American College Health Association Annual Meeting 2018 Lawrence Park MD Medical Director Experimental Therapeutics and Pathophysiology Branch Division of Intramural Research Program National Institute of Mental Health ID: 918922
Download Presentation The PPT/PDF document "Novel and Rapid Treatments for Depressio..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Novel and Rapid Treatments for Depression and SuicidalityAmerican College Health Association Annual Meeting 2018
Lawrence Park, M.D.
Medical Director
Experimental Therapeutics and Pathophysiology Branch
Division of Intramural Research Program
National Institute of Mental Health
Slide2Presenter Disclosure
Lawrence Park
No relationships to disclose
This presentation will discuss off-label (unapproved) uses of ketamine.
The following personal financial relationships with commercial interests relevant to this presentation exist:
Slide3National Institute of Mental Health
Intramural Research Program
NIH Clinical Center
Dedicated research hospital
CORE facilities
Laboratory Resources
Multidisciplinary team
Inpatient unit permits study of unmedicated subjectsTreatment Resistant Depression Population24 year duration of illness50% disabled50% attempted suicide7+ antidepressants ineffective60% ECT ineffective
Mark O. Hatfield Clinical Research Center
Slide4Experimental Therapeutics and Pathophysiology Branch
Drug for
Target A
Placebo
Placebo
Drug for
Target A
Target
Proof of Concept (POC) Study
Improved Treatment
Slide5Drug Development in the past 60 years
Insel
and Skolnick 2006
# of Mechanistically Distinct Drugs
Need to identify new molecular targets
Slide6Mortality Trends By Cause
Peak
Suicide
1965–1995
Current
2009–2012
Heart Disease
(–1.1 Million)
ALL (Leukemia)
(–6,000)
AIDS
(–30,000)
Stroke
(–20,000)
50
75
25
Percent of Peak
Slide7Euthymic
Depressed
Next generation antidepressant
Lag of onset
:
10-14 weeks
Rapid onset
: Hours/day
Problems with Current Antidepressants:
Low remission rates
Lag of onset of antidepressant effects
Questionable efficacy in bipolar depression
Standard antidepressant
(Monoaminergic)
Major Depressive Episode
Initiate Treatment
Depression: The Need for Improved Treatments
Slide8Suicide Remains a Significant Public Health Issue
Slide9Suicide in College Populations
Slide10American College Health Association. American College Health Association- National College Health Assessment II: Reference Group Executive Summary Fall 2017. Hanover MD: American College Health Association; 2018.
12-Month Prevalence
%
So depressed difficult to function39.3Overwhelming anxiety
60.9Seriously considered suicide12.1Attempted suicide1.9Increasing Mental Health Concerns of College Students
Slide11Prudic
and
Sackeim
1999,
Baldessarini 1999; Linehan 1991; Brown 2005; Ballard and Price, 2016Current Treatments for Suicide Risk
Slide12Slide13Glutamate Neuron
Slide14Rapid Antidepressant Effect of Ketamine in Unmedicated Treatment Resistant MDD (n=18)
Zarate et al. Arch Gen Psychiatry 2006
Time
80
230
110
40
Day
3
Day
2
Day
7
8
Weeks
13%
71%
53%
58%
56%
35%
53%
62-65%
35%
Response: 50% decrease in HAMD
Monoaminergic
Antidepressant
Day
1
***p<0.001, **p<0.01, *p<0.05
Minutes
-60
80
230
110
40
Day
1
Day
3
Day
2
Day
7
*
**
**
***
***
***
HAMD Following a Single Ketamine Infusion
Hamilton Depression Rating Scale (HAMD)
Minutes
Slide15Rapid Antidepressant Effect of Ketamine in
Treatment Resistant Bipolar (BP) Depression
Diazgranados et al. Arch Gen Psych 2010
Zarate et al.
Biol
Psych 2012
Replication BP study (n=15)
First BP Study of Ketamine (n=18)
MADRS
-60
80
230
110
40
Day
1
Day
3
Day
2
Day
7
Day
10
Day
14
***
***
***
***
***
***
*
-60
80
230
110
40
Day
1
Day
3
Day
2
Day
7
Day
10
Day
14
***
***
***
***
***
***
***
Time
Ketamine
Placebo
***p<0.001, **p<0.01, *p<0.05
Minutes
Minutes
Slide16Rapid Decreases in Suicidal Ideation (SI)
with Ketamine in MDD and BD
Diazgranados
et al.,
Biol
Psychiatr
2010
***p<0.001, **p<0.01, *p<0.05
Ketamine
Placebo
Suicide Item Score
Minutes
***
***
***
***
***
**
**
Treatment Resistant BD
MADRS Suicide Item (n=15)
Suicide item Score
HAMD Suicide Item (n=66)
-60
40
80
120
230
Day 7
Day 3
Day 2
Day 1
***
***
***
***
***
***
***
Combined MDD+BD
***
Minutes
Slide17Proportion of Study Subjects Without Suicidal Ideation at Each Time Point After Ketamine Administration
Effect of a Single Dose of Ketamine on Suicidal Ideation
Wilkinson, Ballard et al. Am J Psych 2017
Meta-Analysis of Ketamine and Suicidal Ideation (n = 167)
Slide18Wakefulness in Depressed Patients and Healthy Controls
Wakefulness in Depressed Patients
(n = 65)
Wakefulness in Healthy Controls
(n = 22)Data collected using polysomnography
Slide19Wakefulness is Associated with Next-Day Suicidal Ideation in Depressed Patients
Sleep Quality of Depressed
Non-Ideators
Sleep Quality of Depressed
Ideators
Significant time by ideation interaction for sleep between 12 and 4 am, p = .007
Time spent awake at 4 am predicted suicidal ideation the next day when controlling for depression severity, p = .008
Ballard et al. J
Clin
Psychiatr
, 2016
Slide20Relationship Between Wakefulness from 12:00 AM – 4:59 AM and Antisuicidal Response to Ketamine
Vandevoort
et al. J
Clin Psychiatr 2017
Slide21Neurobiology of Suicide Protocol: 15-M-0188Identify patients in current suicidal crisisSuicide attempt or acute suicidal thoughts in last 2 weeks
Admission to inpatient unit– 7SE, CC, NIH
Multimodal assessment to identify biomarkers of suicidal ideation
Dimensional perspective for suicidal thoughts/behaviors Replicate “rapid model paradigm” used for antidepressants treatments to develop rapid-acting anti-suicidal treatmentsEvaluate ketamine and sleep deprivation in suicidal individualsIdentify neural correlates of antisuicidal response
Polysomnography
MEG
PET
MRS
Glu
Structural MRI
fMRI
Slide22Acknowledgements
Chief, ETPB Carlos Zarate
Chief, Non-invasive Neuromodulation Unit [NNU] Sarah Lisanby
SNMD/ETPB/NNU Staff:
Allison NugentElizabeth BallardCristan FarmerWally DuncanBruce Luber
Tom Radman
Nancy Brutsche
Peixiong YuanPeter GochmanDiane Dillard BroadnaxKatherine PrescottNadia HejaziYemisi OlurebiAdilah KirtonJennifer EvansJessica GilbertJoanna SzczepanikAlex NouryLaura WaldmanYumi YiLorie ShoraIntramural Collaborations:PK/PD: Ruin Moaddel, Irving Wainer (NIA), Vijay Ramchandani (NIAAA)Genetics: Francis McMahon (NIMH), David Goldman (NIAAA), Yin Yao (NIMH)
PET: Robert Innis (Mol. Imaging Branch)
Animal studies
: Todd Gould, Panos Zanos (U MD)
Fear/Anxiety Biomarkers
: Christian Grillon
NCATS
: Thomas Craig, Patrick Morris
Mark Niciu
Marc Lener
Bashkim Kadriu
Erica Richards
Tim Barton
Tina Harris
Jessica ReedAnahit MkrtchianZhi-De DengLibby JolkovskyNick Barker
Charles BenderJulia YarringtonBridget ShovestulMark OppenheimerNimesha GerlusChristina GalianoBeverly FalodunDaniel WassermanMorgan Graves
Intramural Research Program, Office of the Clinical Director, NIMH, 7SE (Vicky Liberty, Val Greene, Steve Long, Paula Jacob, Chris Kotila, Margaret Hooks, Jerome Glassman, Jennifer Hammond, Cindy Yeung, Brenda Hausman, Ellen Polignano, Carla Calhoun, Rosemary Payne)OP4, 7SW, MEG/MRI/MRS/PET/SSCC Cores, HSPU
Patients and their familiesExtramural Collaborations:Todd Gould, Zanos Panos, Scott Thompson, Edson Albuquerque, (Univ Maryland)Robert Schwartz (MD Psych Research)Vistagen TherapeuticsGustavo Turecki (McGill University)Brian Roth (University of North Carolina)
Slide23Thank YouNIMH Information about Depression in College Students: https://www.nimh.nih.gov/health/publications/depression-and-college-students/index.shtml
lawrence.park@nih.gov
http://patientinfo.nimh.nih.gov/1-877-MIND-NIH (1-877-646-3644)Moodresearch@mail.nih.gov National Suicide Prevention Lifeline 1-800-273-TALK (8255)