Post-traumatic stress disorder (PTSD) continues to make headlines given multiple military engagements across the world and civilian traumas, and resultant PTSD development continues at an even pace. Currently, antidepressant and cognitive-behavioral therapy have the greatest evidence base but still do not yield a remission of PTSD symptoms in many patients. Off-label and novel treatments continue to be considered for more refractory and disabling cases of PTSD. Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder (MDD). Its mechanism is controversial regarding its potential to create anxiety, but the perceived benefit of a rapid reduction of symptoms makes it worthy for study in animal models of, and possibly human studies in, PTSD. The current literature and theoretical mechanism of action is discussed in this manuscript.Keywords: acute stress, brain-derived neurotropic factor, ketamine, N-methyl-D-aspartate, off-label use, post-traumatic stress disorders, psychological substance-related disorders, receptors, stress disorders, traumatic

Post-traumatic stress disorder (PTSD) is the presence of recurrent, intrusive distressing memories, dreams, dissociative reactions such as flashbacks, and reactions to internal or external cues that symbolize or resemble an aspect of a traumatic event experienced by an individual.1 The traumatic event can be an actual or threatened case of death, serious injury, or sexual assault that affected an individual, close friend, or family member.1 In response to these symptoms, individuals often attempt to avoid situations where they may be reminded about the trauma internally by controlling thoughts, memories, and emotions or externally by avoiding people, places, conversations, and situations that can trigger memories regarding the traumatic event.1 They may also exhibit changes in memory formation. For example, they may display selective amnesia – that is, inability to remember specific details surrounding the trauma that are not related to external causes such as substance use and physical trauma.1 They may also develop a constellation of symptoms that mirrors major depressive disorder (MDD) including negative beliefs and expectations, negative emotional states, anhedonia, and social withdrawal.1 In addition to these symptoms, patients may experience changes in emotional reactivity including irritability, self-destructive behavior, hypervigilance, sleep disturbance, and lack of concentration.1

PTSD has a prevalence of 8.7% in the United States, with a prevalence of 3.5% during any given 12-month period.1 According to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), PTSD has a higher prevalence among military veterans, as well as firefighters, police officers, and emergency medical personnel. Globally, the greatest prevalence is found among survivors of rape, military combat and captivity, and politically motivated genocide.1 Children and adolescents usually show a lower prevalence of PTSD following a traumatic event, although according to the DSM-5 this could reflect inadequate measurement tools. PTSD is more common among Latinos and African Americans as well as American Indians and less common in Asian Americans.1

PTSD is associated with high degrees of disability, making it difficult for an individual to maintain employment and social wellness.1 According to DSM-5, in both community and veteran populations, PTSD is associated with poor social and family relationships, excessive absence from work, and lower income, educational, and occupational success. In addition to the disabilities caused by PTSD alone, there are several comorbidities associated with the disorder. Individuals with PTSD are 80% more likely than those without PTSD to meet the diagnostic criteria for at least one other mental disorder.1 In males, conduct disorder and substance use disorder are common. Other disorders that commonly co-occur include MDD, alcohol use disorder, and anxiety disorders.

The Veteran’s Administration/Department of Defense currently includes the use of selective serotonin reuptake inhibitors (SSRIs) for use as pharmacotherapy for PTSD.2 The SSRIs included in this recommendation are sertraline and paroxetine. Although SSRIs are one of the primary modes of pharmacotherapy for PTSD, there are many drugs that may also be used. For example, serotonin–norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, are also listed as a recommendation for monotherapy in PTSD.2 Other classes of drugs that may be used include imipramine and phenelzine – a tricyclic antidepressant (TCA) and monoamine oxidase inhibitor, respectively.2 These medications are listed with caution though, as they may have potentially serious side effects. One novel treatment not typically included in guidelines is ketamine.

Some researchers suggest that the symptoms experienced in PTSD may be caused by a loss of synaptic connectivity. The stress experienced in PTSD may impair the functioning of synaptic connectivity, which is mostly mediated by glutamate. 3 As glutamate synapses play a crucial role in these neuronal circuits, it is possible that the use of ketamine may enhance synaptic connectivity in these circuits, ultimately reversing the effects of stress.4 Other researchers have examined how prophylactic use of ketamine may have a protective effect against the development of stress-related disorders.5

The clinical background to PTSD and potential use of ketamine is summarized in Box 1. There is a relative paucity of literature regarding the use of ketamine to treat PTSD compared to that emerging for use in refractory MDD management. However, some data exist, and they will be reviewed next.