Oral Ketamine Treatment: An Alternative to Ketamine Infusions

Major Depressive Disorder (MDD)

According to the National Institute of Mental Health (NIMH), major depression — also called major depressive disorder — is a mental illness characterized by two or more weeks of depressed mood and loss of interest in daily activities. Depressive symptoms may include sleep, appetite, concentration, or self-worth changes.

Roughly 8.4% of all adults in the United States, equal to 21 million individuals, have had one or more major depressive episodes. While more common in females, MDD can affect people of sex, gender identity, race, or socioeconomic background.

MDD Treatment

The standard treatments for MDD are psychotherapy — also known as talk therapy — and medication. Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and noradrenaline and specific serotoninergic antidepressants (NaSSAs) are some of the most commonly prescribed antidepressants for MDD.

Hans Eriksson, MD, PhD, CMO of HMNC Brain Health, explained that there is no clear and distinct way to choose which medicine to prescribe. Often, especially in psychiatry, finding the proper medication is a matter of trial and error.

“To some extent, physicians can select medicines based on their side effect profiles, but in psychiatry, we don't have the tools to match a particular medicine with a particular patient,” added Eriksson.

The Mayo Clinic notes that providers may consider multiple factors before prescribing an antidepressant, including the patient’s symptoms, the drug’s side effect profile, family history, drug interactions, pregnancy status, existing health conditions, and drug cost.

Despite using these factors to predict antidepressant response and efficacy, psychiatrists and other mental health professionals have struggled to understand the neuropsychopharmacology behind MDD treatment properly.

Conversely, the oncology space has been matching patients with medicines for decades, using different diagnostic tools to determine the chemotherapy or treatment regimen most likely to yield the best outcome for that patient.

Beyond a limited understanding of efficacy, antidepressants can take a long time to work. On average, antidepressant treatments take 4–6 weeks to begin working, with a risk of adverse events as treatment is initiated.

Additionally, if the first antidepressant prescribed is not adequate, treatment alteration will restart the wait time, causing long-term delays in symptom reduction and resolution.

Other MDD Treatments

In addition to standard medication use, providers may use alternative types of MDD treatment. If medication and psychotherapy are ineffective, some brain stimulation therapies have shown evidence of antidepressant effects.

Possible brain stimulation alternatives to traditional medication include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), magnetic seizure therapy (MST), and deep brain stimulation (DBS).

In addition to brain stimulation, the FDA has approved intranasal esketamine as a rapid antidepressant treatment to be administered under the care of a licensed healthcare professional.

Brain stimulation and ketamine therapies are typically only used when a patient has exhausted other medications.

Treatment-Resistant Depression

Treatment-resistant depression (TRD) is a type of depression that has not responded to multiple treatments. An article published in Neuropsychiatric Disease and Treatment noted that one-third of patients with MDD are not effectively treated with antidepressants.

Once a patient has tried two different types of antidepressant pharmacotherapy without successful symptom reduction or remission, their depression is considered treatment resistant.

Providers may consider augmentation by adding a medication or treatment for patients with TRD. Other alternatives may include psychotherapy and brain stimulation.

More recently, some novel therapies have been explored for TRD, including psilocybin, anti-inflammatories, and ketamine.

Ketamine Therapy

Ketamine was first discovered in the 1960s and was introduced in clinical settings the following decade, in the 1970s. Eriksson revealed that it is often used in emergencies, war zones, earthquakes, and other natural disasters.

Over time, researchers and scientists discovered that low doses of ketamine could provide an antidepressant effect. It is important to note that ketamine has only been approved for treating unipolar depression and is not recommended for bipolar depression or depression with psychotic features.

While ketamine’s mechanism of action is not entirely understood, research and scientific investigation has provided multiple theories.

An article published by UpToDate notes that ketamine is hypothesized to be an opioid receptor agonist, N-methyl-ᴅ-aspartate (NMDA) receptor antagonist, and an α-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptor activator.

“The discovery of ketamine’s antidepressant effects triggered a tremendous interest in ketamine and its first identified target, the NMDA receptor,” noted Eriksson. “Several projects are underway based on NMDA receptor antagonists and different versions of the ketamine concept. The upside with ketamine is that efficacy is quite robust, so the overall magnitude of the effect is somewhat better than what clinicians see with standard antidepressants.”

In addition to having more successful antidepressant effects, ketamine treatment is significantly faster than traditional selective serotonin reuptake inhibitors (SSRIs).

“We're talking about days, not weeks and months, as with SSRIs. So there are obvious upsides with this treatment,” noted Eriksson.

Despite the vital benefits of ketamine treatment, there are also some challenges providers have to consider.

Types of Ketamine Therapy

There are multiple forms of ketamine in the pharmaceutical drug market. One of them is a racemic ketamine mixture that includes (S)- and (D)-enantiomers.

In addition to different mixtures and components, different kinds of ketamine administration have been explored. One of the most widely understood methods is intravenous ketamine infusion. However, the drug can also be administered through intramuscular or subcutaneous injection.

Another route of administration that has been explored — and even approved — is intranasal ketamine, which is also a nasal spray of just the (S)-enantiomer of ketamine, called esketamine, (S)-ketamine, or asketamine.

Side Effects of Ketamine Treatments

Regardless of the ketamine form, patients commonly experience dissociative adverse effects, such as psychosis-like conditions. This component of ketamine makes it highly susceptible to off-label use by people with substance use disorders.

In addition to the dissociative side effects of ketamine therapy, there are also physiological effects. For example, roughly 40% of people given a single dose of IV ketamine have increased heart rate and blood pressure for a limited time after treatment. Although this may seem insignificant, patients with comorbidities like hypertension may compromise their health if they take ketamine.

Patients have also experienced symptoms including anxiety, blurred vision, dizziness, headache, nausea, or vomiting with the use of ketamine.

“The (S)-ketamine label in the United States from the FDA specifies that the medication must be taken under physician or medical personnel supervision,” said Eriksson. “The patients need to be supervised for a couple of hours. That is practically problematic.”

Esketamine has also been linked to hypoesthesia, lethargy, sedation, and vertigo.

Treatment Limitations

Patients must visit the clinic twice weekly for the first four weeks of treatment. After the treatment has been initiated for one month, patients may spend up to half a year coming in weekly or biweekly for their therapy. The time required to start and follow up with ketamine treatment makes it inaccessible for many patient populations that are distant from a clinic or cannot take time off from other responsibilities to get treatment.

“That has negatively impacted uptake in the case of (S)-ketamine. Our organization wonders if there is a way to get the best of both worlds — to capture the good antidepressant effects of ketamine but find a way to avoid the downsides.”

Oral Ketamine

Considering the available ketamine treatments and their limitations, researchers have begun investigating oral ketamine as an alternative.

A 2017 article published in the Journal of Clinical Psychopharmacology explained a case series focusing on 22 patients with TRD given oral ketamine as part of an open-label analysis. The study found that oral ketamine was safe and well tolerated; however, the efficacy of ketamine in the oral form was modest compared to other forms of ketamine.

Since then, research has advanced and attempted to optimize ketamine treatment.

“Together with a Swiss company, Develco, we are now developing the medicine called Ketabon. This is a prolonged-release formulation of oral ketamine,” revealed Eriksson. “Instead of generating a very rapid peak of ketamine, the concentration increases gradually and peaks after about 6.5 hours.”

With an extended-release form, ketamine concentration can build up gradually. While there is no precise data on how that impacts drug tolerability, Eriksson notes that the peak concentration of oral ketamine is much lower than that of IV ketamine. Since ketamine’s action on NMDA receptors causes dissociative side effects, clinicians believe a lower peak dosage has improved tolerability.

While many may wonder whether the lower dose and interaction between the drug and NMDA receptors — contributing to the decrease in side effects — impact drug efficacy, the researchers hypothesize that it will not reduce the drug’s impacts on treatment-resistant depression.

“We believe that interaction is not necessarily needed,” proposed Eriksson. “When the medicine is given orally in a prolonged release formulation, patients have an extensive first-pass metabolism in the liver, which reduces the ketamine concentration relatively quickly.”

“There is a buildup of a downstream metabolite, hydroxynorketamine, known in animal models as an antidepressant. And it is not binding to the NMDA receptor, so it is not causing dissociation. We believe that the hydroxynorketamine, which also has generated interest as a drug on its own, contributes to the antidepressant properties,” he explained.

In the investigator-inititated trial (IIT), Eriksson's team conducted a small randomized controlled trial with academic researchers from the University of Zurich in Switzerland. Initially intending to recruit 99 patients, the study could only recruit 27 patients before it terminated due to constraints caused by the COVID-19 pandemic.

Only ten patients were in the treatment arm of the study. Although Eriksson and the other researchers in the study acknowledge that the trial was small and the data collected may have a large margin of error, they did gain some insight into oral ketamine.

That smaller placebo-controlled study looked at two doses of ketamine. Within two weeks of the trial, the patients on the highest dose of oral ketamine had improved the patients’ Montgomery–Åsberg Depression Rating Scale (MADRS) score by five points more from baseline compared to the placebo.

“The study was underpowered, so we did not formally reach statistical significance,” emphasized Eriksson. “The P-value was 0.15. But we still saw this as an encouraging finding, and the tolerability was also excellent.”

Phase II Clinical Trial

Based on those preliminary findings and the ongoing interest in oral ketamine, researchers developed a phase II clinical study that was slightly larger. They recruited patients from three European countries.

“We decided to run this study as an outpatient study, which is not normal when studying ketamine,” he revealed. “Only the first dose was given under physician supervision. The treatment period was three weeks, with once-daily dosing.”

The study has stopped recruiting patients; however, Hanz noted his surprise at the lack of objections to at-home drug delivery. While the study was double-blind, the researchers had not received reports on problems related to at-home medication administration.

Patient Criteria

To make sure that the clinical trial would get regulatory approval, the researchers used strict criteria for identifying treatment-resistant depression. Patients must have a major depressive episode that has failed under two treatments for six weeks each.

The researchers also excluded patients with suicidal ideations.

Future Directions

“We are optimistic but won’t know the results until we have broken the blind,” Eriksson exclaimed. “This period is fascinating and somewhat stressful when working in a pharmaceutical company, but we hope to have the results relatively soon, and we'll find a way to communicate them appropriately.”

In phase III clinical trials, the researchers hope to learn more about maintaining ketamine’s antidepressant effects and determine the optimal treatment regimen for sustained medication efficacy.

“We expect to evaluate the phase II study during the summer and aim for moving into phase III at the beginning of 2024,” concluded Eriksson.

Editor's Note: This article has been updated to clarify the details of the IIT trial.