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Clinical Case ConferenceFull Access

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

Mr. A, a 35-year-old military veteran with a history of posttraumatic stress disorder (PTSD), bipolar II disorder, alcohol use disorder in full sustained remission, cannabis use disorder, and borderline personality disorder, self-presented to the psychiatric emergency department at the Veterans Administration (VA) hospital, reporting worsening depression and suicidal ideation. He stated that his medication regimen did not alleviate his depression and that suicidal ideation had increased in frequency to multiple times a day, so he came to the emergency department seeking admission. His prescribed medications were 150 mg/day of bupropion, 10 mg h.s. of zolpidem as needed for sleep, and 1 mg/day of lorazepam as needed for anxiety. In addition, he reported taking large amounts of ketamine from a prescriber outside the VA system.

Mr. A reported having undergone many treatments over the past 2 years, including numerous antidepressant trials, ECT, clozapine for refractory suicidal ideation, and transcranial magnetic stimulation, in addition to ketamine infusions as part of a VA research trial investigating the efficacy of ketamine for patients with treatment-resistant PTSD. Of all the treatments, he felt that ketamine was the most effective, so on completion of the research trial, he sought out a ketamine prescriber for out-of-pocket payment. His ketamine use quickly escalated to monthly intravenous infusions and 100-mg oral lozenges taken four times daily. Mr. A had been seeing this provider for nearly a year and taking ketamine at these doses for 8 months at the time of presentation. Additionally, the patient used a cannabis vape pen daily, utilizing variable amounts of tetrahydrocannabinol and cannabidiol. He denied other substance use.

On admission, the psychiatrist noted that the patient was in no apparent distress, was polite and well-groomed, offered good eye contact, and displayed no psychomotor agitation. His thought process was logical and coherent. He reported chronic passive suicidal ideation without specific plans or suicidal intent. Physical and neurologic examinations were unremarkable. A urine toxicology screen was positive for cannabinoids and negative for all other substances tested, including synthetic cannabinoids. The patient’s blood alcohol level was 0.00. Mr. A was admitted to the emergency department for observation overnight, and all outpatient medications were continued, with the exception of ketamine.

By the next day, Mr. A was noted to have a labile affect with increasingly pressured speech. He struggled to keep on topic and demonstrated a perseverative thought process. He reported worsening suicidal ideation. He also demanded discharge without providing any rationale, despite his wish for admission the previous day. Given the abrupt change in clinical presentation and history of suicide attempt, the attending psychiatrist admitted the patient involuntarily to the inpatient psychiatric unit.

Mr. A arrived on the unit that evening, approximately 24 hours after initial presentation. He received 1 mg of lorazepam for anxiety, with little effect, and he did not sleep at all. When the primary team arrived in the morning, Mr. A was highly irritable, intense, and dysphoric. He was observed hitting the wall, banging on the counters, arguing with staff, and yelling into the telephone. A request for interview resulted in a loud refusal, a demand for discharge, and physical posturing. Restraints were prepared by staff, but an additional 2 mg of lorazepam reduced his agitation enough that he could briefly engage in an interview and refrain from further threat of physical violence.

During the interview, Mr. A attributed his agitation to “ketamine withdrawal.” He stated that the cost of ketamine ($600 monthly) was becoming unaffordable, and he would sometimes go a day or two without ketamine. He reported that during these times, he experienced an intense, agitated, and dysphoric state that was only relieved by resuming ketamine. He confirmed that his current level of agitation felt the same as when he had discontinued ketamine on his own. He said that stopping cannabis did not produce similar effects.

A dose of 10 mg of olanzapine led to a further decrease in agitation, so the patient was started on 10 mg h.s. of olanzapine, 2 mg t.i.d. of lorazepam, and 0.1 mg b.i.d. of clonidine. The next day, staff noted that he was calmer, more cooperative, and less labile, although he still reported racing thoughts. He continued to be irritable and labile for the next 2 days, at which time 1500 mg h.s. of valproic acid was added to his medication regimen, which he reported was helpful in managing anxiety and improving concentration. His mood continued to stabilize over several days, and lorazepam was tapered over the course of 1 week. By the time of discharge, 14 days after admission, his olanzapine dosage had been increased to 20 mg h.s. and his valproic acid dosage to 2000 mg h.s.

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 (47). 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 (911). 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.

Department of Psychiatry, Yale University School of Medicine, New Haven, Conn
Send correspondence to Dr. Capurso ().

Presented at the Yale Interventional Psychiatry Service Conference, Yale Psychiatric Hospital, New Haven, Conn., August 7, 2019.

The authors thank Gerard Sanacora, M.D., Ph.D., for his close reading and insightful comments.

Dr. Wilkinson has received contract funding from Janssen, Oui Therapeutics, and Sage Therapeutics for the conduct of clinical trials, administered through Yale University, and he has served as a consultant for Biohaven Pharmaceuticals, Janssen, Oui Therapeutics, and Sage Therapeutics. The other authors report no financial relationships with commercial interests.

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