Authors Accepted Manuscript

Efficacy and Safety of Oral Ketamine versus

Diclofenac to Alleviate Mild to Moderate
Depression in Chronic Pain Patients: A DoubleBlind, Randomized, Controlled Trial
Morteza Jafarinia, Mohsen Afarideh, Abbas
Tafakhori, Mohammad Arbabi, Alireza Ghajar,
Ahmad Ali Noorbala, Maryam Alamdar Saravi,
Elmira Agah, Shahin Akhondzadeh

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DOI:
Reference:

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S0165-0327(16)30620-6
http://dx.doi.org/10.1016/j.jad.2016.05.076
JAD8290

To appear in: Journal of Affective Disorders

Received date: 15 April 2016
Revised date: 30 May 2016
Accepted date: 31 May 2016
Cite this article as: Morteza Jafarinia, Mohsen Afarideh, Abbas Tafakhori,
Mohammad Arbabi, Alireza Ghajar, Ahmad Ali Noorbala, Maryam Alamdar
Saravi, Elmira Agah and Shahin Akhondzadeh, 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, http://dx.doi.org/10.1016/j.jad.2016.05.076
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Efficacy and Safety of Oral Ketamine versus Diclofenac to Alleviate Mild to Moderate
Depression in Chronic Pain Patients: A Double-Blind, Randomized, Controlled Trial
Morteza Jafarinia11, Mohsen Afarideh21, Abbas Tafakhori3; Mohammad Arbabi2,

Alireza

Ghajar2, Ahmad Ali Noorbala1; Maryam Alamdar Saravi1; Elmira Agah3; Shahin Akhondzadeh2*
1

Psychosomatic Research Center, Imam Khomeini Hospital, Tehran University of Medical

Sciences, Tehran, Iran

2

Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences,

Tehran, Iran
3

Iranian Center of Neurological research, Tehran University of Medical Sciences, Tehran, Iran

Correspondence to: Shahin Akhondzadeh,

Psychiatric Research Center, Roozbeh

Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Street, Tehran
13337, Iran. Fax: (+9821)-55412222, Tel: (+9821)-55419113. E-mail: s.akhond@neda.net

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

The first two authors contributed equally to this work.

1

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 postbaseline 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.
Keywords: Oral Ketamine; Diclofenac; Depression; Randomized Controlled Trial
INTRODUCTION
Common pain and depression comorbidities dampen the quality of treatment for each condition
occurring alone. Close to 65% of patients, presenting with depression as the main complaint,
report one or more episodes of pain. Depression is found among 5% to 85% of patients with
recurring pain (Bair et al., 2003).

A recent study found concurrent pain and depressive

symptoms, compared to depression alone, is associated with significantly higher rates of

disability, unemployment, chronic dysfunction, and increasing economic burdens to the
healthcare system (Emptage et al., 2014).
Studying the role of dysregulated glutamatergic system in depression has been receiving growing
attention recently (Naughton et al., 2014).

Regarding the neurobiological mechanisms

underlying fast and sustained antidepressive effects of ketamine, a glutamate N-methyl-Daspartate (NMDA) receptor antagonist, mild and transient psychotomimetic and dissociative
effects are produced 30-40 minutes immediately after application that completely disappear by
40-50 minutes subsequently (Zarate et al., 2006).

Following this first-pass premature

metabolism, antidepressive properties slowly develop at 110 minutes and last for about 7 days
(Zarate et al., 2006). This rapid onset of sustained mechanism of action denotes activation of a
cascade of events involved in the pathophysiology of clinical depression, presumably by directly

targeting AMPA receptors, eEF2K, mTOR activation or GSK-3 suppression (Naughton et al.,
2014).
The injectable form of ketamine has been marketed as a dissociative anesthetic agent for several
decades (Hatton et al., 2013). Since the turn of the century, subanaesthetic doses of intravenous
(IV) ketamine were extensively delineated in treatment of depressive symptoms in single or
repeated infusions (Naughton et al., 2014, McGirr et al., 2015). Despite clear antidepressive
benefits provided by repeated ketamine infusions in a host of previous randomized controlled
trials, a major criticism was directed at the short lived efficacy of this delivery route (McGirr et
al., 2015).

Moreover, greatly owing to the challenges in using hospital-based settings in

otherwise uncomplicated depressive patients, especially for repeated IV ketamine infusions or

practicality any other delivery method, a search for better tolerated and easier to use alternatives
is underway. Recently, research has emerged on the safety and efficacy of intranasal (Lapidus et
al., 2014) or sublingual (Lara et al., 2013) ketamine in refractory depressive episodes. As far as
our understanding however, no randomized clincial trial has evaluated comparative safety and
efficacy of daily oral ketamine in improving the symptoms of depression secondary to chronic
and persistent somatoform pain.
Thus, we aimed to investigate the 6-week safety and efficacy of oral ketamine vs. diclofenac
monotherapy in reducing symptoms of mild-to-moderate depression among patients with chronic
pain.

MATERIAL AND METHODS

Trial Design and Setting

This 6-week, randomized, double-blind, controlled, parallel-group trial was conducted in the
outpatient clinic of Imam Hospital (Tehran University of Medical Sciences, Tehran, Iran)
between January 2015 and December 2015. The institutional review board (IRB) approval for
the trial protocol was formally obtained from the Tehran University of Medical Sciences Board
of Ethics (Grant No: 28734). This trial was conducted according to the tenets laid down in the
Declaration of Helsinki. Written informed consent was obtained from all participants prior to
study entry.

The participants were free to withdraw from the study at any time without

compromising their relationship with their health care provider. The trial was registered at the
Iranian registry of clinical trials (www.irct.ir; trial identifier with the IRCT database:
IRCT201508201556N80).

Trial Participants

Eligible male and female patients, aged 20 to 55 years, had a diagnosis of chronic and persistent
mild-to-moderate headache lasting at least for the preceding 6 months and need for analgesic.
None of the participants had a comorbid malignant or benign tumor diagnosed before or during
the course of this trial. Diagnosis of major depression was established according to the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IVTR).
Patients were required to be mildly or moderately depressed based on having a score < 19 in the 17-

item Hamilton depression rating scale (HDRS) (Hamilton, 1960).

Exclusion criteria were as follows: Receiving any antidepressant medication during the previous
month, receiving electroconvulsive therapy (ECT) during the last two months, diagnosis of other
mental disorder on the DSM-IV axis I, alcohol or substance (with the exception of nicotine)
dependence, severe depression or suicidal ideation (those who were judged to have substantial
risk for suicide by the physician or score >2 on the suicide item of the HDRS), history of
intolerability, hypersensitivity, or allergy to ketamine, history of cardiovascular disease (upon
high clinical suspicion for cardiovascular disease, electrocardiogram monitoring was performed
and positive findings were excluded), current use of theophylline, memantine, or MAOIs; history
of cerebral aneurysms; glaucoma; any intracranial mass; use of medications with significant
drug-drug interactions with ketamine; or increased intracranial pressure; thyroid disease or
cancer and were pregnant or lactating women.

Interventions

Eligible patients randomly received either 50 mg ketamine (50 mg capsules) thrice daily or 50
mg diclofenac three times daily (50-mg capsules) in the same manner for 6 weeks. Formulation
of ketamine capsules used in this study are delineated elsewhere (Yanagihara et al., 1999).
Participants were not allowed to use any other psychotropic medication or undergo behavioral
intervention therapy during the trial course. Medication adherence was measured using weekly
capsule counts justified against participant reports of medication intake to calculate the
proportion of dispensed medication doses that were actually ingested.

Primary and Secondary Outcome Measures

Participants were assessed using the HDRS and the hospital anxiety and depression scale
(HADS) scores at baseline and at week 3 and week 6 post-intervention. HDRS is a validated 17item rating scale that has been widely applied in psychiatric research to measure the severity of
depressive symptoms and also has been used and validated to evaluate treatment efficacy and
severity of depressive symptoms in several clinical trials in Iran (Gharaei et al., 2000 , ). By
comparison, the hospital anxiety and depression scale (HADS) is a well-appreciated, practical
and easy-to-use 14-item auto-questionnaire (Herrmann, 1997) producing two separate 7-item
subscales assessing either depression (HADS subscale for depression) or anxiety (HADS
subscale for anxiety) (Herrmann, 1997, Bjelland et al., 2002, Poole and Morgan, 2006). Based
on the development of depressive symptoms during the preceding week, each question is rated
on a four-point Likert-like scale with the total scale on each subscale potentially rising up to a
maximum total of 21 which indicates the highest depression severity (Johnston et al., 2000,
Herrero et al., 2003). The visual analogue scale (VAS) was used to measure pain intensity (0 to
100, from no pain to worst possible pain). The primary outcome measure was to evaluate
the efficacy of ketamine in improving depressive symptoms compared with diclofenac during the
trial course using the general, linear, repeated-measures model.

The secondary outcome

measures of this trial were achieved by comparison of changes in HDRS scores from baseline to
each time point, response to treatment (defined as 50% reduction in the HDRS score),
remission (defined as HRDS score 7), and severity of pain intensity between the treatment
groups and evaluation of the antidepressant effects of each drug separately. Adverse events were
systematically evaluated at each time point using a checklist. Furthermore, patients were first
asked an open-ended question about any adverse event that was not mentioned on the checklist.

Patients were also asked to immediately inform the research team of any unexpected symptoms
during the course of the trial.
Sample Size Determination

A total sample size of 42 (21 in each arm) was required based on a 57% response success rate to
oral ketamine treatment in the preliminary report of Irwin et al. (Irwin et al., 2013), an 18%
success rate for diclofenac observed in the pilot run of our trial, a two-sided significance level ()
of 5%, and a power of 80%. Assuming a 10% attrition rate, a final sample size of 46 was
calculated.

Protocol of Randomization and Drug Allocation

A computer setup of random number generator was used for randomizing participants to receive
either ketamine or diclofenac by an independent party (allocation ratio 1:1, blocks of four).
Sequentially numbered, sealed, opaque and stapled envelopes were used to conceal treatment
allocations. Aluminum foil placed inside the envelope rendered the envelope content
impermeable to intense light. The study participants, research investigators, and raters were all
blinded to the treatment allocation. Ketamine and diclofenac capsules were indistinguishable
judging by size, shape, color, texture, or odor. At the end of the trial, patients and raters were
asked to guess whether each patient had received ketamine or diclofenac.

Statistical Methods

Statistical Package for the Social Sciences (SPSS Version 19.0. IBM Corp, Release 2010, IBM
SPSS Statistics for Windows, Armonk, NY: IBM Corp) was used for statistical analysis. All
analyses were performed based on the intention-to-treat principles with two post-baseline
measurements. Continuous and categorical data are reported as mean standard deviation (SD)
and number (%) of total participants. Baseline continuous variables were compared using the
independent t-test. The mean difference (MD) between the ketamine and diclofenac groups was
reported as MD (95% CI). A two-factor repeated-measures analysis of variance (ANOVA) was
used to evaluate Time Treatment interaction. Results of Greenhouse-Geisser adjustment were
reported if Mauchlys test of sphericity was significant. To compare score changes from baseline
to each time interval between the two trial arms, the independent t-test and Cohens d effect size
were used. VAS scores were compared across the treatment groups using independent t test at
baseline and at study conclusion. The paired t-test was used to compare HDRS scores at baseline
with each time point in each group. Categorical variables were compared using the 2 test or
Fishers exact test. KaplanMeier estimation with log-rank test was used for comparison of the
time needed to partially respond to treatment between groups. P values <0.05 were considered
the bare minimum to flag statistically significant correlations.

RESULTS
Baseline Characteristics of Study Participants

A total of 79 patients were screened for eligibility; of whom 46 patients were randomly assigned
to receive either ketamine (n = 23) or diclofenac (n =23); 40 patients (divided into 2 equal groups
of 20 for each arm) completed the trial program and remained compliant to their treatment
9

during the course of the study, all of whom had two post-baseline measurements at week 3 and
week 6 (Figure 1). As all dropped out were before week 3, the analysis was performed on 40
patients (20 in each group). As summarized in Table 1, baseline recorded data were comparable
between ketamine or diclofenac treatment arms. During the study, no participating patient
reported discontinuation of medication.
HDRS Score.

Baseline HDRS scores were not significantly different between the ketamine and the diclofenac
intervention groups: mean difference (MD) (95%CI) = 0.50 (1.58 to 1.68); t(38) = 0.062; P
value = 0.951 (Table 1). Two-factor repeated-measures ANOVA demonstrated significant effect
for Time Intervention interaction term on HDRS scores during the course of study: F(2, 76) =
3.406; P value = 0.038 (Figure 2). Improvements in HDRS scores were not significantly
different between treatment groups at week 3 (HDRS reduction for ketamine vs. diclofenac: 5.55
3.86 vs. 3.70 3.42; mean difference: ketaminediclofenac (95% CI): 1.85 (0.48 to 4.18);
Cohens d: 0.51; P Value = 0.117). However, significantly different improvements in HDRS
were observed between treatment groups 6 weeks post-intervention (HDRS reduction for
ketamine vs. diclofenac: 6.95 3.86 vs. 4.10 3.34; mean difference: ketaminediclofenac
(95% CI): 2.85 (0.54 to 5.16); Cohens d: 0.79; P Value = 0.017; Figure 2 and 3).
HADS Subscale for Depression Score.

A two-factor generalized linear Model (GLM) repeated measures on the HADS subscale for
depression score (effect: Time Treatment interaction term) demonstrated a significant reducing
effect on severity of depressive symptoms (F2,76 = 7.77, P value = 0.001, Figure 4). Similar to the
HRDS score, there was no statistically significant difference at baseline of the HADS subscale
10

for depression scores between the ketamine and the diclofenac arms [9.45 1.47 vs. 9.05 1.60;
respectively, MD (95% CI) = 0.40 (0.58 to 1.38), t (38) = 0.82, P value = 0.416]. Score
reductions in HADS depression subscale were significantly greater in the ketamine group by
week (HADS subscale for depression score reduction for ketamine vs. diclofenac: 2.10 0.72 vs.
1.05 1.10; mean difference: ketaminediclofenac (95% CI): 1.05 (0.45 to 1.64); Cohens d:
1.13; P Value = 0.001) and 6 (HADS subscale for depression score reduction for ketamine vs.
diclofenac: 2.85 1.04 vs. 2.10 0.72; mean difference: ketaminediclofenac (95% CI): 0.75
(0.18 to 1.32); Cohens d: 0.84; P Value = 0.012) after intervention (Figure 3 and 4).
VAS Score.

There was no significant difference between the mean VAS scores for ketamine and diclofenac
arms at baseline, 3 weeks post-treatment and at the study end point (72 17.95 vs. 69.50
18.77, P value = 0.669, 55.70 29.91 vs. 55.35 30.07, P value = 0.960, 55.25 26.08 vs. 49.95
30.58, P value = 0.577; respectively, Table 1 and Figure 5). Analysis of GLM repeatedmeasure ANOVA confirmed the effect size of Time Treatment was not significant throughout
the trial period (F1.71, 64.84=0.289, P value = 0.715). Mean (95%CI) difference of changes in the
VAS score between ketamine and diclofenac intervention groups were not statistically different
at week 3, or the study endpoint at week 6 (16.30 17.86 vs. 14.25 14.17; mean difference:
ketaminediclofenac (95% CI): 2.05 (8.27 to 12.37); Cohens d: 0.13; P Value = 0.690 and
16.65 22.67 vs. 19.55 24.69; mean difference: ketaminediclofenac (95% CI): 2.90 (18.07
to 12.27); Cohens d: 0.12; P Value = 0.701; respectively; Figure 3 and 5).
Treatment Response Rates, Remission, Time to Response and Time to Remission.

11

At week 3 of follow-up, the higher number of participants responding to treatment (i.e., 50%
reduction in the HDRS score) in the ketamine arm was not significantly different from the
diclofenac arm although participants in the ketamine arm were more likely to respond to
treatment (P value = 0.008, odds ratio for response: 8.50) 6 weeks post-intervention. Similarly,
significantly higher remission rates (i.e., HDRS 7) were observed for the ketamine group at
week 6 post-treatment (P value =0.031 but not 3 weeks after intervention (Figure 6). Average (
SD) time to response and time to remission intervals in the entire study population were 5.17
0.22 and 5.47 0.19, respectively. Using Kaplan-Meier estimate curves, we observed
participants in the ketamine arm displaying significantly shorter time to response periods
compared with those consuming diclofenac (mean SD time to response: 4.80 0.34 vs 5.55
0.28 weeks, respectively; Log-Rank P value = 0.002). Moreover, patients who were on the
ketamine capsule also achieved significantly faster times to remission (5.25 0.30 vs. 5.70
0.23; Log-Rank P value = 0.013).
Adverse Events.

Frequencies of observed adverse outcomes were not significantly different between intervention
groups (Table 2). No symptom of adverse cardiovascular event occurred in the study population,
which was confirmed by physical examination and normal ECG recordings. No serious adverse
events or deaths were observed. Blurred vision, tremor and abdominal pain affected one
individual in both trial arms. A Transient loss of appetite was the only complication to occur in
one of the patients from the ketamine intervention group, but this did not occur in individuals
receiving diclofenac during the study. No discontinuation of treatment was observed due to drug
adverse events.

12

DISCUSSION
Results from the current 6-week double-blind, controlled and randomized clinical trial
demonstrate significantly superior antidepressant effects (as assessed by the primary outcome
measures, HRDS and HADS subscale for depression scores) for ketamine (50-mg capsules, three
times a day) versus diclofenac (50-mg capsules, three times a day) monotherapy. To the best of
our knowledge, this is the first controlled trial study to support comparative efficacy and safety
of daily oral ketamine administration in reducing symptoms of mild-to-moderate depression
among chronic pain patients. Patients receiving ketamine as treatment for depression achieved
greater response to treatment ( 50% reduction in the HDRS score) and greater remission
(HDRS score 7) rates compared with individuals taking diclofenac as their antidepressant. The
analgesic efficacy for ketamine and diclofenac was comparable as assessed by pain VAS scoring.
The use of both ketamine and diclofenac appeared to be safe and well tolerated, and no serious
adverse event was reported in any of the patients in either groups. Since baseline characteristics
of patients between the trial arms did not differ significantly, this factor is unable to explain the
greater beneficial effect of ketamine on depressive symptom reduction compared with
diclofenac.
Reductions in HADS depression subscale scores were significantly higher in the ketamine arm at
both week 3 and week 6 post-treatment, whereas the HDRS score decreased significantly in the
ketamine treatment group only 6 weeks after study commencement. The HADS depression
subscale score has been developed for use as a valuable screening asset to apply in nonpsychiatric hospital wards (Zigmond and Snaith, 1983). However, the simplicity of HADS has
13

extended its use to outpatient and community settings during the past decade (Dunbar et al.,
2000, Caci et al., 2003). Interestingly, HADS subscale for depression questionnaire revolves
mostly around the component of anhedonia and excludes physical indicators of a depressive
episode (Poole and Morgan, 2006); which may cause unnecessary challenges to assess
depression due to chronic somatic disorders, including chronic pain in our study. Use of HRDS
in the current study complements HADS by additional evaluation of physical parameters of
psychological distress such as dizziness, lethargy, headaches, insomnia, and fatigue (Samaras et
al., 2013). Taken together, our findings serve to suggest broad-spectrum antidepressive
properties of ketamine compared to diclofenac in patients with chronic comorbid pain. However,
this hypothesis needs to be further tested in larger parallel group randomized trials with and
without the use of placebo as the control group.
The current study extends the previously reported literature data by demonstrating more
sustained and prolonged antidepressant effects during a 6-week long trial of oral ketamine,
compared to a 28-day study reported by one previous study of oral ketamine therapy to reduce
symptoms of anxiety and depression (Irwin et al., 2013) in which it took days and up to a week
to see effects of single or repeated infusions of IV ketamine (Aan Het Rot et al., 2012). Very
low dose sublingual ketamine reportedly provides higher bioavailability compared to oral
ketamine (30% vs. 17%, respectively), but no objective data is available on the long-term
duration of action for sublingual ketamine (Lara et al., 2013). Surprisingly, we demonstrated
greater reduction of depressive symptoms by week 6 compared to week 3 post-treatment, which
further endorses the potential role of oral ketamine as a viable long-term option in depression.

14

Currently, precise mechanisms of ketamine action to reduce depressive symptoms are poorly
understood (Aan Het Rot et al., 2012). Chronically depressed patients demonstrate elevated
levels of peripheral brain-derived neurotrophic factor in response to NMDA receptor antagonists,
including ketamine (Haile et al., 2014). This role of ketamine to produce strong neuroplastic
alterations in animal models {Duman and Aghajanian, 2012) may also provide a rationale to
further investigate long-term efficacy of ketamine in treatment of depression. Interestingly,
NMDA receptor agonistic properties may also induce synaptic plasticity. For instance, oral
sarcosine (Huang et al., 2013) and D-cycloserine (Heresco-Levy et al., 2013) (both NMDA
receptor agonists) have been shown to exert antidepressive properties in patients with refractory
depression. Given the dual NMDA receptor features on depressive symptoms, McGirr and
colleagues postulated that NMDA-dependent cellular mechanisms are exquisitely finely tuned
(McGirr et al., 2015). As such, prior to assessment of add-on ketamine therapy on existing
treatments for depression, further studies in this area are warranted to determine proposed
mechanistic effects of ketamine on depression.
IV Ketamine is occasionally associated with transient psychotomimetic effects, but no persistent
or affective switches are expected (McGirr et al., 2015). We administrated oral ketamine with a
fixed daily dosage of 150 mg over a period of 6 weeks. Herein and in accordance with previous
observations (Lapidus et al., 2014, Lara et al., 2013, Irwin et al., 2013), this regimen was safe
and well-tolerated with no serious adverse events. However, repeated daily administration of
ketamine may cause detrimental side effects in the brain. A recent study showed that repeated
intermittent administration of esketamine (S-ketamine), but not R-ketamine, cause loss of cells
with positive parvalbumin (PV)- immunoreactivity in the medial prefrontal cortex which may be

15

associated with psychosis (Yang et al., 2016). As such, R-ketamine appears to be a safer option
for the possible widespread treatment of depression, particularly in the long term,
By confirming the preliminary findings of Irwin et al. (Irwin et al., 2013), we have shown that
oral ketamine administration is capable of exerting effective antidepressive properties previously
delivered only via the IV route. Oral ketamine therapy, as a non-invasive and cost-beneficial
substitute to IV ketamine, obviates common complications associated with repeated infusions of
ketamine, easily produces a clinically meaningful and sustained response over a significant
period of time and is generally highly-accepted by receiving patients in psychiatry. For instance,
painful phlebitis, as a less common complication of chronic IV placement (Macklin, 2003), could
potentially exacerbate an already dreadful state of affairs in comorbid pain and depression,
which underlines the need for finding a non-IV form of ketamine in treatment of patients with
mild-to-moderate depression that is secondary to chronic pain.
Strengths and Limitations

Despite the potential strengths of this study, namely the randomized, double-blind, controlled
design and assessment of depression with two of the most widely used clinical questionnaires
(i.e., HDRS and HADS); this study bears several limitations which should be addressed to
preclude overgeneralization of the findings. Firstly, the sample size was relatively small. This
made it impossible to perform subgroup analyses by demographic data and assessment of the
probable role of different clinical features such as type of headache. Secondly, the current study
also does not offer long-term results of depression treatment by oral ketamine. Depression is
well-known to chronically affect predisposed subjects with a very high probability of relapse and
recurrence (Otte et al., 2012) even more so in those with comorbid and chronic pain (Linton and
16

Bergbom, 2011). Indeed, randomized studies are particularly encouraged to assess whether
long-term antidepressant effects of oral ketamine are as promising as early findings (Irwin et al.,
2013). This also holds true to the side effects that may be observed with greater frequencies in
the long run. Thirdly, since we did not investigate the molecular basis of depression and the
probable mechanisms responsible for the antidepressive effects of the agents used here, it is not
possible to investigate the probable causative relationships. We suggest future studies should
undertake the task of identifying possible short-term and long-term modulators of depression as
activated by ketamine through more elaborately designed studies of cell signaling pathways.
Moreover, oral bioavailability of ketamine has been demonstrated to be comparatively low
(around 17%) due to the rapid first pass metabolism and high conversion into the metabolite
norketamine (Clements et al., 1982). This may potentially cause variable and wide-range
responses in depressed individuals who are receiving daily oral ketamine as their antidepressant.
Finally our study did not target to measure the abuse potential of daily oral ketamine
administrations. This is particularly important in future studies with longer follow-up periods as
repeated use of ketamine can be of high abuse potential in rodents and humans (Dotson et al.,
1995).
CONCLUSION
In conclusion, we have demonstrated oral administration of 50 mg ketamine capsules three times
per day and this appears to be a safe and effective option in improving depressive symptoms of
patients with chronic pain with mild-to-moderate depression. Further studies with larger sample
sizes and longer follow-up durations are warranted to confirm our findings.
Acknowledgement
17

The trial was registered in the Iranian registry of clinical trials (www.irct.ir Registration number:
IRCT201508201556N80). This study was Dr. Morteza Jafarinias postgraduate thesis toward the
Fellowship of Psychosomatic. Current study complies with contemporary laws and regulations in
Iran. The study was supported by a grant from Tehran University of Medical Sciences to
Professor Shahin Akhondzadeh (Grant number: 28734).
Conflict of interest:
the authors declare no conflict of interest.
References:
Aan Het Rot, M. , Zarate CA, Jr., Charney, D.S., Mathew, S.J., 2012. Ketamine for depression:
where do we go from here? Biol. Psychiatry72(7), 537-547.
Bair, M.J., Robinson, R.L., Katon, W., Kroenke, K., 2003. Depression and pain comorbidity: a
literature review. Arch. Intern. Med. 163(20), 2433-2445.
Bjelland, I., Dahl, A.A., Haug, T.T., Neckelmann, D., 2002. The validity of the Hospital Anxiety
and Depression Scale: an updated literature review. J. Psychosom. Res. 52(2), 69-77.
Caci, H., Bayl, F.J., Mattei, V., Dossios, C., Robert, P., Boyer, P., 2003. How does the Hospital
and Anxiety and Depression Scale measure anxiety and depression in healthy subjects?
Psychiatry Res. 118(1), 89-99.
Clements, J.A,, Nimmo W.S,, Grant I.S., 1982. Bioavailability, pharmacokinetics, and analgesic
activity of ketamine in humans. J. Pharm. Sci. 71(5), 539542.

18

Dotson, J.W., Ackerman D.L., West L.J., 1995. Ketamine abuse. J. Drug. Issues. 25(4), 751-757.
Duman, R.S., Aghajanian, G.K., 2012. Synaptic dysfunction in depression: potential therapeutic
targets. Science338(6103), 68-72.
Dunbar, M., Ford, G., Hunt, K., Der, G., 2000. A confirmatory factor analysis of the Hospital
Anxiety and Depression scale: comparing empirically and theoretically derived structures. Br. J.
Clin. Psychol. 39(1), 79-94.
Emptage, N.P., Sturm, R., Robinson, R.L., 2014. Depression and comorbid pain as predictors of
disability, employment, insurance status, and health care costs. Psychiatr. Serv.56(4), 468-74.
Gharaei, B., Mehryar, A.H., Mehrabi, M., 2000. Attribution style in patients with anxiety and depression
comorbidity. Iran. J. Psychiatry. Clin. Psychol. 5(20): 437-442 ( Article in Persian).

Haile, C., Murrough, J.W., Iosifescu, D.V., Chang, L.C., Al Jurdi, R.K., Foulkes, A., Iqbal, S.,
Mahoney, J.J 3rd., De La Garza, R 2nd.,, Charney, D.S., Newton, T.F.,, Mathew, S.J., 2014.
Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatmentresistant depression. International J. Neuropsychopharmacol. 17(2), 331-336.
Hamilton, M., 1960. A rating scale for depression. J Neurol. Neurosurg. Psychiatry23(1), 56.
Hatton, R.C., Patel, J., Low, M.W., Ganesh, O., 2013. Use of Oral Ketamine by Academic
Hospitals in the US. Ann. Pharmacotherapy47(4), 591-592.
Heresco-Levy, U., Gelfin, G., Bloch, B., Levin, R., Edelman, S., Javitt, D.C., Kremer, I., 2013. A
randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. Int. J.
Neuropsychopharmacol. 16(3), 501-506.

19

Herrero, M., Blanch, J., Peri, J.M., De Pablo, J., Pintor, L., Bulbena. A., 2003. A validation study
of the hospital anxiety and depression scale (HADS) in a Spanish population. Gen. Hosp.
Psychiatry25(4), 277-283.
Herrmann, C., 1997. International experiences with the Hospital Anxiety and Depression Scale-a
review of validation data and clinical results. J. Psychosom. Res. 42(1), 17-41.
Huang, C-C., Wei, I.H., Huang, C.L., Chen, K.T., Tsai, M.H., Tsai, P., Tun, R. , Huang, K.H.,
Chang, Y.C., Lane, H.Y., Tsai, G.E., 2013. Inhibition of glycine transporter-I as a novel
mechanism for the treatment of depression. Biol. Psychiatry 74(10), 734-741.
Irwin, S.A., Iglewicz, A., Nelesen, R.A., Lo, J.Y., Carr, C.H., Romero, S.D., Lloyd, L.S., 2013.
Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice
care: a 28-day open-label proof-of-concept trial. J. Palliat. Med. 16(8), 958-965.
Johnston, M., Pollard, B., Hennessey, P., 2000. Construct validation of the hospital anxiety and
depression scale with clinical populations. J. Psychosom. Res. 48(6), 579-584.
Khajavi, D., Farokhnia, M., Modabbernia, A., Ashrafi, M., Abbasi, S.H., Tabrizi, M,
Akhondzadeh, S., 2012. Oral scopolamine augmentation in

moderate to severe major

depressive disorder: a randomized, double-blind, placebo-controlled study. J. Clin. Psychiatry

73(11), 1428-33
Lapidus, K.A., Levitch, C.F., Perez, A.M., Brallier, J.W., Parides, M.K., Soleimani, Feder, A.,
Iosifescu, D.V., Charney, D.S., Murrough, J.W., 2014. A randomized controlled trial of
intranasal ketamine in major depressive disorder. Biol. Psychiatry 76(12), 970-976.

20

Lara, DR., Bisol, L.W., Munari, L.R., 2013. Antidepressant, mood stabilizing and procognitive
effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int. J.
Neuropsychopharmacol. 16(9), 2111-2117.
Linton, S.J., Bergbom, S., 2011. Understanding the link between depression and pain. Scand. J.
Pain 2(2), 47-54.
Macklin, D., 2003, Phlebitis: A painful complication of peripheral IV catheterization that may be
prevented. AJN. 103(2), 55-60.
McGirr, A., Berlim, M.T., Bond, D.J., Fleck, M.P., Yatham, L.N., Lam, R.W., 2015. A
systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of
ketamine in the rapid treatment of major depressive episodes. Psycholog. Med. 45(04), 693-704.
Naughton, M., Clarke, G., O'Leary, O.F., Cryan, J.F., Dinan, T.G., 2014. A review of ketamine
in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical
evidence on proposed mechanisms of action. J. Affect. Disord. 156, 24-35.
Otte, C., Zhao, S., Whooley, M.A., 2012. Statin use and risk of depression in patients with
coronary heart disease: longitudinal data from the heart and soul study. J. Clin. Psychiatry. 73(5),
610-615.
Poole ,N.A., Morgan, J.F., 2006. Validity and reliability of the Hospital Anxiety and Depression
Scale in a hypertrophic cardiomyopathy clinic: the HADS in a cardiomyopathy population. Gen.
Hosp. Psychiatry28(1), 55-58.

21

Samaras, N., Herrmann, F.R., Samaras, D., Lang, P.O., Canuto, A., Forster, A., Hilleret, H.,
Gold, G., 2013. The Hospital Anxiety and Depression Scale: low sensitivity for depression
screening in demented and non-demented hospitalized elderly. Int. Psychogeriatrics. 25(01), 8287.
Yanagihara, Y., Ohtani, M., Matsumoto, M., Kariya, S., Uchino, K., Hiraishi, T., Ashizawa, N.,
Aoyama, T., Yamamura, Y., Iga, T., 1999. [Preparation of ketamine tablets for treatment of
patients with neuropathic pain]. Yakugaku zasshi: J. Pharmaceut. Soc. Japan. 119(12), 980-987.
Yang, C., Han, M., Zhang, J.C., Ren, Q. Hashimoto, K., 2016. Loss of parvalbuminimmunoreactivity in mouse brain regions after repeated intermittent administration of
esketamine, but not R-ketamine. Psychiatry. Res. 239, 281-283.
Zarate, C.A., Singh, J.B., Carlson, P.J., Brutsche, N.E., Ameli, R., Luckenbaugh, D.A., Charney
DS, Manji HK., 2006. A randomized trial of an N-methyl-D-aspartate antagonist in treatmentresistant major depression. Arch. Gen. Psychiatry. 63(8), 856-864.
Zigmond, A.S., Snaith, R.P., 1993. The hospital anxiety and depression scale. Acta. Psychiatrica.
Scand. 67(6), 361-370.

Legends
Figure 1: Flow diagram representing case selection for the trial program

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Figure 2: Comparison of mean SD (as represented by error bars) of HDRS scores at baseline
and weeks post-intervention with ketamine or diclofenac. *denotes that the score difference was
significantly different between intervention groups (P value < 0.05).
Figure 3. Box-plot demonstrating the comparison between score changes of the two trial arms.
HDRS: Hamilton depression rating scale; HADS: hospital anxiety and depression scale; VAS:
visual analogue scale.
Figure 4: Comparison of mean SD (as represented by error bars) of HADS subscale for
depression scores at baseline and weeks post-intervention with ketamine or diclofenac. *denotes
that the score difference was significantly different between intervention groups (P value <
0.05).
Figure 5: Comparison of mean SD (as represented by error bars) of VAS scores at baseline and
weeks post-intervention with ketamine or diclofenac. *denotes that the score difference was
significantly different between intervention groups (P value < 0.05).
Figure 6. Comparison of response to treatment and remission rates at different study points
between the two trial arms.

Table 1: Baseline characteristics of study population.

Ketamine Arm Diclofenac Arm P value

Age (y)

(n=20)

(n=20)

40.7 8.71

38.95 9.22

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0.541

Sex, Male (%)

5 (25)

5 (25)

1.000

Diagnosis, n (%)

0.594

Tension Headache

15 (75)

13 (65)

Chronic Migraine

6 (30)

4 (20)

Vascular Headache

1 (5)

Medication Overuse Headache

1 (5)

Educational Status, n (%)

1.000

Under Diploma

7 (35)

7 (35)

Diploma

8 (40)

8 (40)

University Degree

5 (25)

5 (25)

15 2.36

14.95 2.72

0.951

Baseline HADS Subscale for Depression Score 9.05 1.60

9.45 1.47

0.416

Baseline VAS Score

69.50 18.77

0.669

Baseline HDRS Score

72 17.95

HDRS, Hamilton Depression Rating Scale; HADS, Hospital Anxiety and Depression Scale;
VAS, visual analog scale.

Table 2: Frequency [n (%)] of untoward side effects among the two trial arms.
Side effect

Ketamine Arm (n=20)

Diclofenac Arm (n=20)

P Value

Blurred Vision

1 (5.0)

1 (5.0)

1.000

Tremor

1 (5.0)

1 (5.0)

1.000

Restlessness

1 (5.0)

1.000

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Nervousness

1 (5.0)

1.000

Abdominal Pain

1 (5.0)

1 (5.0)

1.000

Loss of Appetite

1 (5.0)

1.000

reported by Fishers exact test. Abbreviations are given at Table 1.

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Highlights:

We assessed the safety and the efficacy of oral ketamine vs. diclofenac monotherapy in
reducing symptoms of mild to moderate depression among patients with chronic pain.

Significantly lower HDRS scores were observed in the ketamine treatment group as early as 6
weeks post-intervention.

Treatment with ketamine seems to be well tolerated with no serious adverse event.

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