Ask the Pharmacist

Q) I understand there is a new ketamine type treatment for depression. What can you tell me about it?

A) It is a rather sad fact of life that an article written by a pharmacist has so few discussions about new and novel drugs each and every year. This is not because there is a preference to discuss the intricacies of hang nails or legumes but rather there are so few drugs released each year that are anything more than, at best, a “me too” type of affair.

Drug companies seem to love seeing what their neighbours have concocted, vary it a little, than come out with their own version of the molecule hoping to snatch away 10% of the other’s sales which can equate to hundreds of millions of dollars worldwide. However, this week we are truly discussing an innovative approach to tackling treatment resistant depression.

The drug is called Spravato (esketamine is the generic name) and it is the first antidepressant drug with a new mechanism of action that has been approved by the FDA in 30 years. It is brand new to Canada (as of July 22,2020) and only entered the American market back in March of 2019.

It is, in truth, a completely new and different treatment offering real hope for the many people suffering from resistant depression that cycle from one SSRI or SNRI (selective serotonin receptor inhibitor and serotonin/ norepinephrine receptor inhibitor) after another with little relief from their unrelenting disorder.

Before we go into greater detail as to how this drug works, let us take a quick detour to discuss its indication (that is the medical term for what the drug is used for). Major depressive disorder is a leading cause of disability worldwide and Canada is no exception as it is estimated that 11% of men and 16% of women will experience major depression in the course of their lives (note, these percentages would rise significantly if we were to include those who suffer from mild to moderate depressive episodes). While drugs like Prozac (fluoxetine), Cipralex (escitalopram) and Effexor (venlafaxine) and the other SRI’s and SNRI’s are safe and effective treatments for many, up to 1/3 of patients fail to respond adequately to any of them.

People with treatment resistant depression, quite frankly, suffer more than the rest of us. Compared to individuals with regular depression:

  • their episodes tend to last longer
  • they tend to be on more medications
  • they seem to suffer from more side effects from these same drugs (not a surprise given the previous fact)
  • they have higher rates of obesity, co-morbidities (meaning they are more likely to have other diseases as well such as high blood pressure or diabetes) and overall disability.

    As such, there is a screaming need to come up with new solutions to aid these millions of people worldwide. Now, with the entrance of Spravato on the market, there is finally something new for these people to try.

This is a drug that comes from the anaesthetic ketamine which has long been hailed as an underground type treatment for a number of psychological disorders such as PTSD and depression. It is the first drug to utilize the neurotransmitter glutamate which is the most abundant one found in our brain and is involved in just about every major excitatory function that our brain can perform.

Spravato, like its parent ketamine, block N-methyl-D-aspartate (NMDA) receptors in the brain which leads to a rapid rise in glutamate levels and the “activation” of another set of receptors known as AMPA. This AMPA activation is thought to strengthen and restore the connections between nerve cells in our brain that researchers believe have been lost due to exposure to chronic high levels of cortisol. When we are stressed and/or depressed, our body releases the hormone cortisol (often called the stress hormone) and is responsible for both good and bad effects within us. This restoration of the lost or damaged connections occurs in the frontal cortex which is an area of the brain closely related to mood and motivation. What’s more, this whole process occurs shockingly fast.

There is nothing more frustrating in life to battle depression on your own, often for months, before you finally work up the energy/ courage to see your doctor for some help only to be told that the medication you are about to take will likely take several weeks before it begins to make you feel better. With Spravato, similar to the intravenous administration of ketamine, this increased communication between cells seems to occur immediately and patients therefore start to feel symptom improvement within a few hours. This mechanism of action may also explain why Spravato seems to have much longer lasting benefits than other antidepressants as it seems to help maintain remission in numbers that are not seen with other drugs.

It was these two facts, based up on 2 separate studies, which caused the FDA to classify the drug as a “breakthrough” therapy and fast-track its approval. Taking Spravato will be a unique experience. First off, it comes in the form of a nasal spray. It is administered intranasally twice a week for 4 weeks and is then reduced to once a week every week or two thereafter.

It does not have any long-term safety data and there is not much evidence for its effectiveness past a year so at this point many patients will be transitioned off of the drug after a year or so of therapy. As well, before you can begin therapy, all three parties (the patient, the prescriber and the pharmacy) will have to enroll in a program called the Janssen Journey (named after the drug’s manufacturer) and receive training online before they are allowed to begin treatment. Patient’s can give themselves the drug, but….. it must be done at the prescriber’s office or clinic and you must remain there for at least 2 hours after receiving your dose.

This is mandated for two reasons. The first is the drug may cause transient side effects which can be either alarming or dangerous such as transient increases in blood pressure, sedation, confusion, hallucinations and other unpleasant effects. Secondly, the drug can make you feel disassociated. This is the same word we use to describe some of the effects of the opioids and other drugs of abuse. There is that same potential for this drug and given the harm the opioids have inflicted on some patients (and the lawsuits inflicted upon their manufacturers) Janssen is going to these sorts of measures to make sure that the same history will not be repeated.

The long and short of the above, taking this drug is going to be somewhat inconvenient and also expensive!! The cost per dose is around $900 and it is not covered by any government drug plans to our knowledge. The drug also does not work on everyone.

There was indeed the two promising studies that showed the rapid response and the 51% reduction in relapses versus conventional antidepressants. There was also however three other studies in which Spravato failed to show a benefit. That is unfortunate for those individuals that are spending both time (many hours in the doctors’ office) and money (over $1000 every week or two) and is why this medication is considered a last resort.

It is only for those people who have tried at least two other antidepressants without significant benefit and you must be taking one of these previously tried drugs along with Spravato. Due to the risk of vomiting, it is recommended to not eat for two hours before or drink anything within 30 minutes of the dose. Also, it is advised to refrain from driving or operating machinery for the remainder of the day due to the fact they may feel disconnected or sleepy.

Despite the hassles that seem to be associated with this breakthrough treatment, it does offer a light at the end of the tunnel for those who have had their will to live reduced by unrelenting depression and it is hard to put a price on that. For more information about this or any other health care topics, contact your pharmacist.