Examining the Neurobiology
of Exercise & Meditation in
Depression
Rakesh Jain, MD, MPH
Clinical Professor
Department of Psychiatry
Texas Tech University School of Medicine
Texas, USA
(JainTexas@gmail.com)
Physical Exercise & Mental Health
Is It Time To Start Prescribing It?
Depression
Are Current Treatment Options
Giving Us All That We Want?
Let’s Take A Look At STAR*D Results…
STAR*D Remission Rates1-6
Level 1
Level 3
Level 2
Level 4
Patients in Remission
40%
Remission:
(HAM-D17 ≤7)
30%
27.5%
29.9%
20%
21.2%
20.3%
16.1%
13.7%
10%
6.9%
0%
Mono
Mono
High
1Trivedi
Aug
Aug
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Aug
Aug
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Switch
Window of Opportunity
Aug
Aug
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Low
MH et al. Am J Psychiatry. 2006;163(1):28-40; 2Trivedi MH et al. N Engl J Med. 2006;354(12):1243-1252; 3Rush AJ et al. N
Engl J Med. 2006;354(12):1231-1242; 4Nierenberg AA et al. Am J Psychiatry. 2006;163(9):1519-1530; 5Fava M et al. Am J
Psychiatry. 2006;163(7):1161-1172; 6McGrath PJ et al. Am J Psychiatry. 2006;163(9):1531-1541.
And STAR*D Reveals Two Striking
Shortcomings of Current Therapy
1. Low rates of remission
2. High rates of relapse
STAR*D, Sequenced Treatment Alternatives to Relieve Depression.
The Neurobiology of Exercise
Does Exercise Have A Place In The Integrative
View of ‘Mind-Body’ Disruptions In Depression?
Substance
misuse
Pain
Mood
D/Os
Inflammation
Sleep
D/Os
Coronary
artery D/O
Obesity, Insulin &
Lipid abnormalities
Osteoporosis
Neurodegeneration
Neuropsychological impairment
Adapted from Goldstein BI, et al. J Clin Psychiatry. Published online ahead of print,
June 2, 2009.
Neurobiology of Exercise:
A Complex Cascade
External Input
Visual
Olfactory
Accoustic
Gustatory
Somatosensory
Structure
CNS
Cognitive Controls
Repair
Plasticity
Protection
Neurogenesis
Transcription
NA, 5HT,GABA,
Glutamate,
Glycine
BDNF/TrkB
ERK/CREB
NFKB
Hippocampus, Cortex
Executive Controls
Prefrontal & Cingulate Cortex
Emotional Controls
Amygdala, Prefrontal Cortex
Internal
Feedback
“Consequences of
exercise”
Humoral
Factors
Neural
Motivational Controls
Reward, Wanting, Selection
Hypothalamus, Accumbens, VTA
Motor Controls
Motor Cortex
Striatum, Brainstem,
Cerebellum, Spinal Cord
DA
↓
Parkinson’s
Disease
↑
ROS
Primary Afferents
Muscle
“Exercise”
Function
Disease
Learning &
Memory
Behavior
•Social
•Sexual
•Coping
•Addictive
•Escape
•Fight & Flight
•Stress
•Sleep
•Ingestive
Alzheimer’s
Dementia
Schizophrenia
Depression
Sleep Disorders
Obesity
ANS
&
Endocrine
Systems
Energy
Balance
Diabetes
CVD
Cardiovascular Consequences
Immune Control
Metabolic Consequences
Liver, WAT, Pancreas
Thermal Consequences
Dishman RK et al. Obesity. 2006;14(3):345-356.
Gastrointestinal
Control
Immune
Disorder
IBD, Constipation
Colon Cancer
Exercise’s Effects on Hippocampal Cell
Proliferation & Neurogenesis
Ki 67 positive
newly
generated
cells
Van der Borght K, et al. Hippocampus. 2009
DCX positive
young
neuronal cells
# p< 0.10
*** p< 0.001
Fitness & Hippocampal Volume – Further
Reason To Prescribe Exercise
Scatterplots showing increase in fitness (VO2 peak) is related
to increase in hippocampal volume (cm3)
Correlations significant for both left and right
(even after including age, sex, years of education as covariates)
Erickson KI, et al. Hippocampus. 2009; ahead of publication.
Physical Exercise – A Modulator of
Inflammatory Cytokines
Nicklaus BJ, et al. J Am Geriatrics Society. 2008;56:2045-2052.
Are Cytokines Pro-inflammatory In
Adipose Tissues & Anti-inflammatory In
Skeletal Muscles?
C = controls
ED =immediately
after exercise
E2 = 2 hrs. after
exercise
E6 = 6 hrs. after
exercise
Adipose tissue
Muscle tissue
Rosa Neto JC et al. Eur J Appl Physiol. 2009;106(5):697-704.
Exercise’s Effects On Immune
Functioning
Single bout of 45-60 minutes of exercise in sedentary women
Moderate exercise = 45 minutes at 55% VO2 max
Intense exercise = 60 minutes at 70% VO2 max
Giraldo E, et al. Neuroimmunomodulation. 2009;16:237-244.
Does Exercise Make Us ‘Happy’?
Exercise Augments
Endo-Cannabinoid Signaling
Rat study, 8 days of voluntary exercise
CB1 receptor site binding density
Hill MN, et al. Hippocampus. 2010 Apr;20(4):513-23.
Endogenous Opioids & Exercise
“Runner’s High” – It is A True Biological
Phenomenon
VAS Scores before and after exercise.
Euphoria and Happiness were significantly
different (p<.05)
Boecker H et al. Cerebral Cortex. 2008;18:2523-2531.
Reduction in opioid receptor availability
after exercise (red is p<.05)
Age is NO excuse: BDNF Is Positively
Impacted In Young & Old by Exericse
Young and old mice benefited from exercise
* p <0.05
Garza AA, et al. Pharmacology, Biochemistry and Behavior. 2004;77(2):209-220.
So, What Does The Neurobiology
of Exercise Teach Us?
• Physical Exercise directly and
positively impacts the neuroanatomical structure involved in
mood regulation
• This impact is both at a micro and
macro anatomical level
• The inflammatory system is also
positively impacted by Exercise
• Physical Exercise is also a biological
Wellness Intervention
Exercise and Depression
What Do Clinical Studies Reveal?
A Quick Primer on Effect Sizes
Effect size =
mean of one population – mean of another population
standard deviation
0.8
0.5
0.3
0
The Biggest & Best Meta-analysis:
Cochrane Database Weighs In…
• Meta-analysis of 25 studies
• Exercise did improve symptoms of depression
• Evidence suggests that exercise probably needs
to be continued in the longer-term for benefits to
be maintained
• Comparison made with controls, psychotherapy
and pharmacotherapy
Mead GE et al. Cochrane Database of Systemic Reviews. 2008 Oct
8;(4):CD004366.
Exercise vs. Anti-depressants
Mead GE et al. Cochrane Database of Systemic Reviews. 2008 Oct 8;(4):CD004366.
Effect of Different
Types of Exercise
Mead GE et al. Cochrane Database of Systemic Reviews. 2008 Oct 8;(4):CD004366.
Exercise Intensity’s Effect on
Anti-depressant Response
of
VO2 MAX
Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.
of
VO2 MAX
Exercise Frequency’s Effect
on Depression
Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.
Type of Exercise & Its Effect on
Anti-depressant Response
Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.
Exercise Duration (in weeks) &
Effects on Depression
Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.
Exercise Duration &
Effects on Depression
(in minutes)
Rethorst CD, et al. Sports Medicine. 2009;39(6):491-511.
What About Drop-outs
With Exercise?
“ Analysis showed dropout rates for the
exercise treatment were similar to those
found in psycho therapeutic and drug
interventions.”
Compliance with Exercise, while always
a challenge, is no worse than other
therapeutic modalities
Rethorst CD, et al. Sports Medicine 2009. 39(6):491-511.
Exercise, Medication
Compared To Combination
16 week study
Medication = sertraline 50-200 mg per day
Exercise = 3 times per week, total 45 minutes, at least
30 minutes at 70-85 % MHR
Medication treatment, n=48
Exercise, n=53
Blumenthal JA, et al. Arch Intern Med.1999;159:2349-2356.
Combined, n = 55
Long-Term Benefits of
Exercise In Depression
(6 month follow-up after Blumenthal study)
Recovered =
HDRS score of less
than 8 and no
DSM-IV depression
Exercise, n=25
Medication, n=29
Combined, n=29
Partially
Recovered = no
DSM-IV depression
and HDRS score
greater than 7 but
less than 15
Those in the exercise condition were more likely to be partially or
fully recovered and were less likely to have relapsed
Babyak M, et al. Psychosomatic Medicine. 2000; 62:633-638.
Augmentation of Anti-depressants
With Exercise
Average
exercise
frequency=
3/week;
duration
(mean) 55.3
minutes per
session at
week 1; 50.6
minutes at
week 12
12 week study, open label. Patients were on anti-depressants and had a
HDRS score of 14 or greater, all participants n=17; completer sample n = 8
Trivedi MH, et al. Journal of Psychiatric Practice. 2006;12:205-213.
The Best Designed Exercise vs.
Medication Study Yet…
Remission defined as a HAM-D 17 score of 7 or less
Remission Rates:
* Placebo = 31 %
* Home Exercise = 40 %
•Supervised Exercise = 45 %
* Medication = 47 %
Home exercise
n=53
Supervised
exercise n =51
Sertraline n = 49
Placebo n= 49
16 week study
Exercise: 3/week
Sertraline :50200mg/day
Blumenthal JA, et al. Psychosomatic Medicine. 2007;69:587-596.
So, What Do The
Clinical Studies Teach Us?
• Physical Exercise is clearly a helpful
anti-depressant intervention
• Both mono-therapy and combination
with anti-depressants are options
• Short and long term studies are both
positive
• Weight loss is not necessary in order
to benefit from Exercise
Depressed Individuals Aren’t Motivated –
“How Do We Get Them To Exercise?”
• Psycho-education with a twist!
• Use Neurobiological explanations of why
exercise is important
• Monitor
• Coach
• Ask for little to begin with (5 minutes three
times a day to start)
• Ask for daily exercise
Example of Patient Pushback
www.nationalfitnessequipments.com/blog/uploaded_images/mhh_depression_5002-748013.jpg.
Exercise Logs:
KEY to SUCCESS
EXERCISE LOG
My Goals for the week:
1
2
3
Mood Scale:
4 5 6 7
Not
Depressed
8
9
10
Very
Depressed
PLEASE RATE YOUR MOOD BEFORE AND AFTER EXERCISE BY CIRCLING THE APPROPRIATE NUMBER BELOW
MON
Date: _________
TUE
Date: _________
WED
Date: _________
THU
Date: _________
FRI
Date: _________
SAT
Date: _________
SUN
Date: _________
Activity:
Duration:
MOOD
Before: 1 2 3 4 5 6 7 8 9 10
After: 1 2 3 4 5 6 7 8 9 10
Activity:
Duration:
MOOD
Before: 1 2 3 4 5 6 7 8 9 10
After: 1 2 3 4 5 6 7 8 9 10
Activity:
Duration:
MOOD
Before: 1 2 3 4 5 6 7 8 9 10
After: 1 2 3 4 5 6 7 8 9 10
Activity:
Duration:
MOOD
Before: 1 2 3 4 5 6 7 8 9 10
After: 1 2 3 4 5 6 7 8 9 10
Activity:
Duration:
MOOD
Before: 1 2 3 4 5 6 7 8 9 10
After: 1 2 3 4 5 6 7 8 9 10
Activity:
Duration:
MOOD
Before: 1 2 3 4 5 6 7 8 9 10
After: 1 2 3 4 5 6 7 8 9 10
Activity:
Duration:
MOOD
Before: 1 2 3 4 5 6 7 8 9 10
After: 1 2 3 4 5 6 7 8 9 10
Inspiring quote for the week:
www.saundrajain.com/uploads/3/3/5/8/3358541/exercise_log.pdf. Accessed June 3, 2014.
My Fitness Pal:
Food and Exercise Log
“Stay motivated by keeping
an exercise log – track your
progress – it makes a
difference.”
- Anonymous
www.myfitnesspal.com. Accessed June 3, 2014.
What Is The Right ‘Dose’ of Exercise
For The Treatment of Depression?
• It appears to be 14 miles of walking per week
• Sounds like a lot!
• But, it’s 30 minutes of brisk walking per day (2
miles per day @ 4miles/ hour)
• This is a cardio protective AND mood benefitting
dose of exercise
In Conclusion:
Final Words On Exercise
Recommendations
• For general health, adults should achieve a
minimum of 30 minutes a day, of at least
moderate intensity, on five or more days of the
week
• For many people it’s likely that 45-60 minutes of
moderate intensity activity is needed to prevent
obesity
• It can be done either all in one session or through
several shorter bouts of activities 10 minutes or
or more
Daley A. J Clin Psychol Med Settings.2008;15:140-147.
Everything Old is New Again:
An Update on Meditation’s
Neurobiology and Clinical Utility
What Do You Think of
When I Say Meditation?
Dates Back
5000+ Years
Spread to West
Thousands of
Years Later
Buddha:
Meditation
Icon (500 BC)
Popular in the
West Mid-20th
Century
Buddhist &
Hindu-Based
Most Popular
60s & 70s
Researching
the Benefits
University of Florida Interactive Media Lab.
http://iml.jou.ufl.edu/projects/spring05/luft/history.htm. Accessed March 26, 2014.
What Type of Meditation is the Best?
Mindfulness
Compassion
Transcendental
LovingKindness
Qigong
Heart Rhythm
Meditation
Institute for Applied Meditation, University of the Heart. www.iam-u.org/index.php/8-basickinds-of-meditation-and-why-you-should-meditate-on-your-heart. Accessed March 26, 2014.
Mindfulness Meditation
What is Mindfulness Meditation?
Mindfulness: What Is It?
“Paying attention in a particular way:
on purpose, in the present moment,
and nonjudgementally.”
—Dr. Jon Kabat-Zinn
University of Massachusetts Medical Center
Kabat-Zinn J. Coming to Our Senses: Healing Ourselves and the World Through Mindfulness.
New York, NY: Hyperion; 2005.
Meditation + CBT = MBCT
“A Marriage Made in Heaven”
Cognitive
Behavioral
Therapy
Mindfulness
Based
Cognitive
Therapy
Mindfulness
Meditation
CBT = cognitive behavioral therapy; MBCT = mindfulness based cognitive therapy.
Neurobiology and Mindfulness
Is Mindfulness Good for the Brain?
Volumetric Changes in Meditators
MRI brain images
of 20 mindfulness
(Vipassana)
meditators (mean
practice 8.6 years;
2 hours daily) and
compared the
regional gray matter
concentration to that
of non-meditators
matched for sex,
age, education, and
handedness.
Hölzel BK, et al. Soc Cogn Affect Neurosci. 2008;3(1):51-61.
Volumetric Changes Over 8 Weeks of
Mindfulness-Based Therapy: Focus on Amygdala
Stressed but otherwise healthy individuals (N = 26) participated in
an 8-week MBSR intervention.
MBSR = mindfulness-based stress reduction.
Hölzel BK, et al. Soc Cogn Affect Neurosci. 2010;5(1):11-17.
Volumetric Changes in the Hippocampus
with 8 Weeks of Mindfulness-Based Therapy
Anatomical MRI images from 16 healthy, meditation-naive participants were obtained before and
after they underwent the 8-week program. Changes in gray matter concentration were investigated
using voxel-based morphometry, and compared with a waiting list control group of 17 individuals.
GMC = gray matter concentration. Hölzel BK, et al. Psychiatry Res. 2011;191(1):36-43.
Autonomic Nervous System and Inflammatory
Responses, Stress, and Meditation
50 healthy women (mean age = 41.32, range = 30-65), 25 novices and 25 experts, were exposed to
each of the conditions (yoga, movement control, and passive-video control) during 3 separate visits.
Kiecolt-Glaser JK, et al. Psychosom Med. 2010;72(2):113-121.
Evidence-Based Mindfulness
Does Mindfulness Really Help Our Patients?
MBCT and GAD:
Does it Make a Difference?
Baseline
P < .05
Post-intervention
70
60.82
60
48.82
Mean Score
50
40
30
20
10
0
19
16.9
9.7
8.91
BAI
13.8
PSWQ
POMS tensionanxiety
8.82
BDI
N = 11.
↑ scores = ↑ psychological distress.
GAD = generalized anxiety disorder; BAI = Beck Anxiety Inventory; BDI = Beck Depression Inventory;
PSWQ = Penn State Worry Questionnaire; POMS = Profile of Mood States.
Evans S, et al. J Anxiety Disord. 2008;22(4):716-722.
MBCT and Panic Disorder
Does it Make a Difference?
18
0 week
16.8
2nd week
16
Mean Scores
14
4th week
12.6 12.5
8th week
12
10.0
10
8
6.2
6
3.3
4
4.2
3.3
2
0
HAM-A
PDSS
N = 23; P < .01, The decreases of both HAM-A (P < .01) and PDSS (P < .01) became significant
beginning the second week of the MBCT program according to the pairwise comparisons.
HAM-A = Hamilton Anxiety Rating Scale; PDSS = Panic Disorder Specific Scale.
Kim B, et al. J Anxiety Disord. 2010;24(6):590-595.
MBCT: A Promising New Therapy
N = 84.
M-ADM = Medication (antidepressant continuation); Pla+Clin = placebo plus clinical management
(discussion of functionality, support, and limited advice).
Segal ZV, et al. Arch Gen Psychiatry. 2010;67(12):1256-1264.
Online Mindfulness Training:
Looks Promising!
Change from pre- to post-course and follow-up (1 month after course completion)
Change in Depression
Change in Anxiety
12
12
10.98
10.06
10
8
6
5…
4.30
4
2
PHQ-9; Score 0-27
Score Before
Course
Score After
Course
Score One
Month On
Mean GAD-7 Score
Mean PHQ-9 Score
10
8
5.45
6
4.60
4
2
GAD-7; Score 0-21
Score Before
Course
Score After
Course
Time
PHQ-9 = Patient Health Questionnaire; GAD-7 = Generalized Anxiety Disorder 7-item scale.
Krusche A, et al. BMJ Open. 2013;3(11):e003498.
Time
Score One
Month On
Mindfulness is Both
Teachable & Effective
6-week, 10 obese patient group curriculum for providing mindfulness training to obese individuals,
called Mindful Eating and Living (MEAL). Six weekly two-hour group classes (with two monthly
follow-up classes). Content included training in mindfulness meditation, mindful eating, and group
discussion, with emphasis on awareness of body sensations, emotions, and triggers to overeat.
Interpretative ranges: 0.2 =
small, 0.5 = medium, and
0.8 = large
Data are reported as mean, standard deviation in parentheses
Dalen J, et al. Complementary Therapies in Medicine. 2010;18:260-264.
Additional Findings From the MEAL Study
(Mindfulness Eating And Living)
Findings 6 weeks after the 6 week intervention
study – 12 week follow-up. Positive effects on
weight and inflammation reduction persisted
• A mean weight loss of 4 kg (p<0.01)
• Average BMI among all participants went from 37 kg to
35.7 kg over 12 weeks, for a mean BMI loss of 1.3 kg
(p < 0.01)
• There was also a reduction in C-reactive protein
(hsCRP) from 0.30 to 0.24 mg/dl over 12 weeks (p <
0.04)
Dalen J, et al. Complementary Therapies in Medicine. 2010;18:260-264.
Clinical Aspects of Mindfulness
Meditation
Practical Tips for Incorporating Mindfulness
Meditation into Your Busy Clinical Practice
Incorporating Mindfulness into a Busy
Practice: Overcoming Potential Barriers
• Begin a dialogue with patients about
meditation
• Provide handouts on the benefits of meditation
• Encourage the use of meditation apps
• Provide patients with a list of resources
• Refer to clinicians who specialize in
meditation
• Educate about the neurobiological benefits
• Begin or continue your own meditation practice
MBCT Program Overview
MBCT Outline
(8-week program)
THOUGHTS
• Mindfulness facilitator
FEELINGS
• 2 hours a week for 8 weeks
• 1 all day session between weeks 5 and 7
• Daily homework using CDs
• Talk about experiences with home practices,
obstacles, and how to deal with them
SENSATIONS
Patient Downloads and Handouts
• >40 reproducible handouts
• Access to Web site with downloadable
audio recordings of guided mindfulness
practices
• Access to all the reproducibles, ready to
download and print in 8 ½" x 11" size
• Separate Web site for use by patients
featuring the audio recordings only
.
More Mindfulness Resources
MBCT Resources
“The Green Book”
Clinician Guide
“The White Book”
Patient Guide
“The Mindful
Workbook”
Mindfulness Apps
Mindfulness
App
Mindfulness
App II
www.psychcongress.com/saundras-corner/apps/meditation-apps. Accessed March 26, 2014.
Top Three Practical Take-Aways
• Meditation is a powerful clinical intervention leading to
better outcomes
• Meditation is not just a “feel good” intervention but is
supported by strong neurobiological findings
• Meditation is easy to incorporate into a busy clinical
practice using a variety of different resources
Image: http://sphotos-a.xx.fbcdn.net/hphotos-ash3/p480x480/561813_451199408235422_1571466411_n.jpg.
Rakesh Jain, MD, MPH
Clinical Professor
Department of Psychiatry
Texas Tech University School of Medicine
Texas, USA
(JainTexas@gmail.com)
Q&A Session