Schizophrenia, just the facts

Schizophrrnia

Resrawh,

I ( 1988)

3- I8

Elsevier

Review article

SRS 00012

Schizophrenia,

just the facts

What do we know, how well do we know it? Richard Jed Wyatt, Robert C. Alexander, Michael F. Egan and Darrell Neuropsyhiatrv

Branch.

National

In.stitutr

(Received

of

Mental

23 October

Health,

Saint Elizaheths

1987, accepted

Hospital,

2 November

Washington,

G. Kirch DC 20032,

U.S.A.

1987)

The basic facts of schizophrenia are subjectively reviewed in terms of their reproducibility and significance for understanding the disorder. Some of the facts that are either less well known or of greater importance for future investigation are discussed in more detail. The purpose of establishing what we know about schizophrenia is to develop firm ground for generating hypotheses. One attempt to synthesize these facts is outlined. Key words: Biological

mechanism;

Hypothesis;

(Schizophrenia)

INTRODUCTION

With the commencement of a new journal focused on schizophrenia research, it is timely to consider what we know about the disorder. What are ‘the facts’ of schizophrenia? Schizophrenia has probably been with us for thousands of years (Jeste et al., 1985) but it was not until the beginning of the 19th century that Pine1 ( 1798) and Haslam ( 1809) described the syndrome. As in other areas of medicine, psychiatric investigators in the 19th century stressed phenomenology and categorization. Kraepelin published his first comprehensive description of schizophrenia in 1896, calling it ‘dementia praecox’. Shortly thereafter, Bleuler (1950, trans.) renamed the syndrome schizophrenia, emphasizing that it was not a single entity. Since that time, thousands ofjournal articles and books have been published on schizophrenia. Organizing and summarizing this mass of information is a formidable task particularly because of

Correspondence to: R.J. Wyatt, Chief, Neuropsychiatry Branch, National Institute of Mental Health, Saint Elizabeths Hospital, WAW Bldg., Washington, DC 20032, U.S.A.

0920-9964,‘88/$03.50

0

1988 Elsevier Science Publishers

the diversity of approaches and orientations of schizophrenia investigators. For most disorders, there is a set of accepted ideas - the facts as we know them - upon which we build further understanding. Table 1 is our evaluation of some information or facts that we consider important when thinking about schizophrenia. Limited space requires that we comment on only some of the facts, those that might be less well known or that are particularly important for shaping future investigation.

PREVALENCE

The prevalence of schizophrenia worldwide appears to be slightly less than 1%. Systematic examination of that prevalence, however, has several problems. These include the lack of general agreement about what should be the diagnostic criteria of schizophrenia and changes in the prevalence and course of schizophrenia. Since we have no specific biological marker for schizophrenia, the disorder must be described in terms of its signs and symptoms, most of which require considerable

B.V. (Biomedical

Division)

4 TABLE

I

Schizophreniu

,fhcts

und our sub&doe

u.erRhtinR

We evaluated each fact according to a rating of *** for most to j, for least. The first column, reproducibility, asks ‘Is it consistently found?‘The second column rates how primary to the disorder we believe the fact is. A clinical finding that could be explained by chronic institutionalization, exposure to medication, or other confounding variables would get a relatively low rating. Facts with high primary marks should be explained in any complete hypothesis of schizophrenia. Firc~ls

Primrrr) to disorder

Prevalence Schizophrenia has a I % prevalence worldwide. Pockets of high and possibly low prevalence exist. Prevalence of schizophrenia is greater among lower socio-economic

** ** ***

** ** *

***

***

Gender differences Lifetime risk of developing schizophrenia is the same for both genders. M&s have an earlier average age at onset. Mules have a poorer outcome than females. Fern&s have a better response to neuroleptics. Females become worse premenstrually and/or during the post-partum period. Females improve during pregnancy.

*** *** ** ** * *

It**

Familial and genetic factors Schizophrenia is in part familial. Schizophrenia is in part genetic.

*** ***

*** **

Environment Since schizophrenia the environment

***

***

* **

* **

***

**

***

***

*** ** *** * *

*** ** ** ** *

***

*

Age at onset The peak of onset for males is between peak, from about 26 to 45.

Stress Initial schizophrenic Suhsrquent episodes

classes in urban

areas.

18 and 25 years; females have a later and broader

cannot be accounted for in its entirety by a genetic component, (biological and/or psychosocial) plays a significant role.

episodes often occur during times of psychological or physical also relate to stress and decrease by reducing stress.

Season of birth In late spring and early winter months, increase modestly. Variability Schizophrenia is a protean disorder course and ncross patients.

births of schizophrenic

of great variability,

stress.

** * * ** *

individuals

in most measures,

over its

Course of illness Some individuals have one or more episodes and return to normal or near-normal others have a gradual or intermittent course with increasing disability. Some patients have some recovery after many years of illness. The prognosis is better in less well-developed nations. Neuroleptics and ECT may alter schizophrenia’s course, preventing some long-term Improvement sometimes occurs during emergencies. Structural and functional brain abnormalities There are abnormal pneumoencephalograms, electroencephalograms, computed tomographic scans, regional cerebral blood flow, eye tracking, and neurologic signs, deterioration of IQ, and psychophysiological deficits.

function;

deterioratton.

(continued

on next puge)

5

(Table I continued) Reproducibility

FLUS

Primary to disorder

Pharmacological and ECT treatment Antipsychotic or neuroleptic medications are useful in treating most schizophrenic individuals and preventing relapse. Neuroleptics tend to be more effective in treating the productive symptoms (e.g., delusions, hallucinations, and thought disorder) than core or defect symptoms (e.g., restricted atTect, loss of drive, and poverty of speech); nevertheless they have some benelit for the defect symptoms. Neurokptics block dopamine receptors in proportion to their relative clinical potency. Sodium umytal produces brief improvement. ECT produces brief improvement. Stimulants and PCP model schizophrenia Dopamine receptors are increased in brain Polydipsia and hyponatremia A subgroup of patients drinks sodium levels.

excessive amounts

of fluid, maintaining

subjective judgment. There is no universal agreement on which signs and symptoms are diagnostically necessary or sufficient, making comparisons among studies difficult. Using standardized criteria, the World Health Organization (WHO) performed a multi-site, international study that determined that the prevalence of schizophrenia is fairly similar throughout the world (Sartorius et al., 1986). Although the criteria were standardized, there is no general agreement that the best criteria were used. The WHO diagnosis was performed using the Present State Examination (PSE) to make the computer based (CATEGO) and International Classification of Disease-9 (ICD9) classifications. Unlike diagnoses made from the Diagnostic and Statistical Manual of Mental Disorders-III (DSM-III), which requires a minimal duration of 6 months of illness, neither the PSE or ICD9 takes the duration of illness into consideration. Thus it is possible that in the WHO study, brief reactive, substance-induced, and acute bipolar psychoses might have been included under the diagnosis of schizophrenia, blurring the data. As a result, while schizophrenia is a worldwide problem, it remains an open question that its prevalence is generally similar throughout the world. In fact, there is evidence of pockets of high prevalence - such as in Northern Sweden (Book,

***

***

*** *** *** **

** ** * **

***

*

**

*

***

*

very low serum

1978) Western Ireland (Torrey, 1984) and Finland (Vaisanen, 1975). Also, schizophrenia is not evenly distributed, occurring more commonly in lower socio-economic classes of large urban centers (Kohn, 1977). This particular prevalence could be the result of the ‘downward drift’ of those affected. An alternative explanation is that the greater stress encountered in large urban areas may be difficult for persons with diminished coping skills to avoid, and may contribute to a higher incidence of manifest illness. Further explanations include a greater likelihood of contagion in high density, lower socio-economic classes. The prevalence of diagnosed schizophrenia has probably changed in recent years (MunkJorgensen, 1987; Stromgren, 1987). It is of interest that Stromgren reported no change in the prevalence of schizophrenia between 1935 and 1983 for males, but there was a 36% drop for females. The decrease is the result, in part, of changes in diagnostic criteria: the boundaries of schizophrenia have narrowed. The more rigorous use of diagnostic criteria has many determinants. These include the desire to be more precise about what is meant by schizophrenia in research, clinical-care concerns (e.g., recognition of tardive dyskinesia in patients treated with neuroleptic medications), and the desire to use lithium in bipolar illness. The decreased prevalence may also be due to

6

changes in the course of schizophrenia. Kraepelin (1919) found that 59% of catatonics and 75% of hebephrenics reached a ‘terminal state of profound dementia’. Complete recoveries were found in only 4.1%, with social recoveries seen in 17%. Numerous outcome studies since Kraepelin have reported significantly better outcomes, particularly since the introduction of better social (Warner, 1985) and organic therapies. Rates of recovery of functioning in these studies have ranged from 20% to 68%. Several lines of research support the impression that schizophrenia has taken on a milder form in recent years. This is not altogether unexpected given the marked impact of new therapies. One approach is to look at symptomatology and subtype. In the early part of this century, Kraepelin found that 19.5% of a group of narrowly defined schizophrenics were catatbnic (Kraepelin, 19 19). By the 1970s others found that the prevalence of catatonia had markedly decreased to between 5% (Guggenheim and Babigian, 1974) and 10% (Morrison, 1973). Hogarty and Gross (1966) compared the symptomatology of first-admission schizophrenics from a 1953 pre-drug era group and a 1960 post-drug era group, and found that the incidence of catatonia dropped from 38% to 25%. Similarly, Morrison (1974), in a 47-year retrospective study of subtype diagnosis, showed not only that the incidence of catatonia dropped 223-fold, but that this drop occurred in the early 1930s. He also found that the incidence of hebephrenia decreased from 27% (192G1944) to 6% (1945-1966). While this change does not clearly mean that symptoms are less severe, it is suggestive. Lethal catatonia has likewise become uncommon. A recent review (Mann et al., 1986) stated that the incidence reported before 1955 ranged from 0.25% to 3.5%. Two studies from the 1960s found a range of 0.13% (Tolsma, 1967) to 0.5% (Molokov, 1962). This decrease may be partly accounted for by recent improvements in the ability to diagnose organic conditions and medication reactions such as neuroleptic malignant syndrome (Gelenberg, 1976; Fricchione, 1985; Kaufmann and Wyatt, 1987). Tsuang (1982) has noted that catatonic symptoms are more common than hebephrenic or paranoid symptoms in patients with organic psychoses. Finally, the finding that patients in developing countries have a better prognosis than those in

developed nations is of importance. Life in less developed countries may require fewer coping skills and patients may, consequently, encounter less stress, leading to fewer relapses and less chronicity.

AGE AT ONSET

The peak age of onset of schizophrenia for males occurs between 18 and 25 years, while females have a broader peak, from about 26 to 45 (Stromgren, 1987). In a Danish-twin study (Fischer, 1973) the age at onset of schizophrenia in monozygotic concordant twins ranged from 17 to 52 years (mean 29 years) and from 23 to 45 in discordant twins (mean 31 years). The monozygotic twins had a discordant period ranging from 1 to 29 years with a mean of 7.9 years. Thus, there is a large spread over time as the illness develops; most cases become apparent after puberty and others appear well into adult life.

GENDER

DIFFERENCES

As noted above, women as a group have a later onset of schizophrenia than men. Women also tend to have a better outcome (Mendelson et al., 1977). Clinicians have observed that schizophrenic women have premenstrual exacerbations (at a time when estrogen is low), and have more difficulties during the post-partum period and at menopause, yet do relatively well during pregnancy. In one study, Seeman (1983) found that the ratio of the neuroleptic dose required for women compared to the dose required for men gradually increased from 0.7 in the 2&29 year age group to 1.5 in the greaterthan-50 age group. She suggests that estrogen acts as a natural neuroleptic. While acknowledging that many patients who in the past would have been diagnosed as schizophrenic today would be diagnosed as having an affective disorder, it is of interest that Swanson et al. (1964) reported that norethynodrel produced improvement in 21 psychotic women with premenstrual exacerbation of their symptoms. Billig and Bradley (1945) reported that combined treatment with progesterone and electroshock was of definite benefit in ‘postpuberal’ psychosis and premen-

strual exacerbation of pre-existing psychosis. Bower and Altschule (1956) found that treatment with progesterone increased the remission rate of post-partum psychoses to nearly 100%. Similar findings were reported by Tucker (1962).

FAMILIAL

AND GENETIC

FACTORS

The familial and genetic nature of schizophrenia has been well reviewed (Kendler et al., 1985; Kety, 1988). Whether the schizophrenia that runs in families is produced by social-psychological factors, biological-environmental factors, genetic transmission, or some combination of these has, in part, been answered by adoption studies. Such studies indicate that some aspect of the tendency to become schizophrenic is present in the individual’s genes. The mode of genetic transmission and the nature of what is transmitted have not been resolved. In our view, it is likely that what is inherited will be the product of several different genes. An example of different genes producing clinically similar diseases comes from very recent work in bipolar illness. Genetic loci for bipolar illness on separate chromosomes in different pedigrees have been found. One form of illness is autosomally linked (Egeland et al., 1987) and another is on the X chromosome (Baron et al., 1987; Mendlewicz et al., 1987). The gene linkages in bipolar disorder, however, have only been found in a few pedigrees, not others (Detera-Wadleigh et al., 1987) suggesting that there are more, yet to be discovered, genes that encode for bipolar illness. Bassett (1987) has recently described a schizophrenic proband and his affected maternal uncle, each having a trisomy of the long arm of chromosome 5. The proband’s non-affected mother has a balanced abnormality on the same chromosome extra chromosomal material). If this (no abnormality is more than a chance association, this family may prove to be an important resource for identifying a gene for schizophrenia and would provide further evidence of the heterogeneity of the disorder. NOW that a genetic component for schizophrenia is generally accepted, one use for adoption studies, twin studies, and other family studies is to define

the boundaries of the schizophrenia spectrum which disorders are and are not genetically related to schizophrenia? Kety (1988) found that the biological relatives of schizophrenic probands have a high prevalence of schizophrenia and schizotypal personality disorder, but not acute schizophrenia or schizoid or inadequate personality. In a study examining the same issue, Farmer et al. (1987), using DSM-III criteria for diagnosing 26 monozygotic and 34 dizygotic twins from the Maudsley Hospital, found a heritability of 0.85. The monozygotic-to-dizygotic concordance ratio was 5.01. This ratio increased with the addition of patients with the diagnosis of either affective disorder with mood-incongruent delusions, schizotypal personality disorder, or atypical psychosis. When all three were added, the ratio increased to 7.68. On the other hand, the ratio decreased when any other affective, schizophreniform, or paranoid disorders were added. Schizophrenia occurs at a higher frequency than can be explained by accepted rates of genetic mutation in humans. Given the low fertility of schizophrenic individuals (only 70% of that found in the normal population (Medical Research Council Annual Report, 196551966)) the persistence of schizophrenia across generations raises the possibility that something related to the illness may endow the schizophrenic’s relatives (possible ‘carriers’ of the schizophrenic genetic element) with a reproductive advantage. The majority of past research has concentrated on identifying decreased incidences of various forms of physical illness in schizophrenics. Rheumatoid arthritis, for example, is reported to be decreased in schizophrenic women (Mellsop et al., 1974) and schizophrenics are reported to be resistant to surgical and wound shock (Huxley et al., 1964). Carter and Watts (1971) found a reduced incidence of viral illness among the relatives of schizophrenics. Also of importance, these investigators report a higher fertility rate in the relatives of schizophrenics compared with the relatives of psychiatric controls. Erlenmeyer-Kimling and Paradowski ( 1966) also reported an increased fertility rate in the relatives of schizophrenics, in this case comparing the sisters of schizophrenics with women in the general population. A selective advantage of the schizophrenia spectrum was suggested by Book (1953), who

8

described an isolated, North-Swedish community with a high density of schizophrenia. Schizophrenia accounted for 85% of the psychoses, while manicdepressive disorder was virtually absent. In this agrarian community, the summer is short and the sun does not appear during the 6 months of winter. Book proposed that individuals with schizoid personality do well under such conditions and that manicdepressives are likely to migrate. Schizoid personality disorder does not seem related to schizophrenia, as noted above; schizotypal personality disorder, which does appear to be related to schizophrenia, may confer a similar advantage. A selective advantage could arise from genetically determined differences in the immune system, which may be related to schizophrenia. A number of relatively common, inherited, but non-classically Mendelian diseases have been associated with the human leukocyte antigen (HLA) system. Among these are juvenile diabetes, multiple sclerosis, and narcolepsy. Using pooled data from nine studies, McGuffin and Sturt (1986) found that the association of HLA A9 with paranoid schizophrenia arising by chance was very small (P = 0.0003). There have been few studies of the D locus, which has been more closely associated with specific illnesses than the A locus; some work does suggest an association with a specific D locus HLA antigen, and schizophrenia (Miyanaga et al., 1984).

VARIABILITY

Schizophrenia is highly variable across individuals and across time in the same individual. The variability across individuals is attributable in part to the number of entities that seem to make up the syndrome. Historically and, in all likelihood, today schizophrenia is several diseases. At the beginning of the 18th century, the difference between dementia and amentia was just beginning to be realized. Bipolar illness was separated from schizophrenia during the last century; further clarifications came in the early part of this century (Kraepelin, 1919) and again after the widespread introduction oflithium in the 1970s. The clarifications include the ability to distinguish central nervous system syphilis, pellagra, and schizoid and schizophreniform disorders from schizophrenia.

Van der Velde (1976) documented some of the variability in the same individual with time. He demonstrated, for example, large changes in body weight in the 10 years prior to the introduction of neuroleptics. Many observers have assumed that the variability is part of the disorder or perhaps crucial to it.

COURSE

OF ILLNESS

The course of schizophrenia is highly variable. Some individuals have one or several episodes and return to normal or near-normal functioning. Other individuals experience an unremitting deterioration or have an intermittent course with gradually increasing disability (Bleuler, 1978; Watt et al., 1983). This variability is an intriguing element of the illness and we feel that it merits detailed scrutiny. Beginning with Kraepelin, the prevailing opinion has been that the outcome of schizophrenia is almost invariably grim. Many studies now indicate that partial and perhaps complete recovery is possible for some individuals, even after many years of illness. McGlashan (personal communication) has recently reviewed and summarized the findings of ten outcome studies performed between 1963 and 1986. These studies report a marked heterogeneity in outcome, with a significant percentage of patients experiencing complete recovery. Harding et al. (1987) in a retrospective followup study of patients from the Vermont State Hospital, reported an exceptionally favorable outcome. These patients had been ill a mean of 16 years and hospitalized a mean of 6 years prior to the beginning of the study period. At follow-up 32 years later, 68% of the patients had no signs or symptoms (positive or negative) of schizophrenia. 45% were free of any psychiatric symptoms. In another 22% of the patients, the symptom picture at follow-up was more consistent with an affective or organic disorder. Over 60% of the patients had a Global Assessment Scale score indicating good functioning; not one of the 82 patients originally diagnosed as schizophrenic scored in the poor functioning category. McGlashan (personal communication) has hypothesized that a number of positive factors may have contributed to the Vermont State Hospital patients’

9

TABLE Vermont

2 Study: 32 yearjollow-up

phrenic patients (n = 82) (Adapted from Harding et al.

nf’DSM-III-diagnosed

schizo-

( 1987).)

Area qf,fimction

Percent ofpatients

Not in hospital during past year Met with friends every week or two Had one or more moderate-to-very close friends Employed in last year Displayed few or no symptoms Required little or no help in meeting basic needs Led moderate-to-very full life

82 61

68 40 68 81 13

successful outcome. The patients, while they had been in the hospital some time prior to the study, were selected because of their good response to the then recently introduced neuroleptics. They had not left the hospital because placement had been difficult for administrative rather than medical reasons. They had already been placed in an in-hospital rehabilitation program and were able to work for up to 30 h per week prior to entering rehabilitation. Clearly, the results of outcome studies in schizophrenia are dependent on the initial characteristics of the patient sample. While the sample in the Vermont State Hospital study is not broadly representative of schizophrenia, the study does indicate that for many patients the long-term prognosis is hopeful. Some important issues are unanswered about the natural course of the illness. For many individuals the time of onset is difficult to ascertain. For practical purposes, the date of first hospitalization is often used, especially when it and abnormal symptoms and signs are temporally close together. Often, however, there are substantial changes long before hospitalization occurs. It is unclear whether the changes observed in schizophrenia are deterioration in the sense of a dementia or a failure of certain brain systems to develop. The time from the first onset of symptoms to the time the disorder has taken its full toll has not been well studied. McGlashan suggests (personal communication) that loss of functioning appears to bottom out or plateau between 5 and 10 years after

the illness becomes unequivocally established. This does not speak, however, to patients who deteriorate gradually for some years prior to diagnosis. The plateauing in symptoms and the possibility of longterm improvement, however, indicate that schizophrenia is not produced by a continuous process, but that the insult is time limited. Neuroleptics may alter the course of schizophrenia and prevent further deterioration. While the evidence that schizophrenic patients do better while using neuroleptics is striking (Davis, 1985), whether neuroleptics produce long-term benefits has been studied only occasionally. Studies by Greenblatt et al. (1965), May et al. (1976), Johnson et al. (1983), and Crow et al. (1986) provide some information that neuroleptics may prevent long-term deterioration. Greenblatt et al. (1965) studied chronic schizophrenic patients who had been in a state hospital for more than 5 but less than 10 years. Since tranquilizers had been only recently introduced into psychiatry (Greenblatt’s study began in 1956), the patients had had relatively little previous neuroleptic exposure (about half of them had been on phenothiazines and another 15% on reserpine for 5-6 months prior to the study). Any patient who had been given medications was made drug free for at least a month prior to entering the study. One group of patients was transferred from a state hospital to an active, teaching hospital and treated with antipsychotic medications (reserpine or chlorpromazine at 300 mg/day for males and 150 mg/day for females). Another group transferred to the same hospital was given only social therapies and placebo. Of the two groups remaining in the state hospital, one received drug therapy, the other had no drug treatment. Not surprisingly, after 6 months the

TABLE 3 Percent

c~f patients

placebo

or neuroleptic

discharged

(Data

from Greenblatt

Initial

6 months

c,ategorizrd

by initial

6 months qf

treatment

et al. (1965).) Followup

point

of‘trfatment

Neuroleptic No drug

6 months

18 months

36 months”

27 7

21 4

3639 O-4

“At 36 months one patient who had been discharged be assigned to the neuroleptic or placebo treatment

could not group.

10

medicated patients showed greater improvement (as determined by a mental status examination) than the drug-free patients. At the teaching hospital, 7% of the patients with no drug treatment was discharged compared with a discharge rate of 27% for those treated with medications. 30 months after the 6 month drug/no drug period, the patients’ progress was again compared. The initial medication group was still doing much better than the group that had been drug free during the initial 6 months of the study. Of the initial 24 patients who had been discharged, 18 remained in the community continuously. Of these 18, 17 (it is unclear which group the 18th patient had been in) had been in the early medication group. At the state hospital the patients tended to receive the same treatment in the follow-up period as in the experimental period. Patients initially treated without medications were not subsequently placed on medications. This uneven treatment in the follow-up period may have introduced a bias for the state hospital patients. This bias was not present, however, at the teaching hospital. Of the initial drug-free patients, 85% were immediately placed on medications while only two thirds of the initially medication-treated patients were maintained on them. At the teaching hospital, at least 12 of the 13 (it is unclear which group the 13th patient was in) patients discharged at 36 months had been in the initial drug group. May et al. (1976), comparing several modes of treatment for first-break schizophrenic patients over a 6 month period, found that neuroleptic (or ECT) treatment reduced the length of hospital stay, increased the release rate, and decreased the need for use of sedatives and hydrotherapy compared with psychotherapy alone. Following the study, all patients received standard therapeutic interventions. 3 years after the initial hospitalization, the patients who had initially been treated with neuroleptic medications were hospitalized an average of onehalf as often as patients who had been treated with no medication during the initial study. Johnson et al. (1983) studied the outcome of chronic schizophrenic patients whose neuroleptic medication was discontinued after they had been psychiatrically stable for 12-48 months compared with a control group of patients who remained on their neuroleptic medication. Patients whose medication was discontinued had more relapses during

the medication-free period. The patients who relapsed were placed on neuroleptics. 12 months after recovery from the acute symptoms, they had not regained their pre-relapse level of social and work function. They also required a third more medication for maintenance. Crow et al. (1986) followed a group of 120 firstepisode schizophrenic patients who were discharged from full or partial hospital care and were able to maintain that status for at least 30 days. In a randomized controlled trial, the patients were assigned to maintenance neuroleptics or placebo and monitored until relapse for a period of 2 years. Not unexpectedly, the patients on neuroleptics had more time until relapse than those not on neuroleptics. In both neuroleptic-treated and placebo-treated groups, patients symptomatic for less than a year prior to their first admission had greater time to relapse than those who were symptomatic for a year or more prior to their first admission. This data can be interpreted in several ways. Patients who were symptomatic for a longer period have a poorer course in general than those with a more acute onset. Alternatively, early treatment tends to prevent longterm morbidity. While careful examination will demonstrate flaws in all these studies, one interpretation that can be given to this group of studies is that treating schizophrenia with neuroleptics at a time when deterioration would have occurred may slow the process or perhaps prevent further deterioration. If this interpretation is correct, it remains to be seen if the deterioration is psycho-social or physical.

STRESS

Stress is a reaction to or the product of an event or a series of events. Spring (1981) for example, defines stress as a disruption or alteration in biological, physiological, emotional, or behavioral homeostatic functioning. Events that are stressful to one individual may or may not be stressful to another; moreover, such events may be stressful at one time but not at another. Schizophrenia, like many illnesses, appears to be affected by stressful events. Clinically, the initial overt expression of schizophrenic symptoms often occurs during times of psychological or physical stress.

11

The notion that stress occurs prior to the initial schizophrenic episode has been difficult to document although several studies do address it. Steinberg and Durell(l968) examined the records of U.S. Army draftees who entered the service between 1956 and 1960. During the first month of service the rate of hospitalization for schizophrenia was eight times higher than during the second year of service. The investigators felt that early detection accounted for only a small portion of this increase. Similarly, Wagner (1946) found that during 2 months of heavy fighting at Normandy there was a high incidence of psychosis and schizophrenia even among persons previously selected for stability. In another study, Raphael and Himler (1944) reviewed the psychiatric histories of students who enrolled at the University of Michigan between 1930 and 1943. 12% of the cases of schizophrenia were found to occur in the first 2 weeks of school and a total of 44% during the first semester. Dohrenwend and Egri (1981) reviewed data from two studies and found that schizophrenic individuals had more stressful life events in the 3 and 12 month periods prior to initial hospitalization than controls. These investigators point out that one study showed that schizophrenics had a much higher rate of stressful life events in the 3 weeks prior to their first admission than prior to subsequent admissions, suggesting that the stressful events were not a result of schizophrenia. Since these studies were performed before adoption of our current diagnostic criteria, they probably contain some patients in their cohort with diagnoses other than DSM-III schizophrenia. There are better data indicating that subsequent episodes or relapses are related to stress and, importantly, that decreasing stress can decrease TABLE 4 Value CI/ decreasing

(Adapted

stress in presenting

from Goldstein

relapses in schizophrenia

et al. (1987).)

Dose of’

stress

Percent

fiuphena:ine:

reduction

in the 6 months qfter initial

high (25 m,q), low (6 mg)

High High LOW Low

Yes No Yes No

0 17 22 48

rehospitalized episode

relapses. One such study (Goldstein et al., 1978) examined the effect of high (1 ml) and low (0.25 ml) dose of fluphenazine enanthate (injectable) with and without six sessions of crisis-oriented family therapy. Schizophrenic patients who were either in their first or second admissions were studied and then were followed for 6 months. As Table 4 demonstrates, both high- and low-dose neuroleptic groups had fewer relapses when they received crisis therapy than their comparison group, which received the same neuroleptic treatment without crisis intervention.

SEASON

OF BIRTH

During the late spring and early winter months, the number of births of persons who will later become schizophrenic increases modestly. This phenomenon raises some questions. Does being born in the spring/winter months mean that individuals are more likely to be exposed to a viral infection that in time will make them susceptible to schizophrenia? Several authors (Stevens, 1988; Torrey, 1988) have used this finding to speculate about a viral cause for schizophrenia. Others have suggested that the vulnerability is not at term, but during some other gestational period. Mednick et al. (1988), for example, recently reported that in Helsinki there was a high incidence of schizophrenia among a cohort exposed in utero to influenza A2 virus in 1957 during the second trimester of gestation. Are the increased spring/winter births due to an increase in conceptions by parents likely to have schizophrenic children in late spring or early summer? Studying siblings of schizophrenics should help supply an answer to this question: are the siblings also likely to be born in the winter and early spring months? Available studies are divided on the birth dates of siblings. When more studies are performed to answer this question, the investigators will need to add an important control. Since the proband for these studies is always schizophrenic, it gives a non-random starting point for the birth date of the siblings. For example, if the proband is born in April, it is impossible for the next child to be born until at least 9 months later (December). A similar non-random month of birth would be present for a previous sibling.

STIMULANTS, DOPAMINE-LIKE SUBSTANCES, AND PCP AS MODELS SCHIZOPHRENIA

OF

Stimulants such as amphetamines produce a paranoid psychosis that in many respects is similar to acute paranoid schizophrenia. Because amphetamines stimulate central nervous system release of dopamine, the clinical analogy has lent support for the dopamine hypothesis. Also, dopamine agonists and the dopamine precursor L-dopa can produce a schizophrenic-like psychosis. Phencyclidine (PCP) may produce a better model of schizophrenia than traditional stimulants. The PCP model is also important because a PCP receptor and an endogenous PCP ligand have been identified in the brain (Quirion et al., 1984).

STRUCTURAL AND ABNORMALITIES

FUNCTIONAL

BRAIN

Structural abnormalities in schizophrenia were described using the pneumonencephalogram as early as 1927 (Jacobi and Winkler). Since then, histological (Weinberger et al., 1983; Benes and Bird, 1987) and gross structural abnormalities have been intermittently described. More recently, with non-invasive and readily available imaging techniques, structural abnormalities are being routinely described. Over 50 studies have shown computed tomographic (CT) brain abnormalities. So far, the abnormalities are both variable from patient to patient and non-specific. It is unclear if they are primary or secondary to the illness. The data on functional brain abnormalities in schizophrenia are more convincing. Schizophrenia, insofar as it involves symptoms such as thought disorder, hallucinations, and delusions, clearly involves brain dysfunction. Furthermore, abnormal movements, posturing, mannerisms, grimacing, decreased IQ, and abnormal smooth pursuit eye movements, all of which have been reported in schizophrenia, have their origins in the brain. The apparent cortical abnormalities seen on the CT scan (atrophy over the convexity and ventricular enlargement) and reported histopathological abnormalities (such as diffuse periventricular gliosis

and loss of cells in various brain regions) suggest that there is no single site responsible for the illness. Furthermore, it is not known if there is actual loss of brain tissue or simply a failure for the brain to develop fully, and whether the abnormality happens in neurons, glia, or both kinds of cells. DSM-III criterion F for diagnosing schizophrenia requires that it cannot be established that an organic factor initiated and maintained the disturbance. If the structural abnormalities noted above are more than associations, this criterion will have to be changed. Genetic diseases are invariably associated with an organic abnormality, whether structural or enzymatic.

INCREASED DOPAMINE IN THE BRAIN

(D2) RECEPTORS

At least a dozen post-mortem studies have uncovered an increased number of dopamine (D2) receptors in the brains of schizophrenic individuals (Table 5). Furthermore, one study using positronemitting tomography (PET) demonstrated a 2-3fold increase in D2 receptors in the brain (Wonget al., 1986). Since a functional excess of dopamine seems capable of producing many of the more florid symptoms of schizophrenia, the presence of excess receptors for dopamine suggests that the brain may be amplifying the signal for dopamine. Other interpretations also exist, not the least of which is that the TABLE

5

Dopuminr

txpr II (D2)

recrptors

putamen)

of‘autopsied

schiwphrenic

(Adapted

from Jaskiw

and Kleinman

sr

uw inueusrd

in hruins

indiaiduds

(1988).)

U(i)

Lee et al., 1978 Owen et al.. 1978 Rhine et al.. 1980 MacKay et al., 1980 Reynolds et al., 1980 Cross et al.. 1981 Kleinman et al., 1982 Seeman et al., 1984 Pimoule et al., 1985 Toru et al.. 1986 Mita et al., 1986 Hess et al.. 1987

YCS

Yes YCS

NO No Yes

Yes

YC?S Yes Yes YCS

Yes

f cuudatd

13

increased number of dopamine receptors may reflect receptor supersensitivity resulting from neuroleptic treatment. It should be noted that Wong et al’s (1986) PET report was not confirmed by the study by Farde et al. ( 1987), who used a different D2 ligand and a different mathematical model.

PHARMACOLOGICAL TREATMENT

AND

ECT

Perhaps more than any other therapy in medicine, antipsychotic or neuroleptic medications have demonstrated their usefulness in both decreasing symptoms and preventing relapses. ECT, in many fewer studies, has also been shown to be helpful. While neuroleptics tend to be more effective in treating productive symptoms (e.g., delusions, hallucinations, and thought disorder) rather than core or defect symptoms (e.g., restricted affect, loss of drive, and poverty of speech), they have some beneficial effect on the deficit symptoms. The benefit produced by neuroleptics has led to a search for their mechanism of action and to several hypotheses about the cause of schizophrenia. Neuroleptics appear to block dopamine receptors in proportion to their relative clinical potency, supporting the hypothesis that schizophrenics have a functional excess of dopamine in their brains (Wyatt, 1976). Direct evidence for this excess has not emerged. In fact, there is better evidence that some patients have a dopamine deficiency (Wyatt and Weinberger, 1984; Wyatt, 1985, 1986; Wyatt et al., 1988b). Other medications, such as sodium amytal, produce brief improvement, a fact that in recent years has evoked surprisingly little speculation about mechanism. Similarly, ECT use in schizophrenia has fostered little investigation. The potential these agents have for temporary improvement and the good, long-term outcome reported in several followup studies suggest that the defect in some cases of chronic schizophrenia is reversible.

POLYDIPSIA

AND

HYPONATREMIA

As early as 1933, Hoskins and Sleeper found that the daily urine volume for schizophrenic patients

was twice that of normal subjects, a phenomenon that was found to be secondary to excessive fluid intake, or polydipsia. It subsequently became apparent that, in severe cases, this polydipsia may lead to a state of water intoxication in which acute hyponatremia produces confusion, seizures, coma, or even death. Significant numbers of schizophrenic patients are polydipsic, with a small percentage progressing to actual hyponatremic episodes. It is important to note, however, that these phenomena are also observed in psychiatric patients with diagnoses other than schizophrenia. There is some evidence that hyponatremic schizophrenic patients may tend to have a more chronic illness, an undifferentiated sub-type, a poor response to neuroleptics, and ventricular enlargement on CT scans (Illowsky and Kirch, 1988). The underlying pathophysiology of the syndromes of polydipsia and hyponatremia is unclear. It may include a structural hypothalamic defect altering thirst and/or osmo-regulation, inappropriate antidiuretic hormone (ADH) secretion that produces retention of free water, or effects of neuroleptic medications (including possible stimulation of ADH release). The ultimate elaboration of the mechanisms involved in polydipsia and hyponatremia in a subgroup of schizophrenic patients, if not secondary to medications or some other ‘peripheral’ aspect of being ill, in time may provide an opportunity to determine a pathophysiological abnormality related to schizophrenia itself.

SUMMARY

-

THE

FACTS

PLUS

We have outlined ‘the facts’ of schizophrenia as supported by current data. These facts in turn provide a foundation upon which to formulate hypotheses about the nature of schizophrenia. Given the facts as we see them, how do we put them together? We believe that schizophrenia is produced, in part, by a genetic vulnerability or vulnerabilities. It is unclear, however, if every individual who is diagnosed as having schizophrenia has this genetic vulnerability. Moreover, in the absence of a genetic vulnerability, can environmental factors alone produce the disorder? We speculate, both from a historical perspective and from our understanding

14

of other complex medical disorders, that schizophrenia can be caused by genetic abnormalities, environmental factors, or a combination of both. This is consistent with the Bleulerian view that schizophrenia is a group of diseases. The nature of the genetic mechanisms and the etiologically relevant factors in the environment are not known. The factors we have discussed certainly represent some of our best clues in defining these genetic and environmental elements. The findings that substances that act like dopamine are capable of producing a psychosis and that dopamine-blocking agents (neuroleptics) can ameliorate psychosis have led to what may be the most tenacious concept regarding the nature of schizophrenia: the dopamine hypothesis (Wyatt et al., 1988b). While dopaminergic abnormalities could be the primary alteration in schizophrenia, the data suggest that involvement of the dopaminergic system is indirect. Evidence for this statement comes from the observation that neuroleptic medications also have an equipotent clinical effect on psychotic symptoms in affective disorders as well as in. schizophrenia (Wyatt and Torgow, 1976). In both illnesses, haloperidol is about 50 times more potent than chlorpromazine. The correlation for relative equivalent clinical potencies in schizophrenia versus affective disorders holds for all the neuroleptic medications for which there is information. The correlation of relative equivalent clinical potencies also holds when these compounds are compared for their ability to displace dopamine antagonists from brain tissue dopamine receptor sites (Richelson et al., 1984). One might argue that schizophrenia and affective disorders are actually the same disease. Neuroleptics also work in other psychoses, however, where they also tend to have the same relative equivalent clinical potencies. Huntington’s chorea, toxic psychoses, affective disorders, and schizophrenia certainly do not share the same primary disease process. Thus, we are led to conclude that even though neuroleptics may alter psychosis by a common process, not all psychoses are produced by the same etiologic mechanism. The body of work that most clearly indicates a direct relationship between the dopamine system and schizophrenia is the well-replicated finding of an increased number of dopamine receptors in brains of autopsied schizophrenic individuals. If

TABLE

6

A cornpurism used to treat

(Adapted

of equiwlrnt schizophrrnia

from Wyatt

Chlorpromazine Thioridazine Chlorprothixene Acetophenazine Haloperidol Pimozide Mesorldazine Oxypertine Loxapine Perphenazine Thiothixene

&id

potc’ncirs

and the @ectke

and Torgow

100

108 35 22 2.4 I.2 4s 38 I I .6h 8.X 3.2

of nwroleptics

a.5

di.sorders

(1976).)

100 128 42.5 105 2 4 70 30 15

“This is the optimal clinical daily dose for each drug expressed as a percentage of the optimal dose for chlorpromazine; all drugs arc equally efficacious at these doses within each disorder. Spearman rank-order correlation was 0.86; P < 0.0 I. hValue of 0.2 published in original study was in error.

future studies, using PET or other imaging techniques on schizophrenic patients who have never received neuroleptic medications, also find an excess of dopamine receptors, this finding will take on even greater importance. Our own view of the monoamine hypothesis of schizophrenia is that in schizophrenia there is a secondary alteration in brain monoaminergic systems. The etiology of this alteration could be either genetic or produced by environmental insults. In this view, the primary problem usually does not reside in the dopaminergic system. Rather, stress may impinge on this vulnerable system, causing increased release of monoamines (in particular, dopamine). This production of excess dopamine may be responsible for the hallucinations, delusions, formal thought disorder (marked incoherence, derailment, tangentiality, or illogicality), and bizarre or disorganized behavior of schizophrenia. The defect symptoms of schizophrenia, alogia, affective flattening, anhedonia, asociality, avolition, and apathy may be produced either by a direct insult to the brain or through repeated acute episodes. Available data appear to indicate that if schizophrenic patients receive neuroleptics early or

in a sustained fashion, they may have a better longterm outcome and presumably fewer deficit symptoms. This is speculative and must be verified by further study. If this is the case, neuroleptics either may slow down the emergence of defect symptoms directly by pharmacologic effects or indirectly by allowing psychosocial interventions to take place. Patients with schizophrenia fare better when certain stresses are diminished. In animals, acute stress has been shown to increase brain dopamine turnover (Blanc et al., 1980), particularly in the cortex (Thierry et al., 1976). Stimulants such as amphetamine and cocaine, which acutely increase brain dopamine release (Woodrow et al., 1978), over a longer period of time may produce a persistent decrease in brain dopamine (Seiden and Vosmer, 1984; Wyatt et al., 1988a). In animals and humans, decreased dopamine has been associated with symptoms analogous to the defect symptoms of schizophrenia. While there is, however, no direct evidence of decreased dopamine in the brains of schizophrenic individuals, indirect evidence exists. Recently a series of studies described decreased CSF dopamine and/or its metabolites in schizophrenia (Wyatt et al., 1988b). Some of the studies also showed an inverse correlation between the concentration of metabolites of dopamine and the prominence of defect symptoms. Does this decrease in dopamine metabolites in the CSF come from a process analogous to that found in animals treated chronically with stimulants? Is there a toxic substance made from the excess dopamine (Wise and Stein, 1973; Seiden and Vosmer, 1984) or is there a decrease in inhibitory inputs causing a loss of dopaminergic function (Saji and Reis, 1987)? In animals, GABA agonists decrease the activity of dopamine terminals in the cortex during stress (Glowinski, 1978). While there is some evidence that GABA agonists are useful in acute manic psychosis, there is no agreement about whether GABA agonists are useful in treating acute schizophrenic states; this is another area worthy of more research. If there is an alteration in the GABAergic system, does it become more apparent when the dopaminergic system is stressed? Equally intriguing is the question of whether excitatory substances or systems are pathophysiologically relevant. The endogenous PCP-like system and other substances that act at glutamate receptors should be examined

insofar as these substances may be valuable in producing models for schizophrenia. What changes occur in schizophrenic patients who improve with time? Is the loss of dopamine permanent? Are there pharmacological or behavioral ways of preventing the loss of dopaminergic function that might be translated into treatments for schizophrenia? The finding that patients can have temporary improvement with sodium amytal indicates that with pharmacological aid some patients can gain quick, even if brief, remission of symptoms. The question of which DSMIII schizophrenia symptoms are altered by sodium amytal is open to investigation. How can this pharmacological help be prolonged? If this pharmacological improvement is mediated by the GABAergic system, how can it be produced without increasing either tolerance or sedation? The later development of schizophrenia in females and their better prognosis is suggestive that they have some protection. Female gonadotropic hormones may have a neuroleptic effect (Mendelson et al., 1977; Seeman, 1983) that might account for at least some of these differences. At this point, ‘the facts’ of schizophrenia raise more questions than they answer. The dopamine hypothesis, particularly with variations, has with good reason served as a focal point for much valuable research. In terms of future directions, however, it seems that increasing attention can and should be turned toward investigations of the primary etiologic mechanisms underlying whatever dopaminergic dysfunction exists in schizophrenia. Recent advances in molecular genetics, immunology, virology, and a number of other areas may provide vehicles for unraveling the genetic and environmental factors that are ultimately responsible for ‘the schizophrenias’. In the 4th century treatise on the nature of man, Nemesius says: ‘Man crosses the mighty deep, contemplates the range of the heavens, notes the motion, position, and size of the stars, and reaps a harvest from both land and sea . . . He gives order to creation. Devils are subject to him . ..’ (Telfer, 1955) (emphasis added). The demons that produce schizophrenia are not yet under control, but we hope that the renewed interest that accompanies the founding of this journal will lead to a change in the balance of control.

16

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