Ketamine has shown promise for treatment-resistant depression based on its rapid antidepressant effects seen in clinical trials. However, the evidence for its use is still limited. A randomized controlled trial compared a single intravenous dose of ketamine (0.5 mg/kg over 40 minutes) to midazolam in 73 patients with treatment-resistant major depression. Ketamine produced significantly greater improvements in depression scores and response rates at 24 hours based on the primary and secondary outcomes. While adverse effects were common, they were transient. However, the study only assessed a single intravenous dose and longer-term safety and efficacy remain unknown. Overall, more research is still needed regarding appropriate dosing and administration routes before ketamine can be recommended for routine

1. Assessing the
Appropriateness ofOral
Ketamine in Depression:
Ajournalclubapproach
Michael Nguyen
MCPHS University 2017 PharmD Candidate
Massachusetts Board in Registration of
Pharmacy APPE rotation

2. Major
Depressive
Disorder
DSM-IVCriteria for Major Depressive Disorder (MDD)
• Depressed mood or a loss of interest or pleasure in daily activities for more than
two weeks.
• Mood represents a change from the person's baseline.
• Impaired function: social, occupational, educational.
• Specific symptoms, at least 5 of these 9, present nearly every day:
1. Depressed mood or irritable most of the day, nearly every day, as
indicated by either subjective report (e.g., feels sad or empty) or
observation made by others (e.g., appears tearful).
2. Decreased interest or pleasure in most activities, most of each day
3. Significant weight change (5%) or change in appetite
4. Change in sleep: Insomnia or hypersomnia
5. Change in activity: Psychomotor agitation or retardation
6. Fatigue or loss of energy
7. Guilt/worthlessness: Feelings of worthlessness or excessive or
inappropriate guilt
8. Concentration: diminished ability to think or concentrate, or more
indecisiveness
9. Suicidality:Thoughts of death or suicide, or has suicide plan

3. Treatment-
Resistant
Depression
(TRD)
Murrough et. al (authors of article) define this as
“Insufficient response to at least two adequate
antidepressant treatments”
According to Dr. Allison Little, from Oregon Health & Science University,
Portland, Oregon, states that “up to two thirds of patients with major
unipolar depression will not respond to the first medication prescribed”
She definesTRD as insufficient response to at least two adequate
treatments from two different pharmacological classes
According to Serafini et. al, “at least 10-20% of patients suffering from
depression meet criteria for treatment resistant depression.

4. Quick
Audience
Survey
Davidson JR, J Clin Psychiatry 2010;71 Supp E1:e04
So what guideline do you follow?
A. American Psychiatric association
B. BritishAssociation for Psychopharmacotherapy
C. National Institute for Health and Clinical Excellence (NICE)
D. Other guideline
E. Just keep trying SSRI’s… what ever the doctor prescribes

5. Treating Major
Depression
SSRI’s
- Fluoxetine
- Paroxetine
- Citalopram
SNRI’s
-Venlafaxine
- Duloxetine
Dopamine agonist
- Bupropion
Noradrenergic antagonist
- Mirtazapine
Mixed Mechanism
-Vilazodone
-Trazodone
-Vortioxetine
MAOIs
- Isocarboxazid
- Phenelzine
-Tranylcypromine
ECT

6. Assessing
Depression
 MADRS
 10 Item diagnostic tool
 Each item max 6 points – Overall
0-60 (60 is worst)
 0 to 6 – normal] /symptom absent
 7 to 19 – mild depression
 20 to 34 – moderate depression
 >34 – severe depression
 Inventory Of Depression
Symptomatology - .CR
 The score of 32 or above = Mild –
Severe
 Only 28 of the 30 items are scored
because 2 of the items assess
weight and 2 of the items assess
appetite.
 Score ranges from 0-84
 QIDR-SR – 16 item
 Similar to IDRS but completed by
the patient
 Total scores range from 0-27
 The ClinicalGlobal Impression
is rated on a 7-point scale, with the
 severity of illness scale (CGI-S)
using a range of responses from 1
(normal) through to 7 (amongst
the most severely ill patients).
 Improvement (CGI-C) scores
range from 1 (very much
improved) through to 7 (very
much worse)

7. Depression
Score
Comparisons
IDS/QIDS Interpretation.2016

8. Meet our
patient
 AB is a patient who fills his medications at L&C
pharmacy
 Diagnosis:Treatment-Resistant Major Depression
 Medications:
12/18/2015 L&C
Ketamine 30mg Capsules
1 cap PO QD
(#10, DS 10)
R
Weitzman, MD
12/28/2015 L&C
Ketamine 40mg Capsules
1 cap PO QD
(#28, DS 28)
R
Weitzman, MD
1/13/2016 L&C
Ketamine 60mg Capsules
1 cap PO BID
(#56, DS 28)
R
Weitzman, MD
2/8/2016 L&C
Ketamine 80mg Capsules
1 cap PO TID
(#84, DS 28)
R
Weitzman, MD

9. What is
Ketamine?
• NMDA antagonist
• Induces sedation, immobility, and amnesia
• Analgesic
• Emergence phenomena
• Bronchodilator without disrupting airway
• ADRs: Euphoria, emergence phenomena, psychosis,
increased blood pressure, increased muscle tone, opening of
eyes with or without nystagmus , increased myocardial oxygen
consumption (due to tachycardia), minimal respiratory
depression
Pharmacology
NMDA
RECPTOR

10. Ketamine
Continued
• Absorption – 16% orally (~ 5mg of 30 mg orally absorbed)
• Distribution – 10 -15 minutes (2-3Vd = L / kg)
• Metabolism – Hepatic Phase I & II **Children metabolize quicker
• Elimination - Mostly Renal (90%)
Pharmacokinetics
• Labeled indications
• Analgesia
• 0.2 to 0.75 mg/kg over 2 to 3 minutes, followed by
continuous infusion of 5 to 20 mcg/kg/min with or without
supplemental oxygen
• Induction Anesthesia
• 1 to 2 mg/kg (range, 0.5 to 4.5 mg/kg) over 60 seconds
• MaintenanceAnesthesia
• infusion of 0.1 to 0.5 mg/min or one-half to the full
induction dose
Indications and Dosing

11. Ketamine
Capsules exist?
 Ketlar 10, 50 and 100 mg/mL solution for
injection (available in generic)
 API powder
 Costs:
 100mg/ml (10mL) - $98.28 (Hospira) 00409-2051-05
 API 100g - $3400.00 (B&B pharmaceuticals) 63275-9980-05
 Therefore a single 30 mg capsule = $1.02
(not including capsule or other compounding costs)
Cost of introducing Special K into
streets!
Comes at a cost

12. Ketamine for
treatment-
resistant major
depression
• Antidepressant Efficacy of Ketamine inTreatment-Resistant
Major Depression:ATwo-Site Randomized ControlledTrial
Title
• Blinded and Randomized, Phase II
• Baylor College of Medicine (Houston,TX) and
• School of Medicine at Mount Sinai (NewYork City, NY)
Type/Setting
• November 2008 - September 2012 Published 2013, AJP
Time
• Ketamine has no difference in efficacy of changing depression severity when
compared to midazolam 24 hours after infusion
NullHypothesis
• National Institute of Mental Health
• National Institute of Health National Center for AdvancingTranslational Sciences
• Department ofVeteran Affairs
• NRSAD independent investigator’s award (Brain and Behavior research foundation)
• Brown Foundation, Inc
Funding

13. Population
Inclusion Criteria Exclusion Criteria
• Ages 21 – 80
• Primary diagnosis of MDD (DSM-IV)
• Inadequate response to at least 3
therapeutic trials of an
antidepressant (according to
AntidepressantTreatment History
form )
• Either
• History of at least one previous
major depressive episode prior to
the current episodeOR
• The combination of a chronic
major depressive episode and a
score of 32 or greater on the
Inventory of Depressive
Symptomatology – clinician
rated
 Life time history of psychotic illness
or bipolar disorder
 Alcohol or substance abuse within
the previous 2 years
 Unstable medical illness
 Serous and imminent suicidal or
homicidal risk
 Score of less than 27 on the Mini-
Mental State Examination

14. Interventions
116 Patients Screened
73 Randomized
25 Midazolam
0.045 mg/kg IV
over 40 min
48 Ketamine
0.5 mg/kg IV
over 40 min
43 excluded
20 Declined to participate
19Withdrew Consent
4 Did not meet eligibility

15. Endpoints
 Primary outcome:
 Reduction in depression severity (MADRS) 24 hours after
infusion.
 The 24-hour time frame was consistent with peak antidepressant
effect noted in prior studies, and was long enough that acute drug
effects would have passed.
 Secondary outcomes:
 MADRS response rate (reduction in baseline score by ≥50%)
 Quick Inventory of Depressive Symptomatology-Self Report
score change.
 Clinical Global Impression (CGI) scores.
 Durability of benefit up to 7 days after infusion.

16. Statistics
 Modified intention to treat – Included all randomized
with > 1 post baseline measurement
 Planned study group of 72 patients
 Randomly assigned 2:1 ratio (ketamine vs. midazolam)
 80% powered to detect MADRS scores at 24 hours.
 96% powered to detect response rates 24 hours
 General linear modeling and logistic regression were
used to analyze outcomes
 Safety and tolerability was analyzed with descriptive
statistics

17. Baseline
Characteristics

18. Primary
Outcome
Results
 Primary Outcome
 At 24 hours, MADRS score
was significantly more
improved in ketamine group
compared with midazolam
group,
 a difference of
7.95 points
(95% CI, 3.20-12.71).
MADRS scores:
 Ketamine
 baseline: 32.6
 24 hours: 14.77
 Midazolam
 baseline: 31.1
 24 hours: 22.72

19. Secondary
Outcome
Results
 Secondary Outcomes
 MADRS response rates at 24 hours (OR =2.18, p < 0.006)
 Ketamine: 64%
 Midazolam: 28%
 Change in score on the QIDS – SR (p < 0.02)
 Ketamine group was 3.4 points lower
 CGI rating of improved or much improved (OR = 2.31, p< 0.004)
 Ketamine: 62%
 Midazolam: 24%
 Both groups had worsening in MADRS scores from day 1 to day
7, with no identified difference in trajectories as a function of
treatment.
 MADRS and QIDS-SR at day 7 were not significantly different
after adjusting for site and baseline scores,

20. Adverse
effects
Ketamine Midazolam
Dizziness (45%) Dizziness (20%)
BlurredVision (43%) Decreased energy
Headache (32%) Headache (20%)
N&V (34%) N&V (12%)
Dry Mouth (26%) Dry mouth (16%)
Poor Coordination (26%) Poor Coordination (12%)
Poor concentration (6%) General Malaise (28%)
Restlessness (21%) Restlessness (20%)
17% patients in ketamine group had emergence effect
Emergence effect symptoms resolved 2 hours post infusion
Baseline blood pressures were almost the same
Blood pressures 40 minutes post infusion
Ketamine : 140 / 80 mmHg
Midazolam : 111.8 / 67.9 mmHg

21. Author’s
Conclusion
 Data suggests that Ketamine can function as a novel drug for treatment-resistant
major depression due to its rapid antidepressant effects.
 The consistency across the two sites improve external validity.
 Raters were not educated on the adverse effects of ketamine so that there was
no collection bias, improving internal validity
 Midazolam was used as a control because it has similar psychotropic effects
without any antidepressant activity.
 Further studies need to be conducted to assess ketamine’s role
 as an adjunct, many of the screened patients were not able to tolerate psychotropic
washout (17.2%)
 vs. ECT
 vs. Antidepressant + Antipsychotic combos
 long term effects
 “Safety and efficacy of ketamine in depression beyond a single infusion are
largely unknown and that abuse liability and other safety concerns associated
with ketamine dictate a cautious approach to its application outside of research”

22. Critique
 Strengths
 Randomized
 2 study sites
 Diverse population sample
 Adequately Powered
 Use of a control (its difficult to find a drug similar to ketamine)
 Multiple scoring systems
 Weaknesses
 The raters being blinded by not educating them on the adverse effects of
ketamine!
 Sample size was moderate for phase II trial
 Short duration of study, no more statistical analysis after 7 days
 Single dose study
 Exclusion of alcohol or substance abuse within the previous 2 years.

23. So is ketamine
the right drug for
our patient?
Have you ever
seen ketamine
used for
depression?
 This study does not apply to our patient very well.
 Patient is taking ketamine PO, study uses IV
 Patient takes multiple doses, study assesses single dose
 The dose for a 68 kg patient in the study = 34 mg over 40 minutes
 Would be roughly 40 mg PO based on clinical pharmacology information
 Other studies:
 Caddy et al, published a Cochrane database review.
 They searched Cochrane Depression, Anxiety and Neurosis Review Group’s Special
Register in al the way to January 9, 2015 and resulted in 25 studies
 Included : Double or single blinded RCT’s comparing ketamine vs. control in adults with
unipolar depression
 They found that although ketamine is one of the only NMDA antagonist with
efficacy for depression, the evidence is limited
 All studies included had ketamine administered intravenously!
 Surprisingly there is a lot of small studies on ketamine showing its efficacy in
depression!
 More robust data is needed!
12/18/2015 L&C
Ketamine 30mg Capsules
1 cap PO QD
(#10, DS 10)
R
Weitzman, MD
12/28/2015 L&C
Ketamine 40mg Capsules
1 cap PO QD
(#28, DS 28)
R
Weitzman, MD
1/13/2016 L&C
Ketamine 60mg Capsules
1 cap PO BID
(#56, DS 28)
R
Weitzman, MD
2/8/2016 L&C
Ketamine 80mg Capsules
1 cap PO TID
(#84, DS 28)
R
Weitzman, MD

24. This is a
horse…
Google Image Search “horse”

25. This is a person
on ketamine…

26. Questions ?
References
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (1994).Accessed
July 20, 2016. 10.1176/dsm 10.1176/appi.books.9780890420614.dsm-iv
2. Serafini G, Howland R, Rovedi F, Girardi P, Amore M.The Role of Ketamine inTreatment-Resistant Depression: A
Systematic Review. Current Neuropharmacology CN. 2014;12(5):444-461.
doi:10.2174/1570159x12666140619204251.Davidson JRT. Major Depressive DisorderTreatment Guidelines in America
and Europe. J Clin PsychiatryThe Journal of Clinical Psychiatry. 2010;71(suppl E1). doi:10.4088/jcp.9058se1c.04gry.
3. IDS/QIDS Interpretation. IDS/QIDS. http://www.ids-qids.org/. Published 2016.Accessed July 22, 2016.
4. Clinical Pharmacology [database online].Tampa, FL: Gold Standard, Inc.; 2016.
URL:http://www.clinicalpharmacology-ip.com.ezproxymcp.flo.org/default.aspx. Updated February 2016
5. RED BOOK Online search tool Micromedex® 2.0, (electronic version).Truven Health Analytics, GreenwoodVillage,
Colorado, USA. Available at: http://www.micromedexsolutions.com.ezproxymcp.flo.org/ Accessed July 10, 2016)
6. Micromedex® 2.0, (electronic version).Truven Health Analytics, GreenwoodVillage, Colorado, USA. Available at:
http://www.micromedexsolutions.com.ezproxymcp.flo.org/ Accessed July 10, 2016)
7. Little A.Treatment-Resistant Depression.American Family Physician . 2015;80(2):167-173.
http://www.aafp.org/afp/2009/0715/p167.html.Accessed July 9, 2016.
8. Murrough JW, Iosifescu DV, Chang LC, et al.Antidepressant Efficacy of Ketamine inTreatment-Resistant Major
Depression: ATwo-Site Randomized ControlledTrial. American Journal of Psychiatry AJP. 2013;170(10):1134-1142.
doi:10.1176/appi.ajp.2013.13030392
9. Montgomery S. Montgomery Asberg Depression Rating Scale. Psy-World - Montgomery Asberg Depression Rating
Scale. http://www.psy-world.com/madrs.htm. Published 1979.Accessed July 10, 2016.
10. Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976. Rockville, MD, U.S. Department of Health,
Education, and Welfare
11. Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults.
Cochrane Databse of Systematic Reviews 2015. Issue 9.Art. No.: CD011612. DOI: 10.1002/14651858.CD011612.pub2.
12. Google Image Search. Horse image. Google. https://www.google.com/search?espv=2.Accessed July 18, 2016.
13. Waugh R. Photo of horse and special K. Ketamine could be an 'important' new drug for depression. Metro Ketamine
could be an important new drug fordepression Comments. http://metro.co.uk/2015/09/15/ketamine-could-be-an-
important-new-drug-for-depression-5392356/. Published 2015. Accessed July 10, 2016.