Ketamine is used to treat major depressive disorder, especially for individuals who have not responded to conventional therapies. It is primarily utilized for treatment-resistant depression (TRD), defined as the failure to achieve symptom relief after multiple trials of standard antidepressants. Unlike common medications, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), ketamine operates on a different neurochemical system. It is administered in two main forms: racemic ketamine, typically delivered via intravenous (IV) infusion, and esketamine, an FDA-approved derivative used as a supervised nasal spray.
Immediate Onset: The Timeline of Rapid Relief
The distinguishing characteristic of ketamine therapy is the speed at which it alleviates depressive symptoms. Traditional antidepressants often require several weeks of consistent use before clinical improvement is noticed, but ketamine’s effects can appear within hours of a single treatment. For many patients receiving an intravenous infusion, a noticeable reduction in symptoms, including mood, is reported within 4 to 24 hours following the session.
The speed of response varies based on the method of administration. IV ketamine often offers a faster and more robust initial response, with improvement observed after the first session. In contrast, the esketamine nasal spray frequently requires patients to complete a second session before a statistically significant reduction in depressive symptoms is noted. This rapid onset also extends to the reduction of suicidal ideation, which can diminish quickly. However, this immediate relief is an acute effect, typically lasting only a few days to about one or two weeks.
Biological Basis for Rapid Action
Ketamine’s rapid action is rooted in a neurobiological mechanism that bypasses the slower processes of traditional antidepressants. Ketamine functions as an N-methyl-D-aspartate (NMDA) receptor antagonist, temporarily blocking these receptors within the brain’s glutamate system. Glutamate is the primary excitatory neurotransmitter, and its dysregulation is thought to be involved in depression.
Blocking NMDA receptors triggers a cascade resulting in a transient surge of glutamate release, particularly in the prefrontal cortex. This surge stimulates alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The activation of AMPA receptors then activates the intracellular signaling pathway known as the mammalian target of rapamycin (mTOR).
Activation of the mTOR pathway promotes synaptogenesis, the process of forming new synaptic connections between neurons. Since chronic stress and depression can weaken neural connections, ketamine rapidly works to repair and restore these synapses. This effect is supported by an increase in brain-derived neurotrophic factor (BDNF), a protein that supports the growth and survival of neurons. The resulting increase in neural plasticity, the brain’s ability to reorganize itself, underlies the immediate shift in mood and cognitive function.
Sustaining the Effects: Maintenance and Duration
While the initial antidepressant effect of ketamine is rapid, it is not permanent after a single treatment, necessitating a structured, multi-phase treatment protocol. The process begins with an induction phase, which is designed to achieve a substantial reduction in depressive symptoms. This phase typically involves receiving multiple treatments, often six to twelve sessions, administered over a period of two to four weeks.
The goal of the induction phase is to create enough neuroplastic change for the benefits to stabilize and endure. Once a patient has achieved a satisfactory response, they transition into a maintenance phase to sustain the improvements. Maintenance involves receiving “booster” treatments at regular intervals, which varies among individuals.
For some patients, a booster infusion may be required every few weeks, while others can go longer, potentially three to four months, before symptoms begin to reemerge. This individualized approach to maintenance ensures that the therapeutic gains are preserved, as waiting until a full relapse occurs can necessitate restarting a more intensive induction protocol. The duration of the therapeutic effect after a single dose is short-lived, but the sustained management of symptoms is achieved through this ongoing, individualized booster schedule.
Factors Influencing Individual Response
The timeline for symptom relief can be highly variable, as an individual’s response to ketamine is influenced by a combination of clinical and biological factors. Patients presenting with active suicidal ideation, for example, often experience a rapid and dramatic reduction in these thoughts, sometimes even faster than the improvement in general mood symptoms. The route of administration also plays a role, with IV infusions generally offering a higher bioavailability and potentially more consistent and robust initial symptom reduction compared to the nasal spray formulation.
Individual differences in genetic makeup can impact how the body processes and responds to the treatment. Specifically, a variation in the gene that codes for brain-derived neurotrophic factor (BDNF), known as the Val66Met polymorphism, has been associated with an attenuated or weaker response to ketamine. Furthermore, certain baseline peripheral biomarkers, such as lower pretreatment levels of B12 or plasma adiponectin, have been observed to predict a more favorable and rapid antidepressant outcome in some studies. These factors highlight that the ultimate speed and degree of relief are a complex interplay between the treatment itself and the patient’s unique biological profile.