Winter 2021

Intranasal Ketamine and Esketamine for Treatment Resistant Depression

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Nathalie Dagenais, BSc, PharmD1
Franky Liu, RPh, BScPhm, MSc2
Maria Zhang, RPh, BScPhm, PharmD, MSc 2,3
1Hamilton Health Sciences, Hamilton, Ontario
2Leslie Dan Faculty of Pharmacy, University of Toronto
3Centre for Addiction and Mental Health, Toronto, Ontario


BACKGROUND

Depression is the leading cause of disability worldwide, affecting over 298 million people globally1, 2. While its treatment is multimodal, with medications frequently a cornerstone, current pharmacotherapies are limited by delayed onset of clinically significant antidepressant effects and significant relapse rates3. In fact, approximately one-third of individuals with major depressive disorder will experience treatment-resistant depression (TRD), defined as a suboptimal response to two or more appropriate trials of antidepressant therapy4. To address these gaps in treatment, there has been growing interest in the use of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, as well as its newly marketed stereoisomer, esketamine. With the increased use of these agents in hospital and community settings, pharmacists play an invaluable role in optimizing treatment selection, and monitoring medication effectiveness and safety.


KETAMINE AND ESKETAMINE IN TREATMENT RESISTANT DEPRESSION

The 2016 Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline lists intravenous ketamine infusions as an ‘experimental treatment’ reserved for the acute management of TRD in academic depression treatment centres5. Most of the evidence for this recommendation stems from single doses6, 7, though newer evidence suggests that repeated ketamine infusions may prolong the duration of antidepressant response3, 4, 8, 9. Currently, the optimal dose, frequency, and safety of repeated infusions beyond four weeks remain unclear4, 10. Despite its inclusion in the CANMAT guidelines, intravenous ketamine remains largely inaccessible for those with TRD. Understandably, there is much interest in non-parenteral forms of ketamine, including intranasal delivery. There are a variety of important clinical, pharmaceutical, operational, and legal considerations that a pharmacist should evaluate when considering compounded intranasal ketamine. These considerations should be taken in context of the recently available, patented-delivery intranasal esketamine.


INTRANASAL ESKETAMINE

In May 2020, Health Canada approved intranasal esketamine (SPRAVATO®) for the treatment of “major depressive disorder in adults who have not responded adequately to at least two separate courses of treatment with different antidepressants, each of adequate dose and duration, in the current moderate to severe depressive episode.” The medication is to be used in combination with a selective serotonin or norepinephrine reuptake inhibitor11. While the product continues to be reviewed for its cost-effectiveness in Canada and in the United Kingdom, draft recommendations from the UK are negative as there are doubts regarding esketamine’s true efficacy12, 13. Notably, studies compared esketamine simultaneously with an oral antidepressant started de novo, with a matching placebo and an oral antidepressant. This comparator is not reflective of how treatment-resistant depression is typically managed (i.e., an antidepressant augmented with lithium or an antipsychotic, electroconvulsive therapy, and/or psychotherapy)13. Additionally, given the mandatory monitoring period of two hours post medication administration, significant operational issues exist in its implementation.

Table 1: Comparison of intranasal ketamine and esketamine

Compounded intranasal ketamine Parenteral ketamine for intranasal administration Intranasal esketamine (Spravato®)
Commercially available product? No No. Active pharmaceutical ingredient itself is commercially available but not formulated specifically for intranasal administration Yes, inclusive of drug and delivery device
Indicated for treatment resistant depression? No No Yes
Prescribing restrictions? No No Yes, only prescribers and pharmacists who have enrolled in the manufacturer’s program are permitted to prescribe and dispense the medication.
Restrictions in medication distribution No restrictions beyond what is typically expected of narcotic drugs.
Patient access Following a prescription, patient can pick up the medication from a pharmacy of their choice and then self-administer the medication unsupervised Following a prescription, clinic staff must pick up the medication from an authorized retailer. Patient self-administers the medication under the mandatory supervision of a health care provider.
Approximate drug cost (decreases with time as frequency of administration wanes) Variable, ranges to approximately $100 for 30-day supply; does not include cost of atomizer Variable, approximately $100 to $120 for 30-day supply; does not include cost of atomizer Approximately $5000 for first month
Monitoring No mandatory clinical monitoring by a health care provider Mandatory monitoring for 2 hours post-dose by a health care provider
Should be tracked as a general non-methadone controlled compounded substance via the Ontario Narcotic Monitoring System (manual process), using Pseudo-DIN 09857417 Is tracked as ketamine via the Ontario Narcotic Monitoring System using DIN assigned to parenteral ketamine product Is tracked as esketamine via the Ontario Narcotic Monitoring System
Effectiveness: measures of antidepressant effect (e.g., Patient Health Questionnaire-9, Quick Inventory of Depressive Symptoms)
Safety: Dissociation, blood pressure, heart rate, nausea/vomiting, changes in mental status, vertigo, sedation, suicidal ideation, substance use disorder, ulcerative or interstitial cystitis, cognitive impairment

INTRANASAL KETAMINE

Pharmaceutically, intranasal absorption is complicated by high inter- and intra-individual variability, differing with drug formulation, delivery device, insufflation technique and individual patient factors. Intranasal absorption is further limited by administered fluid volume: doses should be divided into 0.1 mL sprays with a maximum volume of 0.3-0.5 mL per nostril to avoid being swallowed and subject to first-pass metabolism14–16.

With a commercially available racemic isolate available, pharmacy professionals should exercise careful professional judgment before proceeding with product formulation: these factors could include consideration for continuity of care; market availability or shortage of products and/or excipients; or compelling socioeconomic factors.

If compounding intranasal ketamine is deemed necessary, it must be compounded from powder or parenteral solution and manually assembled into a syringe fitted with an atomizer, which introduces further variability. Studies examining intranasal ketamine have exclusively used commercially available parenteral ketamine solution17, 18.

If intranasal ketamine is to be inhaled from a solution compounded from powder, rather than the commercially available parenteral formulation, pharmacy professionals should consider the following when deciding to compound a ketamine preparation:

  1. Ketamine as an active pharmaceutical ingredient refers to a racemic mixture of two stereoisomers of (R)-(-)-ketamine and (S)-(+)-ketamine that exist in approximately equal proportion, with distinct medicinal chemical, pharmacodynamic and pharmacokinetic profiles that may complicate replicability in dosage form preparation and therapeutic effect19.
  2. Ketamine is listed as a drug in the Narcotic Control Regulations under the Controlled Drugs and Substances Act and should be adjudicated through the province-wide Narcotic Monitoring System (NMS)20. If it is compounded from a powder without a DIN, it must be submitted using the general non-methadone compounded controlled substance pseudo-DIN (09857417)21.
  3. Special attention to isotonicity and pH are required to ensure patient acceptability and pharmaceutical elegance. For instance, ketamine is a weak organic base that is soluble in low pH. Excipients selected, particularly preservatives, should be chemically compatible to prevent inadvertent precipitation, dose variability and irritation to nasal mucosa22–24. In this regard, preservative addition is generally expected due to its aqueous formulation.
  4. Compounders should observe the requirements outlined in both the USP 795 chapter on Nonsterile Preparations (which lists nasal preparations for local applications)25 and NAPRA guidance documents when setting beyond-use dates and assigning lot numbers26.
  5. Compounders should maintain a robust quality assurance program as part of NAPRA’s Model Standards for Pharmacy Compounding of Non-sterile Preparations; compounders may also consult the USP <795> for nonsterile preparations chapter on quality assurance for guidance on factors to observe25. Documentation should include rationale for excipient choice and/or omission, references to published formulae (if applicable), and quality control parameters which may include pH, mass analyses and/or organoleptic analyses25, 26. These records should be easily retrievable should any clinical issues arise, which could include adverse reaction management and reporting, therapeutic efficacy assessment or assessing batch variance.

Compounding is typically reserved for situations where “there is a therapeutic need or lack of product availability” and should not duplicate “an approved drug product”27. Arguably, with esketamine’s Canadian market entrance, the use of intranasal ketamine, particularly to address treatment-resistant depression, will diminish.

Given the significant burden of illness and caveats in the effectiveness of current antidepressants, there is much interest in non-traditional pharmacotherapies for depression. With their novel mechanism of action and potential efficacy in TRD, ketamine and esketamine have emerged as medications of high interest. However, the quantity and quality of evidence supporting the use of these products vary depending on the formulation, route of administration, and/or dosage form. Pharmacists in all direct patient care settings will need to use their clinical judgment, knowledge of pharmaceutics, and patient care skills to ensure the safe and rational use of these emergent therapies.


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