1. Michelle Widholm
Can Ketamine be used for Patients with Treatment-Resistant Depression?
Major depressive disorder (MDD) is a serious mental illness that effects sixteen million
people every year1. Many patients are subsequently diagnosed with treatment resistant
depression (TRD) which is defined as having an inadequate response to two2,6 FDA approved
antidepressants. Due to inadequate treatments, patients with a diagnosis of TRD are more likely
to suffer disability due to their illness2 and are more likely to attempt suicide3. It is estimated
that, based on response rates for approved anti-depressants, there are currently 2.4-3.5 million
people in the United States with TRD1. Thus it is important to explore other treatment options to
treat acute symptoms in patients suffering from TRD.
Emerging data for various studies have shown that patients with MDD have
abnormalities in their glutamate signaling pathways5, a pathway not currently targeted in
depression therapies. Further studies have shown that glutamate levels were significantly
elevated in patients with MDD6. Based on these findings it is suggested that ketamine, a
glutamate N-methyl-d-aspartate receptor antagonist, would decrease the response to elevated
glutamate levels and the alleviate MDD symptoms. The following studies explore the
effectiveness and safety of ketamine in patients with TRD.
In 2006, Zarate et al6 conducted one of the first randomized control trials testing the
efficacy and safety of ketamine in TRD. Subjects who had a history of two or more failed
antidepressant treatments and had a current Hamilton Depression Rating Scale (HDRS) score of
eighteen or higher were enrolled in the study from inpatient units in the Washington, DC area.
Subjects were excluded if they had a current substance abuse or dependence issue (within the
last three months) or if they were at serious suicide risk. The study enrolled eighteen subjects to
participate in a randomized double-blind crossover trial. After a two-week drug free period

2. Michelle Widholm
subjects received two injections, given one week apart, of either placebo or ketamine
hydrochloride (0.5mg/kg). Subjects were rated on the HDRS, Brief Psychiatric Rating scale
(BPRS), the Young Mania Rating Scale (YMRS) and the visual analog scale sixty minutes
before the infusion. Subjects were again rated at 40, 80, 110, and 230 minutes post infusion and
followed up on days one, two, three, and seven-post infusion. Response criteria was defined as a
50% reduction in the subjects HDRS score from baseline and remission was defined as an HDRS
score of seven or lower.
Of the eighteen subjects receiving or due to receive ketamine during the trial, one subject
discontinued due to medical reasons after their placebo infusion, and four subjects maintained a
response to ketamine and thus did not receive the placebo infusion during the second week.
Subjects who received the ketamine injection showed significant improvements in HDRS
depressed mood and guilt symptoms within 40 minutes post injection (no p-value give). After
one day, 71% of subjects injected with ketamine met response criteria and 29% met remission
criteria. The authors noted that ketamine responders were statistically significant at 24 hours (no
p-value presented), but the amount of remitters were not statistically significant at any time
during the study. None of the placebo injection subjects met either criterion after one day. The
amount of patients who responded to ketamine for at least seven days equaled 35%, and subjects
whose response lasted for over two weeks equaled 11% however these findings were not
statistically significant. On the BPRS and YMRS rating scales subjects were significantly worse
(p<0.001) at forty minutes but showed significant improvement on post injection days one to two
(p<0.001), no specific scores were given. No serious adverse events were seen in either of the
groups. Subjects in the ketamine group were more likely to experience confusion, elevations in

3. Michelle Widholm
blood pressure, euphoria (which did not persist beyond 110 minutes), dizziness, increased libido,
and perceptual disturbances. No adverse effects were statistically significant.
A 2013 follow up study conducted by Murrough JW et al5 compared the effectiveness of
ketamine (0.5mg/kg) to midazolam (0.045mg/kg). Researchers choose midazolam due to its
similar pharmacokinetic profile and similar nonspecific behavioral effects to ketamine. Subjects
were tested against the DSM-V for a clinical diagnosis of MDD before enrollment. Inclusion
also required three response inadequacies to antidepressant treatments according to the
Antidepressant Treatment History Form and a clinically rated Inventory of Depressive
Symptomatology (IDS-C) score of 32 or greater. As with the previous study, subjects were
excluded if they had a history of substance abuse or if they were at imminent suicidal risk.
The trial’s primary outcome was the Montgomery-Asberg Depression Rating Scale
(MADRS). Subjects were assessed by the clinician 24 hours post infusion. Subjects were not
assessed at any time after 24 hours. Response rates for the ketamine group were 64% (p<0.006),
the number needed to treat was 2.8, and the mean reduction in the MADRS score was 7.95 (95%
confidence interval 3.20-12.71) out of 60 total points which equaled a 13% reduction. Adverse
events were most commonly seen at four hours and presented as dizziness, blurred vision,
headache, nausea, vomiting, dry mouth, poor coordination, poor concentration and restlessness.
Eight of the forty-seven subjects in the ketamine group had a significant adverse event of
dissociative symptoms, which resolved within two hours (no p-value given). No other serious
adverse events occurred in any subjects.
A study done later in 2013 by Murrough JW et al2 tested the effects of repeated ketamine
infusions, which differed from the single injections performed in pervious studies. Criteria for
inclusion was a failure of at least two FDA approved agents for depression, a diagnosis of MDD

4. Michelle Widholm
based on DSM-V criteria and a clinically rated IDS-C score of greater than or equal to 32.
Subjects were excluded if they had a history of substance abuse or psychosis.
This trial enrolled 24 subjects, of which 21 subjects completed both phases of the trial.
Subjects were assessed on the MADRS with a response criterion defined as 50% improvement
on this scale. Phase one consisted of six IV infusions of ketamine (0.5mg/kg) given Monday,
Wednesday and Friday over a twelve day period, which was given to all participants. MADRS
was measured 60 minutes prior to the first ketamine infusion, and again at 120 minutes, 240
minutes and 24 hours post infusion. Response rates during this phase were 70.8%, with subjects
showing significant improvements in MADRS scores by two hours. Changes in MADRS scores
from baseline were 18.9±6.6 (p<0.001). These seventeen subjects that met response criteria
following the last infusion of ketamine were then continued to phase II. During phase II, subjects
were followed up twice a week for four weeks then every other week until relapse or until day
eighty-three, which ever day came first. Median day to relapse during phase II was eighteen days
± seven days (no statistical significance was done). Eight subjects during the trial experienced
significant vital changes including elevated blood pressure and heart rate. Other adverse side
effects that were experienced by participants were abnormal sensations (54.2%), blurred vision
(50%), and sleepiness (45.8%).
The above trials show a clear use for ketamine in the acute treatment of TRD. In the
Zarate et al6, and the Murrough JW et al5 trials, subjects were only administered one infusion of
ketamine. Response rates were 71% and 64% respectively by 24 hours, with some patients
responding even sooner than that. In the Murrough JW et al6 response rates were 70.8% however
after the last infusion patients in this study were able to keep a response for eighteen days, longer
than any of the other two studies. Based on these response rates 1.6-2.4 million people could

5. Michelle Widholm
potentially benefit from this treatment option. In all three of the studies patients experienced
similar side effects of blurred vision, dizziness, blood pressure changes, and abnormal
sensations. Murrough et al5 showed that some patients suffered from dissociative symptoms
which lasted for no longer than two hours. Since patients would have to be under inpatient care
during this treatment all these adverse effects would be closely monitored and thus it can be
considered safe. All of the studies to date have tested ketamine using the same dose and have not
followed the patients longer than 83 days. There have also been no studies showing the use of
ketamine with maintenance antidepressant therapy or additional ketamine injections after relapse
has occurred. Another thing that all three of these studies did was excluded patients who had
substance abuse issue, or psychosis. Based on the findings it can be recommended that patients
with TRD without psychosis or substance abuse, who are in an inpatient setting, could safely
receive ketamine 0.5mg/kg for acute depressive symptoms. For those patients who do not
respond to ketamine other antidepressant trials should be done while other treatment options are
researched.
References:
1. Substance Abuse and Mental Health Services Administration. Results from the 2012
National Survey on Drug Use and Health: Mental Health Findings, NSDUH. 2013. Series
H-47, HHS Publication No.13-4805
2. Murrough JW, Perez AM, Pillemer S, Stern et al. Rapid and Long-Term antidepressant
Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression. Biol
Psychiatry. 2013;74(4):250-256.
3. DiazGranados N, Ibrahim L, et al. Rapid Resolution of Suicidal Ideation After a Single
Infusion of an NMDA Antagonist in Patients with Treatment-Resistant Major Depressive
Disorder. J Clin Psychiatry. 2010;71(12):1605-1611.
4. Alison L. Treatment Resistant Depression. Am Fam Physician. 2009;80(2):167-172.
5. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant Efficacy of Ketamine in
Treatment-Resistant Major Depression: A Two-site Randomized Controlled Trial.
American. Am J Psuchiatry. 2013;170(10):1134-1142.
6. Zarate CA, Singh JB, Carlson PJ, et al. A Randomized Trial of an N-methyl-D-aspartate
Antagonist in Treatment-Resistant Major Depression. Arch Gen Psychiatry.
2006;63(8):856-864.