Alcohol and Alcoholism Advance Access published online on March 13, 2008
Alcohol and Alcoholism, doi:10.1093/alcalc/agn016
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Neurobiology and Treatment in Alcoholism—Recent Findings Regarding Lesch's Typology of Alcohol Dependence
Department of Psychiatry and Psychotherapy, University Hospital Erlangen, Germany
* Author to whom correspondence should be addressed at: Department of Psychiatry and Psychotherapy, University Hospital Erlangen, Schwabachanlage 6, D-91054 Erlangen, Germany. Tel: +49-9131-8533001; Fax: +49-9131-8534105; E-mail: thomas.hillemacher{at}uk-erlangen.de
 |
ABSTRACT |
|---|
 TOP ABSTRACT IntroductionConclusionReferences |
|---|
Subtyping in alcohol dependence has become an important issue as studies have proposed different neurobiological mechanisms in alcoholism in the recent years. Studies have shown that alcohol dependence reflects a wide range of different phenotypes, including psychological, social, and neurobiological factors. Different ways of subtyping have been proposed in the last decades, one of them being Lesch's typology of alcohol dependence. Recent investigations have shown that different subtypes of Lesch's typology are associated with specific neurobiological factors which may have important implications for clinical practice. This applies in particular for genetic and neuroendocrinological factors, differences in the regulation of NMDA receptor-mediated glutamatergic neurotransmission, and in response to acamprosate and naltrexone treatment.
|
Introduction |
|---|
|
TOPABSTRACTIntroductionConclusionReferences |
|---|
Alcohol dependence is a highly relevant disease in clinical medicine. Social, psychological, and biological factors influencing the etiogenesis of alcohol dependence are manifold and subject to intensive research worldwide. Moreover, alcohol dependence is a disease particularly characterized by frequent but very different comorbidities. These comorbidities range from medical conditions associated with alcohol consumption such as liver cirrhosis or esophagus varices to psychiatric disorders such as depression, ADHS, personality disorders, or anxiety disorders. Many attempts to classify patients with alcohol dependence have been made in the past. These include biologically orientated typologies (Cloninger et al., 1988
; Babor et al., 1992; Babor and Caetano, 2006) and classifications focusing on behavioral characteristics (Jellinek, 1960). The Lesch typology, which is widely used in Europe and especially in German-speaking countries, tries to integrate biological, social, and psychological factors in one classification (Lesch et al., 1990; Lesch and Walter, 1996). The typology differentiates four subtypes: type 1 (model of allergy) consists of patients with heavy alcohol withdrawal symptoms who tend to use alcohol to weaken detoxification symptoms. Patients of type 2 (model of anxiety or conflict) are characterized by using alcohol as self-medication because of anxiolytic effects. The main characteristic in type 3 patients is an underlying affective disorder (alcohol as an antidepressant) (Kiefer and Barocka, 1999). Type 4 patients (alcohol as adaptation) show pre-morbid cerebral defects, behavioral disorders, and a high social burden. Patients are usually classified at admission for detoxification treatment according to the decision tree developed in 1990 (Lesch et al., 1990). If it is not possible to determine an appropriate medical history at admission, a time period of 5 days is allowed before classification into the referring type. Lesch's typology has been used in many research projects focusing on very different aspects of alcoholism research. This review will try to give an overview of the recent findings focusing on neurobiological aspects and treatment implications regarding the subtypes of Lesch's typology.
Homocysteine and the glutamate system
Various recent studies have shown that elevated serum levels of the sulfur-containing amino acid homocysteine play a crucial role in the neurobiology of alcoholism (Bleich et al., 2005), particularly regarding withdrawal symptoms such as seizures (Bleich et al., 2000a, 2006), cognitive impairment (Wilhelm et al., 2006), and brain atrophy (Bleich et al., 2000b, 2003a). Homocysteine is an excitatory amino acid and leads to an increase of glutamatergic neurotransmission via overstimulation of NMDA receptors (Bleich et al., 2003b, 2004b; Bigal et al., 2007).
Regarding Lesch's typology, it is known that patients of Lesch type 1 tend to suffer from seizures and more prominent withdrawal symptoms than patients of other types of Lesch's typology. In a recent study, it has been shown that homocysteine serum levels are elevated in patients of Lesch's type 1, especially in patients with a history of alcohol withdrawal seizures (Bleich et al., 2004a). As homocysteine acts as a glutamate agonist at the NMDA receptor, it is interesting whether there are differences regarding serum levels of glutamic acid between the different types of Lesch's typology. In a recently published work Walter et al. showed that blood levels of glutamic acid differ between patients of Lesch's typology. In this study, the authors investigated a sample of 159 alcoholics, measuring glutamic acid in peripheral blood and assessing the type of alcohol dependence according to Lesch's typology. As a main finding, patients of types 1 and 4 showed significantly higher levels of glutamic acid than patients of types 2 and 3. The authors interpret these findings in type 1 patients as a "kindling" phenomenon while in type 4 patients elevated glutamic acid values may be related either to compulsivity and/or to the frequent repetition of drinking and withdrawal (Walter et al., 2006).
Taken together, these findings show that particularly patients of Lesch's type 1 and possibly patients of type 4 seem to suffer from changes in glutamatergic pathways which might underline the marked withdrawal symptoms in these groups.
Genetics and Lesch's typology
Many different candidate genes have been identified which may be associated with alcoholism or with specific features of the disease (e.g., withdrawal seizures). However, most of these reports did not include subtyping of alcohol patients. Most recently, a first study investigated Lesch's typology in respect to genetic investigations (Bönsch et al., 2006). Bönsch et al. investigated a sample of 134 alcoholics admitted for detoxification treatment with respect to different MTHFR (methylene-tetra-hydrofolate reductase) genotypes. MTHFR is of crucial importance in the homocysteine pathway, acting as a carbon donator in the remethylation of homocysteine to methionine. Findings of this study revealed a significantly higher frequency of the thermolabile MTHFR (C677T) variant in patients of Lesch's type 4 compared to type 2 and 3 patients. This first study points towards a genetic determination of Lesch's typology.
Another recent study that focused on genetic variants in different subgroups of Lesch's typology found no evidence for a role of different polymorphisms in patients of Lesch's types 1 and 2 (Samochowiec et al., 2008). This investigation included the dopamine transporter (DAT), the D2 receptor (DRD2), the serotonin transporter (5HTT), and the catechol-O-methyltransferase (COMT) polymorphism. However, this study could not provide any results regarding Lesch's type 3 and 4 patients as the number of included subjects was too small for analysis. In conclusion, this second study shows that further studies including larger numbers of patients are necessary to verify these first results and to investigate other candidate genes in respect to different subtypes of Lesch's typology.
Neuroendocrinological findings
Endocrinological changes have particularly been associated with alcohol craving, including changes of the hypothalamus-pituitary-adrenocortical axis (HPA-axis), changes of appetite regulating peptides, and other hormones associated with stress response and dopaminergic neurotransmission.
Several studies have shown that the HPA-axis is disturbed during active drinking, withdrawal, and abstinence (Kiefer et al., 2002b; Kiefer and Wiedemann, 2004). For example, decreased CRH (corticotropin releasing hormone) is associated with elevated craving in alcohol dependence (Fahlke et al., 1994; Olive et al., 2003). Furthermore, studies found low cortisol and ACTH (adrenocorticotropic hormone) serum levels to be associated with increased craving and higher relapse rates (Kiefer et al., 2002b; Junghanns et al., 2003).
Also, other endocrinological changes have been described in alcoholism. Prolactin secretion is closely connected to dopaminergic transmission, reflecting changes of the tuberoinfundibular dopamine pathway. Furthermore, prolactin is known to be elevated in stress situations. A recent study investigated possible associations between prolactin serum levels and alcohol craving during alcohol withdrawal differentiating alcohol-dependent patients using Lesch's typology (Hillemacher et al., 2006b). This study assessed 115 male patients suffering from alcohol dependence according to ICD-10 criteria with the Obsessive Compulsive Drinking Scale (OCDS) during early alcohol withdrawal. Results revealed a significant association between prolactin serum levels and extent of craving measured by the OCDS particularly in Lesch's type 2 patients. This is interesting because patients of Lesch's type 2 are characterized to suffer from anxiety and to use alcohol because of its anxiolytic effects. Anxiety disorders are also known to be associated with elevated stress levels and prolactin elevation (Hollander et al., 1989; Apostolopoulos et al., 1993). This finding may therefore reflect a shared pathophysiological pathway between anxiety disorder and alcohol craving in patients of Lesch's type 2.
Another important neuroendocrinological pathway in the pathogenesis of alcohol craving seems to be the appetite-regulating system. In this context the endocrinological peptides leptin and ghrelin have received most attention. Kiefer et al. firstly described that increased plasma concentrations of leptin may be associated with increased subjective rates of alcohol craving (Kiefer et al., 2001a, 2001b). Other studies showed that leptin plasma concentrations were elevated during chronic alcohol consumption (Nicolas et al., 2001), normalized during withdrawal and abstinence (Wurst et al., 2003). Using a large study sample a recent investigation provided evidence that leptin serum levels are associated with the extent of alcohol craving during early alcohol withdrawal (Hillemacher et al., 2007a). Also, the gastrointestinal peptide ghrelin was shown to be increased in alcohol dependence. Kim et al. found higher ghrelin levels in alcohol abstainers and a positive association with the duration of abstinence (Kim et al., 2005). Other studies described an involvement of ghrelin in the brain reward systems in an animal-experimental study (Jerlhag et al., 2006). A recent investigation described ghrelin levels to be elevated during alcohol withdrawal. However, this study found no association between ghrelin serum levels and alcohol craving (Kraus et al., 2005). In contrast to these findings, another recent investigation from Addolorato and colleagues found significantly lower plasma ghrelin levels in alcoholics and a significant relationship between ghrelin levels and alcohol craving scores (Addolorato et al., 2006).
A recent investigation analyzed the role of these peptides in alcohol craving in respect to Lesch's typology (Hillemacher et al., 2007b). This investigation was based on a sample of 188 patients with alcohol dependence, admitted for alcohol detoxification. Craving was measured using the OCDS. Using general linear models the authors found a significant positive association for leptin in patients of Lesch's types 1 and 2, while ghrelin showed a trend regarding an association with craving in patients of Lesch's type 1. These findings show that appetite-regulating peptides which obviously play an important role in alcohol craving may be of special interest in particular subtypes of patients.
Volume regulating mechanisms and alcohol craving
Other studies focused on differences regarding the association of drinking behavior and alcohol craving between subtypes of Lesch's typology. Different studies have indicated a beverage-dependent influence on craving apart from the association with alcohol intake itself.
Consumption of low alcoholic drinks such as so-called alcohol free beer was found to be associated with increased craving (Long and Cohen, 1989). A recent study found that craving is not only associated with alcohol intake itself but also with the type of consumed alcoholic beverage (Hillemacher et al., 2005). Furthermore, changes in volume-regulating peptides during alcohol intoxication and withdrawal were described recently in various studies (Eisenhofer et al., 1985; Trabert et al., 1992; Taivainen et al., 1995; Kiefer et al., 2002a). These alterations persist in long-term abstinent alcoholics (Döring et al., 2003; Jahn et al., 2004) and an association between craving and changes in volume regulation has been postulated (van Ree et al., 1994; Döring et al., 2003). However, these studies did not perform an analysis regarding different subtypes of alcoholism. A recent investigation analyzed data of 158 male alcoholics to investigate an association between volume intake of alcoholic beverage and alcohol craving in respect to Lesch's typology (Hillemacher et al., 2006d). This preliminary study should help to assess, whether volume-regulating mechanisms may be of different importance in subtypes of Lesch. This investigation found that the daily volume intake of alcoholic beverages correlated significantly with the extent of the OCDS. The effect was strongest in patients of Lesch type 2. These results show that volume intake is associated with alcohol craving and suggest a pathophysiological role of volume-regulating peptides like vasopressin or ANP. These mechanisms may be of special importance in patients of Lesch's type 2 which is interesting because ANP was described to have anxiolytic effects (Bhattacharya et al., 1995; Wiedemann et al., 2001; Herrmann-Lingen et al., 2003).
The "kindling" effect and other important findings
A recent study showed that recurrent detoxifications are associated with elevated alcohol craving (Malcolm et al., 2000), reflecting a "kindling" effect which has also been associated with the elevated risk of alcohol-related seizures after multiple detoxifications (Lechtenberg and Worner, 1991; Becker and Hale, 1993; Anton et al., 1996; Worner, 1996; Boothby and Doering, 2005). However, other investigations found contradictory results (Duka et al., 2002).
A recent study investigated a large patients sample regarding the role of recurrent detoxifications in alcohol craving in respect to the subtyping of Lesch (Hillemacher et al., 2006a). This study examined a sample of 192 patients, using the OCDS to assess the extent of craving during early alcohol withdrawal. Regarding a possible association between the number of previous detoxifications and alcohol craving, findings show a significant correlation for the whole population but particularly for patients of Lesch's type 1. This suggests that the kindling effect may be particularly important in a subgroup of patients. These findings may also help to interpret the previous contradictory findings and underline the importance of subtyping patients with alcohol dependence.
Another interesting investigation focused on the concept of abnormal hemispheric organization in alcoholism. This concept was studied previously in the area of endogenous psychosis and focuses on the frequency of left-handedness (Sperling et al., 2000). In a sample of 250 alcoholic inpatients, Sperling et al. found a significantly higher frequency of left-handedness in type 4 patients of Lesch's typology. According to the authors, left-handedness and therefore abnormal hemispheric organization may be a sign of the cerebral damage which is a characteristic of type 4 patients.
Association with nicotine dependence
Many studies document the well-known association between alcohol and nicotine dependence. Epidemiological investigations found a consistent association between alcohol and nicotine consumption (Zacny, 1990). A recent investigation demonstrated that in alcohol-dependent patients obsessive-compulsive craving is associated with the extent of nicotine dependence (Hillemacher et al., 2006c). We further analyzed these data, comparing patients regarding Lesch's typology of alcohol dependence. The severity of nicotine dependence was assessed using the Fagerström Test for Nicotine Dependence (FTND) (Fagerström et al., 1990; Heatherton et al., 1991), and the extent of alcohol craving was measured using the OCDS (Anton et al., 1996). All patients included in the study suffered from alcohol dependence according to DSM-IV and were assessed after admittance to the detoxification unit. Findings of the Spearman's correlation analysis revealed significant associations particularly in patients of Lesch's type 2 (OCDS total score: r = 0.274, P = 0.045, N = 54; OCDS compulsive subscale: r = 0.319, P = 0.019) and of Lesch's type 4 (OCDS total score: r = 0.527, P = 0.20; N = 19; OCDS compulsive subscale: r = 0.472, P = 0.041). We found no significant associations for Lesch's type 1 (N = 27) and Lesch's type 3 patients (N = 22). Also, no significant correlations with the obsessive subscale of the OCDS could be observed. In conclusion, these findings show that the subtyping of patients with alcohol dependence is also important when investigating associations with other comorbidities like nicotine dependence. Differences in brain pathophysiology between specific patients’ groups—particularly in the prefrontal and the orbitofrontal cortex-–may help to explain these results as these circuits have been associated with compulsive behavior and drug use which may be the link between nicotine dependence and alcohol craving (Volkow et al., 1999; George et al., 2001; Grüsser et al., 2004). The current findings should lead to further investigations regarding the involvement of these circuits in specific patient groups, which may also be of importance for differential treatment strategies.
Implications for therapy
Various studies have investigated different treatment options in respect to Lesch's typology. The United Kingdom Multicentre Acamprosate Study (UKMAS) found no differences in the response to acamprosate regarding Lesch's typology (Chick et al., 2000). However, in this study patients of types 3 and 4 were overrepresented. In the Austrian Acamprosate trial results show a better response to acamprosate in patients of types 1 and 2 (Lesch et al., 2001). Kiefer et al. found that acamprosate was particularly efficacious in patients of Lesch's type 1 while naltrexone was more effective in type 3 and type 4 patients (Kiefer et al., 2005). Also studies on other agents like flupenthixol have been performed. In a large study it was shown that flupenthixol is not only beneficial but also increases relapse rated in abstinent patients (Wiesbeck et al., 2001). In respect to Lesch's typology, Walter et al. showed that flupenthixol has this detrimental effect only in patients of types 1 and 3 (Walter et al., 2001). These findings demonstrate that different types of alcohol-dependent patients do respond to pharmacological interventions in a distinct manner, which should be considered when treating patients with anticraving substances such as acamprosate or naltrexone. Furthermore, a specific subtyping is useful when investigating new treatment options for relapse prevention, such as topiramate or baclofen (Addolorato et al., 2002; Johnson et al., 2003).
|
Conclusion |
|---|
|
TOPABSTRACTIntroductionConclusionReferences |
|---|
The presented findings may lead to two important conclusions. The different studies focusing on very different aspects in alcoholism show that the Lesch typology has a biological and genetic basis (see Fig. 1). Furthermore, dividing patients into subgroups has an important impact for further research strategies as completely different findings might be found regarding neurobiological mechanisms as well as the efficacy of pharmacological treatment. Testing new pharmacological options and psychotherapeutical or psychosocial interventions, it is important to take into account that these may have different efficacy when used in patients of different subgroups. Of course, also other typologies are of high interest in research and therapy (Babor and Caetano, 2006
). A recent analysis comparing different typologies of alcohol dependence supports the concept of four homogeneous types of alcoholism (Hesselbrock and Hesselbrock, 2006). Therefore, Lesch's typology offers a good basis for research and for a better understanding of alcoholism. Further investigations (e.g., a large European multicenter study) should be performed to assess whether Lesch's subtypes of alcoholism are associated with specific electrophysiological, neuroendocrine, genetic, and cognitive markers to confirm that this typology may be useful to define endophenotypes of alcoholism. Approaches for specific typologies are also necessary in other areas of addiction such as nicotine dependence (Lesch et al., 2004).
|
|
References |
|---|
|
TOPABSTRACTIntroductionConclusionReferences |
|---|
Addolorato G., Capristo E., Leggio L., et al. Relationship between ghrelin levels, alcohol craving and nutritional status in current alcoholics. Alcoholism: Clinical and Experimental Research (2006) 30:1933–1937.[CrossRef][Web of Science][Medline]
Addolorato G., Caputo F., Capristo E., et al. Baclofen efficacy in reducing alcohol craving and intake: A preliminary double-blind randomized controlled study. Alcohol and Alcoholism (2002) 37:504–508.
Anton R. F., Moak D. H., Latham P. K. The obsessive compulsive drinking scale: A new method of assessing outcome in alcoholism treatment studies. Archives of General Psychiatry (1996) 53:225–231.
Apostolopoulos M., Judd F. K., Burrows G. D., Norman T. R. Prolactin response to dl-fenfluramine in panic disorder. Psychoneuroendocrinology (1993) 18:337–342.[CrossRef][Web of Science][Medline]
Babor T. F., Caetano R. Subtypes of substance dependence and abuse: Implications for diagnostic classification and empirical research. Addiction (2006) 101(Suppl_1):104–110.[CrossRef][Web of Science][Medline]
Babor T. F., Hofmann M., DelBoca F. K., et al. Types of alcoholics: I. Evidence for an empirically derived typology based on indicators of vulnerability and severity. Archives of General Psychiatry (1992) 49:599–608.
Becker H. C., Hale R. L. Repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures: An animal model of alcohol withdrawal "kindling". Alcoholism: Clinical and Experimental Research (1993) 17:94–98.[CrossRef][Web of Science][Medline]
Bhattacharya S. K., Chakrabarti A., Sandler M., Glover V. Rat brain monoamine oxidase A and B inhibitory (tribulin) activity during drug withdrawal anxiety. Neuroscience Letters (1995) 199:103–106.[CrossRef][Web of Science][Medline]
Bigal M. E., Lipton R. B., Holland P. R., Goadsby P. J. Obesity, migraine, and chronic migraine: Possible mechanisms of interaction. Neurology (2007) 68:1851–61.
Bleich S., Bandelow B., Javaheripour K., et al. Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism. Neuroscience Letters (2003) 335:179–182.[CrossRef][Web of Science][Medline]
Bleich S., Bayerlein K., Hillemacher T., Degner D., Kornhuber J., Frieling H. An assessment of the potential value of elevated homocysteine in predicting alcohol-withdrawal seizures. Epilepsia (2006) 47:934–938.[CrossRef][Web of Science][Medline]
Bleich S., Bayerlein K., Reulbach U., et al. Homocysteine levels in patients classified according to Lesch's typology. Alcohol and Alcoholism (2004) 39:493–498.
Bleich S., Carl M., Bayerlein K., et al. Evidence of increased homocysteine levels in alcoholism: The Franconian alcoholism research studies (FARS). Alcoholism: Clinical and Experimental Research (2005) 29:334–336.[CrossRef][Web of Science][Medline]
Bleich S., Degner D., Bandelow B., von Ahsen N., Rüther E., Kornhuber J. Plasma homocysteine is a predictor of alcohol withdrawal seizures. Neuroreport (2000) 11:2749–2752.[Web of Science][Medline]
Bleich S., Degner D., Javaheripour K., Kurth C., Kornhuber J. Homocysteine and alcoholism. Journal of Neural Transmission Supplement (2000) 60:187–196.[Medline]
Bleich S., Degner D., Sperling W., Bönsch D., Thürauf N., Kornhuber J. Homocysteine as a neurotoxin in chronic alcoholism. Progress in Neuropsychopharmacology and Biological Psychiatry (2004) 28:453–464.[CrossRef][Medline]
Bleich S., Wiltfang J., Kornhuber J. Memantine in moderate-to-severe Alzheimer's disease. New England Journal of Medicine (2003) 349:609–610.
Bönsch D., Bayerlein K., Reulbach U., et al. Different allele-distribution of Mthfr 677 C 
T and Mthfr –393 C a in patients classified according to subtypes of Lesch's typology. Alcohol and Alcoholism (2006) 41:364–367.
Boothby L. A., Doering P. L. Acamprosate for the treatment of alcohol dependence. Clinical Therapeutics (2005) 27:695–714.[CrossRef][Web of Science][Medline]
Chick J., Howlett H., Morgan M. Y., Ritson B. United Kingdom Multicentre Acamprosate Study (UKMAS): A 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol and Alcoholism (2000) 35:176–187.
Cloninger C. R., Sigvardsson S., Gilligan S. B., von Knorring A. L., Reich T., Bohman M. Genetic heterogeneity and the classification of alcoholism. Advances in Alcohol and Substance Abuse (1988) 7:3–16.
Döring W. K., Herzenstiel M. N., Krampe H., et al. Persistent alterations of vasopressin and N-terminal proatrial natriuretic peptide plasma levels in long-term abstinent alcoholics. Alcoholism: Clinical and Experimental Research (2003) 27:849–861.[Web of Science][Medline]
Duka T., Townshend J. M., Collier K., Stephens D. N. Kindling of withdrawal: A study of craving and anxiety after multiple detoxifications in alcoholic inpatients. Alcoholism: Clinical and Experimental Research (2002) 26:785–795.[CrossRef][Web of Science][Medline]
Eisenhofer G., Lambie D. G., Whiteside E. A., Johnson R. H. Vasopressin concentrations during alcohol withdrawal. British Journal of Addiction (1985) 80:195–199.[CrossRef][Web of Science][Medline]
Fagerström K. O., Heatherton T. F., Kozlowski L. T. Nicotine addiction and its assessment. Ear, Nose, and Throat Journal (1990) 69:763–765.[Medline]
Fahlke C., Hard E., Thomasson R., Engel J. A., Hansen S. Metyrapone-induced suppression of corticosterone synthesis reduces ethanol consumption in high-preferring rats. Pharmacology, Biochemistry, and Behavior (1994) 48:977–981.[CrossRef][Web of Science][Medline]
George M. S., Anton R. F., Bloomer C., et al. Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues. Archives of General Psychiatry (2001) 58:345–352.
Grüsser S. M., Wrase J., Klein S., et al. Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics. Psychopharmacology (Berl) (2004) 175:296–302.[CrossRef][Medline]
Heatherton T. F., Kozlowski L. T., Frecker R. C., Fagerstrom K. O. The Fagerstrom Test for Nicotine Dependence: A revision of the Fagerstrom Tolerance Questionnaire. British Journal of Addiction (1991) 86:1119–1127.[CrossRef][Web of Science][Medline]
Herrmann-Lingen C., Binder L., Klinge M., et al. High plasma levels of N-terminal pro-atrial natriuretic peptide associated with low anxiety in severe heart failure. Psychosomatic Medicine (2003) 65:517–522.
Hesselbrock V. M., Hesselbrock M. N. Are there empirically supported and clinically useful subtypes of alcohol dependence? Addiction (2006) 101(Suppl 1):97–103.[CrossRef][Web of Science][Medline]
Hillemacher T., Bayerlein K., Reulbach U., et al. Influence of beer, wine and spirits consumption on craving. Addiction Biology (2005) 10:181–186.[CrossRef][Web of Science][Medline]
Hillemacher T., Bayerlein K., Wilhelm J., et al. Recurrent detoxifications are associated with craving in patients classified as type 1 according to Lesch's typology. Alcohol and Alcoholism (2006) 41:66–69.
Hillemacher T., Bayerlein K., Wilhelm J., et al. Prolactin serum levels and alcohol craving—An analysis using Lesch's typology. Neuropsychobiology (2006) 53:133–136.[CrossRef][Web of Science][Medline]
Hillemacher T., Bayerlein K., Wilhelm J., et al. Nicotine dependence is associated with compulsive alcohol craving. Addiction (2006) 101:892–897.[CrossRef][Web of Science][Medline]
Hillemacher T., Bayerlein K., Wilhelm J., et al. Volume intake and craving in alcohol withdrawal. Alcohol and Alcoholism (2006) 41:61–65.
Hillemacher T., Bleich S., Frieling H., et al. Evidence of an association of leptin serum levels and craving in alcohol dependence. Psychoneuroendocrinology (2007) 32:87–90.[CrossRef][Web of Science][Medline]
Hillemacher T., Kraus T., Rauh J., et al. Role of appetite-regulating peptides in alcohol craving: An analysis in respect to subtypes and different consumption patterns in alcoholism. Alcoholism: Clinical and Experimental Research (2007) 31:950–954.[CrossRef][Web of Science][Medline]
Hollander E., Liebowitz M. R., Cohen B., et al. Prolactin and sodium lactate-induced panic. Psychiatry Research (1989) 28:181–191.[CrossRef][Web of Science][Medline]
Jahn H., Döring W. K., Krampe H., et al. Preserved vasopressing response to osmostimulation despite decreased basal vasopressin levels in long-term abstinent alcoholics. Alcoholism: Clinical and Experimental Research (2004) 28:1925–1930.[CrossRef][Web of Science][Medline]
Jellinek E. M. The Disease Concept of Alcoholism (1960) New Haven, CT: Hillhouse.
Jerlhag E., Egecioglu E., Dickson S. L., Andersson M., Svensson L., Engel J. A. Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: Implications for its involvement in brain reward. Addiction Biology (2006) 11:45–54.[Web of Science][Medline]
Johnson B. A., Ait-Daoud N., Bowden C. L., et al. Oral topiramate for treatment of alcohol dependence: A randomised controlled trial. Lancet (2003) 361:1677–1685.[CrossRef][Web of Science][Medline]
Junghanns K., Backhaus J., Tietz U., et al. Impaired serum cortisol stress response is a predictor of early relapse. Alcohol and Alcoholism (2003) 38:189–193.
Kiefer F., Andersohn F., Jahn H., Wolf K., Raedler T. J., Wiedemann K. Involvement of plasma atrial natriuretic peptide in protracted alcohol withdrawal. Acta Psychiatrica Scandinavica (2002) 105:65–70.[CrossRef][Web of Science][Medline]
Kiefer F., Barocka A. Secondary depression in weaned alcoholics: Implications of Lesch's typology of chronic alcoholism. Alcohol and Alcoholism (1999) 34:916–917.
Kiefer F., Helwig H., Tarnaske T., Otte C., Jahn H., Wiedemann K. Pharmacological relapse prevention of alcoholism: Clinical predictors of outcome. European Addiction Research (2005) 11:83–91.[CrossRef][Web of Science][Medline]
Kiefer F., Jahn H., Jaschinski M., et al. Leptin: A modulator of alcohol craving? Biological Psychiatry (2001) 49:782–787.[CrossRef][Web of Science][Medline]
Kiefer F., Jahn H., Schick M., Wiedemann K. Alcohol self-administration, craving and HPA-axis activity: An intriguing relationship. Psychopharmacology (Berl) (2002) 164:239–240.[CrossRef][Medline]
Kiefer F., Jahn H., Wolf K., Kampf P., Knaudt K., Wiedemann K. Free-choice alcohol consumption in mice after application of the appetite regulating peptide leptin. Alcoholism: Clinical and Experimental Research (2001) 25:787–789.[CrossRef][Web of Science][Medline]
Kiefer F., Wiedemann K. Neuroendocrine pathways of addictive behaviour. Addiction Biology (2004) 9:205–212.[Web of Science][Medline]
Kim D. J., Yoon S. J., Choi B., et al. Increased fasting plasma ghrelin levels during alcohol abstinence. Alcohol and Alcoholism (2005) 40:76–79.
Kraus T., Schanze A., Gröschl M., et al. Ghrelin levels are increased in alcoholism. Alcoholism: Clinical and Experimental Research (2005) 29:2154–2157.[Web of Science][Medline]
Lechtenberg R., Worner T. M. Relative kindling effect of detoxification and non-detoxification admissions in alcoholics. Alcohol and Alcoholism (1991) 26:221–225.
Lesch O. M., Dvorak A., Hertling I., et al. The Austrian multicentre study on smoking: Subgroups of nicotine dependence and their craving. Neuropsychobiology (2004) 50:78–88.[CrossRef][Web of Science][Medline]
Lesch O. M., Kefer J., Lentner S., et al. Diagnosis of chronic alcoholism—Classificatory problems. Psychopathology (1990) 23:88–96.[Web of Science][Medline]
Lesch O. M., Riegler A., Gutierrez K., et al. The European acamprosate trials: Conclusions for research and therapy. Journal of Biomedical Science (2001) 8:89–95.[Web of Science][Medline]
Lesch O. M., Walter H. Subtypes of alcoholism and their role in therapy. Alcohol and Alcoholism (1996) 31(Suppl 1):63–67.
Long C. G., Cohen E. M. Low alcohol beers and wines: Attitudes of problem drinkers to their use and their effect on craving. British Journal of Addiction (1989) 84:777–783.[CrossRef][Web of Science][Medline]
Malcolm R., Herron J. E., Anton R. F., Roberts J., Moore J. Recurrent detoxification may elevate alcohol craving as measured by the Obsessive Compulsive Drinking scale. Alcohol (2000) 20:181–185.[CrossRef][Web of Science][Medline]
Nicolas J. M., Fernandez-Sola J., Fatjo F., et al. Increased circulating leptin levels in chronic alcoholism. Alcoholism: Clinical and Experimental Research (2001) 25:83–88.[CrossRef][Web of Science][Medline]
Olive M. F., Mehmert K. K., Koenig H. N., et al. A role for corticotropin releasing factor (CRF) in ethanol consumption, sensitivity, and reward as revealed by CRF-deficient mice. Psychopharmacology (Berl) (2003) 165:181–187.[Medline]
Samochowiec J., Kucharska-Mazur J., Grzywacz A., et al. Genetics of Lesch's typology of alcoholism. Progress in Neuro-Psychopharmacology and Biological Psychiatry (2008) 32:423–427.[CrossRef][Medline]
Sperling W., Frank H., Martus P., et al. The concept of abnormal hemispheric organization in addiction research. Alcohol and Alcoholism (2000) 35:394–399.
Taivainen H., Laitinen K., Tahtela R., Kilanmaa K., Valimaki M. J. Role of plasma vasopressin in changes of water balance accompanying acute alcohol intoxication. Alcoholism: Clinical and Experimental Research (1995) 19:759–762.[CrossRef][Web of Science][Medline]
Trabert W., Caspari D., Bernhard P., Biro G. Inappropriate vasopressin secretion in severe alcohol withdrawal. Acta Psychiatrica Scandinavica (1992) 85:376–379.[Web of Science][Medline]
van Ree J. M., Kornet M., Goosen C. Neuropeptides and alcohol addiction in monkeys. EXS (1994) 71:165–174.[Medline]
Volkow N. D., Wang G. J., Fowler J. S., et al. Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: Implications in addiction. American Journal of Psychiatry (1999) 156:19–26.
Walter H., Ramskogler-Skala K., Dvorak A., et al. Glutamic acid in withdrawal and weaning in patients classified according to Cloninger's and Lesch's typologies. Alcohol and Alcoholism (2006) 41:505–511.
Walter H., Ramskogler K., Semler B., Lesch O. M., Platz W. Dopamine and alcohol relapse: D1 and D2 antagonists increase relapse rates in animal studies and in clinical trials. Journal of Biomedical Science (2001) 8:83–88.[Web of Science][Medline]
Wiedemann K., Jahn H., Yassouridis A., Kellner M. Anxiolyticlike effects of atrial natriuretic peptide on cholecystokinin tetrapeptide-induced panic attacks: Preliminary findings. Archives of General Psychiatry (2001) 58:371–377.
Wiesbeck G. A., Weijers H. G., Lesch O. M., Glaser T., Toennes P. J., Boening J. Flupenthixol decanoate and relapse prevention in alcoholics: Results from a placebo-controlled study. Alcohol and Alcoholism (2001) 36:329–334.
Wilhelm J., Bayerlein K., Hillemacher T., et al. Short-term cognition deficits during early alcohol withdrawal are associated with elevated plasma homocysteine levels in patients with alcoholism. Journal of Neural Transmission (2006) 113:357–363.[CrossRef][Web of Science][Medline]
Worner T. M. Relative kindling effect of readmissions in alcoholics. Alcohol and Alcoholism (1996) 31:375–380.
Wurst F. M., Bechtel G., Forster S., et al. Leptin levels of alcohol abstainers and detoxification patients are not different. Alcohol and Alcoholism (2003) 38:364–368.
Zacny J. P. Behavioral aspects of alcohol-tobacco interactions. Recent Developments in Alcoholism (1990) 8:205–219.[Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Leggio Understanding and Treating Alcohol Craving and Dependence: Recent Pharmacological and Neuroendocrinological Findings Alcohol Alcohol., July 1, 2009; 44(4): 341 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pombo and O. M. Lesch The Alcoholic Phenotypes among Different Multidimensional Typologies: Similarities and Their Classification Procedures Alcohol Alcohol., January 1, 2009; 44(1): 46 - 54. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||