Efficacy and Safety of Single Intravenous Ketamine Infusion as an Add-on to Escitalopram in Major Depression: A Randomized, Double-blind, Placebo-controlled Study

INTRODUCTION

Major depressive disorder (MDD) is a common psychiatric disorder affecting people of all ages, genders, and different socioeconomic groups in India and all over the world. In 2015, MDD is ranked by the World Health Organization (WHO) as the single largest contributor to global disability, accounting for 7.5% of all years lived with disability.¹

Although effective pharmacological and psychosocial interventions exist, it may take weeks or months before clinically relevant efficacy is apparent.² This further increases suicide risk and illness burden, particularly during the initial days after starting antidepressants.² With the possible exception that drugs with dual serotonin and norepinephrine mechanisms may be marginally more effective than the selective serotonin reuptake inhibitors, currently available drugs for treating depression have marginal differences in efficacy.³ Research over the last decade has focused on the role of glutaminergic system in the pathophysiology of MDD and to expedite antidepressant action.^4,5

Data from published placebo-controlled, double-blind, randomized clinical studies on IV ketamine infusion in the treatment of depression present “compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient.”⁶ Ketamine in subanesthetic doses is safe in healthy individuals and has rapid-onset efficacy in patients with severe and even treatment-refractory depression.⁷ The intermittent use of low, subanesthetic doses of ketamine has not been reported to be associated with cystitis and other medical concerns.⁷

Most trials examining the role of ketamine in the treatment of MDD are crossover studies, limited by small sample sizes, methodological variations, and have targeted treatment-resistant depression, thereby limiting the generalization of the findings. The effects of add-on ketamine on the currently available antidepressants have not been examined, and it is unknown whether concurrent initiation or oral antidepressant treatment with a single IV dose of ketamine could expedite antidepressant efficacy and reduce the lag of the first few weeks until clinically relevant antidepressant effects are seen with oral antidepressants. Hu et al. carried out a 4-week double-blind randomized placebo-controlled trial of single IV dose of ketamine as augmentation to escitalopram in MDD patients and found that ketamine augmentation significantly reduced time to response and remission as compared to placebo.⁸ Additional research is required to elucidate the role of ketamine as an adjunct to existing treatments. In some studies, patient were off medication;^5,9 ongoing medications were continued unchanged in others.^10,11 In this context, consideration to continue necessary antidepressant and other medications during a ketamine trial has been suggested, especially because maintenance of antidepressant treatment will be required, should the patient respond or remit.¹² Therefore, the present study is designed to determine the efficacy, safety, and tolerability of a single IV ketamine infusion as an add-on to escitalopram in patients with MDD; and its methodology is a replication of Hu et al., with few variations.

The primary hypotheses for the present study are the following: (1) rapid response (same or next day) can be achieved in patients with major (unipolar) depression; (2) rapid response (same or next day) can be sustained in patients with unipolar depression; (3) compared to placebo (0.9% IV saline), ketamine augmentation of escitalopram would be associated with significantly shorter time to antidepressant response and remission, faster and clinically significant improvements in depressive symptoms and suicidal thoughts, and acceptable tolerability.

The present study aims to determine the antidepressant effects and safety of low-dose single IV ketamine infusion (0.5 mg/kg over 40 minutes) combined with escitalopram initiation in MDD.

MATERIALS AND METHODS

GENERAL ELIGIBILITY

RESULTS

Sixty patients were randomized to a ketamine group in which patients received escitalopram 10 mg/day + IV ketamine (n = 30) and a placebo group in which patients received escitalopram 10 mg/day + 50 mL saline solution (n = 30).

DISCUSSION

The acute antidepressant efficacy of ketamine has been proven by the number of randomized controlled trials (RCTs) mainly in patients with treatment-resistant depression. But there have been only a few studies on the use of ketamine in routine clinical settings where patients are likely to be on other medications especially antidepressants. To the best of our knowledge, so far there has been one published RCT by Hu et al.⁸ to test the efficacy of ketamine as an augmentation agent to oral antidepressant medication. The present investigation is a methodological replication of the RCT by Hu et al.⁸ with certain differences. In our study, the sample size was doubled. Hu et al. had 55.6% patients with treatment-resistant depression in their study, making it difficult to generalize their results.¹² In our study, 20% of the patients were diagnosed with treatment-resistant depression.

Our study aimed to test whether single-dose IV ketamine when given with conventional oral antidepressant can speed up and augment the response of the latter. Our study differed from Hu et al. in some ways. In present investigation, IV ketamine augmentation of escitalopram showed greater response and remission as compared to placebo. Patients treated with ketamine augmentation demonstrated rapid symptom reduction as evidenced by decline in MADRS scores within 4 hours of infusion and this benefit was sustained till 4 weeks. Majority of the patients achieved response and approximately one fourth of patients achieved remission with ketamine augmentation at 28 days. Patients receiving ketamine did experience dissociative symptoms and mania-like symptoms initially, but it was transient and did not last beyond 24 hours. This finding is consistent with the observations by Zarate et al.⁹ and Murrough et al.¹⁹ but contrary to the finding of Hu et al. No clinically significant adverse effects or tolerability issues were observed in both the study groups warranting treatment discontinuation.

Standard antidepressants have proven efficacy in treating depression but the lag between initiation of drug and clinical response remains a glaring limitation. Ketamine has rapid albeit transient antidepressant effect that wears off by 10 to 12 days.²⁰ At present, there is no satisfactory strategy to prolong its efficacy except for repeated infusions.²¹ However, repeated infusions may run the risk of neurotoxicity as well potential drug abuse.²² The findings of the present investigation show that combining ketamine with escitalopram can give quicker initial response and also potentiate the response to escitalopram over 1 month while avoiding the potential pitfalls of repeated ketamine infusions. Therefore, ketamine augmentation is a potentially beneficial strategy to alleviate initial symptom distress and hasten the recovery in patients with depression.

Despite the novelty of the present RCT, the authors acknowledge certain limitations. It would be desirable to include a third comparison group of patients treated with ketamine alone. However, ethical concerns preclude this endeavor. Time to response analysis using Kaplan–Meier statistic would provide a more comprehensive understanding of the time-based clinical effects of ketamine. Further multicentric studies including groups of antidepressants may provide insight into the clinical efficacy of ketamine in conjunction with antidepressants other than escitalopram.

CONCLUSION

Single-dose IV ketamine augmentation of 10 mg/day escitalopram was efficacious, resulting in more rapid and robust response over 4 weeks. It was safe and tolerable, with dissociative and mania-like symptoms emerging post-infusion being mild and transient which do not warrant treatment discontinuation. Further research into the role of ketamine augmentation in MDD is required for its clinical applicability.

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