Premorbid adjustment in schizophrenia. Part IV. Some biological approaches to research on premorbid functioning in schizophrenia.

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premorbid adjustment in schizophrenia . . .

part IV. some biological approaches to research on premorbid functioning in schizophrenia*

Most research concerning premorbid functioning in schizophrenia has focused on measures of psychosocial adjustment, but biological variables may also provide valuable information about the nature of premorbid adjustment. Research dealing with biological aspects of premorbid functioning has focused on the relationship between premorbid status and two types of variables. One large group of studies has investigated psychophysiological patterns of resting activity and reactivity to stimulation. These investigations have been carried out on patients diagnosed as schizophrenics and also on nonschizophrenic subjects considered at increased risk for becoming schizophrenic (e.g., Mednick and McNeil 1968). A second major group of studies has investigated reactions to neuroleptic medication by patients with various levels of premorbid functioning. In this report, we will review the findings from these research approaches so as to clarify the relationship between premorbid function and biological variables.

Studies of Schizophrenic Patients Much research has been carried out to explore the common hypothesis that there are greater aberrations of psychophysiological functioning in poor than in good premorbid schizophrenics.1 In considering this work, it is well to note several crucial methodological problems discussed by Venables (1975) in a recent review of this research. The first of these problems is the range of technical difficulties inherent in mostelectrophysiological work. The second set of problems arises from the patient's medication status, which poses serious difficulties for the interpretation of physiological and behavioral responses. This consideration is so crucial that it prompted Lang and Buss (1965, p. 100) to recommend, at the conclusion of their comprehensive review

of psychological deficit in schizophrenia, that "No research should be undertaken unless the drug variable is properly controlled." A further methodological concern in this research is the need to control for the duration of patients' previous hospitalizations, so that poor premorbid patients will not exceed their good premorbid counterparts in chronicity (Chapman and Chapman 1973, p. 29). Unfortunately, as noted below, investigators have seldom succeeded in controlling these factors when studying psychophysiological aspects of the premorbid distinction in schizophrenia. In the following review we have attempted, whenever possible, to separate studies of chronic patients from research on acute patients, and to note subjects' medication status: A major focus of psychophysiological research related to premorbid adjustment has centered on differences in tonic arousal and reactivity between poor and good premorbid patients as well as between both types of schizophrenics and normal individuals. This work has yielded conflicting results, as indicated by the summaries in table 1 of the relevant results for chronic and acute patients.

•Reprint requests should be addressed to the senior author at the Department of Psychology, University of Rochester, Rochester, N.Y. 14627. Some of the investigators whose work is reviewed below employed the Elgin Prognostic Scale and, therefore, referred to their schizophrenic patients as process and reactive. In view of the high correlation among prognostic scales (Kokes, Strauss, and Klorman 1977) and for the sake of consistency, throughout most of this review we will refer to such patients as good and poor premorbid schizophrenics. In general, we will identify the scale employed in a particular study only when this information is relevant for evaluating discrepancies among the results from different investigations.

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Rafael Klorman, John S. Strauss, and Ronald F. Kokes

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Table 1. Summary of studies of physiological activity in poor and good premorbid schizophrenics

Investigation

Characteristics of the schizophrenic samples Chronicity

DeVault (1955)

Chronic

Medication status

••

Tonic arousal

Responsivity

Pictures of conflict areas (hostility, sex. dependency), or neutral content. and loud bell

Skin conductance level: No differences between groups

Skin conductance: Poor premorbids had smaller responses than good premorbids or normals.

Heart rate: Good premorbids had faster rates than poor premorbids or normal subjects.

Heart rate: Poor premorbid group had deceleratory reactions whereas goods and normals had acceleratory responses.

Half of good and poor premorbids were medicated

Exercise, cold pressor, mental arithmetic with failure

Heart rate, blood pressure. electromyogram: Poor premorbids were more aroused than good premorbids, who, in turn. exceeded normals' arousal levels.

Heart rate, electromyogram. systolic blood pressure: Differences between premorbid groups were inconsistent. Normals were more responsive than schizophrenics.

Reynolds (1962)

Chronic

Ward and Carlson (1966)

Chronic

Medicated

Paced verbal discrimination

Skin conductance level: No differences between good premorbids, normals, or poor premorbids.

Change in skin conductance level: Greater in good premorbids than normals; least in poor premorbids. Few of these contrasts were significant.

Fenz and Velner (1970)

Poor premorbid group was chronic; good premorbids were ' mixed.

Medicated

Relaxation, continuous white noise, white noise plus light, discrete white noises

Skin conductance level: Normals were higher than poor premorbids. Good premorbids were intermediate and did not differ from the other group.

No differences between premorbid groups during white noise. or noise plus light stress. Normals had slower heart rates, more spontaneous skin conductance deflections, fewer electromyographic bursts, and slower respiratory rates than either schizophrenic group.

Heart rate: Good premorbids and poor premorbids had faster rates than normals. Respiration rate: Good and poor premorbids had faster rates than normals. Spontaneous skin conductance deflections: Normals exceeded both premorbid groups. Elect romyogram: Normals were less tense than either premorbid group.

Magaro (1972)

Chronic and acute groups

Medicated

Size estimation task

Skin conductance level: Acute poors were higher than acute goods or chronic poors or goods. There were no other differences.

Amplitude of skin conductance responses to white noise stimuli was smallest in poor premorbids. Goods' responses had greater amplitude but did not habituate. Normals had the largest initial responses, which habituated Isiwfu II v I O W I u •• y .

No difference


Probably not medicated

Relevant findings Tacit c 1 95KS

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Table 1. Summary of studies of physiological activity in poor and good premorbid schizophrenics—continued Characteristics of the Investigation.

schizophrenic samples Chronicity

Relevant findings Tasks Tonic arousal

Medication status

Responsivity


Sample included medicated patients and some patients not receiving medication.

Form discrimination task

Skin conductance level: Chronic good.patients had higher initial arousal and increased over trials whereas acute poors had the lowest arousal and did not change over trials.

Skin conductance responses: Good premorbid patients' response amplitude increased over trials whereas that of poor premorbid patients decreased over trials.

Thetford, Spohn, and Everds (1972) Spohn, Thetford, and Wood ham (1970)


Patients were medicated, but acutechronic. good-poor. and paranoidnonparanoid subgroups were matched on drug dosage. A portion of the patients were retested after withdrawal of medication.

Span of apprehension for tachistoscopically presented consonants

No differences were found between good and poor premorbids, paranoids and nonparanoids. acutes and chronics on skin conductance level. heart rate, leg electromyogram, or blood volume pulse amplitude.

No differences in responsivity between schizophrenic subgroups were reported.

Crider, Grinspoon, and Maher (1965)

Mixed

Medicated

Auditory stimulation; reaction time

Skin potential level: Good premorbid patients had higher levels.

Fowles et al.

Mixed

Heart rate: No differences were found.

(1970)

Some poor patients were medicated (analyzed separately).

Reaction time repetitive attention

Heart rate: Normals had lower heart rate than schizophrenics. Goods and poors did not differ.

Skin potential response frequency: Schizophrenics were more responsive than normals.

Skin potential level: Poor patients increased less than goods during repetitive tasks or normals during rest.

Goldstein et al. (1969)

Acute

All patients were on placebo

Startle stimulus. stressful film

Skin conductance level: No differences were found between good and poor premorbid patients on resting levels.

Skin conductance responses to both tasks: No amplitude differences were found between goods and poors.

Rice (1970)

Acute

Medicated

Loud tones

Skin conductance level: No differences were found between good and poor premorbid patients.

Skin conductance responses: No differences were found between groups.


Magaro (1973)

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Chronic Patients

Acute Patients The pattern of results from psychophysiological research on acute patients is similarly confusing. One study (Magaro 1972) disclosed higher palmar conductance levels for poor premorbid patients than good premorbid schizophrenics. However, several other investigations of acute patients (Goldstein et al. 1969, Magaro 1973, Rice 1970, Spohn, Thetford, and Woodham 1970, and Thetford, Spohn, and Everds 1972) did not find differences in resting arousal or physiological responsivity between patients of varying premorbid background. Similarly negative results were obtained in a study employing a sample of mixed chronicity (Fowles et al. 1970). The absence of such differences in the study of Goldstein et al. (1969) is especially noteworthy, since these investigators tested patients after a 7-day placebo regimen. The preceding investigations focused almost exclusively on autonomic measures. At least one study of acute schizophrenics dealt with a comparison of asocial (poor premorbid) and nonasocial (good premorbid) schizophrenics' electroencephalographic characteristics (Struve, Becka, and Klein 1972). Most of these patients were unmedicated. The research dealt with an abnor-

The pattern consists of a sharp transient, usually formed by the last wave of a 10-12/sec. frontal spindle, followed by a slow wave; the resulting complex resembles the thumb and hand of a child's mitten; it occurs bilaterally and synchronously over the frontal areas, commonly spreading to the parietal areas, [p. 189] These reactions were investigated under secobarbitalinduced sleep. Asocial patients were equally likely to display or lack this pattern, whereas 19 of 20 nonasocial patients were characterized by the abnormality. This finding is interesting because of its potential neurophysiological implications. In a related context, Quitkin, Rifkin, and Klein (1976) reported that, relative to other schizophrenic subgroups, patients with asocial premorbid histories were characterized by an excess of soft neurologic signs and lower \Q scores. The authors interpreted their results as suggesting that this type of schizophrenia involves brain damage. It is noteworthy that the latter two investigations have pointed to specific types of neurophysiologic abnormalities that may differentiate between good and poor premorbid patients. A direct comparison between these kinds of schizophrenics on frequency of soft neurological signs would be very revealing. A study of visual evoked potentials among acute unmedicated schizophrenics dichotomized on premorbid status was reported by Landau et al. (1975). On a specific component of visual evoked potentials (P100N140), good premorbid patients tested early in hospitalization showed a decrease in response amplitude with increasing light intensity. Four months after the onset of hospitalization the good premorbid patients showed nearly level evoked response amplitude as a function of stimulus brightness. This trend reflected a change in the direction of responses typical of normal controls—increasing amplitude with greater brightness. In contrast, early in hospitalization, poor premorbids displayed a decrease in evoked response amplitude with increasing light brightness while showing some increase at the highest stimulus intensities. Late in hospitalization, the shape of this group's function was reversed. These results suggest the need for further work on evoked response differences between good and poor premorbid schizophrenics.


Studies of chronic patients have disclosed findings of higher physiological arousal among poor than among good premorbid patients (Reynolds 1962) as well as the reverse trend (DeVault 1957 and Magaro 1972). Moreover, several investigators have failed to detect any arousal differences as a function of premorbid status among chronic patients (Fenz and Velner 1970, Magaro 1973, Thetford, Spohn, and Everds 1972, and Ward and Carlson 1966). A report on a sample of mixed chronicity (Crider, Grinspoon, and Maher 1965) indicated that good premorbid patients were characterized by higher skin potential; this relationship was unaffected by medication level. Studies of chronic schizophrenics' reactivity in a variety of experimental situations have yielded similarly contradictory results. Smaller physiological responses were observed in poor premorbid patients by some investigators (DeVault 1957, Fenz and Velner 1970, and Ward and Carlson 1966), whereas others have identified few differences in this regard (Magaro 1973, Reynolds 1962, and Spohn, Thetford, and Woodham 1970).

mality of the sleep electroencephalogram (EEG) termed the B-mitten pattern:

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Overview

Subjects at High Risk for Schizophrenia Another source of information on the relationship between premorbid physiological characteristics and later pathology has been the study of children at increased risk for schizophrenia. High risk research has focused, not so much on the good-poor premorbid dichotomy and its link to outcome, but on the identification of premorbid characteristics that indicate vulnerability to subsequent episodes of schizophrenia. In the present context, it is useful to consider the findings of these investigations with regard to how they might be

Mednick and Schulsinger (1973) reported a study on electrodermal responses during aversive classical conditioning among the offspring of schizophrenic mothers described as process (/V = 207) and of normal parents (N= 104). This conditioning procedure was employed in order to assess the probands' autonomic reactions to an anxiety-eliciting stimulus. The subjects were evaluated in midadolescence with the aim of identifying the distinguishing characteristics of those probands who would be subsequently diagnosed as schizophrenic. Five years after the collection of these data, Mednick and Schulsinger (1968 and 1973) compared the original responses of the 20 high risk subjects who developed serious psychiatric disturbances in the interim with the results from matched subsets of the remaining high risk and normal cohorts. This section will focus on the comparison of the original reactions of the two groups of high risk subjects who were disturbed or well at followup, since the differences between these two samples paralleled those found between the entire high risk and normal samples. Relative to their psychiatrically well counterparts, the high risk children who later became disturbed displayed skin conductance responses of greater amplitude and shorter latency throughout the classical conditioning procedure. In addition, the disturbed group exhibited a less pronounced attenuation of these responses throughout the session. These results supported the hypothesized autonomic overresponsiveness of the preschizophrenic.2 On the other hand, the finding of faster recovery rate of electrodermal responses by the disturbed children caused


The dearth of research on psychophysiological differences related to premorbid adjustment in unmedicated acute schizophrenics may well be due to the difficulty in eliciting the cooperation of such patients or the permission of hospital authorities to suspend medication. However, such data would be especially useful in assessing physiological differences between good and poor premorbid schizophrenics. Such differences might suggest correlates of premorbid adjustment possibly representing physiological factors that serve as mediators between genetic inheritance and the specific course of the schizophrenic disorder. Unfortunately, the evidence reviewed in this section does not support the existence of physiological differences between good and poor premorbid patients. In fact, the findings of Goldstein et al. (1969) would seem to indicate that the absence of these differences is not attributable to methodological factors such as chronicity and drug status. Similarly, Higgins and Peterson's (1967) review of cardiovascular reactivity to infusion of Mecholyl disclosed that this measure is inconsistently related to the premorbid distinction. Recent findings by Gruzelier and Venables (1972, 1973, and 1974), Gruzelier (1973), and Thayer and Silber (1971) have emphasized the extreme variability in arousal and responsivity found within schizophrenic samples. This work has identified one group that is hyperaroused and hyperresponsive and another group with the opposite characteristics. This distinction appeared to be independent of Kraepelinian subtypes, medication level, or chronicity. It would be especially interesting to relate these contrasting physiological tendencies to premorbid background.

related in future work to scores on scales of premorbid adjustment. One of the earliest and most influential applications of the high risk strategy to the study of the antecedents of schizophrenia was the work conducted in Denmark by Mednick and his associates (Mcdnick 1966 and 1970, Mednick and Schulsinger 1968 and 1973, and Mednick, Schulsinger, and Schulsinger 1975). This research was designed to evaluate Mednick's (1958) theory of schizophrenia, which states that the preschizophrenic individual is abnormally anxious, overreacts to stress, and is slow to recover from it. The preschizophrenic's vulnerability to stress-related stimulation prompts "a spiral of anxiety and generalization to an insupportable degree" (Mednick 1958, p. 322). According to Mednick, relief from this anxiety is obtained by irrelevant thoughts and associations (i.e., thought disorder) which help the preschizophrenic indi /idual to escape anxiety.

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Analogous results concerning these samples' heart-rate reactions during the conditioning procedures were reported by Herman (1972). However, the speed of the polygraph recordings (.42 cm/sec) of these handscored interbeat intervals was so slow that accurate measurement must have been extremely difficult. 3

Mednick and his associates (Mednick, Schulsinger, and Schulsinger 1975) have also related the electrodermal characteristics of their disturbed probands to perinatal stress. To explain their data, they invoked hypothalamic involvement due to perinatal anoxia. The burgeoning literature on this issue will not be covered in this article, because it pertains more to etiological factors than to characteristics of the premorbid state. For an excellent review of this area see McNeil and Kaij (1976).

An investigation of relevance to Mednick's work was conducted in Denmark by Van Dyke (1972) on a sample of biological children of chronic schizophrenics who were adopted within the first months of life (/V = 47) and a control group composed of adoptees whose biological parents never manifested psychiatric disorder (N = 47). Notably, only 6 percent of the index sample and none of the controls were classified as schizophrenic in adulthood. A comparable proportion of each group was classified in the schizophrenic spectrum. Subjects were tested in their early thirties, so that they had lived through half of the age of risk for schizophrenia. Van


Mednick to revise his earlier statement that the preschizo- 20 disturbed high risk probands as schizophrenic and phrenic exhibits slow recovery from stress. Instead, another 6 as latent schizophrenics. The comparable Mednick came to view this steeper recovery of skin con- figures for the well group were 2 and 3 cases, respectively. ductance responses as reflecting an inhibitory defensive Physiologic information on these young adult subjects process. should be available soon and will be especially relevant The investigators presented additional relevant evi- for evaluating Mednick's theory. dence of abnormal behavior in these high risk subjects Some methodological problems are relevant to evalwho were disturbed at followup. These youngsters ex- uation of this research. Van Dyke (1972) and Lang ceeded their counterparts on disordered responses on a (1975) have noted advances in research on electrodermal test of continuous word association and on teachers' phenomena (cf. Stern 1972) that have taken place since reports of behavioral disruptiveness. In addition, Med- the initiation of Mednick and Schulsinger's work and nick, Schulsinger, and Schulsinger (1975) related their which raise questions about their results. In particular, it findings on abnormally steep recovery of skin con- has been established that multiple skin conductance ductance deflections among the high risk adolescents responses occur in classical conditioning. These events who were disturbed at followup to comparable results include an earlier response, often interpreted as an orienton actual schizophrenic patients (Ax and Bamford 1970, ing reaction to the conditioned stimulus (CS), a response Gruzelier 1973, Gruzelier and Venables 1972,1973, and preceding the unconditioned stimulus (UCS), and a re1974, and Zahn, Carpenter, and McGlashan 1975). How- sponse following the latter cue. Therefore, CS-UCS ever, Maricq and Edelberg (1975) detected slower elec- intervals spanning several seconds are currently employed trodermal response recoveries in schizophrenics than in this type of research. Unfortunately, the duration of normals, so that a steep recovery of electrodermal re- Mednick and Schulsinger's interval (.5 sec) does not persponses may not show a consistent relationship to schizo- mit separate evaluation of these responses. On the other phrenia. To add to the confusion, there has been some hand, their data clearly indicate that the disturbed high evidence that psychotic depressives may also display ab- risk children are hyperresponsive. With regard to rate of normally fast recoveries (Gruzelier and Venables 1974). 3 recovery of electrodermal responses, Van Dyke (1972, In evaluating Mednick, Schulsinger, and Schulsinger's p. 102) has noted that Mednick and Schulsinger's measure suggestive findings, it must be remembered that at the may be confounded with overall response amplitude. In 5-year assessment many of the disturbed high risk cases earlier reports, Mednick (1966) applied a covariance had not received actual diagnoses of schizophrenia. correction to his measure of recovery rate, but it is These subjects have not yet lived through the age of risk unclear whether this procedure was also followed in for schizophrenia, however, and unimpaired subjects in later work concerning comparisons of high risk children either group may develop the disorder in the future. with or without serious disturbance. These suppositions are supported by a recently reported followup (Mednick, Schulsinger, and Schulsinger 1975) High Risk Research of Relevance to '< of this sample 10 years after the initial assessment. At Mednick's Hypothesis this point, blind psychiatric diagnoses identified 6 of the

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normal parents (/V = 42). These samples were drawn from an initial total group of 145 children, from which 15 subjects were eliminated for dearth of scorable responses and another 42 were dropped in order to match for frequency of electrodermal activity. Unlike skin conductance responses, skin potential activity may be characterized by either positive or negative polarity. Thus, uniphasic, diphasic, or triphasic deflections may occur. Among adults, uniphasic skin potential responses tend to coincide with skin conductance responses of slow recovery, whereas diphasic skin potential responses are associated with fast recovery of conductance deflections (Edelberg 1972). Extrapolating this relationship to children, one might predict from Mednick and Schulsinger's data that children at high risk for schizophrenia would display an excess of diphasic skin potential responses. However, Janes and Stern's, data failed to indicate such a relationship. Among all samples, a tendency to emit diphasic responses was associated with psychopathology, as rated from a battery of personality tests. Thus, these data, although important in their own right, do not show a relationship between risk for schizophrenia and electrodermal measures. On the other hand, these subjects, who averaged around 8 years of age at the time of the study, have not been followed up long enough to detect serious psychiatric impairment.

Additional High Risk Studies A similar lack of differences between high and low risk samples characterized the results obtained by Schachter et al. (1975) in their study of nconates. Despite a very extensive analysis of heart-rate responses, no differences could be detected as a function of whether the subjects were the offspring of a schizophrenic mother. The only measure that differentiated high risk and control babies in two separate replications displayed a complicated relationship with maternal medication level during delivery. Among offspring of mothers with low medication levels, heart rate increased throughout the testing session in high risk subjects and decreased in their counterparts. The opposite results were obtained for babies born to women with high levels of obstetric medication. Despite their reproducibility, these results are difficult to interpret with regard to risk for schizophrenia. As noted by the authors, differences between these samples may emerge at a later age.


Dyke's experimental procedures were identical to Mednick's (1966) except for the extension of the CS-UCS interval, for the reasons outlined above, from .5 to 5 seconds. The results of this careful study provided only limited replication of Mednick and Schulsinger's study. Whereas the index cases significantly exceeded controls on amplitude of skin conductance responses to a neutral tone, only a marginally significant trend in this direction emerged when the same tone was used as the CS in a conditioning paradigm. No differences were obtained in electrodermal response amplitude to the UCS, although the number of responses to that stimulus was higher for index cases. Finally, in contrast to Mednick and Schulsinger's data, no differences were detected between the two groups in electrodermal response latency (or rate of recovery) as measured by an improved index (Edelberg 1970) that is presumably free of correlation with response amplitude. Mednick, Schulsinger, and Schulsinger (1975) have noted that the biological fathers of Van Dyke's (1972) high risk subjects were more frequently characterized by a criminal record than those of controls. Mednick, Schulsinger, and Schulsinger (1975) reviewed evidence suggesting that electrodermal recovery has a genetic component and is exceptionally slow in criminals. Therefore, they proposed that Van Dyke's (1972) sample was not representative of the offspring of schizophrenics. Nevertheless, these observations do not account for the marginal differences in amplitude between Van Dyke's (1972) samples. Mednick, Schulsinger, and Schulsinger's (1975) formulations emphasize the importance of hyperresponsiveness to the UCS, which is hypothesized to elicit anxiety. Notably, Van Dyke obtained weak evidence of overresponsiveness to the UCS by index cases. On the other hand, it is possible that the UCS employed in both investigations (a 4.5-sec 96-dB tone) may not be ideal for evoking conditioning. Of course, ethical considerations forbid the use of electric shock, a more effective UCS, because young children compose most high risk samples. A different conditioning paradigm was employed by Janes and Stern (1976); cool air served as the CS and hot air as the UCS. The autonomic measure investigated was skin potential, an electrodermal phenomenon closely related to skin conductance (Edelberg 1972). The subjects in this investigation included the offspring of schizophrenic {N-21), manic-depressive (/V=19), and

SCHIZOPHRENIA

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Buchsbaum et al. (1976). Reasoning that low levels of both monoaminc oxidase (MAO) and dopamine-betahydroxylase (DBH) had been found in schizophrenics, the investigators selected from a large sample of young and healthy volunteers those subjects characterized by very high or very low levels of platelet MAO. These groups were subdivided, in turn, into high and low levels of DBH. Interestingly, subjects low in both MAO and DBH, as opposed to the rest of the sample, displayed an abnormal tendency of smaller visual evoked response (P100-N140) amplitude when they were instructed to attend to flashes than when these stimuli were irrelevant to the task at hand. Differences between groups were most pronounced at low levels of flash brightness. In addition, subjects low in both MAO and DBH made the greatest number of errors of commission on a test of vigilance-the continuous performance task. Thus, two indices of selective attention were associated with low levels of these enzymes, thereby reproducing the association of abnormal performance and biochemical character-

istics previously identified in schizophrenic patients. An assessment of this cohort's psychiatric functioning provided further evidence that subjects with biochemical characteristics resembling schizophrenics also presented clinical evidence of psychological disturbance (Buchsbaum, Coursey, and Murphy 1976). Indeed, more subjects with low MAO levels than their high MAO counterparts had undergone psychiatric treatment, attempted suicide, or received a conviction or jail sentence for serious criminal offenses. Similar differences were present between the families of low and high MAOprobands. This research represents a promising application of biochemical techniques to the high risk strategy. Followup of the subjects of Buchsbaum et al. (1976) and other high risk samples through the age of risk for schizophrenia would be most informative.

Overview In a recent review, Garmezy and Streitman (1974) summarized several other ongoing research projects on populations at risk for schizophrenia. Many of these studies involve the collection of physiological measures. Since these investigations are still in progress, any evaluation of their results must be tentative. The findings of Mednick and Schulsinger's (1973) seminal study have been replicated only in part. Van Dyke's (1972) findings, as well as preliminary results from the University of Rochester's high risk research (Klein and Salzman 1976) point to a tendency for high risk children to exceed controls in amplitude of skin conductance responses to both conditioned and unconditioned stimuli. However, equivocal or negative evidence has been obtained with regard to latency, habituation, or recovery rate. The consistency across studies of findingsof electrodermal hyperresponsiveness among high risk children may reflect electrodermal lability, as hypothesized by Mednick (1966). Additional data from other autonomically innervated organs would buttress this view. In this regard, Klein and Salzman (personal communication, October 1976) have obtained negative results; their high risk subjects did not differ from control subjects in heartrate reactivity. A somewhat different view of disordered arousal in high risk children and schizophrenics has been advanced by Itil et al. (1974), whose electroencephalographic findings suggest the existence of generalized arousal disorders in the direction of both activation and quiescence.


Whereas the preceding studies employed autonomic measures, Itil et al. (1974) focused on elcctroencephalographic differences between Danish samples of 11-year-old high risk and control childien. The high risk sample was characterized by shorter latencies of several peaks of their auditory evoked responses. An automated frequency analysis of the EEG revealed that the offspring of schizophrenics displayed an excess of slow (delta) and fast (beta) frequencies. In addition, high risk children's EEGs were typified by higher average frequencies, less alpha activity, and less activity of intermediate levels of amplitude. The investigators noted similarities between these findings on the high risk sample and their previous results on chronic schizophrenics as well as child psychotics. These parallel findings support the interpretation that the electroencephalographic deviations from normality characterizing the high risk cohort may reflect a predisposition for schizophrenia. Itil et al. proposed that schizophrenia includes extreme fluctuations in arousal, which are reflected in the excess of slow and fast EEG frequencies. They viewed these aberrations as the result of an imbalance between brain dopaminergic and cholinergic mechanisms. As noted by the authors, these hypotheses could be tested by examination of these subjects when they enter the age of risk for schizophrenia as well as by various psychopharmacologic procedures. A promising step in this direction was taken by

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Certainly, the importance of these various findings must await further assessment of the various samples studied as they enter the age of risk for schizophrenia. That work will provide evidence on whether these measures of physiologic activity may reflect a predisposition for schizophrenia. At this point, it may be questioned whether physiological indices of the diathesis for schizophrenia have been uncovered.

Multivariate research on pharmacologic treatments of schizophrenic patients has disclosed individual differences in schizophrenic patients' reactions to medication (Goldberg et al. 1967 and Klett and Moseley 1965). Although cross-validation of these findings has proven unsuccessful at times (Galbrecht and Klett 1968 and Goldberg et al. 1972), this work has suggested the existence of an ideal match between specific psychotropic medications and patients' clinical characteristics. This section is a review of studies concerned with the relation between premorbid factors and individual differences in pharmacologic response. A large-scale, double-blind drug study by Schooler, Boothe, and Goldberg (1971) revealed differential reactions to phenothiazines by schizophrenics with varying life experiences. Patients characterized by several unfavorable prognostic indicators (e.g., poor work history, unemployed status at the time of hospitalization, psychiatric or medical deferment for military service) derived greater clinical improvement from fluphenazine than chlorpromazine or acetophenazine. A related line of research by Goldstein ct al. (1969) concentrated on differential reactions to thioridazine and placebo by acute schizophrenic inpatients dichotomized on the basis of the Phillips Scale. As noted above, an important control in this group's research was the introduction of a 7-day placebo period before beginning the double-blind administration of the drug and placebo to portions of the sample. Following this drying-out phase, the experimenters assessed subjects' elcctrodcrmal reactions to a startling auditory stimulus and to stressful films as well as their responses to a wordassociation test. These procedures were readministered following the regimen of thioridazine or placebo, depending on the subject's experimental assignment.4 Among poor prcmorbids, the drug had the expected effect of

This pharmacological intervention was applied for 1 or 3 weeks to different halves of the sample. Duration of treatment did not affect the results summarized in the present review, however, so no further mention will be made of this manipulation.


Premorbid Adjustment and Clinical Response to Phenothiazines

reducing electrodermal responsivity to a greater extent than placebo. In contrast, paradoxical effects were obtained for good premorbids. Greater autonomic reactivity was found in good premorbids treated with the tranquilizer than in good premorbids who received placebo. Similarly, increases in comprehension of the film's plot and reduction in deviant word associations as a function of thioridazine therapy could be detected only in poor premorbid patients. The investigators noted that interpretation of these provocative results was tempered by the lack of clinical measures of therapeutic outcome. In addition, the samples investigated were relatively small. However, comparable results were obtained by Magaro (1973) with patients whose receipt of or withdrawal from medication was dictated by their attending physician rather than experimental assignment. In another related investigation, Goldstein (1970) assigned acute schizophrenics dichotomized on the quality of their premorbid history to a 3-week, doubleblind regimen of thioridazine or placebo. As before, an initial 7-day drying-out period was imposed, and patients were tested before as well as after the pharmacological intervention. The measures previously employed were supplemented by two clinical rating scales: The Nurses' Observation Scale for Inpatient Evaluation (NOSIE) and the Inpatient Multidimensional Psychiatric Scale (IMPS). The results on electrodermal reactivity and film comprehension for those patients whose urine levels of phenothiazines at the close of the drying-out period were low largely replicated the findings of the first study. On the other hand, the data derived from patients who entered the hospital with presumptive evidence of extensive prior treatment with phenothiazines (high urine levels of these drugs) did not support the earlier results. The changes detected on the clinical rating scales over the chemotherapeutic trial were congruent with the psychophysiological results for patients with low initial phenothiazine urine levels. Consistently, the poor premorbid patients placed on thioridazine, relative to placebo-treated poor premorbid patients, obtained scores indicative of superior clinical improvement on several scales from the NOSIE (social competence, neatness, and manifest psychosis) and the IMPS (excitability,

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Evidence of differential response to neuroleptics by poor premorbid schizophrenics was also reported by Klein (1968). These patients improved more from treatment with chlorpromazine than imipramine or placebo. In fact, fearful paranoid and childhood asocial patients, who constituted the poor premorbid group, displayed more negative reactions to imipramine than to placebo. These patients' typical reaction to chlorpromazine was "schizoid compliance," i.e., improvement in thought disorder coupled with "passive, fringe of the crowd, compliant, unspontaneous adaptation" (p. 372). Related findings were reported by Klein and Rosen (1973), who performed a 6-week double-blind trial of chlorpromazine or placebo on acute schizophrenics dichotomized on the basis of the Premorbid Asocial Adjustment Scale. Clinical ratings on the Multidimensional Scale for Rating Psychiatric Patients were obtained preceding and following the research. In the asocial (poor premorbid) group, only 11 out of 31 scales (e.g., •depression, bodily concern, shouting, morbid fears)

disclosed better-posttherapy adjustment for placebothan chlorpromazioertreated patieritsfeln contrast, among nonasocial (good premorbid)"patients, 17 scalesdisclosed therapeutic improvement -following treatment with chlorpromazine.-These findings, of cjpirse, are exactly the opposite of GpJclstefn's (1970)* Klein and Rosen (1973) noted the difficulty in comparing these two studies because'of differences in the choice of drug, measures of outcome, and diagnostic procedures. However, they noted that only two of Goldstein's (1970) clinical measures (hostility and perceptual distortion) indicated negative effects for good premorbids coupled with therapeutic improvement for poor premorbids. Apparently, Klein and Rosen (1973) were less impressed with Goldstein's (1970) findings involving other clinical measures on which, thioridazine did not have adverse effects for good premorbids, but merely resulted in smaller differential clinical improvement over a placebo than was the case with poor premorbids. Goldstein (personal communication, February 1976) has noted several additional differences between these investigations. Klein and Rosen's sample consisted of patients referred to chemotherapy after failure of milieu and psychotherapy. The possibility remains, therefore, that this selection procedure may have excluded some (good premorbid?) patients who did not require drugs for clinical improvement. In addition, Klein and Rosen's drug treatment was longer (6 vs. 3 weeks) and involved a schedule requiring a fixed weekly increase in the dose of chlorpromazine, which reached 1,200 mg per day on the final week o f treatment. Goldstein also pointed out that the fixed doseemployed in his 3-week study (400 mgof thioridazjne per day) is; at the bottom of the range recommended by,;;^eftmann; (1975) for treatment of acute schizophrenia. Similarly, Lejtmann urged that treatment-be exteniJld fortip^to 6 to 8 weeks. Thus, it is conceivable that, the conditions, of Goldstein's study did not insure attainrn^nt o f optimal, chemotherapeutic

effects. . /

:

" ... ' _.y.ir'.S::lJ:'-:^^j.rs^.. ' -.

Two other recent investigations of acute schizophrenics maintained oraarjBgimen of phenothiazines after discharge from the hospital are relevant to the present discussiortWLeff ajid.Wing (f971) followed up such patients for 1 year, whjle treating them in doubleblind fashion with chlorpromazine, trifluoperazine, or placebo. Their findings on patients who did not receive this trial of medication are especially pertinent for the present review. Eleven patients whose prognosis, in their


hostility, perceptual distortion, motor agitation, and conceptual distortion). On many of these scales, placebotreated good premorbjd patients improved more than placebo-treated poor premorbids. Moreover, two IMPS scales (hostility and perceptual distortion) yielded the paradoxical findings of greater posttherapy pathology for good premorbid patients who received pharmacotherapy versus good premorbid patients who were administered placebo. With regard to the patients with high initial levels of phenothiazines, Goldstein (1970) reasoned that retrospective consideration of their clinical ratings at the end of -the drying-out period constituted an approximate test of the hypothesis evaluated on the remaining patients at the conclusion of the thioridazine trial, namely that phenothiazines are more helpful for poor than good premorbid schizophrenics. Indeed, some IMPS scales at the end of the drying-out phase revealed higher pathology for poor premorbid patients with low drug levels than those with high levels. Goldstein concluded that phenothiazines may lead to therapeutic improvement only for poor premorbid patients. In fact, the poor premorbids who were discharged from the hospital after the doubleblind part of the study consisted predominantly of patients who received thioridazine. Good premorbids released at this point, on the other hand, were almost equally likely to have received placebo or the active drug.

236

less pretreatment autism, less family distress in having the patient back home, no disruption in early life, living in a parental or conjugal household, relatives are favorable to participation in the study, being female and a homemaker, unemployed, greater satisfaction with his or her role and takes medication regularly. |p. 174| Those patients whose scores placed them at the prognostically favorable end of these scales improved relatively more from medication. On the other hand, those patients scoring at the undesirable extremes of these scales relapsed earlie, and did not benefit much from chlorpromazinc Thus, these findings are in accord with Leff and Wing's (1971) results for patients with poor prognosis but do

not parallel their data for schizophrenics with good premorbid history. Somewhat confusingly, the scales of premorbid adjustment employed by Goldberg et al. (1977) (the Phillips and the Premorbid Asocial Adjustment Scales) were not related to differential outcome of chemotherapy.

Overview Clearly, further research is required to resolve the contradictions among the studies reviewed above. One confounding factor is that some of these reports concerned reactions to pharmacotherapy for an acute schizophrenic episode, while other investigations dealt with maintenance treatment of presumably remitted patients. Because of this and other methodological differences among studies, it is difficult to draw any conclusions of whether good or poor premorbid patients benefit more from phenothiazines. Research on this issue is important and should be pursued with careful sample evaluation, because the demonstration of differential response to pharmacologic agents by patients with contrasting premorbid background might reflect distinct pathophysiologies and etiologies of these schizophrenic subtypes. Alternatively, as suggested by Klein and Rosen (1973), these findings may reflect individual differences in susceptibility to extrapyramidal effects of phenothiazines. One final area of biological research related to premorbid status is the field of genetics. Since this work has been reviewed extensively by Rosenthal (1970), we will limit ourselves in this section to noting the difficulty in relating distinctions concerning premorbid status to genetic hypotheses of schizophrenia. Although it has often been claimed that there is a greater genetic component in the etiology of process than reactive schizophrenia (Buss 1966), Rosenthal's (1970) review of the literature disclosed only a slight trend in this direction. In addition, interpretation of this genetic research in terms of premorbid status is somewhat hazardous, since in most of these studies diagnoses of process or reactive schizophrenia were based only on outcome or symptom type, rather than on measures of premorbid functioning. When this methodological shortcoming is corrected, genetic research may have much to contribute to the understanding of premorbid adjustment. Conclusions Research on

distinctive

biological

characteristics


clinicians' opinion, was too good to warrant medication were excluded from the study. These patients were characterized by a good premorbid personality, the presence of features of "endogenous" depression, and auditory hallucinations. It is noteworthy that although this group of patients was not medicated in the followup period, they had a lower relapse rate than index patients who received placebos (/V=12) or those schizophrenics excluded from the research because their status was judged too precarious to risk assignment to a placebo (A/=15). In fact, among patients excluded from the scries for one reason or another, those schizophrenics who took their prescribed drug regularly (N = 40) had a higher relapse rate than their good-prognosiscounterparts who did not receive drugs or those who were prescribed drugs but did not take them regularly. The authors concluded that patients with poor prognosis probably relapse, regardless of drug treatment, whereas patients with good prognosis tend to avoid rehospitalization even without medication. In their opinion, patients whose premorbid adjustment is intermediate derive the greatest benefit from maintenance phenothiazine therapy. Another examination of the relationship between premorbid adjustment and clinical improvement on a maintenance regimen of phenothiazines was conducted in a large-scale (N = 374) double-blind investigation of maintenance on chlorpromazinc, sociotherapy, or placebo over a 2-year period (Goldberg et al. 1977). This research is exemplary because of its methodological excellence and the replication of reported findings across three treatment clinics. The patients who derived the greatest benefit from chemotherapy, as opposed to placebo, had the following characteristics:


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Acknowledgments For their helpful comments on earlier drafts of this article we thank Michael Goldstein, John Gruzelier, Leonard Salzman, Rhonda Shulman, and Roger Weissberg. We are also grateful to the following individuals who made available to us prepublication copies of their papers or clarifications of their published reports: Monte Buchsbaum, Andrew Crider, Spencer DeVault, Don Fowles, Solomon Goldberg, Therese Herman, Cynthia Janes, Peter Lang, Robert Klein, Thomas McNeil, Sarnoff Mednick, Joy Rice, Herbert Spohn, Peter Venables, and William Ward. The preparation of this review was supported in part by an NIMH Research Scientist Development Award (MH 00006-01) to Dr. Strauss.

The Authors Rafael Klorman, Ph.D., is Associate Professor of Psychology and Psychiatry, University of Rochester, Rochester, N.Y.; John S. Strauss, M.D., is Professor of Psychiatry and Director, Yale Psychiatric Institute, New Haven, Conn.; and Ronald F. Kokes, Ph.D., is Assistant Professor of Psychiatry (Psychology), University of Rochester, Rochester, N.Y.


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Associative interference and premorbid adjustment in schizophrenia.

Premorbid asocial adjustment and outcome in schizophrenia.

Social competence in schizophrenia: premorbid adjustment, social skill, and domains of functioning.

Factors Moderating the Relationship Between Childhood Trauma and Premorbid Adjustment in First-Episode Schizophrenia.

An abbreviated form of the Phillips Rating Scale of Premorbid Adjustment in Schizophrenia.

Deterioration in premorbid functioning in schizophrenia: a developmental model of negative symptoms in drug-free patients.

Trajectories of premorbid childhood and adolescent functioning in schizophrenia-spectrum psychoses: A first-episode study.

Low birth weight and a family history of schizophrenia predict poor premorbid functioning in psychosis.

Premorbid personality and positive and negative symptoms in schizophrenia.

Premorbid teacher-rated social functioning predicts adult schizophrenia-spectrum disorder: a high-risk prospective investigation.

Premorbid adjustment of schizophrenic criminal offenders.

Characterization of premorbid functioning during childhood in patients with deficit vs. non-deficit schizophrenia and in their healthy siblings.

Developmental lag and course of cognitive deficits from the premorbid to postonset period in schizophrenia.

Premorbid self-disorders and lifetime diagnosis in the schizophrenia spectrum: a prospective high-risk study.

The impact of premorbid and current intellect in schizophrenia: cognitive, symptom, and functional outcomes.

Estimation of premorbid functioning after traumatic brain injury.

Demographic features and premorbid personality disorder traits in relation to age of onset and sex in paranoid schizophrenia.

First-rank symptoms and premorbid adjustment in young individuals at increased risk of developing psychosis.

Premorbid social competence construct generalizability across ethmic groups: path analyses with two premorbid social competence components.

Metacognition, symptoms and premorbid functioning in a first episode psychosis sample.

Further data concerning the relation between premorbid adjustment and paranoid symptomatology.

Proteomics Research in Schizophrenia.

Premorbid history and traumatic brain injury.

Psychosis prediction: stratification of risk estimation with information-processing and premorbid functioning variables.