A Potential Case of Acute Ketamine Withdrawal: Clinical Implications for the Treatment of Refractory Depression

Mood disorders are a significant cause of morbidity and mortality. Despite recent advancements in behavioral and pharmacologic therapies, up to 35% of patients with major depressive disorder fail to respond to drug therapy (1). Even when effective, medications can take weeks or months to achieve optimal dosage and improve symptoms (2). It has been shown that even after two or more unsuccessful antidepressant trials, the rate of remission in a subsequent trial is only 13% (3).

Ketamine provides a promising treatment that overcomes many shortcomings of current pharmacologic strategies. Trials have demonstrated that ketamine can produce a robust, though typically transient, antidepressant effect in patients with treatment-refractory depression (4 –7). The efficacy of esketamine, a ketamine enantiomer, in treating depression, even when it coexists with acute suicidality, has also been demonstrated, leading to U.S. Food and Drug Administration (FDA) approval, in 2019, of intranasal esketamine for treatment-resistant depression in adults (8).

While clinical trials have shown meaningful antidepressant effects of ketamine in many patients with treatment-refractory illness, there remains concern that long-term ketamine treatment, especially of high frequency, could have negative health outcomes. Data from observational studies of people abusing ketamine as a recreational drug at high doses several times per week for approximately 1 year have shown cognitive deficits, severe cases of interstitial cystitis, and a risk of delusions (9 –11). Long-term studies of esketamine have been, and continue to be, conducted (12). Fortunately, the long-term data on esketamine, when given according to treatment guidelines, do not suggest similar worrisome clinical sequelae. However, the risk for iatrogenic substance use disorder is difficult to assess in these trials.

Ketamine is a recreational drug of abuse around the world, particularly in southeast Asia; a study in Hong Kong found ketamine to be one of the two most prevalently abused illicit drugs there between 2011 and 2015 (13). While the exact mechanisms underpinning ketamine’s addictive nature are not completely understood, some studies suggest that its antidepressant effect may be dependent on activation of mu opioid receptors (14, 15), leading some to raise concern that ketamine’s addictive potential could be similar to that of opioids (16, 17), though with an attenuated intensity. Given the known potential for abuse of ketamine, and now the growing clinical use of esketamine and ketamine for depression, there is the potential that patients might develop physiologic dependence or outright addiction (18), as demonstrated in the present case. Rates of clinically significant ketamine withdrawal have not been well characterized (19).

Physiologic tolerance to ketamine has been demonstrated in both humans and animal models. It is interesting to note that cases of iatrogenic ketamine abuse deriving from its use as an antidepressant are rare (20). Further, there is no consensus description of a stereotypical ketamine withdrawal syndrome. There is evidence that regular ketamine users can experience dysphoria, anxiety, and cravings on stopping use (21), and the single report in the literature of a patient with ketamine addiction and probable withdrawal symptoms describes the development of tremor, diaphoresis, irritability, and sleep disturbances (22).

The patient presented here represents another potential case of ketamine withdrawal, given the rapid change of mental status on ketamine cessation. The shift from a calm, cooperative demeanor to a highly agitated state was particularly striking. Intriguingly, the syndrome of intense agitation nearly necessitating physical restraint is dramatically different from the other case report in the literature. Furthermore, the time course differs in the two cases, with the previously described patient developing symptoms within 2 hours and our patient developing a more severe withdrawal syndrome overnight. Without further study, it is impossible to say whether either of these cases represents a “typical” ketamine withdrawal syndrome.

In our patient, comorbid cannabis use disorder, bipolar disorder, and borderline personality disorder are all potential confounding factors. While these conditions may account for some of the patient’s clinical presentation, it is notable that he reported experiencing similar reactions following previous occasions of ketamine cessation. Furthermore, regardless of comorbid conditions, given the large amount of ketamine he was regularly taking, the high frequency with which he was taking it, and the long duration of self-treatment, it is likely that he had developed at least a physiologic tolerance to the drug, if not an addiction. The oral bioavailability of ketamine is approximately 20%−30% (23), meaning that the patient was effectively receiving the equivalent of two to three intravenous infusions of ketamine each day at the standard treatment dose of 0.5 mg/kg (7).

The FDA imposed a strict Risk Evaluation and Mitigation Strategy (REMS) as part of esketamine approval, designed to prevent inappropriate treatment, diversion, and adverse effects such as those seen in this patient. While providers adhering to the REMS are likely to prescribe esketamine in a safe and effective manner, REMS adherence is potentially burdensome (24), and for some providers it could serve as a barrier to offering the treatment at all, leading to continued off-label ketamine prescribing, possibly in the irresponsible manner seen in this case. It was hoped that after FDA approval, esketamine might be less expensive than intravenous ketamine, at least from the patient’s perspective. Nevertheless, reimbursement for esketamine has proven challenging in many clinical settings, potentially proving to be a financial hurdle for some patients. This has allowed for continued use of off-label ketamine without significant regulatory oversight and, in some instances, may lead patients away from the use of esketamine, which is tightly regulated.

It remains to be seen how esketamine’s approval and the implementation of REMS will ultimately affect rates of off-label ketamine prescribing. Clearly, research into this area is urgently needed. Providers who have historically treated patients with ketamine off-label may largely replace their practice with esketamine, thereby improving patient safety and likely decreasing rates of iatrogenic adverse effects and addiction. However, if off-label ketamine use remains common, or even expands, it is likely that we will continue to see patients with complications of ketamine treatment, such as the patient reported here. As long as intravenous ketamine continues to be utilized off-label for treatment of depression, prescribers should adhere to existing evidence and expert guidance. For example, adherence to the prohibition of take-home doses, as outlined in a recent consensus statement from the American Psychiatric Association on the use of ketamine, would likely have avoided or mitigated the adverse clinical outcomes described here (25).

This case provides a rare clinical description of a possible severe acute ketamine withdrawal. The signs and symptoms observed in this patient differ from those in previous reports, and this presentation therefore adds to the understanding of this poorly defined clinical scenario. More globally, this case illustrates the gravity and urgency of the need to collect data on the ongoing off-label use of racemic ketamine and how these prescribing trends may be affected by the approval and implementation of esketamine. Given the potentially serious adverse effects of ketamine and esketamine, doing so is essential in order to provide effective, safe, and evidence-based treatments for our patients with treatment-refractory depression.