John Femino, MD, FASAM, MRO

Transcription

1 The Future of Neurobiologically Based Treatments 2013 Fall Conference Addiction Professionals of North Carolina Carolina Beach, NC October 16-18, 2013 John Femino, MD, FASAM, MRO Medical Consultant, Dominion Diagnostics Medical Director, Meadows Edge Recovery Center Fellow and former member of national board of directors American Society of Addiction Medicine

2 Educational Objectives Describe diagnostic and therapeutic genetic approaches List uses of addiction vaccines in clinical practice Apply diagnostic tools for personalized medicine Assess roles of new technologies for risk stratification, early identification and intervention Develop therapeutic interventions by course of illness Implement addiction biology into counseling practice Explain biological rationale for following recovery plan

3 Bio-Psycho-Social / Public Health Model Drug Drug Class Dependence Agent Set Medical Conditions Stage Change Previous Tx Setting Environmental Support Job Stability Enabling Host Environment

4 ASAM Dimensions of Care & Stage of Recovery 1 Intox Detox Attitude Resistance 4 2 Medical Relapse Potential 5 3 Emotional Behavioral Recovery Environment 6

5 Future of Neurobiology : Drugs Drug Development, Safer Meds pro-drug and combination - antagonists Safer dispensation and storage Non Addictive Meds Taper Resistant formulations Vaccine Prescription Monitoring Programs Therapeutic monitoring Detection technology

6 Future of Neurobiology : Biology Genotype & Phenotype Analysis Diagnostic tests Genetic testing - GARS Imaging EEG Electroencephalographic Biofeedback Psychological and Neuro-psychological testing - CPT Addiction severity measurement Urine Drug Testing and Report Analysis

7 Future of Neurobiology : Diagnostic Testing Functional tests Audio analysis emotion detection EEG mapping Functional Imaging fmri, Spect, PET scans Metabolic analysis Proteinomic measurement of tolerance P450 analysis of metabolism Pharmacokinetic - metabolism Cue Reactivity Assessment and Monitoring fmri measure brain functioning Transcranial Magnetic treatments

8 Future of Neurobiology : Environment Setting Measurement of cue reactivity cravings Imaging studies for emotional functioning Behavioral therapies systematic desensitivation fmri feedback - craving reduction and relapse prevention Virtual reality software recreation of environmental factors

9 Future of Neurobiology : Public Safety Public safety technology Alcohol Detection devices personal breathalyzers Vehicle location and driving behaviors Ignition interconnect devices Transdermal and Ambient alcohol detection Breath drug identification Iris and fingerprint recognition

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19 Brain Reward Cascade Unhappy Brain Happy Brain From Ken Blum, MD, PhD : Reward Deficiency Solutions System

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21 The Human Genome In the human genome, there are ~3 billion bases (nucleotides) In humans, there are estimated to be ~30,000 genes (many but not all identified and annotated) Each gene is a sequence of bases or nucleotides Kreek (Rockefeller University) & Hassin (Columbia P&S), 2004

22 Reward Deficiency Syndrome is the True Phenotype

23 The Dopamine D 2 Receptor Gene

24 The Reward Gene

25 Brain Reward Chemistry Differences between those with the DRD2 A2 allele and those with the A1 allele DRD2 Taq A2 allele DRD2 Taq A1 allele Normal Reward Circuitry Healthy Number of Receptor Sites Reduced Receptor Sites From Ken Blum, MD, PhD : Reward Deficiency Solutions System

26 A 1 Gene = 1/3 Lower D 2 Receptors Equates to 100,000,000 people living in the USA

27 A1 = Dopamine Resistance Hypodopaminergic Function I m a normal person minus two drinks Lower number of dopamine receptors Reduced dopamine release Impaired dopamine function Attraction to fix imbalance by using drugs/behaviors that increase dopamine Commonality among addictions cross addiction, behavioral addictions and eating disorders

28 Hypodopaminergic Function Impairs Reward-Dependent Behaviors Inability to cope with stress Reduction of energy expenditure Lower BMR (Energy Conservation) and Fatigue Increased carbohydrate & fat cravings Increased food intake Energy consumption Increased blood pressure Increased % body fat Higher Body Mass Index Blunted reward response to pleasurable experiences Intensified bingeing behavior Addictive behaviors Thrill-seeking behaviors Impulsive behaviors Compulsive behaviors Personality disorders Poor executive function Reduced global cognition

29 Reward Deficiency Syndrome

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31 >1/3 of the Total US Population Carries the DRD2 A1 Gene (Over 100,000,000 people)

32 HAPPINESS GENE MAP 5HT2A CLOCK LEPTIN-OB DBI GABRB3 HTR3B GABRA6 MANEA COMT OPRK1 MAO-A DRD4 ANNKI SLC6A3 OPRM1 DRD2 VMAT2 MLXIPL NOS3 PPARG ADIPOQ STS F T O MTHFR VDR TNF alpha PEMT CHREBP VEGF

33 GARS Study: Candidate Genes GENE/ALLELE Caspi MAOA uvntr Caspi MAOA uvntr DRD4 DAT 5HTTLLR dialletic COMT DRD2 Taq1 DRD3 OPRM1 GABRA3 GABRA3 Number of Subjects Percentage of Low Risk Percentage of Moderate Risk Percentage of High Risk ASI Lifetime Risk Composite

34 Genetic Addiction Risk Score (ARS) Patient MAOA 5HTTLP 5HTTLP SLC6A3 DRD4 DRD2 COMT Any risk allele SEVERITY *ARS CL- 1 3R/3R L/L L A / L A 10R/10R 4R/4R A1/A2 A/G HS CL- 2 4R/4R S/L S/L A 10R/10R 4R/7R A1/A2 A/A MS CL-3 4R/4R S/S S/S 9R/10R 4R/4R A1/A2 G/G LS *Percentage of severity is calculated based on 14 alleles whereby there are 7 different risk alleles. This is then converted to a fraction which represents the ARS. Severity score = 1-36% Low severity; 37-50% =moderate severity; % =High severity.

35 Nutrients at Specific Dosages That Improve Gene Expression & Optimize Reward

36 Mechanism of Action of Nutrient Ingredients

37 fmri, qeeg and Relapse Rate in Response to KB 200

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39 Cocaine Cravings and Euphoria Reward Anticipation Cue induced cravings caused by activation of dopamine rich mesolimbic pathway sets up brain to experience reward and drive goal-directed behavior Control over actions Emotional Response Chasing the high On signal = cravings Off signal = high Repeated doses cause lowering of Ah point and duration of high On signal for cravings increased over successive doses Insula : Body sensation into emotions Cocaine dose relieve cravings in same areas of brain

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41 Greater activation in several areas of interest during marijuana cues compared with neutral cues. Filbey F M et al. PNAS 2009;106: by National Academy of Sciences

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44 fmri response: Stage of Recovery Occipital-temporal-posterior cingulate visual spacial and information processing Anterior cingulate Emotional processing Hippocampus and thalamus Learning, memory and emotional Dorsal striatum Drug seeking and wanting Insula Emotional wanting

45 PET Scan : Dopamine release in anticipation and experience of music

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49 Computerized Audio Analysis of Emotions Opioid-SUBX patients and self-awareness of emotions compared to GP + AA members.

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51 Targeting Brain DNA as an Anti-RDS Strategy

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54 Adenoviral vector delivers the DRD2 gene into the brain of rats

55 Molecular Mechanisms of Neuroadaptation GABA NMDA Opiods/DA/CB1 K+ Cl- Adenyl cyclase Ca+ camp second messengers Na+/Ca+ Protein kinase signal tranduction pathways (PKA/ PKC, CaMK, MAPK etc. ) Fos, CREB, ELK-1, Jun (Transcription Factors) Changes in Gene Expression (Nestler, Neuron, 1996) (Koob, Neuron, 1998)

56 Study of GNR-siRNA nanoplex uptake in DAN cells. Bonoiu A C et al. PNAS 2009;106: by National Academy of Sciences

57 DARPP-32 gene silencing efficiency of GNR-siRNAD nanoplex in DAN cells. Bonoiu A C et al. PNAS 2009;106: by National Academy of Sciences

58 Immunotherapies for Addiction Treatment Vaccines : Antibodies Reduce Brain concentrations of Drug VACCINE Antibodies Binding Site Targeting the drugs, not the receptors Capillary Blood Flow Capillary Blood Flow Brain Brain

59 The Antibody: how it works Cocaine binds in variable region Hinge Cocaine Metabolized (cholinesterases) Antibody free for subsequent binding

60 NicVAX the vaccine

61 Prevent Binding to Brain Receptors

62 New Heroin Vaccine(s) K.D. Janda & G.F. Koob Laboratories at TSRI The Vaccine(s) Hot Plate Test Heroin 1 mg/kg, s.c. 30 min ## p<0.01, ### p<0.001, significant reduction of analgesia vs. Control/KLH group, ### p<0.001, significant reduction of analgesia vs. Control/KLH group

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74 Prevention & Early Identification Vaccine development Personal risk assessment portable breathalyzers DUI detection of drugs Monitoring abstinence during treatment Prevention of drug driving Medicalization and monitoring shift from criminal justice to health care system

75 Diagnostic & Therapeutic Uses Identification of genetic variability Assess functioning of neuronal circuits Measure severity and reactivity of triggers Provide feedback to patient of status Biological basis of diagnosis and risk stratification SBIRT Measure effectiveness of drug treatment

76 Diagnostic & Therapeutic Uses Assess readiness to enter high risk situations Prevent induction of tolerance and slip to become relapse Treat cravings by magnetic Predict metabolic alterations of choice and dose of drug prior to prescribing Increase use of non-drug nutrigenics

77 Diagnostic & Therapeutic Uses Measure emotional blunting Measure executive functioning Increase effectiveness of decisions impulsive reward vs. long term accomplishments Demonstrate effectiveness of non-drug interventions diet, exercise, music, G.O.D. Increase monitoring of abstinence