reverse stress-induced neuronal deficits in animals. However, unfortunately, there are several challenges with utilizing antidepressants for the treatment of PTSD. For example, antidepressants take weeks to produce therapeutic effects. Furthermore, there is a significant number of PTSD patients who don’t respond well to it.

The researchers were compelled by the previously mentioned challenges to examine new classes of drugs for the treatment of PTSD, including ketamine. Ketamine, well known for its use in anesthesia, is a medication that’s being heavily tested for the treatment of PTSD and depression. It works by altering the levels of glutamate, a neurotransmitter responsible for more than 80% of the brain synapses. In depressed patients, studies showed that ketamine increases neural connections within 24 hours of administration. Similarly, In PTSD, a clinical trial showed a significant reduction of symptoms one day following ketamine infusion. More extensive and more definitive clinical trials are underway to determine the efficacy of ketamine in the treatment of PTSD, including a trial from our group.

Although current PTSD therapies are targeting disease-related pathologies, the extent to which these treatments reverse trauma-related brain deficits aren’t entirely known. In animal studies, for example, evidence suggests that antidepressants increase the number and the strength of synapses in the prefrontal cortex and the hippocampus in addition to reversing trauma-related gray matter changes. In humans, only indirect preliminary evidence exists for similar changes following antidepressant treatment.

In conclusion, although the current neurobiological models have opened the doors for novel interventions to treat PTSD, it is essential to keep in mind that the complexity of the disorder makes it challenging and resistant to be fully explained by any set of simplified working models. A better understanding of the neurobiology of PTSD will contribute to the development of novel preventive and treatment interventions.

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