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How Ketamine Is Helping People With Treatment Resistant Depression

ketamine depression
Amelia Walsh
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Medical Editor: Dr. Benjamin Malcolm, PharmD, MPH, BCPP

In recent years, ketamine and the innovation of its use for treating different forms of depression has become increasingly more interesting as it is evident that it can provide rapid relief to persons with treatment-resistant depression.

Depression is the most common cause of disability, but many people experience side effects or do not find adequate relief from conventional treatments. It is estimated that 10-30% are resistant to beneficial effects of traditional antidepressants.

Here are answers to some of the most common questions about the possibility of adding ketamine to a course of treatment for depression.

What is ketamine?

Ketamine was initially used during surgery as an anesthetic and as an alternative to pain medicines like morphine, but it has since been researched and approved for use to help people with treatment-resistant depression.

Experts in the field of mental health are optimistic about the treatment. It can offer significant benefits to those who have been unsuccessfully treated with other medications. It produces a dissociative and psychedelic effect that users find insightful and is linked to clinical improvement.

Ketamine’s landmark studies for depression were done using intravenous infusions, however a nasal spray was approved for use by the Food and Drug Administration (FDA).

It is now offered in therapeutic settings via a variety of administration routes, including infusion, intramuscular injection, intranasally, by mouth, and even sublingually (under the tongue).

When used therapeutically, it is given a few times a week for a few weeks as an initial round of treatment, followed by a period of observation for response. Some may return for treatments on a regular schedule or discontinue use of ketamine after a few rounds of treatment.

Use of ketamine in a clinical setting is evolving, although it appears that ketamine-assisted psychotherapy (KAP) offers significant benefits in treatment response and harm reduction relative to ketamine use in recreational or even supervised settings that do not give supportive psychotherapy.

While it is still unclear as to the exact reasons ketamine works for depression, what is known is that it operates on different neurotransmitters and receptors. Whereas most antidepressants work on neurotransmitters like serotonin, ketamine primarily modulates a neurotransmitter called glutamate, which is involved in brain plasticity and are partially responsible for mood regulation.

Does ketamine really work for depression?

Ketamine is an exciting development because it acts rapidly and tends to produce robust beneficial effects when it does work. Most antidepressants can take weeks to achieve full results and their overall effects are often modest. The opportunity to quickly achieve significant improvement is a welcome innovation.

Ketamine may help repair connections in the brain by inducing a state of neuron plasticity, allowing the potential for significant shifts in negative mood states as well as longer-term change.

Ketamine is not a lifetime commitment when it works well; it is a series of treatments that occur over a relatively short period of time (depending on the case), and can offer lasting symptom relief if successful.

Ketamine for bipolar depression

Bipolar depression is one of the most likely psychiatric conditions to cause suicidal ideation and be resistant to treatment. Ketamine has been studied with mood stabilizers such as lithium or valproic acid and is shown to be effective for bipolar depression. It has some promising studies showing rapid anti-suicidal effects. Use for serious mood disorders such as those with suicidality should be attempted only under the supervision of professionals with close monitoring.

Ketamine for severe and treatment-resistant depression

Typical antidepressants work on what is called the monoamine system, targeting neurotransmitters like dopamine, norepinephrine, and serotonin. They are typically a successful form of treatment for depression, but those suffering from major depressive disorder (MDD) can sometimes be resistant to treatment and be candidates for additional methods of therapy.

Ketamine for major and clinical cases of depression that are resistant to treatment can be effective when other methods alone are not. It can also be used safely and effectively in conjunction with traditional antidepressants, in fact this is how the FDA approved ketamine nasal inhaler, esketamine (Spravato) is intended to be used.

In cases of severe depression, ketamine has offered rapid relief of symptoms in controlled medical studies with transient or short-lived side effects around the time of ketamine administration.

Ketamine is not currently considered the first option for treatment of depression, but it is becoming more and more common for health practitioners to consider it when the most commonly prescribed pharmaceuticals do not provide adequate relief.

Ketamine works quickly, sometimes within hours of receiving treatment. So it could be a game changer for those with severe depression for whom the condition poses a danger.

When major depression is resistant to treatment, it typically means that the common drugs prescribed have not been effective. It can also take weeks to see improvements, if the medicine works at all for the patient. In the meantime, many people are at risk for suicidal ideation and susceptible to the damaging effects of treatment-resistant depression.

Ketamine can improve symptoms within just a few hours of treatment, working on different receptors in the brain and possibly offering long-term relief with multiple doses over time.

How to take ketamine for depression

There are a few different ways you can take ketamine for depression. The right method is different for everyone, and the best way to find out is to speak with a knowledgeable practitioner. Here are the options:

Drip or intravenous infusion

An IV drip (intravenous ketamine treatment is also called an infusion) allows the medicine to bypass the digestive system and enters directly into the bloodstream. It is among the most common ways to receive ketamine treatments for depression and one of the methods with the most data supporting it.

Studies have shown relief within 4 hours and possible remission of depressive symptoms in as little as a week after infusion treatments for certain patients. Infusions may be given in a series of treatments, for example a person may receive a ketamine infusion six times in two to three weeks as an initial round of therapy.

The number of treatments and frequency of administration depends on the type of diagnosis. Typically, symptom relief occurs within one to three treatments, however sustained benefits are more likely with additional treatments (particularly in the case of treatment-resistant depression).

Intravenous infusions are typically administered over 40 minutes, although the user may need to stay at the treatment center to be monitored and receive supportive psychotherapy after administration.

Injections or intramuscular shots

While less well studied, intramuscular (IM) injections of ketamine to treat depression are being studied and could offer the same effective, rapid relief as IV treatment. There’s still more to learn, but the preliminary results appear promising. One major advantage of IM injections compared to IV infusions is the fact that there is no insertion of an IV line or need for an infusion pump, making it simpler for practitioners and patients.

Nasal inhaler

The FDA-approved version of ketamine for treatment-resistant depression is a nasal spray of one type of ketamine or esketamine (Spravato). It’s a nasal spray or inhaler administered by the patient under the supervision of a practitioner.

Two schedules exist for dosage and frequency, one for treatment-resistant depression (TRD) and another for a shorter term of use in addressing major depression with acute suicidal ideation (MDSI) prior to the onset of a standard antidepressant medication.

Treatment of TRD starts with a 56 mg dose as frequency and additional doses are adjusted over the course of 9 weeks, or longer if deemed necessary.

Treatment for MDSI is administered for 4 weeks, with an 84 mg dose taken twice weekly.

A patient takes the medicine themselves, and is then monitored by a practitioner or their trained staff for up to several hours to ensure safety.

Because esketamine can cause disorientation, dizziness, or other side effects during and immediately following treatment, it is important to comply with safety policies during and after treatment, as well as avoid the operation of a vehicle for the rest of the day after use.

Ketamine and psychotherapy

One study about ketamine assisted psychotherapy discusses the administration of small doses of ketamine during a talk therapy session and the benefit of that session to someone suffering from treatment-resistant depression.

Because ketamine can allow a person to be less preoccupied by inhibitions and feel more open to a discussion, these sessions may offer a new way to approach depression therapy and more effectively address factors like previous exposure to trauma. In addition, the authors document beneficial effects of ketamine in larger doses with supportive psychotherapy for many other conditions including PTSD, ADHD, and generalized anxiety.

Psychotherapy is a helpful treatment for depression, whether ketamine is used simultaneously to facilitate a therapy session or the treatments occur at different times. The potential benefits of ketamine can generally promote a greater sense of well-being, increasing the possibility of full participation in the therapeutic process or greater engagement with therapy on behalf of the patient.

Is ketamine legal?

Ketamine is a legally available medicine for anesthesia, depression, and is commonly used for other purposes. It is an ‘essential medicine’ due to its low cost and high utility according to the World Health Organization (WHO). It is the only legal psychedelic therapy available for treating depression in the United States for most people at this time, but that may change.

Ketamine is not legal for recreational purposes, and can be dangerous if used improperly.

Is ketamine treatment approved by the FDA?

The FDA (U.S. Food and Drug Administration) has approved esketamine (Spravato) for the treatment of depression in conjunction with traditional antidepressants.

Use of ketamine outside the FDA-labeled indication is termed ‘off-label’ use.This simply means the FDA has not approved of it for that purpose, although could be quite reasonable to use for that purpose due to supporting studies. Ketamine practitioners using higher doses or routes of administration different than those in formal clinical trials are engaging in ‘off-label’ use. In some cases this could be helpful and offer additional benefit, while in others it may be too experimental and carry increased risks.

Is ketamine for depression safe?

It is important to know that ketamine taken in high doses is used for anesthesia purposes, but does not have the same effect with subanesthetic doses used in depression.

That being said, side effects do occur with low doses administered to treat depression. Study participants have reported symptoms like feeling odd, the sensation of floating, sedation, dissociation, and impaired cognitive abilities. Physical side effects can include increased blood pressures and heart rates, dizziness, vomiting, and headaches.

The long-term effects of treatment with ketamine are not currently known. Further studies are required to discover any risk of lasting impacts that could exist.

The infrequent doses are administered under the supervision of a professional in a clinical setting, followed by health monitoring and observation for a period of time after treatment. This helps ensure safety after treatment, as the common side effects can be dangerous if a person is not supervised until they subside.

Ketamine is not taken daily, and currently not at home without supervision or guidance of a trained practitioner. Working with a practitioner and receiving the medicine with medical supervision is the only way to be confident that treatment will be as safe as possible.

It is important to note that ketamine is commonly misused as a street drug, and can have addictive properties if taken without the guidance and supervision of a practitioner. When used improperly, it has the potential to cause psychological and physical harm such as neurocognitive problems or difficulty functioning normally and lower urinary tract symptoms like a bloody bladder, pain, or inflammation.

Is ketamine for depression addictive?

Ketamine is a schedule III controlled substance in the US and does carry risk of habituation, tolerance, and addiction in recreational or unsupervised settings. Because of the lower dosage and intermittent use pattern of supervised treatments, it’s less likely that you’ll become addicted to ketamine. Currently, most ketamine treatments occur in a clinical setting and not at home.

Always work with a practitioner who can help ensure the correct dose and frequency of ketamine and esketamine to avoid the risk of addiction or dependency. Individual use not regulated by a professional increases the likelihood of abuse, in addition to the dangers of possible side effects in a non-clinical setting.

Is ketamine for depression covered by insurance?

Because ketamine is not considered the first line of defense against depression, some insurance companies will not cover it.

However, some plans will cover ketamine for depression if certain criteria are met, such as trying at least two or more medications that haven’t helped at all on their own. In this case, insurance companies will likely review a case and may require completion of prior authorization procedures.

It is always best to speak with an insurance company for information about what is covered and which steps can be taken to have treatments approved if a plan allows coverage for ketamine treatments.

Where can I get ketamine for depression?

It is not recommended that individuals acquire or use ketamine themselves, as there are serious concerns about dosage and safety that require oversight by a professional. Additionally, attempts at self-medication increase the likelihood of dependency, addiction, and health risks. Ketamine, if deemed appropriate, is only one part of a treatment regimen that may require conjunctive prescription antidepressants, behavioral therapy, or other interventions and lifestyle changes for best results.

As ketamine research continues to provide a greater understanding of its effect on depression, it is becoming more widely available for therapeutic use from mental health professionals. To ensure the quality of a medicine and safe use, connect with an experienced practitioner. They can provide ketamine treatment that is right for a person’s individual needs.

Access a list of practitioners by checking out the Psychable’s directory today.

Academic Sources

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. (2018). Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. The Lancet. 10.1016/S0140-6736(18)32279-7

Glutamate as a neurotransmitter in the healthy brain. Y. Zhou and N. C. Danbolt. Journal of Neural Transmission Volume  121, 799–817(2014). 10.1007/s00702-014-1180-8

Ketamine in Bipolar Disorder: A Review. Alina Wilkowska, Łukasz Szałach, and Wiesław J Cubała. Neuropsychiatric Disease and Treatment Volume 16. 10.2147/NDT.S282208

Efficacy of ketamine therapy in the treatment of depression. Suprio Mandal, Vinod Kumar Sinha, and Nishant Goyal. Indian Journal of Psychology, Volume 61. 10.4103/psychiatry.IndianJPsychiatry_484_18

Intramuscular ketamine in acute depression: A report on two cases. Chilukuri Harihar, Padmavathy Dasari, and Jakka Sriramulu Srinivas. Indian Journal of Psychology, Volume 55. 10.4103/0019-5545.111461

Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy. Jennifer Dore, Brent Turnipseed, Shannon Dwyer, Andrea Turnipseed, Julane Andries, German Ascani, Celeste Monnette, Angela Huidekoper, Nicole Strauss and Phil Wolfson. Journal of Psychoactive Drugs, Volume 51.  10.1080/02791072.2019.1587556

Side-effects associated with ketamine use in depression: a systematic review. Brooke Short MD, Joanna Fong, Veronica Galvez MD, William Shelker MD, and Prof Colleen K Loo MD. The Lancet. 10.1016/S2215-0366(17)30272-9

Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy Jennifer Dore, Brent Turnipseed, Shannon Dwyer, Andrea Turnipseed, Julane Andries, German Ascani, Celeste Monnette, Angela Huidekoper, Nicole Strauss & Phil Wolfson, Journal of Psychoactive Drugs, 51:2, 189-198 10.1080/02791072.2019.1587556

Author bio:
Amelia Walsh
Amelia Walsh
Amelia Walsh is a content writer living in Chicago. She is an avid reader, adventurer, collector of vintage Egyptian revival and brass animals, songwriter, and dancer. Most importantly, she is Arwen's mom.

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