ARTURO G. LERNER, MD Dual Disorders Ward Lev- Hasharon Mental Health Center Netanya, Israel

1. ADDICTION MEDICINE WITH EMPHASIS ON PSYCHOACTIVE SUBSTANCESSchool of Continuing Medical Education Sackler School of Medicine, Tel Aviv UniversityAlcohol use disorders: pharmacology, clinical topics, diagnosis and treatment9 March 2010 ARTURO G. LERNER, MD Dual Disorders Ward Lev- Hasharon Mental Health Center Netanya, Israel artura@lev-hasharon.co.il Cellular 050-6267912 Fax: 09-8980313

2. Alcohol use disorders Alcohol etymology • Alcohol (from Arabic al-kuhool or al -ghoul meaning 'the spirit') refers almost always to ethanol, also known as grain alcohol • Alcohol refers to that chemical substance contained in drinks and perfumes among other uses

3. Alcohol use disorders • Alcoholism is disorder which results in a persistent use of alcohol despite negative consequences • Dipsomania (binge drinking) described a preoccupation with, or compulsion toward the consumption of, alcohol and an impaired ability to recognize the negative effects of excessive alcohol consumption • While the ingestion of alcohol is, by definition, necessary to develop alcoholism, the use of alcohol does not predict the development of alcoholism (addictive reaction hypothesis). The quantity, frequency and regularity of alcohol consumption required to develop alcoholism varies greatly from person to person. In addition some risk factors, including social environment, stress, mental health, genetic predisposition, age, ethnicity and gender have been identified • Alcoholism is a primary chronic relapsing disease characterized by impaired control over drinking, preoccupation with the use of alcohol despite adverse consequences, and distortions in thinking • Glavas MM, Weinberg J (2006). "Stress, Alcohol Consumption, and the Hypothalamic-Pituitary-Adrenal Axis". In Yehuda S, Mostofsky DI. Nutrients, Stress, and Medical Disorders. Totowa, NJ: Humana Press. pp. 165–183 • Chen, CY.; Storr, CL.; Anthony, JC. (Mar 2009). “Early onset drug use and risk for drug dependence problems”. Addict Behav34 (3): 319–22. • Morse RM, Flavin DK (August 1992). "The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism". JAMA : the journal of the American Medical Association268 (8): 1012–4.

4. Alcohol use disorders First line players • Dopamine : Craving, protracted alcohol syndrome and psychological dependence(HVA) • GABA (gamma amynobutyric acid): Physical dependence • Glutamate: Physical dependence (Is synthesized from glutamate -GAD and piridoxine) • Noradrenaline: acute alcoholwithdrawal syndrome • (MHPG) • Serotonin: Co-occurring depression and psychosis (5-HIAA) • Oral topiramate for treatment of alcohol dependence: a randomised controlled trial.Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Lawson K, Javors MA, Ma JZ.Lancet, 2003 May 17;361(9370):1677-85

5. Alcohol use disorders Mechanism of action • Alcohol appears to produce its effects by intercalating itself into membranes and thus increasing fluidity of the membranes, increasing chloride channel activity and enhancing GABA A receptor affinity to GABA neurotransmitter • BZs bind at the interface of the α and γ subunits on the GABA A receptor • Barbiturates mainly bind to the GABA A receptor at the alpha subunit • The GABA A receptor is a protein complex located in the synapses of neurons • All GABA A receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter gamma-aminobutyric acid (GABA) • A subset of GABA A receptor complexes also contain a single binding site for benzodiazepines • The subset of GABA A receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR) • The GABA A receptor is a heteromer composed of five subunits, most commonly two α's, two β's and one γ (α2β2γ). For each subunit, many subtypes exist (α1-6, β1-3 and γ1-3) • GABA A receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects.

6. Alcohol use disorders • Ethanol is a psychoactive substance with complex physiological effects: stimulant and depressant effects • The stimulant effects (primary-minor) of alcohol may lead to the sensitization of brain limbic areas (dopamine reward system) that mediate alcohol reinforcing and pleasurable effects and control the desire to drink • The depressant-sedative effects (secondary-major) of alcohol lead to alcohol dependence by initiating neuroadaptations in glutamate and GABA receptors

7. Alcohol use disorders • Alcohol is a GABA agonist and NMDA antagonist • Alcohol enhances the inhibitory action of GABAergic neurotransmitters by increasing the response (supersensivity: number, affinity and efficiency)of GABA receptors • Alcohol reduces the excitatory action of GLUTAMATergic neurotransmitters by altering the response (subsensitivity) of NMDA receptors • Oral topiramate for treatment of alcohol dependence: a randomised controlled trial.Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Lawson K, Javors MA, Ma JZ.Lancet, 2003 May 17;361(9370):1677-85

8. Thestimulant effect Primary Short term exposure Dopamine related May lead to sensitization Reverse tolerance (“less use more reaction”) Chronic course Desire to drink after withdrawal The depressant effect Secondary Long term exposure GABA and Glutamate related May lead to dependence Physical tolerance (more use less reaction”) Acute course Desire to drink during withdrawal Alcohol use disorders

9. Thestimulant effect Reverse tolerance Psychological dependence Sensitization Desire to drink Chronic condition Psychological assistance Slowly reversible or irreversible syndrome The depressant effect Tolerance Physical dependence Desensitization Necessity to drink Acute condition Medication assistance Reversible syndrome Alcohol use disorders

10. Alcohol use disorders Alcohol and Benzodiazepines • Alcohol appears to additionally act like BZ on BZ receptors • GABA, the major inhibitory neurotransmitter, interacts with GABA type A complex. • BZ receptors ( two central and one peripheral) are contiguous to the GABA type A receptor (endozepines- DBI diazepam binding inhibitor is a protein that modulates GABA receptors ) • Occupation of BZ receptor changes the conformation of the GABA receptor to increase its affinity to GABA neurotransmitter, enhances chloride ion influx and hyper-polarization. • Papadopoulos V, Brown AS (1995). "Role of the peripheral-type benzodiazepine receptor and the polypeptide diazepam binding inhibitor in steroidogenesis.". J. Steroid Biochem. Mol. Biol.53 (1-6): 103–10

11. Alcohol use disorders Alcohol related disorder Extended diagnosis (Non DSM IV TR diagnosis) • Any functional impairment due to alcohol intake or associated behavior in lifetime • “Drinking problem” Multi-axial diagnosis (DSM IV TR diagnosis) • Abuse and dependence

12. Alcohol use disorders Common alcohol associated clinical syndromes (non DSM) • Acute alcohol intoxication • Idiosyncratic alcohol intoxication • Blackouts • Uncomplicated alcohol withdrawal • Alcohol delirium • Delirium Tremens • Withdrawal seizures • Wernicke – Korsakoff syndrome • Alcohol hallucinosis • Alcohol fetal syndrome

13. Alcohol use disorders Acute alcohol intoxication • Slurred speech • Incoordination • Unsteady gait • nystagmus • Impairment in attention or memory • Stupor • Slowed motor performance and decreased thinking ability: 20mg/dL • A breathalyzer(ינשוף) is a device for estimating blood alcohol content (BAC) from a breath sample. 240 mcg/air-liter • “Alcolocks” have been proposed

14. Alcohol use disorders Acute effects of alcohol • Alcohol may exert its primary sedative affects by affecting the major inhibitory neurotransmitter GABA and the major excitatory neurotransmitter glutamate • Acute alcohol intake facilitates GABAergic transmission by enhancing chloride conductance through the GABA A complex (similar to BZ) • Acute alcohol intake inhibits glutamate activity by decreasing cationic conductance through NMDA receptor. • Alcohol effects on dopamine reward system: • Pleasure, reinforcing and craving • Alcohol effects on GABA / NMDA complex: • Acute sedation • Sleep induction • Anticonvulsant effect • Muscle relaxating effects • Physical dependence

15. Alcohol use disorders Chronic effects of alcohol • The chronic effects of alcohol on the GABA (subsensitivity) and NMDA (supersensitivity) systems are generally opposite to the acute effects • The development of tolerance leads to reduced GABAergic activity and increased levels of NMDA activity

16. Alcohol use disorders Idiosyncratic alcohol intoxication • Is a severe alcohol intoxication that develops rapidly after a person consumes a small amount of alcohol • Some persons might have a genetic deficit of alcohol dehydrogenase • Blackouts can follow the intoxication episode • Organic reasons should be ruled out • Perr In. Pathological intoxication and alcohol idiosyncratic intoxication Diagnostic and clinical aspects. J Forensic Sci. 1986 Jul;31 :806-11

17. Alcohol use disorders Blackouts • A blackout is a phenomenon caused by the intake of alcohol or other substance in which long term memory creation is impaired or there is a complete inability to recall the past. Blackouts are frequently described as having effects similar to that of anterograde amnesia, where the subject literally does not remember what has happened in the recent past. • Alcohol appears to block the consolidation of new memories into old memories, a process that is thought to involve the hippocampus and related temporal lobe structures. • Blackouts can generally be divided into two categories, "en bloc" blackouts, and "fragmentary" blackouts. • “En bloc” blackouts are classified by the inability to later recall any memories from the intoxicated period. A person experiencing an “en bloc” blackout may not appear to be doing so, as he can carry on conversations or even manage to accomplish difficult tasks. • Fragmentary blackouts are characterized by the ability to recall certain events from an intoxicated period, yet be unaware that other memories are missing until reminded of the existence of these 'gaps' in memory. This phenomenon is also termed a brownout. Research indicates that fragmentary blackouts, or brownouts are far more common than en bloc blackouts. • PARKER, E.S.; BIRNBAUM, I.M.; AND NOBLE, E.P. Alcohol and memory: Storage and state dependency. Journal of Verbal Learning and Verbal Behaviour 15:691-702, 1976 • ACHESON, S.; STEIN, R.; AND SWARTZWELDER, H.S. Impairment of semantic and figural memory by acute ethanol: Age-dependent effects. Alcoholism: Clinical and Experimental Research 22:1437-1442, 1998

18. Alcohol use disorders Uncomplicated alcohol withdrawal • Tremor • Autonomic hyperactivity (sweating or pulse rate greater than 100) • Insomnia • Nausea or vomiting • Transient visual, or auditory hallucinations or illusions • Psychomotor agitation • Anxiety • Grand mal seizures • This syndrome is roughly NE associated

19. Alcohol use disorders Uncomplicated alcohol withdrawal • Alcohol withdrawal typically begin 6 to 48 hours • Peak within 24 to 48 hours • It gradually resolves within 5 to 7 days after last drink • Tremor may be the only sign • If left untreated alcohol withdrawal might progress to seizures and delirium despite mildness of syndrome

20. Alcohol use disorders Suggested treatment • First line pharmacological agents • Benzodiazepines • Second line pharmacological agents • Carbamazepine • Propanolol • Clonidine • Complex B vitamins • First and second line pharmacological agents are recommended to be administered together • American Society of Addiction Medicine. Guidelines: pharmacological management of alcohol withdrawal. JAMA, July 9, 1997 - Vol. 278, No. 2

21. Alcohol use disorders • Alcohol delirium • confusion • disorientation • cognitive impairments • Alcohol delirium tremens – DT • Psychiatric emergency • Perceptual disturbances • Psychomotor agitation • insomnia • Fear and terror • Violence (not aggression) • High doses of BZ or haloperidol recommended • Hoes MJ (1979) The significance of the serum levels of vitamin B-1 and magnesium in delirium tremens and alcoholism. J Clin Psychiatry; 40 :476-9 • ERWIN, WILLIAM E. MD; WILLIAMS, DIANNE B. PharmD; SPEIR, WILLIAM A. MD(1998) Delirium Tremens. Southern Medical Journa;l 91: 425-432

22. Alcohol use disorders Withdrawal seizures • Generalized • Tonic-clonic • After first seizure there is an increased possibility to have more seizures • Status epilepticus is a rare condition • Seizures can be associated to head injuries, CNS infections, strokes, hypoglycemia, hyponatremia, hypomagnesemia • Nowadays seizures are not supposed to develop with adequate treatment • Management of seizures: BZ (diazepam IV)+ antiepileptic agent • Status epilepticus: neurologist consultation • Antiepileptic loading: carbamazepine and valproate • Schuckit M. A.; Tipp J. E.; Reich T. (1995)  Hesselbrock V. M.; Bucholz K. K.The histories of withdrawal convulsions and delirium tremens in 1648 alcohol dependent subjects. Addiction 90: 1335-1348

23. Wernicke Encephalopathy Acute neurological disorder Ataxia (primarily gait) vestibular dysfunction confusion Ocular motility: abnormalities: horizontal nystagmus, lateral orbital palsy gaze palsy sluggish reaction to light Anisocoria Thiamine deficiency: poor nutritional habits or malabsortion syndrome Treatment: thiamine oral or IV Korsakoff Amnesia (anterograde) Psychosis Dementia Confabulation Alertness Responsiveness Cognitive impairments Treatment: thiamine oral (100- 300 mg/day) Mamillary bodies involvement suspected Alcohol use disorders

24. Alcohol use disorders Alcohol hallucinosis • Persistent auditory perceptual disturbances • They appear after withdrawal • Full insight • Patients relate them to alcohol • Chronic in type • Resistant to treatment • Sometime associated to tinnitus • Small amounts of typical anti-psychotics or carbamazepine may help

25. Alcohol use disorders Fetal alcohol syndrome • Alcohol intake during pregnancy or breast-feeding • Mental retardation • Microcephaly • Cranial malformations • Limb defects • Heart defects • Shortstature

26. Craving Uncontrollable behavior Irreversible behavior Absence of conscious unawareness Wanting Controllable behavior Reversible behavior Presence of conscious unawareness Alcohol use disorders

27. Alcohol use disorders Babor -Type A alcohol dependence • Late onset • Few childhood risk factors • Little family history of alcohol dependence • Mild dependence • Acceptable functioning • Soft core psychopathology • Good treatment response • Babor, Thomas F.; Hofmann, Michael; DelBoca, Frances K.; Hesselbrock, Victor M.; et al Types of alcoholics: Evidence for an empirically derived typology based on indicators of vulnerability and severity. Archives of General Psychiatry. Vol 49, Aug 1992, 599-608.

28. Alcohol use disorders Babor -Type B alcohol dependence • Early onset • Many childhood risk factors • Strong family history of alcohol dependence • Severe dependence • Severe functioning problems • Hard core psychopathology • Poor treatment response • Babor, Thomas F.; Hofmann, Michael; DelBoca, Frances K.; Hesselbrock, Victor M.; et al Types of alcoholics: Evidence for an empirically derived typology based on indicators of vulnerability and severity. Archives of General Psychiatry. Vol 49, Aug 1992, 599-608.

29. Alcohol use disorders Gamma alcohol dependence • Awareness of lack of drinking control • People are unable to stop drinking once they start • Large amounts of alcohol are consumed • When drinking is terminated as a result of illness or lack of money, these people are capable of abstaining for varying periods (dipsomania, binge drinking) • Babor, Thomas F.; Hofmann, Michael; DelBoca, Frances K.; Hesselbrock, Victor M.; et alTypes of alcoholics: Evidence for an empirically derived typology based on indicators of vulnerability and severity. Archives of General Psychiatry. Vol 49, Aug 1992, 599-608.

30. Alcohol use disorders Delta alcohol dependence • Unawareness of lack of drinking control • People are unable to stop drinking once they start • People drink certain amounts each day • When drinking is terminated for some reason alcohol dependence is discovered • They do not know they are alcoholics • Babor, Thomas F.; Hofmann, Michael; DelBoca, Frances K.; Hesselbrock, Victor M.; et alTypes of alcoholics: Evidence for an empirically derived typology based on indicators of vulnerability

31. Alcohol use disorders • The diverse properties of alcohol have provided multiple targets for the pharmacological treatment of alcohol dependence • Several medications combined with psychosocial treatments reduce alcohol consumption and are currently in use

32. Alcohol use disorders Pharmacological treating approach • Target symptoms: withdrawal and craving • Anti-craving medications can be started during withdrawal • DSM IV TR diagnosis – axis III • Basic laboratory screening • Pharmacological agents • Take into consideration side effects profile

33. Alcohol use disorders Laboratory tests in alcohol dependence • GGT (gama glutamyl transpeptidase) levels are high in about 80 % of alcoholics: 11-32 u • MCV ( mean corpuscular volume) is high in about 60 % of alcoholics • Uric acid • Triglycerids • AST ( aspartate aminotransferase) - SGPT: 10-40 u • ALT ( alanine aminotransferase) - SGOT: 10-40 u

34. Alcohol use disorders Medications • Benzodiazepines receptors agonists • Acetaldehyde dehydrogenase inhibitors • Opiate antagonists • Dopamine antagonists • NMDA antagonists • Serotonin antagonists • SRIs, SSRIs and new generation compounds • Antiepileptic agents

35. Generic name ( Representative not exhaustive list) Disulfiram Naltrexone Acamprosate Ondansentron SSRIs SRIs TCAs Tiapride Bromocriptine Lithium Baclofen Trade mark name (Representative not exhaustive list) Antabuse 500 mg Revia 50 mg Campral (333 mg) up to 1998 mg Zofran (4 and 8 mg) up to 16 mg Fluoxetine 20 mg, Fluvoxamine up to 200 mg, Paroxetine 20 mg, Citalopram 20 mg, Sertraline up to 200 mg Clomipramine ( 25) up to 200/300 mg Desipramine up to 200 mg Doparid 100 mg Parilac, Parlodel (2.5) up to 10 mg Lithium 900/1200 mg Baclosal 10 – 25 mg Alcohol use disorders

36. Alcohol use disorders Benzodiazepines receptors agonists • BZs bind to GABA A complex replacing and substituting the withdrawing alcohol. • After stabilization is achieved BZ should be gradually and wisely reduced • Every BZs appear to be effective in controlling in-progress alcohol withdrawal syndrome • Diazepam (available and easy to manage), lorazepam and chlordiazepoxide • IV BZs should be avoided unless seizures develop

37. Alcohol use disordersApproximate Therapeutic Equivalent Doses of Benzodiazepines Generic name Alprazolam Alprazolam XR Chlordiazepoxide Clonazepam Clorazepate Diazepam Lorazepam Oxazepam Triazolam Estazolam Flurazepam Prazepam Temazepam Quazepam Zolpidem Dose (mg) 1 1 25 0.5-1 15 10 2 30 0.25 1 30 80 20 15 10

38. Alcohol use disorders Acetaldehyde dehydrogenase inhibitors • Disulfiram (Antabuse) is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. • Disulfiram is also being studied as a treatment for cocaine dependence, as it prevents the breakdown of DA - a neurotransmitter whose release is stimulated by cocaine. The excess dopamine results in increased anxiety, higher blood pressure, restlessness and other unpleasant symptoms. • Under normal metabolism, alcohol is broken down in the liver by the enzyme alcohol dehydrogenase to acetaldehyde, which is then converted by the enzyme acetaldehyde dehydrogenase to the harmless acetic acid. Disulfiram blocks this reaction at the intermediate stage by blocking the enzyme acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. • As acetaldehyde is one of the major causes of the symptoms of a “hangover" this produces immediate and severe negative reaction to alcohol intake. Some 5–10 minutes after alcohol intake, the patient may experience the effects of a severe hangover for a period of 30 minutes up to several hours. Symptoms include flushing of the skin, accelerated heart rate, shortness of breath, nausea, vomiting, throbbing headache, visual disturbance, mental confusion, circulatory collapse and even death. • Krampe H, Stawicki S, Wagner T, et al. (January 2006). "Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome". Alcoholism, clinical and experimental research30 (1): 86–95

39. Alcohol use disorders Opioid antagonists • Naltrexone is a full opioid competitive receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. • It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade name Revia . • In some countries including the United States, an extended-release formulation is marketed under the trade name Vivitrol. Also in the US, Methylnatrexone Bromide, a closely related drug, is marketed as Relistor, for the treatment of opioid-medications related constipation. • Naltrexone, and its active metabolite 6-β-naltrexol, are competitive antagonists at μ- and κ-opioid receptors, and to a lesser extent at δ-opioid receptors. • Its use in alcohol dependence has been studied and has been shown to be effective. Its mechanism of action in this indication is not fully understood, but as an opioid-receptor antagonist it's likely to be due to the modulation of the dopaminergic mesolimbic pathway which ethanol is believed to activate • Shader, RI. "Antagonists, Inverse Agonists, and Protagonists." Journal of Clinical Psychopharmacology. 2003 Aug; 23(4):321–322 • Sinclair JD (2001). “Evidence about the use of naltrexone and for different ways of using it in the treatment of alcoholism”. Alcohol and Alcoholism36 (1): 2–10 • King A, de Wit H, Riley R, Cao D, Niaura R, Hatsukami D (2006). "Efficacy of naltrexone in smoking cessation: A preliminary study and an examination of sex differences". Nicotine & Tobacco Research8 (5): 671–82 • Krystal et al. Naltrexone in the Treatment of Alcohol Dependence. NEJM 2001; 345: 1734-1739

40. Alcohol use disorders NMDA antagonists • Alcohol inhibits activity of NMDARs, (chronic alcohol consumption leads to the overproduction of these receptors) • Thus, sudden alcohol abstinence causes these excessive numbers of NMDARs to be more active than normal and to produce the symptoms of DT and excitotoxic neuronal death. • Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate (AA) which activates NMDARs. • Acamprosate (Campral) reduces this glutamate surge. The mediation also appears to protects excitotoxicity induced by ethanol withdrawal. • Acamprosate can stabilize the hyperexcitability of glutamate receptors • Acamprosate may reduce protracted withdrawal and craving • Mason BJ. "Treatment of alcohol-dependent outpatients with acamprosate: a clinical review". J Clin Psychiatry 2001;62(suppl 20):42-8 • Mason, BJ; Goodman AM, Chabac S, Lehert P (2006). "Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: The role of patient motivation". J Psychiatr Res40 (5): 383– 393 • Feeney, GF; Connor JP, Young RM, Tucker J, McPherson A (2006). "Combined acamprosate and naltrexone, with cognitive behavioural therapy is superior to either medication alone for alcohol abstinence: A single centre's experience with pharmacotherapy". Alcohol Alcohol41 (3): 321–327 • Tsai G, Coyle JT. 1998. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annual Review of Medicine, 49: 173-184 • De Witte P, Littleton J, Parot P, Koob G. (2005). "Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action." CNS Drugs19 (6): 517-537

41. Alcohol use disorders Serotonin antagonists • Ondansetron (Zofran) is a SE-HT3 antagonist used mainly as an antiemetic to treat nausea and vomiting related to chemotherapy • Ondansetron, up to 16 mg, lowers the cravings for alcohol, especially in early-onset alcoholics • The mechanism of action of ondansetron in reducing alcohol craving is not completely understood • Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB (1994). "Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence". Alcohol Clin Exp Res18 (4): 879–85

42. Alcohol use disorders SRIs, SSRIs and new generation compounds • SSRIs inhibit the reuptake of SE into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft. • High SE levels will both activate the postsynaptic receptors and the presynaptic auto-receptors that serve as a feedback sensor for the cell. • Activation of the auto-receptors by agonists like SE triggers a decrease of serotonin production. • The resulting SE deficiency persists for some time. The body adapts gradually to this situation by lowering or down-regulating the sensitivity of the auto-receptors. • Another adaptive process provoked by SSRIs is the downregulation of postsynaptic 5HT2A receptors. • After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. • This down-regulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. • Most of the serotonin receptors on the surface of the cell are coupled to a G-protein inside it. These proteins activate or inhibit second messengers, which in turn affect trancription factors. • Transcription factors are proteins that fit to the beginning of a gene and tell the cell to start using it. • These (slowly proceeding) neurophysiological adaptations of the brain tissue are the reason why usually several weeks of continuous SSRI use is necessary for the antidepressant effect to become fully manifested and why increased anxiety is a common side effect in the first few days or weeks of use.

43. Alcohol use disorders SRIs, SSRIs and new generation compounds These agents appear to be effective in some co-occurring alcohol use and depressive - anxiety spectrum disorders • Grant BF, Stinson FS, Dawson DA, Chou SP, Dufour MC, Compton W, Pickering RP, Kaplan K: Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 2004; 61:807–816 • Kushner MG, Sher KJ, Beitman BD: The relation between alcohol problems and the anxiety disorders. Am J Psychiatry 1990; 147:685–695 • Randall CL, Johnson MR, Thevos AK, Sonne SC, Thomas SE, Willard SL, Brady KT, Davidson JR: Paroxetine for social anxiety and alcohol use in dual-diagnosed patients. Depress Anxiety 2001; 14:255–262 • Kranzler HR, Burleson JA, Del Boca FK, Babor TF, Korner P, Brown J, Bohn MJ: Buspirone treatment of anxious alcoholics: a placebo-controlled trial. Arch Gen Psychiatry 1994; 51:720–731 • Pettinati HM, Volpicelli JR, Luck G, Kranzler HR, Rukstalis MR, Cnaan A: Double-blind clinical trial of sertraline treatment for alcohol dependence. J Clin Psychopharmacol 2001; 21:143–153 • Garbutt JC, West SL, Carey TS, Lohr KN, Crews FT: Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA 1999; 281:1318–1325

44. Alcohol use disorders GABAB agonists-baclofen • Baclofen is GABAB agonist primarily used to treat spasticity.Its benefitial effects are produced via spinal and supraspinal sites. • Baclofen produces its effect via modulating the GABAB receptor, similar to the drug GHB which also has the same mechanism of action and also similar effects. • However, there are some pharmacological differences in that baclofen appears to have reduced abuse and dependence potential. The modulation of the GABAB receptor is what produces baclofen's range of therapeutic properties • Discontinuation of baclofen can be associated with a withdrawal syndrome which resembles BZ and alcohol withdrawal • BACLOFEN EFFICACY IN REDUCING ALCOHOL CRAVING AND INTAKE: A PRELIMINARY DOUBLE-BLIND RANDOMIZED CONTROLLED STUDY. Addolorato et al.Alcohol Alcohol 2002;37:504-508 • Addolorato, G.; Leggio, L.; Ferrulli, A.; Cardone, S.; Vonghia, L.; Mirijello, A.; Abenavoli, L.; D'Angelo, C. et al. (Dec 2007). "Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study.". Lancet370: 1915-22 • Addolorato G; Leggio L, Abenavoli L, Agabio R, Caputo F, Capristo E, Colombo G, Gessa GL, Gasbarrini G (March 2006). "Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam". Am J Med119 (3): 276.e13–8.

45. Alcohol use disorders Antiepileptic medications • Antiepileptic agents share neurochemical effects with alcohol by inhibiting neuronal excitation and are commonly used to treat alcohol withdrawal during acute detoxification • Antiepileptic agents lack abuse potential • Antiepileptic agentsmay be useful in controlling alcohol cessation short and long term effects

46. Alcohol use disorders Antiepileptic medications in the treatment of alcohol withdrawal and maintenance • Carbamazepine (Tegretol, Teril 200 – 400 mg) • Valproate (Depalept 200 – 500 mg) and valproic acid ( Valporal 200 mg) • Gabapentine (Gabapentin, Neurontin 300-400 mg) • Vigabatrine (Sabrilan 500 mg) • Topiramate (Topamax 25-50 mg) • Lamotrigine (Lamictal and generics) • Oxcarbazepine (Trileptin 300 – 600 mg) • Tiagabine: tiagabine acts as a GABA-uptake inhibitor from synaptic cleft into neurons and glia

47. Benzodiazepines Very effective in treating severe alcohol withdrawal Mainly use in inpatient setting Only short treatment recommended “Craving” for prescriptions in outpatient setting Abuse and dependence potential Discontinuation syndrome: rebound and relapse Antiepileptic agents Very effective in treating mild/moderate alcohol withdrawal Mainly use in outpatient setting Short and long treatment recommended No “craving “ for prescription in outpatient setting No abuse and dependence potential No discontinuation syndrome: rebound and relapse Alcohol use disorders

48. Alcohol use disorders Carbamazepine Mechanisms of action • Primarily, binding to voltage-dependent sodium channels in the inactive state and prolonging their inactivation • Secondarily, reduces voltage-dependent calcium channel activation and therefore synaptic transmission • Additional reduction of currents through NMDA glutamate receptors channels • Anti-kindling/sensitization properties Loading approach • Starting doses of immediate release CBZ 800-1200 mg gradually tapering over two weeks • CBZ CR and SR are not recommended Keep in mind: Hepatitis • Hepatitis associated with increases in liver enzymes particularly transaminases • Choleostasis associated with elevated bilirubin and alkaline phosphatase • Doube-blind,placebo-controlled pilot study of carbamazepine for the treatment of alcohol dependence Mueller et al, Alcohol Clin Exp Res 1997; 21: 86-92

49. Carbamazepine Dose related adverse effects Double or blurred vision Vertigo Gastrointestinal disturbances Task performance impairment Hematological effects Carbamazepine Non-dose related adverse effects Agranulocytosis and aplastic anemia Exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis Acute hepatic failure and hepatitis Pancreatitis Alcohol use disorders

50. Alcohol use disorders Valproate Mechanism of action • Therapeutic effects appears to be through GABA complex • Anti-kindling/sensitization properties Loading approach • 1000-1500 mg in three daily divided doses • Tapering over two weeks • Use of valproic acid in alcohol relapse prevention:a pilot study Brady et al, Drug Alcohol Depend 2002; 67: 323-330