National Institute on Alcohol Abuse and Alcoholism

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National Institute on Alcohol Abuse and
Alcoholism

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

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Demystifying Medicine

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

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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

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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

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Who Are Perpetrators?

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

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Behavioral Symptoms

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

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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

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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

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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 lt.01
• Chi-square
• Plevel of significance, plt.05.

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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 lt0.01
• 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
• Plevel of significance, plt.05.

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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 lt.01 Alcohol Dependence 0
36 lt.01 Cannabis Dependence 0
11 lt.01 Chi-square Plevel of
significance, plt.05.
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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
• Plevel of significance, plt.05.

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Lactate Infusion

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

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Model for understanding the psychopathology of
perpetrators
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Conditioned fear response

slow
defensive behavior autonomic arousal hypoalgesia s
tress homones
rapid
Armony and LeDoux (1997) Davis, Raommie and
Cassell (1994) Siegel, et al. (1999)
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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.

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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.

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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.

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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.

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Mean CMRglc in the right hypothalamus is
significantly lower in perpetrators with alcohol
dependence
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Alcoholic perpetrators of domestic violence,
compared with non-violent alcoholics, have
reduced correlations with the left amygdala ROI
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Alcoholic perpetrators of domestic violence,
compared with healthy controls, have reduced
correlations with the left and right amygdala
ROIs
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Non-violent alcoholics, compared with healthy
controls, have increased correlations between the
left thalamus and left posterior orbitofrontal
cortex ROIs
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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.

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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

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Current research in domestic violence

• Treatment
• fMRI
• Genotyping

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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.

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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.

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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

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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

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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.

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Facial expressions
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Labelling Task (Happy)
Amygdala activation P lt .05
perpetrator
control
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Labelling Task (Anger)
Perpetrators show significant activation in the
Orbitofrontal cortex p lt 0.05
control
perpetrator
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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.

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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.

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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).

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Decreased cortical input enhances fight / flight
/ shutdown behavioral responses
slow
rapid
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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

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SR141716 decreases ethanol consumption in young
rodents
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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.

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Study design
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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

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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