Episodic and Residual Thought Pathology in Chronic Schizophrenics: Effect of Neuroleptics

Transcription

1 394 Episodic and Residual Thought Pathology in Chronic Schizophrenics: Effect of Neuroleptics by Herbert E. Spohn, Lolafaye Coyne, Jan Larson, Frederick Mittleman, Judy Spray, and Kenneth Hayes Abstract We sought to determine the effect of neuroleptic treatment on thought disorder in chronic schizophrenics, using the Thought Disorder Index (TDI). We were able to demonstrate that high levels of thought disorder are found in chronic schizophrenic and schizoaffective patients, while in both bipolar patients and normal controls thought pathology is minimal. Moreover, the TDI appears to be particularly well suited to the characterization of thought disorder in chronic schizophrenics. For total scores on the TDI, we were unable to demonstrate a significant reduction in thought pathology, although it was evident that thought disorder as reflected in the Conceptual Disorganization and Unusual Thought Content subscales of the Brief Psychiatric Rating Scale is significantly reduced by neuroleptics. In analyses of subscores of the TDI reflecting four levels of severity, we were able to show that more severe forms of thought pathology are normalized by neuroleptics, while less severe pathology is largely unaffected. Our results suggest that neuroleptic treatment reduces thought pathology associated with acute episodes, but that somewhat milder, though still disabling, residual thought pathology persists after clinical remission has been attained. In this report we describe a study designed to assess the relation of neuroleptic treatment to thought disorder or, more precisely, to a measure of thought disorder, the Thought Disorder Index (TDI) (Johnston and Holzman 1979) in chronic schizophrenic inpatients. The rationale for this study is multifold. Notwithstanding recent critiques of thought disorder as a pathognomonic symptom of schizophrenia (Pope and Lipinski 1978; Andreasen 1979b), the phenomenon continues to play an important role in the diagnosis of schizophrenia. If neuroleptic treatment normalizes thought disorder in schizophrenics, or modifies it in some other fashion, the validity of diagnosis in medicated patients is jeopardized. From the vantage point of descriptive psychiatry, therefore, it is of some interest to determine the effects of neuroleptic treatment on thought disorder. The absence of thought disorder symptoms reduced or removed by neuroleptic treatment may "bias" diagnostic judgment. Similarly, treaters of schizophrenic patients, be they behaviorists or psychotherapists, have an interest in knowing to what extent neuroleptics reduce thought pathology that may interfere with treatment. In untreated psychotic patients, acute thought pathology may divert attention from therapeutic interventions. Studies of thought disorder continue to interest investigators concerned with the unraveling of the specific nature of cognitive dysfunction in schizophrenia (Chapman and Chapman 1973). Although the focus of interest has shifted in recent years to experimental studies of impairment in the earlier phases of information processing, there continues to be concern with disorders of central processing and with the response or performance side of information processing, i.e., language and communication (Rochester and Martin 1979; Maher 1983). Accordingly, an assessment of neuroleptic Reprint requests should be sent to Dr H E Spohn at the Research Department, The Menninger Foundation, Box 829, Topeka, KS 66601

2 VOL. 12, NO. 3, effects on thought disorder in medicated schizophrenics can play a clarifying role, both for studies of information processing as well as studies of central processing and expressive behavior. There is a growing conviction on the part of investigators concerned with causation that the identification of biological markers (Holzman and Levy 1977) and markers of vulnerability (Nuechterlein and Dawson 1984) is a major step in the direction of the elucidation of etiology in schizophrenia. Quite typically, marker studies seek to determine the state/trait characteristics of behavior identified as having marker status potential. One widely accepted criterion for marker status is its persistence in patients whose clinical remission has resulted from neuroleptic treatment. Thus, another major aim of the present study, and perhaps its theoretically and clinically most interesting one, was to determine whether thought disorder or aspects of thought disorder merit trait (i.e., marker) status by being manifest as residual symptoms after a clinical remission has been achieved by neuroleptic treatment. There is a rather small research literature that bears on neuroleptic effects on thought disorder. We review this literature here in order to show some of the conceptual and methodological problems that must be addressed in any effort to examine neuroleptic treatment-thought disorder relationships. This research literature extends over a period in which major changes in the conceptualization and measurement of thought disorder have taken place. Accordingly, we shall also be concerned with such important recent developments as Andreasen and Olsen's (1982) negative/positive symptom typology. In an early and influential study, Orzack, Kornetsky, and Freeman (1967) found that while a phenothiazine (carphenazine) normalized attentional impairment (vigilance), this neuroleptic failed to affect "cognitive" impairment on the Wechsler Bellevue Digit Symbol Substitution Subtest (Wechsler 1944). This finding was in keeping with a then rather widely held view that phenothiazines were less effective in modifying cognitive functions in schizophrenics than attentional functions. This hypothesis has since been disconfirmed. Moreover, the Digit Symbol Substitution Test can hardly be considered a valid measure of thought disorder. Nonetheless, there is a much greater volume of research addressed to neuroleptic treatment effects on attention/information processing than to drug effects on disorders of central processing and response such as thought disorder, language, and communication. Among the few studies in the latter area is one by Saretsky (1966), who, in a placebo-controlled design that employed measures of "primary process" thinking applied to Rorschach protocols, found that recently hospitalized chronic schizophrenic patients on chlorpromazine "proved to be more capable of handling primary process elements" than placebo-treated patients (p. 247). Moreover, improvement in this respect was positively correlated with clinical improvement, notwithstanding that "degree of thought pathology itself is not directly affected by drug treatment" (p. 247). Unlike the study of Orzack, Kornetsky, and Freeman (1967), Saretsky's (1966) investigation attracted very little attention, is rather rarely cited, and has not been replicated. Three implications of this study are nonetheless of interest. The expression of thought pathology as measured in this study was episodic. That is, on drug treatment, patients verbalized less thought pathology than placebo controls, and less thought pathology than at admission and before drug treatment. Second, there was some residual thought pathology evident even after the achievement of symptomatic remission. Third, there is a hint in Saretsky's data that it was the expression of thought pathology rather than thought pathology itself that was reduced. This latter finding is consonant with an interpretation that self-editing processes were strengthened by neuroleptic treatment. Two studies (Shimkunas, Gynther, and Smith 1966, 1967) reflect both conceptual and methodological problems in the determination of neuroleptic treatment effects on thought disorder. Acutely psychotic chronic schizophrenic patients were assessed on the Gorham Proverbs Test (Gorham 1956), the Wechsler Bellevue, and a global severity rating scale over a 26-week period of phenothiazine treatment. Placebo controls were not used in this study, whose central finding was that while pathology decreased, verbal IQ and proverbs scores did not increase. Upon determining that the proverbs test scores were more highly correlated with verbal IQ than with psychopathology, Shimkunas, Gynther, and Smith (1967) devised an autistic response scoring system that was highly correlated with psychopathology. They found a significant decrease in autistic response frequency over the neuroleptic treatment period. The results of these two studies raise a major conceptual issue in the measurement of thought disorder namely, that of construct validity. The Gorham Proverbs Test, based on

3 396 SCHIZOPHRENIA BULLETIN Goldstein's (1939) theory of impaired abstracting ability, was found to lack construct validity, and the investigators were able to demonstrate construct validity for their autistic response scoring system, which appeared to be more sensitive to neuroleptic treatment than the concrete/abstract scoring system used by Gorham (1956). There is yet another perspective that can be brought to bear on these two studies. It may be that abstract reasoning impairment in chronic schizophrenics is less susceptible to neurolepric normalization than autistic reasoning. This interpretation suggests that some forms of thought pathology persist after symptomatic remission has been attained and are unaffected by drug treatment. Indeed, Harrow et al. (1972) have adduced evidence to this effect. An attempt to replicate the findings of Shimkunas, Gynther, and Smith (1967) using their autistic response scoring system in a placebocontrolled study (Spohn et al. 1977) is instructive with respect to methodological issues. Spohn et al. (1977) did indeed find that in chronic schizophrenics returned to chlorpromazine treatment after a 6-week washout period, frequency of autistic responses on the Gorham Proverbs Test was substantially reduced. It could not be concluded, however, that chlorpromazine specifically reduced thought disorder of the kind measured by the Shimkunas scoring system because placebo control patients who remained testable after extended drug withdrawal also showed reduced autistic responses. Two factors combined to produce this counterintuitive finding. A number of placebo patients relapsed and therefore proved untestable. Accordingly, their data could not be included in drug/placebo comparisons. Also, there were some indications in the data obtained from the placebo patients who remained in remission during the testing period that they benefited from practice on repeated testing with the Gorham Proverbs Test, even though three alternate forms of the test were used. The experience of Spohn et al. (1977) is not an isolated instance of unrepresentative placebo controls due to untestability of early relapsing patients. Payne et al. (1963), in a placebo-controlled study of the effects of a phenothiazine (Proketazine) on overinclusive thinking in chronic schizophrenics which produced negative results, comment: It must be emphasized that this [testable placebo sample] is not completely representative of chronic schizophrenic patients because of the need to eliminate 36% of the originally chosen group on account of disturbed behavior, [p. 530] The Payne and Spohn studies pose very serious design and methodological problems confronting investigators concerned with the determination of neuroleptic effects on cognitive dysfunction in general and thought disorder in particular. The problem is especially acute in placebo-controlled studies using washout and on-placebo periods that are sufficiently long to permit reduction in neuroleptic control of psychotic symptoms. The duration of such periods is not coterminous with the 10- to 14-day washout required for the near total dissipation of drug substance and metabolites from the body system (Lacoursiere and Spohn 1976). It should be added that such problems can be mitigated neither by replacing relapsed placebo controls nor by estimating scores for untestable patients. Perhaps the most successful demonstration of neuroleptic treatment effects on thought disorder is a study by Hurt, Holzman, and Davis (1983), which used the Thought Disorder Index (TDI) (Johnston and Holzman 1979) and involved a sample of schizophrenic inpatients with a relatively short hospitalization experience (80 days). These investigators were able to show that patients placed on haloperidol after a flexible 1- to 3- week washout period, and tested on completion of washout at 1, 3, 5, 12, and 19 days after washout and at discharge, steadily reduced the level of TDI scores (pathological verbalizations on the Rorschach) and that this pattern of TDI reduction was significantly congruent with clinical improvement as rated on the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962). What mars this otherwise rather convincing demonstration of TDI sensitivity to neuroleptic treatment is that a no treatment-placebo control group was tested at only two points in the study period namely, at 5 and 12 days after washout and was not rated on the BPRS on these two occasions. Therefore, it was not possible to perform the same BPRS-TDI trend analyses over the total study period which had shown such convincing congruence in the drug-treated group. If such an analysis had revealed that an increase or no change in TDI scores over the same assessment period for which treated patient data were available was paralleled by a similar pattern of BPRS changes in the placebo group, it would be possible to rule out practice effects on the TDI and the effects of placebo/expectations and nonsomatic treatments on the BPRS ratings as factors leading to the kind of congruence of improvement on the TDI and BPRS in the haloperidoltreated group.

4 VOL. 12, NO. 3, In addition, since the patient group in the study of Hurt, Holzman, and Davis (1983) is only rather sparsely described, it is difficult to determine comparability of this study to most of the studies heretofore discussed, all of which involved clearly chronic schizophrenics. On the other hand, unlike most other studies, the Hurt study did include normal controls and was therefore in a position to demonstrate that even at maximum benefit from neuroleptic treatment, the treated gtoup manifested considerable residual thought pathology. Andreasen's (1979a, 1979b) seminal studies of thought, language, and communication disorder in mania, depression, and schizophrenia have an important bearing on studies of neuroleptic treatment effects on thought disorder in schizophrenia. Of greatest relevance in the present context are her findings that with respect to "Bleulerian" thought disorder, manic and schizophrenic patients cannot be distinguished and, therefore, that Bleulerian symptoms are not pathognonomic of schizophrenia. This finding raises the question of specificity of thought disorder to schizophrenia. With the exception of the study of Hurt, Holzman, and Davis (1983), which used the well-standardized TDI, none of the other above described investigations were concerned with this issue. Moreover, there is undoubtedly considerable variation within this group of studies in diagnostic criteria and reliability in their application. Andreasen and Olsen (1982) related Hughlings-Jackson's distinction between positive and negative symptoms to thought disorder in psychosis by identifying symptoms such as conceptual disorganization, delusions, and hallucinations as positive symptoms and symptoms such as anhedonia, alogia, and amotivation as negative symptoms. Their recommendation that these symptom types or categories be used as diagnostic/ classification dimensions has found rather widespread acceptance. The relevance of these typologies to the study of neuroleptic treatment effects on thought disorder is not quite so salient as that of the specificity issue. Nonetheless, since there are some data suggesting that patients characterized by negative symptoms are less susceptible to neuroleptic treatment than patients with positive symptoms (Buchanan et al. 1975), this typology may have uses in research on neuroleptic treatment effects. This critical literature review provides guidance both for the selection of thought disorder measurement instruments and for design and methodology in the development of a competent study of neuroleptic treatment effects on thought disorder in chronic schizophrenics. More specifically, it is our view that such instruments should be fairly broad-ranging in form and severity of thought pathology assessed, that some degree of construct validity should be demonstrable, and that the diagnostic boundaries of its applicability be specified. In design and methodology, care should be taken to obviate the loss of relapsed, untestable placebo patients, or stated more positively, to ensure that the placebo sample be as representative of the population as the on-drug sample. Moreover, since repeated measurement is inevitably a factor in the design of such studies, practice effects should be minimized and the schedule of repeated assessments in the on-drug group should parallel that in the placebo group. It will be seen below how well these specifications were met in our study. Methods Subjects. The core subject sample in this study comprised 100 chronic schizophrenics who agreed to participate after full disclosure of the nature of their participation and the risks entailed by drug withdrawal. All patients were rediagnosed by a project psychiatrist-social worker team who used the Schedule for Affective Disorders and Schizophrenia-Lifetime Version interview and the Research Diagnostic Criteria (RDC) (Spitzer, Endicott, and Robins 1977). For all subjects, it was determined that they had manifested a therapeutic response to prior neuroleptic treatment. Patients with a history of organicity or substance abuse were excluded. The average age of the sample was years, and average duration of illness was 9.7 years. Average cumulative hospitalization was 6.5 years, and average years of education totaled Twenty-seven percent were female patients. Also recruited to the project were 26 RDC-diagnosed schizoaffective disorder patients and 25 RDCdiagnosed bipolar (bipolar I) patients, as well as 39 normal controls. These diagnostic comparison groups were involved only in data analyses designed to determine TDI specificity. Design. The 100 chronic schizophrenics were randomized to two conditions. A group of 36 patients remained on the active neuroleptic they had received before research entry throughout a 10-week study period. A second group of 64 patients were abruptly withdrawn from neuroleptics and placed on placebo matching in kind and dose the prewithdrawal neuroleptics they had received. No washout was used.

5 398 SCHIZOPHRENIA BULLETIN All patients were tested with an extensive performance test battery including the Rorschach and the Wechsler Adult Intelligence Scale (WAIS) in a baseline session before experimental assignment and while still fully medicated, and four times after experimental assignment at 2- week intervals. Also, on each of the five occasions of testing, patients were rated by a psychiatrist on the BPRS and by two research assistants on the Psychologic Rating Scale (King 1954). Testers, raters, project research nurses, patients, and hospital ward staff were unaware of patient drug status throughout. Forty-four patients in the drug withdrawal condition and five patients in the active medication condition "relapsed" in the course of the 10-week study period. A patient was considered "relapsed" when both ward staff and project research nurses, who daily monitored the research patient's clinical condition, agreed that the first signs of symptom exacerbation were evident. No patient was permitted to undergo full-scale symptom exacerbation. A substantial proportion of relapsed patients were remedicated and completed the full five-test-session schedule. For all relapsed patients, data obtained on the test session closest in time to their relapse were considered to be largely free of neuroleptic medication effects. Changes in test performance (other than those that could be imputed to practice) in the "relapse" session from test performance in the preexperimental assignment baseline session were regarded as reflecting medication effects. Another way of stating this assumption is to say that deterioration in test performance in relapsed patients was regarded as representing dysfunction normalized or otherwise modified by neuroleptic treatment. While reduction in loss of data from untestable placebo patients was an important aim in this design, its effect was to reverse the roles of ondrug and placebo patients in the conventional, independent group drug evaluation design. Patients "on drug" in the present design served as controls for practice and attention effects; the drug-withdrawn, onplacebo patients served as experimental subjects. Drug withdrawal was the independent variable and test performance, the dependent variable. Drug effect hypotheses (i.e., the effect of neuroleptic treatment on thought disorder) were tested by contrasting baseline session to postwithdrawal session test changes in control patients (on drug) with those of experimental subjects (on placebo/ relapsed). A critical methodological problem associated with this unconventional design needs to be addressed. Randomization could not be extended to the "assignment" of drugwithdrawn patients to relapse and nonrelapse conditions. Factors determining when and whether a given patient relapsed could thus not be brought under experimental control by randomization. A consequence of this in the present study was one of significant dependent variable initial level differences among control, relapsed, and nonrelapsed groups. Of the 44 patients who relapsed during the 10-week study period, 21 did so approximately 2 weeks after drug withdrawal, 11 about 4 weeks after withdrawal, and 12 during the remainder of the study period. Accordingly, 21 patients were considered relapsed in the second testing session (session 2), 11 in the third testing session (session 3), 5 in session 4, and 2 in session 5. Comparisons among these differing duration-to-relapse groups by means of multivariate analysis of variance (MANOVA) on BPRS symptom ratings scales, demographic and course of illness variables indicated that these several groups did not differ significantly. In the control group, relapse in five patients occurred in session 3 (for two) and in session 5 (for three). Drug-withdrawn patients who were not considered relapsed in sessions 2, 3, 4, and 5 did differ significantly from controls and relapsers in these several sessions principally in initial level (session 1) test scores, but on other variables as well. That the relapsed patients differed in duration to relapse made possible several independent replicative tests of drug effect hypotheses. We present two such tests in the present report. The first involved data from 21 relapsers, 43 drug-withdrawn nonrelapsers, and 36 controls in session 2. The second test, involving session 3 data, compares relapsers (13: 11 withdrawn and 2 relapsed controls), nonrelapsers (29), controls (33), and 19 patients off drugs in session 2 and remedicated in session 3. Including the latter group in session 3 data analyses assured comparability of the results of analysis of session 2 and session 3 data sets because essentially the same groups of patients were involved in both analyses. Tests, Rating Scales, and Scores. The Thought Disorder Index (TDI) is essentially a system for scoring pathological verbalizations on the Rorschach test and on the WAIS. Pathological verbalizations are weighted according to four levels of severity. "Minimal" severity of thought pathology (to which a.25 weight is assigned) comprises such response characteristics as concreteness, vagueness, wordfinding difficulties, and perseveration. "Mild" severity (.50) reflects,

6 VOL. 12, NO. 3, among others, confused, loose, and fabulized responses. "Moderate" severity (.75) is represented by autistic logic, fluidity, absurd responses, and confabulations. "Maximally severe" responses (1.0) are contaminations, incoherence, and neologisms. The Rorschach and the WAIS were administered in each of the five sessions by a qualified examiner who also administered a series of other tests that will be the subject of subsequent reports. All 10 cards of the Rorschach and four verbal subtests of the WAIS were administered in the baseline session (1) and in session 3. To mitigate practice effects, an achromatic Rorschach card (I), a red and black card (II), and a chromatic card (VIII) only were administered in session 2. Also, on these occasions, two verbal subtests of the WAIS (Vocabulary and Similarities) were administered. Interrater reliability in scoring using the TDI scoring manual, among three experienced clinical psychologists, was found to be r =.84 at the outset. A single senior clinical psychologist member of that group scored all Rorschach and WAIS protocols subsequently. TDI scores employed in data analysis were (1) the sum of severityweighted Rorschach verbalizations corrected by the number of Rorschach responses (TDR) and (2) the sum of weighted responses on the WAIS (TDW). Derived scores used in data analysis were presence (1) or absence (0) of one or more pathological responses on the Rorschach at each of the severity levels. Brief Psychiatric Rating Scale. The 16 symptom subscales of the BPRS were administered by, for the most part, the same psychiatrist within a time band of ±24 hours of testing. Interrater reliability was established at the outset at r =.87. Several scores were derived from various combinations of the BPRS subscales for a variety of purposes in data analysis including a total pathology score, a schizophrenic symptom score (the mean of ratings on all subscales reflecting schizophrenic psychopathology), a positive/negative symptom index based on BPRS subscales: ([Blunted Affect + Emotional Withdrawal] [Conceptual Disorganization + Unusual Thought Content])/([Blunted Affect and Emotional Withdrawal] + [Conceptual Disorganization and Unusual Thought Content]). Psychologic Rating Scale. The Psychologic Rating Scale (King 1954) comprises subscales on which orientation to testing, cooperativeness, performance motivation, and attention to instructions in the test situation were rated by two examiners, one of whom observed patient behavior without awareness of performance efficiency. Interrater reliability was r =.92. The ratings of the latter examiner were considered measures of "General Deficit Functioning" and were used as such in data analyses. Results Brief Psychiatric Rating Scale. In an effort to determine whether patients considered relapsed in session 2 and session 3 did indeed manifest symptomatic exacerbation expected by design, changes in several BPRS scores from session 1 to 2 and from 1 to 3 for relapsed patients were compared with changes in control, nonrelapsed, and remedicated patients (in session 3 only) by analysis of covariance (ANCOVA). Session 1-2 and session 1-3 mean scores for 'Total Pathology" and "Schizophrenic Symptoms" only are shown in table 1. ("Schizophrenic" symptoms represent mean ratings on all those subscales of the BPRS which clearly reflect psychopathology characteristic of schizophrenic patients.) Because of significant initial level differences among the several groups, initial level served as covariate in all analyses. In session 1-2 contrasts, relapsers increased on all BPRS scores, while both controls and nonrelapsed patients decreased. In multivariate analysis of covariance (MANCOVA), Table 1. Brief Psychiatric Rating Scale Total Pathology and schizophrenic symptom group means Group Control Nonrelapsed Relapsed Remedicated Total Pathology Schizophrenic symptoms S1 S2 S1 S3 Group S1 S2 S1 S Note. S1.S2, S3 = session 1, session 2, session Control Nonrelapsed Relapsed Remedicated

7 400 SCHIZOPHRENIA BULLETIN this pattern of differences in change was significant for all scores (p<.01). In session 1-3 contrasts, relapsed patients as well as remedicated patients showed an increase in the several BPRS variables, while control patients remained at the same level in both sessions and nonrelapsed patients decreased somewhat. Again, in MANCOVA, these patterns of change differences were found to be significant (p <.01). Several inferences may be drawn from these findings. Clearly, patients considered relapsed in sessions 2 and 3 manifested symptomatic exacerbation in these sessions. That remedicated patients also showed significant BPRS increases in session 3 implies that for most of these patients remedication had not yet regained symptomatic control and that therefore they could be construed to be in a state of functional relapse. At the same time, mean increases in the BPRS variables in relapsed and remedicated patients, while significant, were not substantial, and in the distributions of BPRS scores in the several comparison groups, there was some degree of overlap. Accordingly, it must be granted that relapsed and remedicated patients were not in a state of acute, florid exacerbation of symptoms as a consequence of drug withdrawal. This inference is supported by the finding that on the Psychologic Rating Scale which was construed to reflect general deficit functioning relapsed and remedicated subjects in sessions 2 and 3 manifested marginally significant (S1-S2, p <.08) or nonsignificant increases (S1-S3, p <.15) over control and nonrelapsed patients. These patterns of findings, in essence, imply that the "independent variable manipulation" aimed at in the design of the study was attained. Drug withdrawal in a substantial number of subjects in sessions 2 and 3 had resulted in symptom exacerbation reflecting some reduction in neuroleptic symptom containment. At the same time, this degree of symptom control reduction was not so great as to leave largely impaired the ability of relapsed and remedicated patients to render a scorable performance on the tests administered in the "relapse" sessions. Several additional analyses were performed with three of the BPRS subscales: "Conceptual Disorganization," "Hallucinations," and "Unusual Thought Content." These analyses were done because the three subscales represent measures of thought disorder independent of the TDI and because they are readily identifiable as "positive symptoms" and were used as such in a Positive/Negative Symptom Index described above. The group means (see table 2) in session 1 for relapsed and remedicated patients were increased in sessions 2 and 3, while controls and nonrelapsed patients showed decreases. ANCOVA indicated that this pattern of change differences for all three subscales was significant (p <.01). One implication of this pattern of findings is that neuroleptic medication tends to normalize thought pathology reflected in these BPRS symptom subscales. Specificity. In order to determine whether in the context of the present study, level of thought pathology as measured by the TDI was specifically characteristic of chronic schizophrenics, TDI scores for the latter were contrasted with TDI scores for 26 (RDC) schizoaffective patients and 25 (RDC) bipolar patients as well as for 39 normal controls. Table 3 shows mean TDI scores on the Rorschach (TDR) and the WAIS (TDW). Because of some departure from normality in most of these distributions of the raw scores, they were transformed by Freeman-Tukey transformations and are shown as such in table 3. Because of mean differences among these four groups in age, sex, and education, these variables served as covariates in oneway ANCOVA. The results of ANCOVAs performed both on TDR and TDW scores were virtually identical. Hence, only the TDR analysis is presented. In ANCOVA contrast of the four groups, an Table 2. Group means on subscales of the Brief Psychiatric Rating Scale Conceptual Disorganization Unusual Thought Content Hallucinations Group S1 S2 S1 S3 S1 S2 S1 S3 S1 S2 S1 S3 Control Nonrelapsed Relapsed Remedicated Note S1, S2, S3 = session 1, session 2, session

8 VOL. 12, NO. 3, Table 3. Thought Disorder Index group means: Schizophrenics, schizoaffectives, bipolars, and normal controls Group Schizophrenics Schizoaffectives Bipolars Normals Mean TDR SD Mean TDW SD Note. TDR = sum of severity-weighted Rorechach verbalizations, corrected by number of Rorschach responses. TDW = sum of weighted responses on the Wechsler Adult Intelligence Scale. F >= 20.73, df = 3/179, p <.001 was obtained. Orthogonal comparisons of schizophrenic patients with schizoaffective patients, and bipolar patients with normal controls, were not significant, while schizophrenic plus schizoaffective patients did differ significantly from bipolar patients and normal controls. These results are interpreted as implying that schizophrenic and schizoaffective patients manifested significantly greater thought pathology on the TDR than bipolar patients and normal controls and that within neither of these two pairs of groups were there significant differences in level of thought pathology. More generally speaking, these results suggest that a much higher level of thought pathology is characteristic not only of schizophrenic patients devoid of affective symptoms but also schizophrenics with marked affective symptomatology than is the case for affective disorder patients and normal controls. Two further implications are worth noting. It comes as something of a surprise, in light of the research literature in this area, that in thought pathology schizoaffectives are more like schizophrenics than affective disorder patients. Moreover, it is equally surprising in light of Andreasen's (1979a) findings of similarities in "Bleulerian" thought pathology between schizophrenics and manic patients that in the present data bipolar patients (most of whom, to be sure, were not acutely psychotic) manifest significantly lower thought pathology on the TDI than schizophrenics. In order to clarify this latter finding, additional ANCOVAs were performed including only the three diagnostic groups and covarying out such nonspecific factors as general deficit functioning, duration of illness, and premorbid adjustment which were correlated positively with TDR in the schizophrenics and were greater in these patients than in the bipolars. ANCOVA applied to these data indicated that the differences continued to be significant (F = 3.822, df «- 2/141, p <.024), although the removal of the three covariates "pulled" the adjusted means somewhat closer together. This finding provides the first hint in the present data that the TDI measures a distinctive form of thought pathology. Correlates of TDI. In a further effort to clarify the nature of thought pathology measured by the TDI in chronic schizophrenics, it was correlated with demographic, symptom, and course of illness variables. In these correlations as well as in all subsequent data analyses, only the TDR was used, largely because it appears to be more sensitive to the elicitation of thought pathology than the TDW. Moreover, in the present as well as all subsequent data analyses, the TDR distributions were found to depart from normality and were accordingly transformed by means of a Freeman-Tukey transformation. More specifically, the variables correlated with TDR were sex, age, education, Total Pathology on the BPRS, the Positive/Negative Symptom Index (also BPRS based; see above), premorbid adjustment, duration of illness, and cumulative hospitalization time. Because of outlier duration-of-illness scores, a log transformation was applied. These correlations are shown in table 4. It will be evident from this table that severity of illness and chronicity indices dominate the correlational picture. The more severely ill and the longer the duration of illness and hospitalization, the greater the TDR thought pathology. The negative correlation of TDR with the Positive/Negative Symptom Index, which is, of course, strongly correlated with Total Pathology, indicates that positive symptoms vary directly with TDR severity. Stepwise multiple regression analysis (also shown in table 4) generally confirms these inferences in demonstrating that length of hospitalization and severity of illness make independent contributions in accounting for TDR variance, and that sex (female patients manifested higher TDRs) and the Positive/ Negative Symptom Index account for about 30 percent of the TDR variance. It is of some interest that the Positive/Negative Symptom Index accounts independently of BPRS Total Pathology for a minimal

9 402 SCHIZOPHRENIA BULLETIN Table 4. Correlates of TDR and stepwise multiple regression analysis Predictors Sex Age Education Positive/negative index Total pathology Premorbid Time hospitalized Duration of illness r * ' '.310' Step Time hospitalized Total pathology Sex Positive/Negative index Incr. R Fto enter Note TDR = sum of severity-weighted Rorschach verbalizations corrected by number of Rorschach responses 'p < 05, 2-tailed 'p <.001, 2-tailed 'p < 01, 2-tailed proportion of TDR variance. The general interpretation of these correlations is that the TDR is particularly sensitive to the kind of thought pathology characteristic of chronic schizophrenic patients and is to a quite limited extent a measure of "Bleulerian" positive symptom thought pathology This does not imply, however, that the TDR is primarily a measure of "negative" symptoms TDR and Medication Effects. In table 5 the core findings of this study are shown: mean TDR in session 1 and session 2 for 21 relapsed patients, 39 nonrelapsed patients, and 31 control patients on active medication; and mean TDR in session 1 and session 3 for 12 patients considered relapsed in the latter session, for 19 patients relapsed in session 2 and remedicated in session 3, 25 nonrelapsed patients, and 28 controls. (All means reflect Table 5. Group means for TDR in sessions 1 and 2, and sessions 1 and 3 Group Controls Nonrelapsed Relapsed Remedicated Session 1 Session TDR Session 1 Session TDR Note MANCOVA contrasts of 3 groups In session 1-2' p < 23, MANCOVA contrasts of control/relapsed in session 1-2 p < 13. MANCOVA contrasts of 4 groups in session 1-3 p < 15, MANCOVA contrasts of controls/relapsed and remedicated, session 1-3. p <.12 TDR = sum of seventy-weighted Rorschach verbalizations corrected by number of Rorschach responses. Freeman-Tukey transformations.) It will be obvious that there were significant initial level differences among the groups in both sessions. Accordingly, after homogeneity of regression of initial level on session 2 or 3 data in all groups was determined, MANCOVA was applied separately to session 1-2 and session 1-3 data. (Means in table 5 are covariance-adjusted.) The results for session 1-2 group comparisons indicated that although TDR in the relapsed group increased from session 1 to 2, while controls and nonrelapsers decreased, this pattern of change differences was not significant (p <.229). Similarly, in session 1 and 3 group comparisons, where both relapsed and remedicated patients increased in session 3, and controls and nonrelapsers decreased, this pattern of change differences was not significant (p <.153). From a design/data-analytic perspective it is, of course, unfortunate that among the patients randomly assigned to the drug withdrawal condition, relapsers and nonrelapsers "self-selected" themselves in such a fashion as to give rise to sharp initial level TDR differences between these two groups. This finding implies differences between relapsers and nonrelapsers on other variables that determine duration to relapse after drug withdrawal. In order to mitigate the effect of these initial level differences on results, additional ANCOVAs were performed from which the apparently aberrant nonrelapsers were removed These comparisons among controls and relapsers in session 1-2, and controls, relapsers, and remedicated patients in session 1-3, seemed justified conceptually. The results are, however, also negative, although the a levels were somewhat reduced (session 1-2, p < 13; session 1-3, p <.12).

10 VOL. 12, NO. 3, In all these analyses, power sufficient to detect anything other than large mean differences was inadequate. It seems probable that with greater power the observed mean differences might have been significant. Even in this eventuality, however, it could not be concluded that the formal thought pathology measured by the TDR is normalized to more than a minimal extent by neuroleptic treatment in chronic schizophrenics. These conclusions led us to a further consideration of the findings obtained in similar analyses of such positive symptom BPRS subscales as Conceptual Disorganization and Unusual Thought Content. For both of these scales (see table 2), with the same statistical power, the effect was large enough to yield significant mean differences with respect to patterns of change among all the comparison groups in sessions 1-2 and sessions 1-3. The directions of change differences suggest that these forms of thought pathology are substantially normalized by neuroleptic medication. These forms of thought pathology are moderately correlated with TDR (see table 4), which is, it will be recalled, a composite score comprising four levels of thought pathology, the more severe of which are defined in terms similar to those of Conceptual Disorganization and Unusual Thought Content. On the basis of these considerations, we undertook a further set of TDR analyses in which this summary score was decomposed into its severityweighted constituents. The aim of these analyses was to test the provisional hypothesis that significant change due to relapse was demonstrable only for the two most severe subscores (see Methods section) and not for the two less severe subscores. A further implication of this hypothesis is that neuroleptic treatment selectively normalized more severe thought pathology while leaving unmodified milder, less severe thought pathology as characterized by the TDR. The scores for these analyses were in binary form: 0 = no pathological responses and 1 = ^ 1 pathological response assigned to each of the four severity levels, "minimal" (.25), "mild" (.50), "moderate" (.75), and "severe" (1.0), for all patients. The proportions of pathological responses at each level in the prewithdrawal session (1) for all patients are shown in figure 1. The proportions are based on responses to all 10 Rorschach cards. It is evident from figure 1 that minimal and mild thought pathology (reflecting concreteness, vagueness, and perseveration, as well as confusion, looseness, and fabulizations) is represented in substantially greater response proportion than moderate and severe thought pathology (reflecting autistic logic, absurd responses, incoherence, and neologisms). This may well explain why the Positive/Negative Symptom Index (comprising, among other subscales, Conceptual Disorganization and Unusual Thought Content) accounted for only a rather small proportion of the total TDR variance. Table 6 presents proportions of present (1) and absent (0) thought pathology for control patients and relapsed patients at minimal, mild, moderate, and severe levels in sessions 1 and 2. For reasons already adduced above, nonrelapsers in session 2 were excluded in the analysis applied to these data. Table 7 shows the same data for controls and relapsed and remedicated patients combined in sessions 1 and 3. Combining the latter two groups seemed justified by the finding that both groups manifested symptomatic exacerbation in session 3. Log linear analysis applied to these data yielded the following results. In session 1-2 (table 6) the x 1 for the interaction of group by proportions of present/absent responses for minimal pathology in session 1 was significant {p <.03), indicating that the relapsed group showed a smaller proportion of pathological responses than the control group. No such significant x' w as obtained in session 2. The joint x 2 for group comparison of the patterns of proportions in both sessions 1 and 2, however, was not significant. For mild thought pathology, neither the within-session interactions with group nor the between-session interactions with group were significant. It is concluded from this pattern of findings that neither control nor relapsed patients manifested an increase in minimal and mild thought pathology in session 2. Indeed, rather the opposite was true. Both groups showed reductions in session 2. At the moderate and severe levels of TDR thought pathology, a Figure 1. Percent thought pathology (TDR) at 4 levels of severity in session 1

11 404 SCHIZOPHRENIA BULLETIN Table 6. Proportions of present/absent thought pathology by levels of TDR severity in sessions 1-2 Group Control Relapsed Minimal (.25) Session 1 Session Session Mild (-50) Session Moderate (.75) Session 1 Session 2 Absent Present Absent Present Absent Present Absent Present Absent Present Absent Present Absent Present Absent Present Note. TDR = sum of severity-weighted Rorschach verbalizations corrected by number ol Rorschach responses. somewhat different pattern emerges. In session 1, at both moderate and severe levels, the relapsed patients manifest a significantly smaller proportion of thought pathology than the controls (p <.01). In session 2, however, this pattern is reversed. Relapsed patients show a significant increase in proportion of both moderate and severe thought pathology, while the controls reduce thought pathology (p <.01). The joint x 2 for session by group interactions at the moderate level (contrasting patterns of proportions between groups in session 1 and session 2) is significant (p < 05), while at the severe level, a marginally significant x 2 (p <.06) is obtained. It thus appears that while at the minimal and mild levels significant differences in proportions of manifest thought pathology between controls and relapsed subjects within or between sessions could not be demonstrated, at the moderate and severe levels, relapsed patients relative to control patients and to themselves in session 1 showed significant increases in proportions of thought pathology in the session in which their relapse was manifest. A similar pattern of results is seen in session 1-session 3 comparisons of controls, and relapsers and remedicated patients combined (see table 7). The x 2 for the interaction of group by proportions of presence/absence of minimal thought pathology in session 1 and session 3 is significant for each session (session 1: p <.02; session 3- p <.001). The joint x 2 contrasting the patterns of proportions between groups in both session 1 and session 3 is also significant (p <.02). Inspection of proportions shown in table 7 for minimal pathology indicates that both in session 1 and session 3 the relapsed/remedicated patients manifested less thought pathology than the controls, although both Severe (1.0) Session 1 Session groups showed a reduction in pathology in session 3 At the mild level in session 1, the group by present/absent proportions X 2 is not significant. In session 3, however, this interaction is significant (p < 002). Moreover, the joint X 2 contrasting the proportion patterns among groups for sessions 1 and 3 is marginally significant (p <.06). It appears, therefore, that while both controls and relapsed/remedicated patients showed reductions in mild thought pathology, the latter group did so to a significantly smaller extent than the former. At both the moderate and severe levels of thought pathology, a different pattern of results obtains. Within-session interactions in sessions 1 and 3 are significant (session 1- p <.01; session 3: p <.01), and between-session interactions are similarly significant (p <.03). Inspection of table 7 indicates that at both moderate and severe Table 7. Proportions of present/absent thought pathology by levels of TDR severity in sessions 1-3 Group Minimal (.25) Mild (.50) Moderate (.75) Severe (1.0) Session 1 Session 3 Session 1 Session 3 Session 1 Session 3 Session 1 Session 3 Absent Present Absent Present Absent Present Absent Present Absent Present Absent Present Absent Present Absent Present Control Relapsed & remedicated Note TDR = sum of severity-weighted Rorschach verbalizations corrected by number of Rorschach responses

12 VOL. 12, NO. 3, levels, relapsed/remedicated patients show a smaller proportion of pathological responses, while in session 3 this pattern is reversed; controls reduce proportions of pathological responses, while these are seen to be increased over session 1 in the relapsed/remedicated patients. From these results, both in session 1-2 and session 1-3 tests, the inference is drawn that neuroleptics tend to normalize moderate and severe thought pathology, while minimal and mild thought pathology is largely unaffected by these drugs. Discussion The central finding in this study is that more severe thought pathology in chronic schizophrenics, here defined both by subscales of the BPRS and scoring categories on the TDI, are to some extent normalized by neuroleptic medication, while less severe levels of thought pathology, specifically defined by types of scoring categories on the TDI, are unmodified by neuroleptic medication. Indeed, it may be said that the neuroleptics are not so much selective in normalizing degree of severity of thought pathology as they are selective in the kind of thought pathology that is reduced. Thus, it may be inferred that vivid, dramatic, gross distortions of reality, delusions, and hallucinations typically associated with an acute episode are reduced and even removed, while a kind of disorientation vis-a-vis reality, as well as concreteness and looseness, persists as residual thought pathology after a clinical remission has been attained by neuroleptic treatment. It remains now to examine the implications of these findings for diagnosis of medicated patients, for treatment and rehabilitation, for experimental study of thought disorder, for mechanisms of drug action, and for thought disorder as a trait in chronic schizophrenia. From the perspective of descriptive psychiatry and diagnostic processes, the present findings suggest that the presenting clinical picture in medicated chronic schizophrenic patients will be to some extent distorted. The probable absence of Andreasen's "positive symptoms" exemplifies this point. Clinical psychologists will identify few severely pathological responses on psychological testing; neuropsychologists may interpret residual thought pathology as reflecting mild brainbased cognitive deficit. In many mental hospitals, psychiatrists, already aware that medication may reduce presenting thought disorder in medicated new admissions, routinely withdraw such patients from neuroleptics in order to obtain a "pure" symptomatic and phenomenological picture. Investigators concerned with the experimental study of thought disorder would be well advised to do the same. Indeed, the present findings lend particular force to Chapman and Chapman's (1973) recommendation that experimental studies of thought disorder should be performed with drug-free schizophrenic patients only. At the same time, studies of language in medicated chronic schizophrenics are unlikely to reflect the full range of communication difficulties. Our findings also have some implications for efforts at therapy and rehabilitation with chronic schizophrenic patients. The psychotherapist will find his medicated chronic schizophrenic patient less distracted by hallucinations and less preoccupied by and fixed on delusions. Thus, the process of therapy will proceed with a somewhat greater degree of attention to the immediate realities of the therapeutic situation. Behavior therapists and social skills trainers (Wallace and Boone 1984) seeking to rehabilitate or even "habilitate" chronic schizophrenic patients have long recognized that such efforts are feasible only with medicated chronic schizophrenics. At the same time, it is generally agreed that social skills training is difficult to generalize and tends not to endure long beyond even persistent training efforts. Perhaps the present findings of residual concreteness, perseveration, vagueness, and looseness in thought processes may reflect the difficulties that social skills trainers encounter. These findings suggest that remitted chronic patients do not experience events as connected. They have little confidence in the continuity of events and in their recurrence under specifiable circumstances. Their ability to derive meaning by induction is impaired. Subjectively, they experience reality as fragmentary, disjointed, and unpredictable. Perhaps most important of all, they sense a terrifying disparity between their ability to cope and the multiple challenges to cope with which family and community confront them. The findings of this study leave unanswered questions regarding specific mechanisms whereby neuroleptic medication reduces the manifestation of the more severe aspects of thought pathology. On the basis of the research literature in this regard, two hypotheses are suggested. The drugs may specifically act on thought pathology such that the frequency with which grossly disordered thinking is in consciousness reduced or even eliminated. On the other hand, neuroleptics may not directly affect thought pathology but may