Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: A double-blind, randomized, controlled trial

This double-blind study (n=40) compared the efficacy and safety of oral ketamine and diclofenac as treatments of mild to moderate depression over a 6-week treatment period and found that ketamine resulted in significant reductions of depression scores above those achieved by diclofenac.

Abstract

“Background: Ketamine is a glutamate N-methyl-d-aspartate receptor antagonist capable of exerting antidepressive effects in single or repeated intravenous infusions. The objective of this study was to investigate the safety and the efficacy of oral ketamine vs. diclofenac monotherapy in reducing symptoms of mild to moderate depression among patients with chronic pain.

Methods: This study is a 6-week, randomized, double-blind, controlled, parallel-group trial with two intervention arms (ketamine, fixed daily dosage of 150 mg vs. diclofenac, fixed daily dosage of 150 mg). Twenty participants in each arm completed the trial program all of whom had two post-baseline measurements at week 3 and week 6. Reduction in depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS) and the hospital anxiety and depression subscale for depression (HADS_Depression) scores at baseline and week 3 and week 6 post-intervention.

Results: Significantly lower HDRS scores were observed in the ketamine treatment group as early as 6 weeks post-intervention (P=0.008). By comparison, mean (±standard deviation) HADS depression subscale scores were significantly lower for individuals receiving ketamine compared to diclofenac for both post-baseline measures at week 3 (6.95±1.47 vs. 8.40±1.6, P=0.005) and week 6 (6.20±1.15 vs. 7.35±1.18, p=0.003).

Limitations: The limitations of the present study were its small sample size and the short-term follow-up period. Conclusions: Oral ketamine appears to be a safe and effective option in improving depressive symptoms of patients with chronic pain with mild-to-moderate depression.”

Authors: Morteza Jafarinia, Mohsen Afarideh, Abbas Tafakhori, Mohammad Arbabi, Alireza Ghajar, Ahmad Ali Noorbala, Maryam Alamdar Saravi, Elmira Agah & Shahin Akhondzadeh

Summary

Ketamine exerts antidepressive effects in single or repeated intravenous infusions.

1. Introduction

Pain and depression comorbidities dampen the quality of treatment for each condition occurring alone, and are associated with higher rates of disability, unemployment, chronic dysfunction, and increasing economic burdens to the healthcare system.

Ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, is believed to have fast and sustained antidepressive effects by directly targeting AMPA receptors, eEF2K, mTOR activation or GSK-3 suppression.

Ketamine has been used as a dissociative anesthetic agent for several decades. However, no randomized clinical trial has evaluated the safety and efficacy of oral ketamine vs. diclofenac monotherapy in improving the symptoms of mild-to-moderate depression among patients with chronic pain.

2.1. Trial design and setting

This 6-week trial was conducted at Imam Hospital (Tehran University of Medical Sciences, Tehran, Iran) and was approved by the institutional review board. Written informed consent was obtained from all participants prior to study entry.

2.2. Trial participants

Patients with mild to moderate depression were eligible if they had a history of headache lasting at least 6 months and needed analgesic. They were also required to be mildly or moderately depressed based on having a score o 19 on the 17-item Hamilton depression rating scale.

2.3. Interventions

Eligible patients received either 50 mg ketamine thrice daily or 50 mg diclofenac three times daily for 6 weeks. Medication adherence was measured using weekly capsule counts justified against participant reports of medication intake.

2.4. Primary and secondary outcome measures

Participants were assessed using the HDRS and HADS at baseline, week 3 and week 6 post-intervention. The HADS is a well-appreciated, practical and easy-to-use 14-item auto-questionnaire producing two separate 7-item subscales assessing either depression or anxiety. Ketamine was evaluated for its efficacy in improving depressive symptoms compared with diclofenac during the trial course using the general, linear, repeated-measures model. Adverse events were systematically evaluated at each time point using a checklist.

2.5. Sample size determination

Based on a 57% response rate to oral ketamine treatment and an 18% success rate for diclofenac, a sample size of 46 was required.

A computer setup of random number generator was used to randomize participants to receive either ketamine or diclofenac. The patients, research investigators, and raters were all blinded to the treatment allocation.

3.1. Baseline characteristics of study participants

A total of 79 patients were screened for eligibility; 46 were randomly assigned to receive either ketamine or diclofenac. 40 patients completed the trial program and remained compliant to their treatment throughout the study.

3.5. Treatment response rates, remission, time to response and time to remission

At week 3 of follow-up, participants in the ketamine arm were not significantly different from those in the diclofenac arm. However, at week 6 post-intervention, participants in the ketamine arm were more likely to respond to treatment and achieve remission faster.

3.6. Adverse events

No serious adverse events or deaths were observed in the study population. One individual experienced transient loss of appetite, but no serious adverse events were observed in the diclofenac group.

4. Discussion

A 6-week double-blind, controlled and randomized clinical trial demonstrated that ketamine (50 mg capsules, three times a day) had significantly superior antidepressant effects versus diclofenac (50 mg capsules, three times a day) monotherapy in reducing symptoms of mild-to-moderate depression among chronic pain patients.

Ketamine significantly reduced depression subscale scores compared to diclofenac in patients with chronic comorbid pain at both week 3 and week 6 post-treatment. The HDRS score decreased significantly in the ketamine treatment group only 6 weeks after study commencement.

A 6-week trial of oral ketamine demonstrated greater reduction of depressive symptoms compared to a 3-week trial, which endorses the potential role of oral ketamine as a viable long-term option in depression.

Ketamine may reduce depressive symptoms by reducing levels of peripheral brain-derived neurotrophic factor, and may also induce synaptic plasticity. Further studies are warranted to determine the precise mechanisms of ketamine action to reduce depressive symptoms.

IV ketamine is occasionally associated with transient psychotomimetic effects, but no persistent or affective switches are expected. Oral ketamine is safe and well-tolerated, but repeated daily administration may cause detrimental side effects in the brain.

We have shown that oral ketamine administration is capable of exerting effective antidepressive properties previously delivered only via the IV route. This makes oral ketamine therapy a non-invasive and cost-beneficial substitute to IV ketamine therapy.

4.1. Strengths and limitations

Although the current study has several strengths, such as a randomized, double-blind, controlled design and assessment of depression with two of the most widely used clinical questionnaires, it also bears several limitations, such as a small sample size and lack of long-term results. The current study did not investigate the molecular basis of depression or the probable mechanisms responsible for the antidepressant effects of the agents used here. Furthermore, the oral bioavailability of ketamine is low and may potentially cause variable and wide-range responses in depressed individuals.

5. Conclusion

Ketamine capsules are safe and effective for treating mild-to-moderate depression in patients with chronic pain.

Acknowledgement

This study was registered in the Iranian registry of clinical trials and was supported by a grant from Tehran University of Medical Sciences.