A unique case of very low‐dose subcutaneous ketamine use: Maintenance option of ketamine for treatment‐resistant depression

Abstract

Numerous studies have demonstrated that low‐dose subanesthetic intravenous ketamine infusion treatment leads to rapid improvement of treatment‐resistant depression. The following case report describes the use of a very low‐dose subcutaneous ketamine as a form of maintenance in a patient with severe treatment‐resistant depression using a retrospective chart review.

Short abstract

Subcutaneous ketamine can be a practical, affordable, and safe technique for treatment‐resistant depression as both acute and maintenance treatment. We describe a titration‐up method for effective and tolerable dosing based on the clinical response.

1. INTRODUCTION

Major depressive disorder (MDD) is a widespread mental illness and severe health condition worldwide. Around 280 million individuals worldwide suffer from depression, making up an estimated 3.8% of the total population.

Ketamine is a rapid‐acting general anesthetic and short‐acting analgesic agent with a well‐established safety profile that has been widely used for more than 50 years in both human and veterinary medicine. ¹ A potent noncompetitive NMDA receptor antagonist, ketamine has, in recent times, been used to treat various psychiatric illnesses, including depression (especially treatment‐resistant depression) and suicidality. ² , ³ , ⁴ , ⁵ Despite the rapid‐acting nature of ketamine, its effects appear to be transient, with a duration of only days to weeks. ⁶ The long‐term safety and effectiveness of ketamine in mood disorders have not been adequately studied despite the need to maintain clinical improvement in short‐term use. The main gaps in knowledge in terms of the longitudinal use of ketamine in psychiatry include; optimal dosage, duration, and frequency of the treatment. Potential complications, such as the risk of developing cystitis, hepatoxicity, neurocognitive changes, and addictive properties, are not well understood.

Therefore, there is an urgent need to establish the potential long‐term benefits, adverse effects, and complications, and in this regard, it is crucial to determine whether the potential side effects outweigh the benefits.

The present case report demonstrates ketamine's longitudinal effectiveness, tolerability, and safety in a patient suffering from treatment‐resistant depression. The information contained herein this case report we believe provides new insights into the effectiveness of ketamine.

2. SUMMARY OF THE CASE

A 42‐year‐old male presented with a more than 15‐year history of severe treatment‐resistant depressive symptomatology, such as depressed mood, insomnia, low appetite, despair, anhedonia, fatigue, depressive cognitions, neurovegetative symptoms, and anxiety with no associated psychotic symptoms. Over time he has experienced a significant decline in his occupational functioning and was socially isolating himself, not enjoying anything in his life. His predicaments affected him in such a way that he was having significant difficulty reading, writing, and focusing, which were quite important aspects of his daily occupational activities. He had experienced suicidal thoughts in the past, without any history of suicide attempts or self‐harm behavior.

He was admitted to a private mental health facility. During the preceding 2 years, his depression had further worsened. The Montgomery‐Asberg Depression Rating Scale (MADRS) was used to measure the severity of depressive symptoms, ⁷ and he scored 42. In addition, the Depression subscale of the Depression Anxiety Stress Scales (DASS) was administered, ⁸ and his score was 30.

Although he had previously experienced OCD symptoms such as compulsive washing and cleaning, they were relatively under control with Clomipramine at 225 mg daily at the time of admission. In addition, he was also diagnosed with Attention Deficit Hyperactivity Disorder (ADHD), which was treated with dexamphetamine, with doses of 10 mg mane and 5 mg midday. He was occasionally using a small dose of alprazolam for anxiety. He was also on Melatonin 4 mg at night for insomnia.

He had been under psychiatric care for several years prior to his presentation. Despite multiple psychopharmacological medications from different classes of antidepressants, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and mood stabilizers/antipsychotics (e.g., lithium, olanzapine, and quetiapine and combinations), he remained severely depressed. He has never had a course in ECT because he was concerned about its side effects and potential complications. He also did not respond to a course of transcranial magnetic stimulation (TMS) previously.

His psychological predicaments were further complicated by existing multiple medical conditions, such as Type II diabetes mellitus, androgen deficiency, hypertension, hypothyroidism, hypercholesterolaemia, and GORD. He was on thyroxine 100 μg mane, glimepiride 2 mg nocte, acarbose 100 mg tds, metformin 1000 mg bd, empagliflozin 10 mg daily, exenatide 10 μg bd, ramipril 10 mg nocte, lercanidipine 20 mg mane, atorvastatin 80 mg mane, finasteride 1.25 mg nocte, indapamide 1.25 mg mane, gabapentin 100 mg bd, and esomeprazole 40 mg mane.

There was no history of alcohol or substance use. There was a possibility of bipolar disorder in his father, who is deceased. There were no childhood traumatic adversities or disadvantages.

3. TREATMENT

The patient was carefully assessed medically and psychiatrically for the suitability of the ketamine trial by a consultant psychiatrist. A second opinion for appropriateness was obtained from a second psychiatrist. Structured safety assessments were conducted pre‐ and post‐treatment for 2 h.

He received a physical examination from the hospital's general practitioner. An ECG was obtained, and pretreatment baseline blood tests were conducted, including liver function tests, renal function tests, urea, and electrolytes. He weighed 100 kg.

The treatment involved twice‐a‐week subcutaneous ketamine commencing at 20 mg (0.2 mg/kg) and titrated up to 35 mg (0.35 mg/kg) twice a week over a period of 4 weeks (see Figure 1) as an augmentation treatment for his current psychopharmacological regime. The protocol regimen allowed a weekly titration of 0.1–0.5 mg/kg. We achieved a sustained clinical response at around 0.35 mg/kg. Although the initial aim was to titrate his dose up to 0.5 mg/kg, his maximum dose was capped at 0.35 mg/kg as his tolerable dose level. Blood pressure and pulse rate were monitored before and 30 min after each dose. He did not experience significant changes in vital signs during initial and maintenance treatment.

FIGURE 1.

Frequency of treatment

In order to monitor safety and tolerability, vital signs and the Brief Psychiatric Rating Scale (BPRS) ⁹ were measured at baseline and at 30‐min intervals for 2 h postdose administration. Urinary side effects were monitored by dipstick urinalysis, done at baseline and on a weekly basis. In addition, a weekly mid‐stream urine sample was collected and tested. His other regular medications have continued.

From the second week, he started to experience significant improvements in his mood symptoms. He was happier, more reactive in affect, and clearer in his head. His MADRS score dropped from 42 to 12 following the completion of the course of ketamine (Figure 2 and Table 1). The DASS Depression subscale dropped from 30 to 8. He reported only mild and transient side effects, such as sedation, feeling spacey, dizziness, lethargy, and dissociations following ketamine administration. There were no psychotic symptoms elicited on the BPRS.

FIGURE 2.

Reduction in MADRS score over the period of initial treatment

TABLE 1.

MADRS Scores in the initial intense treatment period

Weeks	Treatments	MADRS
Week 0	Baseline	42
Week 1	Treatment 1	35
	Treatment 2	32
Week 2	Treatment 1	31
	Treatment 2	26
Week 3	Treatment 1	21
	Treatment 2	17
Week 4	Treatment 1	14
	Treatment 2	12

After a successful course of ketamine, he expressed a desire to receive ongoing maintenance ketamine treatment in an outpatient setting following discharge from the hospital. After obtaining a second opinion about this, it was concluded that maintenance treatment was crucial for the patient to maintain this achieved improvement, wellness, and enhanced occupational functioning. Therefore, after receiving initial hospital treatment, he was given subcutaneous ketamine every 12 days, as his mood was moderately declining after 12 days. Then, the treatment intervals were changed to fortnightly to make it more feasible.

Repeated treatments produced sustained improvements in his depressive symptoms, as evidenced by the drop in MADRS score to 4 during the maintenance period. His dose of ketamine was gradually reduced to 14 mg per fortnight as the higher doses became increasingly sedating for him. During the maintenance treatment period, he was clinically monitored for psychotic symptoms for the first hour after treatment and for the time between previous treatments. He did not experience any adverse events or significant changes in vital signs during initial and maintenance treatment.

He had been taking maintenance for 4 years when this report was submitted. His mental state was stable, and he maintained his occupational functioning well. He has been regularly checked for urine symptoms and received a urinalysis. In addition, every 6–12 months, he receives a second opinion from an independent psychiatrist to continue the treatment. He receives ongoing safety and mental state monitoring and MADRS scoring. Regular checks were made on his vital signs, urine microscopy, and blood tests, including LFT, FBC, and UEs. The patient has not reported any subjective cognitive decline.

4. DISCUSSION

TRD is commonly defined as “a major depressive episode characterized by unipolar depression that does not respond effectively after two trials of antidepressant monotherapy in adequate dosage and durations (at least eight weeks; up to 12 weeks in some cases) and frequently do not respond satisfactorily to numerous sequential treatment regimens”. ¹⁰ , ¹¹ It is linked to economic burden and a decreased health‐related quality of life. ¹² TRD‐related general medical expenses are around 20 times higher than depression that responds to therapy. ¹³

In current clinical practice, psychotherapeutic interventions ¹⁴ and antidepressant medications are usually prescribed for moderate–severe depression. ¹⁴ Current standard antidepressant medications targeting the monoamine system only alleviate depressive symptoms in the 30%–50% range due to insufficient response and intolerability. ¹⁵ Following further pharmaceutical optimization, augmentation strategies, and psychological interventions, 15% of patients will still have substantial depression. ¹⁶ , ¹⁷ Not everyone may be a candidate for brain neurostimulation techniques like TMS or ECT. For example, ECT can produce significant side effects such as short‐ or long‐term memory loss. ¹⁸ , ¹⁹

Nonresponse to therapy can be caused by various individual characteristics, including sociodemographic, genetic, and clinical factors. ²⁰ In depression, chronic stress pathology disrupts synaptic connection due to a change in the brain network caused by the interplay between an individual's biopsychosocial predisposition and disease‐inducing insults such as inflammation and traumatic stress. ²¹ Furthermore, these stress‐related structural and functional brain changes may result in treatment resistance and chronicity. ²²

Rapid and robust improvement of ketamine in individuals with TRD has been proven with placebo‐controlled, double‐blind trials ³ , ²³ , ²⁴ and suicidality. ²⁵ Furthermore, ketamine research has offered new insights into the molecular processes of treating depressive symptoms by restoring normalcy to stress‐induced pathology in the HPA axis, hippocampus, and glutamatergic systems. ²²

In most previous studies, ketamine has been chiefly administered intravenously in 30‐ to 45‐min sessions for the treatment of depressive disorders in the studies in a hospital setting. ³ , ²⁴ , ²⁶ Despite being regarded as a gold standard, intravenous administration has low feasibility and accessibility and is expensive and impractical in real‐world clinical psychiatric settings. ²⁷ In addition, placing IV catheters requires skill and can lead to complications such as malfunction, thrombosis, infection, painful phlebitis, and extravasation, all of which limit systemic access. ²⁸ , ²⁹ , ³⁰ , ³¹

Therefore, subcutaneous use can potentially be a viable, more practical, affordable, and safer technique that does not require equipment and human resources. In addition, subcutaneous use can provide a gradual absorption, which could decrease the adverse effects because of the low plasma concentration, ³² in which the psychomimetic side effects can be prevented by keeping the plasma concentration lower. ³³ Unfortunately, limited studies have been conducted to evaluate the parameters of the subcutaneous use of ketamine, such as dose amount, duration, and frequency of the treatment. A comprehensive evaluation of 12 research on subcutaneous racemic ketamine and esketamine usage in treating depression, including case reports, retrospective studies, and clinical investigations, was recently published, and the results were positive, with transitory side effects and effectiveness comparable to IV ketamine. ³⁴ A randomized, double‐blind multiple‐crossover placebo‐controlled research with 16 unipolar or bipolar‐depressed persons over 60 was followed by an open‐label phase. During the RCT phase, patients received weekly subcutaneous ketamine at a progressive dosage of 0.1 mg/kg, increasing by 0.1 mg/kg each session, up to 0.5 mg/kg. Patients in the open‐label phase received 12 administrations of the remission dosage or 0.5 mg/kg if remission was not achieved with lower doses. In this phase, 12 patients, 5 RCT remitters who relapsed and 7 RCT nonremitters, were given subcutaneous ketamine twice weekly for 4 weeks, followed by weekly for 4 weeks. Two of the seven nonremitters in the RCT achieved remission with repeated doses (0.5 mg/kg). ³⁵

In summary, subcutaneous ketamine will be less invasive and cost‐effective, making its usage more feasible and clinically applicable, particularly for financially disadvantaged patients. Furthermore, subcutaneous usage might provide possible maintenance treatment following response to IV use in some cases, making ketamine more accessible, convenient, and widely available.

The present case report outlines the potential tolerability, safety, and long‐term beneficial effects of very low‐dose subcutaneous ketamine in terms of maintaining psychological wellbeing and occupational functioning in a patient who has been successfully treated in a real‐world setting.

The major component of the treatment was the initial titration‐up method of dosing to find the tolerated dose by monitoring physical and psychotomimetic side effects, then rationalizing the frequency based on the clinical presentation as a conservative approach. Given the lack of an established protocol or consensus on a dosage regimen for long‐term usage, this case report emphasizes the necessity of a case‐by‐case approach in terms of effective dose regimens and treatment intervals in ketamine treatment for mood disorders.

Although this case report requires cautious consideration, it contributes significantly to the field. Given the lack of long‐term studies of subcutaneous ketamine for efficacy, tolerability, and safety, particularly in longitudinal and repeat dosing strategies, the current case report provides excellent clinical insight into the essential parameters for subcutaneous ketamine maintenance treatment. However, further investigations with high‐quality systematic randomized clinical trials are warranted to validate the outcome of this study. Especially comparison studies with subcutaneous and intravenous ketamine delivery are required to examine their efficacy, optimal dosage, pharmacokinetics, and cost‐effectiveness.

AUTHOR CONTRIBUTIONS

Adem T. Can: Data curation; investigation; writing – original draft; writing – review and editing. Daniel F. Hermens: Writing – original draft; writing – review and editing. Jim Lagopoulos: Supervision; writing – original draft; writing – review and editing.

CONFLICT OF INTEREST

None to declare (all authors).

ETHICAL APPROVAL

No ethics were obtained for this single case report.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the Journal's patient consent policy.

Can AT, Hermens DF, Lagopoulos J. A unique case of very low‐dose subcutaneous ketamine use: Maintenance option of ketamine for treatment‐resistant depression. Clin Case Rep. 2022;10:e06675. doi: 10.1002/ccr3.6675

DATA AVAILABILITY STATEMENT

The patient case notes are held by the treating institution, and de‐identified notes can be made available upon request.