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Late-onset schizophrenia: A review
Late-Onset Schizophrenia: A Review Jan Volavka The DSM-Ill sets the upper limit of 45 years for the age of onset of schizophrenia. However, many observations suggest that later onset of schizophrenia is possible. Most of these observations were published by European authors who did not use explicit diagnostic criteria, but not all of these observations can be discounted on that basis. It seems that cases of late-onset schizophrenia exist, that their phenomenology is similar to early-onset schizophrenia, and that they are different in their familial incidence and treatment response from primary affective disorders.
T
HERE IS A GENERAL AGREEMENT that in most cases the first symptoms of schizophrenia appear before the age of 40. However, ever since the establishment of the concept of schizophrenia it has been suggested that this disease, or something very similar to it, may also start later in life. There have been many attempts to separate these psychoses of late onset from the core group of schizophrenias on the basis of clinical symptoms, outcome, familial and other variables. The issue has not been resolved. Although there is no clear-cut split between American and European psychiatrists on the issue of late-onset schizophrenia, most Americans adhere to the Diagnostic and Statistical Manual (DSM-III)’ which is not generally accepted in Europe. The main purpose of this review is to examine the controversy involving late-onset schizophrenia and other paranoid psychoses starting later in life. Kraepelin2 established the concept of paraphrenia as a paranoid psychosis of late onset, characterized by a chronic course, delusions, hallucinations, and limited impact on intelligence. Paranoia is another late-onset paranoid psychosis. In contrast to paraphrenia, there are no hallucinations in paranoia; the disease is characterized by a well organized delusional system and a chronic course without deterioration. The concept of paraphrenia suffered an early blow when a followup of Kraepelin’s patients revealed that more than 50% of “paraphrenics” had developed a schizophrenic deterioration.3 This course was not observed by Roth4 who reported absence of deterioration of personality in cases diagnosed as “late paraphrenia.” The concept of paraphrenia, recently reviewed by Bridge and Wyatt,5.6 has now been largely abandoned, whereas paranoia has survived ‘f8to be included in the DSM-III among paranoid disorders. Can “true” schizophrenia start late in life? The DSM-III leaves no room for doubt: it can start only until the age of 45 (p. 190). Should it start later, it must be called something else. Some of those late-onset cases may be classified as affective disorders, others as atypical paranoid disorder (p. 198). These classifications have obvious and major implications for clinical practice. The treatment and prognosis of affective disorders are different from those for schizophrenia, whereas treatment for atypical paranoid disorder and other such wastebasket categories remains undefined. From the New York University at Manhattan Psychiatric Center, and the Nathan .S Kline Institute for Psychiatric Research. Address reprint requests to Jan Volavka. Manhattan Psychiatric Center, Ward’s Island, NY 10035. @I985 by Grune & Stratton, Inc.
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SCHIZOPHRENIA
Another implication concerns research. Psychopharmacologic, epidemiologic, and familial studies of elderly patients are critically influenced by the diagnostic definitions of their populations. Moreover, it should be realized that while contemporary American studies of schizophrenia are usually limited to the early-onset type, many European studies may include late-onset cases.9 If late-onset schizophrenia is really very different from the early-onset type, or if it does not exist at all, comparisons among such studies are meaningless. One important assumption underlying the age limit of the onset of schizophrenia is that psychoses starting earlier are phenomenologically different from those starting afterwards. If this assumption is correct, there should be very few (if any) cases starting after the age of 45 that meet all the DSM-III criteria for schizophrenia (except for age of onset). A small retrospective studylo suggests that the number of such cases is relatively large, and that the assumption is therefore incorrect. To understand the background of this controversy, it is necessary to review some earlier European observations. Rather than presenting an exhaustive overview of a large number of reports, we will concentrate on several studies which used a relatively large number of subjects. These studies will be reviewed in some detail as they are inaccessible to readers not fluent in German or Russian. EUROPEAN STUDIES One of the most exhaustive studies of late-onset schizophrenia was published by Bleuler.” His report is based on 130 cases of schizophrenia with onset after the age of 40. In Bleuler’s experience, symptoms develop after 40 in approximately 15% of all schizophrenics. He classified his 130 patients into four subgroups (Table 1). Groups 1 through 3 are supposedly characteristic for the late-onset schizophrenia. The ratio of females to males in Bleuler’s sample of late-onset schizophrenics was 1.94: 1. If one assumes that late- and early-onset schizophrenia are the same disease, then one would not expect major genetic differences between them. Bleuler studied the prevalence of schizophrenia among the first-degree relatives of a subgroup of 65 late-onset schizophrenics. He found 16 certain and three probable cases of schizophrenia among the patients’ siblings, and four certain and one probable case among their parents. Of these 24 ill relatives, nine had late-onset and 15 earlyonset schizophrenia. Bleuler interpreted these findings to support his notion that early- and late-onset schizophrenia constitute a single group. On the basis of these findings, Bleuler estimated the morbidity risk of schizophrenia (any age of onset, definite and probable cases) for siblings and parents of the late-onset probands at Table 1. Clinical Subgroups
of BIeulerW Late-Onset Schizophrenics (N = 130) Proportion
of Patients
Subgroup
W)
Paraphrenia-like Depressive and anxious excitement Acute schizophrenic excitement Usual schizophrenia, clinically like cases with earlier onset
19 31 6 44
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9.8% and 4.4% respectively. These estimates are in agreement with those obtained in relatives of schizophrenic probands (any age of onset) when similar diagnostic and interview procedures were used. I2 They are considerably higher than modem estimates of morbidity risk.*3~14 The distribution of the age of onset in Bleuler’s patients is presented in Table 2. We can see that there is no sudden drop in the frequency of occurrence of onset at the 45th year. The retrospective study of Huber and associatesis constitutes a substantial replication of most of Bleuler’s observations. The initial sample of these authors consisted of 644 cases of schizophrenia admitted to a mental hospital between 1945 and 1959. The onset of manifest illness occurred after the age of 40 in 110 (17.1%) of the cases (including the patients who died before the study was concluded). Fifty-five of these 110 cases had first onset of symptoms after the age of 45. Considering the surviving patients only, an onset after 40 occurred in 14% of the cases, a proportion quite close to Bleuler’s estimate of 14.8%. Huber and associates state that they used the concept of late schizophrenia in the same sense as Bleuler did: specifically, their diagnostic criteria included the onset of Schneider’s firstrank symptoms after 40 in the absence of organic brain disease. The ratio of females to males (l-8:1) as well as the distribution of the age of onset in the Huber sample were quite similar to those in the Bleuler sample. The clinical picture of Huber’s patients was dominated by paranoid hallucinations and delusions, whereas hebephrenic and catatonic symptoms were rare. The outcome was more favorable than in schizophrenia of earlier onset, with the rate of all remissions amounting to 30%. Huber and associates report no detailed findings on schizophrenia among their patients’ relatives. The proportion of schizophrenic cases among all relatives of late-onset cases was 19.4%. It is surprising that not a single case of cyclothymiu (affective disorder) was detected among relatives of the late-onset schizophrenics. Angst and associates I6 studied a sample of 709 schizophrenic patients. They reported that the age of onset varied according to the subtype. Paranoid schizophrenia started between the ages of 40 and 50 in 22% of the cases, and after 50 in 13% of the cases. Other types of schizophrenia had an appreciably earlier age of onset (Fig. 1). There was an interaction among the age of onset, diagnostic subtype and sex. In paranoid schizophrenics, the median age of onset was 29 years for males and 37 years for females. A similar difference was found in schizoaffective psychoses, whereas no significant difference in the age of onset was observed between the male and female catatonics. Table 2. Bleuler’V Late-Onset Schizophrenics (N = 130)
Distributionof Onset Age Proportion Age of Onset 40 to 45 lo 50 to 55 to over
44 49 54 59 60
of Patients (“/I 35 33 16 12 4
151
LATE-ONSET SCHIZOPHRENIA
Catatonic Schizophrenia Paranoid Schizophrenia Schizoaffective Psychoses
40 30 20 10
0 lo-
19
20.29
30-39
LO-L9
50-59
60-69
Age
Fig 1. Age of onset (Reprinted with permission.‘6)
The concept of late-onset schizophrenia is also alive in the Russian literature. Rokhlinar7 compared a group of late-onset schizophrenics (defined by onset after 50 years) with a group of early-onset schizophrenics. At the time of her study, the patients in the late-onset group were matched with the early-onset patients on age, sex and clinical type of schizophrenia. This matching also equalized the group for the difficulty in obtaining diagnostic information on elderly relatives. There were 62 late-onset and 58 early-onset patients. Explicit diagnostic criteria for schizophrenia are not given. Both groups showed “affective-delusional attacks.” There were depressive and persecutory delusions, hallucinations, ideas of reference, and catatonic manifestations. First-degree relatives of late-onset and early-onset probands were screened for the presence of mental disease. The number of screened relatives of the late-onset group was 506; the number for the early-onset was 455. Results are summarized in Table 3. The risk for schizophrenia and affective psychoses in first-degree relatives of lateonset probands was significantly smaller than those in relatives of early-onset probands. However, it was greater than for the general population. The risk for schizophrenia was quite close to that reported by M. Bleuler (9.8%).” The morbidity for schizophrenia among relatives of probands with late-onset paranoid psychoses was reported to be greater than in general population but smaller than in relatives of early-onset schizophrenic probands 18.19, these reports are in agreement with Rokhlina’s observations. Rokhlina proposed two hypotheses concerning the genetic transmission of lateonset psychoses: (1) the same genes which transmit the disease also control the age of onset and, (2) the disease-transmitting genes do nof control the age of onset; separate (modifying) genes are responsible for that variable. If the first hypothesis is true, then the ages of onset in the probands should be highly correlated with those of their parents and children - this was not observed. Table 4 displays the Table 3. Morbidity Risks for Schizophrenia and Affective Psychoses in First-degree Relatives in Two Groups of Probands” Probands’
Type of Schizophrenia Early Onset
Late Onset Relatives’
Diagnoses
Schizophrenia Affective psychoses
lP < 0.05.
N
Risk
N
Risk
33 6
10.8” 2.0’
48 18
17.7 6.6
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Table 4. Correlation Coefficients (r) Between Ages of Onset in Probands and Their Relatlves17 Proband’s Late Onset
Type of Schizophrenia Early Onset
Relatives
r
P
r
P
Parents Siblings Offspring
-.20 .51 .02
NS 0.05 NS
-.07 -.03 .lQ
NS NS NS
coefficients of correlation (r) between the ages of onset of psychosis in the probands and in their relatives. It shows a significant positive correlation between the probands and their siblings, but not between the probands and their parents or offspring. The author interprets this finding as supportive of her aforementioned second hypothesis. CRITIQUE OF EUROPEAN STUDIES The studies reviewed share some serious methodological problems. Explicit diagnostic criteria are not provided in any of them, nor is it clear who actually made the diagnoses. No data on the reliability of the diagnoses are given, a particularly important problem in the study of Angst and associates16 which combined patients from seven institutions located in five countries. Furthermore, it appears that the probands’ diagnoses were known to the persons obtaining the family information. This problem makes it difficult to evaluate the estimates of morbidity in relatives, and might partly account for the high estimates reported. There are strong indications in these papers that modern American psychiatrists would rediagnose some cases of “late-onset schizophrenia” as major affective disorders. M. Bleuler” seemed well aware of the problem; he stated that after the age of 40, the border between schizophrenia and “manic-depressive insanity” is even less certain than at an earlier age (p. 259). However, he provided no hint concerning the differential diagnosis between his “depressive and anxious catatonia” and melancholia. In the Huber15 study, the 30% full remissions reported certainly are more suggestive of affective disorder than schizophrenia. Relatively detailed descriptions are provided for four Huber cases; the diagnosis of affective disorder seems quite possible in at least one of them (case 1, p. 61). Huber reports 19.4% schizophrenics among relatives of his patients. This is an unusually high figure for schizophrenia among relatives of schizophrenic probands,i4 but it is close to that reported for affective disorder among relatives of probands with affective disorder. I3 We suspect that at least some of the cases of mental illness among the relatives diagnosed as schizophrenia might be rediagnosed as affective disorders if contemporary American criteria were used. This suspicion is further strengthened by Huber’s amazing finding of no affective disorder among relatives. Perhaps the high estimates of morbidity for schizophrenia among the relatives of Bleuler’s and Rokhlina’s probands may be explained in a similar way. Clinical descriptions of Rokhlina’s probands include “affective-delusional attacks” and depressive delusions, symptoms which suggest that she may have
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153
included some patients meeting contemporary American criteria for Primary affective disorder in her group of “late-onset schizophrenics.” The high female-male ratio reported by Bleuler” and by Huber15 (1.94:1 and 1.8: 1 respectively) may suggest to many readers that patients with affective disorders were included in their samples. A similar inference may be made on the basis of the interaction between age of onset and gender reported by Angst and associates.‘0 The ratio one would expect in schizophrenia diagnosed by contemporary methods is close to 1:l (case 1, p. 186). Bleuler’s ratio is closer to those usually reported in affective disorder.20 In a sample of 61 patients with manic-depressive disease, the female-male ratio was 1.35:1, and the age of onset was after the age of 40 in 21%.?O The number of episodes of illness occurring in the same sample (p. 54) after the age of 40 in females was 73 and in males it was 37; this yields a female-male ratio of 1.97:1 which is strikingly similar to that reported by Bleuler. However, this issue is quite unclear. Although the female-male ratio is close to 1:l when averaged over the entire age range, there is some evidence suggesting an interaction between this ratio and age. The ratio increases with the age of onset, and in cases starting after 35 the ratio may be as high as 1.5:1 .21 The authors reviewed by Seeman are potential targets of the same criticism aimed at the studies of Bleuler, Huber, and Angst: some of the cases could have been diagnosed as affective disorder rather than schizophrenia if different criteria were used. Thus the increased female-male ratio in older patient groups reviewed by Seeman may be a reflection of the fact that the difficulty of the differential diagnosis between schizophrenia and affective disorder increases with the patient’s age at the time of symptom onset. To avoid this circular line of reasoning one would need a very narrowly defined set of schizophrenics, where explicit modern criteria were used to differentiate them from patients with affective disorders, and to examine the interaction between age and gender in that set. Abrams and Taylor (personal communication, 1983) have studied such a set of schizophrenics (age range 14 to 41) and their unpublished data suggest that the female-male ratio does in fact increase with age. So far we discussed the possible confusion between schizophrenia and affective disorder in certain European studies. Paranoia is another disorder which must be distinguished from schizophrenia. Time course is one of the important features differentiating paranoia from schizophrenia: chronic course without deterioration is characteristic for paranoia. Most of the studies we reviewed are cross-sectional or retrospective rather than prospective, and therefore not optimally suited for the study of time course. Furthermore, the diagnostic criteria in most of the studies are not explicit; it is therefore not clear how the differential diagnosis between lateonset schizophrenia and paranoia was made. The European studies we reviewed have many deficiences, but they also have some strengths. They are based on relatively large samples, and the duration of observation is frequently quite long (e.g. an average of 17.8 years in the Huber study). The studies are also reasonably consistent with each other in their estimates of incidence of late-onset schizophrenia, its clinical characteristics, gender ratio and-to some extent-the relatives’ morbidity. If all these authors are wrong, they seem to be wrong in the same way. Certain conclusions can be drawn from these studies. First, schizophrenia or
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schizophrenia-like psychoses do start after the age of 40 and there is no evidence that their incidence suddenly drops to zero at 45. The incidence shows a gradual decline throughout the fifth and sixth decades. Some of these cases would probably de diagnosed as major affective disorder or paranoia using modern criteria, but the few clinical descriptions which are given do not suggest that all of them would be so diagnosed. The evidence indicates that some of these psychoses of late onset are familial, and may be genetically transmitted. It is probable that these psychoses are genetically related to schizophrenia but the precise nature of this relationship cannot be determined without further research. FUTURERESEARCH It is not clear whether late-onset schizophrenia exists, but there are clearly patients with late-onset psychoses who are difficult to classify. The etiology, treatment response, and prognosis of these psychoses are not well defined. These problems cannot be resolved by an arbitrary administrative fiat; new research is urgently needed. One possible approach is that taken by Abrams and Taylor. These authors studied a sample of 465 consecutively admitted patients who were diagnosed using stringent and explicit criteria. The diagnosis was made on the basis of current symptoms, without knowledge of age of onset and other historical variables. In their sample only 7% of the patients satisfied the diagnostic criteria for schizophrenia. Their age of onset of schizophrenic symptoms was 14 to 41 years (personal communication, 1983). These data thus do provide empirical support for the age limit on onset of schizophrenia at 45. Some of the phenomenological differences between late-onset and early-onset schizophrenia may be due to the presence of organic brain disorders which occur more frequently with increasing age. Very little is known about this. GabrieP addressed this question; unfortunately, he provides no definition or measure of “psycho-organic impairment” in his paper. Other phenomenological differences between the late- and early-onset patients might be due to the fact that early-onset patients have generally received more treatment for their condition; furthermore, the effects of prolonged hospitalization and other consequences of schizophrenia are more likely to be observed in this group. We found no published attempts to study these problems. A serious problem shared by studies in this area is the reliability of the determination of the age of onset. Schizophrenia often starts slowly as a gradual evolutionary process, progressing from schizoid personality disorder to psychosis. This development is difficult to trace in retrospective studies. Such studies may reliably determine discrete events such as the first treatment or hospitalization, but these events occur at varying lengths of time after the onset of schizophrenic symptoms. Longitudinal prospective studies are needed to deal with this problem. DISCUSSION There is a controversy regarding late-onset schizophrenia. Certain European observations strongly suggest that such psychoses exist, that their phenomenology is similar to early-onset schizophrenia in many cases, and that they are at least partially different in their phenomenology, familial incidence and treatment response
155
LATE-ONSET SCHIZOPHRENIA
from primary affective disorders. Most European reports are not recent, which may account for the lack of explicit diagnostic criteria. According to DSM-III, schizophrenia cannot start after age 45. Although some data supporting this position exist, we found no report published in any language providing an empirical base for this DSM-III age limit. Patients who meet all the DSM-III criteria for the diagnosis of schizophrenia except for the age of onset do exist, and their classification presents serious problems for clinical practice, research, and for communication among psychiatrists. The nosologic validity of late-onset schizophrenia merits examination with modern research methods. New evidence may support an upper limit on age of onset of schizophrenia. Until such evidence is available, the DSM-III age limit should be set aside. NOTE ADDED IN PROOF
After the completion of this manuscript, two additional papers suggesting that late-onset schizophrenia may occur in contemporary American patients were published.23,24 ACKNOWLEDGMENT We would like to thank Drs. Richard Abrams, Robert Cancro, Thomas Craig, Paul Grof, and Sarnoff A. Mednick for commenting on the manuscript, and Edith Klein, the librarian at the Manhattan Psychiatric
Center,
for her help.
REFERENCES 1. Spitzer RL ted): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington, American Psychiatric Association, 1980 2. Kraepelin E: On paranoid diseases (in German). Zeitschrift fur Gesamte Neurologie und Psychiatric 11:617-638, 1912 3. Mayer W: On paraphrenic psychoses (in German). Zeitschrift fur Gesamte Neurologie und Psychiatric 7 1: 187-206, 1921 4. Roth M: The natural history of mental disorder in old age. J Ment Sci 101:281-301, 1955 5. Bridge TP, Wyatt RI: Paraphrenia: Paranoid states of late life. I. European research. J Am Geriatr Sot 28:193-200, 1980 6. Bridge TP, Wyatt RI: Parpahrenia: Paranoid states of late life. II. American research. J Am Geriatr Sot 28:201-205, 1980 7. Winokur G: Delusional disorder (paranoid). Compr Psych 18:51 l-521, 1977 8. Kendler KS: The nosologic validity of paranoia (simple delusional disorder). Arch Gen Psychiatry 37:699-706, 1980 9. van Ree MM, Verhoeven WMA, de Wied D, et al: The use of the synthetic peptides y-type endorphine in mentally ill patients, in Verebey K (ed): Opioids in Mental Illness: Theories, Observations, and Treatment Possibilities. New York, The New York Academy of Sciences, 1982 p. 486 10. Essa M: Late-onset schizophrenia. Am J Psychiatry 139:1528, 1982 1 I. Bleuler M: Late schizophrenic clinical pictures (in German). Fortschr Neurol Psychiatr 15:259-290, 1943 12. Bleuler E: Lehrbuch der Psychiatric. Berlin, Springer, 1955 13. Tsuang MT, Winokur G, Crowe RT: Morbidity risks of schizophrenia and affective disorders among first degree relatives of patients with schizophrenia, mania, depression, and surgical conditions. Br J Psychiatry 137:497-504, 1980 14. Abrams R, Taylor MA: The genetics of schizophrenia: A reassessment using modern criteria. Am J Psychiatry 140:171-175, 1983
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15. Huber G, Gross G, Schuttler R: Late schizophrenia (in German). Arch Psychiatr Nervenkr 22153-66, 1975 16. Angst J, Baastrup P, Grof P, et al: Statistical aspects of the onset and course of schizophrenic psychoses (in German), in Huber G fed): Verlauf und Ausgang Schizophrenener Erkrankungen. Stuttgart-New York, FK Schattauer, 1973, pp. 67-78 17. Rokhhna ML: A comparative clinico-genetic study of attack-like schizophrenia with late and early manifestations with regard to age (in Russian). Zh Nevropatol Psikhiatr 75:417424, 1975 18. Funding T: Genetics of paranoid psychoses of later life. Acta Psychiatr Stand 37:267282, 1961 19. Kay DWK: Late paraphrenia and its bearing on the aetiology of schizophrenia. Acta Psychiatr Stand 39: 159-169, 1963 20. Winokur G, Clayton PJ, Reich T: Manic Depressive Illness. St Louis, CV Mosby, 1969 21. Seeman VM: Gender differences in schizophrenia. Can J Psychiatry 27:107-l 11, 1982 22. Gabriel E: The influence of psycho-organic factors in old age on the course of socalled late schizophrenias (in German). Psychiatr Clin 7:358-364, 1974 23. Gold DG: Late age of onset schizophrenia: Present but unaccounted for Compr Psychiatry 25:225-237, 1984 24, Rabins P, Pauker S,. Thomas J: Can schizophrenia begin after age 44? COmpr Psychiatry 25:290-294, 1984
T
HERE IS A GENERAL AGREEMENT that in most cases the first symptoms of schizophrenia appear before the age of 40. However, ever since the establishment of the concept of schizophrenia it has been suggested that this disease, or something very similar to it, may also start later in life. There have been many attempts to separate these psychoses of late onset from the core group of schizophrenias on the basis of clinical symptoms, outcome, familial and other variables. The issue has not been resolved. Although there is no clear-cut split between American and European psychiatrists on the issue of late-onset schizophrenia, most Americans adhere to the Diagnostic and Statistical Manual (DSM-III)’ which is not generally accepted in Europe. The main purpose of this review is to examine the controversy involving late-onset schizophrenia and other paranoid psychoses starting later in life. Kraepelin2 established the concept of paraphrenia as a paranoid psychosis of late onset, characterized by a chronic course, delusions, hallucinations, and limited impact on intelligence. Paranoia is another late-onset paranoid psychosis. In contrast to paraphrenia, there are no hallucinations in paranoia; the disease is characterized by a well organized delusional system and a chronic course without deterioration. The concept of paraphrenia suffered an early blow when a followup of Kraepelin’s patients revealed that more than 50% of “paraphrenics” had developed a schizophrenic deterioration.3 This course was not observed by Roth4 who reported absence of deterioration of personality in cases diagnosed as “late paraphrenia.” The concept of paraphrenia, recently reviewed by Bridge and Wyatt,5.6 has now been largely abandoned, whereas paranoia has survived ‘f8to be included in the DSM-III among paranoid disorders. Can “true” schizophrenia start late in life? The DSM-III leaves no room for doubt: it can start only until the age of 45 (p. 190). Should it start later, it must be called something else. Some of those late-onset cases may be classified as affective disorders, others as atypical paranoid disorder (p. 198). These classifications have obvious and major implications for clinical practice. The treatment and prognosis of affective disorders are different from those for schizophrenia, whereas treatment for atypical paranoid disorder and other such wastebasket categories remains undefined. From the New York University at Manhattan Psychiatric Center, and the Nathan .S Kline Institute for Psychiatric Research. Address reprint requests to Jan Volavka. Manhattan Psychiatric Center, Ward’s Island, NY 10035. @I985 by Grune & Stratton, Inc.
LATE-ONSET
149
SCHIZOPHRENIA
Another implication concerns research. Psychopharmacologic, epidemiologic, and familial studies of elderly patients are critically influenced by the diagnostic definitions of their populations. Moreover, it should be realized that while contemporary American studies of schizophrenia are usually limited to the early-onset type, many European studies may include late-onset cases.9 If late-onset schizophrenia is really very different from the early-onset type, or if it does not exist at all, comparisons among such studies are meaningless. One important assumption underlying the age limit of the onset of schizophrenia is that psychoses starting earlier are phenomenologically different from those starting afterwards. If this assumption is correct, there should be very few (if any) cases starting after the age of 45 that meet all the DSM-III criteria for schizophrenia (except for age of onset). A small retrospective studylo suggests that the number of such cases is relatively large, and that the assumption is therefore incorrect. To understand the background of this controversy, it is necessary to review some earlier European observations. Rather than presenting an exhaustive overview of a large number of reports, we will concentrate on several studies which used a relatively large number of subjects. These studies will be reviewed in some detail as they are inaccessible to readers not fluent in German or Russian. EUROPEAN STUDIES One of the most exhaustive studies of late-onset schizophrenia was published by Bleuler.” His report is based on 130 cases of schizophrenia with onset after the age of 40. In Bleuler’s experience, symptoms develop after 40 in approximately 15% of all schizophrenics. He classified his 130 patients into four subgroups (Table 1). Groups 1 through 3 are supposedly characteristic for the late-onset schizophrenia. The ratio of females to males in Bleuler’s sample of late-onset schizophrenics was 1.94: 1. If one assumes that late- and early-onset schizophrenia are the same disease, then one would not expect major genetic differences between them. Bleuler studied the prevalence of schizophrenia among the first-degree relatives of a subgroup of 65 late-onset schizophrenics. He found 16 certain and three probable cases of schizophrenia among the patients’ siblings, and four certain and one probable case among their parents. Of these 24 ill relatives, nine had late-onset and 15 earlyonset schizophrenia. Bleuler interpreted these findings to support his notion that early- and late-onset schizophrenia constitute a single group. On the basis of these findings, Bleuler estimated the morbidity risk of schizophrenia (any age of onset, definite and probable cases) for siblings and parents of the late-onset probands at Table 1. Clinical Subgroups
of BIeulerW Late-Onset Schizophrenics (N = 130) Proportion
of Patients
Subgroup
W)
Paraphrenia-like Depressive and anxious excitement Acute schizophrenic excitement Usual schizophrenia, clinically like cases with earlier onset
19 31 6 44
150
JAN VOLAVKA
9.8% and 4.4% respectively. These estimates are in agreement with those obtained in relatives of schizophrenic probands (any age of onset) when similar diagnostic and interview procedures were used. I2 They are considerably higher than modem estimates of morbidity risk.*3~14 The distribution of the age of onset in Bleuler’s patients is presented in Table 2. We can see that there is no sudden drop in the frequency of occurrence of onset at the 45th year. The retrospective study of Huber and associatesis constitutes a substantial replication of most of Bleuler’s observations. The initial sample of these authors consisted of 644 cases of schizophrenia admitted to a mental hospital between 1945 and 1959. The onset of manifest illness occurred after the age of 40 in 110 (17.1%) of the cases (including the patients who died before the study was concluded). Fifty-five of these 110 cases had first onset of symptoms after the age of 45. Considering the surviving patients only, an onset after 40 occurred in 14% of the cases, a proportion quite close to Bleuler’s estimate of 14.8%. Huber and associates state that they used the concept of late schizophrenia in the same sense as Bleuler did: specifically, their diagnostic criteria included the onset of Schneider’s firstrank symptoms after 40 in the absence of organic brain disease. The ratio of females to males (l-8:1) as well as the distribution of the age of onset in the Huber sample were quite similar to those in the Bleuler sample. The clinical picture of Huber’s patients was dominated by paranoid hallucinations and delusions, whereas hebephrenic and catatonic symptoms were rare. The outcome was more favorable than in schizophrenia of earlier onset, with the rate of all remissions amounting to 30%. Huber and associates report no detailed findings on schizophrenia among their patients’ relatives. The proportion of schizophrenic cases among all relatives of late-onset cases was 19.4%. It is surprising that not a single case of cyclothymiu (affective disorder) was detected among relatives of the late-onset schizophrenics. Angst and associates I6 studied a sample of 709 schizophrenic patients. They reported that the age of onset varied according to the subtype. Paranoid schizophrenia started between the ages of 40 and 50 in 22% of the cases, and after 50 in 13% of the cases. Other types of schizophrenia had an appreciably earlier age of onset (Fig. 1). There was an interaction among the age of onset, diagnostic subtype and sex. In paranoid schizophrenics, the median age of onset was 29 years for males and 37 years for females. A similar difference was found in schizoaffective psychoses, whereas no significant difference in the age of onset was observed between the male and female catatonics. Table 2. Bleuler’V Late-Onset Schizophrenics (N = 130)
Distributionof Onset Age Proportion Age of Onset 40 to 45 lo 50 to 55 to over
44 49 54 59 60
of Patients (“/I 35 33 16 12 4
151
LATE-ONSET SCHIZOPHRENIA
Catatonic Schizophrenia Paranoid Schizophrenia Schizoaffective Psychoses
40 30 20 10
0 lo-
19
20.29
30-39
LO-L9
50-59
60-69
Age
Fig 1. Age of onset (Reprinted with permission.‘6)
The concept of late-onset schizophrenia is also alive in the Russian literature. Rokhlinar7 compared a group of late-onset schizophrenics (defined by onset after 50 years) with a group of early-onset schizophrenics. At the time of her study, the patients in the late-onset group were matched with the early-onset patients on age, sex and clinical type of schizophrenia. This matching also equalized the group for the difficulty in obtaining diagnostic information on elderly relatives. There were 62 late-onset and 58 early-onset patients. Explicit diagnostic criteria for schizophrenia are not given. Both groups showed “affective-delusional attacks.” There were depressive and persecutory delusions, hallucinations, ideas of reference, and catatonic manifestations. First-degree relatives of late-onset and early-onset probands were screened for the presence of mental disease. The number of screened relatives of the late-onset group was 506; the number for the early-onset was 455. Results are summarized in Table 3. The risk for schizophrenia and affective psychoses in first-degree relatives of lateonset probands was significantly smaller than those in relatives of early-onset probands. However, it was greater than for the general population. The risk for schizophrenia was quite close to that reported by M. Bleuler (9.8%).” The morbidity for schizophrenia among relatives of probands with late-onset paranoid psychoses was reported to be greater than in general population but smaller than in relatives of early-onset schizophrenic probands 18.19, these reports are in agreement with Rokhlina’s observations. Rokhlina proposed two hypotheses concerning the genetic transmission of lateonset psychoses: (1) the same genes which transmit the disease also control the age of onset and, (2) the disease-transmitting genes do nof control the age of onset; separate (modifying) genes are responsible for that variable. If the first hypothesis is true, then the ages of onset in the probands should be highly correlated with those of their parents and children - this was not observed. Table 4 displays the Table 3. Morbidity Risks for Schizophrenia and Affective Psychoses in First-degree Relatives in Two Groups of Probands” Probands’
Type of Schizophrenia Early Onset
Late Onset Relatives’
Diagnoses
Schizophrenia Affective psychoses
lP < 0.05.
N
Risk
N
Risk
33 6
10.8” 2.0’
48 18
17.7 6.6
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Table 4. Correlation Coefficients (r) Between Ages of Onset in Probands and Their Relatlves17 Proband’s Late Onset
Type of Schizophrenia Early Onset
Relatives
r
P
r
P
Parents Siblings Offspring
-.20 .51 .02
NS 0.05 NS
-.07 -.03 .lQ
NS NS NS
coefficients of correlation (r) between the ages of onset of psychosis in the probands and in their relatives. It shows a significant positive correlation between the probands and their siblings, but not between the probands and their parents or offspring. The author interprets this finding as supportive of her aforementioned second hypothesis. CRITIQUE OF EUROPEAN STUDIES The studies reviewed share some serious methodological problems. Explicit diagnostic criteria are not provided in any of them, nor is it clear who actually made the diagnoses. No data on the reliability of the diagnoses are given, a particularly important problem in the study of Angst and associates16 which combined patients from seven institutions located in five countries. Furthermore, it appears that the probands’ diagnoses were known to the persons obtaining the family information. This problem makes it difficult to evaluate the estimates of morbidity in relatives, and might partly account for the high estimates reported. There are strong indications in these papers that modern American psychiatrists would rediagnose some cases of “late-onset schizophrenia” as major affective disorders. M. Bleuler” seemed well aware of the problem; he stated that after the age of 40, the border between schizophrenia and “manic-depressive insanity” is even less certain than at an earlier age (p. 259). However, he provided no hint concerning the differential diagnosis between his “depressive and anxious catatonia” and melancholia. In the Huber15 study, the 30% full remissions reported certainly are more suggestive of affective disorder than schizophrenia. Relatively detailed descriptions are provided for four Huber cases; the diagnosis of affective disorder seems quite possible in at least one of them (case 1, p. 61). Huber reports 19.4% schizophrenics among relatives of his patients. This is an unusually high figure for schizophrenia among relatives of schizophrenic probands,i4 but it is close to that reported for affective disorder among relatives of probands with affective disorder. I3 We suspect that at least some of the cases of mental illness among the relatives diagnosed as schizophrenia might be rediagnosed as affective disorders if contemporary American criteria were used. This suspicion is further strengthened by Huber’s amazing finding of no affective disorder among relatives. Perhaps the high estimates of morbidity for schizophrenia among the relatives of Bleuler’s and Rokhlina’s probands may be explained in a similar way. Clinical descriptions of Rokhlina’s probands include “affective-delusional attacks” and depressive delusions, symptoms which suggest that she may have
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153
included some patients meeting contemporary American criteria for Primary affective disorder in her group of “late-onset schizophrenics.” The high female-male ratio reported by Bleuler” and by Huber15 (1.94:1 and 1.8: 1 respectively) may suggest to many readers that patients with affective disorders were included in their samples. A similar inference may be made on the basis of the interaction between age of onset and gender reported by Angst and associates.‘0 The ratio one would expect in schizophrenia diagnosed by contemporary methods is close to 1:l (case 1, p. 186). Bleuler’s ratio is closer to those usually reported in affective disorder.20 In a sample of 61 patients with manic-depressive disease, the female-male ratio was 1.35:1, and the age of onset was after the age of 40 in 21%.?O The number of episodes of illness occurring in the same sample (p. 54) after the age of 40 in females was 73 and in males it was 37; this yields a female-male ratio of 1.97:1 which is strikingly similar to that reported by Bleuler. However, this issue is quite unclear. Although the female-male ratio is close to 1:l when averaged over the entire age range, there is some evidence suggesting an interaction between this ratio and age. The ratio increases with the age of onset, and in cases starting after 35 the ratio may be as high as 1.5:1 .21 The authors reviewed by Seeman are potential targets of the same criticism aimed at the studies of Bleuler, Huber, and Angst: some of the cases could have been diagnosed as affective disorder rather than schizophrenia if different criteria were used. Thus the increased female-male ratio in older patient groups reviewed by Seeman may be a reflection of the fact that the difficulty of the differential diagnosis between schizophrenia and affective disorder increases with the patient’s age at the time of symptom onset. To avoid this circular line of reasoning one would need a very narrowly defined set of schizophrenics, where explicit modern criteria were used to differentiate them from patients with affective disorders, and to examine the interaction between age and gender in that set. Abrams and Taylor (personal communication, 1983) have studied such a set of schizophrenics (age range 14 to 41) and their unpublished data suggest that the female-male ratio does in fact increase with age. So far we discussed the possible confusion between schizophrenia and affective disorder in certain European studies. Paranoia is another disorder which must be distinguished from schizophrenia. Time course is one of the important features differentiating paranoia from schizophrenia: chronic course without deterioration is characteristic for paranoia. Most of the studies we reviewed are cross-sectional or retrospective rather than prospective, and therefore not optimally suited for the study of time course. Furthermore, the diagnostic criteria in most of the studies are not explicit; it is therefore not clear how the differential diagnosis between lateonset schizophrenia and paranoia was made. The European studies we reviewed have many deficiences, but they also have some strengths. They are based on relatively large samples, and the duration of observation is frequently quite long (e.g. an average of 17.8 years in the Huber study). The studies are also reasonably consistent with each other in their estimates of incidence of late-onset schizophrenia, its clinical characteristics, gender ratio and-to some extent-the relatives’ morbidity. If all these authors are wrong, they seem to be wrong in the same way. Certain conclusions can be drawn from these studies. First, schizophrenia or
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schizophrenia-like psychoses do start after the age of 40 and there is no evidence that their incidence suddenly drops to zero at 45. The incidence shows a gradual decline throughout the fifth and sixth decades. Some of these cases would probably de diagnosed as major affective disorder or paranoia using modern criteria, but the few clinical descriptions which are given do not suggest that all of them would be so diagnosed. The evidence indicates that some of these psychoses of late onset are familial, and may be genetically transmitted. It is probable that these psychoses are genetically related to schizophrenia but the precise nature of this relationship cannot be determined without further research. FUTURERESEARCH It is not clear whether late-onset schizophrenia exists, but there are clearly patients with late-onset psychoses who are difficult to classify. The etiology, treatment response, and prognosis of these psychoses are not well defined. These problems cannot be resolved by an arbitrary administrative fiat; new research is urgently needed. One possible approach is that taken by Abrams and Taylor. These authors studied a sample of 465 consecutively admitted patients who were diagnosed using stringent and explicit criteria. The diagnosis was made on the basis of current symptoms, without knowledge of age of onset and other historical variables. In their sample only 7% of the patients satisfied the diagnostic criteria for schizophrenia. Their age of onset of schizophrenic symptoms was 14 to 41 years (personal communication, 1983). These data thus do provide empirical support for the age limit on onset of schizophrenia at 45. Some of the phenomenological differences between late-onset and early-onset schizophrenia may be due to the presence of organic brain disorders which occur more frequently with increasing age. Very little is known about this. GabrieP addressed this question; unfortunately, he provides no definition or measure of “psycho-organic impairment” in his paper. Other phenomenological differences between the late- and early-onset patients might be due to the fact that early-onset patients have generally received more treatment for their condition; furthermore, the effects of prolonged hospitalization and other consequences of schizophrenia are more likely to be observed in this group. We found no published attempts to study these problems. A serious problem shared by studies in this area is the reliability of the determination of the age of onset. Schizophrenia often starts slowly as a gradual evolutionary process, progressing from schizoid personality disorder to psychosis. This development is difficult to trace in retrospective studies. Such studies may reliably determine discrete events such as the first treatment or hospitalization, but these events occur at varying lengths of time after the onset of schizophrenic symptoms. Longitudinal prospective studies are needed to deal with this problem. DISCUSSION There is a controversy regarding late-onset schizophrenia. Certain European observations strongly suggest that such psychoses exist, that their phenomenology is similar to early-onset schizophrenia in many cases, and that they are at least partially different in their phenomenology, familial incidence and treatment response
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from primary affective disorders. Most European reports are not recent, which may account for the lack of explicit diagnostic criteria. According to DSM-III, schizophrenia cannot start after age 45. Although some data supporting this position exist, we found no report published in any language providing an empirical base for this DSM-III age limit. Patients who meet all the DSM-III criteria for the diagnosis of schizophrenia except for the age of onset do exist, and their classification presents serious problems for clinical practice, research, and for communication among psychiatrists. The nosologic validity of late-onset schizophrenia merits examination with modern research methods. New evidence may support an upper limit on age of onset of schizophrenia. Until such evidence is available, the DSM-III age limit should be set aside. NOTE ADDED IN PROOF
After the completion of this manuscript, two additional papers suggesting that late-onset schizophrenia may occur in contemporary American patients were published.23,24 ACKNOWLEDGMENT We would like to thank Drs. Richard Abrams, Robert Cancro, Thomas Craig, Paul Grof, and Sarnoff A. Mednick for commenting on the manuscript, and Edith Klein, the librarian at the Manhattan Psychiatric
Center,
for her help.
REFERENCES 1. Spitzer RL ted): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington, American Psychiatric Association, 1980 2. Kraepelin E: On paranoid diseases (in German). Zeitschrift fur Gesamte Neurologie und Psychiatric 11:617-638, 1912 3. Mayer W: On paraphrenic psychoses (in German). Zeitschrift fur Gesamte Neurologie und Psychiatric 7 1: 187-206, 1921 4. Roth M: The natural history of mental disorder in old age. J Ment Sci 101:281-301, 1955 5. Bridge TP, Wyatt RI: Paraphrenia: Paranoid states of late life. I. European research. J Am Geriatr Sot 28:193-200, 1980 6. Bridge TP, Wyatt RI: Parpahrenia: Paranoid states of late life. II. American research. J Am Geriatr Sot 28:201-205, 1980 7. Winokur G: Delusional disorder (paranoid). Compr Psych 18:51 l-521, 1977 8. Kendler KS: The nosologic validity of paranoia (simple delusional disorder). Arch Gen Psychiatry 37:699-706, 1980 9. van Ree MM, Verhoeven WMA, de Wied D, et al: The use of the synthetic peptides y-type endorphine in mentally ill patients, in Verebey K (ed): Opioids in Mental Illness: Theories, Observations, and Treatment Possibilities. New York, The New York Academy of Sciences, 1982 p. 486 10. Essa M: Late-onset schizophrenia. Am J Psychiatry 139:1528, 1982 1 I. Bleuler M: Late schizophrenic clinical pictures (in German). Fortschr Neurol Psychiatr 15:259-290, 1943 12. Bleuler E: Lehrbuch der Psychiatric. Berlin, Springer, 1955 13. Tsuang MT, Winokur G, Crowe RT: Morbidity risks of schizophrenia and affective disorders among first degree relatives of patients with schizophrenia, mania, depression, and surgical conditions. Br J Psychiatry 137:497-504, 1980 14. Abrams R, Taylor MA: The genetics of schizophrenia: A reassessment using modern criteria. Am J Psychiatry 140:171-175, 1983
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15. Huber G, Gross G, Schuttler R: Late schizophrenia (in German). Arch Psychiatr Nervenkr 22153-66, 1975 16. Angst J, Baastrup P, Grof P, et al: Statistical aspects of the onset and course of schizophrenic psychoses (in German), in Huber G fed): Verlauf und Ausgang Schizophrenener Erkrankungen. Stuttgart-New York, FK Schattauer, 1973, pp. 67-78 17. Rokhhna ML: A comparative clinico-genetic study of attack-like schizophrenia with late and early manifestations with regard to age (in Russian). Zh Nevropatol Psikhiatr 75:417424, 1975 18. Funding T: Genetics of paranoid psychoses of later life. Acta Psychiatr Stand 37:267282, 1961 19. Kay DWK: Late paraphrenia and its bearing on the aetiology of schizophrenia. Acta Psychiatr Stand 39: 159-169, 1963 20. Winokur G, Clayton PJ, Reich T: Manic Depressive Illness. St Louis, CV Mosby, 1969 21. Seeman VM: Gender differences in schizophrenia. Can J Psychiatry 27:107-l 11, 1982 22. Gabriel E: The influence of psycho-organic factors in old age on the course of socalled late schizophrenias (in German). Psychiatr Clin 7:358-364, 1974 23. Gold DG: Late age of onset schizophrenia: Present but unaccounted for Compr Psychiatry 25:225-237, 1984 24, Rabins P, Pauker S,. Thomas J: Can schizophrenia begin after age 44? COmpr Psychiatry 25:290-294, 1984