D-TMS IN ALCOHOLIC PATIENTS: PRELIMINARY DATA ON STRIATAL DOPAMINE TRANSPORTER (DAT) EVALUATED BY 123 I-FP-CIT SPECT AND ON ALCOHOL CRAVING AND INTAKE

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1 !"#$%&'(%)*+%),#-+%.('//##012234*+%5#6'7#8932'%4'/#:(+;#6'<(+3;).3%.#)%2#=()3%# D-TMS IN ALCOHOLIC PATIENTS: PRELIMINARY DATA ON STRIATAL DOPAMINE TRANSPORTER (DAT) EVALUATED BY 123 I-FP-CIT SPECT AND ON ALCOHOL CRAVING AND INTAKE Giovanni Addolorato, M.D. Institute of Internal Medicine, Catholic University of Rome, Italy Agostino Gemelli Hospital, Rome - Italy g.addolorato@rm.unicatt.it Department of Anti-Drug Policies, Office of the Government of Italy

2 ! Alcoholism is characterized by: craving, loss of control, tolerance and physical dependence! The main objectives of treatment are: - to control AWS symptoms - to achieve abstinence/ reduction of intake - to prevent relapse! Psychological approach and counselling are essential components of therapy: efficacy 15-39%! Pharmacotherapy is able to improve the outcomes achievement Edwards and Rollnick, Addiction 1997 Addolorato et al, Neuropsychobiol 2005

3 CRAVING NEUROTRANSMITTER SYSTEMS Dopamine GABA glutamate serotonin opioid Dopamine GABA glutamate serotonin opioid

4 Efficacious Anticraving Medications for Alcohol Dependence Medication Naltrexone (Nalorex and Vivitol ); Nalmefene? Acamprosate (Campral ) Ondansetron (Zofran ) Sodium Oxybate (GHB) (Alcover ) Baclofen (Lioresal and Liofen ) Topiramate (Topamax ) Mechanism of Action Mu opioid receptor inhibitor?oprm1 (label) Glutamate receptor modulation (label) Serotonin- 3 receptor antagonist (off-label) Type B/SERT & 3-UTR GABA-B/ GHB agonist (label in Italy and Austria) GABA-B antagonist (off-label) Alcohol dependent; Severe liver disease GABA/Glutamate modulator Heavy current drinkers (off-label) Addolorato et al, Addictive Behav 2005

5 NIAAA Supported Promising Targets for Novel Agents CRH 1 receptors adrenergic receptors opioid kappa receptors vasopressin V1b receptors NK 1 receptors orexin/hypocretin receptors NPY 2 receptors opioid receptor-like 1 receptors (NOP) NPS receptors adenosine A 2 receptor sigma receptors glutamate mglur 2/3 and 5 receptors GABA A α-1 and α-5 receptors Courtesy of Prof. B. Johnson. Please do not reproduce without permission.

6 Transcranial Magnetic Stimulation TMS

7 HI16>-I16$1J#K1L68H$-#>H$KMJ1H$N6#OHK>P#! Non-invasive technique that allows to stimulate or inhibit the cerebral cortex, exploring cortical excitability and motor conduction! TMS seems to be able to stimulate dopamine release in the striatum

8 Dopamin Transporter (DAT) and DaTSCAN The DAT mediates dopamine reuptake from synap*c clev It modulates dopamine (DA) signaling intensity and dura*on on pre- and post synap*c receptors The radioligand ¹²³I- FP- CIT (DaTSCAN) is a cocaine analogue, which is able to bind the DAT; its administra*on allow to evaluate the DAT availability in the brain

9 LONGITUDINAL PILOT STUDY (IN PROGRESS) To assess the effect of D-rTMS on alcohol intake and alcohol craving in alcoholic patients To investigate DAT availability by 123 I-FP-CIT (DATSCAN) SPECT, in alcoholic patients before and after D-TMS To assess possible correlations between changes in DAT availability and clinical parameters before and after D-TMS

10 PATIENTS (planned 20) Pa*ents: 8 pts (7 m, mean age: 48 ± 9 yrs) with a DSM- IV diagnosis of alcohol dependence Inclusion criteria Drink = = = = Average alcohol consump*on 21 drinks/week (males) and 14 drinks/week (females) Two heavy drinking days/week: > 5 drinks/day for males and > 4 drinks/day for females Esclusion criteria Co- morbid psychiatric axis I disorder AWS Neurological disorder or severe medical illness Previous or current drug abuse other than alcohol and nico*ne Current use of psychotropic medica*ons

11 Clinical evalua*on Physical, psychiatric and neurological examina*on Rou*ne laboratory tests Assessment of daily alcohol consump*on during the last 4 weeks prior to enrolling by Alcohol Time Line Follow- back (TLFB) Psychometric evalua*on Controls (matched for age and gender) 16 healthy social drinkers subjects 12 males, mean age: 43 ± 13 yrs No neurologic and/or psychiatric disorders No use of psychotropic medica*ons or substance abuse

12 [1H$86H># $#%&'()## I81J#*+,# -./01/234'# ]#[)*'%&/# 73&S#)#23).%+/3/#+:#),4+S+,# 2'R'%2'%4'#OQ>KB$AP# $#%&'()## >i1k#*+,# -./01/2345# Patients underwent D-rTMS (10 Htz frequency) 3 times a week, about 10 minutes per session, for 4 consecutive weeks All patients received psychological support counselling and group therapy during the study * 1 standard drink= 12g of absolute alcohol Q';+.()RS34#)%2#-,3%34),# [)();'&'(/# K')%#`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`#>Q# 5IMF$#:#5'$F;# &FI#:#&F9# MMFM#:#&FN# 5MFM#:#55FI# &F9#:#EF9#

13 S*mula*on parameters Amplitude (% motor threshold) 110 Frequency (Hz) 1 (low frequency group); 10 Hz (high frequency group) Train Dura*on (sec) 900 (low frequency group); 3 (high frequency group) # Trains/Session 1 (low frequency group); 40 (high frequency group) Time between trains (sec) 20 (high frequency group) number of pulses/sess 900 (low frequency group); 1200 (high frequency group) Length of each daily D- rtms session 15 minutes (low or high frequency groups). Length of treatment 4 weeks (3 Dmes/week) 13

14 >[8-H# SPECT was performed before D-TMS and after 4 weeks of D-TMS 14j<3/3*+%5#E#@/2.=#Cg8.# 5ME S1hK1JS*#GFHF# GBi8?D/B#%5$9#+ja)b#A2C>1@8CA#=<=38]f#5M'# K./i8?D/B=f#CB72>C.#=3804#Ekb##$&P#08.#=380b## 5M9#Q#5M9#]C3.GQf#^//]#`C?3/.#5FME# I'4+%/&(<4*+%5#j2l8._/.3@#hjKb#J@CB7m=# Cl8B2CD/B#?/..8?D/Bb#3.CB=CQGC>f#?/./BC>f# CBA#=C7GlC>#=>G?8=F# >';3Bj<)%*&)*9'#)%),U/3/5#0.8A8dB8A#dQ8A#eLS=#0>C?8A#/B# =3.GC32]f#?C2AC38#B2?>82=f#023C]8B#/`#8C?@#@8]G=0@8.8#CBA# /B#/??G0G3C>#?/.38Q#%&#CAA8A#?/BD72/2=#3.CB=CQGC>#=>G?8=)#

15 Q1H#)9)3,)C3,3&U#3%#-+%&(+,/#)%2#1,4+S+,34/#C':+('#QBHK>### Control Mean % difference Alcoholic Control * * Alcoholic * * R St # - 16%# L St # - 17%# R Ca# - 10%# L Ca# - 11%# R Pu# - 23%# L Pu# - 22%# >3.%3l4)%&# ('2<4*+%# +:# DF!$BZ[B-$H# C3%23%.# ()*+/# C3,)&'(),,U# :+<%2# 3%# &S'# 7S+,'# /&(3)&<;# )%2# R<&);'%# +:# ),4+S+,34/#3%#4+;R)(3/+%#73&S#S'),&SU#4+%&(+,/# mrngogd#

16 Rela*onship between DAT levels and yrs of alcohol dependence 3,0 RIGHT STRIATUM 3,0 LEFT STRIATUM 2,8 2,8 123 I-FP-CIT UPTAKE 2,6 2,4 123 I-FP-CIT UPTAKE 2,6 2,4 2, Alcohol-dependence duration 2, Alcohol-dependence duration 4,0 RIGHT CAUDATE LEFT CAUDATE 4,0 123 I-FP-CIT UPTAKE 3,6 3,2 123 I-FP-CIT UPTAKE 3,6 3,2 2, Alcohol-dependence duration 2, Alcohol-dependence duration Dura*on of alcohol dependence (yrs) inversely correlated with 123I - FP- CIT binding ra*os in the bilateral striatum and caudate and in the right putamen (p range: )

17 Rela*onship between DAT levels and NDD in 4 weeks before D- TMS Inverse correla*on between total number of drinking days and 123 I- FP- CIT binding ra*os in the bilateral striatum and caudate (p range: )

18 Rela*onship between DAT levels and NAD in 4 weeks before D- TMS Posi*ve correla*ons between total number of abs*ncence days and 123 I- FP- CIT binding ra*os in the bilateral striatum and caudate (p range: )

19 RESULTS: DAT availability aver D- TMS Mann Whitney U Test p<0,05 D-rTMS RIGHT PUT LEFT PUT p= 0.03

20 123 I- FP- CIT SPECT Pre- DrTMS Post- DrTMS Transaxial slices Pre- DrTMS Post- DrTMS

21 DF! $BZ[B-$H#>[8-H### [('BQ(HK># [+/&BQ(HK># [('BQ(HK># [+/&BQ(HK># [('BQ(HK># [+/&BQ(HK>#

22 RESULTS: Clinical Outcomes Pre-Screening S-R Tratment Follow-up Abstinence Days Pre-Screening S-R Treatment Follow-up Sham Real R5#%/

23 RESULTS: Clinical Outcomes Pre-Screening S-R Treatment Follow-up Heavy Drinking Days Pre-Screening S-R Treatment Follow-up Sham Real R5#%/

24 RESULTS: Craving Treatment start Treatment end Follow up Penn Alcohol Craving Scale Sham Real R5#%/ Treatment start Treatment end Follow-up

25 CONCLUSIONS - 1 Reduced striatal DAT availability, showed in some previous imaging studies in drug abuser subjects (methamphetamine, but not alcohol or cocaine) Volkow et al, Arch Neurol 2007; Koob & Volkow, Neuropsychopharmacol 2012 Lower DAT availability in patients with longer duration of alcohol dependence: down-regulation of DAT as a result of long-term alcohol abuse? Higher DAT availability in patients with higher number of abstinence days in the last month before the enrollment dysfunction of DAT might recovery in relation to the abstinence duration?

26 CONCLUSIONS - 2 Modulatory effect of D-TMS group in comparison with Sham on striatal DAT : increased dopamine release and/or concentration in synaptyc cleft likely induced by D-TMS stimulation? Lack of differences in clinical outcomes between D-TMS group in comparison with Sham - low sample size evaluated at the moment? - intensive psychological support (counselling & AA)? - undertreatment with D-TMS?

27 Financial Support European Research Advisory Board (ERAB) Italian Ministry for University, ScienFfic and Technological Research (MURST)

28 Acknowledgements L. Leggio, MD (NIAAA/NIDA); A. Ferrulli, MD; S. Cardone, MD; L. Vonghia, MD (Losanna); A. Mirijello, MD; C. D Angelo, MD; A. Nesci, MD Thank you for you attention