Emerging Uses Of Ketamine Treatment For Depression

Note: The information in this article is not a constitution for medical advice. Consult your primary care provider or another licensed medical physician before considering, starting, changing, or stopping any medication or medical treatment. If you are struggling with substance use, contact the SAMHSA National Helpline at (800) 662-4357 to receive support and resources.

Low-dose ketamine is a controlled substance initially discovered as an anesthetic and pain reliever. Since its discovery, doctors have found it may be an effective alternative for treatment-resistant depression. If you’ve been considering the possibility of ketamine-assisted therapy, it can be helpful to look at the origins of this treatment and how it may be effective. However, talk to your doctor before considering ketamine for depression. 

History of ketamine in medicine

Ketamine was synthesized by a professor at Wayne State University in Detroit, Michigan, in the 1960s. After receiving FDA approval for use in humans in 1970, ketamine was used as an analgesic and sedative during the Vietnam War. In large doses, ketamine can be an effective anesthetic and has been used for many years on humans and animals. Compared to other anesthetics, ketamine had fewer side effects on breathing and blood pressure.

However, doctors discovered that ketamine has some psychoactive properties, causing hallucinations or a "spaced-out" sensation. This discovery prompted ketamine's use as a recreational drug, which resulted in stricter rules regarding its distribution and use. Outside of medical settings, unregulated use of ketamine can cause serious side effects to a person’s physical and mental health. Nonetheless, a recent discovery suggests that ketamine may be able to treat depression. 

What is depression? 

There are several depressive disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Major depressive disorder (MDD) is one of the most prevalent and severe of these conditions, and over 280 million people live with depression worldwide. When individuals refer to “depression,” they are often referring to MDD. 

Symptoms of depression can include but are not limited to the following: 

• Prolonged sadness and a low mood 

• Difficulty finding motivation 

• Appetite changes 

• Sleep changes

• A loss of interest and pleasure in previously enjoyed activities

• A sense of apathy or a lack of emotions 

• Difficulty caring for oneself 

• Suicidal thoughts 

Current medical depression treatments 

Current mainstream antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) were discovered around 60 years ago. However, only about 35% of patients on SSRIs may achieve complete remission, leaving as many as five million people in the US with what’s known as “treatment-resistant depression.”

For individuals who experience therapeutic benefits from SSRIs, the effects may take several weeks to be noticed, and there can be a high rate of symptom relapse. For some individuals, depression can come back. For this reason, there has been an unmet need for antidepressants with more rapid relief, particularly for individuals with stubborn depression or those with suicidal thoughts. 

Note that medications can work differently for everyone, and many people find benefit in antidepressants. If SSRIs or other medications have been prescribed to you by a doctor and work well for you, it may not be necessary to change your treatment. Consult your doctor or psychiatrist before stopping or changing your medication. 

Ketamine and depression: Understanding a new treatment possibility

Ketamine may be effective at improving symptoms of depression. Studies suggest that a sub-anesthetic dose of ketamine may be effective in lessening suicidal thoughts and in improving treatment-resistant depression. One study found that 60% to 70% of clients with treatment-resistant depression responded to ketamine almost immediately. Effects were seen within hours of administration and were sustained for up to two weeks in some patients.

Healthcare providers can still prescribe and use ketamine with clients if they have a license to prescribe medication and offer medical care. However, there may be a few safety concerns to keep in mind, which is why ketamine should only be used with a doctor’s supervision. These safety risks may include the following: 

• Sedation and sleepiness 

• Dissociation 

• Changes in heart rate and blood pressure 

• Racing thoughts 

• Potential for substance misuse or addiction

• Urinary incontinence 

• Respiratory depression 

How does ketamine work?

It isn’t currently known how ketamine might support depressive symptoms. The anesthetic properties of ketamine are thought to occur by its blockade of NMDA glutamate receptors in the brain. Glutamate is one of the brain's major neurotransmitters and fast-acting excitatory molecules. This neurotransmitter contrasts with monoaminergic systems such as serotonin, which are more localized and slow-moving. Ketamine works through the fast-acting glutamate system, consistent with its rapid onset of action.

Studies suggest that ketamine's antidepressant effects may be due to a blockade of NMDA receptors but also its simultaneous enhancement of another type of glutamate receptor: AMPA receptors. The block of NMDA and enhancement of AMPA receptors, together, may cause a rapid release of glutamate in the brain, which is thought to kick-start neuroplasticity (the ability of the brain to grow new neurons and new connections).

Contemporary theories of depression suggest that neuroplasticity is impaired in people with depression and that interventions that promote neuroplasticity may alleviate depression. Conventional antidepressants, as well as behavioral interventions (such as exercise), have been shown to increase neuroplasticity, as well, and are considered safer by the FDA. However, because ketamine appears to work on the glutamate system, it may work more quickly. These results are not confirmed, and more studies are required to understand this treatment fully. 

Safety implications 

Although the use of ketamine in treating depression may seem promising, individuals may have remaining questions and challenges. While a recent systematic review suggests ketamine is a safe treatment for depression in the short term, questions remain about the long-term risks and potential side effects of ketamine treatment.

Because the FDA does not recommend ketamine treatment, it can be crucial to be cautious when interacting with clinics or doctors who claim to offer this treatment. Although licensed doctors can prescribe ketamine, it has been associated with some challenging symptoms and long-term impacts, such as addiction. 

In addition, ketamine's effects may be temporary, as some individuals may experience a relapse in depression symptoms. For this reason, regular infusions of ketamine may be required, which could lead to more significant side effects. Because the treatment is not FDA-approved, insurance companies may not cover it, meaning individuals may have to pay $400 to $800 per infusion. However, talk to your doctor before exploring these options in more detail, and note that there are FDA-approved and evidence-based treatments for treatment-resistant depression that do not include ketamine. 

Alternative support options 

For those who have exhausted contemporary antidepressants or treatment options and still struggle with severe depression, it may be beneficial to consider evidence-based treatments, such as therapy. Many forms of therapy are effective in reducing depression symptoms and can be an option while you explore other treatments. 

Some people with depression may struggle to leave home, making meeting with a mental health professional like a counselor or therapist in person challenging. In these cases, online therapy through a platform like BetterHelp may be beneficial. With internet-based counseling, you can discuss your symptoms with a licensed therapist from the comfort of your home and choose between phone, video, or live chat sessions. You can also try other resources like support groups and journaling prompts. 

Researchers in the mental health field have been investigating the effects of online counseling for more than a decade. One study found that individuals undergoing remote therapy for depression experienced more significant symptom reduction compared to participants on a waitlist.