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Kareemah Muhammad

Lapidus KA, Levitch CF, Perez AM, et al. A Randomized Controlled Trial of Intranasal
Ketamine in Major Depressive Disorder. Biol Psychiatry. 2014

Introduction

o This research was supported by National Institutes of Health via the Mount Sinai Clinical
and Translational science award and a national alliance for research on Schizophrenia and
depression young investigator award from the Brain and Behavior research foundation
(KABL)


o The objective of this study was to test the safety, tolerability, and efficacy of intranasal
ketamine in patients with depression who have failed at least one prior antidepressant
trail
Methods-Design
-Control, cohort, controlled exp, etc.
o Randomized, double-blind cross-over study
-over, parallel, etc.)
o Cross-over study
 Two or more experimental drugs re administrated one after the other in a random
order to the same group of patients
 Advantages: eliminates individual subject differences from the overall treatment
effect, this enhancing the statistical power
 Disadvantages: disease has to remain constant and effects of one treatment must
disappear before the next is applied ; carry-over effects between treatment groups
Allocation concealed/ Blinding
o The order of treatment periods was randomly assigned by the research pharmacy using
permuted blocks of size four
o All study investigators, anesthesiologists, and raters were blind to treatment assignment
 Study drug or placebo was provided in identical syringes, containing clear
solutions (100 mg/ml ketamine in .9% saline or saline alone)

Methods-Patient/Subjects

o Icahn School of Medicine at Mount Sinai institutional review board approved the study
o Written informed consent was obtained from all subjects before participation
o Study is registered at clinicaltrails.gov

o Study participants were recruited from physician referrals, media advisements, and an
academic outpatient psychiatric clinic
o All study treatments were performed at Mount Sinai Medical Center between April 2012
and June 2013

o Inclusion Criteria
 Men and women between the ages of 21-61 years of age
 Women of child bearing age: negative pregnancy test before enrollment
and maintain adequate birth control for duration of study
 A primary diagnosis of major depressive disorder (chronic or recurrent without
psychotic features)—assessed by trained rater with the structured clinical
interview for DSM-IV
 Participants were allowed to remain on stable doses of psychotropic
medication, including antidepressant treatment
 A diagnostic interview with study psychiatrist
 Participants must fail to respond to at least one trial dose/duration of an
antidepressant medication approved by the FDA in the current episode (according
to the antidepressant treatment history form)
 Negative urine toxicology for illicit drugs
 Baseline score ≥ 30 on the inventory of depressive symptoms-clinician rated
o Exclusion Criteria
 Unstable medical or neurologic condition
 Other axis I disorders other than major depressive disorder judged to be the
primary presenting problem
 High risk suicide, substance abuse or dependence in past 6 months
 Any psychotic, bipolar, developmental disorder
 Lifetime abuse or dependence on Ketamine or phencyclidine
 Nasal obstructions or history of nasal surgery
 Unstable medical illness
 Physical exam, vital signs, weight ECG, blood tests, and urinalysis
confirmed absence of unstable medical illness
lled per group
o A total of 1164 patients were enrolled. Of those, 178 patients were enrolled for treatment
of a first recurrence. The fidaxomicin group contained 88 patients and the vancomycin
group had 90 patients.

o Baseline characteristics were not significantly different between groups despite relatively
small sample sizes (P>.05).

Methods-Treatment Regimens

o Participants received 50 mg ketamine hydrochloride and placebo (.9% of saline solution)
 Each of the 5 ketamine applications provided 10 mg of study drug
 Administration were provided over 20 minutes by anesthesiologist in clinical
research unit

o Each treatment period (ketamine and placebo) consisted of 7 days
o In each treatment period assessments occurred at 7 different designated time periods
 +40 min, +120 min, +240 min, +24 hours, +48 hours, +72 hours, and + 7 days
after the START of treatment intervention

Methods-Outcomes Measures

o The primary study outcome was change in depression severity measured by the
Montgomery-Asberg depression rating scale (MADRS) at 24 hours after intervention
 Subjects were rated before each administration (-60 min), +40, +120, and +240,
and 1, 2, 3, and 7 days after each administration

o Secondary measures included:
 Quick inventory of depressive symptomatology-self report (QIDS-SR)
 Hamilton anxiety rating scale (HAM-A)
 Proportion of individuals meeting response or remission criteria
 Response defined as ≥50% decrease in MADRS score from baseline
 Safety and tolerability assessed
 Brief psychiatric rating scale
 Clinician-administered dissociative states scale (CADSS)
 Mood item of young mania rating scale
 Systematic assessment for treatment emergent effects instruments
** Clinically significant changes were defined in protocol as systolic or
diastolic BP >180/100 mmHg or HR >110 bpm.


o After initial 7-day treatment (ketamine or placebo) participants were reassessed for a
sufficient level of depressive symptoms.
 A rating of ≥ 24 defined as inventory depressive symptoms (clinician rated)

Methods-Data Handling

o Intent-to-treat protocol, including all 18 participants with outcome assessment from both
periods
-up
o All 20 eligible participants were randomly assigned to one of two treatment orders. Two
subjects withdrew consent after randomization and did not complete both periods of
treatment
 There were 18 patients who constituted the modified intention to treat sample

o Patients were excluded from the per protocol analysis of reoccurrence due to insufficient
follow up, receiving other therapy for CDI treatment and other non-reported protocol
violations.
Methods-Statistics

o Mixed model approach was used to test effects of treatment (ketamine and placebo)
period and carry-over differences in MADRS score and rates of clinician response
 Mixed model approach accounts for the fact each patient is assessed under both
treatment groups per cross over design
o Treatment effects were quantified as mean difference between groups and associated
95% confidence interval for continuous outcomes and by odds ratio and associated 95%
CI for categorical outcomes
o Patient characteristics and safety and tolerability are summarized using descriptive
statistics


o Power was not set in this study.

Results

o Depressive symptoms after 24 hours of treatment were significantly improved in patients
receiving ketamine compared with patients receiving placebo (p <.001)
o Estimated mean difference in MADRS score between ketamine and placebo groups was
7.6 (95% CI)
o No evidence of residual effect of treatment
o Placebo treatment:
 Response criteria were met by 1 of 18% (6%); Number needed to treat = 2.6
o Ketamine treatment:
 Associated with greater likelihood of response at 24 hours compared to placebo (p
= .033)
 Response criteria were met by 8 out of 18 subjects (44%) after 24 hours of
administration
** Response was defined as a decrease from baseline of at least 50% on
Montgomery Asberg depression rating scale
 In addition to 24 hour outcome, response to ketamine was significantly
different from response at placebo at 40 min, and 48 hours
o Secondary outcome
 Significant improvement on self-reports of depression as measured by the QIDS-
SR at 24 hours
 Ketamine was superior to placebo in improving anxiety symptoms at 24 hours as
measured by HAM-A scores
 Acute psychoyomimetic and dissociative effects
 Hemodynamic effects


o Compliance was not directly mentioned in this article. However, two patients in the
vancomycin treatment group were excluded for protocol violation. Three patients in the
fidaxomicin group were also excluded for protocol violation and another was excluded
for effective concomitant therapy.


o Gastrointestinal upset and infectious conditions were the most commonly reported
adverse events. Safety was assessed by patient interview, recording adverse events,
clinical laboratory tests physical examinations and electrocardiograms.

Conclusions

o Treatment with fidaxomicin was associated with a lower risk of recurrence and a longer
time to recurrence compared to vancomycin in this study.
o Advanced age seems to be a predictor of CDI recurrence. Patients over the age of 65 are
twice as likely as those less than 65 to experience CDI recurrence.


The following 12 Major Considerations in Evaluating Literature should be considered when
critiquing an article


o Power was not set in this study.

o The dosages for both medications were appropriate to treat Clostridium difficile (400mg
of fidaxomicin daily and 500mg of vancomycin daily).

o Yes. Both studies treated patients for 10 days which is standard, then followed them for
28 days (+/- 2 days) after achievement of clinical cure.

o Yes. CDI was confirmed with a stool toxin test and >3 unformed bowel movements in
the 24 hour period preceding randomization.

o Yes. Patients on any other therapy that may treat CDI were excluded from this study.

o Yes, the investigators, sponsor, site personnel and patients were all blinded to treatment
assignment. In addition, the two medications were presented in identical blister packs
with identical instructions.

o Yes. An interactive voice response system or an interactive web response system
assigned a computer-generated randomization number and medication kit number to each
patient.

o Yes. Despite a small sample size, randomization resulted in groups with similar baseline
differences according to statistical analysis.

o Yes. Chi squared test of difference in proportions was used to test efficacy in the two
treatment groups. The researchers also used the Cox proportional hazard model to
determine if age was a predictor of recurrence. Kaplan-Meier analysis using Gehan-
Wilcoxon and log rank tests determined equality across treatment and age strata
considered to be standard, validated, or accepted practice?
o Yes. The Wilcoxon is accepted in practice as a test used to compare two related samples.
The Chi squared test of difference in proportion is also standard for comparing two
treatment groups to one another.
ome/results relevant (i.e.-POEM- would a patient care about this)?
o Results are relevant to patients experiencing CDI and healthcare providers who are faced
with the challenge of treating recurrent CDI. It is a very unpleasant infection for patients
to experience. A treatment option that could reduce recurrence or lengthen the time to
recurrence would be very appealing to patients trying to overcome Clostridium difficile.

o The conclusions in this study were drawn from statistically significant results.
-How does the study fit into practice?
o This study suggests that fidaxomicin may be associated with a lower risk of recurrence
than vancomycin and is also associated with a longer time to recurrence. It may be a
better treatment option for patients experiencing a CDI, especially those over the age of
65.