Schizophrenia and rheumatoid arthritis: a review

Schizophrenia Research, 6 (1992) 1X1-192 0 1992 Elsevier Science Publishers B.V. All rights reserved

SCHIZO

181 0920-9964/92/$05.00

00207

Review article

Schizophrenia and rheumatoid

arthritis: a review

William W. Eaton’, Chris Hayward2 and Ranganathan

Ram3

‘Department of Mental Hygiene, Johns Hopkins University, Baltimore, MD 21205, U.S.A., ‘Department of Psychiatry. Stunford University, Stanford, CA 94305, U.S.A. and 3Deparlment qf Psychialry, State University of New York at Stony Brook, Stony Brook, NY 11794, U.S.A. (Received

22 April

1991; revised version

received

18 September

1991; accepted

24 September

1991)

Fourteen epidemiologic studies of the relationship of rheumatoid arthritis to schizophrenia have been conducted between 1934 and 1985. Twelve of the studies report a lower-than-expected rate of rheumatoid arthritis in populations of schizophrenics. Methodologic weaknesses in the studies are assessed. Nutritional, hormonal, psychosocial, genetic, and immunologic data and theories are briefly reviewed which might explain the epidemiologic results. There is sufficient evidence for the negative association between the two disorders to justify further research. Key words; Rheumatoid

arthritis;

Epidemiology;

Autoimmune

INTRODUCTION

One of the most unusual findings in the epidemiology of schizophrenia is the purported low frearthritis among rheumatoid quency of schizophrenics. This observation has been reported in 12 studies whereas only two studies have presented conflicting evidence. This review will summarize and evaluate the 14 studies which report data concerning the coincidence of schizophrenia and rheumatoid arthritis. Theoretical explanations for the purported dissociation will be considered and future study designs will be discussed. Rheumatoid arthritis is a systemic disease of unknown etiology manifested by inflammatory peripheral arthritis. The peak age of onset is 25 to 55 years of age, and women are affected two to three times more often than men. The prevalence of rheumatoid arthritis varies according to the diagnostic criteria employed; however, estimates using criteria from the American Rheumatism Correspondence to: W.W. Eaton, The Johns Hopkins University, School of Hygiene and Public Health, Department of Mental Hygiene, 624 N. Broadway, Rm. 880, Baltimore, MD 21205, U.S.A.

disorder;

(Schizophrenia)

Association (ARA criteria) yield a frequency in the range of 1 to 3% (Mikkelsen et al., 1967; National Center for Health Statistics, 1966).

EPIDEMIOLOGIC

FINDINGS

Nissen and Spencer (1936) were the first to report frequencies of arthritis in psychiatric patients (Table 1). They visited a state psychiatric hospital and did not observe a single case of arthritis of any kind in 2200 inpatients. This result is surprising given that rheumatoid arthritis affects l-3% of the population and osteoarthritis is present in over 3% of the genera1 population (Mikkelsen et al., 1967). Screening methods were not reported, and it is not difficult to imagine that during a visit to a hospital with 2200 psychiatric inpatients some cases, if not most or even all cases, of arthritis would be overlooked. Gregg (1939) sent a questionnaire to nine hospital superintendents requesting information about cases of bedridden or seriously handicapped arthritis. From a sample of 10,993 psychotic patients over the age of 40, he received reports of only 18

182

I

TABLE Studies

reporling

frequencies

qf rheumutoid

Location

arthritis

in psychiatric

populations

Sample Schizophrenia

Other psychiatric diagnosis

Method qf uscertainmrnl ,for rheumutoid arthritis

Frequency arthrilis

qf‘ rheumatoid

Schizophrenia

Other psychiutric diagnosis

On men and women

Nissen and Spencer (1934)* Gregg (1939)*

Not reported

2200 inpatients

Not reported

0.0%

Massachusetts

Quebec

Trevathan and Tatum (1954) Ehrentheil (1957) Rothermich and Phillips (1963)

Alabama

9000 inpatients

Questionnaire sent to hospital superintendents Medical records, history, physical and radiologic exams Discharge diagnosis

0.16%

Ross et al. (1950)

10,993 psychotic inpatients age 40+ 808 inpatients

Massachusetts Ohio

4500 inpatients 16,000 psychotic inpatients 4494 nonpsychotic inpatients 142,406 inpatients

Osterberg

Baldwin

Mohamed (1982)

Ramsey (1982) Krakowski (1983) Allebeck (1985)

(1978)

(1980)

et al.

et al.

et al.

et al.

800 inpatients

Sweden 1969-70 1969973 England

not given

2314 inpatients

5404 inpatients

Ontario

1 II inpatients

51 inpatients

Toronto and New York

354 age 20-70

Poland

311 age 20-70

Stockholm county

1190 inpatients

621 aff. psych. 3978 neurosis 10152 medical

England

130 inpatients age 40 +

I88 inpatients, age 40 +

Australia

301 inpatients between ages 40-65

0.0%

0.49%

0.011%

Medical records Unspecified screening physical, radiological and serological exam, ARA criteria

0.22% 0.08% 0.38%

Case records, discharge diagnoses. ARA criteria Oxford Record Linkage Study, ICD 8th revision criteria Structured diagnostic interview, serological exam, radiological exam. ARA criteria History, unspecified lab tests, radiological exams History, unspecified lab tests, radiological exams Stockholm Record Linkage ICD Swedish version

0.047%

0.11%

0.09%

0.43%

0.0%

5.8%

0.0017%

0.32% 0.43% 0.43%

History. physical, radiological and ESR ARA criteria History, physical radiological exam, serology, ARA criteria

0.77%

2.7%

0.0%

7.7%**

Range Mean Median

o.o-3.4% 0.77% 0.047%

o.o-9.0% 0.86%*** 0.16%***

3.4%

2.6%

Studies on women onl?

Pilkington

Mellsop (1974)

(1955)

et al.

*These studies lumped together all arthritides. **This is a general population estimate from other studies. ***Does not include Mellsop et al.‘s general female population ‘reference’ group (medical inpatients) of 0.43%.

estimate

of 7.7 in calculation,

or Allebeck

et al.‘s estimate

of

183

cases of severe arthritis (frequency = 0.164%, Table 1). He compared this with the frequency of people who were completely or partially disabled from rheumatism in the entire population of Massachusetts over 40 years of age as reported by the Massachusetts Commissioner of Health. The frequency of rheumatism in the general population was 50 times that of the psychotic patients. Gregg also reported that in 3000 autopsies of psychotic patients, the State Pathologist noted no arthritic joints (data not shown). In addition, in a state school for the ‘feeble-minded’ no cases of bedridden or seriously handicapped arthritis patients were found in a sample of 1962 inpatients (data not shown). Ross et al. (1950) were the first to stratify their sample according to psychiatric diagnoses and to evaluate the sample for the frequency of rheumatoid arthritis specifically. The criteria for the diagnoses of schizophrenia or rheumatoid arthritis were not reported. Using data from medical records and annual histories and physicals, the authors found no cases of rheumatoid arthritis in 800 schizophrenic inpatients. In 808 cases of psychiatric diagnoses other than schizophrenia, four cases of rheumatoid arthritis were observed (frequency = 0.49%; Table 1). Thus, rheumatoid arthritis was rare in all psychiatric groups but least common in those diagnosed as having schizophrenia. Many of those receiving a diagnosis of schizophrenia in 1950 would not meet DSM-III criteria for schizophrenia and would be grouped with the category of other psychiatric diagnoses. This would further reduce the already low frequency of rheumatoid arthritis in the comparison population, suggesting that the finding is not specific for schizophrenia. Trevathan and Tatum (1954) reviewed the discharge diagnoses of 9000 patients admitted to a neuropsychiatric hospital. They located only one case of concurrent psychosis and rheumatoid arthritis (frequency = 0.011%; see Table 1). This finding is remarkable for the rarity of rheumatoid arthritis. However, relying on discharge diagnoses for case ascertainment of rheumatoid arthritis would be expected to yield a low frequency of rheumatoid arthritis. Ehrentheil (1957) reviewed the medical records of 4500 inpatients in a neuropsychiatric hospital for the diagnosis of rheumatoid arthritis. The

sample was not stratified according to psychiatric diagnoses nor were criteria for the diagnosis of rheumatoid arthritis provided. He found only one case of rheumatoid arthritis (frequency = 0.222%; Table 1). Rothermich and Philips (1963) screened 20,494 psychiatric inpatients in Ohio for rheumatoid arthritis using ARA criteria for the diagnosis of rheumatoid arthritis. Suspected cases received radiographic examination and blood tests for latex agglutination and erythrocyte sedimentation rate. Among 16,000 psychotic patients the frequency of rheumatoid arthritis was 0.08%. The frequency of rheumatoid arthritis in the other 4494 psychiatric patients was 0.38% (Table 1). The same screening procedure was performed on 4040 prisoners and the frequency of rheumatoid arthritis was 0.22%. Finally, in a hospital for the criminally insane, none of the 1391 patients had rheumatoid arthritis. The striking aspect of this study is the lack of specificity of the finding. It may be that institutionalization itself is generally protective against developing any arthritic disease. Osterberg (1978) utilized data from the Swedish National Social Welfare Board to review the discharge diagnoses of over 500,000 psychiatric inpatients for arthritic diseases. Criteria for the diagnosis of schizophrenia were from the ICD (the edition used varied with the year of discharge) and ARA criteria were employed for the diagnosis of rheumatoid arthritis. The results of her study revealed low frequencies of rheumatoid arthritis in all psychiatric inpatients. However, the frequencies of rheumatoid arthritis in schizophrenia (frequency= 0.047%) were lower than the frequency of rheumatoid arthritis in other psychiatric diagnoses (frequency =O.ll; Table I). Seven cases of rheumatoid arthritis and schizophrenia occurred contemporaneously, demonstrating that rheumatoid arthritis and schizophrenia are not mutually exclusive diseases. Baldwin (1980) reported frequencies of rheumatoid arthritis and osteoarthritis in various psychiatric diagnoses using data from the Oxford Record Linkage System. These data represent abstracts of clinical records of patients from two counties in England from an eight-year period. The sample is culled from records of 366,862 persons. The Seventh and Eighth Editions of the ICD were used for both the diagnosis of schizophrenia and rheu-

184

matoid arthritis. There were 2314 patients diagnosed as schizophrenic and 5404 with affective disorders. The results showed reduced frequencies of rheumatoid arthritis in all psychiatric diagnoses (0.43%) but particularly in schizophrenia (0.09%). The frequency of osteoarthritis in schizophrenic patients was also reduced compared to other psychiatric patients (0.22% versus 0.65%, respectively; data not shown). Mohamed et al. (1982) searched for rheumatoid arthritis and osteoarthritis in II 1 schizophrenic inpatients and 51 inpatients with other psychiatric diagnoses. The two groups were similar on sociodemographic factors, and in their length of illness. Diagnoses were made according to TCD and ARA criteria. There were no cases of definite or probable rheumatoid arthritis among the schizophrenics, compared with three cases of probable rheumatoid arthritis in the nonschizophrenics, a statistically significant difference. Mohamed et al. noted that in their data the negative association exists for both rheumatoid arthritis and osteoarthritis (data not shown). They suggested the possibility that schizophrenics may have a reduced exposure to trauma. Repeated trauma to joints has been hypothesized to be a predisposing factor for both rheumatoid arthritis and osteoarthritis (Julkenen et al., 1974; Sokoloff, 1979). Ramsay et al. (1982) were the first not to find an unusually low prevalence of rheumatoid arthritis in a sample of schizophrenics. For 354 schizophrenic patients, ages 20-70, diagnosed according to ICD-8 criteria, the frequency of rheumatoid arthritis was 3.4% (Table 1). There was no comparison sample. Krakowski et al. (1983) employed the same design as Ramsay et al., using the same diagnostic criteria for the diagnosis of schizophrenia and rheumatoid arthritis and the same age range, 20-70, for their sample of schizophrenic patients. They also reported frequencies of rheumatoid arthritis which were within the expected range. Among 311 schizophrenic patients the frequency of rheumatoid arthritis was 2.6% (Table 1). Allebeck et al. (1985) reported on a study of the association between schizophrenia and rheumatoid arthritis based on the Stockholm County Medical Information System. This register covers all admissions, medical and psychiatric, of the entire population of the county (approximately 1.5 million

inhabitants). The Swedish version of the ICD was used to select all patients discharged from hospitals during 1971 with the diagnosis of schizophrenia, affective psychosis and neurosis. A 10% sample of all inpatients (IO, 152) was also taken, as a control group. There were 1190 schizophrenics, 621 patients with affective disorders and 3978 patients with neurosis. There were 71 patients with RA in the inpatient control group (prevalence of 0.0043% not shown) as opposed to only 2 patients among the schizophrenics, 2 patients in the affective psychosis group, and 17 patients among the neurotic group. Two studies focus on middle-aged and elderly women, a group which typically has a high rate of arthritis (Table I, bottom). Pilkington (1956) studied 318 women over age 40 with various psychiatric diagnoses (Table 1). Since rheumatoid arthritis is more common in women and the risk goes up with increasing age, this sample represented a high risk group. Physical examinations were performed on the entire sample and if rheumatoid arthritis was suspected, radiographs and an erythrocyte sedimentation rate were obtained. Of the 130 women with schizophrenia, one had rheumatoid arthritis (frequency = 0.77%); whereas five of the 188 women with other psychiatric diagnoses had rheumatoid arthritis (frequency = 2.7%; Table 1). Thus, these frequencies are low for both the schizophrenic patients and the other psychiatric patients. For comparison, the mean of frequencies reported in six population-based studies for women of this age was 7.7% (Adler et al., 1967; Ansell and Lawrence, 1966; Cathcart and O’Sullivan, 1970; Cobb et al., 1957; Lawrence, 1961; Mikkelsen et al., 1967 (adapted from Mellsop et al., 1974)). Mellsop et al. (1974) examined 301 schizophrenic women, ages 40-65, for clinical, radiological, and serological evidence of rheumatoid arthritis and found no cases (Table 1). Criteria for the diagnosis of schizophrenia were taken from the Victoria Mental Health Department’s adaptation of the Eighth International Classification of Disease (ICD), and the diagnosis of rheumatoid arthritis was based on ARA criteria. The frequency of osteoarthritis was also assessed in this study. The observed frequency for osteoarthritis of 29.9% is high for the general population but is actually lower than expected when compared

185

with population-based studies of women in this age range. For example, the HANES I (Health and Nutrition Examination Survey) screened a large probability sample for osteoarthritis by radiologic examination of the hands and feet, the same method used by Mellsop et al., and reported a frequency of 47% in women between the ages of 35 and 65 (National Center for Health Statistics, 1966). Thus, the observed frequencies of both rheumatoid arthritis and osteoarthritis were low in the sample of Mellsop et al. Unlike prior studies, the screening methods utilized by Mellsop et al. were comprehensive. It is noteworthy that both rheumatoid arthritis and osteoarthritis were less common than expected.

METHODOLOGIC

ISSUES

Many of the studies which demonstrate a negative association between rheumatoid arthritis and schizophrenia suffer from methodologic problems which limit the validity of the findings. Ascertainment bias, lack of specific diagnostic criteria, absence of appropriate controls and untested confounding variables are design problems which warrant consideration. Case ascertainment Without an indication to specifically search for cases of arthritis it is likely that many cases may go unnoticed in any clinical setting, but particularly in chronically hospitalized psychiatric inpatients in the historical time period during which some of the earlier studies were completed. In five of the twelve studies which report a dissociation, the frequencies of rheumatoid arthritis are extremely low in all psychiatric inpatients (Table 1; Ehrentheil, 1957; Gregg, 1939; Nissen and Spencer, 1936; Rothermich and Philips, 1963; Trevathan and Tatum, 1954). In the six studies which stratify their sample according to diagnosis the schizophrenics have the lowest rate of rheumatoid arthritis, but the frequency in the other diagnostic categories is also much lower than expected (Table 1; Baldwin, 1980; Mohamed et al., 1982; Osterberg, 1978; Pilkington, 1956; Ross et al., 1950; Allebeck et al., 1985). In addition, rheumatoid arthritis is reported to be rare in a prison population (Rothermich and

Philips, 1963) and in a state school for the ‘feebleminded’ (Gregg, 1939). Three studies report frequencies of osteoarthritis in schizophrenic patients which are less than expected (Baldwin, 1980; Mellsop, 1974; Mohamed et al., 1982). Seven of the studies rely solely on medical records or unspecified screening for the diagnoses of arthritis or rheumatoid arthritis (Baldwin, 1980; Ehrentheil, 1957; Gregg, 1939; Nissen and Spencer, 1936; Osterberg, 1978; Ross et al., 1950; Trevathan and Tatum, 1954). Of the five studies which did thoroughly screen all members of the sample population for the detection of rheumatoid arthritis (Krakowski et al., 1983; Mellsop et al., 1974; Mohamed et al., 1982; Pilkington, 1956; Ramsay et al., 1982) two, Krakowski et al. and Ramsay et al., did not report a low prevalence of rheumatoid arthritis in schizophrenics (Table 1). Criteria for diagnosis Differing criteria for diagnosis may explain some of the differences between schizophrenic and control samples. Five of the studies reviewed provide no criteria for the diagnosis of either rheumatoid arthritis (Ehrentheil, 1957; Ross et al., 1950; Trevathan and Tatum, 1954) or unspecified arthritis (Gregg, 1939; Nissen and Spencer, 1936). The expected frequency of rheumatoid arthritis in a population varies considerably with differing criteria (Cathcart and O’Sullivan, 1970; Valkenburg, 1980). The problem of unspecified diagnostic criteria also applies to the diagnosis of schizophrenia, for which diagnostic criteria are provided in only 6 of the 13 studies (Baldwin, 1980; Krakowski et al., 1983; Mellsop, 1974; Mohamed et al., 1982; Ramsay et al., 1982). Since the diagnosis of schizophrenia has recently become more specific the population samples of schizophrenics in the older studies versus the more recent ones are probably not comparable. Lack of appropriate controls Eight of the fourteen studies reporting data concerning the relationship between rheumatoid arthritis and schizophrenia have no control group (Ehrentheil, 1957; Gregg, 1939; Krakowski et al., 1983; Mellsop, 1974; Nissen and Spencer, 1936; Ramsay et al., 1982; Rothermich and Philips, 1963; Trevathan and Tatum, 1954). The other six studies

186

stratify their sample according to psychiatric diagnoses, with the nonschizophrenic subgroups serving as controls (Baldwin, 1980; Mohamed et al., 1982; Pilkington, 1956; Osterberg, 1978; Ross et al., 1950). If there are factors common to all psychiatric inpatients, such as chronic hospitalization, which produce low rates of rheumatoid arthritis, then use of psychiatric inpatients as controls would minimize the differences in prevalence of rheumatoid arthritis.

tion (Mellsop et al., 1974; Osterberg, 1978; Wyatt et al., 1982). There is evidence that antipsychotics suppress the immune system (Ferguson et al., 1978; Zarrabi, 1979; Gowdy, 1980; Lovett et al., 1978) which might reduce the risk for rheumatoid arthritis.

Confounding variables Schizophrenia would appear to be negatively associated with rheumatoid arthritis in a population with a low average age because of differential age of onset between the two diseases. The typical age range for the onset of schizophrenia is 15-34 (Eaton, 1985) whereas the age range for the onset of rheumatoid arthritis is 25555 (Zvaifler, 1980). To control for age the frequencies of disease should be age specific. Only 6 of the 14 studies reviewed specified age ranges for the samples (Gregg, 1939; Krakowski et al., 1983; Mellsop, 1974; Mohamed, 1982; Pilkington, 1956; Ramsay et al., 1982). Gender should be controlled because the rate of RA is so much higher in women than men, and because it is suspected that schizophrenia may have different etiologies in men and women. Social class should be controlled because the rate of schizophrenia is higher in the lower class (Eaton, 1985), and because lifestyles related to social class may be implicated in the etiology of some forms of arthritis. History of hospitalization is important to consider since chronic hospitalization may protect the individual from trauma which might be related to some forms of arthritis.

In spite of differences in the samples and methods used in these studies there is a consistent lower than expected co-occurrence of schizophrenia and rheumatoid arthritis. In schizophrenics the mean frequency of rheumatoid arthritis in nine studies is 0.77% and the median is 0.47% (Table 1). The mean is heavily influenced by the two outher figures of 3.4% and 2.6% (Ramsay et al., 1982; Krakowski et al., 1983). Since these two frequencies are higher than often reported for the general population and there is no control group, it is wise to focus on the median where their influence is diminished. The median prevalence of about one-half of one percent is lower than the expected l-3% (Mikkelsen et al., 1967). The three studies which are strongest methodologically (Pilkington, 1956; Mellsop et al., 1974; Mohamed et al., 1982) all report results supporting a much stronger inverse relationship than suggested by the comparison of medians.

Neuroleptic exposure The hypothesis that neuroleptics rather than schizophrenia may be protective against rheumatoid arthritis has not been specifically addressed in any study. Six of the fourteen studies which evaluate the association between rheumatoid arthritis and schizophrenia were completed before antipsychotic agents were widely used (Ehrentheil, 1957; Gregg, 1939; Ross et al., 1950; Nissen and Spencer, 1936; Pilkington, 1956; Trevathan and Tatum, 1954). This has led to the assumption that the purported negative association between the two diseases is independent of the effects of medica-

SUMMARY

POSSIBLE

OF FINDINGS

INTERPRETATIONS

In spite of the flawed methods used in many of the studies reviewed here, this relationship is one of the strongest in the literature on the epidemiology of schizophrenia when compared with other possible risk factors (as in Eaton, 1985), and might provide an etiologic clue. Sufficient evidence exists to lead us to consider how such a dissociation might arise. Tryptophan metabolism Taylor (1978) hypothesized that abnormal metabolism of tryptophan could produce a substance which is both schizophrenogenic and protective against rheumatoid arthritis. No abnormality of

187

tryptophan metabolism has been demonstrated in either disease. Two studies showed little or no effect of oral tryptophan in schizophrenia (Chouinard et al., 1978; Gillin et al., 1976) while one study demonstrated a favorable response to oral tryptophan for a subgroup of aggressive schizophrenics (Morand et al., 1983). Prostaglandins Horrobin (1977, 1978, 1979) hypothesized that a deficiency of prostaglandins in schizophrenia is protective against rheumatoid arthritis. The evidence that schizophrenia is a prostaglandin deficiency disease includes the observations that some antipsychotic medications release prolactin, which in turn increases prostaglandin synthesis (Mtabaji et al., 1976; Rillema, 1975); platelets from schizophrenics do not synthesize prostaglandin E, as expected when stimulated by ADP (Abdullah and Hamadah, 1975); the antipsychotic medication clozapine acts as a prostaglandin analogue (Bloss and Singer, 1978); psychosis may improve during an acute febrile episode (Lipper and Werman, 1977) and fever is associated with prostaglandin synthesis (Feldberg, 1976); nutmeg, which inhibits prostaglandins (Bennett et al., 1974), has been reported to cause psychosis (Weiss, 1960); and a positive response to prostaglandin PGEl for the treatment of schizophrenia was reported in three of six patients (Kalya, 1984). Horrobin’s hypothesis is not supported by the observations that anti-inflammatory agents, such as aspirin, which inhibit prostaglandin synthesis, do not commonly cause or worsen schizophrenic symptoms (Abeles, 1977) although Turner (1977) reported a case of psychosis associated with aspirin plus indomethacin; other prolactin releasing medications such as methyldopa and tricyclic antidepressants are not effective in the treatment of schizophrenia (Abeles, 1977); and CSF prostaglandin levels in schizophrenic patients have been reported to be either elevated (Matthe et al., 1980) or normal (Gerner and Merrill, 1983; Linnoila et al., 1983). Corticosteroids Since corticosteroids have a therapeutic effect in rheumatoid arthritis and may occasionally induce psychosis, Trevathan and Tatum (1954) postulated that an imbalance in these hormones may play a role in the proposed relationship between schizo-

phrenia and rheumatoid arthritis. But the relationship of corticosteroid function to schizophrenia is not well established (Brophy et al., 1983; Erb et al., 1981; Tourney and Erb, 1979; Naber et al., 1982; Stokes et al., 1984; Johnson, 1981; Munro et al., 1984; Dewan et al., 1982; Herz et al., 1985; Brown et al., 1979; Carroll, 1976; Gold et al., 198 1). To the extent that the frequencies of arthritides were low in nearly all groups of psychiatric inpatients, elevated cortisol levels perhaps as a response to having a psychiatric disease may have contributed to this nonspecific finding. Psychosocial difSerences Studies of psychosocial factors in rheumatoid arthritis have often dealt with the theme of repressed or contained hostility (Hoffman, 1974). The hostility is thought to be due to a rigid and confining family environment. This social-psychological situation might be opposite to the sudden loss of structure and increase in automony experienced during the crisis period preceding some schizophrenic’s first episode. Fisher (1970) and his colleagues have developed certain methods of scoring responses to Rorschach ink blots which provides an intriguing empirical relationship connecting rheumatoid arthritis and schizophrenia. Responses which tend to indicate the firmness or clarity of boundaries, are labeled ‘barrier’ responses. ‘Penetration’ responses emphasize the weakness of borders. Several studies show that rheumatoid arthritis patients have higher barrier scores, and lower penetration scores, than normals (Fisher, 1970; pp. 208-216). Several other independent studies show that schizophrenic patients have low barrier and high penetration scores - the opposite pattern of the one found with the rheumatoid arthritis patients. This configuration is possibly a result of the processes of living with the two disorders, and offers no theoretical understanding of either disease. However, the data are reliable and consistent, and no overarching theory has subtly influenced their collection or presentation so as to artifactually produce the result. Genetic d@erences Both schizophrenia and RA may be inherited. The first degree relatives of schizophrenics have nearly a ten-fold risk of developing the disease (Eaton, 1985) while those of RA have a 4-fold increase

188

(Lipsky, 1987). Twin studies have revealed that the rate of concordance for the two diseases are higher for monozygotes when compared to dizygotes, the rates being 65% and 12% in schizophrenia (Kendler, 1983) 30% and 5% in rheumatoid arthritis (Lipsky, 1987) respectively. The differences may be explained by a greater role of environmental factors in RA. We were able to locate only one research study reporting rates of RA in relatives of schizophrenics, which showed a decreased rate of RA among parents of schizophrenics in Hawaii (7% of parents of 44 schizophrenics with RA versus 21% of parents of 53 normals with RA). This difference was barely significant at the p= 0.05 level (McLaughlin, 1977). There is considerable linkage research in both disorders. Schizophrenia has been linked to HLA A9, Al (McGuffin and Sturt, 1986) DRl, and DR8 (Miyanaga et al., 1984) but the evidence is not conclusive (e.g. Amar et al., 1988). HLA antigens A2 (Luchins et al., 1980, Rudduck, et al. 1985) A9 (reviewed in Tiwari and Terasaki, 1985) DR4 (Tiwari and Terasaki, 1985) and B27 (Gattaz et al., 1985) have been significantly associated with RA. Gattaz et al., (1985) postulated a bi-directional expression of the B27 antigen, to explain the negative association between the two diseases. Their sample of schizophrenics with B27 did not have arthropathy. There is a small quantity of research literature on the association of other gene markers with both schizophrenia and RA. Rheumatoid arthritis is found to be associated with alpha- 1-antitrypsin (Cox and Hubner, 1976) and immunoglobulin Gm Allotype (Masi and Medsger, 1979) both of which are encoded on the long arm of chromosome 14. Propert (1983) examined and found no association between Gm phenotypes and chronic schizophrenia. In a pedigree study of schizophrenia, McGuffin (1984) has excluded any linkage, with alpha-lantitrypsin and Gm protein genes at recombination fraction 0.5 (Lod scores - 1.311 and - 2.728, respectively). Immunologic

one study found that repeated tonsillitis was a risk factor for RA (Darwish and Armenian, 1987). In contrast, there is one study of relatives of schizophrenics which showed that they were more resistant to viral infections than the general population (Carter and Watts, 1971). The array of conflicting and confusing results pertinent to the immunologic theory of schizophrenia (for reviews see e.g., DeLisi, 1986; Waltrip et al., 1991) contrasts markedly with the relatively well specified pattern of research and clinical observations in this area for RA (e.g. Ziff, 1990; Weiner, In rheumatoid 1991). arthritis the T4:T8 (helper-inducer:suppressor-cytotoxic) cells ratio is increased, and this is detected using monoclonal antibodies. This finding is most common in patients with active joint disease, suggesting that it may be linked to the pathological process of RA (Lipsky, 1986). But studies of counts of leukocytes among psychotic patients have revealed no consistent pattern (reviewed by DeLisi and Crow, 1986; see also Zarrabi et al., 1979; DeLisi et al., 1982; Coffee et al., 1983). Rheumatoid factors (RF’s), i.e., IgM antibodies to IgG, are detected consistently and are utilized as diagnostic tests in RA, but immunoglobulin levels in schizophrenia have been found to be both increased and decreased. It will be illuminating to study systematically the occurrence of RF in a large sample of schizophrenics. A viral etiology of both schizophrenia and rheumatoid arthritis have been proposed and investigated. The viruses to which antibodies have been detected in the serum and CSF of schizophrenics are: measles, mumps, CMV, HSV, varicella zoster, adeno-viruses, influenza virus, rubella and others (King et al., 1985). In RA, the Epstein-Barr viruses (EBV) have been implicated (Lipsky, 1987) and a specific T cell defect which hinders suppression of EBV-induced lymphocyte proliferations has been described (Depper et al., 1981). In schizophrenia, King et al. (1985) showed no differences in antibodies to EBV, in their sample of 222 schizophrenics compared to 143 controls.

and viral theories

There is suggestive epidemiologic evidence that the pathogenicity or virulence of infections has an opposite pattern in schizophrenia than in RA. Persons with RA are more likely to die of infections than the general population (Hochberg, 1981), and

CONCLUSION

The evidence for the negative relationship of schizophrenia to rheumatoid arthritis is not perfect

189

but it is strong. Future studies should explicitly incorporate measurements relevant to as wide a range of possible explanations for the epidemiologic finding as is possible. Among this range of alternative explanations, we find the area of autoimmune disorders to be the most promising. Pert (1977) suggested that studies of psychiatric patients with associated autoimmune disease should be undertaken. Recent literature on rheumatoid arthritis and autoimmunity suggests that there may be a familial diathesis to developing these disorders. Studies of families of schizophrenics, searching for autoimmune and other disorders found within families of patients with RA, such as IDDM, autoimmune thyroid diseases, pernicious anemia, and systemic lupus erythematosus, will cast light on the extent and nature of the negative association between schizophrenia and rheumatoid arthritis. Other approaches to study the phenomenon of the negative association would be a casecontrol study to examine if the presence of RF and other autoantibodies is lower in schizophrenics than in controls. This would test if the negative association between the two diseases reflected a more fundamental immunological difference. The negative association also suggests that the immunopathology of schizophrenia must be studied in more detail and may hold the key to understanding at least some part of the etiology of schizophrenia.

ACKNOWLEDGEMENTS

This work was supported in part by NIMH Grant 44653 to W. W. E., Principal Investigator, and NIMH Grant 44801 to Evelyn Bromet, Principal Investigator. The authors would like to thank Jean Lavelle for assistance in typing and editing.

REFERENCES

Abdullah, Y.H. and Hamadah, K. (1975) Effect of ADP on PGE formation in blood platelets from patients with depression, mania and schizophrenia. Br. J. Psychiatry 127, 591-595. Abeles, J.H. (1977) Schizophrenia as a prostaglandin-deficiency disease. Lancet i, 1319-1320. Adler, E., Abramson, J.H., Elkan, Z., Ben-Hador, S. and

Goldberg, R. (1967) Rheumatoid arthritis in a Jerusalem population. I. Epidemiology of the disease. Am. J. Epidemiol. 85, 3655377. Allebeck, P., Rodvall, Y. and Wistedt, P. (1985) Incidence of rheumatoid arthritis among patients with schizophrenia, affective psychosis and neurosis. Acta Psychiatr Stand. 71, 6155619. Alspaugh, M.A., Jensen, F.C., Rabin, H. and Tan, E.M. (1978) Lymphocytes transformed by Epstein-Barr virus: induction of nuclear antigen reactive with antibody in rheumatoid arthritis. J. Exp. Med. 147, 1018~1027. Amar, A., Zohar, M., Tiwari, J. and Brantbar, C. (1988) HLA Schizophrenia in Israel. Isr. J. Med. Sci. 24, 28-31. Ansell, B.M. and Lawrence, J.S. (1966) Fluoridation and the rheumatic diseases: a comparison of rheumatism in Watford and Leigh. Ann. Rheum. Dis. 25, 67775. Baldwin, J.A. (1980) Schizophrenia and physical disease: a preliminary analysis of the data from the Oxford Record Linkage Study. In: Hemmings, G. (Ed.) The Biochemistry of Schizophrenia and Addiction. MTP Press, Lancaster. Beighton, P., Solomon L. and Valkenburg, H.A. (1975) Rheumatoid arthritis in a rural South African Negro Population. Ann. Rheum. Dis. 34, 136-140. Bennett, A., Grudidge, CF. and Stamford, I.F. (1974) Prostaglandins, Nutmeg, and Diarrhea. N. Engl. J. Med. 109, 110-111. Bloss, J.S. and Singer, G.H. (1978) Neuropharmacology and Behavioral Evaluation of Prostaglandin E2 and I l-Thiol-I 1 Desoxy Protaglandin E2 in the Mouse and Rat. Psychopharmacology 57, 2955302. Brophy, M.H., Rush, A.J. and Crowley, G. (1983) Cortisol, estradiol, and androgens in acutely ill paranoid schizophrenics. Biol. Psychiatry 18, 5833590. Brown, W.A., Johnston R. and Mayfield, D. (1979) The 24. hour dexamethasone suppression test in a clinical setting: relationship to diagnosis, symptoms, and response to treatment. Am. J. Psychiatry 136, 5433547. Carroll, B.J. (1976) Limbic system-adrenal ortex regulation in depression and schizophrenia. Psychosom Med. 38, 106-121. Carter, M. and Watts, C.A.H. (1971) Possible biological advantages among schizophrenics’ relatives. Br. J. Psychiatry 118, 453-460. Checkley, S.A. and Bisley, J.L.T. (1977) Schizophrenia and rheumatoid arthritis. Lancet i, 1258-1259. Chouinard, G., Annable, L., Young, S.N. and Sourkes, T.L. (1978) A controlled study of tryptophan-beneserazide in schizophrenia. Commun. Psychopharmacol. 2, 21-31. Cobb, S., Warren, J.E., Merchant, W.R. and Thompson, D.J. (1957) An Estimate of the prevalence of rheumatoid arthritis. J. Chronic Dis. 5, 630-643. Coffee, C.E., Sullivan, J.L. and Rice, J.R. (1983) T lymphocytes in schizophrenia. Biol. Psychiatry 18, 113-120. Cox, D.W. and Hubner, 0. (1976) RA and alpha-l antitrypsin. Lancet i, 1216-1217. Crow, T.J. (1984) A re-evaluation of the viral hypothesis: is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? Br. J. Psychiatry 145, 243-253. Darwish, M.J. and Armenian, H.K. (1987) A case-control

190 study of rheumatoid arthritis in Lebanon. Int. J. Epidemiol. 16,420-424. DeLisi, L.E. and Crow, T.J. (1986) Is schizophrenia a viral or immunologic disorder. Psychiatr. Clin. North Am. 9, 115-132. DeLisi, L.E., Goodman, S., Neckers, L.M. et al. (1982) Lymphocyte subpopulations in schizophrenic patients. Biol. Psychiatry 17, 1003-1007. DeLisi, L.E. and Wyatt, R.J. (1982) Abnormal immune regulation in schizophrenic patients. Psychopharmacol Bull. 18, 158-163. Depper, J.M. and Zvaifler N.J. (1981) Epstein-Barr virus. Its relationship to the pathogenesis of rheumatoid arthritis, Arthritis Rheumatol. 24 (6) 755561. Dewan, M.J., Pandurangi, A.K., Boucher. M.L., Levy, B.F. and Major L.F. (1982) Abnormal dexamethasone suppression test results in chronic schizophrenic patients. Am. J. Psychiatry 139, 1501-1503. Eaton, W.W. (1985) Epidemiology of Schizophrenia. Epidemiol. Rev. 7, 1099121. Ehrentheil, 0. (1957) Common medical disorders rarely found in psychotic patients. AMA Arch. Neural. Psychiatry 77, 1788186. Erb, J.L., Kadane, J.B., Tourney, G., Michkelson, R., Trader, D., Szabo, R. and Davis, V. (1981) Discrimination between Schizophrenic and control subjects by means of plasma dehydroepiandrosterone measurements. J. Clin. Endocrinol. Med. 52, 181-186. Feldberg, W. (1976) Possible association of schizophrenia with a disturbance in prostaglandin metabolism: a physiological hypothesis. Psychol. Med. 6, 359-396. Ferguson, R.M., Schimidtke, J.R. and Simmons, R.L. (1978) Effects of Psychoactive Drugs on In Vitro Lymphocyte Activation. In: Bergsma, D. and Goldstein, A.L. (Eds.), Neurochemical and Immunologic Components of Schizophrenia (Series: Birth Defects), Vol. 14, no. 5, Liss, New York, NY. Ferrell, P.B., Altcheson, C.T. and Pearson, G.R. (1981) Seroepidemiological study of relationships between Epstein-Barr virus and rheumatoid arthritis. J. Clin. Invest. 61, 681-687. Fisher, S. (1970) Body Experience in Fantasy and Behavior, Appleton-Century-Crofts, New York, NY. Gattaz, W.F., Sietz, A. and Beckmann, H. (1985) A possible association between HLA B27 and vulnerability to Schizophrenia. Pers. Indiv. Diff. 6, 2833285. Gerner, R.H. and Merrill, J.E. (1983) Cerebrospinal fluid prostaglandin E in depression, mania and schizophrenia compared to normals. Biol. Psychiatry 18, 565-569. Gillin, J.C., Kaplan, J.A. and Wyatt, R.J. (1976) Clinical effects of tryptophan in chronic schizophrenic patients. Biol. Psychiatry 11, 635-639. Gold, M.S., Potlash, A.L.C., Extein, 1. and Sweeney, D.R. (1981) Diagnosis of depression in the 1980’s. J. Am. Med. Assoc. 245, 1562p 1564. Gowdy, J.M. (1980) Immunoglobulin levels in psychotic patients. Psychosomatics 21, 751-756. Gregg, D. (1939) The paucity of arthritis among psychotic cases. Am. J. Psychiatry 95. 853. Harvey, J., Latze Arnet, F.C. et al. (1983) Rheumatoid arthritis

in a Chippewa Band II: field study with clinical serologic and HLA-D correlations, J. Rheum. 10, 38-42. Heath, R.G. and Krupp, I.M. (1967) Schizophrenia as an immunologic disorder. I. Arch. Gen. Psychiatry 16, l-9. Heath, R.G. and Krupp, I.M. (1967) Schizophrenia as an immunologic disorder. II. Effects of serum protein fractions on brain function. Arch. Gen. Psychiatry 16, 10-23. Heath, R.G. and Krupp, I.M. (1967) Schizophrenia as an immunologic disorder. III. Effects of antimonkey and antihuman brain antibody on brain function. Arch. Gen. Psychiatry 16, 24-33. Herz, MI., Fava, G.A., Molnar, G. and Edwards, L. (1985) The dexamethasone test in newly hospitalized schizophrenic patients. Am. J. Psychiatry 142, 127-129. Hochberg, M.C. (1981) Adult and juvenile rheumatoid arthritis: current epidemiologic concepts. Epidemiol. Rev. 3, 27744. Hoffman, A.L. (1974) Psychological factors associated with rheumatoid arthritis. Nursing Res. 23, 218-234. Horrobin, D.F. (1979) Schizophrenia: reconciliation of the dopamine, prostaglandin, and opiod concepts and the role of the pineal. Lancet, i, 5299531. Horrobin, D.F. (1977) Schizophrenia as a prostaglandin deficiency disease. Lancet i, 936-937. Horrobin, D.F.. Ally, A.I., Karmali, R.A., Karmazyn. M., Manku, M.S. and Morgan, R.O. (1978) Prostaglandins and schizophrenia: further discussion of the evidence. Psychol. Med. 8, 43348. Johnson, D.A.W. (1981) Study of depressive symptoms in schizophrenia, I. The Prevalence of depression and its possible causes. Br. J. Psychiatry 139, 899101. Julkenen, H., Radanen, J.A. and Kataja, J. (1974) Severe trauma as an etiological factor in rheumatoid arthritis. Stand. J. Rheumatol. 3, 977102. Kalya, H. (1984) Prostaglandin treatment of schizophrenia. Biol. Psychiatry 19. 457-462. Karr. R.W., Rodey, G.E., Lee, T. and Schwartz, B.D. (1980) Association of HLA-DRW4 with rheumatoid arthritis in black and white patients. Arthritis Rheum. 23, 1241-1245. Kato, H., Duff, I.F. and Russell, W.J. (1971) Rheumatoid arthritis and gout in Hiroshima and Nagasaki, Japan: a prevalence and incidence study. J. Chronic Dis. 23, 6599679. Kelleher, M.J. and Copeland, J.R. (1973) Psychiatric diagnosis in Cork and London: results of a cross-national pilot study. J. Ir. Med. Assoc. 66, 553-555. Kendler, K.S. (1983) Overview: a current perspective on twin studies of schizophrenia. Am. J. Psychiatry 140, 141331425. Khoroshko. V.K., Reactii Zivotnogo Organizma na Vvedenie Nervnoi Tkani. Neurotoxini Anaphylaksia Endoxini. Moscow, 1912. (cited in DeLisi and Crow, 1986). King, D.J., Cooper, S.J., Earle, J.A.P., Martin, S.J., McFerran, N.V., Rima, B.K. and Wisdom, G.B. (1985) A survey of serum antibodies to eight common viruses in psychiatric patients. Br. J. Psychiatry 147, 1377144. Krakowski, A.J., Rydzynski, A., Jarosz, M. and Engelsmann, F. (1983) Prevalence of psychosomatic disorders in schizophrenic patients in Poland. In: Krakowski and Kimbal. (Eds.), Pyschosomatic Medicine; Theoretical, Clinical and Transcultural Aspects. Plenum, New York. Lawrence, J.S. (1961) Prevalence of rheumatoid arthritis. Ann. Rheum. Dis. 20, 11-17.

191 Linnoila, M., Whorton, R., Rubinow, D.R., Cowdry, R.W., Ninan, P.T. and Waters, R.N. (1983) CSF prostaglandin levels in depressed and schizophrenic patients. Arch. Gen. Psychiatry 40, 405-406. Linos, A., Northington, J.W., O’Fallan, W.M. and Kurland, L.T. (1980) The epidemiology of rheumatoid arthritis in Rochester, Minnesota. A study of incidence, prevalence and mortality. N. Am. J. Epidemiol. 111, 87-88. Lipper, S. and Werman, D.S. (1977) Schizophrenia and intercurrent physical illness: a critical review of the literature. Compr. Psychiatry 18, 11-22. Lipsky, P.E. (1986) Natural killer cell function in rheumatoid arthritis. Clin. Exp. Rheumatol. 4 30335. Lipsky, P.E. (1987) Rheumatoid Arthritis. In: Braunwald, E., Isselbacher, K.J., Petersdorf, R.G., Wilson, J.D., Martin, J.B. and Fauci, AS. (Eds.), Harrison’s Principles of Internal Medicine. XIth ed., McGraw Hill, New York, NY p. 1423. Lovett, C.L., Ulrich, J.T., Simms, B.G. and Goldstein, A.L. (1978) Effects of Chlorpromazine on antibody production in vitro. In: Bergsma, D. and Goldstein, A.L. (Eds.), Neurochemical and Immunologic Components of Schizophrenia. (Series Birth Defects), Vol. 181, Liss, New York, NY. Luchins, D.J., Weinberger, D.R., Kleinman, J.E.. Neckers, L., Rosenblatt, J.E., Biglow, L.B. and Wyatt, R.J. (1980) Human Leukoryte antigen A2 and psychopathology in chronic schizophrenia. Am. J. Psychiatry 137, 4999500. Masi. A.T. and Medsger, T.A. (1979) Epidemiology of the rheumatic diseases, arthritis and allied conditions. In: McCarthy, D.J., Jr. (Ed). Lea and Febiger, Philadelphia, PA. p. I I. Matthe, A.A., Sedvall. G., Wiesel, F.A. and Nyback. H. (1980) Increased content of immunoreactive prostaglandin E in cerebrospinal fluid of patients with schizophrenia. Lancet i, 16-18. McDermott, M., Molloy, M., Cashin, P. et al. (1986) A multicase family study of rheumatoid arthritis in South West Ireland. Dis. Markers. 4. 103-l I. McGuffin, P. (1983) Is Schizophrenia an HLA-associated disease? Psychol. Med. 13, 31-43. McGuffin, P. and Sturt. E. (1986) Genetic markers in schizophrenia. Human Heredit. 36, 65588. McGuffin, P. (1984) Genetic markers in schizophrenia, Ph.D. Thesis, University of London. McLaughlin, D.G. (1977) Racial and sex differences in length of hospitalization of schizophrenics, VI World Congress of Psychiatry, Honolulu, Hawaii. Mellsop, G.W., Koadlow. L., Syme, J. and Whittingham, S. (1974) Absence of rheumatoid arthritis in schizophrenia. Aust. N. Z. J. Med. 4, 274-252. Mikkelsen, W.M., Dodge, H.F., Duff, I.F. and Kato, H. (1967) Estimates of the prevalence of rheumatic diseases in the population of Tecumseh, Michigan 1959-60. J. Chronic Dis. 20, 351-369. Miyanaga, K., Machiyama, Y. and Juji, T. (1984) Schizophrenic disorders and HLA-DR antigens. Biol. Psychiatry 19, 121-129. Mohamed, S.N., Merskey. H., Kazarion, S. and Disney T.F. (1982) An investigation of the possible inverse relationship between the occurrence of rheumatoid arthritis, osteoarthritis. and schizophrenia. Can. J. Psychiatry 27, 381-383.

Morand, C., Young, S.N. and Ervin, F.R. (1983) Clinical response of aggressive schizophrenics to oral tryptophan. Biol. Psychiatry 18, 575-578. Mourant, A.E., Kopec, A.C. and Domaniewska-Sobezak, K. (1978) Blood Groups and Diseases. Oxford University Press, London. Mtabaji, J.P., Manku, M.S. and Horribin, D.F. (1976) Vascular actions of furosemide and bumetanide on the rat superior mesenteric vascular bed: interactions with prolactin and prostaglandins. Can. J. Physiol. Pharmacol. 54, 357-366. Munro, J.G., Hardiker, T.M. and Leonard, D.P. (1984) The dexamethasone suppression test in residual schizophrenia with depression. Am. J. Psychiatry 141, 250-252. Naber, D., Albus, M., Muller, F., Burke, H., Welter, D., Azkenheil, M. and Hippius, H. (1982)Beta-endorphin, cortisol, and probactin in serum of schizophrenic patients during long-term neuroleptic treatment and after withdrawal: relationships to psychopathology. Psychopharmacol. Bull. 224-226. National Center for Health Statistics. Rheumatoid Arthritis in Adults, United States 1960-1962. Rockville, MD, National Center for Health Statistics, 1966. (Vital and Health Statistics, Series II: Data from the National Health Survey, No. 17) DHEW Publication No. (HRA) 7551297. National Center for Health Statistics. Osteoarthritis in Adults. Rockville, MD, National Center for Health Statistics, 1966. (Vital and Health Statistics, Series II: Data from the National Health Survey, No. 20) DHEW Publication No. (HRA) 6662094. Nissen, H.A. and Spencer, K.A. (1936) The psychogenic problem (endocrinal and metabolic) in Chronic Arthritis. N. Engl. J. Med. 21, 567-581. Osterberg, E. (1978) Schizophrenia and rheumatic disease. Acta Psychiatr. Stand. 58, 339-359. Panayi, G.S., Wooley, P. and Batchelor, J.R. (1978) Genetic basis of rheumatoid disease: HLA antigens, disease manifestations, and toxic reactions to drugs. Br. Med. J. 2, 13261328. Papiha, S.S., Roberts, D.F. and McLeish, L. (1982) Group specific component (GC) subtypes and schizophrenia. Clin. Genet. 22, 321-326. Pert, C.B. (1977) A request for serum samples from psychiatric patients with associated autoimmune disease: is some psychosis caused by an autoimmune response to neurotransmitter receptors. Commun. Psychopharmacol. 1 (3) 30779. Pilkington, T.L. (1956) The coincidence of rheumatoid arthritis and schizophrenia. J. Nerv. Ment. Dis. 124, 604-606. Propert. D.N. (1983) Immunoglobulin allotypes GM and KM in chronic schizophrenia: no apparent association. Psychol. Med. 13, 27-30. Ramsay, R.A., Ananth, J., Engelsmann, F., Krakowski, A.J., Witkower, E.D. and Ghadirian, A.M. (1982) Schizophrenia and psychosomatic illness. J. Psychosom. Res. 26, 33-42. Ramsay, R.A. and Engelsmann, F. (1983) Epidemiology of psychosomatic disorders in schizophrenic patients: methodological issues. Psychother. Psychosom. 40, 148-157. Ramsay, R.A., Krakowski, A.J., Rydzynski, Z., Jarosz, M., Engelsmann, F. and Ananth, J. (1982) International comparisons of the prevalence of psychosomatic disorders in schizophrenic patients. Psychother. Psychosomat. 38, 206-20.

192 Rillema, J.A. (1975) Possible role of prostaglandin F2a in mediating effect of prolactin on RNA synthesis in mammary gland explants in mice. Nature 253, 466-467. Roberts, D.F. (1981) (Editorial), Immunogenetics and schizophrenia. Psychol. Med. 11,41-47. Roos, B.E. (1984) Schizophrenia and viral and auto immune issues. Psychopharmacol. Bull. 20, 514-518. Ross, W.D., Hay, J. and McDowall, M.F. (1950) The association of certain vegetative disturbances with various psychoses. Psychosom. Med. 12, 170-183. Rothermich, N.O. and Philips, V.K. (1963) Rheumatoid arthritis in criminal and mentally ill populations. Arthritis Rheum. 6, 639-640. Rudduck, C., Franzen, G., Hannsen, A. and Rorsman, B.G. (1985) Serum subgroups in schizophrenia. Human Hered. 35, 11-14. Sokoloff, L. (1979) On the pathology and pathogenesis of osteoarthritis. In: D.K. McCarty (Ed.), Arthritis and Allied Conditions. Lea and Febiger, Philadelphia, PA. Solomon, L., Robin G. and Valkenburg, H.A. (1975) Rheumatoid arthritis in an urban South African Negro population. Ann. Rheum. Dis. 34, 128130. Spector, T.D. and Silman, A.J. (1987) Does the negative association of rheumatoid arthritis and schizophrenia provide clues to the etiology of rheumatoid arthritis? Br. J. Rheumatol. 26, 307-310. Stastny, P. (1978) Association of the B-cell alloantigen DRW4 rheumatoid arthritis, N. Engl. J. Med. 298, 8699871. Stastny, P. (1978) HLA-D and la antigens in rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum. 21,5139-5143. Stokes, P.E., Stoll, P.M., Koslow, S.H., Maas, J.W.. Davis, J.M., Swarm, A.C. and Robins, E. (1984) Pretreatment DST and Hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups. Arch. Gen. Psychiatry 41, 251-267. Taylor, W.M. (1978) Schizophrenia, rheumatoid arthritis and tryptophan metabolism. J. Clin. Psychiatry 39, 4999503. Tiwari, J.L. and Terasaki, P.I. (Eds.) (1985) HLA and Disease Associations. Springer New York, NY.

Tourney, G. and Erb, J.L. (1979) Temporal variations in androgens and stress hormones in control and schizophrenic subjects. Biol. Psychiatry 14, 395-404. Trevathan, R.D. and Tatum, J.C. (1954) Rarity of concurrence of psychosis and rheumatoid arthritis in individual patients. J. Nerv. Ment. Dis. 120, 83-84. Turner, P. (1977) Schizophrenia as a prostaglandin deficiency disease. Lancet i, 1058. Tyrrell, D.A.J., Parry, R.P., Row, T.J., Johnstone, E. and Ferrier, I.N. (1979) Possible virus in schizophrenia and some neurological disorders. Lancet i, 8399841. Valkenburg, H.A. (1980) An epidemiologist’s view of rheumatoid arthritis. In: Lawrence, R.C. and Shulman, L.E. (Eds.), Epidemiology of the Diseases: Proceedings from the Fourth International Conference, U.S. Department of Health and Human Services, 16-l-16-15. Waltrip, R.W., Carrigan, D.R. and Carpenter, W.T. (1990) Immunopathology and viral reactivation: a general theory of schizophrenia. J. Nerv. Ment. Dis. 178, 7299738. Weiner, H. (1991) Social and psychobiological factors in autoimmune disease. In: Ader, R., Felten, D.L. and Cohen N. (Eds.), Psychoneuroimmunology, ed. II Academic Press, San Diego, CA, pp. 955-1012. Weiss, G. (1960) Hallucinogenic and narcotic-like effects of powdered myristica (nutmeg). Psychiatr. Q. 34, 346-356. Wyatt, R.J., Cutler, N.R., DeLisi, L.E., Jeste, D.V., Kleinman, J.E., Luchins, D.J., Potkin, S.G. and Weinberger, D.R. (1982)Biochemical and morphological factors in the etiology of the schizophrenic disorders. In: Grinspoon, L. (Ed). Psychiatry 1982. American Psychiatry Press, Washington, DC. Zarrabi, M.H., Zucker, S., Miller, F. et al., (1979) Immunologic coagulation disorders in chlorpromazine-treated and patients. Ann. Intern. Med. 91, 194-199. Ziff, M., (1990) Rheumatoid arthritis: its present and future. J. Rheumatol. 17, 127-133. Zvaifler, N.J. (1980) Rheumatoid arthritis. In: Lawrence, R.C. and Schulman, L.E. (Eds.), Epidemiology of Rheumatic Diseases: Proceedings from the Fourth International Conference. U.S. Department of Health and Human Services.