Age of onset in affective disorder: its correlation with hereditary and psychosocial factors

Journal of Affective Disorders 59 (2000) 139–148www.elsevier.com/ locate / jad

Research report

Age of onset in affective disorder: its correlation with hereditaryand psychosocial factors

˚* ´Lars Johnson , Gunni Andersson-Lundman, Anna Aberg-Wistedt, Aleksander A. Mathe

¨Department of Clinical Neuroscience, Section of Psychiatry, St. Goran’s Hospital, Karolinska Institute, Box 12500, S-11281 Stockholm,Sweden

Received 11 November 1998; received in revised form 30 June 1999; accepted 28 August 1999

Abstract

Background: Affective disorders probably have a multifactorial aetiology, both biological and psychosocial factors may beof importance at onset as well as at relapses. The aim of the study was to investigate how the age of onset of bipolar andunipolar disorder relates to family history of affective disorder, early parental separation and life events. A second purpose ofthis study was to analyze the importance of life events preceding the first and subsequent episodes of affective disorder.Methods: The case records of 282 patients (161 females /121 males; mean age 56) were investigated. They all had aDSM-IV based diagnosis of either bipolar I / II (67%) or unipolar (33%) disorder. Variables, such as family history, earlyparental loss and life events according to Paykel life events scale, were examined. Results: We found a significantly lowerage of onset in bipolar patients with a family history of affective disorder (28.9 vs. 33.9 years).. Bipolar patients withpreceding life events had a higher age of onset (33.1 vs. 28.3 years). Moreover, bipolar patients with heredity, had less lifeevents at onset. For the bipolar, as well as the unipolar group, life stressors more frequently preceded the first episode ofaffective disorder than the subsequent episodes. Limitations: The major limitation of this study is the retrospective approach,with e.g. difficulties to decide whether a life event plays a role in aetiology of affective disorder or is its consequence.Conclusions: Bipolar patients with high constitutional vulnerability have an earlier age of onset and need less stress factorsto become ill. Better knowledge about the stress- and the vulnerability-factors in affective disorder might contribute todevelopment of individually tailored therapeutic strategies in future. 2000 Elsevier Science B.V. All rights reserved.

Keywords: Affective disorder; Age of onset; Hereditary factors; Early parental loss; Life events

1. Introduction the catecholamine (Schildkraut, 1965) and the in-dole-amine deficiency (Coppen, 1967) hypotheses.

Aetiology of affective disorders is probably multi- Later studies led to the hypothesis of abnormalfactorial, both biological and psychological factors regulation of receptor sensitivity (Charney et al.,playing a role. Early biological research resulted in 1981). Psychological research has emphasized the

importance of parental loss, e.g. Brown et al. (1977)reported that loss of the mother before the age of 11*Corresponding author. Tel.: 1 946-8-672-2354; fax: 1 946-8-was associated with a greater risk for depression in672-1908.

E-mail address: [email protected] (L. Johnson) adulthood. Moreover, Parker (1983) reported that

0165-0327/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0165-0327( 99 )00146-9

140 L. Johnson et al. / Journal of Affective Disorders 59 (2000) 139 –148

parental low care /high protection were overrep- their case records were thoroughly investigated. Theresented in depressive patients. inclusion criteria were: DSM-IV-based diagnosis of

The relationship between biological and psycho- either bipolar disorder I / II, or unipolar disordersocial factors and their importance for the course and (recurrent depressive disorder) and current contactoutcome of bipolar and unipolar disorder have also with the centre. The mean treatment time at thebeen investigated. Thus Swann et al. (1990) found a centre was 10.8 years. The majority of the excludedcorrelation between stressful events and some clini- patients were those with other diagnoses, mostlycal and biochemical characteristics of the disease. seasonal affective disorder. A few patients hadOther studies have also found a relationship between discontinued their contact with the centre and somelife events and recurrent affective disorder, in par- had an uncertain diagnosis. The DSM-IV criteriaticular regarding the onset and relapse of illness were applied through repeated semi-structured clini-(Paykel et al., 1969; Patrick et al., 1978; Post et al., cal interviews (APA, 1994). Depressive episodes1986). were rated with MADRS. Patients were screened for

¨Centre for Affective disorders at St. Goran Hospi- physical illness with physical examination and21tal has traditionally focused on diagnosis, treatment routine blood tests (e.g. Hb, Ca , TSH, glucose).

and long-term follow up of patients with affective The university department of psychiatry covers adisorder. Thus most of the patients have been catchment area with over 110 000 inhabitants and allfollowed up for 10–15 years by the same psychiat- the patients with bipolar disorder were referred to therists and a number of patients have been treated at centre. Unipolar patients were usually referred afterthe centre for up to 25–35 years. This gives an the third depressive episode. Therefore it is reason-unique opportunity to investigate possible relation- able to assume that the patient sample was represent-ships between a multitude of variables, e.g. the age able for the general population. During many yearsof onset of illness, hereditary factors, life events, the the centre was the only clinic in the County ofcourse and outcome of the illness, type of treatment, Stockholm that administered bright light therapy,compliance, etc. The primary aims of this study were which explains the high proportion of patients withto investigate possible relationships between her- seasonal affective disorder.editary and psychosocial factors and the age of onset The demographic and clinical data of the patientof bipolar and unipolar affective disorder, and the group are further described in the Results sectionimportance of life events preceding episodes of (Table 1).affective disorder. The main hypothesis was thathigh vulnerability leads to an earlier age of onset ofthe disease. 3. Methods

A retrospective survey of the 282 case records,2. Material hospital periods as well as out-patient visits, was

completed by the same physician. A specific ques-From the population of 400 patients, treated at the tionnaire was designed to facilitate and structure the

centre, 282 patients were included in the study, and data collection. For each patient a life-chart was

Table 1Demographic data

Variable Unipolar disorder Bipolar disorder

Number 92 190Sex (female /male) 60/32 101/89Mean age (range) 58 (22–89) 55 (24–88)Mean age of onset (range) 36.5 (15–73) 31.4 (14–78) P , 0.002Mean years of illness (range) 20.8 (1–59) 23.3 (1–60)Mean number of episodes (range) 6.7 (1–20) 8.2 (1–33)Mean years on lithium (range) 10.1 (0.1–25) 12.3 (0.1–35)

L. Johnson et al. / Journal of Affective Disorders 59 (2000) 139 –148 141

constructed, which in several cases extended for SAS Institute Inc., Cary, NC, USA) was used for thedecades, in one patient for 65 years. Each episode of calculations.mania ( 1 1 ), hypomania ( 1 ), depression, mild-moderate (2) and depression, severe (2 2 ) werenoted in each chart. The categorical variables ex- 4. Resultsamined were (yes /no): (1) Heredity (recurrent affec-tive disorder in first or second degree relative); (2) The demographic data are presented in Table 1.Early parental separation (before 15 years of age: As can be seen, except from the age of onset, theredeath, definitive divorce, adoption, foster home); (3) were no differences between the unipolar and bipolarLife events ( , 12 months before onset / relapse); (4) patients. About two thirds of the patients wereSuicidal attempts (lifetime suicide attempt with at bipolar. Many patients had a long history of illness,least moderate attempt to die). The quantified vari- and patients in both groups have had a substantialables were: (5) Age of onset (first reported episode; number of episodes.in years); (6) Duration of illness (time from the first The age of onset is shown in Fig. 1. As alsoepisode; in years); (7) Life events according to demonstrated in other studies, the mean age wasPaykel Life Events Scale ( 5 PLES) (the degree of higher in unipolar disorder, P , 0.002 (Perris, 1968;life events / stress factors 12 months before the first Angst et al., 1973; Clancy et al., 1974; Burke et al.,episode / relapse was quantified). This scale (Paykel 1990).et al., 1971) has been used to quantify stress factors Table 2 illustrates the age of onset of unipolar orin many earlier studies (Ambelas, 1987; Cassano et bipolar disorder, and how it correlates to sex, familyal., 1989; Ghaiziuddin et al., 1990). history of affective disorder, life events the year

Since all the patients were in treatment at the time before onset, and parental separation in childhood.of the study, it was possible to complete the in- The correlations were statistically examined withformation through interviews and questionnaires, multiple linear regression analysis.which were responded to by 84% of the subjects. The onset of disease occurred significantly earlierEach patient was specifically asked about the family in bipolar patients who had a family history ofhistory of psychiatric disorders and, in addition, the affective disorder (P , 0.03). As displayed in Tablequestionnaire contained specific inquiries regarding 3, in unipolar patients the same stress level wasthe family disease history. needed to elicit the first disease episode regardless of

The following correlations were examined: (I) heredity. In contrast, in the bipolar group, a marked-Age of onset of first episode and (a) heredity, (b) life ly higher level of stress was associated with the onsetevents, (c) separation in childhood, (d) sex (Table 2), of disease in patients without heredity (P , 0.02).(e) number of episodes (Fig. 2), and (f) stresspoints Heredity had no effect on the number of diseaseaccording to PLES. (II) Sex and (a) number of episodes in either the bipolar or unipolar patients.episodes, and (b) number of hospitalizations (Table In bipolar patients the age of onset was sig-6). (III) Heredity and (a) stress-points, and (b) nificantly lower in patients without a history of lifenumber of episodes (Table 3). (IV) Separation in events (P , 0.009). Interestingly, life events did notchildhood and (a) stress-points, and (b) number of affect the age of onset in unipolar patients. Further-episodes (Table 4) more, a positive correlation was observed in bipolar

The study was approved by the Ethical Committee disorder between the age of onset and stress levelof the Karolinska Institute according to PLES at first episode (r 5 0.24, P ,

0.002). No such correlation was found for unipolarpatients. In unipolar patients, the mean age of onset

3.1. Statistical analysis was lower if they had had an early parental sepa-ration. However, using multiple linear regression

Results are given as means with S.D. and S.E.M. analysis the difference did not reach the statisticalMultiple linear regression analysis was used to test level of significance, although the difference wasfor possible relations. significant using Student’s t-test. Table 4 shows that

The JMP computer program (copyright 1995 by in bipolar, but not unipolar patients, higher stress


Fig. 1. Age of onset in bipolar and unipolar affective disorder.

level was associated with the first episode of the heredity for affective disorder differed according todisease in patients who experienced separation in the maternal or paternal heredity (Table 5).childhood. This group was further examined, and it Fig. 2 shows that for bipolar (P , 0.0001), as wellwas found that bipolar patients with early separation as for unipolar patients (P , 0.001) there was aand heredity had 8.8 stresspoints, while bipolar strong negative correlation between the age of onsetpatients with early loss but without heredity had 20 and number of episodes.points on the Paykel Life Events Scale before the Analysis of sex differences (Tables 2 and 6)first episode of illness. shows that men with unipolar illness had a 10-year

We also explored if there was any evidence earlier age of onset compared to women (P 5 0.005).confirming the phenomenon called genomic imprint- Women with bipolar disorder had more episodes ofing, that is if the age of onset in patients with illness and were more frequently hospitalized com-


Table 2aAge of onset in affective disorder (years) : multiple linear regression analysis (examined variables: age, sex, number of episodes, heredity,

life events and separation in childhood)

Yes S.D. S.E.M. No S.D. S.E.M. Estimate P value2Unipolar patients (R 5 0.46)

Heredity 33.8 (48) 11.8 1.71 37.6 (27) 12.7 2.44 2.30 0.428Life events 36.3 (63) 12.2 1.54 36.9 (22) 15.7 3.35 2 4.02 0.246Separation in 30.2 (22) 11.2 2.40 36.7 (50) 12.7 1.79 0.30 0.932childhood

Sex Male Female

30.2 (32) 10.5 1.86 39.9 (59) 13.5 1.76 9.19 0.0052Bipolar patients (R 5 0.52)

Heredity 28.9 (102) 11.8 1.17 33.9 (72) 13.4 1.58 2 3.91 0.026Life events 33.1 (103) 13.0 1.28 28.3 (63) 11.7 1.47 4.73 0.009Separation in 33.5 (43) 11.7 1.79 29.3 (105) 11.8 1.15 1.70 0.360childhood

Sex Male Female

31.8 (89) 12.4 1.31 31.0 (100) 12.7 1.27 0.75 0.662a The number in parentheses indicates the number of patients.

Table 3aHeredity for affective disorder

Unipolar patients Bipolar patients

Yes S.D. S.E.M. No S.D. S.E.M. Yes S.D. S.E.M. No S.D. S.E.M.

Stress-points at

first episode 11.7 (25) 9.7 1.95 12.1 (44) 9.4 1.41 ns 8.6 (93) 9.0 0.93 12.5 (65) 13.8 1.71 P , 0.02

Number of

episodes 7.9 (38) 4.8 0.77 7.2 (24) 4.5 0.91 ns 8.4 (87) 5.5 0.59 7.9 (67) 5.9 0.72 ns

a The number in parentheses indicates the number of patients.

Table 4aSeparation in childhood


Yes S.D. S.E.M. No S.D. S.E.M Yes S.D. S.E.M. No S.D. S.E.M.

Stresspoints

at first episode 9.1 (20) 10.6 2.37 13.7 (47) 9.1 1.33 ns 14.9 (39) 14.6 2.3 9.6 (97) 10.1 1.03 P , 0.02

Number of

episodes 6.4 (16) 5.0 1.20 7.0 (43) 4.7 0.71 ns 6.7 (41) 3.7 0.58 8.6 (91) 6.1 0.64 ns


Table 5aAge of onset in affective disorder

Mother with affective disorder Father with affective disorder

S.D. S.E.M. S.D. S.E.M.

Unipolar disorder 35.1 (16) 12.5 3.11 35.2 (10) 12.5 3.94 nsBipolar disorder 28.4 (37) 10.6 1.75 28.3 (25) 12.2 2.44 ns



Fig. 2. Correlation between age of onset and number of episodes in bipolar (P , 0.0001) and unipolar (P , 0.001) disorder.

pared to men (P values , 0.04 and 0.05, respective- the year before the onset of illness. The percentagely). successively diminished with further number of

Lastly, of all the patients with recurrent affective episodes (r 5 2 0.92, P , 0.0001). As shown in Fig.disorder, 67% had experienced at least one life event 3, when the diagnostic subgroups were examined


Table 6aSex differences in affective disorder


Men Women Men Women

S.D. S.E.M. S.D. S.E.M. S.D. S.E.M. S.D. S.E.M.

Number of

illness episodes 6.7 (25) 4.3 0.85 6.7 (52) 4.9 0.68 ns 7.2 (76) 5.3 0.63 9.1 (89) 6.0 0.64 P , 0.04

Number of

hospitalizations 3.5 (21) 2.5 0.55 3.8 (33) 3.1 0.55 ns 4.5 (75) 5.1 0.59 6.0 (84) 4.2 0.46 P , 0.05


separately, the same results were found. In patients epidemiological, it is conceivable that the selectionwith bipolar disorder, 63% experienced a life event procedures may have contributed to these results.12 months before the onset, but only 30% before the The findings may reflect cultural differences betweenfifth episode (r 5 2 0.75, P 5 0.001). In patients the sexes: men are less likely to seek psychiatric helpwith unipolar disorder, 72% had life events preced- and instead would stay with their general prac-ing the first episode, and only 35% before the fifth titioner. In spite of the ten year earlier age of onsetepisode (r 5 2 0.57, P 5 0.026). of unipolar disorder, men did not have more episodes

compared to women.Our results are supported by three earlier studies,

5. Discussion that found that a positive family history of affectivedisorder is associated with an earlier age of onset

The results of our study show that in bipolar (Mendlewicz et al., 1972; Taylor and Abrams, 1973;disorder, patients with heredity loading compared to Stone, 1989). In contrast, Winokur (1975) did notthose without heredity have an earlier age of onset find this association.and experience a lower degree of stress before the Several studies have demonstrated a relationshiponset of disease. These findings are in line with the between life events and manic episodes (Ambelas,stress–vulnerability model for affective disorder 1987; Joffe et al., 1989; Ellicott et al., 1990; Sclare(Post et al., 1986). The results presented support the and Creed, 1990; Hunt et al., 1992). On the otherfollowing tentative conclusion: in bipolar disorder hand, there are only a few published studies thatpatients who have a family history of affective examined heredity and life events in affective disor-disorder, that is in patients with a higher constitu- der. In line with our findings is the study of Glassnertional vulnerability, a lower stress level will suffice and Haldipur (1983) who found more evidence offor the disease to become clinically manifest, that is, stressful life events in bipolar patients with onsetthey have an earlier age of onset and have had less . 20 years of age, than , 20. Our study is alsolife events at onset. On the other hand, life events consistent with McMahon et al. (1994) who reportedappeared to play a more significant role in bipolar significantly earlier onset in subjects with bilinealpatients with late onset of the disease, which could affective disorder (both parental lines 5 higher ge-imply a lower constitutional load. For both the netic loading). The presented results do not supportbipolar and the unipolar patients there was a strong the findings of genomic imprinting as reported bynegative correlation between the age of onset and the Kato et al. (1996), that is the age of disease onsetnumber of episodes. was the same, irrespectively of whether the source of

For the total group, our results regarding the age heredity was paternal or maternal (see also, Fritze etof onset were similar to earlier studies. However, al., 1996).when men and women were studied separately, in The results in this study showing a negativeunipolar disorder men had a significantly lower age correlation between the age of onset and number ofof onset than women. Since this study was not episodes in bipolar patients are supported by


Fig. 3. Percent of patients with life events preceding the first and subsequent episodes in bipolar (r 5 2 0.75, P 5 0.001) and unipolar(r 5 2 0.57, P 5 0.026) disorder.


Burke, K.C., Burke, J.D., Regier, D.A., Rae, D.S., 1990. Age ofWinokur and Kadrmas (1989). They found thatonset of selected mental disorders in five community popula-patients with more than three episodes were moretions. Arch. Gen. Psychiatry 47, 511–518.

likely to have an early age of onset. In line withCassano, G.B., Akiskal, H.S., Musetti, L., Perugi, G., Soriani, M.,

several other studies (Angst, 1966; Ambelas, 1987; Mignani, V., 1989. Psychopathology, temperament, and pastGhaiziuddin et al., 1990; McPherson et al., 1993) our course in primary major depressions. 2. Toward a redefinition

of bipolarity with a new semistructured interview for depres-results show that life stressors more frequentlysion. Psychopathology 22, 278–288.precede the first episode of mood disorders than the

Charney, D.S., Menekes, D.B., Heninger, G.R., 1981. Receptorsubsequent episodes; this was true both for thesensitivity and the mechanism of action of antidepressive

bipolar and unipolar disorders. treatment. Arch. Gen. Psychiatry 38, 1160–1180.A certain limitation of the presented study is its Clancy, J., Tsuang, M.T., Norton, B., Winokur, W., 1974. The

Iowa 500: a comprehensive study of mania, depression andretrospective approach, with e.g. difficulties to ascer-schizophrenia. J. Iowa Med. Soc. 64, 394–398.tain whether a life event is a cause or a consequence

Coppen, A., 1967. The biochemistry of affective disorders. Br. J.of an affective disorder episode. This aspect isPsychiatry 113, 1237–1264.

shared with all the other retrospective studies. An Ellicott, A., Hammen, C., Gitlin, M., Brown, G., Jamison, K.,additional issue is whether there was some patient 1990. Life events and the course of bipolar disorder. Am. J.

Psychiatry 147, 1194–1198.selection bias, especially among the unipolar pa-Fritze, J., Schneider, B., Maurer, K., 1996. Additive effects, but notients. Considering the fact that all the patients from

synergistic interaction of stressful life-events and genetica rather large catchment area were referred to ourloading in affective disorders. J. Neural. Transm. 103, 1221–

Department, a major bias in the selection of patients 1229.seems unlikely. The unique positive aspects of this Ghaiziuddin, M., Ghaiziuddin, N., Stein, G.S., 1990. Life eventsstudy are the long period of follow-up, the treatment and the recurrence of depression. Can. J. Psychiatry 35, 239–

242.continuity (often the same psychiatrist for . 10Glassner, B., Haldipur, C.V., 1983. Life events and early and lateyears), the extensive case record survey, and the

onset of bipolar disorder. Am. J. Psychiatry 140, 215–217.possibility to complete missing information throughHunt, N., Bruce-Jones, W., Silverstone, T., 1992. Life events and

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Age of onset in affective disorder: its correlation with hereditary and psychosocial factors

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