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Unipolar depression in the aged: determinants of familial aggregation
Journal ofAffective Disorders, 23 (1991) 53-61 0 1991 Elsevier Science Publishers B.V. All rights reserved ADONIS 016503279100121X
53 0165-0327/91/$03.50
JAD 00834
Unipolar depression in the aged: determinants of familial aggregation Wolfgang
Maier, Dirk Lichtermann, Jiirgen Minges, Reinhard Joachim Hallmayer and Thomas Klingler
Heun,
Department of Psychiatry, Unil;ersity of Maim, Maim, F.R.G. (Received 28 September 1990) (Revision received 24 June 1991) (Accepted 1 July 1991)
Summary Late-onset depression (2 60 years) is believed to be less associated with a risk of depression in first-degree relatives than early-onset depression. However, family studies in elderly probands fitting the current methodological standards of family studies are not available. The reported family study in geriatric inpatients with unipolar major depression (n = 92) supported the proposed relationship between age at onset and the proposed familial loading. A comparison to families of age-matched controls (n = 33) revealed that relatives of probands with late-onset depression are still at an increased risk of depression. However, late-onset depression was not more common in families of probands with late-onset depression than in families of probands with early-onset depression. Besides the age at onset, the recurrence of depressive episodes defined distinct patterns of familial aggregation.
Key words:
Unipolar
depression;
Geriatric
depression;
Introduction Nearly all the recent family studies in unipolar depression interviewing most of the first-degree relatives found unipolar depression to be familial and age at onset in probands to be inversely correlated with the risk of depression in first-de-
Address for correspondence: W. Maier, M.D., Department of Psychiatry, University of Mainz, Untere Zahlbacher Strasse 8, D-6500 Mainz, F.R.G.
Age at onset;
Recurrent
depression;
Family
study
gree relatives (Winokur et al., 1975; Winokur, 1979; Mendlewicz and Baron, 1981; Smeraldi et al., 1983; Bland et al., 1986; Weissman et al., 1986; Price et al., 1987; Gershon et al., 1982). As a consequence, it might be expected that lateonset depression (2 60 years) is less familial than early-onset depression in elderly probands (age 2 60 years). Unfortunately, family studies fitting the current standards for recruitment and assessment (Weissman et al., 1986a) are restricted to probands younger than 60 years. Some studies in
54
depression in the aged using structured or semistructured clinical interviews have reported that familial loading is reduced in late-onset depression (Angst, 1966; Mendlewicz, 1976), but as operationalized diagnoses were not available at that time, both studies referred to clinical diagnoses that were not explicitly defined and perhaps were not comparable to other diagnostic conventions. Burvill et al. (1989) and Musetti et al. (1989) also found this relationship between age at onset and familial loading in aged probands, but they did not use the family study method and relied on the family history technique; controversial results have also been found applying the family history technique (Greenwald and Kramer-Ginsberg, 1988). Given the methodological limitations of these previous reports, the hypothesis of a lower familial load in late-onset depression (2 60 years) as compared to early-onset depression must be considered to be preliminary. In particular, the most recent studies based on the family history approach report an extremely low lifetime prevalence: Burvill et al. (1989) and Greenwald and Kramer-Ginsberg (1988) found less than 8% of probands to have a positive family history in any of their first-degree relatives. Musetti et al. (1989) compared groups of probands defined by different ages at onset without stratifying for age, which may bias the results in favor of an increased familial risk in early-onset probands; furthermore, unipolar and bipolar disorders were not kept separate. In conclusion, there is presently not a single published family study comparing late- and early-onset depression in the aged fulfilling methodological conditions that are considered to be crucial for drawing valid conclusions from family studies (Weissman et al., 1986a). The assumption of a lower lifetime risk of depression in relatives of probands with late-onset depression (2 60 years) compared to probands with early-onset depression provokes the question if late-onset depression is associated with an increased familial risk of affective disorders compared to the risk in the general population. Two previous family studies conducted in probands younger than 60 years (Price et al., 1987; Bland et al., 1986) propose that the familial risk in probands with late-onset depression (i.e., age at onset between 40 and 60 years) is not increased
compared to families of healthy controls. Angst (1966), however, found depression to be more common in relatives of probands with late-onset depression than in the general population. Family studies in aged probands with late-onset unipolar depression controlled by families of never mentally ill probands matched for age to the depressed elderly patients are required to address this issue; however, this kind of study is not available. Consequently, it can currently not be decided (a) if late-onset depression (2 60 years) is associated with an increased familial risk of depression compared to healthy controls, (b) if late-onset depression is familial, and (c) if the inverse relationship between age at onset and familiality is also valid for probands over the age of 60 years. The present family study was conducted in probands with psychiatric disorders between 20 and 70 years old and in matched control probands recruited in the general community. This presentation will focus on the unipolar depressed probands aged between 60 and 70 years in order to contribute to the afore-mentioned problems. Methods Sampling of probands
and relatirles
This sample is part of a comprehensive family study conducted at the Department of Psychiatry in Mainz. Participants of this study are probands and their families with unipolar major depression aged between 20 and 70 years (n = 228) recruited between January 1988 and July 1990; rates of psychiatric disorders in families of the subsample recruited between January 1988 and August 1989 have been reported in a recent paper (Maier et al., 1990). The probands were randomly selected from consecutively admitted inpatients; patients with severe somatic diseases requiring intensive medical care or likely to modify the psychopathological state were excluded. Especially patients with a history of seizures and of severe and chronic dementia were excluded. The exclusion of patients with severe somatic conditions also reduces the frequency of probands with depression reactive to somatic disorders. This report focuses on unipolar major depression in probands aged between 60 and 70 years
55
age at onset (see Results) was difficult especially in some parents who had died very long ago, this report will mainly refer to siblings and children of probands. This report will therefore primarily refer to the lifetime risks in the probands’ siblings and children. As can be seen in Table 1, the families of the elderly depressed probands and the healthy controls are comparable for family structure and age of the family members.
and their families graded by age at onset of depression (n = 91 patients). The control probands were recruited from the general population assisted by a marketing company; the control probands were matched to a random subsample of the patients by age, sex, educational status, and area of residence. In both comparison groups, probands without at least one living first-degree relative who was available for being personally interviewed were excluded. After interviewing the probands and their available first-degree relatives, possible confounding factors were eliminated by selecting control probands without any axis I disorder as defined by RDC; these healthy control probands (n = 33) and their families were used as the comparison group to families of elderly probands with unipolar depression. This selection procedure of control families and the subsequent screening of control probands for the absence of psychiatric disorders is in agreement with the recommendations of Kendler (1988). Family studies in the elderly are hampered by the fact that the parents of the probands very often died several decades before the study is conducted. As identification of caseness and of
TABLE
Psychopathological assessment of probands and families Personal interviews in probands and their relatives were conducted using an extended version of the Schedule for Affective Disorders and Schizophrenia @ADS-LA; Mannuzza et al., 19861 which has been used by the majority of recently published family studies. This interview collects information on signs and symptoms necessary to make RDC diagnoses. The relatives of probands were also asked for the history of psychiatric syndromes in the other members of the same family (with the exception of the probandl using the family history approach (Mannuzza et al., 1985). The family history method provides a semi-structured interview for RDC diagnoses of
1
DESCRIPTION
OF THE FAMILY
STUDY Proband
SAMPLE subtype
Unipolar major depression age at onset (years) 2 40 Probands (age 2 60 years) Number Sex ratio (male %) Mean age ( f SD) (years) Relatices (children, siblings) Number Number living Number interviewed Sex ratio (male %) Mean age ( f SD) (years)
21 31% 65.9
Healthy controls
41-59
26 23% 65.9
r 60
45 30% 67.5
(+3.5)
(*3.4)
(k3.9)
33 40% 64.5 (k3.9)
83 59 44 39% 50.1 (+ 18.5)
99 74 60 43% 51.4 ( f 19.0)
180 138 102 45% 52.1 (k20.1)
139 105 85 42% 49.4 (* 17.9)
major affective, schizoaffective, and schizophrenic disorders, of alcoholism, drug abuse, and eating disorders. The personal interviews and the family history assessments were conducted by 11 research assistants (advanced medical students with clinical experience in psychiatry or young physicians) after a common training of at least 20 sessions with all instruments to be used. Test-retest reliabilities for all diagnostic categories to be discussed in this paper were tested separately and were acceptable (K values higher than 0.75); the reliability study will be published separately (Leboyer et al., 1991). Final diagnostic
assessment
This paper reports RDC diagnoses for axis I disorders. The diagnostic procedure was based on the best-estimate procedure (Leckman et al., 1982): two experienced psychiatrists combined the information obtained from personal interview (if available) which included an RDC diagnosis by the interviewers, family history information obtained by all sources available also including RDC diagnoses by the interviewers, and the case notes (if available) in order to decide on a final RDC diagnosis; if the material collected for a relative or a proband included divergent RDC diagnoses, the two psychiatrists discussed all the material and came to an agreement. The same procedure was applied to probands and relatives. The bestestimate procedure was performed independently for probands and relatives; interviewers and clinicians proposing the final RDC diagnosis were blind to the diagnostic assessments in any of the other members of the family. The reported diagnostic assessments are lifetime diagnoses guided by a hierarchical procedure: schizophrenia has priority over schizoaffective disorder which is followed by bipolar and then by unipolar major affective disorders. The term ‘bipolar disorder’ is used as proposed by RDC and thus consists of bipolar I (manic episode) and bipolar II disorder (i.e., major depressive episode and hypomania or cyclothymia). Subclassification
The continuum needs categorial
by age at onset
of ages at onset of depression subclassification for reasons of
simplicity. Various definitions of the subclassification of unipolar depression by age at onset have been proposed in the literature (e.g., Mendlewicz and Baron, 1981; Burvill et al., 1989; Price et al., 1987; Greenwald and Kramer-Ginsberg, 1988). We joined the majority of authors in defining late age at onset as 60 years or later. Alternatives proposed for defining early onset are younger than 30 years, younger than 40 years, younger than 50 and younger than 60 years. As a compromise, we used 40 years or younger for defining early onset and additionally considered a medium age at onset between 40 and 60 years. Statistical methods
Lifetime risks in relatives as reported in Tables 2-4 are age-corrected percentages of cases among the first-degree relatives using the StriimgrenWeinberg method as proposed by Gershon et al. (1982) using log normal distributions for modeling the age at onset. Lifetime risks are calculated separately for personally interviewed relatives and relatives with family history information only. If no significant (P = 0.05) differences between the two methods were found by the chi-square test (Breborowicz and Trzebratowska-Trzeciak, 1976) the two risks were pooled. Comparisons between groups of probands by percentages of affected relatives are based on lifetable analyses (Cox multivariate proportional hazard model; Lee, 1980) simultaneously controlling for independent variables that may affect the risk of major depression in relatives. Ratios of the age-specific incidence (relative risks, hazards) of major depression in different groups of relatives are obtained by this method while the following independent variables enter into the model simultaneously: interview status of the relative (i.e., personally interviewed versus only family history information), sex of the relative, sex and age of the proband. Statistical significances of effects were determined by the chi-square statistic using maximum likelihood estimates. Results Relative frequency of illness by proband interciew status and generation
Table probands
group,
1 shows that the three groups of elderly and the elderly healthy control probands
are comparable by (a> sex and age; (b) sex and age of their family members; Cc) percentage of personally interviewed and living first-degree relatives. In the families of depressed patients unipolar major depression was diagnosed in 34 of the 220 personally interviewed children and siblings (16.5%) and in 20 of the 152 children and siblings with family history information only (13.2%). In the families of control probands five of the 85 personally interviewed relatives (5.9%) and two of the 54 relatives with family history information only (3.8%) received a diagnosis of unipolar major depression. As predicted by the paper of Andreasen et al. (19861, these figures indicate that the family history method is less sensitive than the family study approach in detecting unipolar depression in family members. However, the differences of relative frequencies between the personally interviewed relatives and those that had not been available failed to be statistically significant (chi-square test P = 0.051, and consequently, the two subsamples of relatives (interviewed or not interviewed) were pooled. Furthermore, all parents of the probands were dead; 20 among the 184 parents of the 92 probands with unipolar depression and three among the 66 parents of the 33 control probands were diagnosed as unipolar major depression using information collected with the family history method. As age at onset of this disorder was
TABLE
Subtyping by age at onset Table 2 shows the lifetime morbid risks for major psychiatric disorders in families by proband group. As the personally interviewed and the not personally interviewed relatives do not significantly (P = 0.05) differ in lifetime risk of any disorder in any proband group listed in Table 2, the risks refer to the total sample of siblings and children including those not personally interviewed. The results shown in Table 2 favor the following hypotheses. (a) Unipolar major depression is familial even if depression starts later than the age of 60 years. (b) The degree of familial aggregation is inversely correlated with the age at onset of depression in elderly probands. The following hazard ratios compare relatives of patients with those of healthy controls using the proportional hazard model: compared to relatives of healthy controls, the lifetime risks in relatives of elderly probands with unipolar depression are significantly (P = 0.05) increased for unipolar depression in each of the three proband groups, but not so for bipolar disorder, schizoaf-
2
LIFETIME MORBID MAJOR DISORDERS Proband
difficult to determine in some of those parents with a lifetime diagnosis who had died more than 20 years ago, we will in the subsequent analysis only refer to siblings and children of the probands.
RISKS (%, AGE-CORRECTED) OF FIRST-DEGREE RELATIVES
subtype
Diagnosis Unipolar depression
Unipolar depression (age of probands 2 60 years) age at onset I40 years age at onset 41-59 age at onset
Healthy controls (age of probands
years
2 60 years
2 60 years)
27.8% (16/83) 23.4% (16/99) 17.3% (22/190)
AND RELATIVE FREQUENCIES (IN OF AGED PROBANDS BY PROBAND’S
PARENTHESES) AGE AT ONSET
of relatives Bipolar depression
Schizoaffective disorder
3.1% (2/831 2.0% (2/991 2.8% (4/190)
(l/83) 0.0% (O/991 1.0% (2/190)
1.0%
Schizophrenia
0.0% (O/831 0.0% (O/99) 0.0% (O/190)
Alcoholism/ drug abuse
15.4% (9/83) 11.3% (7/99) 9.0% (12/190)
7.9%
2.3%
0.0%
0.0%
6.9%
(7/139)
(2/1391
(O/139)
(O/1391
(7/1391
FOR
58
fective disorder or schizophrenia. Only the relatives of probands with early age at onset were at a substantially increased risk of alcoholism (P = 0.06) as compared to relatives of controls. However, the age at onset of depression in probands and in first-degree relatives is not positively correlated to a significant extent (Pearson correlation 0.20, P r 0.05). Table 3 shows that in all proband groups depression occurs most frequently as early-onset depression. Late-onset depression in relatives only shows a tendency to being familial: the proportional hazard analysis did not find any significantly (P = 0.05) increased risk of late-onset depression in relatives of elderly patients as compared to relatives of elderly healthy controls (hazard ratio 1.5, P 2 0.10); the relatives reporting depression before the age of 60 years were excluded in this analysis. Other subtypes of depression It was further explored if subtypes of unipolar major depression without reference to age at onset provide additional clues to distinguishing between different degrees of familial aggregation. The following subclassifications of depressed probands were tested: (1) at least one depressive episode with melancholia versus no melancholic episode; (2) primary unipolar depression versus secondary unipolar depression; (3) recurrent unipolar major depression versus single episode of unipolar depression. The Cox proportional hazard model was again used for comparing the risk of unipolar depres-
TABLE
3
LIFETIME MORBID RISKS (%, AGE-CORRECTED) DEPRESSION SUBDIVIDED BY AGE AT ONSET VIDED BY AGE AT ONSET Proband
sion in relatives between each of these three pairs of probands’ subtypes. The list of independent variables (interview status, sex of the relative, sex and age of the proband) was supplemented in this analysis by the age at onset of depression in probands in order to test the additional contribution of any of the three manners of subtyping to the risk in relatives. Distinguishing between recurrent and single episodes showed the maximal effect (hazard ratio) among these three manners of subtyping which however failed to be significant (hazard ratio 1.7, P = 0.09). The relative risks for the two further manners of subtyping were less than 1.3 indicating no relevant difference between the two subgroups of probands (P 2 0.10). Unipolar depression in probands and relatives was therefore additionally broken by the recurrence of episodes and lifetime morbid risks were calculated for each subtype of depression (Table 4). Late-onset depression with recurrent episodes in probands is associated with a higher familial risk for unipolar depression than late-onset depression with only a single episode (hazard ratio 1.4), but not significantly so (P > 0.05). It is obvious from Table 4 that recurrent depression aggregates in families of probands with recurrent depression. The lifetime risk of unipolar depression in relatives of elderly probands with a single episode is not significantly increased compared to relatives of controls (hazard ratio 1.7, P > 0.05); recurrent depression in relatives, on the other hand,
Relatives’
subtype
Unipolar depression (age of probands 2 60 years) age at onset I40 years age at onset 41-59 years age at onset > 60 years Healthy controls (age of probands
2 60 years)
AND FREQUENCIES OF FIRST-DEGREE
(IN PARENTHESES) OF UNIPOLAR RELATIVES OF AGED PROBANDS
age at onset
4 40 years
41-59
years
> 60 years
14.1% (8) 12.8% (8) 9.6% (11)
11.5% (7) 9.3% (6) 6.1% (8)
1.9% (1) 2.5% (2) 2.5% (3)
6.3% (5)
0.8% (1)
0.9% (1)
MAJOR SUBDI-
59 TABLE
4
LIFETIME MORBID RISKS (%, AGE-CORRECTED) AND RELATIVE VERSUS RECURRENT UNIPOLAR MAJOR DEPRESSION BY AGE AGED PROBANDS SUBDIVIDED BY AGE AT ONSET Proband
Unipolar
subtype
depression
Single episode Unipolar depression (age of probands 2 60 years) age at onset r 60 years; single episode age at onset
2 60 years; recurrent
age at onset 41-59 age at onset
Healthy controls (age of probands
years; recurrent
5 40 years; recurrent
2 60 years)
is associated with a significantly increased risk of depression compared to controls (hazard ratio 2.6, P = 0.01). Discussion Major findings In agreement with the majority of reports on family history in geriatric patients with late-onset unipolar depression (Burvill et al., 1989; Angst, 1966; Mendlewicz, 19761, a lower lifetime risk of unipolar depression was found in siblings and children of those patients compared to relatives of geriatric patients with early-onset depression. As the depressed probands with various ages at onset were located within a narrow age range (60-70 years), the age structure and the mean age in relatives of the comparison groups are similar; the differences found in this study can therefore not be due to a confounding age effect or to secular trends (birth cohort effects) which are responsible for an increased risk in younger subjects Klerman et al., 1985). Furthermore, in agreement with Mendlewicz and Baron (1981) and Winokur (1979), a tendency to an increased risk of alcoholism was found among families of probands with early-onset depression.
FREQUENCIES (IN PARENTHESES) OF SINGLE AT ONSET IN FIRST-DEGREE RELATIVES OF
in relatives Recurrent
9.7%
3.7%
(6/80) 7.7%
(2/80) 11.8%
(5/110) 13.8%
(9/110) 10.1%
(9/99) 12.6% (7/83)
(7/99) 16.0% (9/831
5.6%
2.8%
(5/139)
(2/139)
The impact of age at onset In spite of the lower lifetime risk of unipolar depression in families of probands with late-onset unipolar depression, this risk is still significantly higher than in families of age-matched healthy control probands. This result confirms Angst’s (1966) observation that late-onset depression is associated with a higher rate of affective disorders in families than is found in the general population. On the other hand, there are some discrepancies with the Yale family study (Price et al., 1987) who reported no increased familial risk of unipolar depression in depressed probands with age at onset between 40 and 60 years. This discrepancy might be explained by the impact of other subtypes of the probands’ depression: in agreement with Bland et al. (1984) we found that families of depressed probands with only a single episode and late onset (2 60 years in this study and r 40 years in the study by Price et al.) are not at an increased familial risk of depression compared to families of healthy controls. Variations of percentages of single-episode depressions in late-onset probands might therefore explain discrepant findings in comparison to control probands. The familial aggregation of early-onset depres-
60
sion seems to be more specific than the familial aggregation of late-onset depression: the risk of early-onset depression is elevated in famihes of probands with early-onset depression, but not in families of probands with late-onset depression; on the other hand late-onset depression occurs with a simiIar frequency in families of probands with late- and early-onset depression. However. as the mean age in relatives of the various proband groups is not higher than 50 years, the inherent power for the identification of differences with regard to frequencies of late-onset depression is low in our sample. The different patterns of familial aggregation in early- and late-onset depression suggest a comparison to dementia of the Alzheimer type; different patterns of familial aggregation in earlyand late-onset conditions define two different patterns of familial aggregation in Alzheimer disease, too (Farrer et al., 1990). But there are major differences among the two disorders with respect to familial aggregation: (a) late-onset unipolar depression does not breed true as lateonset Alzheimer disorder does; (b) early-onset unipolar depression is associated with an increased familial loading (compared to late-onset major depression) whereas early-onset Alzheimer disease does not show this pattern (Farrer et al., 1990). Furthermore, the monotonic trend across the three ranges of ages at onset favors a linear inverse relationship between age at onset and familial aggregation of unipolar major depression; there is no evidence for a non-linear relationship proposing a natural boundary between early- and late-onset depression; this is for example the case in Alzheimer disease with an age of 58 years (Farrer et al., 1990). The differences found between early- and late-onset depression are likely to reflect a linear relationship between age at onset and familial aggregation. Consequently, the arbitrarily chosen conventions of discriminating between early, medium, and late onset do not reflect valid boundaries in the age at onset continuum; these boundaries only represent conventions for a handy lay-out of the data on age at onset. The impact of the recurrence of episodes The recurrence of episodes was found
to be
associated with an increased familial risk of depression in late-onset depressions. Only a single family study in aged probands (older than 60 years) with late-onset depression has examined the impact of recurrence and could not find the familial risk to be significantly influenced by a multiplicity of episodes (Angst, 1966). As this previous study was conducted 2.5 years ago, quite different techniques for the assessment of psychopathology were used which may explain this discrepancy; especially thresholds for caseness might have been substantially higher in those times and consequently milder previous episodes had probably not been regularly identified. The impact of recurrence of episodes on the familial risk as observed in this study is furthermore in agreement with a series of more recent family studies in younger probands (aged 20-60) (Weissman et al., 1986; Leckman et al., 1984). Furthermore, it was shown that recurrent episodes were mainly found in relatives of probands with recurrent episodes. This observation favors a breeding true of the subtype of recurrent unipolar depression. As the subtypes defined by ranges of ages at onset did not show any similar familial homogeneity, it is simultaneously shown that early age at onset and multiplicity of episodes do not reflect the same phenomenon described in different terms. It has been speculated (Burvill et al., 1989) that late-onset single episodes in probands are most often induced by organic conditions or are, alternatively, reactive to organic disorders; therefore, they should not be associated with an increased familial risk of depression. Our study indicates that this hypothesis is only true if caseness in relatives is defined by recurrence of episodes; the familial aggregation of single-episode depression cannot convincingly be explained by the occurrence of organic disorders which are usually not familial by themselves. The familial pattern of unipolar depression as found in this study is compatible with a severity model of liability with the strength of recurrence defining severity; in agreement with this model single-episode depression aggregates in families of depressed probands regardless of the number of episodes whereas recurrent episodes only aggregate in probands with recurrent major depression.
61
Acknowledgement This paper was supported by funding from the German Research Foundation (Ma-1142/1-l). References Andreasen, N.C., Rice, J., Endicott, J., Reich, T. and Coryell, W. (1986) The family history approach to diagnosis: how useful is it’? Arch. Gen. Psychiatry 43, 421-429. Angst, J. (1966) Zur Atiologie und Nosologie endogener depressiver Psychosen. Springer Verlag, Berlin. Bland, R.C., Newman, S.C. and Orn, H. (1986) Recurrent and nonrecurrent depression. Arch. Gen. Psychiatry 43, 10851089. Breborowicz, G. and Trzebratowska-Trzeciak, 0. (1976) A method for testing differences in morbidity risk for affective psychoses. Acta Psychiatr. Stand. 54, 353-358. Burvill, P.W., Hall, W.D., Stampfer, H.G. and Emmerson, J.P. (1989) A comparison of early-onset and late-onset depressive illness in the elderly. Br. J. Psychiatry 155, 673-679. Farrer, L.A., Myers, R.H., Cupples, L.A., St. George-Hyslop, P.H., Bird, T.D., Rossor, M.N., Mullan, M.J., Polinsky, R., Nee, L., Heston, L., Van Broeckhoven, C., Martin, J.J., Crapper-McLachlan, D. and Growdon, J.H. (1990) Transmission and age-at-onset patterns in familial Alzheimer’s disease: evidence for heterogeneity. Neurology 40, 395403. Gershon, ES., Hamovit, J., Guroff, J.J., Dibble, E., Leckman, J.F., Sceery, W., Targum, S.D., Nurnberger, G.I., Goldin, L.R. and Bunney, W.E. (1982) A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch. Gen. Psychiatry 39, 1157-l 167. Greenwald, B.S. and Kramer-Ginsberg, E. (1988) Age at onset in geriatric depression: relationship to clinical variables. J. Affect. Disord. 15, 61-68. Kendler, K.S. (1988) Familial aggregation of schizophrenia and schizophrenia spectrum disorders. Arch. Gen. Psychiatry 45, 377-383. Klerman, G.L., Lavori, P.W., Rice, J., Reich, T., Endicott, J., Andreasen, NC., Keller, M.B. and Hirschfeld, R.M. (1985) Birth cohort trends in rates of major depressive disorder among relatives of patients with affective disorder. Arch. Gen. Psychiatry 42, 689-693. Leboyer, M., Maier, W., Lichtermann, D., Teherani, M., D’Amato, T., Franke, P., Lepine J.-P. and Minges, J. (1991) The reliability of the SADS-LA in a family study setting. Eur. Arch. Psychiatry Clin. Neurosci. (in press).
Leckman, J.F., Sholomskas, D., Thompson, W.D., Belanger, A. and Weissman, M.M. (1982) Best estimate of lifetime psychiatric diagnosis. A methodological study. Arch. Gen. Psychiatry 39, 879-883. Leckman, J.F., Weissman, M.M., Prusoff, B.A., Caruso, K.A., Merikangas, K.R., Pauls, D.L. and Kidd, K.K. (1984) Subtypes of depression. Arch. Gen. Psychiatry 41, 833-838. Lee, E. (1980) Statistical Methods for Survival Data Analysis. Wadsworth, Belmont, CA. Maier, W., Lichtermann, D., Hallmayer, J., Heun, R. Marx, A. and Benkert, 0. (1990) The transmission of affective and schizophrenic disorders in families: evidence for a unitary concept of major psychiatric disorders? Submitted. Mannuzza, S., Fyer, A.J., Endicott, J., Klein. D.F. and Robins, L.N. (1985) Family Informant Schedule and Criteria (FIX). Anxiety Disorder Clinic, New York State Psychiatric Institute, New York. Mannuzza, S., Fyer, A.J., Klein, D.F. and Endicott, J. (1986) Schedule for Affective Disorders and Schizophrenia-Lifetime Version (modified for the study of anxiety disorders): rationale and conceptual development. J. Psychiatr. Res. 20, 317-325. Mendlewicz, J. (1976) The age factor in depressive illness: some genetic considerations. J. Gerontol. 31, 300-303. Mendlewicz. J. and Baron, M. (1981) Morbidity risks in subtypes of unipolar depressive illness: differences between early and late onset forms. Br. J. Psychiatry 139, 463-466. Musetti, L., Perugi, G., Soriani, A., Rossi, V.M., Cassano, G.B. and Akiskal, H.P. (1989) Depression before and after age 65. Br. J. Psychiatry 1.55, 330-336. Price, R.A., Kidd, K.K. and Weissman, M.M. (1987) Early onset (under age 30 years) and panic disorder as markers for etiologic homogeneity in major depression. Arch. Gen. Psychiatry 44, 434-440. Weissman, M.M., Merikangas, K.R., John, K., Wickramaratne, P., Prusoff, B.A. and Kidd, K.K. (1986a) Familygenetic studies of psychiatric disorders. Arch. Gen. Psychiatry 43, 1104-1116. Weissman, M.M., Merikangas, K.R., Wickramaratne, P., Prusoff, B.A., Leckman, J.F. and Pauls, D.L. (1986b) Understanding the clinical heterogeneity of major depression using family data. Arch. Gen. Psychiatry 43. 430-434. Winokur, G. (1979) Unipolar depression. Is it divisible into autonomous subtypes? Arch. Gen. Psychiatry 36, 47-52. Winokur, G., Cadoret, R., Baker, M. and Dorzab, J. (1975) Depression spectrum disease versus pure depressive disease: some further data. Br. J. Psychiatry 127, 75-77.
53 0165-0327/91/$03.50
JAD 00834
Unipolar depression in the aged: determinants of familial aggregation Wolfgang
Maier, Dirk Lichtermann, Jiirgen Minges, Reinhard Joachim Hallmayer and Thomas Klingler
Heun,
Department of Psychiatry, Unil;ersity of Maim, Maim, F.R.G. (Received 28 September 1990) (Revision received 24 June 1991) (Accepted 1 July 1991)
Summary Late-onset depression (2 60 years) is believed to be less associated with a risk of depression in first-degree relatives than early-onset depression. However, family studies in elderly probands fitting the current methodological standards of family studies are not available. The reported family study in geriatric inpatients with unipolar major depression (n = 92) supported the proposed relationship between age at onset and the proposed familial loading. A comparison to families of age-matched controls (n = 33) revealed that relatives of probands with late-onset depression are still at an increased risk of depression. However, late-onset depression was not more common in families of probands with late-onset depression than in families of probands with early-onset depression. Besides the age at onset, the recurrence of depressive episodes defined distinct patterns of familial aggregation.
Key words:
Unipolar
depression;
Geriatric
depression;
Introduction Nearly all the recent family studies in unipolar depression interviewing most of the first-degree relatives found unipolar depression to be familial and age at onset in probands to be inversely correlated with the risk of depression in first-de-
Address for correspondence: W. Maier, M.D., Department of Psychiatry, University of Mainz, Untere Zahlbacher Strasse 8, D-6500 Mainz, F.R.G.
Age at onset;
Recurrent
depression;
Family
study
gree relatives (Winokur et al., 1975; Winokur, 1979; Mendlewicz and Baron, 1981; Smeraldi et al., 1983; Bland et al., 1986; Weissman et al., 1986; Price et al., 1987; Gershon et al., 1982). As a consequence, it might be expected that lateonset depression (2 60 years) is less familial than early-onset depression in elderly probands (age 2 60 years). Unfortunately, family studies fitting the current standards for recruitment and assessment (Weissman et al., 1986a) are restricted to probands younger than 60 years. Some studies in
54
depression in the aged using structured or semistructured clinical interviews have reported that familial loading is reduced in late-onset depression (Angst, 1966; Mendlewicz, 1976), but as operationalized diagnoses were not available at that time, both studies referred to clinical diagnoses that were not explicitly defined and perhaps were not comparable to other diagnostic conventions. Burvill et al. (1989) and Musetti et al. (1989) also found this relationship between age at onset and familial loading in aged probands, but they did not use the family study method and relied on the family history technique; controversial results have also been found applying the family history technique (Greenwald and Kramer-Ginsberg, 1988). Given the methodological limitations of these previous reports, the hypothesis of a lower familial load in late-onset depression (2 60 years) as compared to early-onset depression must be considered to be preliminary. In particular, the most recent studies based on the family history approach report an extremely low lifetime prevalence: Burvill et al. (1989) and Greenwald and Kramer-Ginsberg (1988) found less than 8% of probands to have a positive family history in any of their first-degree relatives. Musetti et al. (1989) compared groups of probands defined by different ages at onset without stratifying for age, which may bias the results in favor of an increased familial risk in early-onset probands; furthermore, unipolar and bipolar disorders were not kept separate. In conclusion, there is presently not a single published family study comparing late- and early-onset depression in the aged fulfilling methodological conditions that are considered to be crucial for drawing valid conclusions from family studies (Weissman et al., 1986a). The assumption of a lower lifetime risk of depression in relatives of probands with late-onset depression (2 60 years) compared to probands with early-onset depression provokes the question if late-onset depression is associated with an increased familial risk of affective disorders compared to the risk in the general population. Two previous family studies conducted in probands younger than 60 years (Price et al., 1987; Bland et al., 1986) propose that the familial risk in probands with late-onset depression (i.e., age at onset between 40 and 60 years) is not increased
compared to families of healthy controls. Angst (1966), however, found depression to be more common in relatives of probands with late-onset depression than in the general population. Family studies in aged probands with late-onset unipolar depression controlled by families of never mentally ill probands matched for age to the depressed elderly patients are required to address this issue; however, this kind of study is not available. Consequently, it can currently not be decided (a) if late-onset depression (2 60 years) is associated with an increased familial risk of depression compared to healthy controls, (b) if late-onset depression is familial, and (c) if the inverse relationship between age at onset and familiality is also valid for probands over the age of 60 years. The present family study was conducted in probands with psychiatric disorders between 20 and 70 years old and in matched control probands recruited in the general community. This presentation will focus on the unipolar depressed probands aged between 60 and 70 years in order to contribute to the afore-mentioned problems. Methods Sampling of probands
and relatirles
This sample is part of a comprehensive family study conducted at the Department of Psychiatry in Mainz. Participants of this study are probands and their families with unipolar major depression aged between 20 and 70 years (n = 228) recruited between January 1988 and July 1990; rates of psychiatric disorders in families of the subsample recruited between January 1988 and August 1989 have been reported in a recent paper (Maier et al., 1990). The probands were randomly selected from consecutively admitted inpatients; patients with severe somatic diseases requiring intensive medical care or likely to modify the psychopathological state were excluded. Especially patients with a history of seizures and of severe and chronic dementia were excluded. The exclusion of patients with severe somatic conditions also reduces the frequency of probands with depression reactive to somatic disorders. This report focuses on unipolar major depression in probands aged between 60 and 70 years
55
age at onset (see Results) was difficult especially in some parents who had died very long ago, this report will mainly refer to siblings and children of probands. This report will therefore primarily refer to the lifetime risks in the probands’ siblings and children. As can be seen in Table 1, the families of the elderly depressed probands and the healthy controls are comparable for family structure and age of the family members.
and their families graded by age at onset of depression (n = 91 patients). The control probands were recruited from the general population assisted by a marketing company; the control probands were matched to a random subsample of the patients by age, sex, educational status, and area of residence. In both comparison groups, probands without at least one living first-degree relative who was available for being personally interviewed were excluded. After interviewing the probands and their available first-degree relatives, possible confounding factors were eliminated by selecting control probands without any axis I disorder as defined by RDC; these healthy control probands (n = 33) and their families were used as the comparison group to families of elderly probands with unipolar depression. This selection procedure of control families and the subsequent screening of control probands for the absence of psychiatric disorders is in agreement with the recommendations of Kendler (1988). Family studies in the elderly are hampered by the fact that the parents of the probands very often died several decades before the study is conducted. As identification of caseness and of
TABLE
Psychopathological assessment of probands and families Personal interviews in probands and their relatives were conducted using an extended version of the Schedule for Affective Disorders and Schizophrenia @ADS-LA; Mannuzza et al., 19861 which has been used by the majority of recently published family studies. This interview collects information on signs and symptoms necessary to make RDC diagnoses. The relatives of probands were also asked for the history of psychiatric syndromes in the other members of the same family (with the exception of the probandl using the family history approach (Mannuzza et al., 1985). The family history method provides a semi-structured interview for RDC diagnoses of
1
DESCRIPTION
OF THE FAMILY
STUDY Proband
SAMPLE subtype
Unipolar major depression age at onset (years) 2 40 Probands (age 2 60 years) Number Sex ratio (male %) Mean age ( f SD) (years) Relatices (children, siblings) Number Number living Number interviewed Sex ratio (male %) Mean age ( f SD) (years)
21 31% 65.9
Healthy controls
41-59
26 23% 65.9
r 60
45 30% 67.5
(+3.5)
(*3.4)
(k3.9)
33 40% 64.5 (k3.9)
83 59 44 39% 50.1 (+ 18.5)
99 74 60 43% 51.4 ( f 19.0)
180 138 102 45% 52.1 (k20.1)
139 105 85 42% 49.4 (* 17.9)
major affective, schizoaffective, and schizophrenic disorders, of alcoholism, drug abuse, and eating disorders. The personal interviews and the family history assessments were conducted by 11 research assistants (advanced medical students with clinical experience in psychiatry or young physicians) after a common training of at least 20 sessions with all instruments to be used. Test-retest reliabilities for all diagnostic categories to be discussed in this paper were tested separately and were acceptable (K values higher than 0.75); the reliability study will be published separately (Leboyer et al., 1991). Final diagnostic
assessment
This paper reports RDC diagnoses for axis I disorders. The diagnostic procedure was based on the best-estimate procedure (Leckman et al., 1982): two experienced psychiatrists combined the information obtained from personal interview (if available) which included an RDC diagnosis by the interviewers, family history information obtained by all sources available also including RDC diagnoses by the interviewers, and the case notes (if available) in order to decide on a final RDC diagnosis; if the material collected for a relative or a proband included divergent RDC diagnoses, the two psychiatrists discussed all the material and came to an agreement. The same procedure was applied to probands and relatives. The bestestimate procedure was performed independently for probands and relatives; interviewers and clinicians proposing the final RDC diagnosis were blind to the diagnostic assessments in any of the other members of the family. The reported diagnostic assessments are lifetime diagnoses guided by a hierarchical procedure: schizophrenia has priority over schizoaffective disorder which is followed by bipolar and then by unipolar major affective disorders. The term ‘bipolar disorder’ is used as proposed by RDC and thus consists of bipolar I (manic episode) and bipolar II disorder (i.e., major depressive episode and hypomania or cyclothymia). Subclassification
The continuum needs categorial
by age at onset
of ages at onset of depression subclassification for reasons of
simplicity. Various definitions of the subclassification of unipolar depression by age at onset have been proposed in the literature (e.g., Mendlewicz and Baron, 1981; Burvill et al., 1989; Price et al., 1987; Greenwald and Kramer-Ginsberg, 1988). We joined the majority of authors in defining late age at onset as 60 years or later. Alternatives proposed for defining early onset are younger than 30 years, younger than 40 years, younger than 50 and younger than 60 years. As a compromise, we used 40 years or younger for defining early onset and additionally considered a medium age at onset between 40 and 60 years. Statistical methods
Lifetime risks in relatives as reported in Tables 2-4 are age-corrected percentages of cases among the first-degree relatives using the StriimgrenWeinberg method as proposed by Gershon et al. (1982) using log normal distributions for modeling the age at onset. Lifetime risks are calculated separately for personally interviewed relatives and relatives with family history information only. If no significant (P = 0.05) differences between the two methods were found by the chi-square test (Breborowicz and Trzebratowska-Trzeciak, 1976) the two risks were pooled. Comparisons between groups of probands by percentages of affected relatives are based on lifetable analyses (Cox multivariate proportional hazard model; Lee, 1980) simultaneously controlling for independent variables that may affect the risk of major depression in relatives. Ratios of the age-specific incidence (relative risks, hazards) of major depression in different groups of relatives are obtained by this method while the following independent variables enter into the model simultaneously: interview status of the relative (i.e., personally interviewed versus only family history information), sex of the relative, sex and age of the proband. Statistical significances of effects were determined by the chi-square statistic using maximum likelihood estimates. Results Relative frequency of illness by proband interciew status and generation
Table probands
group,
1 shows that the three groups of elderly and the elderly healthy control probands
are comparable by (a> sex and age; (b) sex and age of their family members; Cc) percentage of personally interviewed and living first-degree relatives. In the families of depressed patients unipolar major depression was diagnosed in 34 of the 220 personally interviewed children and siblings (16.5%) and in 20 of the 152 children and siblings with family history information only (13.2%). In the families of control probands five of the 85 personally interviewed relatives (5.9%) and two of the 54 relatives with family history information only (3.8%) received a diagnosis of unipolar major depression. As predicted by the paper of Andreasen et al. (19861, these figures indicate that the family history method is less sensitive than the family study approach in detecting unipolar depression in family members. However, the differences of relative frequencies between the personally interviewed relatives and those that had not been available failed to be statistically significant (chi-square test P = 0.051, and consequently, the two subsamples of relatives (interviewed or not interviewed) were pooled. Furthermore, all parents of the probands were dead; 20 among the 184 parents of the 92 probands with unipolar depression and three among the 66 parents of the 33 control probands were diagnosed as unipolar major depression using information collected with the family history method. As age at onset of this disorder was
TABLE
Subtyping by age at onset Table 2 shows the lifetime morbid risks for major psychiatric disorders in families by proband group. As the personally interviewed and the not personally interviewed relatives do not significantly (P = 0.05) differ in lifetime risk of any disorder in any proband group listed in Table 2, the risks refer to the total sample of siblings and children including those not personally interviewed. The results shown in Table 2 favor the following hypotheses. (a) Unipolar major depression is familial even if depression starts later than the age of 60 years. (b) The degree of familial aggregation is inversely correlated with the age at onset of depression in elderly probands. The following hazard ratios compare relatives of patients with those of healthy controls using the proportional hazard model: compared to relatives of healthy controls, the lifetime risks in relatives of elderly probands with unipolar depression are significantly (P = 0.05) increased for unipolar depression in each of the three proband groups, but not so for bipolar disorder, schizoaf-
2
LIFETIME MORBID MAJOR DISORDERS Proband
difficult to determine in some of those parents with a lifetime diagnosis who had died more than 20 years ago, we will in the subsequent analysis only refer to siblings and children of the probands.
RISKS (%, AGE-CORRECTED) OF FIRST-DEGREE RELATIVES
subtype
Diagnosis Unipolar depression
Unipolar depression (age of probands 2 60 years) age at onset I40 years age at onset 41-59 age at onset
Healthy controls (age of probands
years
2 60 years
2 60 years)
27.8% (16/83) 23.4% (16/99) 17.3% (22/190)
AND RELATIVE FREQUENCIES (IN OF AGED PROBANDS BY PROBAND’S
PARENTHESES) AGE AT ONSET
of relatives Bipolar depression
Schizoaffective disorder
3.1% (2/831 2.0% (2/991 2.8% (4/190)
(l/83) 0.0% (O/991 1.0% (2/190)
1.0%
Schizophrenia
0.0% (O/831 0.0% (O/99) 0.0% (O/190)
Alcoholism/ drug abuse
15.4% (9/83) 11.3% (7/99) 9.0% (12/190)
7.9%
2.3%
0.0%
0.0%
6.9%
(7/139)
(2/1391
(O/139)
(O/1391
(7/1391
FOR
58
fective disorder or schizophrenia. Only the relatives of probands with early age at onset were at a substantially increased risk of alcoholism (P = 0.06) as compared to relatives of controls. However, the age at onset of depression in probands and in first-degree relatives is not positively correlated to a significant extent (Pearson correlation 0.20, P r 0.05). Table 3 shows that in all proband groups depression occurs most frequently as early-onset depression. Late-onset depression in relatives only shows a tendency to being familial: the proportional hazard analysis did not find any significantly (P = 0.05) increased risk of late-onset depression in relatives of elderly patients as compared to relatives of elderly healthy controls (hazard ratio 1.5, P 2 0.10); the relatives reporting depression before the age of 60 years were excluded in this analysis. Other subtypes of depression It was further explored if subtypes of unipolar major depression without reference to age at onset provide additional clues to distinguishing between different degrees of familial aggregation. The following subclassifications of depressed probands were tested: (1) at least one depressive episode with melancholia versus no melancholic episode; (2) primary unipolar depression versus secondary unipolar depression; (3) recurrent unipolar major depression versus single episode of unipolar depression. The Cox proportional hazard model was again used for comparing the risk of unipolar depres-
TABLE
3
LIFETIME MORBID RISKS (%, AGE-CORRECTED) DEPRESSION SUBDIVIDED BY AGE AT ONSET VIDED BY AGE AT ONSET Proband
sion in relatives between each of these three pairs of probands’ subtypes. The list of independent variables (interview status, sex of the relative, sex and age of the proband) was supplemented in this analysis by the age at onset of depression in probands in order to test the additional contribution of any of the three manners of subtyping to the risk in relatives. Distinguishing between recurrent and single episodes showed the maximal effect (hazard ratio) among these three manners of subtyping which however failed to be significant (hazard ratio 1.7, P = 0.09). The relative risks for the two further manners of subtyping were less than 1.3 indicating no relevant difference between the two subgroups of probands (P 2 0.10). Unipolar depression in probands and relatives was therefore additionally broken by the recurrence of episodes and lifetime morbid risks were calculated for each subtype of depression (Table 4). Late-onset depression with recurrent episodes in probands is associated with a higher familial risk for unipolar depression than late-onset depression with only a single episode (hazard ratio 1.4), but not significantly so (P > 0.05). It is obvious from Table 4 that recurrent depression aggregates in families of probands with recurrent depression. The lifetime risk of unipolar depression in relatives of elderly probands with a single episode is not significantly increased compared to relatives of controls (hazard ratio 1.7, P > 0.05); recurrent depression in relatives, on the other hand,
Relatives’
subtype
Unipolar depression (age of probands 2 60 years) age at onset I40 years age at onset 41-59 years age at onset > 60 years Healthy controls (age of probands
2 60 years)
AND FREQUENCIES OF FIRST-DEGREE
(IN PARENTHESES) OF UNIPOLAR RELATIVES OF AGED PROBANDS
age at onset
4 40 years
41-59
years
> 60 years
14.1% (8) 12.8% (8) 9.6% (11)
11.5% (7) 9.3% (6) 6.1% (8)
1.9% (1) 2.5% (2) 2.5% (3)
6.3% (5)
0.8% (1)
0.9% (1)
MAJOR SUBDI-
59 TABLE
4
LIFETIME MORBID RISKS (%, AGE-CORRECTED) AND RELATIVE VERSUS RECURRENT UNIPOLAR MAJOR DEPRESSION BY AGE AGED PROBANDS SUBDIVIDED BY AGE AT ONSET Proband
Unipolar
subtype
depression
Single episode Unipolar depression (age of probands 2 60 years) age at onset r 60 years; single episode age at onset
2 60 years; recurrent
age at onset 41-59 age at onset
Healthy controls (age of probands
years; recurrent
5 40 years; recurrent
2 60 years)
is associated with a significantly increased risk of depression compared to controls (hazard ratio 2.6, P = 0.01). Discussion Major findings In agreement with the majority of reports on family history in geriatric patients with late-onset unipolar depression (Burvill et al., 1989; Angst, 1966; Mendlewicz, 19761, a lower lifetime risk of unipolar depression was found in siblings and children of those patients compared to relatives of geriatric patients with early-onset depression. As the depressed probands with various ages at onset were located within a narrow age range (60-70 years), the age structure and the mean age in relatives of the comparison groups are similar; the differences found in this study can therefore not be due to a confounding age effect or to secular trends (birth cohort effects) which are responsible for an increased risk in younger subjects Klerman et al., 1985). Furthermore, in agreement with Mendlewicz and Baron (1981) and Winokur (1979), a tendency to an increased risk of alcoholism was found among families of probands with early-onset depression.
FREQUENCIES (IN PARENTHESES) OF SINGLE AT ONSET IN FIRST-DEGREE RELATIVES OF
in relatives Recurrent
9.7%
3.7%
(6/80) 7.7%
(2/80) 11.8%
(5/110) 13.8%
(9/110) 10.1%
(9/99) 12.6% (7/83)
(7/99) 16.0% (9/831
5.6%
2.8%
(5/139)
(2/139)
The impact of age at onset In spite of the lower lifetime risk of unipolar depression in families of probands with late-onset unipolar depression, this risk is still significantly higher than in families of age-matched healthy control probands. This result confirms Angst’s (1966) observation that late-onset depression is associated with a higher rate of affective disorders in families than is found in the general population. On the other hand, there are some discrepancies with the Yale family study (Price et al., 1987) who reported no increased familial risk of unipolar depression in depressed probands with age at onset between 40 and 60 years. This discrepancy might be explained by the impact of other subtypes of the probands’ depression: in agreement with Bland et al. (1984) we found that families of depressed probands with only a single episode and late onset (2 60 years in this study and r 40 years in the study by Price et al.) are not at an increased familial risk of depression compared to families of healthy controls. Variations of percentages of single-episode depressions in late-onset probands might therefore explain discrepant findings in comparison to control probands. The familial aggregation of early-onset depres-
60
sion seems to be more specific than the familial aggregation of late-onset depression: the risk of early-onset depression is elevated in famihes of probands with early-onset depression, but not in families of probands with late-onset depression; on the other hand late-onset depression occurs with a simiIar frequency in families of probands with late- and early-onset depression. However. as the mean age in relatives of the various proband groups is not higher than 50 years, the inherent power for the identification of differences with regard to frequencies of late-onset depression is low in our sample. The different patterns of familial aggregation in early- and late-onset depression suggest a comparison to dementia of the Alzheimer type; different patterns of familial aggregation in earlyand late-onset conditions define two different patterns of familial aggregation in Alzheimer disease, too (Farrer et al., 1990). But there are major differences among the two disorders with respect to familial aggregation: (a) late-onset unipolar depression does not breed true as lateonset Alzheimer disorder does; (b) early-onset unipolar depression is associated with an increased familial loading (compared to late-onset major depression) whereas early-onset Alzheimer disease does not show this pattern (Farrer et al., 1990). Furthermore, the monotonic trend across the three ranges of ages at onset favors a linear inverse relationship between age at onset and familial aggregation of unipolar major depression; there is no evidence for a non-linear relationship proposing a natural boundary between early- and late-onset depression; this is for example the case in Alzheimer disease with an age of 58 years (Farrer et al., 1990). The differences found between early- and late-onset depression are likely to reflect a linear relationship between age at onset and familial aggregation. Consequently, the arbitrarily chosen conventions of discriminating between early, medium, and late onset do not reflect valid boundaries in the age at onset continuum; these boundaries only represent conventions for a handy lay-out of the data on age at onset. The impact of the recurrence of episodes The recurrence of episodes was found
to be
associated with an increased familial risk of depression in late-onset depressions. Only a single family study in aged probands (older than 60 years) with late-onset depression has examined the impact of recurrence and could not find the familial risk to be significantly influenced by a multiplicity of episodes (Angst, 1966). As this previous study was conducted 2.5 years ago, quite different techniques for the assessment of psychopathology were used which may explain this discrepancy; especially thresholds for caseness might have been substantially higher in those times and consequently milder previous episodes had probably not been regularly identified. The impact of recurrence of episodes on the familial risk as observed in this study is furthermore in agreement with a series of more recent family studies in younger probands (aged 20-60) (Weissman et al., 1986; Leckman et al., 1984). Furthermore, it was shown that recurrent episodes were mainly found in relatives of probands with recurrent episodes. This observation favors a breeding true of the subtype of recurrent unipolar depression. As the subtypes defined by ranges of ages at onset did not show any similar familial homogeneity, it is simultaneously shown that early age at onset and multiplicity of episodes do not reflect the same phenomenon described in different terms. It has been speculated (Burvill et al., 1989) that late-onset single episodes in probands are most often induced by organic conditions or are, alternatively, reactive to organic disorders; therefore, they should not be associated with an increased familial risk of depression. Our study indicates that this hypothesis is only true if caseness in relatives is defined by recurrence of episodes; the familial aggregation of single-episode depression cannot convincingly be explained by the occurrence of organic disorders which are usually not familial by themselves. The familial pattern of unipolar depression as found in this study is compatible with a severity model of liability with the strength of recurrence defining severity; in agreement with this model single-episode depression aggregates in families of depressed probands regardless of the number of episodes whereas recurrent episodes only aggregate in probands with recurrent major depression.
61
Acknowledgement This paper was supported by funding from the German Research Foundation (Ma-1142/1-l). References Andreasen, N.C., Rice, J., Endicott, J., Reich, T. and Coryell, W. (1986) The family history approach to diagnosis: how useful is it’? Arch. Gen. Psychiatry 43, 421-429. Angst, J. (1966) Zur Atiologie und Nosologie endogener depressiver Psychosen. Springer Verlag, Berlin. Bland, R.C., Newman, S.C. and Orn, H. (1986) Recurrent and nonrecurrent depression. Arch. Gen. Psychiatry 43, 10851089. Breborowicz, G. and Trzebratowska-Trzeciak, 0. (1976) A method for testing differences in morbidity risk for affective psychoses. Acta Psychiatr. Stand. 54, 353-358. Burvill, P.W., Hall, W.D., Stampfer, H.G. and Emmerson, J.P. (1989) A comparison of early-onset and late-onset depressive illness in the elderly. Br. J. Psychiatry 155, 673-679. Farrer, L.A., Myers, R.H., Cupples, L.A., St. George-Hyslop, P.H., Bird, T.D., Rossor, M.N., Mullan, M.J., Polinsky, R., Nee, L., Heston, L., Van Broeckhoven, C., Martin, J.J., Crapper-McLachlan, D. and Growdon, J.H. (1990) Transmission and age-at-onset patterns in familial Alzheimer’s disease: evidence for heterogeneity. Neurology 40, 395403. Gershon, ES., Hamovit, J., Guroff, J.J., Dibble, E., Leckman, J.F., Sceery, W., Targum, S.D., Nurnberger, G.I., Goldin, L.R. and Bunney, W.E. (1982) A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch. Gen. Psychiatry 39, 1157-l 167. Greenwald, B.S. and Kramer-Ginsberg, E. (1988) Age at onset in geriatric depression: relationship to clinical variables. J. Affect. Disord. 15, 61-68. Kendler, K.S. (1988) Familial aggregation of schizophrenia and schizophrenia spectrum disorders. Arch. Gen. Psychiatry 45, 377-383. Klerman, G.L., Lavori, P.W., Rice, J., Reich, T., Endicott, J., Andreasen, NC., Keller, M.B. and Hirschfeld, R.M. (1985) Birth cohort trends in rates of major depressive disorder among relatives of patients with affective disorder. Arch. Gen. Psychiatry 42, 689-693. Leboyer, M., Maier, W., Lichtermann, D., Teherani, M., D’Amato, T., Franke, P., Lepine J.-P. and Minges, J. (1991) The reliability of the SADS-LA in a family study setting. Eur. Arch. Psychiatry Clin. Neurosci. (in press).
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