Although there are several potential approaches to consider for maintaining an initial acute antidepressive response to intravenous ketamine, none of the reviewed options have direct empirical support for this specific indication. This lack of evidence substantially weakens the ability to make strong clinical recommendations, which require a reasonably high degree of certainty about the comparative utility of the proposed treatments and their respective risks of harm, over the long term, to people with treatment-resistant unipolar or bipolar depression who have responded acutely to intravenous ketamine. Mindful of not only these large knowledge gaps but also the need to address an increasingly common clinical scenario, we provide some preliminary guidance that can be considered based on the available but limited clinical evidence and on practice experience.
When Maintenance Treatment With Ketamine Is Chosen
In our experience, most patients who respond to intravenous ketamine will opt for additional ketamine treatments, either as a sole therapy or in the context of changing or modifying treatment with antidepressants or mood-stabilizing medications (discussed later). Given the lack of established efficacy and safety of maintenance treatment with repeated doses of ketamine, due caution is warranted, given the unknown efficacy and safety profile over the long term (
5,
41).
Before acute-phase ketamine treatment is started, patients should be made aware that additional ketamine treatment is only one of potentially several options available for maintaining clinical benefit (see
Box 1). The potential risks should also be revisited with patients who are considering ketamine maintenance treatment, even if they have tolerated repeated acute-phase treatments. In our experience, continuation of the effective acute-phase dose (nearly always 0.5 mg/kg IV, infused over 40–60 minutes) can be safely administered for maintenance-phase treatment. After an acute response to ketamine, we typically provide continuation-phase infusions administered once weekly for four weeks, followed by a systematic increase in the time interval between infusions, usually with a concurrent change in treatment with conventional antidepressants or mood-stabilizing medications and psychosocial treatment.
Although long-term safety and benefit are still relatively uncertain, maintenance-phase treatment with ketamine may be practicable in the context of a rigorous informed consent process combined with protocol-driven treatment decisions. The informed consent process emphasizes the reasonable expectation (but not a guarantee) of short-term benefit and the relative absence of evidence of long-term effectiveness and safety. Clinical protocols should include a clear delineation of team members and their roles, specific treatment procedures, eligibility criteria, procedures for clinical evaluation by an anesthesiologist when necessary, specific go– no-go decision rules for providing and discontinuing acute- and maintenance-phase treatment with ketamine, and procedures for systematically assessing and managing adverse effects (
Box 2). A gradual decrease in the frequency of ketamine infusions should be conducted with the goal of eventually stopping ketamine treatment, if possible. When stopping ketamine is not possible, the systematic approach to symptom and side-effect monitoring described earlier is crucial for identifying a minimum frequency of ketamine administrations needed to maintain therapeutic benefit and the earliest point in time when treatment-limiting adverse effects may be occurring.
We believe that rigorous informed consent and protocol-driven procedures can help strike a reasonable balance between a compelling clinical need for rapid-acting antidepressive therapy with ketamine against its unknown longer term effectiveness and safety profile—all within the context of very close psychiatric follow-up (
42). Such an approach should also include regular communication with the clinician who is administering ketamine treatments and regular assessment of efficacy (supplemented by the use of standardized depression and adverse effect rating scales), short- and long-term side effects, and behaviors suggesting a heightened risk of addiction to ketamine and other substances. Repeated doses of ketamine carried out over an indefinite period may be expected to lead to a high cumulative out-of-pocket cost burden, which may limit this approach for many patients.
How About Oral Ketamine?
As discussed earlier, antidepressive effects of oral ketamine have been demonstrated in a handful of studies with varying methodological quality, but research into the efficacy of oral ketamine for extending the acute antidepressive effects of intravenous or intranasal ketamine is lacking. Still, oral ketamine has some practical advantages that may increase its appeal for some patients (
Box 4). Oral ketamine is available at a relatively low cost and can be administered outside of medical settings, without direct clinical monitoring. Additionally, oral administration of ketamine follows traditional antidepressant-prescribing practices involving licensed prescribers and community pharmacies, suggesting ease of implementation and dissemination. Oral ketamine (created in compounding pharmacies) has been used worldwide for chronic pain for decades—particularly in the United Kingdom, where oral ketamine pain guidelines exist (
46) and advice is offered through the National Institute for Clinical Excellence (
47).
On the other hand, oral ketamine is poorly absorbed, with estimates ranging from 15% to 25% absorption with oral ingestion and up to 30% with sublingual dosing (
19,
48). The erratic absorption pharmacokinetics of oral ketamine may lead to practical challenges when trying to select potentially effective antidepressive doses. Extrapolation of a typical intravenous ketamine dose of 0.5 mg/kg to oral dosing is only approximate, suggesting a three- to fivefold initial target; for an 80 kg individual getting a 40-mg IV dose, an oral dose may range from 120 to 200 mg. The published literature also documents very wide ranges and frequencies of dose administration, ranging from once weekly to three times daily (
20,
23). Our own clinical experience parallels that of the Toronto case series report of 100 to 300 mg every three days (
49), with occasional higher doses and more frequent administrations. Twice-weekly dosing of 100–300 mg resembles, pharmacokinetically, the dose delivered by the FDA-approved twice-weekly intranasal esketamine. In our experience, compounding pharmacies are often able to formulate oral capsules or tablets with a typical monthly prescription cost of under $100 USD.
Because of the lack of studies investigating oral ketamine for extending acute antidepressive responses to intravenous ketamine, the use of oral ketamine for this specific purpose must be considered a low-priority option. However, for patients with treatment-resistant unipolar or bipolar depression who express a desire to undergo a therapeutic trial of oral ketamine after an acute response to intravenous ketamine, preliminary considerations for clinical use can be provided based on clinical experience and available but limited research. Once a patient consents to treatment with oral ketamine, their prior experience on intravenous ketamine should be reviewed with respect to dosing, efficacy, and side effects. As with most oral agents, lower doses would be initiated, efficacy and side effects would be monitored, and dosing would be adjusted. An initial upper limit of dosing of five times the previous intravenous dose can be declared, and procedures for the first dose should be discussed. The first dose may be administered in the office with clinical monitoring by staff and a family member for two hours. The typical dosing strategy is 100 mg of oral ketamine every Monday and Thursday at bedtime, with the patient reporting both efficacy and side effects by phone the next day. As is the case with ketamine and esketamine, the long-term antidepressive efficacy and safety of oral ketamine for treatment-resistant unipolar or bipolar depression is unknown. Once there is confidence in the safety of oral ketamine, doses are increased by 50 mg per dose every one to two weeks, until a maximum of 300 mg twice per week is achieved. The patient can be seen every two to three weeks face to face during the titration period. Otherwise, we again advise adopting the same protocol-driven practices for follow-up and monitoring with the use of oral ketamine as was recommended earlier for intranasal esketamine and intravenous racemic ketamine.
When Switching Conventional Antidepressants or Mood Stabilizers
In our experience, patients with treatment-resistant unipolar major depression who present for ketamine therapy often have not been offered or have refused therapeutic trials of older antidepressants, including TCAs or MAOIs. Broadly, most antidepressants are about equally effective, with only small advantages for some (
52). Although this observation is based mainly on studies of patients who were not necessarily treatment resistant, it suggests that there may be considerable latitude in choosing another antidepressant after ketamine (
Box 6). If an antidepressant has not been previously used, one recommendation, based on the Cipriani et al. study (
52), is to consider using one of the three antidepressants with the best margin of efficacy and tolerability, specifically, agomelatine, escitalopram, or vortioxetine (
53). Another approach is to consider TCAs or MAOIs as a maintenance strategy after acute response to ketamine, although efficacy is not proven. However, there is evidence suggesting that oral MAOIs and TCAs may be effective for at least some patients who do not respond to other types of antidepressants (
54–
60), although remission rates are often very low at the stage of treatment resistance when these medications are considered (
54,
61). Still, we typically recommend that patients and their families consider these treatments before undergoing a therapeutic trial of ketamine.
For purposes of extending a positive antidepressive response to ketamine, case literature and a drug interactions database search suggest that depressed patients can be safely transitioned to TCAs, oral MAOIs, or newer antidepressants while receiving ketamine without clinically significant drug-drug interactions (
18,
62–
65). There is a hypothetical risk of sympathetic overactivation with the use of ketamine for patients who are being treated with MAOIs (
65). Therefore, close monitoring is warranted, and consultation with a colleague in anesthesia may be helpful when transitioning to new antidepressants, especially MAOIs. If possible, the transition to TCAs or oral MAOIs should occur before initiating acute ketamine treatment; otherwise, more ketamine infusions may be needed to ensure that antidepressive benefits are maintained during the several weeks required for the new antidepressant to achieve therapeutic effects. This may be especially important for treatment with MAOIs, which requires a washout period after tapering and stopping the previous antidepressant and other interacting drugs.
Similarly, for patients with bipolar disorders, it may be necessary to consider switching to medications or medication combinations that have not been used during the current depressive episode. For instance, in our experience, many ketamine-treated patients with bipolar disorders have not been offered therapeutic trials of at least one (and often more than one) second- or third-line option for bipolar depression, as defined by practice guidelines (
66–
70). In our experience, these agents have usually been avoided owing to their adverse effect profiles or potential for clinically significant drug-drug interactions. Most of these agents can be safely administered while acute-phase ketamine is being given (
62). Theoretically, CYP2B6 and CYP3A4 inducers, such as carbamazepine, may reduce the overall exposure and, by extension, the therapeutic effects of ketamine (
18). As such, carbamazepine may be a low-priority treatment option for patients receiving acute- or maintenance-phase ketamine.
Common adjuncts to antidepressants or mood-stabilizing medications may be expected to be reasonably well tolerated while patients are receiving ketamine or esketamine, although there may be a risk of added sedation with some agents, such as trazodone; other sleep-promoting medications; buspirone; and certain second-generation antipsychotic drugs (
62). There is a possible risk of further reduction in seizure threshold when bupropion is administered with ketamine, although this specific interaction has not been previously reported (
62). Benzodiazepines, often used with mood stabilizers and antidepressants to manage comorbid anxiety symptoms and associated distress, may limit or delay the therapeutic effects of ketamine (
71,
72) and are, therefore, best avoided, especially within 24 hours of ketamine treatment. Intravenous ketamine appears to be about equally efficacious for anxious and nonanxious treatment-resistant major depressive disorder (
73), suggesting that concomitant benzodiazepines may not be needed for such patients when treated with ketamine.
There is no evidence related to prioritizing and sequencing potential next-step conventional antidepressants or mood-stabilizing therapies after successful treatment with ketamine for people with treatment-resistant unipolar or bipolar depression. As such, the process of selecting and trialing subsequent treatments will be iterative, and much support and encouragement by the treatment team will be needed. The entire treatment armamentarium should be considered, including evidence-supported psychosocial treatment, which, in our experience, is often overlooked. Empirical evidence is limited regarding the use of pharmacogenetics testing as a decision support tool for selecting antidepressants, although some studies have demonstrated clinical utility for pharmacogenomics testing–guided prescription of antidepressants (
74). When pharmacogenetics testing results have already been obtained, this information can be considered when making decisions about next-step treatment selection and dosing (
75). HLA-A and HLA-B testing is recommended before the use of carbamazepine and oxcarbazepine for reducing the risk of severe cutaneous drug reactions, regardless of the patient’s ethnic group (
76). For patients who appear to have tried nearly all available options, it may be necessary to conduct a detailed review of therapeutic trials of medication to determine whether any involved inadequate doses, drug levels, or time on a given medication or medication combination. Medications not associated with any discernible benefit after an adequate therapeutic trial may be excluded from further consideration. However, agents that were associated with a partial response can be considered for another trial at a more optimal (usually higher) dose relative to the previous trial or in combination with other medications in the hopes of achieving a better overall response.
Medications that were previously tried and found to be potentially beneficial but poorly tolerated may also be revisited—for these medications, alternative formulations (liquids, orally dissolving tablets, sprinkles, etc.) may be better tolerated than solid tablets. Some patients may be willing to undergo therapeutic trials of medications associated with a more burdensome adverse effect profile, absent any significant safety concerns, after lacking response to several rounds of treatment with other medications. The practice of conducting such a detailed review of past medication trials requires patience on the part of the patient and practitioner and, often, the help of pharmacy records, additional medical records, and collateral historians.