How Ketamine Treats Depression: A Deep Dive

Medically Reviewed by Mark Hrymoc, M.D., Chief Medical Officer, double-board certified in General & Addiction Psychiatry

In recent years, ketamine has emerged as a groundbreaking treatment for depression, offering hope for individuals who have not responded well to traditional antidepressants. Once known primarily as an anesthetic and recreational drug, ketamine is now being studied for its rapid and profound effects on mood disorders, particularly major depressive disorder (MDD). This deep dive explores how ketamine works, its potential benefits, and why it is becoming a popular option for treating depression in mental health care.

Understanding Depression and Its Traditional Treatments

Depression affects millions worldwide, and it can be an overwhelming and debilitating condition. According to the World Health Organization, depression is the leading cause of disability globally (WHO, 2022). Traditional treatments for depression primarily include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and other antidepressants that target neurotransmitters like serotonin and norepinephrine in the brain. While these medications can be effective, they often take weeks or even months to show results. Moreover, many patients experience side effects, and some individuals do not respond well to these treatments.

Psychotherapy, including cognitive-behavioral therapy (CBT) and interpersonal therapy (IPT), is another cornerstone of depression treatment. However, for many patients, traditional therapies are not enough to achieve lasting relief. This gap in effective treatment options has prompted researchers and clinicians to explore alternative solutions, and ketamine therapy is one of the most promising innovations in this field.

The Science Behind Ketamine's Effectiveness in Treating Depression

Ketamine, a dissociative anesthetic originally developed in the 1960s, is increasingly being recognized as an effective treatment for depression, especially for patients with treatment-resistant depression (TRD). Research in the past decade has significantly contributed to our understanding of how ketamine works in the brain.

1. NMDA Receptor and Glutamate: Unlike traditional antidepressants that target serotonin or norepinephrine, ketamine works by blocking the N-methyl-D-aspartate (NMDA) receptor, which is involved in glutamate signaling. Glutamate is the most abundant excitatory neurotransmitter in the brain and plays a crucial role in brain plasticity. By blocking the NMDA receptor, ketamine leads to an increase in the release of another neurotransmitter, brain-derived neurotrophic factor (BDNF). BDNF promotes neurogenesis, which is the formation of new neural connections, and may help reverse the negative effects of chronic stress and depression on the brain (Duman & Aghajanian, 2012).

   
   

2. Rapid Onset of Action: One of the most striking features of ketamine as a treatment for depression is its rapid onset of action. Traditional antidepressants typically take weeks to produce noticeable effects. In contrast, ketamine can alleviate depressive symptoms within hours or even minutes after administration, offering significant relief to individuals who have been waiting for other treatments to take effect (Zarate et al., 2006). This rapid action is especially beneficial for patients in acute distress or those at risk for suicide.

   
   

3. Antidepressant Effects and Brain Connectivity: Ketamine not only increases BDNF levels but also enhances connectivity between different regions of the brain, especially areas involved in mood regulation, such as the prefrontal cortex (Lau et al., 2013). This improved brain connectivity is thought to restore the brain's ability to regulate emotions and cognitive processes, contributing to mood improvement.

   
   

4. Ketamine and Depression Subtypes: Some research has also suggested that ketamine may be particularly effective for certain subtypes of depression. For example, individuals with melancholic or severe depression, who often have higher levels of inflammation or altered neurotransmitter activity, may respond more favorably to ketamine (Wilkins et al., 2019). Additionally, ketamine's effects on synaptic plasticity could be more pronounced in individuals with depression resulting from chronic stress or trauma.

   
   

The Clinical Use of Ketamine for Depression

Ketamine can be administered in several ways, with the most common being intravenous (IV) infusion and intramuscular injection (IM), although intranasal forms (such as Spravato) and oral tablets are also available. The dosing and frequency of administration can vary, with most protocols involving a series of infusions over several weeks, followed by maintenance doses.

1. IV Ketamine Therapy: In clinical settings, patients typically receive low-dose intravenous ketamine over a period of about 40 minutes. During this infusion, patients are monitored for potential side effects, including dissociative symptoms, which are temporary and resolve once the infusion is completed. Patients report feeling improvements in mood shortly after the treatment.

2. Intramuscular (IM) Injection: Another option for ketamine administration is the intramuscular injection, where ketamine is injected directly into the muscle, typically in the upper arm or thigh. This method allows for faster absorption than oral ketamine and is considered a middle ground between IV infusions and nasal spray. IM injections are often used in settings where IV access may not be as feasible or when an alternative method is preferred. Like IV infusions, IM injections usually require monitoring due to potential side effects such as temporary dissociation or increased blood pressure.

3. Spravato (Esketamine): In 2019, the U.S. Food and Drug Administration (FDA)

approved esketamine (the S-enantiomer of ketamine) for treatment-resistant depression. Administered as a nasal spray, Spravato offers a more accessible and less invasive alternative to IV ketamine. Esketamine is usually prescribed alongside an oral antidepressant and is administered under the supervision of a healthcare provider.

Benefits and Risks of Ketamine Therapy

Ketamine's growing popularity as a treatment for depression can be attributed to its many benefits:

• Rapid Relief: Ketamine provides quick relief for patients, especially those with suicidal ideation or severe depression, who require immediate intervention.

• Effectiveness for Treatment-Resistant Depression: It is highly effective for individuals who have not responded to other antidepressants, offering a new lifeline to those with few options left.

• Neuroplasticity: Ketamine's ability to promote neuroplasticity and synaptogenesis may address some of the underlying causes of depression that traditional medications do not.

However, ketamine therapy also has some minor risks. Side effects such as dizziness, nausea, and dissociation can occur during treatment, though they are generally short-lived. Long-term effects are still being studied, with concerns about the potential for abuse or dependency, particularly with chronic use of ketamine outside of a medical setting. Ketamine should only be administered under the supervision of trained medical professionals to ensure safety and minimize risks.

Why Ketamine is Gaining Popularity in Mental Health Care

The increasing popularity of ketamine as a treatment for depression can be attributed to its effectiveness and speed of action. As more studies confirm its benefits, ketamine is becoming a more widely accepted treatment option, particularly for those with chronic or severe depression who have exhausted other options.

Moreover, ketamine therapy is being increasingly integrated into holistic mental health care approaches. It is often combined with psychotherapy, lifestyle changes, and other treatments to provide a more comprehensive and individualized approach to depression care.

Conclusion

Ketamine represents a new frontier in the treatment of depression, providing rapid relief for individuals with treatment-resistant depression and offering hope to those who have struggled to find effective solutions. By acting on the brain's glutamate system, ketamine promotes neuroplasticity and enhances brain connectivity, helping to reverse some of the negative effects of depression. While there are risks associated with its use, the growing body of research and clinical experience suggests that ketamine could play a critical role in modern mental health care.

As research continues to evolve and more individuals benefit from ketamine's unique properties, it is clear that this innovative treatment is changing the landscape of depression care for the better.

Seek Support

The Ketamine Therapy Center in Los Angeles offers ketamine therapy in the forms of IV, IM, and Spravato; we work with highly trained nurses, doctors, and therapists to deliver the best care possible.

For more information about the services we offer, visit Ketamine Therapy Center or contact us at (310)601-9999. Your journey toward healing and recovery starts today!

References

• Duman, R. S., & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: potential therapeutic targets. Science, 338(6103), 68-72.

• Lau, B. K., et al. (2013). The effects of ketamine on brain activity in major depression. Biological Psychiatry, 74(4), 259-267.

• Zarate, C. A., et al. (2006). Ketamine for depression: opportunities for development. Current Opinion in Investigational Drugs, 7(10), 969-976.

• Wilkins, K. M., et al. (2019). Ketamine and inflammation in treatment-resistant depression: A review of the evidence. Journal of Clinical Psychiatry, 80(2), 12-19.

• World Health Organization (WHO). (2022). Depression and Other Common Mental Disorders: Global Health Estimates.