Alcohol, Stress and the Brain:
Effects on Alcohol Relapse and
Recovery
RAJITA SINHA, Ph.D.
DEPARTMENT OF PSYCHIATRY,
NEUROBIOLOGY AND CHILD STUDY
YALE UNIVERSITY SCHOOL OF MEDICINE
Data from 878 outpatients classified on the basis of primary drug of
abuse (cocaine, marijuana, opioid, alcohol). Survival distribution function
is shown on the y axis, which represents the proportion of patients
surviving relapse and remaining abstinent during the assessment period
of 350 days shown on the x axis
Sinha R, Current Psych. Rep. 2011
How Can We Understand Alcohol
Relapse and Recovery?
MAJOR CHALLENGE:
Relapse is a highly common phenomena!
Multiple relapse precipitants: stressors, negative
moods, boredom, drug related stimuli (people,
places and things) and temptations.
What leads to a specific lapse or relapses
across episodes of recovery may be different in
the same individual and of course be different
across individuals.
Why Focus on Understanding
Alcohol Relapse and Recovery?
POTENTIAL BENEFITS:
Identify biomarkers of alcohol relapse:
Develop and validate measures that drive
alcohol relapse and jeopardize recovery.
Personalized Medicine:
– Use those biomarkers to identify those most at risk for
relapse and treatment failure
– Develop specific treatments to reverse those effects
and help those most susceptible to high alcohol
relapse risk and to jeorpardizing recovery.
Chronic Alcohol-related Changes
Associated with Early Recovery
Behavioral/Mood Changes
Altered Stress Neurobiology
Alcohol Craving – reactivity to
alcohol related stimuli
Alterations in CRF-HPA axis
function
Increased stress, anxiety, and
irritability
High sympathetic arousal and
lower parasympathetic tone
Sleep problems
Noradrenergic dysregulation
Cognitive Problems
Decreased activity of D2
receptors
Brain Atrophy:
Change in gray and white
volume, brain proteins
Decreased responsiveness of the
frontal cortex; lower GABA
Studying Relapse/Recovery in
Humans
STRESS,
Chronic Drug
Intake/Withdrawal
DRUG CUES,
DRUGS
CRF, NA, Glutamate
Altered DA, GABA, 5HT,
NPY, BDNF, eCB,
Opioids/POMC peptides
Effects on
Relapse?
Possible Biomarkers?
•Structural brain changes
• Altered negative emotion and
anxiety and drug craving
• Altered HPA axis, autonomic
and other biochemical function
•Altered response in brain
emotional and motivational
circuits
Drug
Craving
Enhanced Alcohol Craving in 4week Abstinent Alcoholics
5
**
Alcohol Craving
4
Group X Condition interaction:
[2,108 = 20.1; p<.0001]
**
3
2
**
**
1
0
S
N
Peak
C
S'
N'
C'
Average
Black bars: AD patients; Grey bars: SD Controls
Sinha et al., 2009; 2011
Higher Stress-Induced and Cue-Induced Alcohol
Craving is Predictive of Time to Alcohol
Relapse During Follow-up
1.0
Stress-induced Craving
Estimated Survival Function
Estimated Survival Function
1.0
0.8
0.6
0.4
S_CRV = 0.0
S_CRV = 0.5
S_CRV = 1.0
0.2
S_CRV = 2.6
S_CRV = 4.3
S_CRV = 6.0
0.0
0
20
40
60
Time to Relapse (Days)
80
Alcohol cue-induced Craving
0.8
0.6
0.4
C_CRV = 0.0
C_CRV = 0.5
C_CRV = 1.1
0.2
C_CRV = 2.9
C_CRV = 4.6
C_CRV = 6.4
0.0
100
0
20
40
60
80
Time to Relapse (Days)
Cox Proportional Hazards Regression: Stress-induced alcohol craving
(X2=4.86 p<.03; HR: 1.16) and alcohol cue-induced craving (X2=5.75, p<.02;
HR: 1.18) were each predictive of time to alcohol relapse.
Sinha et al., Archives of General Psychiatry, 2011
100
Altered Stress Physiology:
Abstinent Patients vs. Controls
0.30
Basel Salivary Cortisol (µg/dl)
Heart Rate at Baseline (bpm)
72
70
68
66
64
62
0.28
0.26
0.24
0.22
0.20
0.18
0.16
60
AD
CO
Group
HC
AD
CO
Group
Heart rate: AD=Coc>HC (p<.01); Cortisol: AD>HC (p<.03)
data combined across studies (Fox et al., 2007; Sinha et al., 2009;
summarized in Sinha, Addiction Biology, 2009)
HC
Higher Neutral State the Cort/ACTH AUC
Ratio (adrenal sensitivity), Greater the
Likelihood of Relapse
1.0
0.8
0.6
N_C/A ratio = 0.0
N_C/A ratio = 0.1
0.4
N_C/A ratio = 0.5
0.2
N_C/A ratio = 0.9
N_C/A ratio = 1.3
N_C/A ratio = 1.7
0.0
0
20
40
60
Time to Relapse (Days)
80
100
Estimated Survival Function
Estimated Survival Function
1.0
0.8
0.6
N_C/A ratio = 0.0
N_C/A ratio = 0.1
0.4
N_C/A ratio = 0.5
0.2
N_C/A ratio = 0.9
N_C/A ratio = 1.3
N_C/A ratio = 1.7
0.0
0
20
40
60
80
Time to Heavy Relapse (Days)
Cox Proportional Hazards Regression: Cort/ACTH ratio during neutral
(X2=7.24, p<.007; HR: 2.16) and stress exposure (X2=5.37, p<.02; HR: 1.62)
were predictive of time to alcohol relapse.
Sinha et al., Archives of General Psychiatry, 2011
100
Smaller gray matter volume in
abstinent alcoholics vs Controls
(p<.01 FWE corrected)
a)
b)
Patient vs. Controls:
a) Lateral frontal region
b) Medial frontal regions
(BA 24, SMA region 6)
c)
Whole brain voxel based morphometry (VBM),
controlling for age, sex, total intracranial volume
c) Parietal – occipital
region
Rando et al., American J of
Psychiatry, 2011
Smaller GMV is Predictive of Future
Alcohol Relapse in Abstinent Alcoholics
(Rando et al., Am J of Psychiatry, 2011)
Parietal Occipital Cluster
Medial Frontal Region
1.0
Estimated Survival Function
Estimated Survival Function
1.0
0.8
0.6
0.4
Mean - 2SD : 6.01
Mean - 1SD : 6.90
Mean
: 7.79
Mean + 1SD : 8.68
Mean + 2SD : 9.57
0.2
0.0
0.8
0.6
0.4
Mean - 2SD : 7.17
Mean - 1SD : 8.22
Mean
: 9.27
Mean + 1SD : 10.32
Mean + 2SD : 11.37
0.2
0.0
0
10
20
30
40
Time to Relapse (Days)
50
60
0
10
20
30
40
50
Time to Relapse (Days)
Estimated survival risk functions for specific gray matter volume values for mean
(in red) and at +/-1 and +/-2 SD above and below the mean for, (a) the medial
frontal cluster (X2 = 6.97, p < .008, HR = .51, CI = .31-.84) and, (b) the
parietal-occipital cluster (X2 = 6.90, p < .009. HR = .57, CI = .38 -.87).
60
Disrupted Neural Response to Stress and
Relaxed Scenarios in Recovering Alcoholics
(AD)s versus Controls (HC) (p<.01 WBC)
Seo et al., JAMA Psychiatry, 2013
Greater mPFC activity during neutral
relaxed state predicts shorter
time to future alcohol relapse
Neutral VmPFC
Estimated Survivorship Function
1.0
Mean - 2SD : -0.44
Mean - 1SD : -0.23
Mean : -0.02
Mean + 1SD : 0.19
Mean + 2SD : 0.4
0.8
0.6
0.4
0.2
0.0
0
10
20
30
40
Time to Relapse (Days)
50
60
Greater relapse risk
with less deactivation
in the medial PFC,
shown at specific
percent signal change
values
Cox Proportional Hazards Regression Model: X2=8.4, p<.002, HR:6.6; (6.6 times greater
likelihood of relapse) (controlling for craving and years of alcohol use)
Blunted stress-related medial pre-frontal
activity predicts shorter time to
alcohol relapse
Stress - Neutral VmPFC
Estimated Survivorship Function
1.0
Mean + 2SD : -0.66
Mean + 1SD : -0.32
Mean : -0.02
Mean - 1SD : 0.36
Mean - 2SD : 0.70
0.8
0.6
0.4
0.2
0.0
0
10
20
30
40
50
60
Greater relapse risk
with blunted stressrelated activity in the
medial PFC, shown
at specific percent
signal change values
Time to Relapse (Days)
Age = 37, Balc_avguseperuse = 13
Cox Proportional Hazards Regression Model: X2=5.16, p<.02, HR: 0.25 (75% increased
likelihood of relapse)
Seo et al., JAMA Psychiatry (2013)
Jeopardizing Recovery: The
Alcohol Relapse Risk Phenotype
The Psychobiological and Neural Response Profile of
Relapse Risk:
– Increased anxiety and provoked alcohol craving
– High cortisol/ACTH ratio and altered stress
endocrine responses (NPY , BDNF and
anandamide)
– Hyperresponsive brain during neutral relaxed state
associated with greater anxiety and alcohol craving
and blunted PFC response with stress.
– Smaller gray matter volume in medial frontal and
posterior regions
Sinha R, Current Psychiatry Reports, 2011
Effect of Past and Recent
Trauma on Alcohol Intake
No Trauma
Past Trauma
Recent Trauma
Both
**p<.01;
Large Adult Community Sample (N=847) - comprehensively assessed for
Past and Recent Trauma and Alcohol Intake
Hermes, Sinha et al., ACNP, 2015
Effects of Recent Trauma on Brain
Activation During Neutral and Stress
During Neutral/Relaxing State
Stress - Neutral
Significantcorrelationbetweennumberofrecenttraumaticeventsandneutral
relaxedconditionincreasedactivationintheventromedialprefrontalcortex
(VmPFC),anteriorcingulatecortex(ACC),ventralstriatum(VS),posteriorcingulate
cortexandprecuneusregions,anddecreasedVmPFC/ACCresponseduringstress
wascorrelatedwithfrequencyofrecentstress/traumaevents(Wholebrain
corrected,p<0.05).
Hermes,Sinhaetal.,ACNP2015
Prefrontal Control of Stress,
Craving and Behavior
HOT
SPOT
Can we reverse the effects of
chronic alcohol and trauma to
improve recovery outcomes?
– Medications
– Behavioral Strategies
– Adjunct wellness strategies
80.0
30.0
**
25.0
**
70.0
20.0
Baseline
15.0
End
PCL-C
PTSD Dream Rating Scale
Prazosin Improves Dream Ratings and
Decreases PTSD Clinical Symptoms
Baseline
60.0
End
10.0
50.0
5.0
0.0
PLA
PZ
40.0
PLA
PZ
** p<.05; PLA: PLACEBO; PZ: PRAZOSIN
Taylor, Raskind et al., Biological Psychiatry, 2008
Prazosin decreases stress-induced alcohol
craving, anxiety and negative emotions in
the laboratory (N=17)
a) Alcohol Craving
STRESS IMAGERY
NEUTRAL IMAGERY
ALCOHOL CUE IMAGERY
1.6
1.4
1.2
1.8
1.0
1.6
0.8
1.4
0.6
1.2
0.4
1.0
0.2
0.8
0.0
0.6
0.4
p<.04
a) Alcohol Craving
S>N, p<.0001
STRESS IMAGERY
NEUTRAL IMAGERY
ALCOHOL CUE IMAGERY
C>N, p<.0001
p<.04
S>N, p<.0001
c) Negative Emotion
C>N, p<.0001
8
PLACEBO
PRAZOSIN
0.2Subjective response to stress, alcohol cue and neutral imagery in which means and standard errors represent data
Figure 1a:
collapsed0.0
across peak and recovery time-points. Note: PZ < PL following exposure to stress imagery (p<.04)
PLACEBO
PRAZOSIN
b)
Anxiety
Figure 1a: Subjective response to stress, alcohol cue and neutral imagery in which means and standard errors represent data
1.5
nxiety - change from
Anxiety
baseline
- change from baseline
STRESS
IMAGERY
collapsed across peak and recovery time-points. Note: PZ < PL following exposure to stress
imagery (p<.04)
NEUTRAL IMAGERY
ALCOHOL CUE IMAGERY
1.0
p<.0001
b)
1.5
0.5
1.0
0.0
0.5
-0.5
S>N, p<.0001
C>N, p<.0001
Negative Emotion - Change from baseline
Alcohol Craving -Alcohol
changeCraving
from baseline
- change from baseline
1.8
6
p<.003
4
S>N, p<.0001
C>N, p=.001
2
0
-2
PLACEBO
Anxiety
STRESS IMAGERY
NEUTRAL IMAGERY
ALCOHOL CUE IMAGERY
PRAZOSIN
c) Figure 1c: Subjective response to stress, alcohol cue and neutral imagery in which means and standard errors represent
STRESS IMAGERY
NEUTRAL IMAGERY
ALCOHOL CUE IMAGERY
data collapsed across peak and recovery time-points. Note: PZ < PL following exposure to stress imagery(p<.003)
p<.0001
Fox et al., Alcoholism: Clinical and
Experimental Research (2011)
S>N, p<.0001
C>N, p<.0001
0.0
-1.0
PLACEBO
PRAZOSIN
Prazosin normalizes prefrontal activation
during stress and cue exposure in alcohol
dependent patients (N=14)
PRAZOSIN – PLACEBO
(A) Drug Cue
(B) Stress
Sinha Lab: Preliminary data: unpublished
In Conclusion
Specific blood and brain biomarkers of alcohol
relapse: These have been identified and now we
are working to validate these biomarkers.
Personalized Medicine Goal 1: Identify those are
most vulnerable at treatment entry or during early
recovery
Personalized Medicine Goal 2: Developing specific
treatments to reverse chronic alcohol and trauma brain
effects to help those most susceptible to high alcohol
relapse risk and to jeorpardizing recovery.
Acknowledgements
Yale Interdisciplinary Stress Center
Collaborators:
Sara Blaine, Ph.D.
Peter Morgan, MD, PhD
Joseph Guarnaccia, MD
Cheryl Lacadie, MS
Kwang-ik Hong, MS
Kenneth Rando, MS
Robert Beech, MD, PhD
Dongju Seo, PhD
Helen Fox, Ph.D.
Keri Tuit, Psy.D.
Verica Milivojevic, Ph.D.
Robert Fulbright, MD
Todd Constable, Ph.D.
Supported by National Institutes of Health Common Fund
and the National Institute of Alcohol Abuse and Alcoholism