Interest in the use of ketamine for the treatment of depression has risen in recent years. Two clinicians discussed the lessons they have learned in using ketamine and esketamine as adjunctive therapies over the past 4 years for patients with treatment-resistant depression and suicidal thoughts during the American Psychiatric Nurses Association (APNA) 36th Annual Conference held October 19 to 22, 2022, in Long Beach, California.

The Ketamine Service at McLean Hospital offers both intravenous (IV) ketamine and intranasal esketamine for adults struggling with depression, particularly major depressive disorder and bipolar disorder. The development of a ketamine service using a clinical team approach to patient management has proved safe and effective, noted Paula Bolton, MS, CNP, ANP-BC, program director of the Ketamine Service, and colleague Courtney Miller, RN, ADN, BA. Nurses (advanced practice registered nurses [APRNs] and registered nurses) are involved in the management of these clinics.

Intravenous ketamine has long been FDA approved as a general anesthetic for IV or intramuscular administration. When used at lower subanesthetic doses, antidepressant effects have been found in clinical trials of IV ketamine, and this agent has been used off-label for the treatment of acute suicidality, bipolar disorder, and treatment-resistant depression, explained Bolton.

Intranasal ketamine is FDA approved for adults with treatment-resistant depression and depression symptoms in adults with major depressive disorder (MDD) with suicidal thoughts or actions.

Administration Differences: IV Ketamine vs Intranasal Esketamine

Major differences between these 2 formulations are that IV ketamine has a limited course of treatment. In general, IV ketamine is administered twice a week for 8 weeks with a period of taper with plans for resumption of treatments or booster series of infusions should depressive symptoms return. By contrast, intranasal esketamine is a maintenance medication that is dosed twice a week for 4 weeks in the acute phase and then once a week. “Once [a patient’s] mood is staying stable at once a week, we’ll try to push it out to once every 2 weeks and keep pushing it out as far as we can while keeping their moods stable,” said Miller. “Most of our patients are on a once every 2-week schedule.”

Esketamine administration can be prohibitive because it requires having someone take the patient home from treatment and remain with them for the rest of the day. Appointments for intranasal ketamine are also longer (2.5-3 hours) than for IV ketamine in general because of Risk Evaluation and Mitigation Strategy (REMS) monitoring requirements. Other treatment considerations are shown in the Table.

Table. Treatment Considerations With IV Ketamine and Intranasal Esketamine

IV KetamineIntranasal Esketamine
Pretreatment assessmentsPretreatment assessments
Day-of-treatment assessments
• Self-assessments
• Nursing assessments
• Weight, blood pressure, pulse, oxygen saturation
Day-of-treatment assessments
• Self-assessments
• Nursing assessments
• Blood pressure, pulse, oxygen saturation
Monitoring during treatment:
• Infusion issues
• Blood pressure elevation
• Dissociative effects
• Side effects
• Return to baseline within 30 min
Monitoring during treatment:
• Administration issues
• Blood pressure elevation
• Dissociative effects
• Side effects
• Return to baseline at 2 hours
Peripheral IV/infusion pumpPost-treatment REMS documentation
Source: Bolton P, Miller C.

Cost considerations should also be factored into treatment decisions, the researchers said. Health insurance coverage for these treatments is increasing, but for many patients treatment may be cost-prohibitive if their insurance does not cover it. Intravenous ketamine may not be covered by insurance and as a result, may cost more in up-front, out-of-pocket expenses, whereas insurance is starting to cover the intranasal esketamine. However, intranasal esketamine may be more expensive in the long run because it is used as ongoing maintenance treatment.

Although ketamine treatment appears to be a logical choice for patients hospitalized for suicide ideation and severe depression because of the faster onset of action compared with traditional antidepressants, navigating treatment following discharge can be a “logistical nightmare” as clinicians are unable to guarantee that insurance will cover the treatment following discharge, the presenters said. This may impact the ability to continue effective treatments after discharge.

Clinical Outcomes in Depression and Suicidality

The researchers presented clinical findings from their institution showing that implementation of IV and intranasal ketamine services has led to decreases in mean scores in the Quick Inventory of Depressive Symptomatology (QUIDS) rating scale over time and in all domains of the Behavior and Symptom Identification Scale (Basis-24) with the greatest decreases found in death/suicide thoughts (from 1.4 to 0.7). These improvements in scores were found in both men and women as well as patients of all ages.

When to Switch From IV to Intranasal Ketamine?

Recently, clinicians at McLean have started switching patients from IV ketamine to intranasal esketamine treatment if they are unable to taper off of the IV formulation while remaining stable.

“If a patient is coming once a week for IV ketamine and we try to taper them out to 10 days and then 2 weeks but they are crashing in between, we might recommend switching over to esketamine because it is designed as a maintenance medication,” said Miller. In contrast, if the patient requires a more robust response, they may be switched from intranasal to IV ketamine.

Another change is that the ketamine service is now taking a proactive maintenance approach to IV treatments by tracking each patient’s remission window and prebooking booster series before depressive symptoms return as a safety net. For intranasal ketamine, the interval between maintenance treatments also fluctuates based on patients’ symptoms.  

Other new strategies are that trained mental health workers are used to observe patients taking esketamine during the required monitoring time. The service also stopped requiring electrocardiography monitoring during IV ketamine treatments as cardiac abnormalities during treatment, with the exception of elevation in blood pressure, have not been found.

Clinical Pearls on Ketamine and Esketamine

The researchers outlined other pearls of wisdom from their experience with ketamine treatment:

  • Intranasal esketamine may take longer to show response (up to 6 treatments) than previously thought
  • Intranasal esketamine may affect patients differently if they are congested
  • Ketamine does not have any effect on memory, unlike other treatment modalities such as electroconvulsive therapy

The researchers concluded that IV ketamine infusion clinics are effective and manageable and that starting an intranasal esketamine service for maintenance therapy is feasible.

“Once you overcome some of the operational challenges and you get skilled nurses, both psychiatric-mental health nurses and APRNs, working alongside psychiatrists … operating a ketamine service can be exciting because results in patients with chronic depression can be dramatic,” Bolton concluded.


Bolton P, Miller C. Ketamine treatment strategies: 4 years of experience in a clinical setting. Presented at: APNA 36th Annual Conference; October 19-22, 2022; Long Beach, CA.