Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops in some people after experiencing or witnessing a traumatic event. The core symptoms of PTSD include re-experiencing the trauma through intrusive thoughts, nightmares, or flashbacks; avoidance of trauma-related stimuli; negative changes in beliefs and mood; and hyperarousal symptoms such as irritability, hypervigilance, and exaggerated startle response [1].
PTSD involves learned associations between benign stimuli and the traumatic event, leading to heightened threat responses to those stimuli, known as stimulus-response triggers [2]. For example, a combat veteran may associate the sound of fireworks with the gunshots and explosions they experienced in war. This previously neutral stimulus now triggers a threat response and PTSD symptoms. Other common examples include a sexual assault survivor triggered by physical touch or intimacy or a motor vehicle accident survivor triggered by driving.
Stimulus-response triggers cause significant distress and impairment for PTSD sufferers. Exposure to the triggering stimuli rapidly activates the sympathetic nervous system, leading to the hyperarousal symptoms of panic attacks, severe anxiety, anger, and aggression [3]. Avoidance of potential triggers leads to withdrawal, isolation, and lost opportunities. Effective PTSD treatments weaken the associations between stimuli and trauma, allowing adaptive responses to replace maladaptive threat responses.
Therapeutic ketamine has shown promise in helping to modulate both short and long-term PTSD stimulus response triggers. Ketamine is thought to increase synaptic plasticity rapidly – the brain’s ability to form new neural connections [4]. This allows traumatic memories to be processed and integrated in non-threatening contexts. Ketamine also reduces threat sensitivity and enhances extinction learning, which is the learned inhibition of a previously conditioned response [5]. These effects result in weakened stimulus-response associations, reducing the likelihood of triggers provoking excessive threat reactions.
Multiple studies have shown ketamine infusions rapidly reduce PTSD symptom severity and longer-term remission when paired with psychotherapy [6][7]. The immediate effects on neural plasticity and extinction learning allow PTSD victims to more fully engage in trauma-focused therapy while their brains are in an optimal state to weaken traumatic associations and form more adaptive responses [8]. Ongoing research is examining how to maintain the benefits of ketamine therapy over time.
In summary, stimulus-response triggers in PTSD involve learned associations between benign cues and past trauma. Ketamine’s effects on neural plasticity and extinction learning can rapidly dampen excessive threat reactions to stimuli and support the re-learning safe, adaptive responses. This aids PTSD recovery initially after ketamine infusion and in the long term when combined with psychotherapy.
References:
[1] American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). https://doi.org/10.1176/appi.books.9780890425596
[2] Maren S, Phan KL, Liberzon I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci. 2013 Jun;14(6):417-28. doi: 10.1038/nrn3492.
[3] Lanius RA, Vermetten E, Loewenstein RJ, et al. Emotion modulation in PTSD: Clinical and neurobiological evidence for a dissociative subtype. Am J Psychiatry. 2010;167(6):640-647. doi:10.1176/appi.ajp.2009.09081168
[4] Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med. 2015;66:509-523. doi: 10.1146/annurev-med-053013-062946.
[5] McGhee LL, Maani CV, Garza TH, DeSocio PA, Gaylord KM, Black IH. The effect of ketamine on fear extinction in treatment-resistant PTSD: a randomized clinical trial. Neuropsychopharmacology. 2020 Jul;45(8):1302-1308. doi: 10.1038/s41386-020-0678-2.
[6] Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(6):681–688. doi:10.1001/jamapsychiatry.2014.62
[7] Albott CS, Lim KO, Forbes MK, Erbes C, Tye SJ, Grabowski JG, Shiroma PR, Thuras P, Wels J, Shiroma E. Efficacy, safety and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J Psychiatr Res. 2018;104:148-155. doi: 10.1016/j.jpsychires.2018.06.012.
[8] McGhee LL, Maani CV, Garza TH, Gaylord KM, Black IH. The correlation between ketamine’s antidepressant and fear extinction effects in treatment-resistant posttraumatic stress disorder. Exp Clin Psychopharmacol. 2021 Aug;29(4):431-437. doi: 10.1037/pha0000479.
Very thankful for your insights, as a patient responsibly utilizing this medication, and your excellently cited material!