# Presentation: 128081

## National Institute on Alcohol Abuse and Alcoholism 

**Section of Clinical Studies **
**David T. George, M.D.**

##    Demystifying Medicine

- Alcohol and domestic violence
- Background
- Behavioral Characteristics
- Diagnoses
- Research Findings
- Model
- Treatment
- Alcohol treatment

## Domestic Violence in the United States

- 20% to 30% of all men and women will be assaulted by their spouse/significant other at some time in their lives
- Domestic violence accounts for:
- 		1)  20% of all emergency room visits
- 		2)  50% of all police calls
- 		3)  30% of all female murders

## Literature Review

- 70% of perpetrators have an alcohol problem
- Most studies focus on psychosocial issues:
- 		1) power/control
- 		2) learned behaviors
- Minimal emphasis given to biological concomitants

## Who Are Perpetrators?

- Multiple fights during childhood
- Violence typically occurs in the home
- Blame others
- Impulsive behaviors
- Alcohol calms them down

## Behavioral Symptoms

- Racing thoughts
- Super sensitive to environmental stimuli
- Mood swings
- Calm
- Shutdown
- Flight
- Fight
- Stalking

## Triggers and symptoms associated with domestic violence

- Triggers manifested by partner
- A “look”
- A “tone” of voice
- Symptoms manifested by perpetrators
- Autonomic activation
- Escalating anxiety
- Fear

## Study participants

- Healthy comparison subjects
- Non-violent alcoholics
- Perpetrators of domestic violence
- 		Multiple episodes of domestic violence
- 		Violence not limited to periods of intoxication
- 		No diagnosis of bipolar, schizophrenia
- 		Normal MRI
- All subjects were:
- In good health and on no medications
- No history of seizures or major head trauma
- Sober for at least three weeks prior to research

## Comparison of non-violent/violent alcoholics: Axis I diagnoses show alcoholic perpetrators have a higher proportion of anxiety related disorders than non-violent alcoholics

- _	__	__	__	__	__	__	__	__	_
**Axis I Diagnosis****	****Non-violent ****	****Perpetrators with**
**	****	****	****	****alcoholics****	****alcohol dependence**
**	****      ****	****	**** ****	****(N = 37)****	****(N = 18)**
_***	***__***	***__***	***__***	***__***	***__**	**__**	**__**    **__**	**__**   **__***P***__***	***_
**Major Depression ****	****      6****	****  ****	****      8****	****	****0.03**
**Panic Attack ****	****	****      1****	****  ****	****      4****	****	****0.02**
**Social Phobia****	****	****      5****	****  ****	****      7****	****	****0.04**
**Obsessive-Compulsive         0****	****  ****	****      3****	****	****0.01**
**Generalized Anxiety ****	****      0****	****  ****	****      6****	****	****<.01**
- _	__	__	__	__	__	__	__	__	_
**Chi-square**
***P*****=level of significance, p<.05.**

## Comparison of non-violent/violent alcoholics: Axis II diagnoses show alcoholic perpetrators have a higher proportion of cluster B and C personality disorders than non-violent alcoholics

- _	__	__	__	__	__	__	__	__	__  _
**Axis II Diagnosis      ****	****Non-violent ****	****Perpetrators with**
**	****	****	****	****alcoholics****	****alcohol dependence**
**	****      ****	****	**** ****	****(N = 37)****	****(N = 18)**
_***	***__***	***__***	***__***	***__***	***__**	**__**	**__**    **__**	**__**     **__***P***__***	***_
**Cluster B personality disorders**
**Borderline ****	**** ****	****  8****	****	****   15    ****	****	****<0.01**
**Antisocial ****	**** ****	****  4****	****  ****	****     9    ****	****	****   0.02**
**Cluster C personality disorders**
**Dependent****	****	****  2****	****	****     6 ****	****     ****	****   0.01**
**Obsessive-Compulsive****	****  6****	****  ****	****     8      ****	****  ****	****   0.03**
**Passive-Aggressive****	****  1****	****  ****	****     4      ****	****	****   0.02**
- _	__	__	__	__	__	__	__	__	_
**Chi-square**
***P*****=level of significance, p<.05.**

## Comparison of perpetrators with/without alcohol dependence: Axis I diagnoses show that perpetrator groups only differ in substance abuse related diagnoses

- _	__	__	__	__	__	__	__	__	__	_
**Axis I Diagnosis****	****Perpetrators without****	****Perpetrators with**
**	****	****      ****	****	****alcohol dependence ****	****alcohol dependence ****	****	****	****	****(N = 12)****	****	****(N = 18)**
_***	***__***	***__***	***__***	***__***	***__**	**__**	**__**    **__**	**__**   **__**	**__***P***__***	***_
**Organic Mood****	**** ****	****      0****	****	****	****      21****	****	****<.01**
**Alcohol Dependence****	****      0****	****	****	****      36****	****	****<.01**
**Cannabis Dependence ****	****      0****	****	**** ****	****      11****	****	****<.01**
- _	__	__	__	__	__	__	__	__	__	_
**Chi-square**
***P*****=level of significance, p<.05.**

## Comparison of perpetrators with/without alcohol dependence for Axis II diagnoses

- _	__	__	__	__	__	__	__	__	__	__  _
**Axis II Diagnosis      ****	****Perpetrators with****	****out****	****Perpetrators with**
**	****	****      ****	****	****alcohol dependence ****	****alcohol dependence ****	****	****	****	****(N = 12)****	****	****	****(N = 18)**
_***	***__***	***__***	***__***	***__***	***__***	***__***	***__***    ***__**	**__**        **__**	**__**  **__***P***__***	***_
**Borderline ****	**** ****	****     5****	**** ****	****	****     15****	****	****0.02**
- _	__	__	__	__	__	__	__	__	__	_
**Chi-square**
***P*****=level of significance, p<.05.**

## Lactate Infusion

- Double-blind, placebo-controlled
- 10cc/kg of 0.5M sodium lactate infused over 20 minutes
- Videotaped

## Slide 14

## Model for understanding the 

- Model for understanding the
- psychopathology of perpetrators

## Conditioned fear response

- rapid

**defensive behavior**
**autonomic arousal**
**hypoalgesia**
**stress homones**

- Armony and  LeDoux (1997)
- Davis, Raommie and Cassell (1994)
- Siegel, et al. (1999)

- slow

## Importance of cortex - amygdala connections

- Bard (1928) - Animals are more likely to respond to environmental stimuli with “defensive rage” following cortical ablation at the level of the high midbrain.
- Morgan et al., (1993) -  Animals with lesions to the dorsal medial prefrontal cortex exhibit increased fear reactivity.
- Morgan et al., (1993 and 1995) - Lesions to the medial prefrontal cortex impair the ability of an animal to extinguish conditioned fear responses.

## Importance of cortex - amygdala connections

- Garcia et al., (1999) - The presence of threatening stimuli causes the amygdala to decrease the firing rate of the medial prefrontal cortex neurons.
- Hariri et al., (2000) – Angry and fearful faces increase rCBF to the amygdala in healthy controls.  Cognitive labeling of the angry and fearful faces caused a decrease in to the amygdala and a simultaneous increase in rCBF to the right prefrontal cortex.

## Conceptualization for the etiology of domestic violence

- “Threats” (i.e., looks, tones of voice) trigger a conditioned fear response, which is out of proportion to the stimulus, and may result in the expression of fear-induced aggression.
- The misinterpretation of “threat” arises from a abnormality in the structures and/or pathways that mediate fear-induced aggression.

## PET (18FDG) imaging: to study the neural structures and pathways involved in fear conditioning/fear induced aggression

- MRI and 18FDG PET were obtained for each subject.
- Regions of interest (ROIs) were manually drawn around each desired structure on MR images.
- T1-weighted MRI scan was co-registered to its corresponding PET volume using a modified surface matching algorithm (Besel et al., 1992).
- The average glucose count within each structure (i.e., ROI) was then computed from its corresponding matching PET.
- The CMRglc value for each ROI is the mean value of all voxels within the ROI. These values are absolute CMRglc values.
- Continuous auditory performance task (Cohen et al., 1992) was performed during the brain uptake of 18FDG to ensure all participants were in a similar cognitive state.
- Pressing a button in response to the higher pitched of two tones while ignoring the lower pitched tone.

## Mean CMRglc in the right hypothalamus is significantly lower in perpetrators with alcohol dependence   

|  | Healthy Controls
mean+SD
N=10 | Non-violent Alcoholics
mean+SD
N=11 | Perpetrators w Alc. Depend.
mean+SD
N=8 | df | F | p |
| --- | --- | --- | --- | --- | --- | --- |
| Right Posterior Orbitofrontal Cortex  | 7.55+1.44 | 7.48+1.21 | 6.78+1.21 | 2,26 | 0.95 | .40 |
| Left Posterior Orbitofrontal Cortex  | 7.60+1.78 | 7.55+0.85 | 7.43+0.72 | 2,26 | 0.04 | .96 |
| Right Amygdala  | 5.65+1.06 | 5.28+0.76 | 5.02+0.43 | 2,26 | 1.39 | .27 |
| Left Amygdala  | 5.73+0.90 | 5.35+0.94 | 5.01+0.64 | 2,26 | 1.61 | .22 |
| Left Basal Forebrain  | 8.82+2.01 | 8.07+1.55 | 7.58+1.19 | 2,26 | 1.32 | .29 |
| Right Basal Forebrain  | 8.63+1.89 | 7.96+1.65 | 7.22+1.07 | 2,26 | 1.71 | .20 |
| Right Hypothalamus  | 7.73+1.38 | 6.96+1.28 | 5.69+0.86 | 2,26 | 6.28 | .01 |
| Left Hypothalamus  | 7.55+1.61 | 6.68+1.30 | 5.98+0.77 | 2,26 | 3.24 | .06 |
| Anterior Cingulate Cortex  | 7.10+1.26 | 6.82+0.87 | 6.52+0.68 | 2,26 | 0.78 | .47 |
| Posterior Cingulate Cortex  | 7.49+1.38 | 6.98+0.97 | 6.78+0.86 | 2,26 | 1.03 | .37 |
| Left Caudate  | 5.84+0.94 | 6.47+1.30 | 6.00+0.75 | 2,26 | 1.01 | .38 |
| Right Caudate  | 6.07+1.28 | 6.36+1.12 | 6.34+0.86 | 2,26 | 0.21 | .81 |
| Left Thalamus | 7.79+1.90 | 8.30+1.59 | 7.48+0.54 | 2,26 | 0.71 | .50 |
| Right Thalamus | 7.74+1.90 | 8.38+1.43 | 8.02+0.73 | 2,26 | 0.51 | .61 |

## Alcoholic perpetrators of domestic violence, compared with non-violent alcoholics, have reduced correlations with the left amygdala ROI

## Alcoholic perpetrators of domestic violence, compared with healthy controls, have reduced correlations with the left and right amygdala ROI’s

## Non-violent alcoholics, compared with healthy controls, have increased correlations between the left thalamus and left posterior orbitofrontal cortex ROI’s

## Do the differences in correlations indicate different motivations to drink alcohol?

- The increased correlation found in non-violent alcoholics makes them more susceptible to conditioned positive reinforcement or cues.
- Alcoholic perpetrators drink alcohol to decrease anxiety.

## Lumbar Puncture

- Lumbar puncture was performed in the left lateral decubitus position after over-night bed rest and fast
- 5-HIAA was quantified by gas chromatography-mass spectrometry

## Slide 27

## Slide 28

## Current research in domestic violence

- Treatment
- fMRI
- Genotyping

## Treatment of perpetrators of domestic violence

- There are no effective treatments for domestic violence.
- Primary Hypothesis:
- Fluoxetine will be more effective than placebo in decreasing measures of aggression, anxiety, and depression in a select group of perpetrators of domestic violence.

## Why fluoxetine? 

- Perpetrators without alcoholism have lower CSF 5-HIAA than non-violent controls.
- 5-HT acts in the medial prefrontal cortex to modulate freezing behaviors.
- 5-HT input at the amygdala, the medial hypothalamus, and the PAG is involved with the control/expression of fight/flight behaviors.
- Fluoxetine has been shown to be effective in previous aggression studies.

## Study design

- Perpetrators of domestic violence are being randomized to receive up to 40 mg of fluoxetine or placebo per day for a duration of 3 months.
- Psychotherapy
- Education
- Cognitive-Behavioral

##  Outcome measures

- M-Overt Aggression Scale
- Anger, Irritability, Assault Questionnaire
- Hamilton Depression Rating Scale
- Spielberger State Anxiety Inventory
- The Drinker Inventory of Consequences
- Straus Conflict Tactics
- Spouse/Significant other interview
- Partner Abuse Scale (non-physical and physical)
- Dyadic Interaction Paradigm
- Point Subtraction Aggression Paradigm

## Functional MRI

- Angry and fearful facial expressions will activate the amygdala.
- Labeling the angry/fearful facial expressions will not decrease the amygdala activation in the perpetrators as compared to non-violent comparison subjects.
- Fluoxetine will normalize the difference between perpetrators and non-violent comparison subjects.

## Facial expressions

## Labelling Task (Happy)

**control**

**perpetrator**

- Amygdala activation P < .05

## Labelling Task (Anger)

**control**

**perpetrator**

- Perpetrators show significant activation
-  in the Orbitofrontal cortex p < 0.05

## Genotyping

- Background
- Fluoxetine is thought to exert its therapeutic effect by binding to the serotonin transporter (5-HTT).
- The long (l) and short (s) variants of the promoter have different transcription efficiencies.
- Smeraldi showed that individuals with the l/l and l/s alleles had better antidepressant response to fluvoxamine than subjects with s/s allele.
- Harari using fMRI demonstrated healthy controls with either s/s or l/s alleles have a greater increase in amygdala activation in response to fearful stimuli than healthy controls with l/l alleles.

## Genotyping hypotheses

- Perpetrators with either l/s or s/s alleles will have greater amygdala activation when presented fearful or angry faces in the fMRI, than perpetrators with the l/l allele.
- Outcome measures will show an interaction between fluoxetine and genotype.

## Effect of alcohol administration on fear conditioning

- Alcohol increases the neural transmission from the medial hypothalamus to the PAG facilitating defensive rage (Schubert et al. 1996).

## Decreased cortical input enhances fight / flight / shutdown behavioral responses

- slow

- rapid

## Clinical trial of the cannabinoid CB1 receptor antagonist, SR141716

- Endogenous cannabinoids have been implicated in the control of appetitive behaviors in animals and humans.
- SR141716 reduces food intake in rodents and obese people
- SR141716 reduces ethanol drinking in rodents

## SR141716 decreases ethanol consumption in young rodents

## Hypothesis

- SR141716 will be more effective than placebo to reduce voluntary drinking in a select group of young, healthy, non-treatment seeking individuals who consume between 20 and 40 drinks per week.

## Study design

## Outcome measures

- Primary:
- Drinks consumed during self-administration
- Secondary:
- Alcohol Urge Questionnaire
- Biphasic Alcohol Effect Scale
- Videotape of alcohol self-administration
- ACTH / cortisol
- Insulin / glucose

## Collaborators

- Paolo DePetrillo 			Vijay Ramchandani
- Dasha Dotson			Stanley Rapoport
- Linda Doty 				Robert Rawlings
- Aryeh Herman 			Norman Salem
- Joe Hibbeln 				Jasmin Salloum
- Debra Hill 				Erick Singley
- Daniel Hommer 			John Umhau
- George Kunos 			Wendol Williams
- Monte Phillips
- 6 West/Outpatient Clinic Nursing Staff