National Institute on Alcohol Abuse and Alcoholism Section of Clinical Studies David T. George, M.D.1 1 Demystifying Medicinen nAlcohol and domestic violenceBackgroundBackgroundBehavioral CharacteristicsBehavioral CharacteristicsDiagnosesDiagnosesResearch FindingsResearch FindingsModelModelTreatmentTreatmentn nAlcohol treatment2 2Domestic Violence in the United Statesn n20% to 30% of all men and women will be 20% to 30% of all men and women will be assaulted by their spouse/significant other assaulted by their spouse/significant other at some time in their livesat some time in their livesn nDomestic violence accounts for:Domestic violence accounts for:1) 20% of all emergency room visits1) 20% of all emergency room visits2) 50% of all police calls2) 50% of all police calls3) 30% of all female murders3) 30% of all female murders3 3Literature Reviewn n70% of perpetrators have an alcohol problemn nMost studies focus on psychosocial issues: 1) power/control2) learned behaviorsn nMinimal emphasis given to biological concomitants4 4Who Are Perpetrators?n nMultiple fights during childhoodMultiple fights during childhoodn nViolence typically occurs in the homeViolence typically occurs in the homen nBlame othersBlame othersn nImpulsive behaviorsImpulsive behaviorsn nAlcohol calms them downAlcohol calms them down5 5Behavioral Symptomsn nRacing thoughtsRacing thoughtsn nSuper sensitive to environmental stimuliSuper sensitive to environmental stimulin nMood swingsMood swings CalmCalm ShutdownShutdown FlightFlight FightFight StalkingStalking6 6Triggers and symptoms associated with domestic violencen nTriggers manifested by partnerA “look”A “look”A “tone” of voice A “tone” of voice n nSymptoms manifested by perpetratorsAutonomic activation Autonomic activation Escalating anxietyEscalating anxietyFearFear7 7Study participantsn nHealthy comparison subjects Healthy comparison subjects n nNon-violent alcoholics Non-violent alcoholics n nPerpetrators of domestic violencePerpetrators of domestic violenceMultiple episodes of domestic violenceMultiple episodes of domestic violenceViolence not limited to periods of intoxicationViolence not limited to periods of intoxicationNo diagnosis of bipolar, schizophreniaNo diagnosis of bipolar, schizophreniaNormal MRI Normal MRI n nAll subjects were:All subjects were: In good health and on no medicationsIn good health and on no medications No history of seizures or major head traumaNo history of seizures or major head trauma Sober for at least three weeks prior to researchSober for at least three weeks prior to research8 8Comparison of non-violent/violent alcoholics: Comparison of non-violent/violent alcoholics: Axis I diagnoses show alcoholic perpetrators Axis I diagnoses show alcoholic perpetrators have a higher proportion of anxiety related have a higher proportion of anxiety related disorders than non-violent alcoholicsdisorders than non-violent alcoholicsAxis I DiagnosisAxis I DiagnosisNon-violent Non-violent Perpetrators withPerpetrators withalcoholicsalcoholicsalcohol dependencealcohol dependence (N = 37)(N = 37)(N = 18)(N = 18) P PMajor Depression Major Depression 6 6 8 80.030.03Panic Attack Panic Attack 1 1 4 40.020.02Social PhobiaSocial Phobia 5 5 7 70.040.04Obsessive-Compulsive 0Obsessive-Compulsive 0 3 30.010.01Generalized Anxiety Generalized Anxiety 0 0 6 6.01.01Chi-squareChi-squareP P=level of significance, p.05.=level of significance, p.05. 9 9Comparison of non-violent/violent alcoholics: Axis II Comparison of non-violent/violent alcoholics: Axis II diagnoses show alcoholic perpetrators have a higher diagnoses show alcoholic perpetrators have a higher proportion of cluster B and C personality disorders proportion of cluster B and C personality disorders than non-violent alcoholicsthan non-violent alcoholics Axis II Diagnosis Axis II Diagnosis Non-violent Non-violent Perpetrators withPerpetrators withalcoholicsalcoholicsalcohol dependencealcohol dependence (N = 37)(N = 37)(N = 18)(N = 18) P PCluster B personality disordersCluster B personality disordersBorderline Borderline 8 8 15 15 0.010.01Antisocial Antisocial 4 4 9 9 0.02 0.02Cluster C personality disordersCluster C personality disordersDependentDependent 2 2 6 6 0.01 0.01Obsessive-CompulsiveObsessive-Compulsive 6 6 8 8 0.03 0.03Passive-AggressivePassive-Aggressive 1 1 4 4 0.02 0.02Chi-squareChi-squareP P=level of significance, p.05.=level of significance, p.05. 1010Comparison of perpetrators with/without Comparison of perpetrators with/without alcohol dependence: Axis I diagnoses show alcohol dependence: Axis I diagnoses show that perpetrator groups only differ in substance that perpetrator groups only differ in substance abuse related diagnosesabuse related diagnosesAxis I DiagnosisAxis I DiagnosisPerpetrators withoutPerpetrators withoutPerpetrators withPerpetrators with alcohol dependence alcohol dependence alcohol dependence alcohol dependence (N = 12)(N = 12)(N = 18)(N = 18) P POrganic MoodOrganic Mood 0 0 21 21.01.01Alcohol DependenceAlcohol Dependence 0 0 36 36.01.01Cannabis Dependence Cannabis Dependence 0 0 11 11.01.01Chi-squareChi-squareP P=level of significance, p.05.=level of significance, p.05. 1111Comparison of perpetrators Comparison of perpetrators with/without alcohol dependence for with/without alcohol dependence for Axis II diagnosesAxis II diagnoses Axis II Diagnosis Axis II Diagnosis Perpetrators withPerpetrators withoutoutPerpetrators withPerpetrators with alcohol dependence alcohol dependence alcohol dependence alcohol dependence (N = 12)(N = 12)(N = 18)(N = 18) P PBorderline Borderline 5 5 15 150.020.02Chi-squareChi-squareP P=level of significance, p.05.=level of significance, p.05. 1212Lactate Infusionn nDouble-blind, placebo-controlledn n10cc/kg of 0.5M sodium lactate infused over 20 minutesn nVideotaped1313BEHAVIORAL (Sum of the video ratings for speech, breathing, facial grimacing, and motor activity of the hands/arms and legs.)FEAR PANIC RAGE VIDEOAVE(mean SD)HCSN=23N-V ALCN=19PERPN=282.12.00.50.70.50.70.10.34.54.9p .001 p = .002p = .005p .001p .0012.91.40.30.30.40.40.10.35.12.84.93.31.10.81.21.00.90.813.39.3LACTATE INFUSION VIDEOTAPE RESULTSp - value1414Dysfunctional fear conditioningpathwaysAnxiety/Phobic disordersMisinterpret environmental stimuliSHUTDOWNActiveINWARDSelf-injuriousOUTWARDPhysical abuseActivePassive FLIGHTPerceived “threat”FIGHTModel for understanding the psychopathology of perpetrators1515Conditioned fear responserapiddefensive behaviorautonomic arousalhypoalgesiastress homonesArmony and LeDoux (1997)Davis, Raommie and Cassell (1994)Siegel, et al. (1999)slow1616Importance of cortex - amygdala connectionsn nBard (1928) - Animals are more likely to respond to Bard (1928) - Animals are more likely to respond to environmental stimuli with “defensive rage” environmental stimuli with “defensive rage” following cortical ablation at the level of the high following cortical ablation at the level of the high midbrain. midbrain. n nMorgan et al., (1993) - Animals with lesions to the Morgan et al., (1993) - Animals with lesions to the dorsal medial prefrontal cortex exhibit increased dorsal medial prefrontal cortex exhibit increased fear reactivity.fear reactivity.n nMorgan et al., (1993 and 1995) - Lesions to the Morgan et al., (1993 and 1995) - Lesions to the medial prefrontal cortex impair the ability of an medial prefrontal cortex impair the ability of an animal to extinguish conditioned fear responses.animal to extinguish conditioned fear responses.1717Importance of cortex - amygdala connectionsn nGarcia et al., (1999) - The presence of threatening Garcia et al., (1999) - The presence of threatening stimuli causes the amygdala to decrease the firing stimuli causes the amygdala to decrease the firing rate of the medial prefrontal cortex neurons.rate of the medial prefrontal cortex neurons.n nHariri et al., (2000) Angry and fearful faces Hariri et al., (2000) Angry and fearful faces increase rCBF to the amygdala in healthy controls. increase rCBF to the amygdala in healthy controls. Cognitive labeling of the angry and fearful faces Cognitive labeling of the angry and fearful faces caused a decrease in to the amygdala and a caused a decrease in to the amygdala and a simultaneous increase in rCBF to the right simultaneous increase in rCBF to the right prefrontal cortex.prefrontal cortex.1818Conceptualization for the etiology of domestic violencen n“Threats” (i.e., looks, tones of voice) trigger “Threats” (i.e., looks, tones of voice) trigger a conditioned fear response, which is out of a conditioned fear response, which is out of proportion to the stimulus, and may result proportion to the stimulus, and may result in the expression of fear-induced in the expression of fear-induced aggression. aggression. n nThe misinterpretation of “threat” arises from The misinterpretation of “threat” arises from a abnormality in the structures and/or a abnormality in the structures and/or pathways that mediate fear-induced pathways that mediate fear-induced aggression.aggression.1919PET (PET (1818FDG) imaging: to study the neural FDG) imaging: to study the neural structures and pathways involved in fear structures and pathways involved in fear conditioning/fear induced aggressionconditioning/fear induced aggressionn nMRI and MRI and 1818FDG PET were obtained for each subject.FDG PET were obtained for each subject.n nRegions of interest (ROIs) were manually drawn around each desired Regions of interest (ROIs) were manually drawn around each desired structure on MR images.structure on MR images.n nT1-weighted MRI scan was co-registered to its corresponding PET volume T1-weighted MRI scan was co-registered to its corresponding PET volume using a modified surface matching algorithm (Besel et al., 1992).using a modified surface matching algorithm (Besel et al., 1992).n nThe average glucose count within each structure (i.e., ROI) was then The average glucose count within each structure (i.e., ROI) was then computed from its corresponding matching PET.computed from its corresponding matching PET.n nThe CMRglc value for each ROI is the mean value of all voxels within the The CMRglc value for each ROI is the mean value of all voxels within the ROI. These values are absolute CMRglc values.ROI. These values are absolute CMRglc values.n nContinuous auditory performance task (Cohen et al., 1992) was performed Continuous auditory performance task (Cohen et al., 1992) was performed during the brain uptake of during the brain uptake of 1818FDG to ensure all participants were in a similar FDG to ensure all participants were in a similar cognitive state.cognitive state. Pressing a button in response to the higher pitched of two tones while Pressing a button in response to the higher pitched of two tones while ignoring the lower pitched tone.ignoring the lower pitched tone.2020Mean CMRglc in the right hypothalamus is Mean CMRglc in the right hypothalamus is significantly lower in perpetrators with alcohol significantly lower in perpetrators with alcohol dependence dependence 2121Alcoholic perpetrators of domestic violence, Alcoholic perpetrators of domestic violence, compared with non-violent alcoholics, have compared with non-violent alcoholics, have reduced correlations with the left amygdala reduced correlations with the left amygdala ROIROILeft Thalamusr = .89r = -.58Anterior CingulateRight Posterior Orbitofrontal CortexRight Basal ForebrainRight ThalamusPearson correlations: O Alcoholics versus O Perpetratorsr = .91r = -.03r = .85r = -.21r = .67r = -.48r = .80r = -.39LeftAmygdala2222Alcoholic perpetrators of domestic violence, Alcoholic perpetrators of domestic violence, compared with healthy controls, have reduced compared with healthy controls, have reduced correlations with the left and right amygdala correlations with the left and right amygdala ROIsROIsLeft Thalamusr = .53r = -.58Anterior CingulateRight Posterior Orbitofrontal CortexPearson correlations: O Healthy Controls versus O Perpetratorsr = .84r = -.03r = .80r = -.21LeftAmygdalaRightAmygdalaLeft Thalamusr = .63r = -.522323Non-violent alcoholics, compared with healthy Non-violent alcoholics, compared with healthy controls, have increased correlations between controls, have increased correlations between the left thalamus and left posterior the left thalamus and left posterior orbitofrontal cortex ROIsorbitofrontal cortex ROIsLeft Posterior Orbitofrontal CortexPearson correlations: O Healthy Controls versus O Alcoholicsr = .13r = .88LeftThalamus2424Do the differences in correlations indicate different motivations to drink alcohol?n nThe increased correlation found in non-The increased correlation found in non-violent alcoholics makes them more violent alcoholics makes them more susceptible to conditioned positive susceptible to conditioned positive reinforcement or cues.reinforcement or cues.n nAlcoholic perpetrators drink alcohol to Alcoholic perpetrators drink alcohol to decrease anxiety.decrease anxiety.2525Lumbar Puncturen nLumbar puncture was performed in the left lateral decubitus position after over-night bed rest and fastn n5-HIAA was quantified by gas chromatography-mass spectrometry2626Current research in domestic violencen nTreatmentn nfMRIn nGenotyping2727Treatment of perpetrators of domestic violencen nThere are no effective treatments for domestic violence.n nPrimary Hypothesis:Fluoxetine will be more effective than Fluoxetine will be more effective than placebo in decreasing measures of placebo in decreasing measures of aggression, anxiety, and depression in a aggression, anxiety, and depression in a select group of perpetrators of domestic select group of perpetrators of domestic violence.violence.2828Why fluoxetine? n nPerpetrators without alcoholism have lower CSF 5-Perpetrators without alcoholism have lower CSF 5-HIAA than non-violent controls.HIAA than non-violent controls.n n5-HT acts in the medial prefrontal cortex to 5-HT acts in the medial prefrontal cortex to modulate freezing behaviors.modulate freezing behaviors.n n5-HT input at the amygdala, the medial 5-HT input at the amygdala, the medial hypothalamus, and the PAG is involved with the hypothalamus, and the PAG is involved with the control/expression of fight/flight behaviors. control/expression of fight/flight behaviors. n nFluoxetine has been shown to be effective in Fluoxetine has been shown to be effective in previous aggression studies.previous aggression studies.2929Study designn nPerpetrators of domestic violence are being randomized to receive up to 40 mg of fluoxetine or placebo per day for a duration of 3 months.n nPsychotherapyEducationEducationCognitive-BehavioralCognitive-Behavioral3030 Outcome measuresn nM-Overt Aggression ScaleM-Overt Aggression Scalen nAnger, Irritability, Assault QuestionnaireAnger, Irritability, Assault Questionnairen nHamilton Depression Rating ScaleHamilton Depression Rating Scalen nSpielberger State Anxiety InventorySpielberger State Anxiety Inventoryn nThe Drinker Inventory of ConsequencesThe Drinker Inventory of Consequencesn nStraus Conflict TacticsStraus Conflict Tacticsn nSpouse/Significant other interviewSpouse/Significant other interview Partner Abuse Scale (non-physical and physical)Partner Abuse Scale (non-physical and physical) Dyadic Interaction ParadigmDyadic Interaction Paradigmn nPoint Subtraction Aggression ParadigmPoint Subtraction Aggression Paradigm3131Functional MRIn nAngry and fearful facial expressions will Angry and fearful facial expressions will activate the amygdala.activate the amygdala.n nLabeling the angry/fearful facial expressions Labeling the angry/fearful facial expressions will not decrease the amygdala activation in will not decrease the amygdala activation in the perpetrators as compared to non-violent the perpetrators as compared to non-violent comparison subjects.comparison subjects.n nFluoxetine will normalize the difference Fluoxetine will normalize the difference between perpetrators and non-violent between perpetrators and non-violent comparison subjects.comparison subjects.3232Facial expressions3333controlperpetratorAmygdala activation P .053434controlperpetratorPerpetrators show significant activation in the Orbitofrontal cortex p 0.053535Genotypingn nBackgroundBackground Fluoxetine is thought to exert its therapeutic effect by Fluoxetine is thought to exert its therapeutic effect by binding to the serotonin transporter (5-HTT).binding to the serotonin transporter (5-HTT). The long (l) and short (s) variants of the promoter The long (l) and short (s) variants of the promoter have different transcription efficiencies.have different transcription efficiencies. Smeraldi showed that individuals with the l/l and l/s Smeraldi showed that individuals with the l/l and l/s alleles had better antidepressant response to alleles had better antidepressant response to fluvoxamine than subjects with s/s allele.fluvoxamine than subjects with s/s allele. Harari using fMRI demonstrated healthy controls with Harari using fMRI demonstrated healthy controls with either s/s or l/s alleles have a greater increase in either s/s or l/s alleles have a greater increase in amygdala activation in response to fearful stimuli than amygdala activation in response to fearful stimuli than healthy controls with l/l alleles.healthy controls with l/l alleles.3636Genotyping hypothesesPerpetrators with either l/s or s/s alleles Perpetrators with either l/s or s/s alleles will have greater amygdala activation will have greater amygdala activation when presented fearful or angry faces in when presented fearful or angry faces in the fMRI, than perpetrators with the l/l the fMRI, than perpetrators with the l/l allele.allele.Outcome measures will show an Outcome measures will show an interaction between fluoxetine and interaction between fluoxetine and genotype.genotype.3737Effect of alcohol administration on fear conditioningn nAlcohol increases the neural transmission from the medial hypothalamus to the PAG facilitating defensive rage (Schubert et al. 1996).3838Decreased cortical input enhances fight / flight / shutdown behavioral responsesSHUTDOWNFLIGHTOUTWARDPhysical AbuseINWARDSelf-injuriousActivePassiveActiveFIGHTslowrapid3939Clinical trial of the cannabinoid CB1 receptor antagonist, SR141716n nEndogenous cannabinoids have been implicated in the control of appetitive behaviors in animals and humans.SR141716 reduces food intake in rodents SR141716 reduces food intake in rodents and obese peopleand obese peopleSR141716 reduces ethanol drinking in SR141716 reduces ethanol drinking in rodentsrodents4040SR141716 decreases ethanol consumption in young rodents4141Hypothesisn nSR141716 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.4242Study design4343Outcome measuresn nPrimary: Drinks consumed during self-administrationDrinks consumed during self-administrationn nSecondary:Alcohol Urge QuestionnaireAlcohol Urge QuestionnaireBiphasic Alcohol Effect ScaleBiphasic Alcohol Effect ScaleVideotape of alcohol self-administrationVideotape of alcohol self-administrationACTH / cortisolACTH / cortisolInsulin / glucoseInsulin / glucose4444CollaboratorsPaolo DePetrillo Paolo DePetrillo Vijay Ramchandani Vijay Ramchandani Dasha DotsonDasha DotsonStanley RapoportStanley RapoportLinda Doty Linda Doty Robert RawlingsRobert RawlingsAryeh Herman Aryeh Herman Norman Salem Norman Salem Joe Hibbeln Joe Hibbeln Jasmin Salloum Jasmin Salloum Debra Hill Debra Hill Erick SingleyErick SingleyDaniel Hommer Daniel Hommer John UmhauJohn UmhauGeorge Kunos George Kunos Wendol WilliamsWendol WilliamsMonte PhillipsMonte Phillips6 West/Outpatient Clinic Nursing Staff6 West/Outpatient Clinic Nursing Staff4545