Introduction

Despite decades of research in treatment options, depressive disorders remain a major cause of disease burden worldwide (James et al., 2018). While antidepressant options have expanded over the years, the onset of their therapeutic effect is typically several weeks. As a result, there has been a growing interest and research around novel rapid-acting antidepressant agents (Witkin et al., 2019).

Since the initial report by Berman et al. (2000), the anesthetic agent ketamine, at subanesthetic doses, has been of particular interest with the potential for rapid effect in treatment-resistant depression (TRD). The mechanism of antidepressant action of ketamine is not fully understood but might involve N-methyl-D-aspartate receptor antagonism (Trullas and Skolnick, 1990; Muthukumaraswamy et al., 2015) and downstream mechanisms (e.g. mammalian target of rapamycin activation and brain-derived neurotrophic factor upregulation) enhancing synaptic plasticity (Maltbie, Kaundinya and Howell, 2017; Kraus et al., 2020). Other modifications in brain functioning have been observed in regions involved in the modulation of mood and stress response, including lowering of subgenual cingulate activity (Morris et al., 2020), and reduced burst activity of the lateral habenula (Yang et al., 2018).

Ketamine for depression is typically administered as racemic (R, S)-ketamine given in an intravenous (IV) infusion over 40 min. Racemic parenteral ketamine does not have regulatory approval, but the S-enantiomer, esketamine, has been approved as a nasal spray for adjunctive treatment of major depressive disorder in Canada (CADTH, 2020) and the USA (FDA, 2019). Despite the absence of regulatory approval, consensus (Sanacora et al., 2017) and international expert opinions for parenteral ketamine treatment have been published (McIntyre et al., 2021). Recently, the evidence for IV ketamine efficacy has been reviewed by the Canadian Network for Mood and Anxiety Treatments (Swainson et al., 2021), suggesting level 1 evidence for single-infusion IV ketamine with level 3 evidence for repeated infusions.

While much of the research has focused on the IV infusion route of administration, alternative parenteral options such as subcutaneous (SC) and intramuscular (IM) routes, with high (>90%) bioavailability (McIntyre et al., 2021) and relatively stable rate of absorption, can achieve plasma concentrations similar to those reported after IV infusion (Loo et al., 2016). The benefits of these alternate routes include ease of administration (no need for starting an IV line nor continuous infusion requiring infusion pump) and reduced staff training in IV medication administration. The parenteral ketamine dose for treatment of depression has varied from 0.1 to 1 mg/kg, with a typical dose of 0.5–1 mg/kg in most studies (Wan et al., 2015; Andrade, 2017). In the case of subanesthetic amounts of ketamine dosed at 0.5 mg/kg, an ‘average’ 70 kg individual would require 35 mg, or 0.7 ml (50 mg/ml), which is well within the typical 1.5 ml limit for SC injection into the abdomen or upper arm with little pain or injection site adverse effects (Mathaes et al., 2016).

These pragmatic factors suggest that SC ketamine may be simpler and easier to administer than the IV route while achieving similar efficacy and safety. However, to date, only a limited number of reports have been published in the literature on the use of SC ketamine in the treatment of depression. A recent systematic review of SC ketamine (Cavenaghi et al., 2021) including two randomized clinical trials, five case-reports and five retrospective studies utilizing various dose-titration approaches showed rapid antidepressant effect. In this report, we present a case series of patients with TRD utilizing an inpatient clinical SC ketamine protocol with well-defined dose scheduling, rigorous psychiatric and side effect monitoring.

Methods

A working group at the University of British Columbia (UBC) Hospital, Vancouver, Canada, comprised a collaboration between the BC Neuropsychiatry Program, UBC Mood Disorders Centre, and the Vancouver General/UBC Hospital Neurostimulation Program developed a clinical protocol with documentation, monitoring, and standardized operating procedures defined for physicians and nurses. The full clinical treatment protocol was approved by the Vancouver General/UBC Hospital Pharmacy and Therapeutics Committee and is available online (Tham et al., 2022) (OSF link: https://osf.io/ag6u7). The UBC Clinical Research Ethics Board approved the use of deidentified clinical data for case reporting (H21-02384).

To summarize the protocol, patient inclusion criteria were: inpatients more than 18 years old; able to provide consent; diagnosed with diagnostic and statistical manual of mental disorders-5 major depressive disorder or bipolar disorder by clinician assessment; and TRD defined as persisting depressive symptoms not responding to adequate trials of at least two antidepressants and at least one adjunctive medications (e.g. second-generation antipsychotics, lithium, thyroid hormone; if bipolar, quetiapine, lamotrigine, or lurasidone). Exclusion criteria were: current psychosis; active alcohol and substance use disorders in the preceding 6 months; history of ketamine abuse; significant personality disorder; unstable medical condition; uncontrolled hypertension; recent seizure; elevated intracranial pressure, aneurysmal vascular disease/arteriovenous malformation; pregnancy/breastfeeding; and sensitivity to ketamine, esketamine, or related compounds. While not specified in the inclusion/exclusion criteria, patients could be refractory to previous psychotherapy to previous electroconvulsive therapy (ECT) or other neuromodulation techniques.

Preketamine assessment

Clinical history, physical examination, weight, vital signs, and urine drug screen were done prior to the first treatment to ensure eligibility, along with bloodwork, including complete blood count, electrolytes, liver function tests, renal functions, thyroid-stimulating hormone, and pregnancy test as appropriate. In addition, an electrocardiogram was performed within the previous 30 days. The procedure, risks, and potential side effects of parenteral ketamine were discussed with patients, and informed consent was obtained.

Ketamine treatment procedure

Ketamine treatments were conducted twice weekly in the ECT recovery room. Although the presence of an anesthesiologist was not required within the clinical protocol, ketamine treatments occurred concurrently during ECT procedures, and an anesthesiologist was available in the immediate area. Medications potentially affecting ketamine response and tolerability including benzodiazepines, opioid antagonists, and lamotrigine (Anand et al., 2000; Williams et al., 2018; Andrashko et al., 2020) were held the night before and the morning before treatments. Patients were allowed a small breakfast up to 2 h before treatment with sips of water thereafter. Pretreatment vital signs including heart rate, oxygen saturation, and blood pressure were documented. Blood pressure was ensured to be below 140/90 mmHg before ketamine administration.

Racemic ketamine hydrochloride (50 mg/ml) was administered as SC bolus into the abdomen or upper outer area of the arm by a nurse/physician. Over the next 60 min, patients were monitored by a psychiatric nurse in an adjacent room for the emergence of adverse events. As required by local best practice, staff certified in Advanced Cardiac Life Support (ACLS) protocols were available in the event of severe reactions. Patients were instructed to relax and could choose to listen to soothing music. After 60 min, patients returned to the inpatient ward to continue their day and all regular medications resumed.

Dosing algorithm

Although the treatment protocol was approved for both SC and IM administration, all patients chose SC ketamine. The starting dose was 0.25 mg/kg for at least two treatments. If response was deemed inadequate, the dose could be increased to 0.5 mg/kg for at least two treatments and then, if needed, further increased to 0.75 mg/kg (maximum dose). This protocol allowed for up to six treatments, but the total number of treatments provided varied depending on clinical response/tolerability, as well as discussions with the treating physicians and patients.

Monitoring

For the first 60 min following dosing, vital signs including blood pressure were recorded every 15 min. At 45 min, the Clinician-Administered Dissociative Symptom Scale (CADSS-6) (Rodrigues et al., 2021) was administered. In the event of severe emotional distress, lorazepam 0.5 mg sublingually could be given. Final vital signs were recorded at 2- and 4-h posttreatment.

Measurement-based care was followed using depression, anxiety, and suicidality scales (Hong et al., 2021) throughout the treatment course. Depression severity was assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS) (Montgomery and Åsberg, 1979) and Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) (Rush et al., 2003). Clinical response was defined as at least 50% reduction in scores from baseline to endpoint, whereas remission was defined as endpoint scores of MADRS ≤10 (Hawley et al., 2002) and QIDS-SR16 ≤6 (Rush et al., 2003). Self-reported anxiety was assessed with the Generalized Anxiety Disorder Scale (GAD-7) (Spitzer et al., 2006). The Columbia–Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011) was used to monitor suicidal ideation. Finally, the CNS Vital Signs computerized neurocognitive test battery (CNS-VS Cog) (Gualtieri and Johnson, 2006) was administered before the first ketamine treatment and then within 24 h after the last treatment to measure the change in various cognitive domains.

Results

Here, we report on the results obtained for the first 10 consecutive patients with TRD referred from June 2021 to December 2021. The patients were either admitted from the emergency room to inpatient psychiatry or referred from outpatient psychiatrists requesting inpatient assistance with treatment-resistant cases.

Patient characteristics

All patients were evaluated by study authors (J.T. and A.D.) to satisfy the eligibility criteria. In total, the 10 patients were evenly balanced with five men and five women. Table 1 summarizes key demographics and clinical features including age, duration of current depressive episode, comorbidities and number of treatments with antidepressants, adjunctive medications tried during the current episode, and illness severity as measured with the MADRS, QIDS-SR16, and GAD-7.

Table 1 - Clinical characteristics of patients (n = 10) with descriptive statistics Characteristic Mean SD Range Age (years) 42.3 15.5 21–72 Duration of current episode (months) 23.6 16 10–60 Diagnosis – primary mood disorder Major depressive disorder 9 ND ND Bipolar I depression 1 Diagnosis – comorbid conditions among 10 cases Conversion disorder 2 ND ND Anorexia nervosa 1 Medical condition affecting CNS Multiple sclerosis 2 ND ND Remote hypertensive hemorrhagic stroke 1 Significant small vessel ischemic changes 1 # of antidepressants tried during current depressive episode of adequate duration & dose 3.4 ND 2–5 # of augmenting medications tried during current depressive episode for at least 4 weeks duration 1.9 ND 1–3 Course of ECT tried before ketamine during this episode 1 ND ND Pretreatment MADRS 30.8 6.7 20–44 Pretreatment QIDS-SR16 17.8 3.0 14–23 Pretreatment GAD-7 12.5 3.2 8–17

CNS, central nervous system; ECT, electroconvulsive therapy; GAD-7, Generalized Anxiety Disorder scale; MADRS, Montgomery–Åsberg Depression Rating Scale; ND, no data; QIDS-SR16, quick inventory of depressive symptomatology, self-rated.

Patient average age was 42.3 years with a range between 21 and 72 years. Nine (90%) of the cases had major depressive disorder with one (10%) diagnosed with bipolar I disorder currently in a persistent depressive episode of 10 months. On average, the patients reported persistent depression for 23.6 months. At baseline, the patients experienced high moderate to severe depression (average pretreatment MADRS and QIDS-SR16 scores of 30.8 and 17.8, respectively).

As a group, these patients had several psychiatric and medical comorbidities. Two cases had comorbid conversion disorder with seizure-like attacks, one case with anorexia nervosa, and four cases with medical conditions demonstrated on neuroimaging (two with multiple sclerosis in remission, one with hypertensive hemorrhage in the left basal ganglia 3 years ago, and one with significant small-vessel ischemic changes).

Among the 10 cases, antidepressants tried during this depressive episode before ketamine treatment included selective serotonin reuptake inhibitors (fluoxetine, citalopram, and escitalopram), serotonin modulators (vilazodone and vortioxetine), serotonin and norepinephrine reuptake inhibitors (venlafaxine, desvenlafaxine, and duloxetine), TCA (clomipramine), as well as other classes (trazodone, mirtazapine, and bupropion). Augmenting agents already tried among the patients included quetiapine, lithium, aripiprazole, brexpiprazole, olanzapine, thyroid hormone, buspirone, lamotrigine, and dextroamphetamine. One patient had an index course of ECT (10 treatments), which failed to elicit a significant response, and was switched to the ketamine protocol within 2 weeks of the last ECT treatment. On average, patients had failed to respond with three antidepressants and two augmenting agents during the current depressive episode.

Ketamine treatment effects

As per the protocol, treatments were stopped once remission was achieved with some clinical leeway up to the maximum of six treatments. None of the patients stopped early due to side effects or intolerability. One case (10%) responded adequately to two doses of 0.25 mg/kg and was discontinued. The remainder were treated with the higher 0.5 mg/kg dose with one (10%) requiring a total of three treatments, three (30%) had four treatments, one (10%) had five treatments, and four (40%) received the full six treatments. Of those four patients that received six treatments, only one was increased to the highest 0.75 mg/kg dose due to inadequate antidepressant effect and absence of psychological/perceptual effects during treatment at 0.5 mg/kg.

Figure 1 shows the results of the clinician-rated MADRS, patient-rated QIDS-SR16, and patient-rated GAD-7 scores pretreatment and after the indicated number of ketamine treatments for each case. Figure 2 shows the average MADRS score across the treatment time points. Not all patients required up to the full six treatments available, reflected in the reduced total numbers by treatments 5/6.

Fig. 1:

Individual Montgomery–Åsberg Depression Rating Scale (MADRS); quick inventory of depressive symptomatology, self-rated (QIDS-SR16,); Generalized Anxiety Disorder Scale (GAD-7) scores across treatment sessions.

Fig. 2:

Average Montgomery–Åsberg Depression Rating Scale (MADRS) scores across treatment sessions. CI, confidence interval; MADRS, Montgomery–Åsberg Depression Rating Scale.

Overall, patients had a significant reduction in MADRS score from baseline to endpoint (mean change ± SD: −24.2 ± 10.2). At the end of the treatment course, using response criterion defined as at least 50% reduction in MADRS, 8/10 (80%) of patients demonstrated response and all responders achieved remission with final MADRS 10 or less. The self-reported QIDS-SR16 demonstrated response in 6/10 (60%) of the cases as defined by at least 50% reduction in the score, with 5/10 (50%) achieving remission defined as QIDS-SR16 ≤ 6. Similarly, 6/10 (60%) of cases demonstrated at least 50% reduction in anxiety scores as measured by the self-rated GAD-7.

Of the eight cases that achieved remission as defined with the MADRS, four were within two treatments at a dose of 0.25 mg/kg. The other four achieved remission with the dose increased to 0.5 mg/kg by four treatments. Only one patient was given the 0.75 mg/kg dose for treatments 5 and 6 but did not achieve remission.

Suicidal ideation monitored with the C-SSRS showed that five patients had active ideation pretreatment. Ideations stopped within 24 h after the first treatment in 4/5 (80%); one case was a nonresponder with persistent suicidal ideation with no specific plans or intent.

CNS-VS Cog screens of cognitive performance were available for nine patients (one of the patients was discharged before posttreatment cognitive testing). Patients did not complain of persistent cognitive change, nor did the data reflect significant differences (Fig. 3).

Fig. 3:

CNS-VS cognitive screen results, pre- and posttreatment standard scores (n = 9). CI, confidence interval; CNS-VS, CNS Vital Signs computerized cognitive battery.

Ketamine adverse events

In total, there were 45 individual ketamine treatments performed. Treatments proceeded without any severe adverse events. The CADSS-6 dissociative symptom scale captured at 45 min postketamine bolus showed only mild symptoms (mean ± SD across all treatments: 0.91 ± 1.2; range, 0–4). No patients required lorazepam for emotional distress. At these subanesthetic SC doses, vital signs showed only mild and transient elevations in heart rate and blood pressure during the first 60 min (Fig. 4) with no physical distress reported. There was a tendency for cardiovascular effects to peak within 15 min of the ketamine bolus with mean systolic blood pressure (SD) increased by 8 mmHg (14.8) and heart rate increased by 1.1 bpm (11.6). In addition, analysis of individual treatments showed dose-related effect, with mean blood pressure increasing +6.8 mmHg (16.3, n = 10) at 15 min when administered at 0.25 mg/kg and +10.2 mmHg (9.9, n = 9) at 0.5 mg/kg. No patients required pharmacological intervention for the blood pressure increases. By 2 and 4 h, systolic blood pressure returned to baseline, but heart rate increased as patients resumed their normal physical activities.

Fig. 4:

Mean elevation in systolic blood pressure and heart rate during 60-min monitoring, 2 h, and 4 h after SC ketamine bolus. BP, blood pressure; CI, confidence interval; HR, heart rate; SC, subcutaneous.

Feasibility

Without the need for IV access nor an infusion pump, the protocol was relatively easy to implement at UBC Hospital. The single SC bolus was simpler to administer than a 40-min IV infusion and well accepted by patients. Orientation for inpatient psychiatrists was provided to familiarize clinicians to the ordering and monitoring procedures. Likewise, nurses were oriented to the procedures without issues. Patients found the SC ketamine treatment and monitoring straightforward. There were no early terminations due to adverse events nor withdrawal of consent.

Discussion

As a clinical work group, we were aware of the issues regarding the provision of parenteral ketamine as an off-label treatment including questions around adequacy of research evidence, the lack of ‘maintenance’ treatments and long-term safety data for those who respond to an acute treatment series, and the diversion and abuse potential of ketamine (Singh et al., 2017; Ryan and Loo, 2017). We developed the SC ketamine protocol on the basis of ensuring the safety of the patients, that due diligence has been performed for appropriate inclusion/exclusion criteria, and that limitations have been clearly defined as part of the informed consent process.

The results from these initial 10 cases utilizing SC racemic ketamine are encouraging. Significant, rapid reduction in MADRS scores was observed after the first treatment and was maintained throughout the treatment course. Patient-rated QIDS-SR16 depression and GAD-7 anxiety scales likewise showed a reduction over the course of SC ketamine treatment. Improvement in the QIDS-SR16 scores did not appear as rapidly as the MADRS scores, perhaps as a result of the scale asking patients to rate symptoms over the ‘last 7 days’ rather than since the previous assessment. In total, 80% of patients satisfied criteria for response and remission on the MADRS, and 60% achieved response with 50% meeting criteria for remission using the QIDS-SR16. These results with SC ketamine are comparable to response rates seen in studies utilizing multiple-dose IV racemic ketamine protocols (aan het Rot et al., 2010; Murrough et al., 2013; Singh et al., 2016). All patients who responded to SC ketamine could be discharged back to the community within 2 days after the last treatment. A surprising observation was that both patients with comorbid conversion disorder (functional neurological disorder) manifesting daily to weekly seizure-like attacks experienced essentially complete remission and both have remained free from these physical manifestations at 3 months follow-up.

Two patients did not show response in either the MADRS or QIDS-SR16. One patient had comorbid eating disorder and the other had significant psychosocial stressors at the time of the treatments. Comorbid factors in the perpetuation of depression may require further evaluation to better understand ketamine response and refine inclusion/exclusion criteria.

There were no safety issues encountered during the treatments. Elevations in blood pressure and heart rate were transient within the initial 60-min monitoring period. Psychological effects of SC ketamine were mild, including subjectively ‘feeling relaxed’ and ‘more talkative’. Perceptual changes included mild sound sensitivity, apparent brightness and enhanced contrast in the visual field, altered depth perception, and visual vestibular latency. Two patients described ‘entheogenic’ effects such as ‘feeling loved’, or being ‘one with others’ during the treatments. Psychological and perceptual side effects reportedly peaked between 15 and 30 min. As such, the 45-min CADSS-6 likely did not capture the peak intensity of dissociative symptoms; nevertheless, none of the patients reported distress severe enough to stop treatment.

The strengths of this report include the real-world patients and a simple clinical protocol utilizing standard measures for measurement-based care. Limitations of this report include the lack of a control condition, open-label treatment, and a limited number of cases with varied comorbidities. Measurements of serum ketamine level would also be beneficial for correlation with clinical effect and comparison to IV ketamine studies.

Characteristics of the SC ketamine protocol including the starting dose at 0.25 mg/kg may be reviewed with further clinical experience. At this time, it is encouraging that even at this lower starting dose, we have observed rapid antidepressant effect. A starting dose of 0.5 mg/kg might be reasonable for most individuals.

Given these encouraging results, SC ketamine is a promising and feasible alternative to IV ketamine infusions that may improve accessibility for patients with TRD. Although we conducted our protocol in a hospital inpatient setting, SC ketamine could be administered in an outpatient setting if appropriate monitoring and safety procedures (e.g. availability of ACLS and airway management) were in place. Placebo-controlled trials and prospective follow-up studies should be conducted to better understand the effects and duration of action of SC ketamine in clinical use.

Acknowledgements

Cognitive testing results were obtained with the assistance of Samantha Huang and Vanessa Evans.

Conflicts of interest

A.D. was partly supported by an unrestricted fellowship grant from Janssen Canada. R.W.L. has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from: Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, Grand Challenges Canada, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Medscape, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer, Sanofi, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. For the remaining authors, there are no conflicts of interest.

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