What is the mechanism of action of ketamine (0.5 milligrams per kilogram intravenous over 40 minutes) in an adult with chronic, treatment‑refractory post‑traumatic stress disorder?

Ketamine Mechanism of Action in Treatment-Refractory PTSD

Ketamine functions as a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor—an ionotropic glutamate receptor—which blocks glutamate transmission and subsequently increases AMPA receptor activation, leading to rapid enhancement of synaptic plasticity through downstream activation of BDNF and mTOR signaling pathways. 1, 2

Primary Molecular Mechanism

• Ketamine blocks NMDA receptors in an open-channel manner, preventing glutamate from binding and thereby modulating excitatory neurotransmission in the central nervous system 1, 3
• This NMDA receptor antagonism triggers a cascade that increases AMPA receptor throughput, which is critical for the rapid therapeutic effects observed in PTSD and depression 2, 3
• The major circulating metabolite norketamine demonstrates activity at the same NMDA receptor with approximately one-third the affinity of the parent compound 1

Downstream Neuroplastic Effects

• Ketamine activates brain-derived neurotrophic factor (BDNF) signaling, which promotes neuronal survival and synaptic remodeling 2
• The mechanistic target of rapamycin (mTOR) pathway is upregulated, leading to increased protein synthesis and synaptogenesis that underlies the sustained therapeutic effects beyond the drug's half-life 2
• These molecular changes enhance synaptic plasticity and may reverse the impaired neural connectivity characteristic of chronic PTSD 4, 2

Clinical Pharmacodynamics in PTSD

• At the 0.5 mg/kg dose infused over 40 minutes, ketamine produces rapid reduction in PTSD symptom severity within 24 hours, with effects persisting for days after a single infusion 5, 6
• The therapeutic mechanism appears to involve modification of fear memory expression through altered memory reconsolidation and enhanced fear extinction processes 4, 2
• Ketamine's effects on PTSD symptoms may be partially independent of its antidepressant properties, though both conditions often co-occur and respond to treatment 3, 5

Dose-Dependent Considerations

• Sub-anesthetic doses (0.5 mg/kg over 40 minutes) produce therapeutic effects with manageable dissociative symptoms, whereas higher anesthetic doses may paradoxically worsen PTSD symptoms through increased psychomimetic effects and altered fear memory systems 7, 6
• The dissociative anesthetic state is characterized by profound analgesia, maintained pharyngeal-laryngeal reflexes, and cardiovascular stimulation through indirect sympathomimetic activity 1
• Psychotomimetic effects including hallucinations (20% incidence) and nightmares (12% incidence) occur at the 0.5 mg/kg dose but are typically transient and resolve without intervention 8, 1

Neurocognitive Effects

• Repeated ketamine infusions at 0.5 mg/kg do not worsen cognitive function and may actually improve working memory in patients with comorbid PTSD and depression 9
• Lower baseline working memory and slower processing speed predict greater symptom improvement, suggesting ketamine may be particularly effective in patients with cognitive impairment 9

Cardiovascular and Respiratory Effects

• Ketamine increases blood pressure, heart rate, and cardiac output through inhibition of central and peripheral catecholamine reuptake, with blood pressure elevations of 10-50% above baseline that typically resolve within 15 minutes 1
• Unlike benzodiazepines and opioids, ketamine maintains respiratory drive and is a potent bronchodilator, making it safer from a respiratory standpoint 1, 10

Metabolism and Duration

• Ketamine undergoes N-dealkylation primarily via CYP2B6 and CYP3A4 to form norketamine, which is further metabolized to hydroxynorketamine compounds 1
• The redistribution half-life from the CNS is approximately 2.5 hours, but therapeutic effects persist for 2-3 days after single infusion due to sustained neuroplastic changes 1, 8