doi 10.1708/2925.29414 | Scarica il PDF (98,9 kb) Riv Psichiatr 2018;53(3):123-127 Pharmacological treatment of alcohol use disorder. Scientific evidence titolo - split_articolo,controlla_titolo - art_titolo Pharmacological treatment of alcohol use disorder. Scientific evidence title - controlla_titolo - art_title Trattamento farmacologico del disturbo da uso di alcol. Evidenze scientifiche autori - vau_aut_id FABIO ATTILIA1, ROBERTA PERCIBALLI1, CLAUDIA ROTONDO1, IDA CAPRIGLIONE1, SILVIA IANNUZZI1, MARIA LUISA ATTILIA1, MARIO VITALI2, GIOVANNI ALESSANDRINI3, MARIA CONCETTA MARCELLA SCAMPORRINO1, MARCO FIORE4, MAURO CECCANTI1, INTERDISCIPLINARY STUDY GROUP CRARL - SITAC - SIPaD - SITD - SIPDip testo - art_testo *E-mail: email@example.com affiliazione_autori - art_affiliazioni 1Centro di Riferimento Alcologico della Regione Lazio (CRARL), Sapienza University of Rome, Italy 2ASUR Marche-AV4, Italy 3ASL Viterbo, General Medicine, Viterbo, Italy 4Institute of Cell Biology and Neurobiology (IBCN-CNR), Rome, Italy riassunto - art_riassunto SUMMARY. Pharmacological treatment of alcohol use disorder represents an essential core of the therapeutic project in a multidisciplinary approach. While non-drug treatment is evolving, from a medical perspective few pharmacotherapies are available; in particular acamprosate, naltrexone and more recently nalmefene among anticraving drugs, disulfiram as an antidipsotropic medication. New studies are focusing on off-label drugs. Moreover, scientific evidence has to support any therapeutic indication which should be tailored on patient needs and comorbidity by considering the individual bio-psycho-social profile. Follow-up is essential in order to assess patient compliance to treatment and monitoring outcomes. parolechiave - lingua - vke_key_id KEY WORDS: alcohol use disorder, anticraving drugs, follow-up. abstract - art_abstract RIASSUNTO. La terapia farmacologica nei pazienti con disturbo da uso di alcol riveste un ruolo centrale nel progetto terapeutico, altamente contestualizzato in un approccio multidisciplinare. Sebbene i trattamenti non farmacologici per la dipendenza da alcol risultino ben strutturati e in continua evoluzione, dal punto di vista medico le possibilità di intervento sono realmente ristrette, con poche molecole a disposizione approvate per il disturbo da uso di alcol: nello specifico, l’acamprostato, il naltrexone e, più recentemente, il nalmefene tra gli anticraving; il disulfiram tra gli avversivanti. Nuovi approcci sperimentali stanno cercando di ampliare tale gamma attraverso l’utilizzo di farmaci off-label. Evidenze scientifiche devono supportare l’indicazione terapeutica, quest’ultima deve dimostrarsi “cucita” sulle esigenze del paziente e sulle comorbilità presenti tenendo conto del profilo bio-psico-sociale individuale. Fondamentale risulta il follow-up per valutare la ritenzione in trattamento e il monitoraggio degli outcome alcologici. keyword - lingua - vke_key_id PAROLE CHIAVE: disordine da uso di alcol, terapia anticraving, follow-up. testo - art_testo INTRODUCTION The goal of drug treatment, during the rehabilitation phase, is the maintenance of abstinence, by preventing relapse or decreasing the number of relapses, to reduce organic damage. A multidisciplinary approach to alcoholism consists of a combination of pharmacotherapy (namely anti-craving drugs and psychiatric drugs when necessary) and psychological support to create the most suitable therapy for each individual bio-psycho-social profile1. Thus, the new concept of “tailor-made” therapy responds to these needs. Developments in genetics and the use of off-label drugs are expanding the range of available drugs resulting in new alternative therapies and an improvement of the effectiveness of traditional drugs. ANTICRAVING DRUGS Acamprosate Acamprosate (ACA) is used in alcohol dependence due to its modulation of glutamatergic transmission via its effects on NMDA receptors. Owing to its tolerability and safe profile, Acamprosate is extremely versatile2,3. ACA is administered at the dosage of 666 mg three times per day. Dosage reductions are required for patients weighing <60 kg and for those with renal impairment4. Since ACA is cleared by the kidneys, where there is a severe renal failure, the drug is contraindicated. Studies on pregnancy and Child-Pugh class C cirrhosis do not exist5. The effectiveness of the drug is evident in relapse but not in the case of heavy drinking2. (Recommendation A1 of Table 1)5. Naltrexone Naltrexone (NTX) is an opioid antagonist, blocking mu-opioid receptors located in brain areas that have been implicated in reward pathways associated with alcohol. Its effectiveness is related to the reduction of the number of days of alcohol consumption and alcoholic drinks consumed in one drinking episode6. NTX has been found to be superior to a placebo in maintaining abstinence and in preventing relapse3,7. Its effectiveness increases if combined with psychotherapy8. NTX is contraindicated in liver failure while it is used with caution in case of liver disorders, even in mild forms5. Furthermore, NTX is contraindicated in patients who use opioids since it may cause withdrawal symptoms. The initial dose is 25 mg for the first 4-5 days, then 50 mg daily. Doses may be increased to 100-150 mg daily3. NTX is particularly effective in patients presenting a family history of alcohol use disorder (AUD)9, and /or those presenting with early onset and antisocial behavior10. In individuals presenting the genetic polymorphism G, which codes for the mu opioid receptor (OPRM1), this drug has been found to be to be more effective at a dosage of 100 mg/day11. (Recommendation A1 of Table 1). Nalmefene Nalmefene is an antagonist at mu- and delta-opioid receptors and a partial agonist to the kappa receptors12,13. It decreases reinforcing effects of alcohol, thus helping reduce consumption by modulating the opioid system14,15: nalmefene is the first drug to have been approved in Europe with the goal to reduce consumption in heavy alcohol drinkers12. Nalmefene represents the “as needed approach” in which the drug must be administered 1-2 hours before the expected alcohol consumption. The maximum dosage is one pill per day. Contraindications are a recent history of opioid use, renal and liver failures, recent episodes of alcohol withdrawal syndrome (AWS) or hallucinations16,17. (Recommendation A2 of Table 1). ANTIDIPSOTROPIC MEDICATIONS Disulfiram Disulfiram exhibits an antidipsotropic effect. It has been the first drug available for AUD treatment and still represents the drug of choice in some countries. It inhibits the conversion of acetaldehyde in acetic acid by blocking the aldehyde dehydrogenase 2 (ALDH2) in the liver and in the brain, resulting in an accumulation of acetaldehyde 18.This compound, in high concentrations, creates a specific reaction characterized by nausea, vomiting, headache, flushing on the face and neck and more rarely vertigo, blurred vision, hypotension and syncope19. Disulfiram is contraindicated in the case of hepatic impairment, cardiovascular diseases, psychosis, or cognitive impairment, pregnancy or in patients who plan to have children. Absolute abstinence is required some days before the start of treatment and patients must sign the informed consent. The administration of the drug should have placed under the supervision of a relative. Because of its contraindications and its lack of convenience Disulfiram is not commonly used 20,21. (Recommendation A2 of Table 1). OTHER DRUGS Baclofen Baclofen is an agonist of GABA-B receptors. It inhibits dopaminergic activity and it is used for spasticity22. In recent years, studies have been conducted to assess the effectiveness in reducing alcohol cravings in patients presenting AUD; however, data require confirmation for its use23. (Recommendation B2 of Table 1). Varenicline Varenicline is a partial agonist of α4β2 nicotinic receptors exhibiting high affinity and high selectivity. It is used in nicotine dependence24-26 and it has been used in AUD only recently27. It activates acetylcholine nicotinic receptor α7 which is implicated in the reward pathway associated with alcohol28. Some studies have detected the effectiveness of Varenicline but further studies are required to assess its therapeutic use29. (Recommendation B2 of Table 1). Sodium oxybate Sodium oxybate, besides being a medication for AWS treatment, is approved in Italy and Austria in preventing relapse and decreasing craving. Despite its effectiveness, studies conducted thus far are not reliable because of their small sample sizes. Therefore, future studies should use random sampling and employ large sample sizes with standardized assessment scales to be valid. Moreover, it is important to monitor for abuse in multi-drug abusers and in patients presenting dual diagnosis30-32. (Recommendation B2 of Table 1). NEW APPROACHES OF PHARMACOGENETICS IN THE TREATMENT OF ALCOHOL USE DISORDER Alcohol addiction is a complex disease that results from a variety of genetic and environmental influences. The variety of factors activates several individual pathophysiological mechanisms leading to the development and progression of AUD. In support of this hypothesis, numerous studies have been conducted demonstrating the existence of slight differences in the population at the genetic level (i.e., polymorphisms) that may increase the vulnerability in developing dependence or determining some characteristics of the disease such as severity of drinking, craving, the age of onset, etc. After such genetic variations were identified, they were used to study the best response to treatment with drugs in terms of therapeutic efficacy and tolerability. Studies have been conducted on both the main drugs used in alcohol dependence (NTX and ACA) and on the off-label drugs (topiramate, ondansetron, sertraline and olanzapine). Naltrexone Studies conducted on alcohol dependence and treatment with NTX have shown that some individuals having alcohol problems present a deficit of endogenous opioids33 along with genetic markers (i.e., polymorphisms) predictive of pharmacological response. In particular, studies have focused on the single-nucleotide polymorphism (SNP) rs1799971 concerning OPRM1 gene, which determines the A118G variation at the nucleotide level34 resulting in the amino acid substitution Asn40Asp at the protein level. The presence of the G allele is associated with: an increased binding capacity for β-endorphin, a reduction in mRNA levels and in the synthesis of the protein-receptor35,36, as well as a more efficient response to NTX at a dose of 100 mg/day37. Other studies have investigated whether NTX is effective in some patients at a dosage of 50 mg/day and they showed that a response was possible in individuals presenting the variable number of tandem repeat polymorphism (VNTR from 7 to 11) of DRD4 gene44. To summarize, since the G allele is more common among Caucasian and Asiatic people, the use of NTX would be most beneficial in these populations. Acamprosate It was FDA approved for AUD treatment in 2004. Researchers studying populations have identified polymorphisms able to predict response to treatment with ACA, in particular: the C1412T polymorphism of GABRB2 gene, the SNP rs13273672 polymorphism of GATA4 gene and the PER2Brdm1 mutation of PER2 gene. The first two are associated with the physiological response to alcohol, the latter is associated with the response to ACA. A preclinical study on mice carriers of the gene mutation PER2 showed a reduction of alcohol consumption following the administration of ACA 37. The same study focused on alcohol consumption in a population of Caucasian individuals treated with ACA, showing that the individual carriers of at least one mutated allele, within a regulatory region of PER2, showed a lower alcohol intake (<300 g/die) than those who do not carry the mutated allele. However, these findings need to be replicated in independent studies to validate the importance of pharmacogenetics to treatment. Ondansetron Ondansetron was FDA approved for the treatment of nausea, postoperatively and in chemotherapy. This drug has a high affinity for the 5-HT3 receptors which regulate the release of dopamine. While alcohol induces an increase of dopamine, ondansetron reduces the release of the neurotransmitter by blocking the 5-HT3 receptors. Several studies38 investigated the effectiveness of ondansetron by dividing alcoholic individuals into two subgroups based on their genotype for the promoter region of the SLC6A4 gene coding for the serotonin transporter (5-HTTLPR L/S polymorphism). The study showed that the patients with the LL genotype treated with ondansetron responded better in terms of alcohol amount and days of abstinence, compared to the other subgroups. Based on these results, researchers have further investigated genotype LL carriers, by analyzing the role of a functional polymorphism of the SLC6A4 gene (rs1042173 [T/G] SNP). The result was that individuals who carry both 5-HTTLPR LL polymorphism and rs1042173 TT polymorphism, treated with ondansetron at the dosage of 0.5 mg/die, present a more effective response to the drug. Unfortunately, the sample of this exploratory study was too small to be validated. Topiramate Topiramate was FDA approved for the treatment of epilepsy in 1996 and for the treatment of migraine in 2004. It has been tested in multiple clinical trials since it could be promising in AUD treatment. Topiramate decreases reinforcing effects of alcohol and craving39. A meta-analysis40, based on data from seven random studies (2003-2014), suggested that topiramate might have beneficial effects in AUD treatment but because of its many side effects, the use is limited. The most common side effects are cognitive dysfunction41, paresthesia42, and taste abnormalities43. Pharmacogenetics studies were conducted on an SNP for the GRIK1 gene coding for one of the main receptors of topiramate: the Gluk1 receptor. The rs2832407 polymorphism is a substitution of the nucleotide C/A. Rav et al.44 suggested that patients with at least one copy of A allele (AC or AA) treated with 300 mg of topiramate, presented an increased risk of experiencing adverse events compared to patients with two copies of the C allele (CC). Furthermore, in 2014 Kranzler et al.45, by dividing patients based on their genetic profile (CC, AA, or AC), compared the efficacy of 200 mg of topiramate versus placebo. This study has shown that only CC patients received a real benefit from topiramate, while no difference was found between the drug and placebo in patients with at least one A allele. Sertraline Sertraline was FDA approved for the treatment of depression in 2002 and for the treatment of generalized anxiety disorder in 2003. Sertraline belongs to the selective serotonin reuptake inhibitors (SSRI) drug classification. In 2009 Kenna et al.46, by randomly administering a placebo, ondansetron and sertraline to 21 patients at a dose of 200 mg/die for three weeks, suggesting beneficial effects resulted from sertraline on some individuals carrying the 5-HTTLPR LL polymorphism. These individuals were the subject of further studies for the investigation of an SNP, a rs25531 substitution of the nucleotide A/G in the upstream promoter region of the SLC6A4 gene. The study showed that patients who responded to the administration with sertraline carried the LALA profile, that exhibits a totally functional serotonin transporter and a late onset of AUD 47. These individuals showed a good response up to 3 months after the discontinuation of the drug. Olanzapine Olanzapine was FDA approved for the treatment of schizophrenia and bipolar disorder only. It is an atypical antagonist of D2 and D4 receptors which determines a decrease in craving for alcohol48. The DRD4 gene of dopamine presents a VNTR polymorphism, with a number of repetitions that varies from 2 to 11 which allows for the division of individuals in two subgroups: those with a number of repetitions between 2 and 6, classified as DRD4 S and those with more than 7 repetitions, classified as DRD4 L. Association studies between this variation and AUD have showed that individuals who carry the L allele exhibit greater craving after alcohol intake49,50. Another study has investigated the association olanzapine-DRD4 showing that olanzapine reduces craving to the L allele carriers only, while no benefits were observed in S allele carriers51. CONCLUSIONS Scientific evidence must support therapeutic indications appropriate to the needs of each patient and their comorbidities by considering the individual bio-psycho-social profile52-57. Thus, the combination of pharmacotherapy, psychological and psychiatric support is necessary, as are the follow-up and the monitoring of clinical outcomes. Conflict of interests: the authors have no conflict of interests to declare. **Interdisciplinary Study Group - Centro Riferimento Alcologico Regione Lazio (CRARL), Società Italiana per Il Trattamento dell’Alcolismo e delle sue Complicanze (SITAC), Società Italiana Patologie da Dipendenza (SIPaD), Società Italiana delle Tossicodipendenze (SITD), Società Italiana di Psichiatria e delle Dipendenze (SIPDip): Giovanni Addolorato, Vincenzo Ailotta, Giuseppe Barletta, Egidio Battaglia, Gemma Battagliese, Valentina Carito, Onofrio Casciani, Pietro Casella, Fernando Cesarini, Mauro Cibin, Rosaria Ciccarelli, Paola Ciolli, Giovanna Coriale, Angela Di Prinzio, Roberto Fagetti, Emanuela Falconi, Michele Federico, Giampiero Ferraguti, Daniela Fiorentino, Simona Gencarelli, Angelo Giuliani, Antonio Greco, Guido Intaschi, Luigi Janiri, Angela Lagrutta, Giuseppe La Torre, Giovanni Laviola, Roberta Ledda, Lorenzo Leggio, Claudio Leonardi, Anna Loffreda, Fabio Lugoboni, Simone Macrì, Rosanna Mancinelli, Massimo Marconi, Icro Maremmani, Marcello Maviglia, Marisa Patrizia Messina, Martino Mistretta, Franco Montesano, Michele Parisi, Esterina Pascale, Fabiola Pisciotta, Giampaolo Spinnato, Alessandro Valchera, Valeria Zavan. biblio_titolo - ignora REFERENCES bibliografia - art_bibliografia 1. Soyka M, Lieb M. Recent developments in pharmacotherapy of alcoholism. Pharmacopsychiatry 2015; 48: 123-35. 2. Rösner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev 2010; (9):CD004332. 3. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 2014; 311: 1889-900. 4. Plosker GL. Acamprosate: a review of its use in alcohol dependence. Drugs 2015; 75: 1255-68. 5. European Association for the Study of Liver. EASL Clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012; 57: 399-420. 6. Rösner S, Hackl-Herrwerth A, Leucht S, Vecchi S, Srisurapanont M, Soyka M. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 2010; (12): CD001867. 7. Maisel NC, Blodgett JC, Wilbourne PL, et al. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction 2013; 108: 275-93. 8. Jarosz J, Miernik K, Wachal M, et al. Naltrexone (50 mg) plus psychotherapy in alcohol-dependent patients: a meta-analysis of randomized controlled trials. Am J Drug Alcohol Abuse 2013; 39: 144-60. 9. Krishnan-Sarin S, Krystal JH, Shi J, Pittman B, O’Malley SS. Family history of alcoholism influences naltrexone-induced reduction in alcohol drinking. Biol Psychiatry 2007; 62: 694-7. 10. Kiefer F, Jiménez-Arriero MA, Klein O, Diehl A, Rubio G. Cloninger’s typology and treatment outcome in alcohol-dependent subjects during pharmacotherapy with naltrexone. Addict Biol 2008; 13: 124-9. 11. Oslin DW, Berrettini W, Kranzler HR, et al. A functional polymorphism of the mu-opioid receptor gene is associated with Naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 2003; 28: 1546-52. 12. Keating GM. Nalmefene: a review of its use in the treatment of alcohol dependence. CNS Drugs 2013; 27: 761-72. 13. Gianoulakis C. Influence of the endogenous opioid system on high alcohol consumption and genetic predisposition to alcoholism. J Psychiatry Neurosci 2001; 26: 304-18. 14. Walker BM, Valdez GR, McLaughlin JP, Bakalkin G. Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence. Alcohol 2012; 46: 359-70. 15. Nealy KA, Smith AW, Davis SM, Smith DG, Walker BM. k-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats. Neuropharmacology 2011; 61: 35-42. 16. Paille F, Martini H. Nalmefene: a new approach to the treatment of alcohol dependence. Subst Abuse Rehabil 2014; 5: 87-94. 17. Van den Brink W, Sørensen P, Torup L, Mann K, Gual A; SENSE Study Group. Long-term efficacy, tolerability and safety of nalmefene as-needed in patients with alcohol dependence: a 1-year, randomized controlled study. J Psychopharmacol 2014; 28: 733-44. 18. Vasiliou V, Malamas M, Marselos M. The mechanism of alcohol intolerance produced by various therapeutic agents. Acta Pharmacol Toxicol 1986; 58: 305-10. 19. McMahon FG. Disulfiram-like reaction to a cephalosporin. JAMA 1980; 243: 2397. 20. Jørgensen CH, Pedersen B, Tønnesen H. The efficacy of disulfiram for the treatment of alcohol use disorder. Alcohol Clin Exp Res 2011; 35: 1749-58. 21. Spithoff S, Kahan M. Primary care management of alcohol use disorder and at-risk drinking: Part 2: counsel, prescribe, connect. Can Fam Physician 2015; 61: 515-21. 22. Imbert B, Alvarez JC, Simon N. Anticraving effect of baclofen in alcohol-dependent patients. Alcohol Clin Exp Res 2015; 39: 1602-8. 23. Leggio L, Garbutt JC, Addolorato G. Effectiveness and safety of baclofen in the treatment of alcohol dependent patients. CNS Neurol Disord Drug Targets 2010; 9: 33-44. 24. Oncken C, Gonzales, Nides M, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med 2006; 166: 1571-7. 25. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 2006; 166: 1561-8. 26. Tonstad S, Tønnesen P, Hajek P, Williams KE, Billing CB, Reeves KR; Varenicline Phase 3 Study Group. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 2006; 296: 64-71. 27. McKee SA, Harrison EL, O’Malley SS, et al. Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 2009; 66: 185-90. 28. Bowers BJ, McClure-Begley TD, Keller JJ, Paylor R, Collins AC, Wehner JM. Deletion of the alpha7 nicotinic receptor subunit gene results in increased sensitivity to several behavioral effects produced by alcohol. Alcohol Clin Exp Res 2005; 29: 295-302. 29. Plebani JG, Lynch KG, Rennert L, Pettinati HM, O’Brien CP, Kampman KM. Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence. Drug Alcohol Depend 2013; 133: 754-8. 30. Leone MA, Vigna-Taglianti F, Avanzi G, Brambilla R, Faggiano F. Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses. Cochrane Database Syst Rev 2010; (2): CD006266. 31. Brambilla R, Vigna-Taglianti F, Avanzi G, Faggiano F, Leone M. et al. [Gamma-hydroxybutyrate (GHB) for mid/long term treatment of alcohol dependence: a systematic review]. Riv Psichiatr 2012; 47: 269-80. 32. Skala K, Caputo F, Mirijello A, et al. Sodium oxybate in the treatment of alcohol dependence: from the alcohol withdrawal syndrome to the alcohol relapse prevention. Expert Opin Pharmacother 2014; 15: 245-57. 33. Oslin DW, Berrettini W, Kranzler HR, et al. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 2003; 28: 1546-52. 34. Anton RF, Oroszi G, O’Malley S, et al. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: Results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry 2008; 65: 135-44. 35. Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 1998; 95: 9608-13. 36. Mague SD, Isiegas C, Huang P, et al. Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior. Proc Natl Acad Sci U S A 2009; 106: 10847-52. 37. Spanagel R, Pendyala G, Abarca C, et al. The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 2005; 11: 35-42. 38. Johnson BA, Ait-Daoud N, Seneviratne C, et al. Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry 2011; 168: 265-75. 39. Johnson BA, Rosenthal N, Capece JA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 2007; 298: 1641-51. 40. Blodgett JC, Del Re AC, Maisel NC, Finney JW. A meta-analysis of topiramate’s effects for individuals with alcohol use disorders. Alcoholism Clin Exp Res 2014; 38: 1481-8. 41. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 2003; 361: 1677-85. 42. Kampman KM, Pettinati HM, Lynch KG, Spratt K, Wierzbicki MR, O’Brien CP. A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence. Drug Alcohol Depend 2013; 133: 94-9. 43. Johnson BA, Rosenthal N, Capece JA, et al.; Topiramate for Alcoholism Study Group. Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial. Arch Intern Med 2008; 168: 1188-99. 44. Ray LA, Miranda R Jr, MacKillop J, et al. A preliminary pharmacogenetics investigation of adverse events from topiramate in heavy drinkers. Exp Clin Psychopharmacol 2009; 17: 122-9. 45. Kranzler HR, Covault J, Feinn R, et al. Topiramate treatment for heavy drinkers: Moderation by a GRIK1 polymorphism. Am J Psychiatry 2014; 171: 445-52. 46. Kenna GA, Zywiak WH, McGeary JE, et al. A within-group design of nontreatment seeking 5-HTTLPR genotyped alcohol-dependent subjects receiving ondansetron and sertraline. Alcohol Clin Exp Res 2009; 33: 315-23. 47. Kranzler HR, Armeli S, Tennen H, et al. A double-blind, randomized trial of sertraline for alcohol dependence: moderation by age of onset [corrected] and 5 hydroxytryptamine transporter-linked promoter region genotype. J Clin Psychopharmacol 2011; 31: 22-30. Erratum in: J Clin Psychopharmacol 2011; 31: 576. 48. Hutchison KE, Swift R, Rohsenow DJ, Monti PM, Davidson D, Almeida A. Olanzapine reduces urge to drink after drinking cues and a priming dose of alcohol. Psychopharmacology (Berl) 2001; 155: 27-34. 49. Hutchison KE, McGeary J, Smolen A, Bryan A, Swift RM. The DRD4 VNTR polymorphism moderates craving after alcohol consumption. Health Psychol 2002; 21: 139-46. 50. Ceccanti M, Inghilleri M, Attilia ML, et al. Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. A pilot study. Can J Physiol Pharmacol 2015; 93: 283-90. 51. Hutchison KE, Wooden A, Swift RM, et al. Olanzapine reduces craving for alcohol: a DRD4 VNTR polymorphism by pharmacotherapy interaction. Neuropsychopharmacology 2003; 28: 1882-8. 52. Ciafrè S, Fiore M, Ceccanti M, et al. Role of Neuropeptide Tyrosine (NPY) in ethanol addiction. Biomed Reviews 2016; 27: 27-39. 53. Ciafrè S, Carito V, Tirassa P, et al. Ethanol consumption and innate neuroimmunity. Biomed Reviews 2018; 28: 49-61. 54. Ceccanti M, Hamilton D, Coriale G, et al. Spatial learning in men undergoing alcohol detoxification. Physiol Behav 2015; 149: 324-30. 55. Ceccanti M, Carito V, Vitali M, et al. Serum BDNF and NGF modulation by olive polyphenols in alcoholics during withdrawal. J Alcohol Drug Depend 2015; 3: 214-9. 56. Ceccanti M, Coriale G, Hamilton DA, et al. Virtual Morris Task Responses in individuals in an abstinence phase from alcohol. Can J Physiol Pharmacol 2018; 96: 128-36. 57. Carito V, Ceccanti M, Ferraguti G, et al. NGF and BDNF alterations by prenatal alcohol exposure. Curr Neuropharmacol 2017 Aug 24.