How Can We Better Monitor the Safety of Ketamine Treatment for Depression?

What you need to know

• Ketamine is increasingly used to treat depression, but there is no standardized system for monitoring its safety, especially long-term effects.
• Current safety monitoring has limitations, including lack of standards for generic ketamine and limited data on long-term or cumulative effects.
• The Ketamine Side Effect Tool (KSET) provides a comprehensive framework for assessing both acute and longer-term safety of ketamine treatment.

The rise of ketamine as an antidepressant

Ketamine, a drug long used as an anesthetic, has emerged over the past two decades as a promising new treatment for depression. Unlike conventional antidepressants, ketamine acts on the glutamate system in the brain, specifically blocking NMDA receptors. This unique mechanism allows ketamine to produce rapid antidepressant effects, often within hours or days, compared to the weeks it typically takes for traditional antidepressants to work.

Ketamine has shown particular promise for treating severe depression that has not responded to other treatments, known as treatment-resistant depression. It may also rapidly reduce suicidal thoughts. As a result, the use of ketamine for depression is expanding quickly in clinical practice.

There are a few different forms of ketamine in use:

1. Generic racemic ketamine - This is the traditional form that has been used for decades as an anesthetic. It contains equal parts of two mirror-image molecules called enantiomers. When used for depression, it is considered “off-label” use.

2. Esketamine - This is one of the two enantiomers found in racemic ketamine. An intranasal formulation of esketamine has been approved in many countries specifically for treatment-resistant depression.

3. Arketamine - This is the other enantiomer. It is still being researched and is not yet approved for clinical use.

Current gaps in safety monitoring

While the effectiveness of ketamine for depression has been well-demonstrated in clinical trials, there are some important limitations in our current understanding of its safety:

1. Lack of standardized monitoring: For generic ketamine, which is used off-label, there are no standard guidelines for monitoring side effects. This leaves it up to individual doctors to decide how to track potential problems.

2. Limited long-term data: Most studies have only looked at the safety of ketamine over short periods, typically up to 4 weeks for generic ketamine or 48 weeks for intranasal esketamine. However, in practice, many patients receive treatment for much longer periods.

3. Varied treatment approaches: Ketamine can be given in many different ways - intravenously, intramuscularly, orally, nasally, etc. It can also be given at different doses and frequencies. The relative safety of these different approaches has not been thoroughly studied.

4. Passive reporting: Many studies have relied on patients to voluntarily report side effects, rather than actively checking for them. This can lead to underestimating the true rate of side effects.

5. Use of non-specific scales: Some studies have used general psychiatric rating scales to assess side effects, rather than tools designed specifically for ketamine’s unique effects.

The need for comprehensive safety monitoring

Given these gaps in our knowledge, there is a pressing need for a standardized, comprehensive approach to monitoring the safety of ketamine treatment. This is especially important as ketamine moves from carefully controlled research settings into wider clinical use.

Monitoring needs to cover both the immediate effects that occur during and shortly after each ketamine dose, as well as potential longer-term or cumulative effects that might develop with repeated treatments over months or years.

Some specific areas of concern include:

1. Dissociation: Ketamine can cause feelings of detachment from one’s body or surroundings.

2. Sedation: Ketamine may cause drowsiness or sleepiness.

3. Blood pressure changes: Ketamine can cause temporary increases in blood pressure.

4. Urinary tract problems: Long-term, heavy use of ketamine (primarily seen in recreational users) has been associated with bladder issues.

5. Cognitive effects: There are questions about whether long-term ketamine use might impact memory or other cognitive functions.

6. Dependence: While ketamine is not considered highly addictive when used as prescribed, there is still a need to monitor for signs of dependence, especially with long-term use.

The Ketamine Side Effect Tool (KSET)

To address these needs, a group of international experts in ketamine research and clinical use have developed the Ketamine Side Effect Tool (KSET). This comprehensive tool is designed to standardize safety monitoring for all forms of ketamine treatment used in psychiatry.

The KSET consists of four modules:

1. Screening: This assesses any pre-existing medical issues that might make ketamine use risky for a particular patient.

2. Baseline: This establishes the patient’s symptoms before starting ketamine, to allow for comparison later.

3. Acute Treatment: This is used immediately after each ketamine dose to assess immediate side effects. It includes a record of vital signs and a checklist to determine if the patient is ready to be discharged.

4. Follow-up: This assesses potential medium- and long-term side effects at later follow-up appointments.

The KSET uses a standardized severity rating scale to capture both acute side effects (like high blood pressure or dissociation) and potential longer-term effects (like urinary symptoms or signs of dependence). It’s designed to be completed by a clinician, though some parts can be filled out by the patient to save time.

Key features of the KSET include:

• Comprehensive coverage: It assesses physical, psychiatric, psychotomimetic (mind-altering), and cognitive side effects.

• Active surveillance: Rather than waiting for patients to report problems, it prompts clinicians to actively check for specific side effects.

• Ketamine-specific: Unlike general psychiatric rating scales, the KSET is tailored to the unique effects of ketamine.

• Flexible: It can be used with all forms of ketamine (racemic, esketamine, arketamine) and all routes of administration.

• Long-term monitoring: It provides a framework for assessing effects over extended periods of treatment.

The importance of responsible implementation

The rapid adoption of ketamine for depression treatment brings both great promise and significant responsibility. The history of medicine provides cautionary tales of treatments that were initially hailed as breakthroughs, only to reveal serious long-term side effects after widespread use. The opioid crisis is a stark reminder of what can happen when the long-term risks of a medication are not fully appreciated or monitored.

By implementing comprehensive safety monitoring tools like the KSET, clinicians can help ensure that ketamine’s potential as a revolutionary depression treatment is realized while minimizing risks to patients. Careful monitoring and data collection will allow the medical community to build a clearer picture of ketamine’s long-term safety profile and refine treatment protocols to maximize benefits and minimize risks.

Conclusions

• Ketamine shows great promise for treating severe depression, but current safety monitoring has significant limitations.
• The Ketamine Side Effect Tool (KSET) provides a standardized, comprehensive framework for assessing both acute and long-term safety of ketamine treatment.
• Implementing tools like the KSET is crucial for responsible clinical use of ketamine and for building our understanding of its long-term safety profile.

The KSET is currently freely available for use in both clinical and research settings. As more centers adopt this tool, it will facilitate the creation of a global registry of ketamine side effects. This collaborative effort will be invaluable in furthering our understanding of ketamine’s safety and optimizing its use in depression treatment.