Alcohol and Alcoholism Advance Access originally published online on June 2, 2006
Alcohol and Alcoholism 2006 41(5):505-511; doi:10.1093/alcalc/agl042
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GLUTAMIC ACID IN WITHDRAWAL AND WEANING IN PATIENTS CLASSIFIED ACCORDING TO CLONINGER'S AND LESCH'S TYPOLOGIES
1 Department of Psychiatry, 2 Department of Internal Medicine, Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria and 3 Université de Louvain, 1, Croix du Sud, B-1348 Louvain-la-Neuve, Belgium
* Author to whom correspondence should be addressed at: E-mail: henriette.walter{at}meduniwien.ac.at
(Received 28 March 2006; first review notified 11 April 2006; in revised form 20 April 2006; accepted 28 April 2006)
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONOBJECTIVESSUBJECTS AND METHODSRESULTSDISCUSSIONSUMMARYCONCLUSIONREFERENCES |
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Aims: Though glutamic acid is well known as a working excitatory in the CNS, its impact on the modulation of alcohol withdrawal symptoms and withdrawal fits are not yet clear. The study has been undertaken to examine the levels of glutamic acid in chronic alcohol-dependent patients at different stages of alcohol withdrawal and weaning and to examine any existence of any differences according to Cloninger's and Lesch's typologies. Patients and methods: One hundred and fifty-nine alcohol-dependent patients were assessed according to Cloninger's and Lesch's typologies and related to abstinence duration, age, and gender. Blood samples were taken for mean corpuscular volume (MCV), gamma-glutamyltransferase (GGT) and glutamic acid, in order to find primarily any differences in glutamic acid according to the typologies, age, abstinence duration, and liver damage. Results: There was no significant association between Cloninger's and Lesch's typologies. Cloninger's types 1 and 2 had an equal distribution of GGT and duration of abstinence, while Lesch's type I had more patients with high GGT, and more patients who were sober for a maximum of 2 days. Unlike in Lesch's types, glutamic acid levels did not differ according to Cloninger's types, as significantly higher glutamic acid values were found in Lesch's types I and IV. Glutamic acid values did not differ significantly in different age groups. Conclusions: Our study findings of varying glutamic acid levels seen in Lesch's typology, higher in types I and IV than in types II and III, are of significant clinical value and can be interpreted differently, as in type I high levels of glutamic acid is seen as a kindling phenomenon, while in type IV elevated levels might be related to either compulsivity of frequent repetition of drinking or withdrawal.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONOBJECTIVESSUBJECTS AND METHODSRESULTSDISCUSSIONSUMMARYCONCLUSIONREFERENCES |
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Alcoholic beverages are from the pharmaceutical point of view ‘rich acting’ compounds, and both acute as well as chronic alcohol intoxications influence neurotransmission in nearly all signalling systems. Dopamine, serotonin, endorphin, CB1, glutamate, and GABA are currently given importance, especially for new withdrawal treatments and relapse prevention trials. Amongst the different transmitter systems the role of glutamate and GABA transmission in alcohol withdrawal and weaning has been widely discussed (Dahchour and De Witte, 2000
, 2003a, b; De Witte, 2004). Although it is agreed that an imbalance between these amino acids can be held responsible for at least part of ethanol withdrawal symptoms, their precise role in the mediation of craving and relapse as well as their impact on the occurrence of withdrawal seizures is still unclear (Lesch et al., 1997; Geerlings and Lesch, 1999; Dahchour and De Witte, 2003b; De Witte, 2004; Kiefer et al., 2005).
Moreover, there is a growing need for biochemical measurements, yielding more information than the diagnoses of chronic alcoholism according to DSM-IV or ICD-10, taking into consideration the heterogeneity of alcohol-dependent patients. The varying alcohol-related disabilities, intensity of withdrawal symptoms, and the differing results of pharmaceutical relapse prevention trials clearly show that different biological vulnerabilities should be considered in research and therapy (Lesch et al., 1996; Walter et al., 2001; Hester and Miller, 2003; Kiefer et al., 2005; Lesch and Soyka, 2005). Both Cloninger's and Lesch's typologies validate these questions, and can be assessed easily. Cloninger's typology is based on personality and predisposition traits. It postulates two types of alcoholics (Cloninger et al.,1981; Cloninger, 1987). Type 1 is ‘milieu-limited’, defined as late onset, few familial alcohol-dependence antecedents, slower progress, milder alcoholism, important environmental influence, and minimal criminality. Cloninger type 2 is ‘male-limited’ with characteristics including early onset, paternal type 2 alcoholism, severe alcoholism, little environmental influence, and frequent criminality. The personality profile proposed by Cloninger, using the Tridimensional Personality Questionnaire, is higher Novelty-Seeking, lower Harm Avoidance, and lower Reward Dependence in type 2 than in type 1 patients.
Lesch's typology has been derived from a long-term prospective study (18 years) and differentiates four types of alcoholics: type I with severe withdrawal and mainly somatic dependence; type II with alcohol consumption as a coping strategy against anxiety, frequently becoming aggressive when intoxicated; type III with alcohol consumption against depression; and type IV with cerebral disturbances or damage before the termination of brain development (Lesch et al., 1990, 1991, 1996; Poldrugo and Lesch, 1994; Lesch and Walter, 1996). High alcohol intake and development to addiction in type IV renders problems that add to several pre-existing life-complicating factors. Type I has high methanol elimination rates in contrast to type IV with low methanol elimination rates. Hence, the present hypothesis is that alcoholism is noxious via high levels of acetaldehydes in type I and by longer alcohol presence in the blood in type IV (Sprung et al., 1988). Also, polyneuropathy (severe polyneuropathy is one of the definition criteria, though not exclusively, for Lesch type IV) could relate to that prolonged presence of alcohol in the blood. Contrary to other typologies, used in research and treatment of alcoholism, Lesch's typology has taken somatic, mental, and social factors into consideration. The impact of this view on diagnosis and treatment of alcohol dependence has so far been verified by several investigations (Sperling et al., 2000; Lesch et al., 2001; Walter et al., 2001; Bleich et al., 2004; Hillemann et al., 2006). Therapy studies found different relapse rates according to the four Lesch types, when studying dopamine antagonists, opiate antagonists, glutamate-, and GABA-modulating compounds (Lesch and Walter, 1996; Walter et al., 2001; Nimmerrichter et al., 2002; Kiefer et al., 2005). The four subgroups of Lesch's typology, defined by the decision tree, published in 1990, reflect different aetiologies, origin, and development of craving and prognoses of the illness course (Lesch et al., 1990) (Fig. 1). These differences can be assumed to reflect different biological vulnerabilities, which might be related to differences in glutamic acid levels.
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We hypothesized higher glutamic acid levels in Cloninger type 2 patients and in Lesch type I and IV patients, being severe forms of alcoholism.
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OBJECTIVES |
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TOPABSTRACTINTRODUCTIONOBJECTIVESSUBJECTS AND METHODSRESULTSDISCUSSIONSUMMARYCONCLUSIONREFERENCES |
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Our aim was to examine the distribution of glutamic acid in alcohol-dependent patients in different stages of alcohol withdrawal and weaning, diagnosed with the two different typologies of Cloninger and Lesch.
We further examined to see whether any correlation existed between age, gamma-glutamyltransferase (GGT), and mean corpuscular volume (MCV) to glutamic acid values and to verify whether high levels of glutamic acid were expected after detoxification and their decrease with rising duration of abstinence.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONOBJECTIVESSUBJECTS AND METHODSRESULTSDISCUSSIONSUMMARYCONCLUSIONREFERENCES |
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Patients' description
Between 1 October 2000 and 30 April 2002 a total of 216 alcohol-dependent patients [149 male (69%) and 67 female (31%)], diagnosed according to DSM-IV and ICD-10, were consecutively included in the study. The heterogeneity of alcohol dependence was assessed by Cloninger's and Lesch's typologies. For Cloninger's typology we used the criteria used by von Knorring et al. (1987
). Lesch's typology was assessed by the PC-guided version of the decision tree (Fig. 1). Different clinical trials have already used this assessment procedure (Lesch and Walter, 1996; Sperling et al., 2000; Lesch et al., 2001; Walter et al., 2001; Bleich et al., 2004; Kiefer et al., 2005; Hillemann et al., 2006). One hundred and fifty-nine patients were assessed according to both Cloninger's typology [Cloninger type 1: 71.7% (n = 114); Cloninger type 2: 28.3% (n = 45)] and Lesch's typology [Lesch type I: 11.3% (n = 18); Lesch type II: 55% (n = 88); Lesch type III: 22.0% (n = 35); and Lesch type IV 11.3% (n = 18)] (Tables 1 and 2).
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The mean age was 46.4 years [standard deviation (SD): 10.4] with a range from 19 to 78 years. In four cases the age data were missing. We defined three age groups: age up to 35 years (12.7%; n = 27), between 36 and 49 years (52.8%; n = 112), and 50 years and more (34.4%; n = 73).
In a time-line follow-back assessment, we defined the patients' drinking behaviour and divided them into three categories: (i) withdrawal, that is, sober for 0–2 days, (ii) short abstinence, that is, 3–20 days sober, and (iii) sobriety of >20 days (Tables 1 and 2).
Out of a total of 162 patients, 78 (48.1%) had been sober for 0–2 days, 55 (34%) patients had been sober between 3 and 20 days, and 29 (17.9%) patients had been sober for >20 days. (See Tables 1 and 2.)
We correlated glutamic acid with age, GGT, MCV, and days of abstinence (Pearson correlation). Besides calculating the correlations, we decided to separate the following groups, because this group allocation was discussed by the Plinius Maior Society as being one possibility of group separation (O.M.Lesch; personal communication), though it did not find its way to publication (The Plinius Maior Society, 1994): GGT group 1 (up to 38 U/l; i.e. normal value), GGT group 2 (39–76 U/l), and GGT group 3 (>76 U/l; i.e double the normal value); MCV group 1 (
94 fl), MCV group 2 (94.1–97.9 fl), and MCV group 3 (
98 fl); age group 1 (up to 35 years), age group 2 (36–49 years), and age group 3 (50 years and older); as well as days of abstinence group 1 (sober for 0–2 days), group 2 (sober for 3–20 days), and group 3 (sober for >20 days).
Assessment of glutamic acid
Blood specimens were taken from the antecubital vein and were placed in lithium heparin bottles, centrifuged immediately at 3000 r.p.m. for 15 min and the serum stored at –20°C. All biochemical tests were performed using serum stored at –20°C. Two hundred and fifty microlitres of serum were mixed with 250 µl seraprep; after 15 min of incubation the 500 µl were centrifuged at 13,000 r.p.m., and the supernatant was then filtered using 0.22 µm filter.
Glutamic acid was analysed by an automated HPLC technique (Pharmacia Biotech Biochrome 20 system) with UV detection after reaction with ninhydrin reagent.
Statistical analysis
For normally distributed variables (tested by the Kolmogorov–Smirnov test), we used analysis of variance (ANOVA) (Duncan test in addition), respectively t-test for independent variables. For not normally distributed variables we used the Kruskal–Wallis test, respectively Mann–Whitney U-test. Nominal data were calculated by Chi-squared test. All statistical tests were two-sided, and a P-value < 0.05 was considered significant. For correlations we used the Pearson correlation test.
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RESULTS |
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Typologies
Cloninger's and Lesch's types were not significantly associated to each other (Chi-square; P = 0.053), though 81.5% of Cloninger type 1 patients were also in Lesch's typology in a mild illness course (Lesch type II and III). Only 33.3% of Cloninger's type 2 patients were allocated to Lesch's severe courses (types I and IV).
GGT data were available for a total of 168 patients (mean value: 108.75; SD: 166.50). In 150 patients with both GGT and a Cloninger's typology assessment, 72.7% (n = 109) were allocated to Cloninger type 1 and 27.3% (n = 41) to Cloninger type 2. No significant difference was found (U-test).
GGT data were available for a total of 151 patients with both GGT and Lesch's typology assessment. A total of 10.6% (n = 16) were allocated to Lesch type I, 56.3% (n = 85) to Lesch type II, 21.9% (n = 33) to Lesch type III, and 11.3% (n = 17) to Lesch type IV. As the Kruskal–Wallis test was significant (P < 0.05), we calculated with Mann–Whitney U-test the differences between the four Lesch types. Significant differences were observed between types I and II (P < 0.05) and between types I and III (P < 0.005) (Fig. 2).
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MCV data were available for a total of 165 patients (mean value: 93.12; SD: 6.5). Out of a total of 146 patients with both MCV measurement and Cloninger's typology, 71.9% (n = 105) were allocated to Cloninger type 1 and 28.1% (n = 41) to Cloninger type 2. Out of a total of 147 patients with both MCV and Lesch's typology assessment, 11.6% (n = 17) were allocated to Lesch type I, 55.8% (n = 82) to Lesch type II, 21.8% (n = 32) to Lesch type III, and 10.9% (n = 16) to Lesch type IV. For both typologies no significant differences of MCV were found (Table 2).
Glutamic acid
Typologies. Cloninger's typology did not show correlations with the amino acids measured. In Lesch's type I glutamic acid had the highest mean value with 142.98 (SD: 113.20) µmol/l (P < 0.05; Kruskal–Wallis). The Mann–Whitney U-test showed that the significant difference of glutamic acid values was between Lesch types I and II (P < 0.05), between Lesch types I and III (P < 0.005), between Lesch types II and IV (P < 0.05), and between Lesch types III and IV (P < 0.05) (Fig. 3).
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Days of abstinence. We had defined abstinence according to three categories: (i) sober for 0–2 days (withdrawal), (ii) sober between 3 and 20 days (short abstinence), and (iii) >20 days of sobriety. Glutamic acid levels showed no significant differences between the three categories of abstinence.
Age. We categorized the age groups into three groups: group 1 (up to 35 years), group 2 (36–49 years), and group 3 (50 years and older). Glutamic acid levels were not significantly different between the groups.
Gender. No significant gender-related difference in glutamic acid levels could be found. Although glutamic acid was markedly higher in men (mean value: 100.42; SD: 84.52) than in women (mean value: 72.45; SD: 51.52), the difference did not reach the level of significance (P = 0.12; Kruskal–Wallis).
Gamma-GT. We categorized three GGT-groups: GGT group 1 (up to 38 U/l), GGT group 2 (39–76 U/l), and GGT group 3 (>76 U/l). Glutamic acid showed a significant correlation with GGT. Glutamic acid was highest in the GGT > 76 group (P < 0.001; Kruskal–Wallis H-test). The Mann–Whitney U-test showed that the significant difference was between ‘GGT up to 38’ and ‘GGT 39–76’ (P < 0.001), between ‘GGT up to 38’ and ‘GGT > 76’ (P < 0.001), and between ‘GGT 39–76’ and ‘GGT > 76’ (P < 0.05) (Fig. 4).
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MCV. Glutamic acid did not differ between the three MCV groups we had defined before (
94; 94.1–97.9, and 98). A Pearson correlation between days of abstinence and MCV values showed a significant decrease of MCV with increase of abstinence duration (r = –0.194). Furthermore, a significant correlation between MCV values and GGT values could be observed (r = 0.227).
We found a significant positive correlation between glutamic acid and GGT (r = 0.564). No significant correlations have been found between glutamic acid values and days of abstinence, age, and MCV.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONOBJECTIVESSUBJECTS AND METHODSRESULTSDISCUSSIONSUMMARYCONCLUSIONREFERENCES |
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A number of preclinical and clinical studies suggest that the glutamate system has been implicated in withdrawal, craving, addiction memory, and even in the addictive process itself (Soyka and Preuss, 2003
; De Witte et al., 2005). NMDA modulators and NMDA antagonists have been found to act in distinct subgroups as anti-craving drugs. Those findings relate to glutamic acid in the brain and not to serum levels of glutamic acid, but a relation between both is given by Alfredsson et al. (1988). Their findings suggest that the glutamic acid levels in the extracellular fluid of brain are maintained at 
10% of those of the blood (Alfredsson et al., 1988).
In our study, significantly more patients of Lesch's type I and type IV showed highest glutamic acid levels in contrast to patients of types II and III, who had very low levels of glutamic acid. This may be explained by the severe withdrawal, which is typical for type I, and by repeated withdrawals in type IV. Though both types I and IV have high glutamic acid levels, we assume different reasons for that finding. First, we know from other studies (Lesch and Walter, 1996; Lesch et al., 2001; Kiefer et al., 2005; Lesch and Soyka, 2006) that acamprosate is significantly more effective in type I than in type IV. Secondly, it is known that a severe withdrawal has kindling effects on the risk of alcohol-related seizures (Lechtenberg and Worner, 1991; Becker and Hale, 1993; Booth and Blow, 1993; Moak and Anton 1996; Worner, 1996).
Lesch's type I is characterized by a significantly higher frequency of withdrawal seizures than the other Lesch types (Bleich et al., 2004). Patients of type I suffer from severe withdrawal symptoms and use alcohol mainly to cope with detoxification symptoms. In types II and III, withdrawal is mild, though usually longer lasting, and recurrent detoxifications do not seem to result in kindling effects. Hence, we interpret our results on higher glutamic acid in type I as a kindling effect, characterized by a progressive increase in response to drinking, based on a vulnerability related to the NMDA system. The complex biological basis of kindling needs to be determined yet, but our results are in favour of previous studies indicating that alterations in amino acidergic neurotransmission seem to be involved (Loscher et al., 1993). As delirium tremens occurs only in type I patients, we suggest performing further studies related to a possible association of glutamic acid and delirium tremens.
Type IV is characterized by an unfortunate illness course, whereby patients crave compulsively and relapse frequently. This is explained by the criteria required for the diagnosis of type IV: damage during brain development, followed by behavioural disorders that lead to low resistance to an alcohol-seducing social setting. Research on factors influencing craving has shown that recurrent detoxifications elevate craving for alcohol (Malcolm et al., 2000), whereas other studies found contradictory results (Duka et al., 2003). Our study corroborates Malcom et al.'s findings and is also in line with recent findings (Hillemacher et al., 2006). The higher glutamic acid levels in type IV patients seem to be correlated to repeated withdrawals. We suggest, therefore, performing relapse prevention trials with new glutamate antagonists in this group of severely disturbed patients with a poor treatment outcome. These results further validate the importance of classifying alcohol-dependent patients using a specific typology encompassing social, mental, and somatic factors. This may explain why Cloninger's typology did not yield any correlations to levels of serum glutamic acid. It might also reflect the difference of diagnostic validity between these two typologies.
In Lesch type I, significantly more patients had high GGT and high glutamic acid levels. This unfolds the question whether high levels of glutamic acid might be also due to liver damage. Certainly this remains being a yet unsolved puzzle, but GGT measurement seems interesting in this context, because GGT, being located in the external part of cell membranes, has been postulated to be involved in transporting glutamic acid and other amino acids into cells via the glutamyl cycle. There, among other amino acids, glutamic acid is needed for formation of glutathione, being essential for the detoxification systems of the liver (Mutlib et al., 2001). Liver damage is furthermore associated with ammonia increase, which might induce glutamic acid release from liver cells by reversal of glutamate transporters, as it is known for astrocytes (Rose, 2006).
A limitation to the study is that 55.6% of Lesch type I and 61.1% of type IV patients were—at the time of the investigation—sober for a maximum of 2 days. However, the other types had high rates of ‘up to 2 days sober’ patients too (type II: 46.1%; type III: 40%) and glutamic acid did not rise to levels as in types I and IV.
With regard to craving, endorphines and dopamine seem to relate mainly to positive expectancies, while stress reduction and relief-associated craving relate to glutamic acid/aminobutyric acid, norepinephrine, and eventually corticotropine releasing factor. Glutamic acid is frequently offered by internet pharmacies for support in alcohol withdrawal, which, according to our results, might be dangerous. On the other hand, glutamic acid may have protective effects on the heart muscle and seems to be beneficial for benign prostatic hyperplasia (Feinblatt and Gant 1958; Damrau, 1962; Thomassen et al., 1991). Monosodium glutamate is also used as flavour enhancer, and is for non-alcoholics generally free of side effects.
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SUMMARY |
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TOPABSTRACTINTRODUCTIONOBJECTIVESSUBJECTS AND METHODSRESULTSDISCUSSIONSUMMARYCONCLUSIONREFERENCES |
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Glutamic acid value, GGT, MVC, age, and duration of abstinence did not correlate to Cloninger's types. Lesch's type I had more patients with high GGT, and more patients who were sober for up to 2 days. Significantly higher glutamic acid values were found in Lesch's types I and IV. Glutamic acid values did not differ significantly in different age groups, nor between the groups of abstinence duration. Even in the Pearson correlation no significant correlations between glutamic acid values and days of abstinence, age, and MCV values could be observed. A strong correlation was found between glutamic acid and GGT values.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONOBJECTIVESSUBJECTS AND METHODSRESULTSDISCUSSIONSUMMARYCONCLUSIONREFERENCES |
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Glutamic acid levels seem to be influenced by liver function and seem to relate to subgroups of alcohol dependence. Our study findings of higher glutamic acid levels seen in Lesch types I and IV of alcohol dependence are of significant clinical value, which may need further replication to consider them as a biological marker.
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