The not so little matter of how to dose ketamine in patients with depression

It is almost axiomatic with most drugs and for most disorders in psychiatry that whatever elicits response and remission during the acute phase of illness will prevent relapse and recurrence of illness during the maintenance phase of treatment. Logically, this principle should apply to ketamine, as well, when the drug is used for patients with depression; thus, at the very least, the treatment, if effective, should be continued into the short-term until the patient is stable enough to be maintained on another treatment, such as a conventional oral antidepressant drug.

In this context, in this issue of the journal, d'Andrea et al.¹ propose a different strategy. They suggest that, in patients for whom the treatment is indicated, such as those with treatment-refractory depression (TRD), twice weekly intravenous (IV) ketamine (0.50–0.75 mg/kg) can be used for the first 2–3 weeks followed by twice weekly intranasal (IN) esketamine (56–84 mg), in treatment responders, for the next 2 weeks. IN esketamine can then be continued in the same dose at once-weekly frequency as maintenance therapy. Thus, IV ketamine serves as a bridge to continuation and maintenance with IN ketamine. The authors base their suggestion on the assumption that the IV route is preferable as the initial option because it is associated with faster onset of benefit; and this assumption is based on an examination of secondary outcomes in a retrospective, nonrandomized, nonblind, observational study.²

Their suggestion is reasonable in principle. However, there are some matters to be considered. For example, the line of treatment moves from IV to IN routes, from a racemic drug to an enantiomer, and between doses (0.50 mg/kg IV to 56 mg IN and 0.75 mg/kg IV to 84 mg IN) that have not been shown to be bioequivalent. There are also some practical matters: IV ketamine is an elaborate way of dosing the drug and requires at least temporary hospital admission, and IN esketamine is a patented product; in consequence, the former is inconvenient, and both are expensive and therefore impractical in everyday care in developing countries that are poor in medical infrastructure and low in per capita income.

When oral dosing is default for most treatments, how did we get into a situation like this? The story probably started in 1994 when, in a randomized, double-blind, saline-controlled, crossover trial, Krystal et al.³ found that IV ketamine, dosed at 0.5 mg/kg and infused across 40 min, produced positive, negative, dissociative, cognitive, and other symptoms in 19 healthy volunteers; in contrast, a 0.1 mg/kg ketamine infusion resulted in negligible effects. Six years later, in another randomized, double-blind, saline-controlled, crossover trial, Berman et al.⁴ found that ketamine but not saline was associated with substantial antidepressant improvement, within 72 h of infusion, in nine patients in a major depressive episode. These authors employed the ketamine dosing method that separated from placebo in the study by Krystal et al.³; that is, 0.5 mg/kg infused across 40 min.

A further 6 years later, in a landmark study with the same randomized, double-blind, saline-controlled, crossover design, Zarate et al.⁵ found that ketamine was associated with large antidepressant benefits at 1 day in 18 patients with TRD; the benefits attenuated but were still evident at 1 week. These authors also administered IV ketamine in the dose of 0.5 mg/kg across 40 min.

Ketamine has now been administered by an impressively large number of routes in an impressively large number of formulations. Thus, for various indications in medicine and psychiatry, ketamine has been administered sublingually, buccally, orally, intranasally, intravenously, intramuscularly, subcutaneously, rectally, by nebulization, and by other routes in immediate-release tablets, extended-release tablets, capsules, lozenges, sprays, liquid for injection, and other formulations. Nevertheless, there are only two dosing approaches that are common in the management of depression. One is to administer IV racemic ketamine, 0.5–0.8 mg/kg across 40 min and the other is to administer IN esketamine, in the fixed dose of either 56 or 84 mg, using a single-use proprietary device. The former approach may have persisted because of tradition. The latter, somewhat unusual approach (for a psychotropic drug), has emerged because of regulatory approval of an industry initiative; for a treatment to be patented, novelty is key.

Tradition is sticky, as is obvious from an inspection of attitudes, beliefs, and behaviors in most walks of life. Many traditions, though, are driven by reasons, some of which may actually be reasonable. In the case of ketamine, the IV route may have been chosen because ketamine was introduced as an anesthetic drug, and anesthetic drugs are administered by IV or inhalational routes with dosing usually based on body weight. Importantly, dosing depressed patients per kg body weight and by infusion would reduce the risk of the patient experiencing ketamine-induced anesthesia with the added advantage that the treatment could immediately be stopped should unpleasant adverse effects arise. Also importantly, the efficacy of IV ketamine is large and well-established, and this might itself be considered by many as sufficient reason to persist with the approach. For those who are interested, Erstad and Barletta⁶ provide a discussion on pharmacokinetics relevant to per kg body weight IV ketamine dosing in nonanesthetic contexts.

There are other considerations, also, for favoring IV ketamine. For example, IV ketamine tends to be associated with prominent neuropsychiatric, including dissociative, effects, and these may facilitate the combination of psychotherapy with ketamine therapy. Some even believe that these effects are necessary for benefit or are at least a marker of benefit; however, the belief is probably unfounded because, for example, dissociation does not predict treatment outcomes⁷ and because tolerance develops to the adverse effects of ketamine but not to its benefits.⁸

When IV ketamine is backed by strong evidence and with reasons for route and dosing, and when IN ketamine is backed by regulatory approval, why consider other ways of dosing the drug for TRD? Simply stated, because there are limitations associated with both. As noted earlier, IV ketamine requires temporary hospitalization and IV and IN ketamine are both expensive treatments. IV ketamine may deliver a precise dose, but that dose may have an imprecise effect because of, for example, differences in body fat composition.⁶ IN ketamine does not require to be administered as the S-isomer in a proprietary dispenser. Instead, racemic ketamine, in liquid for injection formulation, can be poured into a cannister that delivers a metered volume per spray; this device can then be used for IN dosing. Such cannisters can be purchased at low prices, online, and can be reused by patients who require repeated dosing with ketamine.

But, the cheapest and most convenient way to take a medicine is to swallow it; that is, to take it by the oral route, usually in the comfort of one's home. Many studies, including randomized controlled trials, have examined oral dosing with ketamine, and some of these examined domiciliary self-administration across many months of follow up.^{9, 10} So, why is not ketamine being administered orally? One problem is the poor oral bioavailability that is commonly stated to be about 20%–25%.^{9, 10} Another problem is the poor breadth and quality of evidence in support of the safety and efficacy of oral ketamine.^{9, 11} From a prejudicial perspective, the simplicity and inexpensiveness of oral dosing^{10, 12} reduces the profitability of the treatment in a ketamine clinic.

Interindividual differences in pharmacokinetics are not a barrier to oral dosing. For example, there can be an up to 20-fold variation in the steady state concentration of a psychotropic drug for a given dose of that drug,¹³ but most drugs in psychiatry are nevertheless administered orally. This is because, even with drugs that have poor oral bioavailability, all that is necessary in clinical trials is to conduct dose-ranging studies to define the boundaries for optimum dosing, and all that is necessary in clinical practice is to uptitrate the dose of the drug based on efficacy and adverse effects. This is actually what clinicians have been doing in all branches of medicine for decades, seeking recourse to therapeutic blood level monitoring only in specific circumstances. In this context, it may be noted that oral dosing with racemic ketamine has for decades been used in the management of chronic pain, including cancer-related pain.^{14, 15}

So, the bottom line is that the potential for ketamine to globally revolutionize the treatment of depression is to conduct dose-ranging clinical trials of oral racemic ketamine across population demographics. As examples, clinical trials could be conducted for depression in adults and in the elderly, in special populations defined by medical comorbidities, and so on; that is, exactly as one would in the development of a new drug. But, who will invest in the conduct of such studies for a drug that is out of patent?¹²

This article was unfunded.

I have no conflicts to declare with regard to the contents of this article.