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National Institute on Alcohol Abuse and Alcoholism

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.

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National Institute on Alcohol Abuse and Alcoholism

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  1. National Institute on Alcohol Abuse and Alcoholism Section of Clinical Studies David T. George, M.D.

  2. Demystifying Medicine • Alcohol and domestic violence • Background • Behavioral Characteristics • Diagnoses • Research Findings • Model • Treatment • Alcohol treatment

  3. 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

  4. 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

  5. Who Are Perpetrators? • Multiple fights during childhood • Violence typically occurs in the home • Blame others • Impulsive behaviors • Alcohol calms them down

  6. Behavioral Symptoms • Racing thoughts • Super sensitive to environmental stimuli • Mood swings • Calm • Shutdown • Flight • Fight • Stalking

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

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

  14. LACTATE INFUSION VIDEOTAPE RESULTS (mean ± SD) HCS N-V ALC PERP p - value N=23 N=19 N=28 2.1±2.0 2.9±1.4 4.9±3.3 p < .001 BEHAVIORAL (Sum of the video ratings for speech, breathing, facial grimacing, and motor activity of the hands/arms and legs.) 0.5±0.7 0.3±0.3 1.1±0.8 p = .002 FEAR PANIC 0.5±0.7 0.4±0.4 1.2±1.0 p = .005 RAGE 0.1±0.3 0.1±0.3 0.9±0.8 p < .001 VIDEO AVE 4.5±4.9 5.1±2.8 13.3±9.3 p < .001

  15. OUTWARD • Physical • abuse FIGHT Active Anxiety/Phobic disorders Misinterpret environmental stimuli Perceived “threat” • INWARD • Self-injurious Dysfunctional fear conditioning pathways FLIGHT Active SHUTDOWN Passive Model for understanding the psychopathology of perpetrators

  16. Cortex Sensory Stimuli Thalamus Amygdala Conditioned fear response slow defensive behavior autonomic arousal hypoalgesia stress homones rapid Armony and LeDoux (1997) Davis, Raommie and Cassell (1994) Siegel, et al. (1999)

  17. 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.

  18. 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.

  19. 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.

  20. 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.

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

  22. Le f t A m y g d a l a r = .89 r = -.58 Left Thalamus r = .91 r = -.03 Anterior Cingulate r = .85 r = -.21 Right Posterior Orbitofrontal Cortex r = .67 r = -.48 Right Basal Forebrain r = .80 r = -.39 Right Thalamus Pearson correlations: O Alcoholicsversus O Perpetrators Alcoholic perpetrators of domestic violence, compared with non-violent alcoholics, have reduced correlations with the left amygdala ROI

  23. r = .53 r = -.58 Left Thalamus Left Amygdala r = .84 r = -.03 Anterior Cingulate Right Posterior Orbitofrontal Cortex r = .80 r = -.21 Right Amygdala r = .63 r = -.52 Left Thalamus Pearson correlations: O Healthy Controlsversus O Perpetrators Alcoholic perpetrators of domestic violence, compared with healthy controls, have reduced correlations with the left and right amygdala ROI’s

  24. Left Thalamus Left Posterior Orbitofrontal Cortex r = .13 r = .88 Pearson correlations: O Healthy Controlsversus O Alcoholics Non-violent alcoholics, compared with healthy controls, have increased correlations between the left thalamus and left posterior orbitofrontal cortex ROI’s

  25. 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.

  26. 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

  27. Current research in domestic violence • Treatment • fMRI • Genotyping

  28. 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.

  29. 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.

  30. 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

  31. 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

  32. 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.

  33. Facial expressions

  34. Labelling Task (Happy) Amygdala activation P < .05 perpetrator control

  35. Labelling Task (Anger) Perpetrators show significant activation in theOrbitofrontal cortex p < 0.05 control perpetrator

  36. 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.

  37. 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.

  38. 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).

  39. OUTWARD Physical Abuse FIGHT Active Cortex Sensory Stimuli INWARD Self-injurious Thalamus Active FLIGHT Amygdala Passive SHUTDOWN Decreased cortical input enhances fight / flight / shutdown behavioral responses slow rapid

  40. 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

  41. SR141716 decreases ethanol consumption in young rodents

  42. 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.

  43. Study design

  44. 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

  45. 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

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