Mechanisms Beyond NMDA Receptor Antagonism

1. Activation of AMPA Receptors:

   In addition to NMDA receptor antagonism, ketamine activates AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, enhancing synaptic plasticity and synaptogenesis, which play key roles in improving neural network function [(6)].

2. Anti-inflammatory Effects:

   Ketamine exhibits strong anti-inflammatory properties by reducing levels of inflammatory cytokines like IL-6 and TNF-α, particularly benefiting patients with depression associated with chronic inflammation [(7)].

3. Activation of the mTOR Pathway:

   Ketamine activates the mTOR (mammalian target of rapamycin) signaling pathway, increasing synaptic protein production and synaptic flexibility, which is a critical factor in its rapid antidepressant effects [(8)].

4. Reduction of Oxidative Stress:

   Ketamine reduces oxidative stress and improves redox balance in neurons, preventing oxidation-related damage and providing protective effects [(9)].

5. Effects on Neurotransmitters:

   Ketamine modulates neurotransmitter systems like dopamine and serotonin, which enhances its antidepressant effects [(10)].

Short-Term Effects and Continuation Therapy

The effects of ketamine are short-term, typically lasting up to 72 hours, as per most studies. Therefore, it is logical to use ketamine as an initial medication to rapidly reduce depressive symptoms, followed by continuation therapy with other antidepressants.

Using maintenance antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), after the short-term effects of ketamine can help prevent symptom recurrence.

Ketamine in Electroconvulsive Therapy (ECT)

Studies have shown that using ketamine as an anesthetic induction agent during ECT for depressive patients can enhance the therapeutic response [(11)]. Additionally, its effect on lowering the seizure threshold can facilitate seizure induction [(1)]. However, there is insufficient evidence regarding the use of ketamine as a long-term maintenance therapy.

Plasma Levels and Dosage

Ketamine exhibits antidepressant effects at plasma levels of 70-200 ng/mL, whereas levels of 2000-3000 ng/mL are necessary for anesthetic purposes [(2)]. Evidence indicates that reaching the antidepressant dosage has minimal respiratory effects on patients. However, it may lead to increased heart rate and blood pressure in some individuals. Physicians should be prepared to manage potential cardiovascular complications.

Therefore, this treatment should be administered in a shock therapy room under the supervision of an anesthesiology specialist. Moreover, ketamine injection may induce transient dissociative and psychotic-like experiences. Medical staff and physicians must be familiar with managing potential behavioral complications

Related :The Risks and Rewards of At-Home Ketamine Therapy: A Comprehensive Guide

Adverse Effects

Short-Term Adverse Effects:

Ketamine's side effects are typically short-term and limited to the infusion period or up to 60 minutes after. Common adverse effects include:

• Headache

• Nausea and vomiting

• Blurred vision

• Dizziness

• Reduced concentration

• Agitation

Up to 80 minutes post-injection, increased heart rate and blood pressure may occur. Severe side effects include:

• Cognitive impairment

• Transient dissociative symptoms

• Urinary problems, particularly cystitis

• Ketamine misuse: Due to this risk, prescribing ketamine outside a hospital setting should be avoided.

Indications for Ketamine Injection:

• Major depressive disorder without psychotic symptoms

Contraindications for Ketamine Injection:

• Uncontrolled cardiovascular disease

• Active psychosis

• Pregnancy

• Moderate to severe liver disease

• Increased intracranial pressure

• Increased intraocular pressure

Pre-Treatment Measures

Before proceeding with ketamine injection:

• Obtain informed consent from the patient or their family.

• Record the patient’s vital signs.

• Assess underlying medical conditions based on the treating physician’s discretion.

• Review the patient’s current medications.

• Evaluate suicide risk by an anesthesiology specialist and assess cardiovascular and respiratory status if necessary.

During Ketamine Treatment

• Monitor respiratory status, particularly oxygen saturation, through continuous monitoring.

• Assess the patient’s cardiovascular status.

• Monitor the patient’s level of consciousness.

• Nurses should be vigilant about the criteria for halting the infusion.

• Ensure readiness for managing cardiovascular or behavioral complications during the infusion.

An initial lower dose (0.3 mg/kg) is recommended for patients with a BMI over 30. Clinical responses and potential side effects should be carefully monitored. Gradual dose increases can be implemented if needed and tolerated. Due to increased distribution volume and potentially reduced drug clearance in obese patients, standard dosages may not reach therapeutic plasma levels. Plasma level monitoring is advised in such cases.

Dosing for Special Populations

• High BMI Patients: Calculate Ideal Body Weight (IBW) as follows:

  • Men: 50 + [2.3 × height (in inches above 60)]

  • Women: 45.5 + [2.3 × height (in inches above 60)] Administer ketamine based on IBW at 0.3-0.5 mg/kg.

• Elderly Patients: Due to physiological changes such as reduced liver and kidney function

, use a lower initial dose (0.25-0.3 mg/kg).

Post-Treatment Measures

• Monitor the patient's cardiovascular, respiratory, and neurological status during at least 90 minutes of observation in the recovery room under nursing supervision.

• Before discharge, ensure the patient has returned to their baseline functional level. If they were treated as outpatients, verify that they are accompanied by a trusted individual.

To enhance long-term outcomes:

• Encourage lifestyle modifications, including regular physical activity, sufficient sleep, and proper nutrition.

• Promote stress management techniques like meditation, yoga, or breathing exercises.

Treatment Frequency

While there is variability, most evidence supports administering ketamine three times a week for at least two weeks. For some patients, periodic maintenance injections under specialist supervision combined with other treatments may be effective.

Related: Ketamine vs. Esketamine: Are These Mind-Altering Medications Safe for Treating Depression?