Journal of Gerontology 1976, Vol. 31. No. 3. 300-303

The Age Factor in Depressive Illness Some Genetic Considerations Mien Mendlewicz, MD, PhD2 The age of onset of depressive illness may have an association with the genetic character and clinical course of the disorder. There are several genetic models of depressive disorder that are based on differences in age of onset. According to a multifactorial model, for example, a late onset would indicate a smaller genetic and greater environmental component. A correlation has been found between positive family history of affective illness and early age of the first episode. The presence or absence of a family history of affective illness has also been found to be distinguished by pharmacology, physiology, symptomatology, and severity. It is therefore recommended, for purposes of treatment, that a family history be gathered on patients with depressive illness.

subgroups. Most of the recent biological studies

in affective disorders differentiate between a "bipolar" form of depression, in which patients experience both mania and depression and a "unipolar" form with depression only. The depressive episodes are often characterized by depressed mood along with symptoms of a physiological shift such as decrease in appetite, sleep disturbance, and low energy level, often accompanied by guilt, difficulty in concentration, and suicidal thoughts. Manic episodes include such symptoms as euphoria, hyperactivity, decreased need for sleep, pressure of speech, flight of ideas, and irritability. Psychotic symptoms such as hallucinations and delusional ideas are not rare during depressive or manic phases. This sometimes makes it difficult to discriminate between affective disorders and schizophrenia. This classification into bipolar and unipolar forms of affective disorder is based on clinical, biologic, and genetic distinctions. Clinical features differentiating the two types (apart from the presence of manic episodes in bipolar patients and its absence in unipolar patients) include an increased prevalence of postpartum disorder in bipolar patients compared to unipolars and an increase in suicidal behavior in bipolar patients (Angst & Perris, 1968; Leonhard, Korff, & Shulz, 1962; Winokur & Clayton, 1967). Bipolar patients also show more lethargy, less agitation, and more hypersomnia during their depression than do unipolar patients. The age of onset is also significantly earlier in bipolar psychosis than in unipolar psychosis (Winokur 'Revision of presentation made at the Symposium on Age Differentiation in Depressive Illness (J. Zubin, PhD, Chairman; Lissy F. Jarvik, MD, PhD, Organizer) at the 25th Annual Scientific Meeting of Gerontological Society, San Juan, Puerto Rico, Dec. 18, 1972. J Dept. of Medical Genetics, New York State Psychiatric Institute, 722 West 168 St., New York, 10032.

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& Clayton, 1967). Most bipolar patients become affectively ill in their 30s, while unipolar patients tend to become sick in their mid-40s. Biological differences between the two psychoses were first reported by Perris (1966), who noted that bipolar patients in remission had a lower threshold to visual stimuli than unipolar patients. Studies performed at the National Institute of Mental Health reported that bipolar patients had an "augmenting" pattern and unipolar patients a "reducing" pattern of average cortical evoked response (Buchsbaum, Goodwin, Murphy, & Borge, 1971). The urinary excretion of 17-hydroxycorticosteroids was reduced in depressed bipolar patients compared to unipolar patients (Dunner, Gershon, Goodwin, & Bunney, 1972). In addition, biochemical studies of enzymes involved in norepinephrine metabolism have provided some support for differentiating depressed patients into bipolar and unipolar types. Erythrocyte catechol-omethyltransferase activity was found to be lower in women with unipolar illness than women with bipolar illness (Cohn, Dunner, & Axelrod, 1970), and monoamine oxidase activity was found to be lower in bipolar patients compared to unipolar patients (Murphy & Weiss, 1972). This last finding is a very important one, since monoamine oxidase plays a critical role in the regulation of the intracellular metabolism of several neurotransmitters, and this property has been used in creating a new series of specific antidepressive drugs, i.e., the MAO inhibitors. This enzyme is also very important from a genetic point of view in light of the recent report (Nies, Robinson, Lamborn, & Lampert, 1973) that plasma MAO activity appears to be genetically determined and that in women its activity increases with age (Robinson, Davis, Nies, Ravaris, & Sylvester, 1971). This age-related factor in MAO activity has

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suspected that the syndrome ITcalledis now depression includes different genetic

DEPRESSION: GENETICS A ND THE A GE FA CTOR

cause those cases whose onset is concurrent with the process of aging may have a greater environmental component than younger cases. However, other investigators (Stenstedt, 1952; Woodruff, Pitts, & Winokur, 1964) have not confirmed these findings. Another possible mode of transmission to consider is single gene inheritance. Kallmahn (1954) suggested, on the basis of twin studies, that bipolar illness is determined by a major autosomal gene. Winokur, Clayton, & Reich (1969) have presented data showing that bipolar illness appears to be transmitted in anX-linked dominant fashion. In our own studies, We have shown strong evidence for linkage between bipolar illness and color blindness (Mendlewicz, Fleiss, & Fieve, 1972). Our results also suggest that bipolar illness and the Xg blood group are within measurable distances from each other (Mendlewicz, Fleiss, & Fieve, 1975). Although the above results support the existence of an Xlinked dominant factor in the transmission of bipolar illness in certain families, the X-linked model cannot account for instances of fatherson transmission of the illness, which have been observed in our own material (Mendlewicz & Rainer, 1974). Other modes of transmission may thus determine the bipolar trait, a fact, if confirmed, that would indicate that bipolar illness is an heterogeneous entity. There are several methodological problems which make some results difficult to compare with one another. Ascertainment biases in family studies are almost impossible to avoid when one studies selected samples of hospitalized patients. There is further variation in the diagnostic and statistical procedures on these samples. Some investigators have studied "endogenous depressive" patients or "neurotic depressives" without further clarifying their diagnostic criteria. Risks given for relatives are not always expressed in morbidity risks, thus lacking age correction. Few family studies have examined sufficient numbers of relatives. It is almost impossible to ensure blindness to the proband's diagnosis or age of onset in these studies. We consider the age of onset to be the age at first episode, but some investigators have used the age at first hospitalization as the criterion for age of onset. The event of hospitalization may, however, reflect the tolerance of the family or community for the patient's behavior, rather than the actual onset of the illness. In a comparative study of two

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been hypothesized as one of the predisposing factors in the development of depression in elderly people. The above clinical and biological differences described between bipolar and unipolar depressive illnesses suggest that these two syndromes constitute different genetic entities. This claim is now supported by family studies showing that bipolar and unipolar depression are genetically different (Angst & Perris, 1968; Leonhard et al., 1962; Perris, 1966; Winokur et al., 1967). These studies are based on estimating morbidity risks for affective illness in the relatives of bipolar and unipolar patients. The morbidity risk for a disease is the probability of developing it during a lifetime (i.e., if one survives the risk period for this disease). Leonhard (Leonhard et al., 1962) in Berlin was the first investigator to make a clear distinction between bipolar and unipolar forms of affective disorders. He and his collaborators showed that bipolar patients tend to have bipolar and unipolar relatives while unipolar patients have unipolar relatives only. The risk for all affective illness is greater in the relatives of bipolar patients compared to unipolar patients. These findings have since been confirmed by Angst (1966) in Switzerland, Perris (1966) in Sweden, and Winokur et al. (1967) in America. It has also been reported that depressive disorders appearing at a late age may be genetically different from early-onset forms. Schulz (1951) has shown the morbidity risk for parents of depressive probands with a late onset to be 9.3% compared to 15.7% for the parents of probands with an early onset. Hopkinson (1964) has also shown that the risk in firstdegree relatives of depressive patients with an age of onset above 50 was 8.3% compared to 20.1 % for the relatives of probands with an age of onset below 50. Angst (1966), Kay (1959) and Mendlewicz, Fieve, Rainer, & Fleiss (1972) have drawn similar conclusions. This is exactly what one might expect to find in a polygenic theory of affective disorder. Polygenic inheritance (also called, more appropriately, multifactorial) is characteristic of traits like stature, intelligence, or blood pressure, which are generally termed quantitative traits. This type of inheritance is usually determined by a combination of multiple interacting genes and environmental factors. According to a multifactorial theory, morbidity risk for relatives of patients with a late onset should be lower be-

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MENDLEWICZ

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Table 1. Onset of Bipolar Illness. Age at first hospitalization

FH + .

FH-*

7 11 10

7 12 11

Total

28

30

Average age

36.0

35.7

Age at first episode 40

18 8 4

9 13 8

Total

30

30

Average age

27.7

32.0

40

• F H + = Positive family history of bipolar illness. FH- = Negative family history of bipolar illness.

fective illness in unipolar patients is a more puzzling question, because one has to eliminate the possibility of a schizophrenic illness in young patients experiencing depression. Winokur (1973) has done extensive family studies of unipolar patients and proposes to classify them according to their age of onset. "Depression Spectrum Disease" appears in early onset unipolars and is characterized by a family history of depression, alcoholism, and sociopathy. "Pure Depressive Illness" is of late onset and is characterized by the presence of only depression in the family. This hypothesis that acknowledges heterogeneity in unipolar illness is an interesting one but it needs confirmation and further investigation. It would be of interest to use this classification in therapeutic trials to see whether these two syndromes have differential responses to psychoactive drugs, including lithium. The age of onset is probably an important clinical variable in the genetic study of affective illness because, apart from defining a specific risk period, it also provides an indication of severity of the illness. It should not be used, however, as the sole criterion for classifying affective psychosis, but rather as a means of biologically studying subgroups within the bipolar and unipolar diseases. Because o? the conflicting data and the methodological problems described above, it is still not clear whether early onset depression and late onset depression in bipolar or unipolar patients represent different genetic subgroups of these illnesses. Two models of depressive disorders within the bipolar-unipolar classification remain consistent with reported family studies: (1) a dichotomy between a genetically determined form of depressive disorder starting early in life and another form with a weaker genetic component appearing later in life as a reaction to environmental factors, (2) a continuum of depressive disorders of which two extremes are contrasted by studying early versus late-onset forms of the disease. In the latter model, there would be an inverse correlation between the age of onset of depression and the strength of the genetic component. Further research on the genetics of depressive disorders is of crucial importance to distinguish between these two models. A better and more specific description of the genetic mechanisms underlying a group of diseases like the affective disorders is crucial to

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matched groups of manic-depressive patients with and without a family history of the illness, the age at first hospitalization did not discriminate between the two groups of patients, but the age at first episode was found to be significantly earlier in the patients with a positive family history (Mendlewicz et al., 1972b) (See Table 1). The average age at first admission to a hospital was similar in both groups: 36 years. The age at first episode however, was significantly different. Sixty percent of the patients with a positive family history, compared to 30% of those with a negative family history, experienced their first episode at or before the age of 25 years. The statistical methods used to analyze family data are often not sensitive enough to correct for the age distribution of the sample studied regarding the risk period for the illness, i.e., counting as unaffected those individuals who have not yet passed the risk period underestimates the morbidity rates. Family data collected on younger patients are more reliable, because sibs and parents are often still alive whereas data collected on patients with a late onset tend to underestimate the morbidity risks in older relatives, some of whom may have disappeared from observation because of death or moving. The age of onset of a disease is often an important clue to its genetic character. Is it thus relevant, as in diabetes and certain forms of muscular dystrophy to speak about a "juvenile" type and a late onset type of depressive illness? In our own population of more than 200 patients suffering from bipolar illness, the age of onset for the disease varies from 16 to 69 years, although there is a peak between the ages of 30 and 45. The first episode often tends to be a depression. The onset of af-

DEPRESSION: GENETICS AND THE AGE FACTOR

Kay, B. Observations on the natural history and genetics of old age psychoses: A Stockholm material, 1936-1937. Proceedings of Royal Society of Medicine, 1959,52, 2932. Leonhard, K., Korff, I., & Shulz, H. Die Temperamente in den Familien der monopolaren und bipolaren phasischen Psychosen. Psychiatria et Neurologia, 1962, 143, 416-434. Mendlewicz, J., Fieve, R. R., Rainer, J. D., & Fleiss, J. L. Manic-depressive illness: A comparative study of patients with and without a family history. British Journal of Psychiatry, 1972,120, 523-530. (a) Mendlewicz, J., Fieve, R. R., & Stallone, F. Relationship between the effectiveness of lithium therapy and family therapy. American Journal of Psychiatry, 1973, 130, 1011-1013. Mendlewicz, J.,Fleiss, J.L., & Fieve, R.R. Evidence for Xlinkage in the transmission of manic-depressive illness. Journal of American Medical Assn., 1912,222, 16241627.(b) Mendlewicz, J., Fleiss, J. L., & Fieve, R. R. Linkage studies in affective disorders: The Xg blood group and manic-depressive illness. In R. Fieve, D. Rosenthal, & H. Brill (Eds.), Genetics and psychopathology. Johns Hopkins Univ. Press, Baltimore, 1975. Mendlewicz, J., & Rainer, J. D. Morbidity risk and genetic transmission in manic-depressive illness. American Journal of Human Genetics, 1974,26, 692-701. Murphy, D. L., & Weiss, R. Reduced monoamine oxidase activity in blood platelets from bipolar depressed patients. American Journal of Psychiatry, 1972, 128, 1351-1357. Nies, A., Robinson, D. S., Lamborn, K. R., &Lampert, R. P. Genetic control of platelet and plasma monoamine oxidase activity. Archives of General Psychiatry, 1973, 28, 834-838. Perris, C. A study of bipolar (manic-depressive) and unipolar recurrent psychoses (I-X). Acta psychiatrica scandinavicasuppi, 1966,794, 1-189. Robinson, D. S., Davis, J. M., Nies, A., Ravaris, C. L., & Sylvester, D. Relations of sex and aging to monoamine oxidase activity of human brain, plasma, and platelets. REFERENCES Archives of General Psychiatry, 1911,24, 536-539. Angst, J. Zur Atiologie und Nosologie endogener depressiver Psychosen. Monographie aus dem gesamt- Schulz, B. Auszahlungen in der Verwandtschaft von nach Erkrankungsalter und Geschlecht gruppierten Manischgebiete der Neurologie und Psychiatrie, 1966,112. Depressiven. Archiv fur Psychiatrie und NervenkrankAngst, J., & Perris, C. Zur Nosologie endogener heiten, 1951,756,560-576. Depression: Vergleich der Ergbnisse der UntersuchunStallone, F., Shelley, E., Mendlewicz, J., & Fieve, R. R. gen. Archiv fur Psychiatrie und Nervenkrankheiten, The use of lithium in affective disorders: A double blind 1968,210, 373-386. study of prophylaxis in bipolar illness. American JourBuchsbaum, M., Goodwin, F. K., Murphy, D. L., & nal of Psychiatry, 1973,130, 1006-1010. Borge, G. Average evoked responses in affective disorders. American Journal of Psychiatry, 1911,128, 19-25. Stenstedt, A. A study in manic-depressive psychosis. Acta psychiatrica scandinavica, suppl., 1952, 79, 1-111. Cohn, C. K., Dunner, D. L., & Axelrod, J. Reduced Winokur, G. The types of affective disorders. Journal of catechol-o-methyltransferase activity in red blood cells Nervous & Mental Disease, 1973,156, 82-96. of women with primary affective disorders. Science, Winokur, G., & Clayton, P. J. Family history studies, 1. 1970,770, 1323-1324. Two types of affective disorders separated according to Dunner, D. L., Gershon, E. S., Goodwin, F. K., & Bunney, genetic and clinical factors. In J. Wortis (Ed.), Recent W. E., Jr. Excretion of 17-hydroxycorticosteroids in advances in biological psychiatry. Plenum Press, New unipolar and bipolar depressed patients. Archives of York, 1967. General Psychiatry, 1912,26, 360-363. Winokur, G., Clayton, P. J., & Reich, T. Manic-depressive Hopkinson, G. A genetic study of affective illness in paillness. Mosby, St. Louis, 1969. tients over 50. British Journal of Psychiatry, 1964,110, 244-254. Woodruff, R., Pitts, F. N., Jr., & Winokur, G. Affective disorders, II. A comparison of patients with and withKallmann, F. J. Genetic principles in manic-depressive out a family history of affective disorder. Journal of psychoses. In P. Hoch & J. Zubin (Eds.), Depression. Nervous & Mental Disease, 1964,139, 49-52. Grune&Stratton, New York, 1954.

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our understanding of psychopathological processes. The genetic approach not only contributes to our nosology, but it can help isolate homogeneous subgroups of patients for the study of biological determinants and treatment response in affective illness. This last aspect is of great importance for the psychiatrist and the general practitioner for whom depression occupies a great part of their practice. It is critically important for them to come first of all to an accurate diagnosis before choosing a specific therapeutic attitude. Taking an accurate family history should be a necessary step to making a diagnosis. It can help to determine whether a depressed patient belongs to the bipolar or unipolar group, since the presence of bipolar illness in the patients' relatives may suggest that this patient is actually suffering from a bipolar psychosis. This would have direct implication for therapy since it has been shown that lithium carbonate is effective in preventing mania and to some extent depression in bipolar patients (Stallone, Shelley, Mendlewicz, & Fieve, 1973). Furthermore, there is some evidence that lithium prophylaxis of mania may be most effective in patients with a strong family history of bipolar illness (Mendlewicz, Fieve, & Stallone, 1973). All the above studies, although not yet conclusive, do emphasize the value for both researchers and clinicians of a system of classification of depressive disorders that takes heredity into account.

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The age factor in depressive illness: some genetic considerations.

The age of onset of depressive illness may have an association with the genetic character and clinical course of the disorder. There are several genet...
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