Ketamine vs. Electroconvulsive Therapy (ECT) for Treatment-Resistant Depression: The ELEKT-D Study

What is Electroconvulsive Therapy?

Electroconvulsive Therapy (ECT) is a medical treatment most commonly used for patients with severe major depression or bipolar disorder that has not responded to other treatments. During ECT, a patient is placed under general anesthesia, and small electric currents are passed through the brain, intentionally triggering a brief seizure. ECT is believed to cause changes in brain chemistry that can quickly reverse symptoms of certain mental health conditions. The procedure is typically administered two to three times a week for a total of six to twelve treatments.

However, ECT carries several potential risks and disadvantages. Memory loss is one of the most common side effects, affecting both short-term and long-term memory. Patients may also experience confusion immediately after the procedure, which can last from a few minutes to several hours, and in some cases, for even longer periods. Physical side effects such as headaches, muscle aches, and jaw pain can occur due to the seizure activity induced during treatment. Additionally, ECT can temporarily increase heart rate and blood pressure, posing risks for individuals with preexisting heart conditions. The need for general anesthesia during ECT introduces further risks, including allergic reactions and complications related to breathing. While ECT can be highly effective for certain individuals, these potential risks and disadvantages should be carefully considered and discussed with a healthcare provider.

What is Ketamine Therapy?

Ketamine therapy involves the use of low doses of ketamine, a medication traditionally used at high doses as an anesthetic, to treat various mental health conditions and chronic pain. Initially recognized for its rapid antidepressant effects, ketamine has gained attention as a treatment option for patients who have not responded well to conventional therapies. For a comprehensive review of ketamine therapy, be sure to read, "An Overview of Ketamine Therapy for the Treatment of Mental Health Disorders and Pain."

How Ketamine Therapy Works

1. Mechanism of Action: Ketamine works primarily by blocking NMDA receptors in the brain, which are involved in mood regulation and pain perception. This leads to an increase in the neurotransmitter glutamate, promoting synaptic plasticity and brain connectivity, which can alleviate symptoms of depression and pain.
2. Administration: Ketamine can be administered in several forms:
   • Intravenous (IV) Infusion: This is the most common method, involving a controlled infusion of ketamine over a set period, usually 40 minutes to an hour.
   • Intramuscular (IM) Injection: Less common but still used, particularly in certain clinical settings.
   • Oral and Sublingual Tablets: These forms are less frequently used due to variability in absorption and effects.
   • Nasal Spray: Esketamine (Spravato), a derivative of ketamine, is an FDA-approved nasal spray for treatment-resistant depression.

Conditions Treated with Ketamine Therapy

1. Depression: Particularly treatment-resistant depression (TRD), where other medications and therapies have not been effective.
2. Anxiety Disorders: Including generalized anxiety disorder (GAD) and social anxiety disorder (SAD).
3. Post-Traumatic Stress Disorder (PTSD): Helping to reduce symptoms of PTSD by promoting neuroplasticity and reducing hypervigilance.
4. Chronic Pain: Conditions such as complex regional pain syndrome (CRPS) and fibromyalgia may benefit from ketamine's pain-relieving properties.
5. Obsessive-Compulsive Disorder (OCD): Emerging evidence suggests ketamine may reduce symptoms of OCD.

Benefits and Considerations of Ketamine Therapy

Ketamine therapy offers several significant benefits. One major advantage is its rapid onset; patients often experience relief within hours or days, unlike traditional antidepressants, which can take weeks. Additionally, ketamine has shown remarkable efficacy in cases where other treatments have failed, providing new hope for individuals with treatment-resistant conditions. Furthermore, ketamine promotes neuroplasticity, enhancing the brain's ability to reorganize and form new neural connections, which can lead to longer-lasting benefits.

While ketamine therapy is effective, it comes with some considerations. Potential side effects include dizziness, nausea, and increased blood pressure, though these are generally short-lived and manageable. The long-term effects of repeated ketamine use are still being studied, so it is important to weigh the potential benefits against the unknown long-term implications. Additionally, ketamine therapy is not typically a first-line treatment and is usually reserved for cases where other treatments have been unsuccessful.

Protocol and Monitoring

Ketamine therapy should be administered under the supervision of medical professionals, often in specialized clinics. A comprehensive protocol includes medical evaluation, preparation, administration, and post-treatment monitoring to ensure safety and maximize therapeutic outcomes. Ketamine-assisted psychotherapy (KAP) combines the administration of ketamine with traditional psychotherapy to enhance therapeutic outcomes. In KAP, ketamine is used to induce a non-ordinary state of consciousness, allowing patients to explore their thoughts and emotions more deeply and with reduced resistance.

The ELEKT-D Trial

The ELEKT-D trial was a multicenter study conducted across five academic medical centers in the United States. It aimed to compare the effectiveness of intravenous ketamine and ECT for patients with nonpsychotic TRD. The study enrolled 403 participants aged 21 to 75 years, all of whom were in a current depressive episode of at least moderate severity. Participants were randomly assigned to receive either six ketamine infusions or nine ECT sessions over three weeks.

Key Findings:

Response Rates:

• Moderately Severe to Severe Depression: Participants with a baseline QIDS-SR16 score ≤20 had a greater reduction in depression severity with ketamine compared to ECT.
• Very Severe Depression: Participants with a QIDS-SR16 score >20 showed greater improvement with ECT earlier in treatment (by week 2), but both groups had similar outcomes by the end of the 3-week period.

Inpatient vs. Outpatient Status:

• Outpatients: Greater reduction in depression severity with ketamine compared to ECT.
• Inpatients: Greater reduction with ECT compared to ketamine.

Associated Factors:

• Premorbid Intelligence* (NAART-35 Score): Participants with lower scores (<85) had higher response and remission rates with ketamine than with ECT. The difference was less pronounced in those with higher scores (≥85).

* Premorbid intelligence refers to the cognitive abilities an individual had before the onset of a disease or disorder that affects cognitive functioning. The North American Adult Reading Test (NAART-35) is a commonly used measure to estimate premorbid intelligence. It involves reading aloud a list of words with irregular spellings that are unlikely to be sounded out phonetically. The test assumes that the ability to pronounce these irregular words is resistant to decline due to neurological conditions, thus providing an estimate of an individual's baseline cognitive abilities.

• Concurrent Medication Use: Concurrent atypical antipsychotic medication use was associated with higher remission rates with ketamine (42.9%) compared to ECT (10.6%).
• Comorbid PTSD: Greater improvement in depression severity with ECT in participants with comorbid PTSD compared to those without.
• Baseline Cognitive Function (MoCA Score): Lower baseline MoCA scores were associated with greater improvement in depression severity with ketamine.
• BMI: Higher BMI was associated with greater reduction in depression severity with both ketamine and ECT.

Clinical Implications

The study underscores that while both ketamine and ECT are effective for treatment-resistant depression (TRD), the choice of treatment should be tailored to specific patient characteristics. Key factors influencing treatment decisions include the severity of depression, inpatient or outpatient status, premorbid intelligence, concurrent medication use, and comorbid conditions. The findings suggest that ketamine may be particularly beneficial for outpatients with moderately severe or severe TRD. Conversely, ECT may be more suitable for inpatients and those with very severe depression.

Conclusion

Given the differing profiles of ketamine and ECT, shared decision-making between patients and clinicians is crucial. Patients' preferences, baseline depression severity, and treatment setting should be considered when choosing between these treatments. The potential benefits of ketamine, such as rapid onset of action and outpatient administration, must be weighed against the more established but intensive nature of ECT.

The ELEKT-D trial highlights the importance of personalized treatment approaches for TRD. Both ketamine and ECT are effective, but certain clinical features can guide treatment selection to optimize outcomes. Future research should continue to explore these associations and expand our understanding of how to best use these treatments in clinical practice.