03/12/19

Hype and Concern with Esketamine

© lightwise | 123rf.com

Just before Valentine’s Day in 2019 an FDA advisory panel voted in favor (14 yes, 2 no, 1 abstain) of approving esketamine for the treatment of adult patients with treatment resistant depression (TRD). Psychiatry Advisor reported the decision was based on 5 Phase 3 studies. Patients in the studies had a diagnosis of Major Depression and a history of inadequate response to at least two previous antidepressants, the FDA criteria for TRD. Two of the five studies “showed that esketamine nasal spray plus a newly initiated oral antidepressant was associated with a statistically significant, clinically meaningful, rapid, and sustained improvement of depression symptoms.” So why are some experts concerned and hesitant?

In a STAT News article, Dr. Wendy Marsh said overall, esketamine is definitely of value. Dr. Eric Turner, a psychiatrist who serves on the FDA advisory committee, but couldn’t attend the recent meeting, said: “There’s sort of a split in academia. Some are cheering for something new and others are more skeptical.” Part of the concern is what the label “Treatment Resistant Depression” allows. Writing for Mad in America in “Nasal Spray for Depression? Not So Fast,” Kim Witczak said TRD is the new buzzword that allows drug companies to obtain FDA fast tracking or designation as a “breakthrough therapy.”

Such designation gives the pharmaceutical company the ability to present smaller, fewer clinical trials in order to get their drug to market quicker. While most approved antidepressants currently on the market had to show effectiveness data from at least two positive short-term trials, Janssen only presented one positive short-term trial and the second is an incomplete picture as it is from a withdrawal trial. Janssen’s other trials failed to meet their primary endpoints for efficacy.

Janssen, a subsidiary of Johnson & Johnson, submitted five Phase 3 studies: three short-term, one maintenance and one long-term safety study. One of the positive studies was a randomized trial in adults under the age of 65 with TRD who were started on an oral antidepressant and esketamine. After one month, around 70% of patients taking esketamine responded, where just over 50% in the placebo group had. The second positive study was a maintenance-of-effect study, where participants who responded to esketamine in one of the short-term studies are randomly assigned to either continue with the drug or be switched to a placebo. The FDA typically wants two successful studies, “but historically, withdrawal studies haven’t counted towards the total.”

Eric Turner said: “The threshold has been two adequate and well-controlled trials. In this case, they only got one.” Based on that, he would have voted no had he been at the meeting. Julie Zito was at the meeting and was one of the two advisory committee members who did vote “no,” thinking the risks if esketamine outweighed the benefits. If the drug was approved, she would like to see providers, patients and the families of patients keep tabs on possible side effects and how well the drug is working.

Dr. Gerard Sanacora, a psychiatrist who has been involved in several esketamine trials and has also served as a consultant to Janssen, said: “This is gonna be the big question: How do we use this in the clinic?” Current treatment protocol calls for esketamine to be given twice a week for the first month, then reduced to once a week or once every two weeks during the maintenance phase. But there are still questions about long-term treatment with esketamine, including how long to keep a patient on the medication and what the risks of long-term use might be.

Kim Witzcak also noted there were successful suicides that occurred during the clinical trials that were glossed over or presented as unrelated to esketamine. The FDA “Briefing Document” for the committee indicated there were three successful suicides; all were esketamine-treated subjects. After parsing the differences between all three cases, the Briefing Document said: “Given the small number of cases, the severity of the patients’ underlying illness, and the lack of a consistent pattern among these cases, it is difficult to consider these deaths as drug-related.” Witzcak said: “In my opinion, we need more information on the potential link to suicide before an assumption can be made that it’s safe.”

The adverse events identified in the Briefing Document as of the greatest concern were sedation, dissociation, and increased blood pressure; most of which occurred within the first two hours of administration. In order to minimize the risk of misuse and abuse of esketamine, the committee has proposed the following Risk Evaluation Mitigation Strategies (REMS). The FDA can require REMS for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. “REMS are not designed to mitigate adverse events of a medication, rather, it focuses on preventing, monitoring and/or managing a specific serious risk by informing, educating and/or reinforcing actions to reduce the frequency and/or severity of the event.”

First, they would ensure esketamine is only dispensed to hospitals, certified outpatient pharmacies, and certified outpatient sites of care. A healthcare professional would monitor patients when they self-administer esketamine and then watch for transient dissociative and blood pressure changes until the patient is stable to leave the healthcare setting.

Second, pharmacies, practitioners and healthcare settings that dispense the drug would be specially certified to be sure esketamine is not dispensed directly to patients. They would be educated about the risks of esketamine and the importance of monitoring patients after the dose is self-administered.

Third, prescribers would register patients in the REMS program. “As part of the enrollment process, patients would be informed of the risks and the need for patients to report adverse events to their provider between patient visits.”

But Witzcak said she thinks most of the FDA Advisory Committee members vote for these controversial drugs and assume the REMS program will address any of their potential safety concerns. “What they fail to realize is that the REMS program is not enforceable and the drug companies are responsible for managing and reporting to the FDA.” She does not trust the drug companies and the FDA to do what they said they would do.

Eric Turner was also concerned with the hype around esketamine. He’s worried that although there is evidence that esketamine works, it will be seen and hyped as superior to other drugs for treatment-resistant depression or as a therapy that can produce rapid results—”two points he says studies don’t yet support.” Gerard Sanacora said patients will often wonder why they can’t just try the drug before seeing whether they respond to standard oral antidepressants. He is concerned the excitement over esketamine will lead patients to want it as a first-line treatment; or even a cure. “The danger is having it so positively portrayed. . . . I’ve been around enough to know this is not necessarily a condition [depression] that responds to miracle drugs.”

The drug is a chemical mirror of ketamine, used as an anesthetic and abused recreationally as “Special K.” For several decades ketamine has been known to be a drug of abuse. And in 1999 it was designated as a Schedule III controlled substance. Ketamine is abused for its dissociative and hallucinogenic effects. It also exists as a popular “club drug” used at nightclubs and raves. Like ketamine, esketamine would be a Schedule III controlled substance. Hopefully the hype over esketamine will not overshadow the potential dangers and adverse events.

On March 4, 2019 the NPR show, All Things Considered, said the FDA was expected to approve esketamine. Courtney Billington, the president of Janessen Neuroscience said if approved, it would be marketed under the brand name Spravato. While he confirmed it will only be available in approved and certified treatment centers and limited to patients who have unsuccessfully tried at least two other antidepressants, it was predicted that doctors already comfortable prescribing ketamine will continue to do so. A psychiatrist or physician can prescribe ketamine without the restrictions that will be applied to esketamine. “The generic form is cheap and can be taken at home in a nasal spray once patients know the right dose.”

Then on March 5, 2019 the FDA approved esketamine (Spravato). Johnson & Johnson, the parent company for Janessen, said the wholesale cost of each esketamine treatment will be in the $590 to $885 range, depending on the dose. As an aside, there will likely be a tolerance built with Spravato over time, requiring increased doses for the same antidepressant effect. The projected J&J price means that the recommended twice-weekly treatments during the first month will cost at least $4,720 to $6,785. Treatments afterwards will cost about half as much. A ketamine infusion directory stated the costs for ketamine infusion range from $400 to $2,000.

Spravato contains a boxed warning that cautions “patients are at risk for sedation and difficulty with attention and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug.” Stop a minute and think about this. Spravato has been approved for treatment-resistant depression, and the noted side effects include misuse/abuse of the drug itself and suicidal thoughts and behaviors! And the work around coming at some point will be the development of a nasal spray device that can be used with ketamine without the restrictions applied to Spravato.  In pursuit of the newest possible “treatment” for depression, FDA has crossed a boundary into territory that apparently sets aside the maxim to “First do no harm” when approving drugs. Are the risks of Spravato really worth it?

I’ve written several articles here addressing concerns with ketamine or esketamine. This is the twelfth one. See: “Falling Down the K-Hole,” “Esketamine Craze” and “Is Ketamine Really Safe & Non-Toxic?” for more information; or just search for ketamine or esketamine. You can read “Bait and Switch: the Great Ketamine ‘Breakthrough’” for a personal story about someone who almost enrolled in one of the failed clinical trials.

10/8/14

Falling Down the K-Hole

Over the past few years, there has been an increased interest in using ketamine to treat depression and other psychiatric disorders, such as PTSD. It is fast acting relief for symptoms of both depression and PTSD. For depression, it is effective within two hours and was reported to help a greater proportion of individuals than traditional antidepressants.  Sounds like there is tremendous potential here, right? Maybe.

A 2006 study by lead author Carlos Zarate and other researchers found that subjects receiving a single dose of ketamine “showed significant improvement in depression” within 110 minutes after injection. “Robust and rapid antidepressant effects resulted from a single intravenous dose of [ketamine]; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.” However,  it was reported by Franz Vallenweider and Michael Kometer that: “all but 2 of the patients relapsed within 2 weeks after a single dose of ketamine.”

A 2011 study (and here) confirmed the alleviation of major depressive symptoms within two hours from a single, low-dose of ketamine. Its effects lasted up to two weeks. The researchers suggested that ketamine appeared to work so quickly by increasing the synthesis of BDNF, or brain-derived neurotropic factor. The increase in BDNF is caused by ketamine deactivating a chemical that normally suppresses BDNF production. “BDNF is a nerve factor that helps brain cells grow and develop new neurons.”

A 2012 study by lead author Matthew Sanjay and others reviewed the emerging literature on the potential rapid-onset antidepressant properties of ketamine. They cited data from a 2009 study that ketamine was associated with “rapid reductions in explicit and implicit suicidal cognitions within the first 24 hours.” They also noted a report from the NIMH where patients previously non-responsive to ECT (electro convulsive therapy) “showed significant improvement in depressive symptoms.”

There were acute impairment of working, episodic and semantic memory, but it did not effect the retrieval of previously learned information. The acute impairments were also temporary. There were no residual deficits found 3 days after drug administration. The Sanjay study concluded that enthusiasm for the early ketamine studies should be tempered by concerns for the validity of these studies; that the antidepressant action is short lived; and uncertainty regarding its safety with a depressed population. “Accordingly, ketamine therapy remains a highly experimental treatment approach for MDD and adoption in psychiatric practice settings at this time is premature.”

Another 2012 article, “Ketamine for Depression: Where Do We Go from Here?” said that while adverse effects had generally been mild, some patients experienced brief changes in blood pressure, heart rate, or respiration. They supported further research of ketamine to treat mood disorders. “However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.”

A 2013 study reported in the American Journal of Psychiatry was a randomized controlled study. Ketamine again demonstrated rapid antidepressant effects. It added further support to studies showing that NMDA receptor modulation as a potential mechanism for “accelerated improvement in severe and chronic forms of depression.” Reservations on its use in clinical practice were again expressed because of its short action and safety concerns.

Ketamine is not a new drug. It was developed in 1962 by Parke-Davis and is used as an anesthetic in human and veterinary medicine, usually in combination with another sedative drug. It has been used for several decades as a recreational drug under nicknames such as “Special K,” “K” or “Ket.” It makes users feel disassociated or disconnected from their body and can cause hallucinations. The user can feel sleepy, sluggish, confused or clumsy. They may babble, appear drunk, or have trouble remembering who they are.

It comes as a clear liquid and a white or off-white powder. It can be injected, mixed in a drink as a date-rape drug or sprinkled on tobacco or marijuana and smoked.  It is virtually tasteless and causes a person to become disoriented, confused, suggestible, easily manipulated and compliant.

The victim is usually compliant, suggestible, and shows no overt resistance. As a result they can be easily led into a private setting and usually do not resist whatever is done to them. When given in a sufficient dose the victim has no memory of what happened. On the street this period of dissociated amnesia is called ‘being stuck in the K hole.’

The K-hole state can mimic catatonic schizophrenia, out-of-body experiences or near-death experiences. Since it is an anesthetic drug, ketamine could cause vomiting with its use. And “eating or drinking before taking the drug increases the risk of choking on one’s own vomit.” It is addictive, classified as a Schedule III drug by the DEA. Taken with other sedating drugs like alcohol, the effects of slowing or shutting down the central nervous system are increased. It is possible to overdose on it.

The 2014 Global Synthetic Drugs Assessment reported that ketamine is widely misused in East and South-East Asia; more than in the Americas and Europe. “Extensive ketamine use has also been reported in Brunei Darussalam, India, Myanmar and Singapore.” Between 2008 and 2011, 60% of global ketamine seizures occurred in mainland China and Hong Kong.

In “A Word to the Wise About Ketamine,” Alan Schatzberg noted that the data on ketamine as an antidepressant is still relatively limited. He said that without more data on what ketamine can do clinically, and knowing it can be a drug of abuse, “it is difficult to argue that patients should receive an acute trial of ketamine for refractory depression.” Waiting until there was greater understanding about its effects and risks was his recommendation. Although the recent studies are exciting and open up new avenues for depression research, “until we know more, clinicians should be wary about embarking on a slippery ketamine slope.”

The almost unbridled enthusiasm over the potential of ketamine to treat depression needs to be reined in. We don’t want to find ourselves “falling down the k-hole” instead of exploring ketamine’s potential to treat depression.