What is Ketamine?
Ketamine is classified pharmacologically as an uncompetitive NMDA receptor antagonist. This means that Ketamine blocks a brain receptor called NMDA.
Ketamine was synthesized in the 1960´s and approved by the US Food and Drug Administration (FDA) in 1970 to be used as an anaesthetic. More recently, Ketamine has been repurposed for the use in psychiatry and has proven to be effective in the treatment of several psychiatric disorders, such as Treatment Resistant Depression (TRD) and Post-Traumatic Stress Disorder (PTSD). For these disorders, Ketamine is used at lower doses, below the anaesthetic threshold.
How does Ketamine work?
The dominant view on how Ketamine produces its antidepressant effects (often rederred to as “mechanism of action”), is that Ketamine promotes and facilitates synaptogenesis (the formation of new synapses).
It does this by blocking the NMDA receptors which are located on inhibitory neurons, called GABA interneurons. When Ketamine blocks the NMDA receptor, the inhibitory effect of the GABA interneurons disappears. In turn, this leads to an increase in the firing of another set of neurons called pyramidal cells with a consequent final increase in glutamate levels. Glutamate is a neurotransmitter and the primary excitatory neurotransmitter in the brain.
Therefore the NMDA receptor plays a pivotal role in the synaptic transmission and synaptic plasticity. Contrary to conventional antidepressants, Ketamine does not act within weeks, but may act much faster, occasionally even in 24 hours. Therefore it has been suggested to be a different class of antidepressant, called a fast-acting antidepressant.
There is also evidence that Ketamine's mechanism of action can extend beyond glutamate and impact on other neurotransmitter systems. However, more research is needed to fully understand which mechanisms contribute to the antidepressant and psychiatric benefits of Ketamine.
Chemically, Ketamine consists of a mix of two versions of the same compound, ‘r-ketamine’ and ‘s-ketamine’ (sometimes referred to as ‘esketamine’). In our clinic we use the ‘standard’ ketamine, i.e. the mixture of r- and s- ketamine (also called racemic ketamine).
A recent meta-analysis, (a statistical analysis which combines the results of multiple scientific studies), has assessed the comparative efficacy of esketamine and ketamine for the treatment of depression. 24 studies, representing 1877 patients, were included in this study. Results showed that racemic ketamine, relative to esketamine, demonstrated a greater overall treatment response as well as improved remission rates.
Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders. 2021 Jan 1;278:542-555.
Who is eligible to receive Ketamine?
Ketamine is a new treatment for people who have been suffering from depression and are still unwell despite having received adequate antidepressant medication (i.e. people who have ‘Treatment-Resistant Depression’ or TRD for short).
Before you start the Ketamine treatment, you will have a full assessment by a psychiatrist to ensure that Ketamine is likely to help with your depression and is going to be safe for you.
If you suffer from other psychiatric problems such as PTSD or Anxiety Disorder, you will be able to discuss this with our psychiatric team and they will confirm your eligibility. If your psychiatrist considers you to be a suitable candidate for Ketamine treatment, our team will contact him and discuss the treatment.
There are also some contra-indications to the use of ketamine, such as having a history of psychosis, traumatic brain injury, active substance use or allergy to Ketamine. Our team will review your medical history and you will have the opportunity to discuss your eligibility for treatment.
What are the side effects?
As with all medicines, ketamine is associated with a risk of side effects (you will have plenty of opportunities to ask about those). However, when used in the clinic, ketamine is a very safe drug.
The most common side effect is dissociation. You can experience this as a feeling of dizziness, drowsiness, light-headedness or even as a floating sensation. This normally peaks within 40min after the administration and usually resolves within 1–2 hours.
You may also experience changes in your blood pressure and heart rate. These are, for most healthy individuals, of little consequence. However, if you have a condition affecting your heart, brain or blood vessels, such as an aneurysm or a recent heart attack, even a transient increase would pose a serious risk to your health. Thus, it is very important that you disclose any cardiovascular or cerebrovascular condition you have.
Finally, some people also experience nausea and occasionally vomiting. It is important you avoid having a big meal before your treatment. Our medical team can provide you with anti nausea drugs if you experience this side-effect.
Before you start the ketamine treatment, you will have a full assessment by a psychiatrist to ensure that ketamine is likely to help with your depression and is going to be safe for you. In addition, he/she will check with your usual physician if there are any particular risks, given your own history, and will organise laboratory investigations, as required.
During the infusion, you can: rest, listen to music through headphones, keep your eyes open or closed or wear an eye mask. Some people find it comforting to have a particular object with them. Throughout the session, a clinician will monitor side effects and in particular monitor your blood pressure and heart rate before and after ketamine administration. If your blood pressure is quite high before ketamine administration, we will have to wait until it has reduced before giving you the medication and, if it doesn’t, reschedule the session.
Chronic users of high-dose ketamine can develop bladder problems. This is an adverse consequence of ketamine that has never been reported in clinics where the drug is used intermittently and at low doses, like in our clinic.
Is Ketamine Addictive?
Similarly to many other pharmacological agents, ketamine has also been used recreationally. Normally when used recreationally ketamine is given intranasal and typically in higher doses than when used for the treatment of mental health disorders. The long-term use of ketamine recreationally can lead to tolerance but not to physical dependence.
However, studies have shown that when ketamine was administered in the clinic for the treatment of depression, there was no subsequent increased risk of abuse. Even higher doses of ketamine than those we use in this clinic are not ‘rewarding’ per se, making it unlikely that they may cause addiction. However, to minimise risk, if you have a history of addictive disorders, this will be carefully reviewed by the psychiatrist, before a ketamine session is organised.
Can I continue taking my medication?
As someone suffering from depression or anxiety disorders, it is normal for you to be currently medicated with psychiatric drugs, such as antidepressants, mood stabilizers, benzodiazepines or antipsychotics. Ketamine can be given while taking these medications and it is expected for you to continue with your ongoing treatment. Our in-house psychiatrist and anaesthesiologists will review your medical chart and will advise you beforehand if there is the need to reduce or stop any other medication that you are currently taking.
Inclusion and Exclusion criteria
The following Inclusion and Exclusion criteria will be used:
- 18 to 65 years old;
- Meet criteria for TRD (i.e. depression that has not responded to two or more trials of antidepressant treatment, appropriate in dose and duration and in the current episode presenting with a score >19 on Beck Depression Inventory-II) or PTSD;
- Not meeting ICD-10 criteria for dependence on any substance other than caffeine or tobacco (F1x.2);
- Agreeable to comply with the Ketamine protocol, including, where required, urine drug testing, pregnancy test, amongst others;
- Capable of giving informed consent as defined by Good Clinical Practice (GCP) guidelines;
- If a woman of childbearing age, willing to use an effective method of contraception.
- Uncontrolled hypertension (>140/90mm Hg);
- Body mass index <16 or >35;
- History of psychosis;
- Previous diagnosis of substance dependence/severe substance misuse disorder;
- Intellectual disability or neuropsychological impairment;
- History of seizures;
- Currently taking daily prescribed medication contraindicated in the ketamine SPC;
- Cirrhosis or liver function tests greater than three times normal levels;
- Current, active suicidal ideation;
- Other significant comorbid mental or physical health problem assessed by the clinician;
- Allergic reaction to ketamine or excipients
About Pasithea Therapeutics
The US subsidiary of Pasithea Therapeutics was founded by Dr Tiago Reis Margues and Dr Elliot Nadelson. In the US, Pasithea Therapeutics has partnered with The IV Doc.
The IV Doc was founded co-founded by Dr Elliot Nadelson, the company already has over 50,000 patients in 30 cities and an established network of 800 medical professionals. The IV Doc has been operating for over 7 years.
All infusion services are provided by a dedicated network of anesthesiologists and in-house board-certified psychiatrists specialized to treat mental health problems.
Dr Tiago Reis Margues
CEO of Pasithea Therapeutics, Leading Psychiatrist
Dr Marques is a fellow at Imperial College London and a lecturer at the Institute of Psychiatry, King’s College London. Dr Marques is also a psychiatrist at Maudsley Hospital, rated as one of the top three psychiatry centres in the world. His research focuses on topics including the mechanism of action of psychiatric medication and the unveil of novel treatment targets. Dr Marques has co-authored international treatment guidelines and written book chapters, including in the leading book in the field, “Neurobiology of Mental Illness”.
Dr Elliot Nadelson
Managing Director of Pasithea Clinics USA
Dr. Nadelson is an American Board-Certified Urologist and the co-founder and CEO of The I.V. Doc®. The IV Doc software and technology platform has enabled their clinical affiliates to treat over 50,000 patients and establish relationships with over 800 clinicians over the past seven years.