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Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study

  • Yoav Domany (a1), Maya Bleich-Cohen (a2), Ricardo Tarrasch (a3), Roi Meidan (a4), Olga Litvak-Lazar (a5), Nadav Stoppleman (a6), Shaul Schreiber (a7), Miki Bloch (a8), Talma Hendler (a9) and Haggai Sharon (a10)...
Abstract
Background

Ketamine has been demonstrated to improve depressive symptoms.

Aims

Evaluation of efficacy, safety and feasibility of repeated oral ketamine for out-patients with treatment-resistant depression (TRD).

Method

In a randomised, double-blind, placebo-controlled, proof-of-concept trial, 41 participants received either 1 mg/kg oral ketamine or placebo thrice weekly for 21 days (ClinicalTrials.gov Identifier: NCT02037503). Evaluation was performed at baseline, 40 and 240 min post administration and on days 3, 7, 14 and 21. The main outcome measure was change in Montgomery–Åsberg Depression Rating Scale (MADRS).

Results

Twenty-two participants were randomised to the ketamine group, and 19 to the control, with 82.5% (n = 33) completing the study. In the ketamine group, a decrease in depressive symptoms was evident at all time points, whereas in the control group a decrease was evident only 40 min post administration. The reduction in MADRS score on day 21 was 12.75 in the ketamine group versus 2.49 points with placebo (P < 0.001). Six participants in the ketamine group (27.3%) achieved remission compared with none of the controls (P < 0.05). The number needed to treat for remission was 3.7. Side-effects were mild and transient.

Conclusions

Repeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in out-patients with TRD, and was well tolerated. These results suggest that add-on oral ketamine may hold significant promise in the care of patients suffering from TRD in the community.

Declaration of interest

None.

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Copyright
Corresponding author
Correspondence: Yoav Domany, 5546 East Galbraith Road, Cincinnati, Ohio 45236, USA. Email: yoavdomany@gmail.com
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These authors contributed equally to the work.

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References
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14Schoevers, RA, Chaves, TV, Balukova, SM, Rot, MA, Kortekaas, R. Oral ketamine for the treatment of pain and treatment-resistant depression. Br J Psychiatry 2016; 208: 108–13.
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26Grunebaum, MF, Galfalvy, HC, Choo, TH, Keilp, JG, Moitra, VK, Parris, MS, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry 2017: 175: 327–35.
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Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study

  • Yoav Domany (a1), Maya Bleich-Cohen (a2), Ricardo Tarrasch (a3), Roi Meidan (a4), Olga Litvak-Lazar (a5), Nadav Stoppleman (a6), Shaul Schreiber (a7), Miki Bloch (a8), Talma Hendler (a9) and Haggai Sharon (a10)...
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eLetters

Oral ketamine for treatment-resistant depression

Devavrat Harshe, Assistant Professor, Department Of Psychiatry, D Y Patil Medical College, Kolhapur. India
Yugesh Rai, MIT Core Trainee, Essex Partnership University NHS Trust, Colchester, UK.
Ramdas Ransing, Assistant Professor, Department Of Psychiatry, BKL Walawalkar Rural Medical College, Ratnagiri, India
Sachin Nagendrappa, Junior Resident, Department Of Psychiatry, National Institute Of Mental Health And Neurosciences, Bengaluru, India.
Chittaranjan Andrade, Professor & Head, Department Of Psychopharmacology, National Institute Of Mental Health & Neurosciences, Bengaluru, India.
13 February 2019

Sir,

Domany et al (1) reported the first randomized controlled trial (RCT) of oral ketamine in outpatients with treatment-resistant depression. A discussion of the paper in eJCIndia (2) led to the identification of several concerns that we briefly explain.

The authors described sample size estimation for clinical improvement in a test-retest design, something that is incorrect when their objective was to conduct an RCT; they should have powered the study for a hypothesis related to a parallel group design. They did not state how drop outs and missing data were handled in the analysis. They stated that “remission and response were analysed using t-tests for independent samples”; surely they meant that remission and response were compared between groups using the Chi square test?

They made no attempt to blind subjects to the bitter taste of ketamine (3) with a masking agent in the placebo group, something that would have been quite easy to do. Although they stated that “at day 28 the effect was maintained with the MADRS scores still significantly lower than baseline”, they provided no data in support.

In their discussion, they wrongly stated that Al Shirawi et al (4) used ketamine in the dose of 50 mg; this was actually only a starting dose, and patients could receive a dose of as much as 300 mg (the mean dose in the study was 222 mg). Finally, and on a minor note, they repeatedly stated that ketamine has an unstable oral bioavailability. Perhaps ‘poor and variable’ would have been a more appropriate phrase than ‘unstable’.

References:

1 Domany Y, Bleich-Cohen M, Tarrasch R, Meidan R, Litvak-Lazar O, Stoppleman N et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry 2019; 214:20-26.

2 Thakurdesai A, Ghosh A, Menon V, Sahoo S, Tripathi A, Harshe D, Andrade C. Electronic journal clubs for capacity building: A case study in psychiatry as a model for medical disciplines in developing countries. Asian J Psychiatr. 2018; 34:93-97.

3 Andrade C. Ketamine for depression, 4: In what dose, at what rate, by what route, for how long, and at what frequency? J Clin Psychiatry 2017; 78: e852-57.

4 Al Shirawi MI, Kennedy SH, Ho KT, Byrne R, Downar J. Oral ketamine in treat- ment-resistant depression: a clinical effectiveness case series. J Clin Psychopharmacol 2017; 37: 464–7.

... More

Conflict of interest: None declared

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Potential Differences in Antidepressant Effects of Oral Ketamine Liquid Suspension Versus Compounded Capsules

Joshua Daniel Rosenblat, Chief Resident of Psychiatry, Clinician Scientist Program, University of Toronto
13 February 2019

To the Editors:

It was with great interest that I read the recent article by Domany et al. (2019) regarding the antidepressant effects of oral ketamine in treatment resistant depression (1). In brief, the authors found a rapid and robust antidepressant effect of oral ketamine (liquid suspension 1mg/kg thrice weekly) compared to placebo, with clinically and statistically significant antidepressant effects observed within 40 minutes of the first dose. These robust effects persisted over the course of the 21-day trial with a between group difference in Hamilton Depression Rating Scale (HRDS) scores of 10.2 in favour of ketamine versus placebo on day 21 compared to baseline. These results strongly differ compared to previous randomized controlled trials (RCTs), which demonstrated minimal benefits of oral ketamine compared to controls (2,3). Jafarinia et al. (2016) found no significant improvements after 3 weeks of treatment (p=0.12). At week 6, a small between group difference of only 2.8 on the HDRS was observed (p=0.017) [minimal clinically important difference (MCID) of the HDRS is >3] (2). Similarly, Arabzadeh et al. (2018) found minimal benefit of oral ketamine compared to placebo over the course of their 6-week trial, with between group difference in HDRS scores of only 3.4 (week 2), 2.6 (week 4) and 1.9 (week 6) in favour of ketamine, below the MCID for the HDRS (3). The between group difference on the HDRS of only 2-3 observed by Jafarinia et al. and Arabzadeh et al. is in stark contrast with the >10-point difference found by Domany et al. (1-3).

Numerous factors may explain the differences in outcomes, namely, differences in samples (e.g., level of treatment resistance, baseline depressive symptom severity, psychiatric and medical comorbidity and demographic factors), the intervention (e.g., different ketamine doses and dosing schedules) and study design (e.g., adequate blinding, characteristics of control group and other sources of study bias). These factors are fairly generalizable to comparing study results for any intervention, however, oral ketamine may have an additional important factor to consider, namely, the use of oral capsules versus a liquid oral suspension. Notably, Domany et al. used a liquid oral suspension and had rapid and robust antidepressant effects. Conversely, Jafarinia et al. and Arabzadeh et al. used capsules with limited antidepressant effects. Moreover, the effects reported in open label trials, retrospective chart reviews, case series and case reports similarly show a fairly consistent pattern of limited effects with ketamine capsules with potent effects with the oral liquid suspension (4,5).

Numerous factors may explain the differences in outcomes of capsules versus liquid suspension, including pharmacokinetic differences, which may be particularly important for ketamine, as the rate of infusion plays an important role in both efficacy and adverse effects for intravenous ketamine, suggesting there may be an optimal ‘effective infusion rate,’ which might differ with liquid (increased immediate bioavailability with some sublingual absorption as well) versus capsules. Alternatively, the observation of differential antidepressant effects with liquid suspension versus capsule might be entirely spurious and better explained by the other differences in samples, dosing and study design. Functional unblinding of the participants may also be a factor as the liquid suspension is bitter (in the absence of added flavour), whereas the capsules are tasteless. Nevertheless, investigators and clinicians should not assume the effects of liquid versus capsules of ketamine are equivalent.

References:

1 Domany Y, Bleich-Cohen M, Tarrasch R, Meidan R, Litvak-Lazar O, Stoppleman N, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. The British Journal of Psychiatry 2019; 214: 20–6.

2 Jafarinia M, Afarideh M, Tafakhori A, Arbabi M, Ghajar A, Noorbala AA, et al. Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: A double-blind, randomized, controlled trial. Journal of Affective Disorders 2016; 204: 1–8.

3 Arabzadeh S, Hakkikazazi E, Shahmansouri N, Tafakhori A, Ghajar A, Jafarinia M, et al. Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial. Journal of Affective Disorders 2018; 235: 236–41.

4 Al Shirawi MI, Kennedy SH, Ho KT, Byrne R, Downar J. Oral Ketamine in Treatment-Resistant Depression: A Clinical Effectiveness Case Series. J Clin Psychopharmacol 2017; 37: 464–7.

5 Schoevers RA, Chaves TV, Balukova SM, Rot M aan H, Kortekaas R. Oral ketamine for the treatment of pain and treatment-resistant depression. The British Journal of Psychiatry 2016; 208: 108–13.

... More

Conflict of interest: None declared

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Is ketamine read for outpatient use as antidepressant?

Weiwei Wu, Department of Neurology, Union Hospital, Fujian Medical University
Qingguo Zhu, Fujian Provincial Clinical College, Fujian Medical University; Department of Urology, Fujian Provin
Liefu Ye, Fujian Provincial Clinical College, Fujian Medical University; Department of Urology, Fujian Provin
Yongbao Wei, Fujian Provincial Clinical College, Fujian Medical University; Department of Urology, Fujian Provin
Tao Li, Fujian Provincial Clinical College, Fujian Medical University; Department of Urology, Fujian Provin
04 February 2019

Domany et al.1 designed a small number of randomized clinical trial including 41 patients with resistant depression and gave them oral ketamine or placebo, and they concluded repeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in these outpatients1. In fact, this is a great try for ketamine use for outpatients. However, in our opinion, outpatient use of ketamine may be only a pretty fantasy and it is not a good opportunity in a real word right now.

Indeed, accumulating researches confirmed the rapid antidepressant effect of ketamine2 . And it seems patients benefit from in its low-dose and short-term use without causing too much negative impacts2. Even ketamine is considered as the most important discovery in depression treatment during the past half century. However, these researchers seem to be a bit over-optimistic about ketamine in depression treatment. First, the lifetime prevalence of depression is 1.5% to 19.0% and the 12 months prevalence of chronic type is 9.3-23.0%3 . This means a large number of patients may need to take the drug for a long time or even for a lifetime. But drug resistance may happen, and the therapeutic effect of ketamine declined with its increasing uses. Then a larger dosage or longer time of ketamine may be needed to enhance its treatment effect, ketamine thus may be likely abused and addiction happens. These indicate the current principle of ketamine may not meet the actual clinical needs, conversely, the harm becomes unpredictable. Second, even a short-term use cause lots of adverse effects. Multiple acute and chronic side effects were reported by 92% and 20% studies, respectively2 . Unlike other diseases may only affect the patient and the family, outpatient use of ketamine may pose a serious public threat. Even a dose can increase the risk of a traffic accident4 . For the patient of long-term use over even 3 months, it may cause multiple system damages and bring tough problems. Take urinary system for example, ketamine not only causes lower urinary symptoms, but also bladder contracture, resulting in bladder augmentation or cystectomy. It affects renal function as well, bringing renal disfunction and even uremia. Even it makes the possibility of bladder tumor5 . Repeated ketamine uses will make the above problems progressively aggravated. We have accounted a lot of such cases, and even a patient of 28 years old suffered from brain atrophy, then uremia, myasthenia and aphasia, and finally died from multiple organ failure after chronic ketamine abuse. Finally, but most importantly, supervision loopholes exist in the management of outpatients treated with ketamine. Thus, the tragic story of "Mr. A" happened6. Unfortunately, still no effective measure has been established to avoid this tragedy and more “Mr. As” will emerge.

We think ketamine is not read for outpatient use unless its potential side effects of abuse is solved and effective measures of supervision are launched. Another possibility is that a new antidepressant may be discovered and give a more promise future alongside the mechanism of ketamine further revealed.

Acknowledgments:

This study was supported by Joint Funds for the Innovation of Science and Technology, Fujian province (2017Y9064).

Email: weiyb2008@163.com (Wei Yongbao) or taoli_1974@sina.com (Li Tao).

References:

1 Domany Y, Bleich-Cohen M, Tarrasch R, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry 2019; 214:20-26

2 Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry 2018; 5:65-78

3 Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health 2013; 34:119-138

4 Hayley AC, Green M, Downey LA, et al. The acute and residual effects of escalating, analgesic-range doses of ketamine on driving performance: A simulator study. Prog Neuropsychopharmacol Biol Psychiatry 2018; 86:83-88

5 Zhong D, Yu F, Chen J, et al. Bladder leiomyosarcoma in a patient with chronic ketamine abuse: A case report. Can Urol Assoc J 2015; 9:E514-E516

6 Schak KM, Vande VJ, Johnson EK, et al. Potential Risks of Poorly Monitored Ketamine Use in Depression Treatment. Am J Psychiatry 2016; 173:215-218
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Conflict of interest: None declared

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