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Life events and biological vulnerability: A study of life events and platelet MAO activity in depressed patients
Psychiatry Research, 12, Ill- 120
111
Elsevier
Life Events and Biological Events and Platelet MAO Hjkdis
Perris, Lars von Knorring,
Received May 25,1983; revisedversion
Vulnerability: A Study of Life Activity in Depressed Patients Lars Oreland, and Carlo Perris
received October 14.1983; accepted December31.1983.
Abstract. The present study investigated the possible relationship between platelet monoamine oxidase (MAO) activity and life events. From the general hypothesis that the impact of life events should be seen against the background of an individual’s vulnerability, it was assumed that low platelet MAO patients would need fewer life events to develop a psychopathological condition and that they would experience more negatively those events that occurred. Patients (n q 127) of both sexes suffering from various kinds of depressive disorders participated in the study. There were 39 unipolar patients, I1 bipolar patients, 43 patients suffering from neurotic-reactive disorder, and 34 patients suffering from an unspecified depressive disorder. No statistically significant differences in MAO activity were found in this series among the diagnostic subgroups. Younger patients predominated among those with the lowest MAO values. As expected, low MAO patients reported a lower number of life events than patients in the highest MAO quartile, and had experienced those events more negatively. Key Words. Monoamine
oxidase,
depressive
disorder,
vulnerability,
life events.
Over the last few decades evidence linking psychopathological disorders and central monoamine systems has accumulated. As a result, attention has also come to be focused on enzymes that are important for the synthesis and metabolism of biogenic amines. Among these enzymes, monoamine oxidase (MAO: EC1.4.3.4.) is one of the most thoroughly investigated in relation to various psychopathological conditions. MAO is present in most tissues in the organism but has, in relation to clinical conditions, mostly been studied in platelets, in which the enzyme exists in a single catalytic form (Fowler et al., 1979). Implicit in the studies of platelet MAO has been the assumption that the activity of this enzyme somehow reflects central monoaminergic activity. Considerable support for this assumption has come from the demonstration of a significant correlation with levels of 5hydroxyindoleacetic acid (SHIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) in healthy control subjects (Oreland et al., 1981~). The hypothesis has been advanced that platelet MAO and brain serotonergic capacity are controlled by the same (genetic?) factors (Oreland et al., 1981b; Oreland and Fowler, 1982; Oreland and Shaskan, 1983). The most consistent link, so far, between the psyche and platelet MAO activity has been found in studies of personality. Several studies have shown a correlation between low platelet MAO activity and sensation seeking behavior in healthy subjects (Fowleret al., 1982).
Hjordis Perris, Dr. med. SC., is Carlo Perris, M.D., is Professor Sweden. Lars Oreland, M.D., Gothenburg. Sweden. (Reprint 01651781/84/$03.00
Research Psychologist; Lars von Knorring, M.D., is Associate Professor; and Head, Department of Psychiatry, Ume& University, S-901 85 Umei, is Professor, Department of Pharmacology, University of Gothenburg, requests to Dr. H. Perris.)
o 1984 Elsevier Science Publishers
B.V.
112 With regard to affective disorders. low piatelet MAO activity has been reported to occur in bipolar depressive patients (Murphy and Weiss, 1972; Landowski et al., 1975; Leckman et al., 1977; Wyatt et al., 1979). In other studies, however, higher levels of platelet MAO activity have been found in bipolar depressives (Dunner et al., 1971; Nies et al., 1974). In unipolar depressives platelet MAO activity has been reported to be unchanged (Murphy and Weiss, 1972; Coperet al., 1979) or high (Landowski et al., 1975; Mann, 1979; Reveleyet al., 1981). No difference between unipolars and bipolars was found by Gottfries et al. (1980). Suicidal behavior has repeatedly been connected to low platelet MAO activity (Buchsbaum et al., 1977a, 19776; Gottfries et al., 1980). Schizoaffective psychosis has been associated with both extremes of the platelet MAO distribution. Schildkraut et al. (1978) found platelet MAO activity to be highly significantly elevated in “schizophrenia-related” depression but found no differences between 13 unipolar endogenous depressives and controls. On the other hand, Eckert et al. (1980) reported low platelet MAO activity in cycloid psychosis. Finally, several studies have linked chronic alcoholism with low platelet MAO activity (Wiberg et al., 1977; Major and Murphy, 1978; Sullivan et al., 1978; Agarwal et al., 1979). Since MAO activity has been shown to be largely under genetic control (Nies et al., 1973; Murphy, 1973; Winter et al., 1978; Pandey et al., 1979), and since it is a relatively stable characteristic of individuals (Murphy and Wyatt, 1975), low platelet MAO activity seems to represent a genetic vulnerability factor associated with psychopathology in general rather than being characteristic of a single psychopathological disorder (for review, see Haier et al., 1980). In recent years, great interest has also been paid to the occurrence of stressful life events before the onset of psychopathology or at least before hospital admission (for reviews, see Dohrenwend and Dohrenwend, 1976; Barrett, 1979; Perris, 1980). No clear-cut relationships have emerged linking life events to any particular mental disorder. In fact, an increased frequency of stressful events has been found in almost every kind of psychiatric illness, and in connection with the onset of several somatic disorders as well. The theoretical formulations behind studies of life events in psychiatric populations have seldom been stated. Among the exceptions are the investigations by Brown et al. (1975, 1977), who made an attempt to link later life events with unfavorable conditions during childhood, and maintained that such a combination represented a set of factors that would predispose a person to depression. Beck (1967), Paykkl(1978, 1979) and Barrett (I 979) have also suggested that the importance of life events for the occurrence of depression should be considered against the background of individual vulnerability. In the course of a comprehensive investigation concerned with life events and depressive disorders, we decided (Perris, in press) to approach the problem from a multifactorial point of view because we assumed that biological, psychological, and social variables might increase a subject’s vulnerability to life events. Our starting point in this approach is to be found in Freud’s (1920) concept of “Erganzungsreihe.” According to this concept, the more vulnerable an individual is, the less severe are the external events needed to precipitate a mental breakdown. Because the platelet MAO activity seems to represent a vulnerability factor contributing to the development of
113 psychopathology, it appeared possible that there might be some relationship between platelet MAO activity and life events in psychiatric patients. In particular it was assumed that in a population of depressed patients, the lower the platelet MAO activity, the fewer stressful life events would be found. It was also assumed that subjects with low MAO activity would experience life events more negatively than patients with medium or high levels of platelet MAO activity. Methods Patients. Depressed patients (age range 18-65 years) consecutively admitted to the Department of Psychiatry, Umed University, participate, if they agree, in a comprehensive research project concerned with various clinical, social, biological, and psychological aspects of depression. For the purpose of the present investigation, the first 127 patients who entered the study have been considered. Diagnostic Classification. Subtype diagnoses were made by two independent and experienced psychiatrists (L. von Knorring and C. Perris) according to criteria described elsewhere (Perris, 1973; d’Elia et al., 1974). In brief, a bipolar patient must have experienced at least one episode of depression and one of mania. A unipolar diagnosis requires at least three separate episodes of depression. Reactive-neurotic depression describes a depressive disorder that occurred in close proximity to a psychologically understandable traumatic event in a subject with a neurotic personality development. Unspecifieddepressive disorders are those that do not meet criteria for inclusion in the other subgroups. The patients have also been diagnosed according to the criteria of Feighner et al. (1972) the ICD-9 of the World Health Organization (1978) and DSM-fII(American Psychiatric Association, 1980). (See Tables I and 2 for further information concerning the sample.)
Table 1. Distribution
of the series by sex and age Age group (years)
Sex
~2 =
21-30
31-40
41-50
51-60
61-
Total
7
20
6
50
Male
11
6
Female
14
16
16
20
9
77
Total
25
22
25
40
15
127
4.28,
df = 4. NS.
of Life Events. Life events that had occurred within the last year and within 3 months proceding the onset of the depressive disorder were assessed (by H. Perris) using a specially constructed life events inventory. Details about the inventory and its administration have been given elsewhere (Perris, in press). In brief, the inventory investigates the occurrence of 56 events similar to those contained in other life events inventories. The inventory also assesses how the subject reacted to the event (using a 5-point scale in which I = very positively and 5 = most negatively), whether the event was expected, whether the event was controllable by the subject, and how the subject adjusted to the event. As in previous studies (von Knorring et al., 1980; Perris, in press), the inventory was used as a guide for a semistructured interview that took place when the patient had clearly improved from the depressive condition. Assessment
114
In the analyses the events comprised in the inventory have also been grouped into different categories (“negative,” “positive,” “ambivalent, ““entrance” into and “exit” from the social field, and “object loss”) as described in detail in a previous article “controllable, ” “uncontrollable,” (Perris, in press). These groupings correspond to a large extent to similar groupings used by other authors (Myers et al., 1972; Brown, 1974; Paykel, 1974) in studies of life events and depression.
Table 2. Dlstrlbution
UmeH clarslflcatlon
of the series based on different classification
systems
Feighner criteria1 Primary Secondary Deflnlte
Probable
Definite
Probable
Not depressed
Unipolar
26
7
-
-
-
Bipolar Unspecified RND
7 0 14
1 6 11
6 1
1 1
3 15 16
UmeP clasrlflcatlon Unipolar Bipolar Unspecified RND
Umel clarslflcatlon
ED-9 classlflcatlon 296.1 296.3-5 32 2 1
296.6-9
296.0
300.4
309-l
9
1 -
5 -
-
-
-
9 2
6 30
6
1 3
DSM-III clarrlflcatlon 296.2 296.3
296.5
296.6
309.4
309.0
Unipolar Bipolar Unspecified
2 4
33 12
7 1
4 1 2
2
-
RND
6
16
-
7
4
7
1. Only 119 subjects
of Platelet MAO Activity. Platelet MAO activity was assessed without knowledge of either the diagnostic classification of the patients or the results of the study of life events. After the patients’ hospital admission, blood samples (4.5 ml) were drawn from the patients into siliconized Vacutainer @ tubes containing 0.5 ml of 3.1% sodium citrate solution (Becton-Dickinson, Grenoble, France). About I ml of platelet-rich plasma (PRP). obtained by sedimentation of the erythrocytes for 2-4 hours at room temperature, was transferred to a siliconized test tube with a siliconized pipet. A platelet count was then made using an electronic counter (Coulter Counter, Dunstable. England) and the PRP was then stored at -70°C. When all the samples in the series had been collected, estimation of MAO activity was carried out after thawing and subsequent low energy sonication for 60 seconds at 4’C. All samples were analyzed twice at the same time using ( t4C) /?-phenylethylamine (PEA) and ( r4C) tryptamine as substrates (for details, see Eckert et al., 1980). The activity is expressed as nmoles x 10m9of substrate oxidized/platelet/ minute. Since in the present series. as in several previous studies, the results obtained with the two substrates proved to be highly correlated (r = 0.87). only those obtained with tryptamine are used here. Determination
Statistical Analysis. The distribution of MAO series, by sex, and by subtype diagnosis. Possible have been assessed both by calculating the mean groups and as a product-moment correlation. For
activity has been investigated in the whole relationships between MAO activity and age values for MAO activity in the different age the analysis of possible relationships between
115 platelet MAO activity and life events, the MAO activity has been divided into quartiles and the distribution of the life events compared for the lowest, the highest, and the two central quartiles. The mean number of life events has been calculated for periods of 3 months, 4-12 months, and the whole year before the onset of the depressive episode. Frequencies of all the events and of the events grouped in different ways were also calculated in relation to subdivisions of the patients based on MAO activity. Intergroup differences were tested by analysis of variance (for means), and by x2 test (for frequencies). Possible correlations between the scaled experience of life events and MAO activity were also investigated. All statistical analyses were carried out at the UmeSi Computer Center (UMDAC) using standard programs in the SPSS. The 5% level was accepted as the level of significance in a difference or in a correlation.
Results Distribution of MAO Activity. Females showed nonsignificantly higher MAO activity than male patients (female: 0.12, SD 0.06; male: 0.14, SD 0.06). Patients in the oldest age groups showed slightly higher mean MAO values; the correlation coefficient with age was low (r= 0.22). No significant differences in MAO activity were found among the diagnostic subgroups (Table 3). However, the number of individuals is low, especially for some subgroups, and the results need reanalysis in our large series. The reanalysis will also include a comparison with healthy subjects (von Knorring et al., 1984).
Table 3. Distribution of MAO activity diagnostic subgroups
in the
MAO activity Dlaanostic
wow
Mean
SD
39
0.21
0.08
Bipolar
11
0.24
0.08
Unspecified
34
0.23
0.09
Neurotic-reactive
43
0.21
0.08
Unipolar
f = 0.76, df = 3. 123, NS
Platelet MAO Activity and Life Events. The distribution of the series subdivided into quartiles of MAO activity did not show any significant sex or diagnostic subgroup differences. However, a significant difference emerged when age was investigated. The youngest patients (21-30 years) appeared to be overrepresented in the lowest MAO quartile (Table 4). Table 4. Distribution of the series according to MAO activity (quartiles) in relation to age groups MAO auartlle
Age groups 21-30
31-40
41-50
51-60
61-
Lowest quartile
13
3
4
10
1
Middle quartiles
7
14
14
20
7
Highest quartile
6
5
7
9
6
116 As hypothesized, patients in the highest MAO quartile experienced more events @ < 0.05) in the period 4 months to 1 year before the onset of depression, and also significantly more events classified as “exit from the social field” (Tables 5 and 6). Table 5. Distribution of total number of events reported in the period 4 months to 1 year before depression onset in patients subdivided according to levels of MAO activity No. of patients in the MAO subgroups No. of events
Lowest quartile
0
Middle half
Highest quartile
2
10
1
l-2
12
19
11
3-4
14
14
11
3
19
10
>!i
Table 6. Number of patients with “exit” events 4-12 months before depression onset MAO No. of “exit” events
Lowest quartile
Middle half
Highest quartile
0
23
44
20
1
3
15
13
2
5
3
1
X2 = 10.2.
df = 4, p < 0.05
Also, in line with our hypothesis, significantly more of the patients in the lowest MAO quartile scored their experience of the event as “negative” or “very negative”(Table 7). On the other hand, no difference in the total number of events was found between patients in the lowest and the highest MAO groups when events occurring during the 3 months preceding the onset of depression were considered. Table 7. Distribution of patients in relation to the experience life events as “negative” or “very negative” Lowest MAO quartile No.
event experienced
“negative” One or
more
events
as “negative” X2 = 4.10
iYates).
Middle and highest MAO quartiles
as
or “very negative”
1
13
32
81
experienced
or “very negative” df = 1. p < 0.05.
of
117 When a categorization of events was taken into account, patients in the lowest MAO quartile, apparently in contrast with our hypothesis, reported significantly more events classified as “entrance into the social field” (p < O.OS), and significantly more events classified as “controllable” @ < 0.001) and as reflecting a “conflict” (p < 0.001). However, since patients in the lowest MAO quartile were significantly younger than the others, and since younger patients had previously been found to report more events than older patients (Perris, in press), separate calculations for patients grouped in different age groups were also made. When age was corrected for, the differences in number of reported events in the 3 months preceding the depressive episode no longer appeared to be significant.
Discussion The results of the present study supported our hypothesis that low platelet MAO activity probands would have experienced a lower number of stressful life events before becoming depressed than those with higher levels of MAO activity and, moreover, experienced them more negatively. Thus, patients in the middle half and in the highest MAO quartile reported-at least for the period 4 months to 1 year before the onset of depression-more events in total than patients in the lowest quartile. Furthermore, patients in the lowest MAO quartile reported a significantly more negative experience of the events. No difference in number of events was found between probands in the lowest and in the highest quartile in the 3-month period immediately preceding the onset of depression. An analysis of the type of events reported by the patients in the different MAO groups showed that the younger patients in the lowest quartile had experienced more events classified as “controllable, ” “entrance into the social field,” and “conflict” than the patients in the other groups. In contrast, the older patients in the highest MAO quartile had experienced more events classified as “exit from the social field.” Thus, it seems that low MAO patients more negatively evaluate events which might be less severe than those experienced by patients in the highest quartile. Such an interpretation applies at least to the difference between “entrance” into and “exit” from the social field. In a previous study (Perris, in press) younger patients reported significantly more events than older ones. In this study younger patients were overrepresented in the low MAO group, but nevertheless patients in the low MAO group reported fewer events than patients in the highest MAO group. The fact that the difference in total number of events applies only to the period 4 months to 1 year before the onset of depression and not to the 3-month period preceding the onset of depression might reflect the patients’ difficulty in correctly determining the onset of depression, despite every effort made to assess it at the time of the interviews. Obviously, the results reported here should be regarded cautiously because of the small number of patients in our series, and because of the well-known uncertainties of retrospective evaluations of events. However, our results do seem to suggest a relationship between level of platelet MAO activity and tolerance level for
118
stressful life events in individuals most likely explanation for such activity is a biological marker for already predisposed to depressive
who ultimately become depressed. At present, the a relationship seems to be that low platelet MAO personality characteristics that make an individual disorders more vulnerable to stressful events.
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Gottfries, C.-G., von Knorring, L., and Oreland, L. Platelet monoamine oxidase activity in mental disorders: 2. Affective psychoses and suicidal behaviour. Progress in Neuro-Psychopharmacology, 4, 185 (1980). Haier, R.J., Buchsbaum, M.S., Murphy, D.L., Gottesman, I.I., and Coursey, R.D. Psychiatric vulnerability, monoamine oxidase and the averaged evoked potential. Archives of General Psychiatry, 37, 340 (1980). von Knorring, L., Jacobsson, L., Perris, C., and Perris, H. Reactivity to incoming stimuli and the experience of life events. Nemopsychobiology, 6,297 (1980). von Knorring, L., Perris, C., Oreland, L., Eisemann, M., and Perris, H. Platelet MAO activity in affective disorders: Relationship to diagnostic groups. Submitted for publication (1984). Landowski, J., Lysiak, W., and Angielski, S. Monoamine oxidase activity in blood platelets from patients with cyclophrenic depressive syndromes. Biochemical Medicine, 14,347 (1975). Leckman, J.F., Gershon, E.S., Nichols, A.S., and Murphy, D.L. Reduced MAO activity in first degree relatives of individuals with bipolar affective disorders. Archives of General Psychiatry, 34,601 (1977). Major, L. F., and Murphy, D.L. Platelet and plasma monoamine oxidase activity in alcoholic individuals. British Journal of Psychiatry, 132, 548 (1978). Mann, J. Altered platelet monoamine oxidase activity in affective disorders. Psychological Medicine, 9, 792 (1979). Murphy, D.L. Technical strategies for the study of catecholamines in man. In: Usdin, E., and Snyder, S., eds. Frontiers in Catecholamine Research. Pergamon Press, Oxford, p. 1077 (1973). Murphy, D.L., and Weiss, R. Reduced monoamine oxidase activity in blood platelets from bipolar depressed patients. American Journal of Psychiafry. 128. 1351 (1972). Murphy, D.L., and Wyatt, R.J. Enzyme studies in the major psychiatric disorders: 1. In: Freedman, D.X., ed. The Biology of the Major Psychoses: A Comparative Analysis. Raven Press, New York, p. 277 (1975). Myers, J.K., Lindenthal, J.J., Pepper, M.P., and Ostrander, D.K. Life events and mental status: A longitudinal study. Journal of Health and Social Behaviour, 13,398 (1972). Nies, A., Robinson, D.S., Harris, L.S., and Lamborn, K.R. Comparison of monoamine oxidase substrate activity in twins, schizophrenics, depressives and controls. In: Usdin, E., ed. Neuropsychopharmacology of Monoamines and Their Regulatory Enzymes. Raven Press, New York (1974). Nies, A., Robinson, D.S., Lamborn, K.R., and Lampert, R.P. Geneticcontrol ofplatelet and plasma monoamine oxidase activity. Archives of General Psychiatry, 28, 834 (1973). Oreland, L., and Fowler, C.J. Brain and platelet MAO activities in relation to central monoaminergic activity in mice and men. In: Kamijo, K., Usdin, E., and Nagatsu, T., eds. Monoamine Oxidase: Basic and Clinical Frontiers. Excerpta Medica, Amsterdam, p. 312 (1982). Oreland, L., and Shaskan, E.G. Monoamine oxidase activity as a biological marker. Trends in Pharmacological Science. August, p. 339 (1983). Oreland, L., Wiberg, A., Asberg, M., Trlskman, L., Sjostrand, L.,Thortn, P., Bertilsson, L., and Tybring, Cl. Platelet MAO activity and monoamine metabolites in cerebrospinal fluid in depressed and suicidal patients and in healthy controls. Psychiarry Resenrch, 4,21 (19810). Oreland, L., Wiberg, A. Asberg., and Fowler, C.J. Monoamine oxidase activity in platelets as related to monoamine oxidase activity and monoaminergic function in the brain. In: Angrist, B., Burrows, G.D., Lader, M., Lingjaerde, O., Sedvall, G., and Wheatley, D., eds. Recent Advances in Neuropsychopharmacology: Advances in the Biosciences. Vol. 3 1. Pergamon Press, Oxford, p. 195 (1981b). Pandey, G.N., Dorus, E., Shaughnessy, R., Gaviria, M., Val, E., and Davis, J. Reduced platelet MAO activity and vulnerability to psychiatric disorder. Psychiatry Research, 2, 315 (1979).
120 Paykel, E.S. Life stress and psychiatric disorder: Application of the clinical approach. In: Dohrenwend, B.S., and Dohrenwend, B.P.. eds. Stressful Life Events: Their Nature and Effects. John Wiley & Sons, New York, p. 217 (1974). Paykel, E.S. Contribution of life events to causation of psychiatric illness. Psychological Medicine,
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111
Elsevier
Life Events and Biological Events and Platelet MAO Hjkdis
Perris, Lars von Knorring,
Received May 25,1983; revisedversion
Vulnerability: A Study of Life Activity in Depressed Patients Lars Oreland, and Carlo Perris
received October 14.1983; accepted December31.1983.
Abstract. The present study investigated the possible relationship between platelet monoamine oxidase (MAO) activity and life events. From the general hypothesis that the impact of life events should be seen against the background of an individual’s vulnerability, it was assumed that low platelet MAO patients would need fewer life events to develop a psychopathological condition and that they would experience more negatively those events that occurred. Patients (n q 127) of both sexes suffering from various kinds of depressive disorders participated in the study. There were 39 unipolar patients, I1 bipolar patients, 43 patients suffering from neurotic-reactive disorder, and 34 patients suffering from an unspecified depressive disorder. No statistically significant differences in MAO activity were found in this series among the diagnostic subgroups. Younger patients predominated among those with the lowest MAO values. As expected, low MAO patients reported a lower number of life events than patients in the highest MAO quartile, and had experienced those events more negatively. Key Words. Monoamine
oxidase,
depressive
disorder,
vulnerability,
life events.
Over the last few decades evidence linking psychopathological disorders and central monoamine systems has accumulated. As a result, attention has also come to be focused on enzymes that are important for the synthesis and metabolism of biogenic amines. Among these enzymes, monoamine oxidase (MAO: EC1.4.3.4.) is one of the most thoroughly investigated in relation to various psychopathological conditions. MAO is present in most tissues in the organism but has, in relation to clinical conditions, mostly been studied in platelets, in which the enzyme exists in a single catalytic form (Fowler et al., 1979). Implicit in the studies of platelet MAO has been the assumption that the activity of this enzyme somehow reflects central monoaminergic activity. Considerable support for this assumption has come from the demonstration of a significant correlation with levels of 5hydroxyindoleacetic acid (SHIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) in healthy control subjects (Oreland et al., 1981~). The hypothesis has been advanced that platelet MAO and brain serotonergic capacity are controlled by the same (genetic?) factors (Oreland et al., 1981b; Oreland and Fowler, 1982; Oreland and Shaskan, 1983). The most consistent link, so far, between the psyche and platelet MAO activity has been found in studies of personality. Several studies have shown a correlation between low platelet MAO activity and sensation seeking behavior in healthy subjects (Fowleret al., 1982).
Hjordis Perris, Dr. med. SC., is Carlo Perris, M.D., is Professor Sweden. Lars Oreland, M.D., Gothenburg. Sweden. (Reprint 01651781/84/$03.00
Research Psychologist; Lars von Knorring, M.D., is Associate Professor; and Head, Department of Psychiatry, Ume& University, S-901 85 Umei, is Professor, Department of Pharmacology, University of Gothenburg, requests to Dr. H. Perris.)
o 1984 Elsevier Science Publishers
B.V.
112 With regard to affective disorders. low piatelet MAO activity has been reported to occur in bipolar depressive patients (Murphy and Weiss, 1972; Landowski et al., 1975; Leckman et al., 1977; Wyatt et al., 1979). In other studies, however, higher levels of platelet MAO activity have been found in bipolar depressives (Dunner et al., 1971; Nies et al., 1974). In unipolar depressives platelet MAO activity has been reported to be unchanged (Murphy and Weiss, 1972; Coperet al., 1979) or high (Landowski et al., 1975; Mann, 1979; Reveleyet al., 1981). No difference between unipolars and bipolars was found by Gottfries et al. (1980). Suicidal behavior has repeatedly been connected to low platelet MAO activity (Buchsbaum et al., 1977a, 19776; Gottfries et al., 1980). Schizoaffective psychosis has been associated with both extremes of the platelet MAO distribution. Schildkraut et al. (1978) found platelet MAO activity to be highly significantly elevated in “schizophrenia-related” depression but found no differences between 13 unipolar endogenous depressives and controls. On the other hand, Eckert et al. (1980) reported low platelet MAO activity in cycloid psychosis. Finally, several studies have linked chronic alcoholism with low platelet MAO activity (Wiberg et al., 1977; Major and Murphy, 1978; Sullivan et al., 1978; Agarwal et al., 1979). Since MAO activity has been shown to be largely under genetic control (Nies et al., 1973; Murphy, 1973; Winter et al., 1978; Pandey et al., 1979), and since it is a relatively stable characteristic of individuals (Murphy and Wyatt, 1975), low platelet MAO activity seems to represent a genetic vulnerability factor associated with psychopathology in general rather than being characteristic of a single psychopathological disorder (for review, see Haier et al., 1980). In recent years, great interest has also been paid to the occurrence of stressful life events before the onset of psychopathology or at least before hospital admission (for reviews, see Dohrenwend and Dohrenwend, 1976; Barrett, 1979; Perris, 1980). No clear-cut relationships have emerged linking life events to any particular mental disorder. In fact, an increased frequency of stressful events has been found in almost every kind of psychiatric illness, and in connection with the onset of several somatic disorders as well. The theoretical formulations behind studies of life events in psychiatric populations have seldom been stated. Among the exceptions are the investigations by Brown et al. (1975, 1977), who made an attempt to link later life events with unfavorable conditions during childhood, and maintained that such a combination represented a set of factors that would predispose a person to depression. Beck (1967), Paykkl(1978, 1979) and Barrett (I 979) have also suggested that the importance of life events for the occurrence of depression should be considered against the background of individual vulnerability. In the course of a comprehensive investigation concerned with life events and depressive disorders, we decided (Perris, in press) to approach the problem from a multifactorial point of view because we assumed that biological, psychological, and social variables might increase a subject’s vulnerability to life events. Our starting point in this approach is to be found in Freud’s (1920) concept of “Erganzungsreihe.” According to this concept, the more vulnerable an individual is, the less severe are the external events needed to precipitate a mental breakdown. Because the platelet MAO activity seems to represent a vulnerability factor contributing to the development of
113 psychopathology, it appeared possible that there might be some relationship between platelet MAO activity and life events in psychiatric patients. In particular it was assumed that in a population of depressed patients, the lower the platelet MAO activity, the fewer stressful life events would be found. It was also assumed that subjects with low MAO activity would experience life events more negatively than patients with medium or high levels of platelet MAO activity. Methods Patients. Depressed patients (age range 18-65 years) consecutively admitted to the Department of Psychiatry, Umed University, participate, if they agree, in a comprehensive research project concerned with various clinical, social, biological, and psychological aspects of depression. For the purpose of the present investigation, the first 127 patients who entered the study have been considered. Diagnostic Classification. Subtype diagnoses were made by two independent and experienced psychiatrists (L. von Knorring and C. Perris) according to criteria described elsewhere (Perris, 1973; d’Elia et al., 1974). In brief, a bipolar patient must have experienced at least one episode of depression and one of mania. A unipolar diagnosis requires at least three separate episodes of depression. Reactive-neurotic depression describes a depressive disorder that occurred in close proximity to a psychologically understandable traumatic event in a subject with a neurotic personality development. Unspecifieddepressive disorders are those that do not meet criteria for inclusion in the other subgroups. The patients have also been diagnosed according to the criteria of Feighner et al. (1972) the ICD-9 of the World Health Organization (1978) and DSM-fII(American Psychiatric Association, 1980). (See Tables I and 2 for further information concerning the sample.)
Table 1. Distribution
of the series by sex and age Age group (years)
Sex
~2 =
21-30
31-40
41-50
51-60
61-
Total
7
20
6
50
Male
11
6
Female
14
16
16
20
9
77
Total
25
22
25
40
15
127
4.28,
df = 4. NS.
of Life Events. Life events that had occurred within the last year and within 3 months proceding the onset of the depressive disorder were assessed (by H. Perris) using a specially constructed life events inventory. Details about the inventory and its administration have been given elsewhere (Perris, in press). In brief, the inventory investigates the occurrence of 56 events similar to those contained in other life events inventories. The inventory also assesses how the subject reacted to the event (using a 5-point scale in which I = very positively and 5 = most negatively), whether the event was expected, whether the event was controllable by the subject, and how the subject adjusted to the event. As in previous studies (von Knorring et al., 1980; Perris, in press), the inventory was used as a guide for a semistructured interview that took place when the patient had clearly improved from the depressive condition. Assessment
114
In the analyses the events comprised in the inventory have also been grouped into different categories (“negative,” “positive,” “ambivalent, ““entrance” into and “exit” from the social field, and “object loss”) as described in detail in a previous article “controllable, ” “uncontrollable,” (Perris, in press). These groupings correspond to a large extent to similar groupings used by other authors (Myers et al., 1972; Brown, 1974; Paykel, 1974) in studies of life events and depression.
Table 2. Dlstrlbution
UmeH clarslflcatlon
of the series based on different classification
systems
Feighner criteria1 Primary Secondary Deflnlte
Probable
Definite
Probable
Not depressed
Unipolar
26
7
-
-
-
Bipolar Unspecified RND
7 0 14
1 6 11
6 1
1 1
3 15 16
UmeP clasrlflcatlon Unipolar Bipolar Unspecified RND
Umel clarslflcatlon
ED-9 classlflcatlon 296.1 296.3-5 32 2 1
296.6-9
296.0
300.4
309-l
9
1 -
5 -
-
-
-
9 2
6 30
6
1 3
DSM-III clarrlflcatlon 296.2 296.3
296.5
296.6
309.4
309.0
Unipolar Bipolar Unspecified
2 4
33 12
7 1
4 1 2
2
-
RND
6
16
-
7
4
7
1. Only 119 subjects
of Platelet MAO Activity. Platelet MAO activity was assessed without knowledge of either the diagnostic classification of the patients or the results of the study of life events. After the patients’ hospital admission, blood samples (4.5 ml) were drawn from the patients into siliconized Vacutainer @ tubes containing 0.5 ml of 3.1% sodium citrate solution (Becton-Dickinson, Grenoble, France). About I ml of platelet-rich plasma (PRP). obtained by sedimentation of the erythrocytes for 2-4 hours at room temperature, was transferred to a siliconized test tube with a siliconized pipet. A platelet count was then made using an electronic counter (Coulter Counter, Dunstable. England) and the PRP was then stored at -70°C. When all the samples in the series had been collected, estimation of MAO activity was carried out after thawing and subsequent low energy sonication for 60 seconds at 4’C. All samples were analyzed twice at the same time using ( t4C) /?-phenylethylamine (PEA) and ( r4C) tryptamine as substrates (for details, see Eckert et al., 1980). The activity is expressed as nmoles x 10m9of substrate oxidized/platelet/ minute. Since in the present series. as in several previous studies, the results obtained with the two substrates proved to be highly correlated (r = 0.87). only those obtained with tryptamine are used here. Determination
Statistical Analysis. The distribution of MAO series, by sex, and by subtype diagnosis. Possible have been assessed both by calculating the mean groups and as a product-moment correlation. For
activity has been investigated in the whole relationships between MAO activity and age values for MAO activity in the different age the analysis of possible relationships between
115 platelet MAO activity and life events, the MAO activity has been divided into quartiles and the distribution of the life events compared for the lowest, the highest, and the two central quartiles. The mean number of life events has been calculated for periods of 3 months, 4-12 months, and the whole year before the onset of the depressive episode. Frequencies of all the events and of the events grouped in different ways were also calculated in relation to subdivisions of the patients based on MAO activity. Intergroup differences were tested by analysis of variance (for means), and by x2 test (for frequencies). Possible correlations between the scaled experience of life events and MAO activity were also investigated. All statistical analyses were carried out at the UmeSi Computer Center (UMDAC) using standard programs in the SPSS. The 5% level was accepted as the level of significance in a difference or in a correlation.
Results Distribution of MAO Activity. Females showed nonsignificantly higher MAO activity than male patients (female: 0.12, SD 0.06; male: 0.14, SD 0.06). Patients in the oldest age groups showed slightly higher mean MAO values; the correlation coefficient with age was low (r= 0.22). No significant differences in MAO activity were found among the diagnostic subgroups (Table 3). However, the number of individuals is low, especially for some subgroups, and the results need reanalysis in our large series. The reanalysis will also include a comparison with healthy subjects (von Knorring et al., 1984).
Table 3. Distribution of MAO activity diagnostic subgroups
in the
MAO activity Dlaanostic
wow
Mean
SD
39
0.21
0.08
Bipolar
11
0.24
0.08
Unspecified
34
0.23
0.09
Neurotic-reactive
43
0.21
0.08
Unipolar
f = 0.76, df = 3. 123, NS
Platelet MAO Activity and Life Events. The distribution of the series subdivided into quartiles of MAO activity did not show any significant sex or diagnostic subgroup differences. However, a significant difference emerged when age was investigated. The youngest patients (21-30 years) appeared to be overrepresented in the lowest MAO quartile (Table 4). Table 4. Distribution of the series according to MAO activity (quartiles) in relation to age groups MAO auartlle
Age groups 21-30
31-40
41-50
51-60
61-
Lowest quartile
13
3
4
10
1
Middle quartiles
7
14
14
20
7
Highest quartile
6
5
7
9
6
116 As hypothesized, patients in the highest MAO quartile experienced more events @ < 0.05) in the period 4 months to 1 year before the onset of depression, and also significantly more events classified as “exit from the social field” (Tables 5 and 6). Table 5. Distribution of total number of events reported in the period 4 months to 1 year before depression onset in patients subdivided according to levels of MAO activity No. of patients in the MAO subgroups No. of events
Lowest quartile
0
Middle half
Highest quartile
2
10
1
l-2
12
19
11
3-4
14
14
11
3
19
10
>!i
Table 6. Number of patients with “exit” events 4-12 months before depression onset MAO No. of “exit” events
Lowest quartile
Middle half
Highest quartile
0
23
44
20
1
3
15
13
2
5
3
1
X2 = 10.2.
df = 4, p < 0.05
Also, in line with our hypothesis, significantly more of the patients in the lowest MAO quartile scored their experience of the event as “negative” or “very negative”(Table 7). On the other hand, no difference in the total number of events was found between patients in the lowest and the highest MAO groups when events occurring during the 3 months preceding the onset of depression were considered. Table 7. Distribution of patients in relation to the experience life events as “negative” or “very negative” Lowest MAO quartile No.
event experienced
“negative” One or
more
events
as “negative” X2 = 4.10
iYates).
Middle and highest MAO quartiles
as
or “very negative”
1
13
32
81
experienced
or “very negative” df = 1. p < 0.05.
of
117 When a categorization of events was taken into account, patients in the lowest MAO quartile, apparently in contrast with our hypothesis, reported significantly more events classified as “entrance into the social field” (p < O.OS), and significantly more events classified as “controllable” @ < 0.001) and as reflecting a “conflict” (p < 0.001). However, since patients in the lowest MAO quartile were significantly younger than the others, and since younger patients had previously been found to report more events than older patients (Perris, in press), separate calculations for patients grouped in different age groups were also made. When age was corrected for, the differences in number of reported events in the 3 months preceding the depressive episode no longer appeared to be significant.
Discussion The results of the present study supported our hypothesis that low platelet MAO activity probands would have experienced a lower number of stressful life events before becoming depressed than those with higher levels of MAO activity and, moreover, experienced them more negatively. Thus, patients in the middle half and in the highest MAO quartile reported-at least for the period 4 months to 1 year before the onset of depression-more events in total than patients in the lowest quartile. Furthermore, patients in the lowest MAO quartile reported a significantly more negative experience of the events. No difference in number of events was found between probands in the lowest and in the highest quartile in the 3-month period immediately preceding the onset of depression. An analysis of the type of events reported by the patients in the different MAO groups showed that the younger patients in the lowest quartile had experienced more events classified as “controllable, ” “entrance into the social field,” and “conflict” than the patients in the other groups. In contrast, the older patients in the highest MAO quartile had experienced more events classified as “exit from the social field.” Thus, it seems that low MAO patients more negatively evaluate events which might be less severe than those experienced by patients in the highest quartile. Such an interpretation applies at least to the difference between “entrance” into and “exit” from the social field. In a previous study (Perris, in press) younger patients reported significantly more events than older ones. In this study younger patients were overrepresented in the low MAO group, but nevertheless patients in the low MAO group reported fewer events than patients in the highest MAO group. The fact that the difference in total number of events applies only to the period 4 months to 1 year before the onset of depression and not to the 3-month period preceding the onset of depression might reflect the patients’ difficulty in correctly determining the onset of depression, despite every effort made to assess it at the time of the interviews. Obviously, the results reported here should be regarded cautiously because of the small number of patients in our series, and because of the well-known uncertainties of retrospective evaluations of events. However, our results do seem to suggest a relationship between level of platelet MAO activity and tolerance level for
118
stressful life events in individuals most likely explanation for such activity is a biological marker for already predisposed to depressive
who ultimately become depressed. At present, the a relationship seems to be that low platelet MAO personality characteristics that make an individual disorders more vulnerable to stressful events.
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