Oral and Intranasal Ketamine Use in Treatment-Resistant Catatonia: A Clinical Case Report

Background

Catatonia is a potentially life-threatening psychomotor syndrome that exists in more than 10% of patients with acute psychiatric illness [1]. The mortality rate has been reported as nearly 10% [2–4]. The most common symptoms of catatonia are immobility (100%), staring (92%), mutism (85%), withdrawal/ refusal to eat (78%), posturing/grimacing (73%), and rigidity (66%) [5]. This constellation of symptoms increases the risk of further problems, such as dehydration, malnutrition, deep vein thrombosis, pressure ulcers, and muscle contractures. Although heavily studied in the schizophrenia population, catatonia was later found to be associated with various psychiatric, neurological, and medical conditions [6,7]. While autoimmune dysregulation, especially glutamatergic hypofunction, was proposed to be highly related to the underlying pathological mechanism [8], the exact pathophysiology of catatonia is still unknown. Some previous studies hypothesized the involvement of decreased activity at the gamma-aminobutyric acid A and dopamine D2 receptors and increased N-methyl-D-aspartate (NMDA) activity [9,10]. This theory is in part evidenced by the treatments that have been found effective. Benzodiazepines, particularly lorazepam, are the standard treatment and can also be used as a diagnostic tool. If benzodiazepines are ineffective, electroconvulsive therapy (ECT) is considered second line and could be highly successful. A limited number of case reports have shown NMDA antagonists amantadine and memantine, as well as the nonbenzodiazepine hypnotic zolpidem, to improve catatonic symptoms [11–13].

Ketamine is an NMDA receptor antagonist and a dissociative hallucinogen medication that has been used as a general anesthetic and as an antidepressant for treatment of depression [14]. Ketamine has been administered as an intravenous (i.v.) infusion for treatment-resistant depression and suicidal ideation, although this has many obstacles, particularly in the community setting. Esketamine is the active S(+) enantiomer of ketamine and is a more potent NMDA antagonist [15]. It is specifically used as a therapy for treatment-resistant depression (TRD) and for major depressive disorder with co-occurring suicidal ideation or behavior [16]. Less common is the use of oral or sublingual ketamine. Ketamine has low oral bioavailability (17%) [17]. A clinical trial in which ketamine was dosed orally at 1 mg/kg 3 times a week showed it was successful at treating TRD [18]. Sublingual administration of liquid ketamine provides better bioavailability (30%) [19]. One small study found as little as 0.1 mL of 100 mg/mL (ie, 10 mg, administered as 2 drops) sublingual ketamine to be effective in treating TRD [20]. A recent, larger study found success in treatment of TRD with ketamine administered as a rapidly dissolving sublingual tablet [21].

Two previous case reports noted the use of i.v. ketamine as a one-time treatment for acute catatonia. In the first case, a 23-year-old man presented with acute-onset catatonia. He had a similar episode 1 year prior. His symptoms were reversed with 12.5 mg of ketamine, administered as 2.5-mg boluses every 3 min. At the 3-week follow-up, he had no relapse of symptoms [22]. A second case reported a 44-year-old woman with major depressive disorder, anxiety, and obsessive-compulsive disorder who presented to the Emergency Department (ED) with catatonic symptoms and had a history of recurrent cata-tonic episodes. She was treated in the ED with 10 mg of i.v. ketamine administered over 10 min. Unlike her previous similar presentations, she was able to be discharged the same day. She was symptom free for 5 months [23]. To fill the knowledge gap, we present a case of using ketamine for long-term management of recurrent catatonia. To the best of our knowledge, this is also the first case of using the combination of sublingual ketamine and esketamine nasal spray (due to lack of insurance coverage) for treatment-resistant catatonia.

Case Report

The patient was a 63-year-old woman with an extensive psychiatric history. In her 20s she was diagnosed with bipolar I, schizoaffective, bipolar type, and TRD. In total, she had 12 psychiatric admissions: 8 for depression, 2 for mania, and the most recent 2 for catatonia. She had no history of self-harm, suicide attempts, or alcohol or drug use. She had a lengthy list of medication trials, including 7 antipsychotics, 3 mood stabilizers, 2 stimulants, and 9 antidepressants. None of these were recounted as being particularly helpful for her. A course of 12 ECT treatments at age 55, 18 TMS treatments at age 60, and another round of 22 ECT treatments at age 62 were ineffective. Her medical history included chronic kidney disease, hypothyroidism, erosive esophagitis, hypertension, gastroesophageal reflux disease.

The patient initially presented to the ED in March 2021 for a catatonic condition with mutism, psychomotor retardation, poor intake, and a 70-pound (26%) weight loss. During her interview, she was very slow to respond and used mostly one-word answers. Her partner reported that she had not “been herself” in years and had been in a depressive episode since the previous summer. She had not seen a psychiatrist since December, and over the past month she had stopped taking all psychotropic medications. She could not identify a reason for the noncompliance. The reported prescribed medications included clozapine 200 mg daily (not taking), venlafaxine extended release 112.5 mg daily (not taking), lisinopril 20 mg daily, omeprazole 40 mg daily, and levothyroxine 137.5 mcg daily. A computed tomography head scan was unremarkable. She scored 25/30 on the Montreal Cognitive Assessment. An HIV screen and urine drug screen were negative. She was started on paliperidone 6 mg daily, as she had no previous trials of it. After 9 days on the adult unit, she was transferred to the Psychiatric Intensive Care Unit owing to worsening catatonia and paranoia. She denied a lorazepam challenge. After 9 days in the Psychiatric Intensive Care Unit, she developed acute renal failure, secondary to her decreased intake, and was transferred to medical service. After resolution, she was discharged to a rehabilitation facility but quickly returned to the ED owing to fast decompensation and inability to perform activities of daily living. She showed no response to a 1-mg oral lorazepam challenge. An hour later, another 1 mg of oral lorazepam was administered, again without any response. During this admission, her second lifetime round of ECT began. She continued to have low activity, spending most of the day and night in her bed. Methylphenidate 10 mg daily was started to address her severe depression and low energy. Sertraline 50 mg daily was also started. Neuropsychiatric testing suggested a frontotemporal/subcortical pattern of dysfunction, although it was noted it was difficult to determine the severity of her cognitive impairment owing to her difficulty with engagement. Follow-up magnetic resonance imaging then found no evidence of frontal temporal dementia. She stayed inpatient for over 1 month before being discharged home in June 2021. Despite still being symptomatic, her family felt she should return home due to her length of stay.

In December 2021, she was brought to the ED again by a family member because they were unable to care for her. Reportedly, she had poor intake and had been “either in bed or laying on the couch for 24 hours a day and had not showered in over a month.” In her time as an outpatient prior to this admission, ECT had been discontinued after 22 treatments, owing to lack of improvement. Severe mutism and psychomotor retardation were noticed during the admission interview. She scored 6 on the Bush-Francis Catatonia Screening Instrument. She then scored 12 on the Bush-Francis Catatonia Rating Scale (BFCRS): 1 point for immobility/stupor, 1 point for mutism, 2 points for staring, 1 point for stereotypy, 1 point for rigidity, 2 points for withdrawal, 3 points for ambitendency, and 1 point for autonomic abnormality [4]. Her score initially reduced to 5 after 2 mg i.v. lorazepam, but unfortunately quickly increased back to 10 after 3 days. Due to her initial positive response, she was started on oral lorazepam 1.5 mg 3 times a day before eventually being transitioned to diazepam 7.5 mg 3 times a day as a trial, based on its longer half-life. On December 9, 2021, she was started on 50 mg of sublingual ketamine twice a week, as our facility does not administer i.v. ketamine. She did not experience any dissociation or hallucinations following administration. Her BFCRS decreased steadily, until she was discharged a week later with a BFCRS of 2. Her medications on discharge included twice weekly 50 mg sublingual ketamine, 7.5 mg diazepam 3 times a day, extended-release methylphenidate 54 mg daily, paliperidone 6 mg daily, sertraline 200 mg daily, and levothyroxine 125 mcg daily. Over the weekend, she missed a dose of sublingual ketamine and her condition noticeably declined. She returned to the ED with concerns of being in a similar condition. Her family member reported her “sitting in weird positions and not moving, even though they look uncomfortable.” Her BFCRS was 11. She was readmitted to the same unit, with sublingual ketamine resumed. Her diazepam was switched back to lorazepam at 2 mg 3 times a day. Progressively, she improved and was discharged home 11 days later. Figure 1 depicts the timeline of BFCRS score change with ketamine treatment. Unfortunately, no additional BFCRS scores were obtained during this readmission, owing to her quick clinical improvement. At discharge, she was noted to demonstrate some response lag with short answers, but had significant improvement with increased spontaneous speech. She also endorsed increased appetite and personal hygiene, and regularly ambulated on the unit. Based on DSM-5 criteria, her final diagnosis was schizoaffective, bipolar subtype. Shortly after her discharge, her paliperidone was switched to 42 mg lumateperone daily, as its partial D2 receptor agonism lessens D2 receptor blockade, which could have contributed to her catatonic symptoms. She was also able to be slowly weaned to 0.5 mg of lorazepam twice a day.

The outpatient course after this hospitalization was uneventful. She continued taking 50 mg of sublingual ketamine twice a week, until her insurance approved esketamine nasal spray approximately a month later. She then took 56 mg of esketamine twice a week for 3 weeks before increasing the dose to 84 mg twice a week. Due to a change in insurance approval, after a month and a half, she was then switched to 1 dose of esketamine 84 mg a week that she supplemented with 1 sublingual dose of ketamine 150 mg per week.

Discussion

Here, we report a patient with treatment-resistant catatonia who had a marked improvement with the combination of sublingual ketamine and esketamine nasal spray. In the year prior to starting ketamine, the patient had 4 psychiatric admissions, totaling 69 days spent as an inpatient. After her final discharge, her functioning continued to improve while on the maintenance ketamine. She steadily began resuming her baseline activities, such as cooking, driving, socializing with friends and family, walking her dogs, visiting the nail salon, and traveling. To date, she has remained out of the hospital for 13 months.

Some 20% to 40% of patients with catatonia do not respond to standard treatment with benzodiazepines, ECT, or a combination of the two [4,24–26]. Chronic catatonia is more likely to be treatment resistant [27]. Given the success of ketamine in the treatment of TRD, the moderate success of other NMDA antagonists at treating catatonia, and the recently published case reports of ketamine treating catatonia, ketamine may find a role in the treatment of treatment-resistant catatonia. Its diversity in route of administration, as well as its rapid onset and lack of respiratory depression make it an attractive treatment choice. Interestingly, ketamine has been found to be pro-catatonic in animal studies [28,29], indicating a complex mechanism may be at play. In this case, we chose ketamine because of its rapid effect in TRD, our previous experience of using sublingual formulation in this population [30], the newly available esketamine nasal spray, and previously published case reports of ketamine treating acute catatonia. While other NMDA receptor antagonists have been studied both preclinically and clinically to have relatively modest antidepressant effects [14,31], unfortunately, we did not try them on this patient during her catatonic phase.

The recent approval of esketamine nasal spray provides a more practical option to i.v. infusions, but insurance approval can be difficult to obtain, and without insurance it is likely cost prohibitive. The FDA also ruled it must be administered under supervision, further reducing access. This patient’s treatment was initially delayed awaiting insurance approval of esketamine, then after a month and a half of twice weekly doses, insurance reduced approval to 1 dose per week. Here, sublingual ketamine was invaluable to bridge the gaps created by insurance and also to supplement dosing to maximize the clinical benefit. Although sublingual ketamine has a low absorption rate and limited bioavailability from a pharmacokinetics perspective, due to its cost-effectiveness and aforementioned reasons, we advocate its utilization in patients with urgent needs, when an FDA-approved formulation cannot be immediately obtained. It also may be safer for at-home administration than oral administration, as a lower dose is required to reach the same plasma concentration.

The limitations of this case report include its retrospective design and lack of data points (ie, BFCRS scores). Its results may not be able to be generalized, and like many other case reports, we cannot establish a cause-effect relationship between ketamine treatment and the clinical outcome of catatonia improvement.

Conclusions

This case is the first to use a combination of the sublingual ketamine and esketamine nasal spray for treatment-resistant catatonia when other treatment choices failed to be effective. Additionally, this is the first report of a patient maintained on ketamine/esketamine to prevent relapse of catatonia. Sublingual ketamine or intranasal esketamine may be an avenue of treatment for other patients with treatment-resistant catatonia.