- Email: [email protected]
Morbidity risk for psychiatric disorders in families of probands with affective disorders divided according to levels of platelet MAO activity
P.yychiatrl, Research, 15, 211-279 Elsevier
271
Morbidity Risk for Psychiatric Disorders in Families Probands With Affective Disorders Divided According Levels of Platelet MAO Activity
of to
Lars von Knorring, Sonja Holmgren, Received
December
Carlo Perris, Lars Oreland, and Hjijrdis Perris
Martin
Eisemann,
12, 1983; revised version received April 16. 1984; accepted May 16, 1984.
Abstract. In a series comprising 166 subjects with affective disorders, the lowest and highest quartiles in the male and female platelet monoamine oxidase (MAO) distribution, respectively, were included. The morbidity risk in the first-degree relatives (parents and siblings) of these low and high platelet MAO subjects was determined. First-degree relatives of low platelet MAO probands were found to have an increased morbidity risk for neurotic-reactive depressions and for alcoholism. The results seem to be in line with the biological high-risk paradigm, indicating that platelet MAO could be a biological marker for increased vulnerability. First-degree relatives of high platelet MAO probands were found to have an increased morbidity risk for bipolar affective disorders.
Key Words. Affective genetics.
disorders,
platelet
monoamine
oxidase,
morbidity
risk,
Studies of morbidity risk among relatives of probands, and a comparison of the results with findings obtained in epidemiological investigations, are among the first steps in the identification of a possible genetic component in the causation of a given disorder. There is now ample evidence in the literature that the morbidity risk for affective disorders is increased among first-degree relatives of probands with affective disorders as compared with the general population (Perris et al., 1982). Thus far, however, family studies have told us little about the nature of the genetic component involved, since attempts to link affective disorders with known genetic markers have not found consistent results. One possible biological marker of interest in this connection is the enzyme monoamine oxidase (MAO, EC 1,4,3,4) in platelets (Buchsbaum et al., 1976; Fowler et al., 1980; Oreland and Shaskan, 1983). Naturally, this enzyme activity must in its turn correlate to some parameter(s) in the central nervous system. Indeed, a correlation seems to exist between platelet MAO activity and some properties of the central serotonin system (Oreland et al., 1981). In patients with affective disorders, contradictory results have been reported as concerns the activity of platelet MAO. In some studies, no differences were found
Lars von Knorring, M.D., is Associate Professor, Carlos Perris, M.D., is Professor, Martin Eisemann, Dr. med. SC., and Sonja Holmgren, Nurse, are Research Associates, and Hjkdis Perris, Dr. med. SC., is Research Psychologist, Department of Psychiatry, Umea University, Umel, Sweden. Lars Oreland, M.D., is Professor, Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden. (Reprint requests to Dr. L. van Knorring, Dept. of Psychiatry, UmeH University, S-901 85 Umei, Sweden.) 0165.1781/85:$03.30
0 1985 Elsevier Science Publishers
B.V
272 between healthy volunteers and subjects with affective disorders (not divided into unipolars and bipolars) (Gershon et al., 1979; Maubach et al., 198 1). In the same way, Edwards et al. (1978) were unable to demonstrate any significant differences in platelet MAO activity between healthy controls or patients with unipolar or bipolar affective disorders. In other studies, however, patients with unipolar affective disorders have been found to have high platelet MAO activity (Nies et al., 1971, 1974; Klaiber et al., 1972; Belmaker et al., 1976; White et al., 1980; Oreland et al., 1981). In another series of studies, patients with affective disorders have been found to have low platelet MAO activity. In these studies, most patients are of the bipolar type (Murphy and Weiss, 1972; Murphy et al., 1974; Landowski et al., 1975; Sullivan et al., 1978; Gershon et al., 1979; Orsulak et al., 1978). In still other studies, patients with affective disorders have as a group been found to have low platelet MAO activity as compared to healthy volunteers (Puzynski et al., 1983; von Knorring et al., 1985~). However, patients with unipolar and bipolar affective disorders did not differ significantly from healthy volunteers. Instead, the low platelet MAO activities were found in patients with undifferentiated affective disorders (Puzynski et al., 1983) or patients with adjustment disorders with depressed mood (von Knorring et al., 1985~). Consistent findings of low platelet MAO activities have, however, been reported in subjects sensitive to external stressors, as well as those with tendencies to alcohol or drug abuse and suicidal behavior. Thus, low platelet MAO activities have been reported in subjects with adjustment disorders with depressed mood (von Knorring et al., 1985a), in alcoholics (Wiberg et al., 1977; Major and Murphy, 1978; von Knorring and Oreland, 1978; Pandey et al., 1980), and in patients with suicidal behavior (Buchsbaum et al., 1977; Gottfries et al., 1980; von Knorring et al., 1985b). Platelet MAO activities seem to be under genetic control (Murphy, 1976; Winter et al., 1978; Pandey et al., 1979; Rice et al., 1982), and in family studies, parents of low MAO probands have been shown to have significantly lower platelet MAO activities than parents of high MAO probands (Puchall et al., 1980). Thus, if low platelet MAO activity is a biological marker of vulnerability, it would appear interesting to investigate the incidence of psychiatric disorders among firstdegree relatives of low MAO probands. An increased incidence has already been demonstrated in some studies. Buchsbaum et al. (1976) reported an eightfold increase in the incidence of suicide and suicide attempts in the relatives of low MAO subjects as compared to the relatives of high MAO subjects. In a 2-year followup (Coursey et al., 1982), the low MAO subjects reported more mental health problems in their families, especially depression, alcoholism, and suicide attempts. In other studies, low platelet MAO activities have been reported in relatives of patients with manic-depressive disorders, especially if the relatives themselves had bipolar I illness or alcoholism (Pandey et al., 1980) and in relatives of alcoholics (Schuckit et al., 1982). However, negative results have also been reported (Goldin et al., 1983). The aim of the present investigation has been to study the morbidity risk for psychiatric disorders in first-degree relatives of probands with affective disorders, divided according to the platelet MAO activity in the proband (high or low). The hypothesis
273 was that the relatives of the low MAO probands would have an increased incidence of psychiatric disorders, especially alcoholism, suicide, and reactive depression. The incidence of unipolar or bipolar affective psychosis, on the other hand, could be higher or similar to that of the relatives of the high MAO probands, depending upon whether or not the vulnerability factor is related to the occurrence of depressive disorders. Methods The Series. Depressed patients of both sexes, in the age range 18-70 years, consecutively admitted to the Department of Psychiatry at the Umea University between 1977 and 1980, were included, independently of any diagnostic subdivision made a priori, in a comprehensive study of depression in its various biological, psychological, and social aspects. All patients were investigated immediately after admission to the ward, and before active pharmacological treatment began. Most of the patients were completelydrugfreeat the time of the investigation, but some had received small and irregular doses of tricyclics and/ or minor tranquilizers during the last weeks preceding admission (corresponding to imipramine < 50 mg/day or diazepam < 10 mg/day). Among the particular studies carried out on this series, t!rere has been a family study (Perris et al., 1982) encompassing, in a first step, all first-degree relatives. On the same series, an assessment of the level of platelet MAO activity has also been made. The somewhat smaller sample size in the current study is due exclusively to occasional technical or administrative factors and is not the result of any systematic selection. The subdivision of subjects into high or low MAO subgroups is still a difficult question. According to Rice et al. (1982), only the upper 5% of the platelet MAO activity distribution should be genetically homogeneous. In most of the studies in which subjects with low platelet MAO activity have been found to have certain personality characteristics or a certain vulnerability, however, low platelet MAO activity has been defined as the lowest IO%, the lowest 25Yc, or the lowest third of the distribution (e.g., Buchsbaum et al., 1976; Coursey et al., 1982; von Knorring et al., 1984). Thus, the best delineation of the low platelet MAO subgroup is still unclear. In the present study, low and high platelet MAO activities have been defined as the lowest and highest quartiles of the male and female distribution, respectively. The lowest quartile of the female subdistribution included 24 subjects with platelet MAO activities ranging from 0.96 to 3.84 nmoles/ lo9 platelets/ minute (mean 2.95, SD 0.82) while the highest quartile included 25 females with platelet MAO activities ranging from 5.72 to 11.98 (mean 6.81, SD 1.48). The lowest quartile in the male subdistribution included 16 subjects with platelet MAO activities ranging from 1.51 to 3.08 (mean 2.52, SD 0.48), while the highest quartile included 16 males with platelet MAO activities ranging from 5.20 to 9.06 (mean 6.40, SD 1.05). The composition of the series as concerns age, age at onset, sex, and diagnostic subdivision is shown in Table 1. The diagnostic criteria are about the same as used in earlier studies (Perris et al., 1982). Unipolar affective disorders. These include patients who have had at least three separate episodes of depressions of a psychotic severity (i.e., with impaired reality testing); or patients who have had at least two episodes of psychotic depressions if the subject is 45 years old or more and if there is a verified family history of recurrem depressive episodes among the first-degree relatives; or patients who have had at least three separate episodes of severe depressions, with melancholic features, occurring apparently independently of stressful life events. In no instances are episodes of mania (hypomania) allowed. Bipolar affective disorders. Patients in this category are those who had been treated for at least one depressive and one manic episode. A hypomanic episode has been considered as an expression of bipolarity when (1) it occurred between episodes of depression and warranted medical care; (2) it occurred at the beginning of an episode that later became depressive; or (3) it occurred at the end of a depressive episode and lasted long enough to warrant a change of treatment from antidepressive to sedative.
274
Table 1. Age, age at onset, sex distribution, and diagnoses in the low and high platelet MAO subgroups, respectively, as well as the number of parents and siblings in the investigated groups Low MAO
High
MAO
(n = 40)
(n = 41)
41.2
47.9
Age1 Mean SD Age
range
(years)
2.3
2.6
23-68
22-69
30.2
34.5
Age at onset2 Mean
1.7
SD Sex (M/F) Depressive
1.9
16/24
16125
13
13
diagnoses
Unipolars Bipolars Neurotic-reactives
5
6
14
11
8
11
Number
of parents
78
79
Number
of siblings
132
173
Unspecified
1. t = 2.21, p < 0.05. 2. t = 1.66. NS.
Neurotic-reactive depressions. This category is defined by depressive episodes in subjects with a verified history of a neurotic personality disorder mainly of a depressive, asthenic, neurasthenic, or passive-dependent type; or depressive episodes occurring as an understandable reaction to the impact of a stressful life event. The disorder must be characterized by a dominant depressive symptomatology that affects the subject’s feeling of well-being and social functioning. The procedure for the assessment of secondary cases has been described in detail elsewhere (Perris et al., 1982). Our approach has been both of the family history type and the family study type, in the sense that information has been primarily obtained from the probands themselves during the longstanding contact with them in connection with the studies mentioned above; the family history has usually been verified by at least one of the proband’s closest relatives. Furthermore, as our Department is the only psychiatric service available in the intake area, and since the population in the region is rather stable, there have been good opportunities to control for possible unreported episodes of psychiatric care in the relatives. The diagnostic assessments of secondary cases for whom medical records were available, (n = 75) have been made independently by two experienced psychiatrists who were not aware of the diagnosis of the proband or the result of the platelet MAO estimation. In the five instances when disagreement among the diagnosticians did occur, the records were discussed at a joint session, still without knowledge of the proband’s diagnosis, until agreement was reached; if disagreement persisted, the case was assigned to the group of unspecified depressive disorders. For the calculation of the percentage morbidity risk (MR%), the population at risk has been corrected by using Weinberg’s abridged method (Weinberg, 1925). For the affective disorders, a risk period between the ages of 15to 70 years was used. For schizophrenia, the risk period of 15 to 50 years was taken into account, whereas for alcoholism all individuals above 15 years were included. Platelet MAO Activity. Samples of blood (5 ml) were drawn into vacutainer tubes containing sodium citrate, and the red cells were allowed to self-sediment. The platelet concentration in the
275 platelet-rich plasma was counted by a Coulter counter and the plasma was frozen at -7O’C. After thawing, the samples were sonicated for I minute and 50 ~1 transferred to test tubes containing 50 ~1 of 0.1 M potassium phosphate buffer, pH 7.8, to which had been added radiolabeled substrate to a final concentration of 50 pCcMand a radioactivity of about 50,000 cpm. Incubation was performed for 10 minutes at 36°C. The reaction was then stopped by addition of 30 /*l of 1 M HCl. The metabolites formed were extracted by short vigorous shaking into 750 ~1 of toluene ethyl acetate 1: 1, saturated with water. After a short centrifugation, 500 ~1 of the organic layer was transferred into 10 ml of scintillation liquid and the radioactivity were obtained from New England estimated. 14C-P-phenylethylamine and ‘%I-tryptamine Nuclear, Boston, MA. All experiments were performed in duplicate and blindly, and the results are expressed as nmoles of substrate metabolized per 109 platelets per minute. This method is a modification of that previously described and discussed (Eckert et al., 1980; Fowler et al., 1980). In line with earlier studies (Fowler et al., 1980), the correlation between the platelet MAO activities obtained by means of the two substrates was high (r = 0.78) and, thus, in the present study, only the MAO distribution obtained with tryptamine as a substrate was taken into account. Statistics. Frequency distributions were tested by means of the x2 test. When fewer than five subjects were included in one cell, Yates correction was made. When one cell did not include any subjects at all, the Fisher exact probability test was used. Differences between means were tested using Student’s t test.
Results The morbidity risks of psychiatric disorders in first-degree relatives (parents and siblings) of low and high platelet MAO probands with affective disorders are presented in Table 2. Significant differences occurred as concerns three diagnoses. First-degree relatives of low platelet MAO probands were found to have a significantly higher morbidity risk for neurotic-reactive depression as well as for alcoholism. By contrast, first-degree relatives of high platelet MAO probands were found to have a significantly higher risk for bipolar affective disorders. Table 2. Morbidity risk for psychiatric disorders in first-degree relatives (parents and siblings) of low and high high MAO probands with affective disorders Low MAO (n = 40)
High MAO (n = 41)
At risk Cases MR%l
At risk Cases MR%l
Unipolars Neurotic-reactive Unspecified
depressions
depression
Statistics2
112.5
8
7.1
137
8
5.8
NS
112.5
8
7.1
137
1
0.7
p < 0.02 NS
112.5
4
3.6
137
9
6.6
Suicides
112.5
2
1.8
137
2
1.5
NS
Bipolars
112.5
-
-
137
6
4.4
p < 0.05
112.5
137
All affective
disorders
22
19.6
26
19.0
Schizophrenia
150
4
2.7
190.5
4
2.1
NS
Alcoholism
201
8
4.0
230
1
0.4
p i 0.05
112.5
2
1 .a
137
8
5.8
NS
112.5
12
10.7
137
22
16.0
NS
Other
diagnoses
Subjective disturbance treatment
NS
without
1. MR% = cases/subjects at risk X 100. 2. See Methods section.
216 The eight cases of alcoholism occurred in eight different families. In five of these cases, the proband had a neurotic-reactive depression; in two cases, the proband had a unipolar affective disorder; and in one case, the proband had an unspecified affective disorder. The eight cases of neurotic-reactive depressions in the first-degree relatives occurred in five different families. In two cases, the proband had a bipolar affective disorder; in one case, the proband had a unipolar disorder; in one case, the proband had a neurotic-reactive depression; and in one case, the proband had an unspecified affective disorder. Otherwise no significant differences occurred between the two groups. The picture was quite consistent also if the male and female probands were considered separately. Relatives of the low MA Omales had a significantly higher risk of alcoholism (6.3% versus O%, Fisher exact probability test,p=0.021) and a tendency toward a higher risk for neurotic-reactive depressions (11.1% versus 1.9%, x2, Yates 2.15, NS). In the first-degree relatives of the high MAO males, there was a tendency toward a higher risk for bipolar affective disorders (5.6% versus O%, Fisher exact probability test,p = 0.158). In the first-degree relatives of low MAOfemales, there were tendencies toward a higher risk for neurotic-reactive depressions (4.4% versus O%, Fisher exact probability test, p 0.089) and alcoholism (2.5% versus 0.7%, x2, Yates 0.45, NS). In the first-degree relatives of high MAOfemales, there was a tendency toward a higher risk for bipolar affective disorders (3.6% versus O%, Fisher exact probability test, p = 0.163). Because the low MAO probands were significantly younger than the high MAO probands, age-matched groups were formed. In this subsample comprising 27 low MAO probands (9 males, 18 females, mean age 44.4 years) and 27 high MAO probands (9 males, 18 females; mean age 44.4 years), the same tendencies occurred (Table 3). First-degree relatives of low platelet MAO probands had a significantly higher morbidity risk for neurotic-reactive depression as well as for alcoholism. As concerns bipolar affective disorders, however, no significantly higher morbidity risk was found in first-degree relatives of high platelet MAO probands. q
q
q
Discussion In the present study, first-degree relatives of low platelet MAO probands with affective disorders have been found to have a significantly higher morbidity risk for neurotic-reactive depressions and for alcoholism. The result is quite consistent in the male and female subsamples and also if an age-matched subsample is formed. The results seem to be in line with earlier studies (Buchsbaum et al., 1976; Coursey et al., 1982). The result is also in line with the hypothesis that platelet MAO may be regarded as a biological marker of increased vulnerability (Buchsbaum et al., 1976; Oreland and Shaskan, 1983). Thus, the increased vulnerability seems to exist both in the probands with low platelet MAO activity and in their relatives. The fact that there are families characterized by an increased risk of neurotic-reactive depressions (most common in females) and of alcoholism (most common in males) seems to be in line with Winokur’s
277 Table 3. Morbidity risk for psychiatric disorders in first-degree relatives (parents and siblings) of low and high high MAO probands with affective disorders: Age- and sex-matched subsample (n = 54) Low MAO (n = 27) At risk Cases Unipolars Neurotic-reactive Unspecified
depressions
depression
Suicides Bipolars
MR%l
High MAO (n = 27) At risk Cases
BAR%1
Statistics2
82.5
5
6.1
76
3
3.9
82.5
a
9.7
76
-
-
NS
82.5
2
2.4
76
5
6.6
NS
82.5
2
2.4
76
1
1.3
NS
p < 0.01
82.5
-
-
76
3
3.9
NS
82.5
17
20.6
76
12
15.8
NS
Schizophrenia
109.5
3
2.7
107
4
3.7
Alcoholism
145
6
4.1
128
-
-
82.5
1
1.2
76
3
3.9
NS
82.5
a
9.7
76
7
9.2
NS
All affective
Other
disorders
diagnoses
Subjective
disturbance
without
treatment 1. MR% 2. See
NS
p < 0.02
= cases/subjects at risk Methods section.
X 100.
(1979) description
of depression spectrum disease. In the present study, there is no evidence of an increased suicide rate in the first-degree relatives of probands with low platelet MAO activity. However, the sample size is small, comprising only four suicides in the relatives. In earlier studies (Gottfries et al., 1980; van Knorring et al., 1985b), we have found low platelet MAO activities in probands who had attempted suicide by active methods but normal platelet MAO activities in subjects who had attempted suicide by passive methods. The present sample size does not permit such a subdivision. There is a large literature indicating increased vulnerability and an increased incidence of psychiatric disorders in subjects with low platelet MAO activity and in their relatives, but less has been written about subjects with high platelet MAO activites. However, Puchall et al. (1980) demonstrated an increased incidence of what they called high-MAO-related disorders (major or minor depression and depressive personality) in relatives of high MAO subjects. In the present study, there is an increased morbidity risk of bipolar affective disorders in the first-degree relatives of probands with high platelet MAO. As concerns probands with unipolar or bipolar affective disorders, the overall picture is confusing and high, normal, and low platelet MAO activities have been reported. In our own studies, we tend to find normal (von Knorring et al., 1985~) or high (Oreland et al., 1981) platelet MAO activities in probands with bipolar affective disorders. The present finding of an increased morbidity risk for bipolar affective disorders in the first-degree relatives of high platelet MAO probands seems to be in line with the hypothesis that if there is a relationship between bipolar affective disorders and MAO activity, the relationship is to high levels. However, this hypothesis should be tested in a larger family study of patients with clear bipolar affective disorders. Acknowledgment. The research reported was supported, in part, by grants from the Swedish Medical Research Council (Grant Nos. 4145, 5244, 5740).
278 References Belmaker, R.H., Ebbesen, K., Ebstein, R., and Rimon, R. Platelet monoamine oxidase in schizophrenia and manic-depressive illness. British Journal of Psychiatry, 129, 227 (1976). Buchsbaum, M.S., Coursey, R.D., and Murphy, D.L. The biological high-risk paradigm: Behavioral and familial correlates of low platelet monoamine oxidase activity. Science, 194,339 (1976). Buchsbaum, M.S., Haier, R., and Murphy, D.L. Suicide attempts, platelet monoamine oxidase, and the averaged evoked response. Acta Psychiatrica Scandinavica, 56,69 (1977). Coursey, R.D., Buchsbaum, M.S., and Murphy, D.L. Two-year followup of subjects and their families defined as at risk for psychopathology on the basis of platelet MAO activities. Neuropsychobiology. 8, 5 1 (1982). Eckert, B., Gottfries, C.-G., von Knorring, L., Wiberg, A., and Winblad, B. Brainand platelet monoamine oxidase activity in mental disorders: I. Schizophrenics and cycloid psychotics. Progress
in Neuro-Psychopharmacology,
4, 57 (1980).
Edwards, D.J., Spiker, D.G., Kupfer, D.J., Foster, G., Neil, J.F., and Abrams, L. Platelet monoamine oxidase in affective disorders. Archives of General Psychiatry, 35, 1443 (1978). Fowler, C.J., von Knorring, L.. and Oreland, L. Platelet monoamine oxidase activity in sensation seekers. Psychiatry Research, 3, 273 (1980). Gershon, E.S., Targum, S.D., and Leckman, J.F. Platelet monoamine oxidase (MAO) activity and genetic vulnerability to bipolar (BP) affective illness. Psychopharmacology Bulletin, 15, 27 (1979). Goldin, L.R., Gershon, E.S., Targum, S.D., Sparks, R.S., and McGinnis, M. Segregation and linkage analysis of patients with bipolar, unipolar, and schizo-affective mood disorders. American
Journal
of Human
Genetics,
35,274
(1983).
Gottfries, C.-G., von Knorring, L., and Oreland, L. Platelet patients with suicidal behavior and in subgroups of affective Psychopharmacology,
4, 185 (1980).
Klaiber, E.L., Broverman, estrogen therapy on plasma American
Journal
von Knorring, oxidase activity Progress
monoamine oxidase activity in psychoses. Progress in Neuro-
D.M., Vogel, W., Kobayashi, Y., and Moriarty, D. Effects of MAO activity and EEG driving response in depressed women.
of Psychiatry,
128, 1492 (1972).
L., and Oreland, L. Visual averaged evoked responses and platelet monoamine as an aid to identify a risk group for alcoholic abuse: A preliminary report.
in New-o-Psychopharmacology,
2, 385 (1978).
von Knorring, L., Oreland, L., and Winblad, B. Personality traits related to monoamine oxidase (MAO) activity in platelets. Psychiatry Research, 12, 11 (1984). von Knorring, L., Perris, C., Oreland, L., Eisemann, M., and Perris, H. Platelet MAO activity in affective disorders. Relationship to diagnostic subgroup. Unpublished manuscript (1985~). von Knorring, L., Perris, C., Oreland, L., Eisemann, M., and Perris, H. Platelet MAO activity in affective disorders. Relationship to suicidal behavior. Unpublished manuscript (19856). Landowski, J., Lysiak. W., and Angielski, S. Monoamine oxidase activity in blood platelets from patients with cyclophrenic depressive syndromes. Biochemical Medicine, 14,347 (1975). Major, L.F., and Murphy, D.L. Platelet and plasma amine oxidase activity in alcoholic individuals. British Journal of Psychiatry. 132, 548 (1978). Maubach, M., Diebold, K., Fried], W., and Pr9opping, P. Platelet MAO activity in patients with affective psychoses and their first degree relatives. Pharmacopsychiatry, 14, 87 (1981). Murphy, D.L. Clinical, genetic, hormonal, and drug influences on the activity of human platelet monoamine oxidase. In: Wolstenholme, G.E.W., and Knight, J., eds. Monoamine Oxidase and Its Inhibition. Elsevier/ Excerpta Medics/North-Holland, Amsterdam, p. 341 (1976). Murphy, D.L., Belmaker, R., and Wyatt, R.J. MAO in schizophrenia and other behavioral disorders. Journal of Psychiatric Research, 11, 22 1 ( 1974).
279
Murphy, D.L., and Weiss, R. Reduced monoamine oxidase in blood platelets from bipolar depressed patients. American Journal of Psychiarry, 128, 1351 (1972). Nies, A., Robinson, D.S., Harris, L.S., and Lamborn, K.R. Comparison of monoamine oxidase substrate activities in twins, schizophrenics, depressives and controls. Advnnces in Biochemical
Psychopharmacology,
12, 59 (1974).
Nies, A., Robinson, D.S., Ravaris, C.L., and David, J.M. Amines and monoamine oxidase in relation to aging and depression in man. Psychosomatic Medicine, 33, 470 (1971). Oreland, L., and Shaskan, E.G. Monoamine oxidase activity as a biological marker. Trends in Pharmacological Sciences, August, p. 339 (1983). Oreland, L., Wiberg, A., Asberg, M., Traskman, L., Sjostrand, L., Thoren, P., Bertilsson, L., and Tybring, G. Platelet MAO activity and monoamine metabolites in cerebrospinal fluid in depressed and suicidal patients and in healthy controls. Psychiatry Research, 4, 2 1 (198 1). Orsulak, P.J., Schildkraut, J.J., Schatzberg, A.F., Cole, J., Gudeman, J., and Rohde, W. Differences in platelet monoamine oxidase activity in subgroups of schizophrenic and depressive disorders. Biological Psychiatry, 13, 637 (1978). Pandey, G.N., Dorus, E., Shaughnessy, R., and Davis, J.M. Genetic control of platelet monoamine oxidase activity: Studies of normal families. Life Sciences, 25, 1173 (1979). Pandey, G.N., Dorus, E., Shaughnessy, R., Gaviria, M., Val, E., and Davis, J.M. Reduced platelet MAO activity and vulnerability to psychiatric disorders. Psychiatry Research, 2, 3 15 (1980).
Perris, C., Perris, H., Ericsson, U., and von Knorring, L. The genetics of depression: A family study of unipolar and neurotic-reactive depressed patients. Archiv f;r Psychiatric und Nervenkrankheiten.
232,
137 (1982).
Puchall, L.B., Coursey, R.D., Buchsbaum, M.S., and Murphy, D.L. Parents of high-risk subjects defined by levels of monoamine oxidase activity. Schizophrenia Bulletin, 6,338 (1980). Puzynski, S., Hauptmann, M., and Zaluska, M. Studies on biogenic amine metabolizing enzymes (DBH, COMT, MAO) and pathogenesis of affective illness: III. Platelet monoamine oxidase activity in endogenous depression. ACM Psychiatrica Scandinavica, 67, 10 I (I 983). Rice, J., McGuffin, P., Goldin, L.R., Shaskan, E.G., and Gershon, E.S. Platelet monoamine oxidase activity: Evidence for a single major locus. Psychiatry Research, 7, 325 (1982). Schuckit, M.A., Shaskan, E., Duby, J., Vega, R., and Moss, M. Platelet monoamine oxidase activity in relatives of alcoholics. Archives of General Psychiatry, 39, 137 (1982). Sullivan, J.L., Stanfield, C.N., Maltbie, A.A., Hammet, E., and Cavenar, J.O. Stability of low blood platelet monoamine oxidase activity in human alcoholics. Biological Psychiatry, 13, 391 (1978).
Weinberg, W. Methoden und technik der statistik mit besonderer berucksichtigung der sozialbiologie. In: Gottstein, A., ed. Handbuch der sozialen Hygiene und Gesundheitsfursorge. Springer, Berlin (1925). White, K., Shih, J., Fong, T., Young, H., Gelfand, R., Boyd, J., Simpson, G., and Sloane, B. Elevated plasma monoamine oxidase activity in patients with non-endogenous depression. American
Journal
of Psychiatry,
137,
1258 (1980).
Wiberg, A, Gottfries, C.-G., and Oreland, L. Low platelet monoamine oxidase activity in human alcoholics. Medical Biology, 55, 18 1 (1977). Winokur, G. Familial (genetic) subtypes of pure depressive disease. American Journal of Psychiatry.
136, 9
1I ( 1979).
Winter, H., Herschel, M., Propping, P., Friedl. enzymes (DBH, COMT, MAO) of catecholamine Psychopharmacology,
57,63
(1978).
W., and Vogel, F. A twin study on three metabolism: Correlations with MMPI.
271
Morbidity Risk for Psychiatric Disorders in Families Probands With Affective Disorders Divided According Levels of Platelet MAO Activity
of to
Lars von Knorring, Sonja Holmgren, Received
December
Carlo Perris, Lars Oreland, and Hjijrdis Perris
Martin
Eisemann,
12, 1983; revised version received April 16. 1984; accepted May 16, 1984.
Abstract. In a series comprising 166 subjects with affective disorders, the lowest and highest quartiles in the male and female platelet monoamine oxidase (MAO) distribution, respectively, were included. The morbidity risk in the first-degree relatives (parents and siblings) of these low and high platelet MAO subjects was determined. First-degree relatives of low platelet MAO probands were found to have an increased morbidity risk for neurotic-reactive depressions and for alcoholism. The results seem to be in line with the biological high-risk paradigm, indicating that platelet MAO could be a biological marker for increased vulnerability. First-degree relatives of high platelet MAO probands were found to have an increased morbidity risk for bipolar affective disorders.
Key Words. Affective genetics.
disorders,
platelet
monoamine
oxidase,
morbidity
risk,
Studies of morbidity risk among relatives of probands, and a comparison of the results with findings obtained in epidemiological investigations, are among the first steps in the identification of a possible genetic component in the causation of a given disorder. There is now ample evidence in the literature that the morbidity risk for affective disorders is increased among first-degree relatives of probands with affective disorders as compared with the general population (Perris et al., 1982). Thus far, however, family studies have told us little about the nature of the genetic component involved, since attempts to link affective disorders with known genetic markers have not found consistent results. One possible biological marker of interest in this connection is the enzyme monoamine oxidase (MAO, EC 1,4,3,4) in platelets (Buchsbaum et al., 1976; Fowler et al., 1980; Oreland and Shaskan, 1983). Naturally, this enzyme activity must in its turn correlate to some parameter(s) in the central nervous system. Indeed, a correlation seems to exist between platelet MAO activity and some properties of the central serotonin system (Oreland et al., 1981). In patients with affective disorders, contradictory results have been reported as concerns the activity of platelet MAO. In some studies, no differences were found
Lars von Knorring, M.D., is Associate Professor, Carlos Perris, M.D., is Professor, Martin Eisemann, Dr. med. SC., and Sonja Holmgren, Nurse, are Research Associates, and Hjkdis Perris, Dr. med. SC., is Research Psychologist, Department of Psychiatry, Umea University, Umel, Sweden. Lars Oreland, M.D., is Professor, Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden. (Reprint requests to Dr. L. van Knorring, Dept. of Psychiatry, UmeH University, S-901 85 Umei, Sweden.) 0165.1781/85:$03.30
0 1985 Elsevier Science Publishers
B.V
272 between healthy volunteers and subjects with affective disorders (not divided into unipolars and bipolars) (Gershon et al., 1979; Maubach et al., 198 1). In the same way, Edwards et al. (1978) were unable to demonstrate any significant differences in platelet MAO activity between healthy controls or patients with unipolar or bipolar affective disorders. In other studies, however, patients with unipolar affective disorders have been found to have high platelet MAO activity (Nies et al., 1971, 1974; Klaiber et al., 1972; Belmaker et al., 1976; White et al., 1980; Oreland et al., 1981). In another series of studies, patients with affective disorders have been found to have low platelet MAO activity. In these studies, most patients are of the bipolar type (Murphy and Weiss, 1972; Murphy et al., 1974; Landowski et al., 1975; Sullivan et al., 1978; Gershon et al., 1979; Orsulak et al., 1978). In still other studies, patients with affective disorders have as a group been found to have low platelet MAO activity as compared to healthy volunteers (Puzynski et al., 1983; von Knorring et al., 1985~). However, patients with unipolar and bipolar affective disorders did not differ significantly from healthy volunteers. Instead, the low platelet MAO activities were found in patients with undifferentiated affective disorders (Puzynski et al., 1983) or patients with adjustment disorders with depressed mood (von Knorring et al., 1985~). Consistent findings of low platelet MAO activities have, however, been reported in subjects sensitive to external stressors, as well as those with tendencies to alcohol or drug abuse and suicidal behavior. Thus, low platelet MAO activities have been reported in subjects with adjustment disorders with depressed mood (von Knorring et al., 1985a), in alcoholics (Wiberg et al., 1977; Major and Murphy, 1978; von Knorring and Oreland, 1978; Pandey et al., 1980), and in patients with suicidal behavior (Buchsbaum et al., 1977; Gottfries et al., 1980; von Knorring et al., 1985b). Platelet MAO activities seem to be under genetic control (Murphy, 1976; Winter et al., 1978; Pandey et al., 1979; Rice et al., 1982), and in family studies, parents of low MAO probands have been shown to have significantly lower platelet MAO activities than parents of high MAO probands (Puchall et al., 1980). Thus, if low platelet MAO activity is a biological marker of vulnerability, it would appear interesting to investigate the incidence of psychiatric disorders among firstdegree relatives of low MAO probands. An increased incidence has already been demonstrated in some studies. Buchsbaum et al. (1976) reported an eightfold increase in the incidence of suicide and suicide attempts in the relatives of low MAO subjects as compared to the relatives of high MAO subjects. In a 2-year followup (Coursey et al., 1982), the low MAO subjects reported more mental health problems in their families, especially depression, alcoholism, and suicide attempts. In other studies, low platelet MAO activities have been reported in relatives of patients with manic-depressive disorders, especially if the relatives themselves had bipolar I illness or alcoholism (Pandey et al., 1980) and in relatives of alcoholics (Schuckit et al., 1982). However, negative results have also been reported (Goldin et al., 1983). The aim of the present investigation has been to study the morbidity risk for psychiatric disorders in first-degree relatives of probands with affective disorders, divided according to the platelet MAO activity in the proband (high or low). The hypothesis
273 was that the relatives of the low MAO probands would have an increased incidence of psychiatric disorders, especially alcoholism, suicide, and reactive depression. The incidence of unipolar or bipolar affective psychosis, on the other hand, could be higher or similar to that of the relatives of the high MAO probands, depending upon whether or not the vulnerability factor is related to the occurrence of depressive disorders. Methods The Series. Depressed patients of both sexes, in the age range 18-70 years, consecutively admitted to the Department of Psychiatry at the Umea University between 1977 and 1980, were included, independently of any diagnostic subdivision made a priori, in a comprehensive study of depression in its various biological, psychological, and social aspects. All patients were investigated immediately after admission to the ward, and before active pharmacological treatment began. Most of the patients were completelydrugfreeat the time of the investigation, but some had received small and irregular doses of tricyclics and/ or minor tranquilizers during the last weeks preceding admission (corresponding to imipramine < 50 mg/day or diazepam < 10 mg/day). Among the particular studies carried out on this series, t!rere has been a family study (Perris et al., 1982) encompassing, in a first step, all first-degree relatives. On the same series, an assessment of the level of platelet MAO activity has also been made. The somewhat smaller sample size in the current study is due exclusively to occasional technical or administrative factors and is not the result of any systematic selection. The subdivision of subjects into high or low MAO subgroups is still a difficult question. According to Rice et al. (1982), only the upper 5% of the platelet MAO activity distribution should be genetically homogeneous. In most of the studies in which subjects with low platelet MAO activity have been found to have certain personality characteristics or a certain vulnerability, however, low platelet MAO activity has been defined as the lowest IO%, the lowest 25Yc, or the lowest third of the distribution (e.g., Buchsbaum et al., 1976; Coursey et al., 1982; von Knorring et al., 1984). Thus, the best delineation of the low platelet MAO subgroup is still unclear. In the present study, low and high platelet MAO activities have been defined as the lowest and highest quartiles of the male and female distribution, respectively. The lowest quartile of the female subdistribution included 24 subjects with platelet MAO activities ranging from 0.96 to 3.84 nmoles/ lo9 platelets/ minute (mean 2.95, SD 0.82) while the highest quartile included 25 females with platelet MAO activities ranging from 5.72 to 11.98 (mean 6.81, SD 1.48). The lowest quartile in the male subdistribution included 16 subjects with platelet MAO activities ranging from 1.51 to 3.08 (mean 2.52, SD 0.48), while the highest quartile included 16 males with platelet MAO activities ranging from 5.20 to 9.06 (mean 6.40, SD 1.05). The composition of the series as concerns age, age at onset, sex, and diagnostic subdivision is shown in Table 1. The diagnostic criteria are about the same as used in earlier studies (Perris et al., 1982). Unipolar affective disorders. These include patients who have had at least three separate episodes of depressions of a psychotic severity (i.e., with impaired reality testing); or patients who have had at least two episodes of psychotic depressions if the subject is 45 years old or more and if there is a verified family history of recurrem depressive episodes among the first-degree relatives; or patients who have had at least three separate episodes of severe depressions, with melancholic features, occurring apparently independently of stressful life events. In no instances are episodes of mania (hypomania) allowed. Bipolar affective disorders. Patients in this category are those who had been treated for at least one depressive and one manic episode. A hypomanic episode has been considered as an expression of bipolarity when (1) it occurred between episodes of depression and warranted medical care; (2) it occurred at the beginning of an episode that later became depressive; or (3) it occurred at the end of a depressive episode and lasted long enough to warrant a change of treatment from antidepressive to sedative.
274
Table 1. Age, age at onset, sex distribution, and diagnoses in the low and high platelet MAO subgroups, respectively, as well as the number of parents and siblings in the investigated groups Low MAO
High
MAO
(n = 40)
(n = 41)
41.2
47.9
Age1 Mean SD Age
range
(years)
2.3
2.6
23-68
22-69
30.2
34.5
Age at onset2 Mean
1.7
SD Sex (M/F) Depressive
1.9
16/24
16125
13
13
diagnoses
Unipolars Bipolars Neurotic-reactives
5
6
14
11
8
11
Number
of parents
78
79
Number
of siblings
132
173
Unspecified
1. t = 2.21, p < 0.05. 2. t = 1.66. NS.
Neurotic-reactive depressions. This category is defined by depressive episodes in subjects with a verified history of a neurotic personality disorder mainly of a depressive, asthenic, neurasthenic, or passive-dependent type; or depressive episodes occurring as an understandable reaction to the impact of a stressful life event. The disorder must be characterized by a dominant depressive symptomatology that affects the subject’s feeling of well-being and social functioning. The procedure for the assessment of secondary cases has been described in detail elsewhere (Perris et al., 1982). Our approach has been both of the family history type and the family study type, in the sense that information has been primarily obtained from the probands themselves during the longstanding contact with them in connection with the studies mentioned above; the family history has usually been verified by at least one of the proband’s closest relatives. Furthermore, as our Department is the only psychiatric service available in the intake area, and since the population in the region is rather stable, there have been good opportunities to control for possible unreported episodes of psychiatric care in the relatives. The diagnostic assessments of secondary cases for whom medical records were available, (n = 75) have been made independently by two experienced psychiatrists who were not aware of the diagnosis of the proband or the result of the platelet MAO estimation. In the five instances when disagreement among the diagnosticians did occur, the records were discussed at a joint session, still without knowledge of the proband’s diagnosis, until agreement was reached; if disagreement persisted, the case was assigned to the group of unspecified depressive disorders. For the calculation of the percentage morbidity risk (MR%), the population at risk has been corrected by using Weinberg’s abridged method (Weinberg, 1925). For the affective disorders, a risk period between the ages of 15to 70 years was used. For schizophrenia, the risk period of 15 to 50 years was taken into account, whereas for alcoholism all individuals above 15 years were included. Platelet MAO Activity. Samples of blood (5 ml) were drawn into vacutainer tubes containing sodium citrate, and the red cells were allowed to self-sediment. The platelet concentration in the
275 platelet-rich plasma was counted by a Coulter counter and the plasma was frozen at -7O’C. After thawing, the samples were sonicated for I minute and 50 ~1 transferred to test tubes containing 50 ~1 of 0.1 M potassium phosphate buffer, pH 7.8, to which had been added radiolabeled substrate to a final concentration of 50 pCcMand a radioactivity of about 50,000 cpm. Incubation was performed for 10 minutes at 36°C. The reaction was then stopped by addition of 30 /*l of 1 M HCl. The metabolites formed were extracted by short vigorous shaking into 750 ~1 of toluene ethyl acetate 1: 1, saturated with water. After a short centrifugation, 500 ~1 of the organic layer was transferred into 10 ml of scintillation liquid and the radioactivity were obtained from New England estimated. 14C-P-phenylethylamine and ‘%I-tryptamine Nuclear, Boston, MA. All experiments were performed in duplicate and blindly, and the results are expressed as nmoles of substrate metabolized per 109 platelets per minute. This method is a modification of that previously described and discussed (Eckert et al., 1980; Fowler et al., 1980). In line with earlier studies (Fowler et al., 1980), the correlation between the platelet MAO activities obtained by means of the two substrates was high (r = 0.78) and, thus, in the present study, only the MAO distribution obtained with tryptamine as a substrate was taken into account. Statistics. Frequency distributions were tested by means of the x2 test. When fewer than five subjects were included in one cell, Yates correction was made. When one cell did not include any subjects at all, the Fisher exact probability test was used. Differences between means were tested using Student’s t test.
Results The morbidity risks of psychiatric disorders in first-degree relatives (parents and siblings) of low and high platelet MAO probands with affective disorders are presented in Table 2. Significant differences occurred as concerns three diagnoses. First-degree relatives of low platelet MAO probands were found to have a significantly higher morbidity risk for neurotic-reactive depression as well as for alcoholism. By contrast, first-degree relatives of high platelet MAO probands were found to have a significantly higher risk for bipolar affective disorders. Table 2. Morbidity risk for psychiatric disorders in first-degree relatives (parents and siblings) of low and high high MAO probands with affective disorders Low MAO (n = 40)
High MAO (n = 41)
At risk Cases MR%l
At risk Cases MR%l
Unipolars Neurotic-reactive Unspecified
depressions
depression
Statistics2
112.5
8
7.1
137
8
5.8
NS
112.5
8
7.1
137
1
0.7
p < 0.02 NS
112.5
4
3.6
137
9
6.6
Suicides
112.5
2
1.8
137
2
1.5
NS
Bipolars
112.5
-
-
137
6
4.4
p < 0.05
112.5
137
All affective
disorders
22
19.6
26
19.0
Schizophrenia
150
4
2.7
190.5
4
2.1
NS
Alcoholism
201
8
4.0
230
1
0.4
p i 0.05
112.5
2
1 .a
137
8
5.8
NS
112.5
12
10.7
137
22
16.0
NS
Other
diagnoses
Subjective disturbance treatment
NS
without
1. MR% = cases/subjects at risk X 100. 2. See Methods section.
216 The eight cases of alcoholism occurred in eight different families. In five of these cases, the proband had a neurotic-reactive depression; in two cases, the proband had a unipolar affective disorder; and in one case, the proband had an unspecified affective disorder. The eight cases of neurotic-reactive depressions in the first-degree relatives occurred in five different families. In two cases, the proband had a bipolar affective disorder; in one case, the proband had a unipolar disorder; in one case, the proband had a neurotic-reactive depression; and in one case, the proband had an unspecified affective disorder. Otherwise no significant differences occurred between the two groups. The picture was quite consistent also if the male and female probands were considered separately. Relatives of the low MA Omales had a significantly higher risk of alcoholism (6.3% versus O%, Fisher exact probability test,p=0.021) and a tendency toward a higher risk for neurotic-reactive depressions (11.1% versus 1.9%, x2, Yates 2.15, NS). In the first-degree relatives of the high MAO males, there was a tendency toward a higher risk for bipolar affective disorders (5.6% versus O%, Fisher exact probability test,p = 0.158). In the first-degree relatives of low MAOfemales, there were tendencies toward a higher risk for neurotic-reactive depressions (4.4% versus O%, Fisher exact probability test, p 0.089) and alcoholism (2.5% versus 0.7%, x2, Yates 0.45, NS). In the first-degree relatives of high MAOfemales, there was a tendency toward a higher risk for bipolar affective disorders (3.6% versus O%, Fisher exact probability test, p = 0.163). Because the low MAO probands were significantly younger than the high MAO probands, age-matched groups were formed. In this subsample comprising 27 low MAO probands (9 males, 18 females, mean age 44.4 years) and 27 high MAO probands (9 males, 18 females; mean age 44.4 years), the same tendencies occurred (Table 3). First-degree relatives of low platelet MAO probands had a significantly higher morbidity risk for neurotic-reactive depression as well as for alcoholism. As concerns bipolar affective disorders, however, no significantly higher morbidity risk was found in first-degree relatives of high platelet MAO probands. q
q
q
Discussion In the present study, first-degree relatives of low platelet MAO probands with affective disorders have been found to have a significantly higher morbidity risk for neurotic-reactive depressions and for alcoholism. The result is quite consistent in the male and female subsamples and also if an age-matched subsample is formed. The results seem to be in line with earlier studies (Buchsbaum et al., 1976; Coursey et al., 1982). The result is also in line with the hypothesis that platelet MAO may be regarded as a biological marker of increased vulnerability (Buchsbaum et al., 1976; Oreland and Shaskan, 1983). Thus, the increased vulnerability seems to exist both in the probands with low platelet MAO activity and in their relatives. The fact that there are families characterized by an increased risk of neurotic-reactive depressions (most common in females) and of alcoholism (most common in males) seems to be in line with Winokur’s
277 Table 3. Morbidity risk for psychiatric disorders in first-degree relatives (parents and siblings) of low and high high MAO probands with affective disorders: Age- and sex-matched subsample (n = 54) Low MAO (n = 27) At risk Cases Unipolars Neurotic-reactive Unspecified
depressions
depression
Suicides Bipolars
MR%l
High MAO (n = 27) At risk Cases
BAR%1
Statistics2
82.5
5
6.1
76
3
3.9
82.5
a
9.7
76
-
-
NS
82.5
2
2.4
76
5
6.6
NS
82.5
2
2.4
76
1
1.3
NS
p < 0.01
82.5
-
-
76
3
3.9
NS
82.5
17
20.6
76
12
15.8
NS
Schizophrenia
109.5
3
2.7
107
4
3.7
Alcoholism
145
6
4.1
128
-
-
82.5
1
1.2
76
3
3.9
NS
82.5
a
9.7
76
7
9.2
NS
All affective
Other
disorders
diagnoses
Subjective
disturbance
without
treatment 1. MR% 2. See
NS
p < 0.02
= cases/subjects at risk Methods section.
X 100.
(1979) description
of depression spectrum disease. In the present study, there is no evidence of an increased suicide rate in the first-degree relatives of probands with low platelet MAO activity. However, the sample size is small, comprising only four suicides in the relatives. In earlier studies (Gottfries et al., 1980; van Knorring et al., 1985b), we have found low platelet MAO activities in probands who had attempted suicide by active methods but normal platelet MAO activities in subjects who had attempted suicide by passive methods. The present sample size does not permit such a subdivision. There is a large literature indicating increased vulnerability and an increased incidence of psychiatric disorders in subjects with low platelet MAO activity and in their relatives, but less has been written about subjects with high platelet MAO activites. However, Puchall et al. (1980) demonstrated an increased incidence of what they called high-MAO-related disorders (major or minor depression and depressive personality) in relatives of high MAO subjects. In the present study, there is an increased morbidity risk of bipolar affective disorders in the first-degree relatives of probands with high platelet MAO. As concerns probands with unipolar or bipolar affective disorders, the overall picture is confusing and high, normal, and low platelet MAO activities have been reported. In our own studies, we tend to find normal (von Knorring et al., 1985~) or high (Oreland et al., 1981) platelet MAO activities in probands with bipolar affective disorders. The present finding of an increased morbidity risk for bipolar affective disorders in the first-degree relatives of high platelet MAO probands seems to be in line with the hypothesis that if there is a relationship between bipolar affective disorders and MAO activity, the relationship is to high levels. However, this hypothesis should be tested in a larger family study of patients with clear bipolar affective disorders. Acknowledgment. The research reported was supported, in part, by grants from the Swedish Medical Research Council (Grant Nos. 4145, 5244, 5740).
278 References Belmaker, R.H., Ebbesen, K., Ebstein, R., and Rimon, R. Platelet monoamine oxidase in schizophrenia and manic-depressive illness. British Journal of Psychiatry, 129, 227 (1976). Buchsbaum, M.S., Coursey, R.D., and Murphy, D.L. The biological high-risk paradigm: Behavioral and familial correlates of low platelet monoamine oxidase activity. Science, 194,339 (1976). Buchsbaum, M.S., Haier, R., and Murphy, D.L. Suicide attempts, platelet monoamine oxidase, and the averaged evoked response. Acta Psychiatrica Scandinavica, 56,69 (1977). Coursey, R.D., Buchsbaum, M.S., and Murphy, D.L. Two-year followup of subjects and their families defined as at risk for psychopathology on the basis of platelet MAO activities. Neuropsychobiology. 8, 5 1 (1982). Eckert, B., Gottfries, C.-G., von Knorring, L., Wiberg, A., and Winblad, B. Brainand platelet monoamine oxidase activity in mental disorders: I. Schizophrenics and cycloid psychotics. Progress
in Neuro-Psychopharmacology,
4, 57 (1980).
Edwards, D.J., Spiker, D.G., Kupfer, D.J., Foster, G., Neil, J.F., and Abrams, L. Platelet monoamine oxidase in affective disorders. Archives of General Psychiatry, 35, 1443 (1978). Fowler, C.J., von Knorring, L.. and Oreland, L. Platelet monoamine oxidase activity in sensation seekers. Psychiatry Research, 3, 273 (1980). Gershon, E.S., Targum, S.D., and Leckman, J.F. Platelet monoamine oxidase (MAO) activity and genetic vulnerability to bipolar (BP) affective illness. Psychopharmacology Bulletin, 15, 27 (1979). Goldin, L.R., Gershon, E.S., Targum, S.D., Sparks, R.S., and McGinnis, M. Segregation and linkage analysis of patients with bipolar, unipolar, and schizo-affective mood disorders. American
Journal
of Human
Genetics,
35,274
(1983).
Gottfries, C.-G., von Knorring, L., and Oreland, L. Platelet patients with suicidal behavior and in subgroups of affective Psychopharmacology,
4, 185 (1980).
Klaiber, E.L., Broverman, estrogen therapy on plasma American
Journal
von Knorring, oxidase activity Progress
monoamine oxidase activity in psychoses. Progress in Neuro-
D.M., Vogel, W., Kobayashi, Y., and Moriarty, D. Effects of MAO activity and EEG driving response in depressed women.
of Psychiatry,
128, 1492 (1972).
L., and Oreland, L. Visual averaged evoked responses and platelet monoamine as an aid to identify a risk group for alcoholic abuse: A preliminary report.
in New-o-Psychopharmacology,
2, 385 (1978).
von Knorring, L., Oreland, L., and Winblad, B. Personality traits related to monoamine oxidase (MAO) activity in platelets. Psychiatry Research, 12, 11 (1984). von Knorring, L., Perris, C., Oreland, L., Eisemann, M., and Perris, H. Platelet MAO activity in affective disorders. Relationship to diagnostic subgroup. Unpublished manuscript (1985~). von Knorring, L., Perris, C., Oreland, L., Eisemann, M., and Perris, H. Platelet MAO activity in affective disorders. Relationship to suicidal behavior. Unpublished manuscript (19856). Landowski, J., Lysiak. W., and Angielski, S. Monoamine oxidase activity in blood platelets from patients with cyclophrenic depressive syndromes. Biochemical Medicine, 14,347 (1975). Major, L.F., and Murphy, D.L. Platelet and plasma amine oxidase activity in alcoholic individuals. British Journal of Psychiatry. 132, 548 (1978). Maubach, M., Diebold, K., Fried], W., and Pr9opping, P. Platelet MAO activity in patients with affective psychoses and their first degree relatives. Pharmacopsychiatry, 14, 87 (1981). Murphy, D.L. Clinical, genetic, hormonal, and drug influences on the activity of human platelet monoamine oxidase. In: Wolstenholme, G.E.W., and Knight, J., eds. Monoamine Oxidase and Its Inhibition. Elsevier/ Excerpta Medics/North-Holland, Amsterdam, p. 341 (1976). Murphy, D.L., Belmaker, R., and Wyatt, R.J. MAO in schizophrenia and other behavioral disorders. Journal of Psychiatric Research, 11, 22 1 ( 1974).
279
Murphy, D.L., and Weiss, R. Reduced monoamine oxidase in blood platelets from bipolar depressed patients. American Journal of Psychiarry, 128, 1351 (1972). Nies, A., Robinson, D.S., Harris, L.S., and Lamborn, K.R. Comparison of monoamine oxidase substrate activities in twins, schizophrenics, depressives and controls. Advnnces in Biochemical
Psychopharmacology,
12, 59 (1974).
Nies, A., Robinson, D.S., Ravaris, C.L., and David, J.M. Amines and monoamine oxidase in relation to aging and depression in man. Psychosomatic Medicine, 33, 470 (1971). Oreland, L., and Shaskan, E.G. Monoamine oxidase activity as a biological marker. Trends in Pharmacological Sciences, August, p. 339 (1983). Oreland, L., Wiberg, A., Asberg, M., Traskman, L., Sjostrand, L., Thoren, P., Bertilsson, L., and Tybring, G. Platelet MAO activity and monoamine metabolites in cerebrospinal fluid in depressed and suicidal patients and in healthy controls. Psychiatry Research, 4, 2 1 (198 1). Orsulak, P.J., Schildkraut, J.J., Schatzberg, A.F., Cole, J., Gudeman, J., and Rohde, W. Differences in platelet monoamine oxidase activity in subgroups of schizophrenic and depressive disorders. Biological Psychiatry, 13, 637 (1978). Pandey, G.N., Dorus, E., Shaughnessy, R., and Davis, J.M. Genetic control of platelet monoamine oxidase activity: Studies of normal families. Life Sciences, 25, 1173 (1979). Pandey, G.N., Dorus, E., Shaughnessy, R., Gaviria, M., Val, E., and Davis, J.M. Reduced platelet MAO activity and vulnerability to psychiatric disorders. Psychiatry Research, 2, 3 15 (1980).
Perris, C., Perris, H., Ericsson, U., and von Knorring, L. The genetics of depression: A family study of unipolar and neurotic-reactive depressed patients. Archiv f;r Psychiatric und Nervenkrankheiten.
232,
137 (1982).
Puchall, L.B., Coursey, R.D., Buchsbaum, M.S., and Murphy, D.L. Parents of high-risk subjects defined by levels of monoamine oxidase activity. Schizophrenia Bulletin, 6,338 (1980). Puzynski, S., Hauptmann, M., and Zaluska, M. Studies on biogenic amine metabolizing enzymes (DBH, COMT, MAO) and pathogenesis of affective illness: III. Platelet monoamine oxidase activity in endogenous depression. ACM Psychiatrica Scandinavica, 67, 10 I (I 983). Rice, J., McGuffin, P., Goldin, L.R., Shaskan, E.G., and Gershon, E.S. Platelet monoamine oxidase activity: Evidence for a single major locus. Psychiatry Research, 7, 325 (1982). Schuckit, M.A., Shaskan, E., Duby, J., Vega, R., and Moss, M. Platelet monoamine oxidase activity in relatives of alcoholics. Archives of General Psychiatry, 39, 137 (1982). Sullivan, J.L., Stanfield, C.N., Maltbie, A.A., Hammet, E., and Cavenar, J.O. Stability of low blood platelet monoamine oxidase activity in human alcoholics. Biological Psychiatry, 13, 391 (1978).
Weinberg, W. Methoden und technik der statistik mit besonderer berucksichtigung der sozialbiologie. In: Gottstein, A., ed. Handbuch der sozialen Hygiene und Gesundheitsfursorge. Springer, Berlin (1925). White, K., Shih, J., Fong, T., Young, H., Gelfand, R., Boyd, J., Simpson, G., and Sloane, B. Elevated plasma monoamine oxidase activity in patients with non-endogenous depression. American
Journal
of Psychiatry,
137,
1258 (1980).
Wiberg, A, Gottfries, C.-G., and Oreland, L. Low platelet monoamine oxidase activity in human alcoholics. Medical Biology, 55, 18 1 (1977). Winokur, G. Familial (genetic) subtypes of pure depressive disease. American Journal of Psychiatry.
136, 9
1I ( 1979).
Winter, H., Herschel, M., Propping, P., Friedl. enzymes (DBH, COMT, MAO) of catecholamine Psychopharmacology,
57,63
(1978).
W., and Vogel, F. A twin study on three metabolism: Correlations with MMPI.