0733-M14/9I J3(«I + (U«1 Pcrgumon Press pk © 1991 Medical CIHUKII on Alcoholism
Alcohol i Alcoholism. Vol 26. No 4. pp 4119-416 1991 Printed in G r e n Britain
PLATELET MONOAMINE OXIDASE ACTIVITY IN TYPE 1 AND TYPE 2 ALCOHOLISM ANNE-LIIS VON KNORRING,* JARMILA HALLMAN,t LARS VON KNORRINGt and LARS ORELAND* 'Department of Child and Adolescent Psychiatry, Uppsala University. S-750 17 Uppsala; tDepariment of Psychiatry, Uppsala University. S-751 85 Uppsala; and ^Department of Medical Pharmacology, Uppsala University. POB 593, S-751 24 Uppsala, Sweden (Received 3 June 1990; accepted in revised form 14 May 1991) Abstract — Earlier studies have identified at least two distinct subtypes of alcoholism. Type 2 is characterised by high heritability, early onset, frequent social complications and mixed misuse With regard to temperament, the type 2 alcoholics score high in impulsiveness and sensationseeking behaviour. Type 1 alcoholics have a later onset, lower degree of heritability and rarely there is misuse of illegal drugs. In the present study, 37 type 1 and 62 type 2 male alcoholics were compared with 36 male controls with regard to platelet monoamine oxidase (MAO) activity, which is a stable biological marker, inversely correlated to personality traits such as impulsiveness and sensation seeking. The platelet MAO activity was found to be lower in type 2 alcoholics when compared both with healthy controls and with type 1 alcoholics. Also, the type I alcoholics had lower platelet MAO activity than the controls. The result confirms a previous study and validates the subclassification of alcoholism according to the type 1 and 2 concept. This should be of value for future studies concerning etiology, epidemiology, treatment and prevention of alcoholism.
INTRODUCTION Alcoholism is not a unitary concept and several typologies have been proposed (e.g. Jellinek, 1960). A division into two groups, one which is accompanied by antisocial behaviour and early onset and the other which is not, was suggested by Coid (1982) and Stabenau (1984). In the Stockholm adoption studies, it was demonstrated that there are at least two distinct subgroups of alcoholism (Cloninger et al., 1981). One form, type 1, was characterised by influences from both genetic and environmental factors. Teenage onset was rare and there was only minimal criminality among the biological relatives. The other form, type 2, was highly heritable. The biological fathers had an early onset of alcohol misuse and were often registered for serious and recurrent criminality. Type 1 alcoholism occurred in both sexes, while type 2 was restricted to males. The adoption studies were based on data collected from official registers or hospital 409
records and no clinical examination was done. In later clinical studies, however, the validity of this classification has been verified. When the two subgroups were defined from the presence and absence of early onset and social complications, the type 2 alcoholics were found to have more alcoholism and depression among their first degree relatives, and when the two types were studied with regard to personality traits, the type 2 alcoholics differed from both controls and type 1 alcoholics with a higher degree of sensation seeking and extraversion-related traits (Oreland et al., 1985; von Knorring et al., 1985; von Knorring et al., 1987a). An enzyme of great interest in connection with alcoholism is monoamine oxidase (MAO; E.C.: 1.4.3.4.). Thus, low MAO activity has been found in the brains of alcoholics (Oreland et al., 1983), in the platelets of alcoholics (Wiberg et al., 1977; Faraj, 1987; for a review see Oreland et al., 1985) and in the relatives of alcoholics (Major and Murphy, 1978; Puchall
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etal., 1980; Alexopoulose/a/., 1983), supporting the hypothesis that the low MAO activity is a biological marker for vulnerability to misuse (Buchsbaum et al., 1976). A non-significant trend in the same direction was found by Schuckit et al. (1982) on a rather small series of alcoholics. Such a vulnerability might be linked to impulsive personality traits, since low platelet MAO activity, in several studies, has been correlated with sensation seeking, impulsiveness and monotony avoidance both in males and females (Schalling et al., 1987). These personality traits, as well as low platelet MAO activity, have recently been reported to be related to alcoholism, particularly type 2 (Orelandera/., 1985; von Knorringetal., 1985; Pandey et al., 1988). In line with those findings is the low platelet MAO activity demonstrated in teenage boys with mixed alcohol and illegal drug misuse (von Knorring et al., 1987b). It should be pointed out, however, that the temperament linked to low platelet MAO activity makes low MAO subjects be overrepresented also among such groups as, e.g. mountaineers and violent offenders (for a recent review see Oreland, 1991). The aim of the present study was to find further experimental support for the conception that low platelet MAO activity is linked to alcoholism of type 2, but not type 1.
MATERIALS AND METHODS Subjects The series of alcoholics answered a questionnaire with standardised questions about their own habits, problems and symptoms when drinking as well as criminality and social situation. There were also some questions about the psychiatric morbidity of family members. In total the study included 99 subjects out of 107 consecutive males, treated as inpatients at the Department of Psychiatry, Umea University. All the patients met the DSM-I1I-R criteria for alcoholic dependence (American Psychiatric Association, 1987). Eight of the 107 patients were excluded as blood samples either were not obtained or had to be discarded for technical reasons. The 99 alcoholics were classified into type 1 or 2 according to the results from earlier studies (von Knorring et al., 1985; von Knorring et al., 1987a; see also below). In this way the alcoholics were divided into 37 type 1 alcoholics with a mean (± S.D.) age of 49.5 ± 10.0 years and 62 type 2 alcoholics with a mean age of 38.0 ± 8.0 years. Clinical characteristics of the subjects are shown in Table 1. The controls also answered the same questionnaire about drinking habits, drug use, etc., as the probands and consisted of 36 healthy
Table 1. Clinical characteristics of the male alcoholics divided into type I (N = 37) and type 2 (/V = 62)
First alcohol consumption (age) (mean ± S.D.) First subjective alcohol problems (age) First treatment contact (age) Glue misuse Cannabis misuse Amphetamine misuse Illegal use of minor tranquillisers Aggressive after alcohol consumption Absent from work due to alcoholism Lost job due to alcoholism Arrested when drunk Drunk when driving Other forms of criminality
Type 1
Type 2
18.0 ± 4.0 36.3 ± 7.7 41.9 ± 9.7 1 (3%)
16.3 ± 3.3 23.8 ± 4.7 27.8 ±7.1 17 (27%) 29 (47%) 12 (19%) 13(21%) 34 (55%) 57 (92%) 29 (47%) 55 (89%) 42 (68%) 32 (52%)
0 0 0
7 (19%) 28 (76%) 7 (19%) 24 (65%) 18 (49%) 2 (5%)
PLATELET MONOAMINE OXIDASE ACTIVITY
males (mean age 34.6 ± 8.0 years). They were working at Umea University or were their relatives. All were personally known by the investigators and thus alcohol misuse or a history of severe mental or personality disorders could be ruled out. Only one of the controls reported symptoms of aggressivity when drunk. Type 2 alcoholism was defined as follows. (A) There is a pattern of pathological alcohol use, shown either as: (i) inability to cut down/stop drinking; (ii) remaining continuously intoxicated during at least two days; (iii) two or more amnesic periods for events occurring when intoxicated (black-outs); or (iv) continuation of drinking despite the knowledge of having a persistent or recurrent physical problem, which is caused or exacerbated by alcohol use. (B) There are at least three symptoms of impairment in social or occupational functioning due to alcohol use such as: 1. violence while intoxicated 2. absence from work or school 3. loss of job 4. legal difficulties (arrest for intoxicated behaviour or other arrests or imprisonments) 5. traffic accidents while intoxicated 6. arguments or difficulties with family or friends because of excessive alcohol use. (C) Either marked tolerance or withdrawal symptoms as defined in DSM-III-R criteria (1987). (D) Onset of subjective problems before 25 years of age and first treatment contact before age of 30. However, since in the present study, we had problems in defining the age of onset in a correct manner due to the patients' inability to give a reliable history, only first treatment contact before 30 years of age defined early onset. The mean age at first treatment was 27.8 years and the standard deviation was 7.1. This means that many had their first treatment contact during their adolescence or early adulthood. Type 1 alcoholism was defined as follows. (A) Definition of pathological alcohol use as above under A. (B) The alcoholics did not fulfil the impairment in social or occupational functioning
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according to the criteria for type 2 alcoholism as above under B. (C) Either marked tolerance or withdrawal symptoms as above under C. (D) Onset of subjective problems after 25 years and treatment contact after 30 years of age. A special check-list was used to get information about the families of the subjects and about their social situation (von Knorring et al., 1985). Depression in the relatives was defined from the subject's responses in the standardised questionnaire. In fact, a depression was regarded if the family member had consulted a doctor, or if it was clear from the description that a doctor ought to have been consulted. Platelet MA O activity As it has been shown that platelet MAO is stable over time, although with a transient increase during the first 3-4 weeks of the abstinence period (Wiberg, 1979; Major et al., 1981), all alcoholics were investigated either immediately while still intoxicated, or after at least 4 weeks of total abstinence. Samples of blood (5 ml) were drawn into Vacutainer® tubes containing sodium citrate, and the red cells allowed to self sediment for approximately 4 hr. After removing about 1 ml of platelet-rich plasma by careful suction, the platelet concentration was counted by the Coulter® Counter (Dunstable, U.K.) and the plasma frozen at -70°C. After thawing, the samples were sonicated for 1 min and estimation of the enzyme activity performed as described previously (Hallman et al., 1987J by incubation at 37°C for 4 min with ' 4 Ctryptamine, final concentration 50 |iM, or l4 C-2-phenylethylamine, final concentration 50 uM (New England Nuclear, Boston, MA, U.S.A.) as the substrate. The two substrates were used in parallel in order to increase the reliability of the estimation, and the estimations carried out in duplicate and the mean values used. Similar results with regard to differences between the groups were obtained with either of the two substrates (correlation coefficient (r) 0.88 and 0.75 for the controls and the alcoholics, respectively). As a further control of the reliability of the estimation, a
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standard platelet MAO preparation was estimated 26 times with each substrate at regular intervals during the estimation of alcoholics and controls. The mean activities of this standard were 2.69 ± 0.42 and 11.15 ± 0.90 nmoles of substrate oxidised/min platelets with tryptamine and 2-phenyiethylamine, respectively. Thus, the coefficients of variation for the estimations were 15.53 and 8.1%, respectively, during the period of estimation. Statistics Differences between means were tested by means of analysis of variance (ANOVA) and of the Student's /-test. Frequencies of distributions were tested by means of chi2. When there were less than five subjects in one cell Yate's correction was used. The MAO activity in the healthy volunteers showed no correlation with age (r (Pearson's corr) = 0.04). Thus no correction for age was necessary. When frequency distributions of platelet MAO activities were compared between controls, type 1 and type 2 alcoholics, respectively, the activities were expressed as standard deviations above or below the mean of the healthy controls.
min in controls, types 1 and 2 alcoholics, respectively, with 2-phenylethylamine as the substrate (Table 3). The corresponding figures with tryptamine as the substrate were 2.79 ± 0.94, 2.00 ± 0.57 and 1.60 ± 0.68 nmoles/101" platelets/min, respectively. Thus, the type 2 alcoholics had highly significantly lower platelet MAO activity than both controls and type 1 alcoholics. The type 1 alcoholics also had lower platelet MAO activity than the controls, but with a lower degree of significance (Table 3). The distribution of the platelet MAO activity is shown in Fig. 1. As a cutting point for low MAO activity we used -1.0 S.D. for the controls (towards 2-phenylethylamine), which would delineate the lowest mode and the lowest part of the moderately low mode of the Table 3. Platelet MAO activity (towards 2-phenylethylamine (2-pea) and tryptamine) expressed as nmoles of substrate metabolised/10"' platelets/min) in controls (N = 36), type 1 alcoholics (JV = 37) and type 2 alcoholics (N = 62) Platelet MAO activity towards 2-pea
Tryptamine
11.48 ± 4. II 9 .67 ± 3..09 7.33 ± 2..58
2.79 ± 0.94 2.00 ± 0.57 1.60 ± 0.68
RESULTS A significantly higher frequency of depression and a tendency towards a higher frequency of alcoholism were found in the mothers or fathers of type 2 alcoholics when compared with the type 1 alcoholics (Table 2). Platelet MAO activities were 11.48 ± 4.11 (mean ± S.D.) (100%), 9.67 ± 3.09 (84%) and 7.33 ± 2.58 (64%) nmoles/1010 platelets/
Controls (mean ± S.D.) Alcoholics, type 1 Alcoholics, type 2
Statistical analysis on the results with 2-pea: F = 20.20, P < 0.0001 (ANOVA); type 1 vs type 2, / = 4.02, P < 0.0005; type 1 vs control, I = 2.12, P < 0.05 (Student's itest). With tryptamine: F = 30.79, P < 0.0O01 (ANOVA), type 1 vs type 2, / = 3.12. P < 0.005; type 1 vs control, / = 4.32, P < 0.0005.
Table 2. Depression or alcoholism in mothers and fathers of the alcoholics (/V = 99) divided into type 1 (/V = 37) and type 2 (JV = 62). Chi2 with Yate's correction if less than 5 subjects in a cell Type 1 Alcoholism Alcoholism Alcoholism Depression Depression Depression
in father in mother in mother or father in father in mother in mother or father
9 (24%) 1 (3%) 10 (27%) 1 (3%) 0 1 (3%)
Type 2 25 (40%) r 6 (10%) 29 (47%) r 6 (10%) x > 8 (13%) X", 13 (21%) X".
= = = = = =
2 .63 0 .82 3 .78 0 .82 3 .60 4 .95
ns ns ns (P < 0 1) ns ns (P < 0 1) (P 0.05)
PLATELET MONOAMINE OXIDASE ACTIVITY 9 8 7 6 5 4 3 " a 3
- -, -
- i
Controls
2
1 0
r
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1 0
^
6
-
4
o u
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Typel
-
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-
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20
Typ«2 15 10 5 0
j
-
- 5 - 4 - 3 - 2 - 1 0 1 2 3 4 5 SD above and below the mean or the controls Fig. 1. Platelet MAO activities in controls (N = 36), type 1 alcoholics (N = 37) and type 2 alcoholics (N = 62). Platelet MAO activities are expressed as S.D. above or below the mean of the controls (M = 11.48, S.D. = 4.11 nmolesof 2phenylethylamine metabolised/10'" platelets/min). Chrtest for activities above and below -1.0 S.D.; controls vs type 1 vs type 2; chi2 = 17.5. P < 0.0001
pentamodal distribution of MAO distribution shown by Cloninger et al. (1985) in a large material of Swedish recruits. Using such a cutting point, 33/62 of the type 2 alcoholics had low platelet MAO activity vs 9/37 of the type 1 alcoholics and 5/36 of the healthy volunteers. The differences between the three groups, between type 2 and controls and between type 2 and type 1 were statistically significant (chi2 = 18.00, P < 0.001; chi2 = 13.25, P < 0.001; chi2 = 6.79, P < 0.01). The type 1 alcoholics, however, did not differ from the controls (chi2 = 0.7, ns). The platelet concentration in the platelet-
413
rich plasma (x 10-Vu.l) was 501 ± 87 (mean ± S.D.) in the controls and 352 ± 141 and 383 ± 192 in the type 1 and type 2 alcoholics, respectively. There was a highly significant difference between the groups (F = 1639, P < 0.0001 ANOVA). A post hoc analysis with Student's /-test resulted in a highly significant difference between the alcoholics and the controls (t = 4.24, P < 0.0005), while there was no difference between the two groups of alcoholics (t = 0.88, ns). When a simple regression between platelet concentration and MAO activity was calculated on the combined group of alcoholics, no correlation was found (r = 0.02 and -0.04, respectively, with 2phenylethylamine and tryptamine as the substrates). DISCUSSION Etiologic heterogeneity of alcoholism has been suggested in the Stockholm Adoption Study (Cloninger et al., 1981) as well as in familial studies (Gilligan et al., 1987) of alcoholism. In clinical studies on alcoholics, it was demonstrated that subjects fulfilling DSM-IIIR criteria for alcohol dependence could be subdivided into two separate groups essentially following the criteria that are derived from the symptomatology of the biological fathers of adopted-away sons with type 2 alcoholism in the Stockholm Adoption Study (Cloninger et al., 1981). The clinical criteria were defined by von Knorring et al. (1985). The main finding in the present study is a replication of the clinical subdivision of type 1 and type 2 alcoholism and, as in the earlier study, the subgroups could be differentiated by means of platelet MAO activity. Type 2 alcoholism is characterised by an early onset, familial loading, sensation seeking personality and social complications or criminality, as well as by low platelet MAO activity. The results in the present study are in accordance with the results of our earlier studies. Type 2 alcoholics have an early onset of alcohol problems, as well as an early treatment contact. They also frequently have social complications, such as legal problems, criminality, fights when intoxicated, arrests because of driving when intoxicated and loss of
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job. Type 2 alcoholics also use illegal drugs to a great extent. By definition type 2 alcoholics are antisocial. Many of them might as well suffer from antisocial personality disorder or conduct disorder preceding the onset of alcoholism as suggested by Irwin et al. (1990). However, this question has not been possible to elucidate in the present study. There is also a high incidence of familial alcoholism and 'depression' among type 2 alcoholics. The definition of depression and alcoholism in this study is not defined by clear criteria based on DSM-III. Similar findings of a high incidence of familial alcoholism and depression have also been found in other studies, in which the characteristics for division of alcoholics into subgroups have been based on the typology obtained from the Stockholm Adoption Study (Pandey et al., 1988; Buydens-Branchey et al., 1989). Another approach to define the two types of alcoholism has been used by Gilligan et al. (1988), who characterised type 2 alcoholism by early onset of inability to abstain from ethanol complicated by reckless driving and fighting while intoxicated. The types 1 and 2 alcoholics have been found to differ with regard to personality traits. Thus, type 2 alcoholics showed more sensation seeking behaviour according to Zuckerman's sensation seeking scales and a higher impulsivenesssensation seeking-psychopathy factor according to the Karolinska Scales of Personality (KSP) (Oreland et al., 1985; von Knorring et al., 1985; von Knorring et al., 1987a). As this kind of personality trait is correlated with low MAO activity (Buchsbaum et al., 1976; Ward et al., 1987; Schalling et al., 1987), it could be expected that type 2 alcoholics should have low MAO activity. This has, indeed, been found in three earlier studies on small numbers of alcoholics (von Knorring et al., 1985; Pandey et al., 1988; Sullivan et al., 1990) and could be replicated in the present study on larger and entirely new material. It has previously been shown that alcoholics have lower concentration of platelets in blood than controls (Wallerstedt, 1977; Haselager and Vreeken, 1977; Currie and Kaegi, 1977), which was also found in the present study. Low platelet MAO activity in alcoholics has, however, been shown irrespective of whether
the method for estimation of the activity was based on the platelet count (Wiberg et al., 1977) or per unit of platelet protein (Major and Murphy, 1978), presuming that the blood sample was drawn either acutely or after about 4 weeks of abstinence. Thus, it has repeatedly been shown that there is a transient increase in the activity during the abstinence reaction after alcohol misuse (Wiberg, 1979; Major et al., 1981). Direct evidence for the notion, that the effect of alcohol on platelet concentration in blood did not have any influence on the present result with MAO activities (calculated as activity per platelet), was provided by the fact that the platelet concentration did not differ between the alcoholics of type 1 and type 2, and that no correlation was found between platelet concentration and MAO activity (see Results). Low MAO activity in alcoholics has been found in several studies during the last two decades, both in brain (Oreland et al., 1983) and in platelets (Wiberg et al., 1977; Major and Murphy, 1978; Fowler etal., 1981; Lykouras et al., 1987; Faraj, 1987). There are also reports of low platelet MAO activity in relatives of alcoholics (Puchall et al., 1980; Alexopoulos et al., 1983) in support of the view that low platelet MAO activity is a genetic marker for vulnerability to, e.g. drug misuse (see Oreland et al., 1984; Oreland and Hallman, 1988). In retrospect, however, it seems likely that the findings in those studies, at least in those concerning platelet MAO, were derived from the portion of alcoholics in the series who could have been classified as belonging to type 2. There is a lot of evidence supporting the hypothesis that platelet MAO activity is correlated to central serotonergic activity (Oreland and Shaskan, 1983; Oreland and Hallman, 1988), and, thus, the type 2 alcoholics would be characterised by a serotonergic deficit. A similar hypothesis about a subgroup of alcoholics with low serotonergic activity was recently suggested by Roy and Linnoila (1988) and Moss (1987). Further support for the hypothesis is provided by the fact that the type 2 alcoholics and other low platelet MAO probands have similarities in their personality trait profile to patients with psychiatric disorders
PLATELET MONOAMINE OXIDASE ACTIVITY
characterised by aggressive and suicidal behaviour, which has repeatedly been shown to be associated with low levels of CSF-5HIAA (Traskman et al., 1981; Roy and Linnoila, 1988; Roy et al., 1989). Also in line with the hypothesis is the finding that depressed patients with a family history of alcoholism had significantly lower CSF-5HIAA levels than patients without alcoholic relatives (Rosenthal et al., 1980). It is likely that alcoholics characterised as type 2 might require another strategy of treatment than those characterised as type 1. Thus, the favourable results reported with serotonin uptake blockers (Naranjo et al., 1989; Gorelick, 1989; Gill and Amit, 1989) might be more or less confined to one of the two types. Also, when considering prevention, it should be of value to know that type 2 alcoholics are at high risk for illegal drug misuse as well. In either case, estimation of platelet MAO activity could be of value for a more correct characterisation of the alcoholic patient. However, both in the present series and in the previous ones, there has been a considerable number of alcoholics in whom the classification, based on anamnestic data, did not agree with the platelet MAO activity. Thus, it remains to be elucidated whether the anamnestic data or the platelet MAO activity most truly reflected their vulnerability for misuse.
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Webster, M. H. and Goodwin, F. K. (1980) Monoamine metabolites in cerebrospinal fluid of depressive subgroups. Psychiatry Research 2, 113-119. Roy, A., De Jong. J. and Linnoila, M. (1989) Cerebrospinal fluid monoamine metabolites and suicidal behaviour in depressed patients. Archives of General Psychiatry 46, 609-612. Roy, A. and Linnoila, M. (1988) Suicidal behaviour, impulsiveness and serotonin. Ada Psychiatnca Scandinavica 78, 529-535. Roy, A., Virkkunen, N. and Linnoila, M. (1987) Reduced central serotonin turnover in a subgroup of alcoholics? Progress in Neuropsychopharmacol Biological Psychiatry 11, 173-177. Schalling, D., Asberg, M., Oreland, L. and Edman, G. (1987) Markers for vulnerability to psychopathology. Temperament traits associated with platelet MAOactivity. Ada Psychiatrica Scandtnavica 76, 172-182. Schuckit, M. A., Shaskan, E , Duby, J., Vega, R and Moss, M. (1982) Platelet monoamine oxidase activity in relatives of alcoholics Archives of General Psychiatry 39, 137-140. Stabenau, J. R. (1984) Implications of family history of alcoholism, antisocial personality and sex differences in alcohol dependence. American Journal of Psychiatry 141, 1178-1182. Sullivan, J. L., Baenziger, J. C., Wagner, D L , Rauscher, F. P., Nurnberger Jr, J. I. and Holmes, J. S. (1990) Platelet monoamine oxidase in subtypes of alcoholism. Biological Psychiatry 27, 911-922. Traskman, L., Asberg, M., Bertilsson, L. and Sjostrand, L. (1981) Monoamine metabolites in cerebrospinal fluid and suicidal behaviour. Archives of General Psychiatry 38, 631-637. Wallerstedt, S. (1977) Effects of alcohol on blood-cells. Lancet 2, 1178-1179. Ward, P. B., Catts, S. V., Norman, T. R., Burrows, G. D. and McConaghy, N. (1987) Low platelet monoamine oxidase and sensation seeking in males: an established relationship? Ada Psychiatrica Scandinavica 75, 86-90. Wiberg, A., Gottfries, C.-G. and Oreland, L. (1977) Low platelet monoamine oxidase activity in human alcoholics. Medical Biology 55, 181-186. Wiberg, A. (1979) Increase in platelet monoamine oxidase activity during controlled abstinence after alcohol abuse. Medical Biology 57, 133-134.
Alcohol i Alcoholism. Vol 26. No 4. pp 4119-416 1991 Printed in G r e n Britain
PLATELET MONOAMINE OXIDASE ACTIVITY IN TYPE 1 AND TYPE 2 ALCOHOLISM ANNE-LIIS VON KNORRING,* JARMILA HALLMAN,t LARS VON KNORRINGt and LARS ORELAND* 'Department of Child and Adolescent Psychiatry, Uppsala University. S-750 17 Uppsala; tDepariment of Psychiatry, Uppsala University. S-751 85 Uppsala; and ^Department of Medical Pharmacology, Uppsala University. POB 593, S-751 24 Uppsala, Sweden (Received 3 June 1990; accepted in revised form 14 May 1991) Abstract — Earlier studies have identified at least two distinct subtypes of alcoholism. Type 2 is characterised by high heritability, early onset, frequent social complications and mixed misuse With regard to temperament, the type 2 alcoholics score high in impulsiveness and sensationseeking behaviour. Type 1 alcoholics have a later onset, lower degree of heritability and rarely there is misuse of illegal drugs. In the present study, 37 type 1 and 62 type 2 male alcoholics were compared with 36 male controls with regard to platelet monoamine oxidase (MAO) activity, which is a stable biological marker, inversely correlated to personality traits such as impulsiveness and sensation seeking. The platelet MAO activity was found to be lower in type 2 alcoholics when compared both with healthy controls and with type 1 alcoholics. Also, the type I alcoholics had lower platelet MAO activity than the controls. The result confirms a previous study and validates the subclassification of alcoholism according to the type 1 and 2 concept. This should be of value for future studies concerning etiology, epidemiology, treatment and prevention of alcoholism.
INTRODUCTION Alcoholism is not a unitary concept and several typologies have been proposed (e.g. Jellinek, 1960). A division into two groups, one which is accompanied by antisocial behaviour and early onset and the other which is not, was suggested by Coid (1982) and Stabenau (1984). In the Stockholm adoption studies, it was demonstrated that there are at least two distinct subgroups of alcoholism (Cloninger et al., 1981). One form, type 1, was characterised by influences from both genetic and environmental factors. Teenage onset was rare and there was only minimal criminality among the biological relatives. The other form, type 2, was highly heritable. The biological fathers had an early onset of alcohol misuse and were often registered for serious and recurrent criminality. Type 1 alcoholism occurred in both sexes, while type 2 was restricted to males. The adoption studies were based on data collected from official registers or hospital 409
records and no clinical examination was done. In later clinical studies, however, the validity of this classification has been verified. When the two subgroups were defined from the presence and absence of early onset and social complications, the type 2 alcoholics were found to have more alcoholism and depression among their first degree relatives, and when the two types were studied with regard to personality traits, the type 2 alcoholics differed from both controls and type 1 alcoholics with a higher degree of sensation seeking and extraversion-related traits (Oreland et al., 1985; von Knorring et al., 1985; von Knorring et al., 1987a). An enzyme of great interest in connection with alcoholism is monoamine oxidase (MAO; E.C.: 1.4.3.4.). Thus, low MAO activity has been found in the brains of alcoholics (Oreland et al., 1983), in the platelets of alcoholics (Wiberg et al., 1977; Faraj, 1987; for a review see Oreland et al., 1985) and in the relatives of alcoholics (Major and Murphy, 1978; Puchall
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etal., 1980; Alexopoulose/a/., 1983), supporting the hypothesis that the low MAO activity is a biological marker for vulnerability to misuse (Buchsbaum et al., 1976). A non-significant trend in the same direction was found by Schuckit et al. (1982) on a rather small series of alcoholics. Such a vulnerability might be linked to impulsive personality traits, since low platelet MAO activity, in several studies, has been correlated with sensation seeking, impulsiveness and monotony avoidance both in males and females (Schalling et al., 1987). These personality traits, as well as low platelet MAO activity, have recently been reported to be related to alcoholism, particularly type 2 (Orelandera/., 1985; von Knorringetal., 1985; Pandey et al., 1988). In line with those findings is the low platelet MAO activity demonstrated in teenage boys with mixed alcohol and illegal drug misuse (von Knorring et al., 1987b). It should be pointed out, however, that the temperament linked to low platelet MAO activity makes low MAO subjects be overrepresented also among such groups as, e.g. mountaineers and violent offenders (for a recent review see Oreland, 1991). The aim of the present study was to find further experimental support for the conception that low platelet MAO activity is linked to alcoholism of type 2, but not type 1.
MATERIALS AND METHODS Subjects The series of alcoholics answered a questionnaire with standardised questions about their own habits, problems and symptoms when drinking as well as criminality and social situation. There were also some questions about the psychiatric morbidity of family members. In total the study included 99 subjects out of 107 consecutive males, treated as inpatients at the Department of Psychiatry, Umea University. All the patients met the DSM-I1I-R criteria for alcoholic dependence (American Psychiatric Association, 1987). Eight of the 107 patients were excluded as blood samples either were not obtained or had to be discarded for technical reasons. The 99 alcoholics were classified into type 1 or 2 according to the results from earlier studies (von Knorring et al., 1985; von Knorring et al., 1987a; see also below). In this way the alcoholics were divided into 37 type 1 alcoholics with a mean (± S.D.) age of 49.5 ± 10.0 years and 62 type 2 alcoholics with a mean age of 38.0 ± 8.0 years. Clinical characteristics of the subjects are shown in Table 1. The controls also answered the same questionnaire about drinking habits, drug use, etc., as the probands and consisted of 36 healthy
Table 1. Clinical characteristics of the male alcoholics divided into type I (N = 37) and type 2 (/V = 62)
First alcohol consumption (age) (mean ± S.D.) First subjective alcohol problems (age) First treatment contact (age) Glue misuse Cannabis misuse Amphetamine misuse Illegal use of minor tranquillisers Aggressive after alcohol consumption Absent from work due to alcoholism Lost job due to alcoholism Arrested when drunk Drunk when driving Other forms of criminality
Type 1
Type 2
18.0 ± 4.0 36.3 ± 7.7 41.9 ± 9.7 1 (3%)
16.3 ± 3.3 23.8 ± 4.7 27.8 ±7.1 17 (27%) 29 (47%) 12 (19%) 13(21%) 34 (55%) 57 (92%) 29 (47%) 55 (89%) 42 (68%) 32 (52%)
0 0 0
7 (19%) 28 (76%) 7 (19%) 24 (65%) 18 (49%) 2 (5%)
PLATELET MONOAMINE OXIDASE ACTIVITY
males (mean age 34.6 ± 8.0 years). They were working at Umea University or were their relatives. All were personally known by the investigators and thus alcohol misuse or a history of severe mental or personality disorders could be ruled out. Only one of the controls reported symptoms of aggressivity when drunk. Type 2 alcoholism was defined as follows. (A) There is a pattern of pathological alcohol use, shown either as: (i) inability to cut down/stop drinking; (ii) remaining continuously intoxicated during at least two days; (iii) two or more amnesic periods for events occurring when intoxicated (black-outs); or (iv) continuation of drinking despite the knowledge of having a persistent or recurrent physical problem, which is caused or exacerbated by alcohol use. (B) There are at least three symptoms of impairment in social or occupational functioning due to alcohol use such as: 1. violence while intoxicated 2. absence from work or school 3. loss of job 4. legal difficulties (arrest for intoxicated behaviour or other arrests or imprisonments) 5. traffic accidents while intoxicated 6. arguments or difficulties with family or friends because of excessive alcohol use. (C) Either marked tolerance or withdrawal symptoms as defined in DSM-III-R criteria (1987). (D) Onset of subjective problems before 25 years of age and first treatment contact before age of 30. However, since in the present study, we had problems in defining the age of onset in a correct manner due to the patients' inability to give a reliable history, only first treatment contact before 30 years of age defined early onset. The mean age at first treatment was 27.8 years and the standard deviation was 7.1. This means that many had their first treatment contact during their adolescence or early adulthood. Type 1 alcoholism was defined as follows. (A) Definition of pathological alcohol use as above under A. (B) The alcoholics did not fulfil the impairment in social or occupational functioning
411
according to the criteria for type 2 alcoholism as above under B. (C) Either marked tolerance or withdrawal symptoms as above under C. (D) Onset of subjective problems after 25 years and treatment contact after 30 years of age. A special check-list was used to get information about the families of the subjects and about their social situation (von Knorring et al., 1985). Depression in the relatives was defined from the subject's responses in the standardised questionnaire. In fact, a depression was regarded if the family member had consulted a doctor, or if it was clear from the description that a doctor ought to have been consulted. Platelet MA O activity As it has been shown that platelet MAO is stable over time, although with a transient increase during the first 3-4 weeks of the abstinence period (Wiberg, 1979; Major et al., 1981), all alcoholics were investigated either immediately while still intoxicated, or after at least 4 weeks of total abstinence. Samples of blood (5 ml) were drawn into Vacutainer® tubes containing sodium citrate, and the red cells allowed to self sediment for approximately 4 hr. After removing about 1 ml of platelet-rich plasma by careful suction, the platelet concentration was counted by the Coulter® Counter (Dunstable, U.K.) and the plasma frozen at -70°C. After thawing, the samples were sonicated for 1 min and estimation of the enzyme activity performed as described previously (Hallman et al., 1987J by incubation at 37°C for 4 min with ' 4 Ctryptamine, final concentration 50 |iM, or l4 C-2-phenylethylamine, final concentration 50 uM (New England Nuclear, Boston, MA, U.S.A.) as the substrate. The two substrates were used in parallel in order to increase the reliability of the estimation, and the estimations carried out in duplicate and the mean values used. Similar results with regard to differences between the groups were obtained with either of the two substrates (correlation coefficient (r) 0.88 and 0.75 for the controls and the alcoholics, respectively). As a further control of the reliability of the estimation, a
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standard platelet MAO preparation was estimated 26 times with each substrate at regular intervals during the estimation of alcoholics and controls. The mean activities of this standard were 2.69 ± 0.42 and 11.15 ± 0.90 nmoles of substrate oxidised/min platelets with tryptamine and 2-phenyiethylamine, respectively. Thus, the coefficients of variation for the estimations were 15.53 and 8.1%, respectively, during the period of estimation. Statistics Differences between means were tested by means of analysis of variance (ANOVA) and of the Student's /-test. Frequencies of distributions were tested by means of chi2. When there were less than five subjects in one cell Yate's correction was used. The MAO activity in the healthy volunteers showed no correlation with age (r (Pearson's corr) = 0.04). Thus no correction for age was necessary. When frequency distributions of platelet MAO activities were compared between controls, type 1 and type 2 alcoholics, respectively, the activities were expressed as standard deviations above or below the mean of the healthy controls.
min in controls, types 1 and 2 alcoholics, respectively, with 2-phenylethylamine as the substrate (Table 3). The corresponding figures with tryptamine as the substrate were 2.79 ± 0.94, 2.00 ± 0.57 and 1.60 ± 0.68 nmoles/101" platelets/min, respectively. Thus, the type 2 alcoholics had highly significantly lower platelet MAO activity than both controls and type 1 alcoholics. The type 1 alcoholics also had lower platelet MAO activity than the controls, but with a lower degree of significance (Table 3). The distribution of the platelet MAO activity is shown in Fig. 1. As a cutting point for low MAO activity we used -1.0 S.D. for the controls (towards 2-phenylethylamine), which would delineate the lowest mode and the lowest part of the moderately low mode of the Table 3. Platelet MAO activity (towards 2-phenylethylamine (2-pea) and tryptamine) expressed as nmoles of substrate metabolised/10"' platelets/min) in controls (N = 36), type 1 alcoholics (JV = 37) and type 2 alcoholics (N = 62) Platelet MAO activity towards 2-pea
Tryptamine
11.48 ± 4. II 9 .67 ± 3..09 7.33 ± 2..58
2.79 ± 0.94 2.00 ± 0.57 1.60 ± 0.68
RESULTS A significantly higher frequency of depression and a tendency towards a higher frequency of alcoholism were found in the mothers or fathers of type 2 alcoholics when compared with the type 1 alcoholics (Table 2). Platelet MAO activities were 11.48 ± 4.11 (mean ± S.D.) (100%), 9.67 ± 3.09 (84%) and 7.33 ± 2.58 (64%) nmoles/1010 platelets/
Controls (mean ± S.D.) Alcoholics, type 1 Alcoholics, type 2
Statistical analysis on the results with 2-pea: F = 20.20, P < 0.0001 (ANOVA); type 1 vs type 2, / = 4.02, P < 0.0005; type 1 vs control, I = 2.12, P < 0.05 (Student's itest). With tryptamine: F = 30.79, P < 0.0O01 (ANOVA), type 1 vs type 2, / = 3.12. P < 0.005; type 1 vs control, / = 4.32, P < 0.0005.
Table 2. Depression or alcoholism in mothers and fathers of the alcoholics (/V = 99) divided into type 1 (/V = 37) and type 2 (JV = 62). Chi2 with Yate's correction if less than 5 subjects in a cell Type 1 Alcoholism Alcoholism Alcoholism Depression Depression Depression
in father in mother in mother or father in father in mother in mother or father
9 (24%) 1 (3%) 10 (27%) 1 (3%) 0 1 (3%)
Type 2 25 (40%) r 6 (10%) 29 (47%) r 6 (10%) x > 8 (13%) X", 13 (21%) X".
= = = = = =
2 .63 0 .82 3 .78 0 .82 3 .60 4 .95
ns ns ns (P < 0 1) ns ns (P < 0 1) (P 0.05)
PLATELET MONOAMINE OXIDASE ACTIVITY 9 8 7 6 5 4 3 " a 3
- -, -
- i
Controls
2
1 0
r
PP
•a
'>
1 0
^
6
-
4
o u
2
.o E 3
Z
Typel
-
Z 8
r-
-
"h
0
20
Typ«2 15 10 5 0
j
-
- 5 - 4 - 3 - 2 - 1 0 1 2 3 4 5 SD above and below the mean or the controls Fig. 1. Platelet MAO activities in controls (N = 36), type 1 alcoholics (N = 37) and type 2 alcoholics (N = 62). Platelet MAO activities are expressed as S.D. above or below the mean of the controls (M = 11.48, S.D. = 4.11 nmolesof 2phenylethylamine metabolised/10'" platelets/min). Chrtest for activities above and below -1.0 S.D.; controls vs type 1 vs type 2; chi2 = 17.5. P < 0.0001
pentamodal distribution of MAO distribution shown by Cloninger et al. (1985) in a large material of Swedish recruits. Using such a cutting point, 33/62 of the type 2 alcoholics had low platelet MAO activity vs 9/37 of the type 1 alcoholics and 5/36 of the healthy volunteers. The differences between the three groups, between type 2 and controls and between type 2 and type 1 were statistically significant (chi2 = 18.00, P < 0.001; chi2 = 13.25, P < 0.001; chi2 = 6.79, P < 0.01). The type 1 alcoholics, however, did not differ from the controls (chi2 = 0.7, ns). The platelet concentration in the platelet-
413
rich plasma (x 10-Vu.l) was 501 ± 87 (mean ± S.D.) in the controls and 352 ± 141 and 383 ± 192 in the type 1 and type 2 alcoholics, respectively. There was a highly significant difference between the groups (F = 1639, P < 0.0001 ANOVA). A post hoc analysis with Student's /-test resulted in a highly significant difference between the alcoholics and the controls (t = 4.24, P < 0.0005), while there was no difference between the two groups of alcoholics (t = 0.88, ns). When a simple regression between platelet concentration and MAO activity was calculated on the combined group of alcoholics, no correlation was found (r = 0.02 and -0.04, respectively, with 2phenylethylamine and tryptamine as the substrates). DISCUSSION Etiologic heterogeneity of alcoholism has been suggested in the Stockholm Adoption Study (Cloninger et al., 1981) as well as in familial studies (Gilligan et al., 1987) of alcoholism. In clinical studies on alcoholics, it was demonstrated that subjects fulfilling DSM-IIIR criteria for alcohol dependence could be subdivided into two separate groups essentially following the criteria that are derived from the symptomatology of the biological fathers of adopted-away sons with type 2 alcoholism in the Stockholm Adoption Study (Cloninger et al., 1981). The clinical criteria were defined by von Knorring et al. (1985). The main finding in the present study is a replication of the clinical subdivision of type 1 and type 2 alcoholism and, as in the earlier study, the subgroups could be differentiated by means of platelet MAO activity. Type 2 alcoholism is characterised by an early onset, familial loading, sensation seeking personality and social complications or criminality, as well as by low platelet MAO activity. The results in the present study are in accordance with the results of our earlier studies. Type 2 alcoholics have an early onset of alcohol problems, as well as an early treatment contact. They also frequently have social complications, such as legal problems, criminality, fights when intoxicated, arrests because of driving when intoxicated and loss of
414
A.-L. VON KNORRING et al
job. Type 2 alcoholics also use illegal drugs to a great extent. By definition type 2 alcoholics are antisocial. Many of them might as well suffer from antisocial personality disorder or conduct disorder preceding the onset of alcoholism as suggested by Irwin et al. (1990). However, this question has not been possible to elucidate in the present study. There is also a high incidence of familial alcoholism and 'depression' among type 2 alcoholics. The definition of depression and alcoholism in this study is not defined by clear criteria based on DSM-III. Similar findings of a high incidence of familial alcoholism and depression have also been found in other studies, in which the characteristics for division of alcoholics into subgroups have been based on the typology obtained from the Stockholm Adoption Study (Pandey et al., 1988; Buydens-Branchey et al., 1989). Another approach to define the two types of alcoholism has been used by Gilligan et al. (1988), who characterised type 2 alcoholism by early onset of inability to abstain from ethanol complicated by reckless driving and fighting while intoxicated. The types 1 and 2 alcoholics have been found to differ with regard to personality traits. Thus, type 2 alcoholics showed more sensation seeking behaviour according to Zuckerman's sensation seeking scales and a higher impulsivenesssensation seeking-psychopathy factor according to the Karolinska Scales of Personality (KSP) (Oreland et al., 1985; von Knorring et al., 1985; von Knorring et al., 1987a). As this kind of personality trait is correlated with low MAO activity (Buchsbaum et al., 1976; Ward et al., 1987; Schalling et al., 1987), it could be expected that type 2 alcoholics should have low MAO activity. This has, indeed, been found in three earlier studies on small numbers of alcoholics (von Knorring et al., 1985; Pandey et al., 1988; Sullivan et al., 1990) and could be replicated in the present study on larger and entirely new material. It has previously been shown that alcoholics have lower concentration of platelets in blood than controls (Wallerstedt, 1977; Haselager and Vreeken, 1977; Currie and Kaegi, 1977), which was also found in the present study. Low platelet MAO activity in alcoholics has, however, been shown irrespective of whether
the method for estimation of the activity was based on the platelet count (Wiberg et al., 1977) or per unit of platelet protein (Major and Murphy, 1978), presuming that the blood sample was drawn either acutely or after about 4 weeks of abstinence. Thus, it has repeatedly been shown that there is a transient increase in the activity during the abstinence reaction after alcohol misuse (Wiberg, 1979; Major et al., 1981). Direct evidence for the notion, that the effect of alcohol on platelet concentration in blood did not have any influence on the present result with MAO activities (calculated as activity per platelet), was provided by the fact that the platelet concentration did not differ between the alcoholics of type 1 and type 2, and that no correlation was found between platelet concentration and MAO activity (see Results). Low MAO activity in alcoholics has been found in several studies during the last two decades, both in brain (Oreland et al., 1983) and in platelets (Wiberg et al., 1977; Major and Murphy, 1978; Fowler etal., 1981; Lykouras et al., 1987; Faraj, 1987). There are also reports of low platelet MAO activity in relatives of alcoholics (Puchall et al., 1980; Alexopoulos et al., 1983) in support of the view that low platelet MAO activity is a genetic marker for vulnerability to, e.g. drug misuse (see Oreland et al., 1984; Oreland and Hallman, 1988). In retrospect, however, it seems likely that the findings in those studies, at least in those concerning platelet MAO, were derived from the portion of alcoholics in the series who could have been classified as belonging to type 2. There is a lot of evidence supporting the hypothesis that platelet MAO activity is correlated to central serotonergic activity (Oreland and Shaskan, 1983; Oreland and Hallman, 1988), and, thus, the type 2 alcoholics would be characterised by a serotonergic deficit. A similar hypothesis about a subgroup of alcoholics with low serotonergic activity was recently suggested by Roy and Linnoila (1988) and Moss (1987). Further support for the hypothesis is provided by the fact that the type 2 alcoholics and other low platelet MAO probands have similarities in their personality trait profile to patients with psychiatric disorders
PLATELET MONOAMINE OXIDASE ACTIVITY
characterised by aggressive and suicidal behaviour, which has repeatedly been shown to be associated with low levels of CSF-5HIAA (Traskman et al., 1981; Roy and Linnoila, 1988; Roy et al., 1989). Also in line with the hypothesis is the finding that depressed patients with a family history of alcoholism had significantly lower CSF-5HIAA levels than patients without alcoholic relatives (Rosenthal et al., 1980). It is likely that alcoholics characterised as type 2 might require another strategy of treatment than those characterised as type 1. Thus, the favourable results reported with serotonin uptake blockers (Naranjo et al., 1989; Gorelick, 1989; Gill and Amit, 1989) might be more or less confined to one of the two types. Also, when considering prevention, it should be of value to know that type 2 alcoholics are at high risk for illegal drug misuse as well. In either case, estimation of platelet MAO activity could be of value for a more correct characterisation of the alcoholic patient. However, both in the present series and in the previous ones, there has been a considerable number of alcoholics in whom the classification, based on anamnestic data, did not agree with the platelet MAO activity. Thus, it remains to be elucidated whether the anamnestic data or the platelet MAO activity most truly reflected their vulnerability for misuse.
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