A continuous publication, open access, peer-reviewed journal ACCESS ONLINE REVIEW Ketamine as treatment for post-traumatic stress disorder: a review Felix Liriano1, Candace Hatten MD2, Thomas L Schwartz MD1 1College of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA; 2Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center, Bronx, NY 10467, USA Abstract symptoms makes it worthy for study in animal models of, and Post-traumatic stress disorder (PTSD) continues to make possibly human studies in, PTSD. The current literature and headlines given multiple military engagements across the world theoretical mechanism of action is discussed in this manuscript. and civilian traumas, and resultant PTSD development continues Keywords: acute stress, brain-derived neurotropic factor, at an even pace. Currently, antidepressant and cognitive- ketamine, N-methyl-D-aspartate, off-label use, post-traumatic behavioral therapy have the greatest evidence base but still stress disorders, psychological substance-related disorders, do not yield a remission of PTSD symptoms in many patients. receptors, stress disorders, traumatic. 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 Citation for treatment-resistant major depressive disorder (MDD). Its Liriano F, Hatten C, Schwartz TL. Ketamine as treatment for post- mechanism is controversial regarding its potential to create traumatic stress disorder: a review. Drugs in Context 2019; 8: anxiety, but the perceived benefit of a rapid reduction of 212305. DOI: 10.7573/dic.212305 Introduction self-destructive behavior, hypervigilance, sleep disturbance, and lack of concentration.1 Post-traumatic stress disorder (PTSD) is the presence of recurrent, intrusive distressing memories, dreams, dissociative PTSD has a prevalence of 8.7% in the United States, with reactions such as flashbacks, and reactions to internal or a prevalence of 3.5% during any given 12-month period.1 external cues that symbolize or resemble an aspect of a According to Diagnostic and Statistical Manual of Mental traumatic event experienced by an individual.1 The traumatic Disorders, Fifth Edition (DSM-5), PTSD has a higher prevalence event can be an actual or threatened case of death, serious among military veterans, as well as firefighters, police officers, injury, or sexual assault that affected an individual, close friend, and emergency medical personnel. Globally, the greatest or family member.1 In response to these symptoms, individuals prevalence is found among survivors of rape, military combat often attempt to avoid situations where they may be reminded and captivity, and politically motivated genocide.1 Children and about the trauma internally by controlling thoughts, memories, adolescents usually show a lower prevalence of PTSD following and emotions or externally by avoiding people, places, a traumatic event, although according to the DSM-5 this could conversations, and situations that can trigger memories reflect inadequate measurement tools. PTSD is more common regarding the traumatic event.1 They may also exhibit among Latinos and African Americans as well as American changes in memory formation. For example, they may display Indians and less common in Asian Americans.1 selective amnesia – that is, inability to remember specific details surrounding the trauma that are not related to external PTSD is associated with high degrees of disability, making causes such as substance use and physical trauma.1 They may it difficult for an individual to maintain employment and also develop a constellation of symptoms that mirrors major social wellness.1 According to DSM-5, in both community and depressive disorder (MDD) including negative beliefs and veteran populations, PTSD is associated with poor social and expectations, negative emotional states, anhedonia, and social family relationships, excessive absence from work, and lower withdrawal.1 In addition to these symptoms, patients may income, educational, and occupational success. In addition experience changes in emotional reactivity including irritability, to the disabilities caused by PTSD alone, there are several Liriano F, Hatten C, Schwartz TL. Drugs in Context 2019; 8: 212305. DOI: 10.7573/dic.212305 1 of 7 ISSN: 1740-4398 REVIEW – Ketamine as treatment for post-traumatic stress disorder: a review drugsincontext.com comorbidities associated with the disorder. Individuals with Ketamine pharmacotherapy and PTSD are 80% more likely than those without PTSD to meet the diagnostic criteria for at least one other mental disorder.1 mechanism of action In males, conduct disorder and substance use disorder are Ketamine has been traditionally used as an alternative to common. Other disorders that commonly co-occur include general anesthesia. It produces ‘dissociation’ between the MDD, alcohol use disorder, and anxiety disorders. thalamaco-neocortical and limbic systems.6 This dissociation The Veteran’s Administration/Department of Defense is thought to be both functional and electrophysiological currently includes the use of selective serotonin reuptake in nature. Clinically, individuals given ketamine exhibit a inhibitors (SSRIs) for use as pharmacotherapy for PTSD.2 The state of catalepsy in which the eyes remain open and have a SSRIs included in this recommendation are sertraline and slow nystagmus.6 During this state, the individuals maintain paroxetine. Although SSRIs are one of the primary modes corneal and light reflexes.6 Patients become flaccid, but are of pharmacotherapy for PTSD, there are many drugs that awake. Ketamine doses here tend to be higher than those may also be used. For example, serotonin–norepinephrine used in the MDD management. Minor central nervous system reuptake inhibitors (SNRIs), such as venlafaxine, are also (CNS) changes have been reported and include disruption listed as a recommendation for monotherapy in PTSD.2 Other of an individual’s ability to understand the environment and classes of drugs that may be used include imipramine and organize thoughts leading to emergence delirium or psychosis.7 phenelzine – a tricyclic antidepressant (TCA) and monoamine Ketamine activity occurs at the N-methyl-D-aspartate-type 2 oxidase inhibitor, respectively. These medications are listed glutamate (NMDA) receptor as an antagonist.8,9 It has been with caution though, as they may have potentially serious studied in greater detail recently due to its potential use as side effects. One novel treatment not typically included in an antidepressant agent.10 NMDA receptor activation has guidelines is ketamine. been shown to increase formation of spontaneous intrusive Some researchers suggest that the symptoms experienced memories (depressive or anxious), and high activity of the in PTSD may be caused by a loss of synaptic connectivity. NMDA receptor may be a risk factor for actually developing The stress experienced in PTSD may impair the functioning PTSD.11 As ketamine functions as an antagonist to the NMDA of synaptic connectivity, which is mostly mediated by receptor, it may be a promising drug target to lower PTSD glutamate.3 As glutamate synapses play a crucial role in these symptoms as such. 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 Rationale for use of ketamine examined how prophylactic use of ketamine may have a PTSD has been described as a state of hyperarousal plagued by protective effect against the development of stress-related intrusive thoughts, flashbacks, and nightmares. Given that these disorders.5 intrusive thoughts have been linked to NMDA over activity, The clinical background to PTSD and potential use of animal studies have shown some of the potential anxiolytic ketamine is summarized in Box 1. There is a relative paucity properties of NMDA antagonism by using ketamine. Zhang of literature regarding the use of ketamine to treat PTSD and colleagues conducted an animal study in which mice and compared to that emerging for use in refractory MDD rats were subjected to contextual fear to simulate PTSD.10 In management. However, some data exist, and they will be this study, rats were subjected to inescapable foot shocks reviewed next. and were subjected to a time-dependent sensitization (TDS). Box 1. Clinical background to PTSD and potential use of ketamine. 1. PTSD is often a difficult-to-treat psychiatric disorder, and currently there exists only one pharmacological class of medication approved for the treatment of these symptoms. The SSRIs offer a treatment advantage of a low side-effect rate, but unfortunately a full remission of PTSD symptoms is often difficult to obtain. 2. Off-label augmentation options exist (atypical antipsychotics, mood stabilizers, hypnotics, and anxiolytics), but all have limited trials and limited efficacy in regard to PTSD treatment. 3. Ketamine is a controversial controlled medication that is gaining popularity in its off-label use in treatment-resistant MDD where it is noted to have an ultra-rapid onset of efficacy but also is limited by its offset of effect over 1–2 weeks. 4. Ketamine likely is more controversial in the use for anxiety disorder as it dampens NMDA receptor activity, and there are some thoughts that it may theoretically increase anxiety instead of helping. Given the treatment-resistant nature of PTSD