Ketamine as treatment for post-traumatic stress disorder: a review

Post-traumatic stress disorder (PTSD) is characterised by recurrent intrusive memories, dissociative reactions such as flashbacks, avoidance of trauma-related cues, alterations in cognition and mood, and heightened arousal. The extracted text notes a lifetime prevalence of 8.7% in the United States and a 12-month prevalence of 3.5%. PTSD is more common in certain occupational groups (for example, military veterans, firefighters, police, and emergency medical personnel) and in survivors of rape, combat, captivity, and mass violence. High rates of comorbidity are emphasised: individuals with PTSD are much more likely to meet criteria for other psychiatric disorders, including major depressive disorder (MDD), substance use disorders, and anxiety disorders, and PTSD is associated with substantial functional impairment across social, occupational, and educational domains. Current first-line pharmacotherapy consists of selective serotonin reuptake inhibitors (SSRIs), notably sertraline and paroxetine, with serotonin–norepinephrine reuptake inhibitors (SNRIs) and older antidepressants used in some cases. The authors highlight that many patients do not achieve full remission with available treatments and that augmentation strategies have limited evidence. Ketamine is introduced as a candidate novel therapy: preclinical and clinical observations suggest that stress-related reductions in synaptic connectivity—mediated by glutamatergic systems—might be reversed by NMDA receptor antagonism, and ketamine has been proposed both as a rapid-acting antidepressant and as a possible treatment or prophylactic agent for stress-related disorders including PTSD. The review sets out to summarise the existing preclinical and clinical evidence regarding ketamine’s therapeutic potential and safety in PTSD, noting a relative paucity of literature compared with research in treatment-resistant MDD.

The extracted text does not present a formal Methods section or describe a systematic search strategy, inclusion/exclusion criteria, databases searched, date ranges, or risk-of-bias assessment. From the body of the review it is apparent that the paper is a narrative review that draws on a mixture of evidence types. Specifically, the authors discuss animal experiments (rodent models of contextual fear, chronic social defeat, learned helplessness, chronic corticosterone exposure and inescapable stress paradigms), one published human double-blind randomized controlled crossover trial, multiple case reports (adult and paediatric), and several retrospective observational analyses of ketamine exposure (including peri-traumatic use in accident or burn patients and outpatient oral ketamine series). The review therefore synthesises preclinical mechanistic data, acute and prophylactic rodent studies, controlled clinical data where available, and anecdotal/retrospective clinical observations. No formal meta-analytic or statistical pooling methods are described in the extracted text.

Preclinical findings: Animal studies reported in the review indicate several potentially relevant effects of ketamine in stress and fear paradigms. In chronic social defeat and related stress models, single or repeated subanaesthetic ketamine reduced immobility in forced swim tests (interpreted as reduced helplessness), protected against stress‑induced social avoidance in open‑field/social interaction assays, and partially normalised hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Amat and colleagues found that a single intraperitoneal ketamine dose (10 mg/kg in Sprague Dawley rats) given 2 hours, 1 week, or 2 weeks before uncontrollable stress blocked the behavioural consequences of that stress and prevented stress‑induced increases in extracellular serotonin in the basolateral amygdala. Zhang and colleagues reported that chronic ketamine administration after a time‑dependent sensitisation procedure reduced contextual freezing in rodents and reversed stress‑associated decreases in hippocampal brain‑derived neurotrophic factor (BDNF); sertraline produced similar effects and in some measures yielded shorter freezing times than ketamine. These studies are presented as supporting both therapeutic and prophylactic potential and as consistent with a mechanistic model in which NMDA antagonism and upregulation of BDNF restore synaptic connectivity impaired by chronic stress. Controlled clinical data: The clearest clinical evidence cited is a double‑blind, randomised, crossover trial by Feder and colleagues involving 41 chronic PTSD patients who underwent a 2‑week medication washout and then received intravenous ketamine and intravenous midazolam two weeks apart in randomised order. The primary outcome was PTSD symptom severity at 24 hours post‑infusion measured with the Impact of Event Scale‑Revised (IES‑R). Ketamine produced significantly greater improvement in IES‑R scores at 24 hours compared with midazolam. The trial also reported antidepressant effects on comorbid depressive symptoms. In crossover analyses, seven patients who received ketamine first remained significantly improved at 2 weeks versus one patient who received midazolam first. Case reports and series: Several case reports described rapid and marked symptomatic improvement after single ketamine infusions across treatment‑refractory adult and paediatric patients, with effect durations typically in the order of 1–2 weeks. Examples include a 26‑year‑old combat veteran who reported complete reduction of anxiety and depression from day 1 to day 14 before relapse began, a 23‑year‑old veteran whose PCL‑M score fell from 66 to 29 with improvement lasting roughly 15 days, and a 7‑year‑old child whose behavioural control improved for 8–13 days after brief intraoperative ketamine doses. A retrospective outpatient series of oral/sublingual ketamine described reductions in psychiatric hospital admissions (reported as approximately 70% per patient) and shorter lengths of stay after treatment, although details on sample characteristics and controls are limited in the extracted text. Safety and adverse events: Safety findings across studies were mixed. A retrospective study of 56 accident victims found that peri‑traumatic administration of S‑ketamine was associated with increased acute dissociation, re‑experiencing and avoidance, and with higher subsequent PTSD symptom levels, whereas racemic ketamine produced only slight acute symptom increases and no long‑term differences. Two retrospective burn‑patient analyses from the same group yielded different results: an earlier study reported a lower PTSD prevalence among patients who received ketamine (27% versus 46% in those who did not), while a larger follow‑up (n=289) found no statistically significant difference (24% versus 26.98%, p=0.582). In the Feder RCT one patient discontinued because of dissociative effects and three required β‑adrenergic antagonists for transient hypertension; the most common short‑term side effects were blurred vision, dry mouth, restlessness, fatigue, nausea/vomiting, poor coordination and headache. A 37‑patient retrospective outpatient oral ketamine series reported no serious adverse events, no medical emergencies, and no documented psychiatric disturbances, with only transient lightheadedness, sedation, and dissociative effects noted. The review also flags ketamine’s status as a controlled, potentially addictive substance and mentions pharmacokinetic considerations (noting CYP2C9 induction and CYP3A4 inhibition) as relevant to concomitant psychoactive medications.

The review concludes that ketamine shows promise as a rapid‑acting intervention for PTSD, producing substantial short‑term reductions in PTSD and comorbid depressive symptoms across preclinical models, a randomized controlled crossover trial, case reports and retrospective series. The authors interpret the weight of evidence as consistent with a mechanism in which NMDA receptor antagonism and subsequent upregulation of BDNF and synaptic connectivity reverse stress‑related neural changes, which could account for both therapeutic and prophylactic effects observed in animal models. At the same time, the review emphasises important uncertainties and safety considerations. Data are limited: the human evidence beyond the Feder trial consists chiefly of case reports and retrospective analyses, and results from peri‑traumatic exposure studies are inconsistent—S‑ketamine was associated with worse outcomes in one retrospective study. The clinical benefits reported tend to be rapid but transient, commonly lasting 1–2 weeks after a single administration, and optimal dosing schedules, the effects of repeated administrations, and long‑term safety remain unresolved. The authors note potential adverse effects including transient dissociation, cardiovascular responses requiring intervention in a small number of cases, and the medication’s controlled/addictive status. They further acknowledge methodological limitations in the literature cited, such as small samples, lack of controls in case series, and possible confounding in retrospective peri‑traumatic studies (for example, differences in injury severity). Implications emphasised by the authors include the need for larger, rigorous clinical trials to define efficacy, dose‑response and maintenance strategies, comparative studies with standard treatments, and further investigation of prophylactic uses in predictable high‑stress settings. They conclude that, while ketamine may become a useful option for patients who do not respond to conventional therapies, more systematic research is required to establish its role, optimise protocols, and fully characterise risks.