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Symptomatology and electrodermal activity as predictors of neuroleptic response in young male schizophrenic inpatients
145
Psychiatry Research, 42:145-158 Elsevier
Symptomatology of Neuroleptic Inpatients Eva M. Lindstrijm,
and Electrodermal Activity as Predictors Response in Young Male Schizophrenic
Lennart
S. bhlund,
Leif H. LindstrGm,
and Arne
ohman
Received July 16, 1991; revised version received Fehruar_ta20, 1992; accepted April 20, 1992. Abstract. This study examined whether the response to treatment with neuroleptic medication in 21 schizophrenic patients could be predicted from symptomatology, electrodermal activity, and premorbid adjustment. Positive symptoms and high levels of electrodermal activity were associated with a good response to conventional neuroleptic drugs. However, multivariate analysis indicated that symptomatology was the only independent predictor of treatment response. Key Words. Psychopharmacology, skin conductance.
autonomic
nervous system, positive symptoms,
discovery and continuing refinement of neuroleptic medications have contributed greatly to the relief of disturbing symptoms in patients with schizophrenia. However, only 60-70% of schizophrenic patients improve when medicated with neuroleptic drugs (e.g., Davis et al., 1980; Lewander et al., 1990). Thus, a large number of patients show little or no benefit from such treatment. This variability in treatment response depends on a number of factors such as gender (Seeman, 1986), chronicity (Clark et al., 1972), dosage (Baldessarini et al., 1988), length of treatment (Baldessarini et al., 1988), and the type of criteria used to assess treatment gains (Manchanda et al., 1988). A persistent problem with neuroleptic treatment regimes concerns the variety of side effects that occur in a significant proportion of patients, independent of whether they benefit from the treatment. Among the most acute disabilities are akathisia, akinesia, anxiety, dystonia, and dysphoria (Lingjaerde, 1988). Tardive dyskinesia is a particularly severe, sometimes irreversible, late side effect that strikes about 10-20’30 of treated patients (Hlggstram, 1984). Some reports suggest that side effects tend to be more severe in patients with a poor treatment response-for example, those with primarily negative symptoms (Montague et al., 1989). Thus, it is crucial to delineate The
Eva M. Lindstriim, M.D., is Psychiatrist, Department of Psychiatry, University of Uppsala, Sweden. Lennart S. ohlund, M.Sc., is Research Psychologist, Department of Clinical Psychology, University of Uppsala, Sweden. Leif H. LindstrGm, M.D., Ph.D., is Professor, University of Uppsala, Sweden, and Senior Psychiatrist, V&z& Hospital. Arne ijhman, Ph.D., is Professor, Department of Clinical Psychology, University of Uppsala, Sweden. (Reprint requests to Prof. A. ohman, Dept. of Clinical Psychology, University of Uppsala, P.O. Box 1225, S-75 I 42 Uppsala, Sweden.) 0165-1781/92/$05.00
@ 1992 El sevier Scientific
Publishers
Ireland
Ltd
146 prognostic indicators that could aid the clinician in deciding which patients should be given neuroleptic medication. At least four different factors have been suggested to predict treatment response: (1) Background factors such as poor premorbid adjustment (Klein et al., 1973) and an early age of onset of first symptoms (Andreasen et al., 1990) have been associated with poor neuroleptic response. (2) Clinical characteristics, such as predominantly negative symptoms as assessed by rating scales (Csernansky et al., 1985) or a poor information processing capacity as measured by the span of apprehension test (Marder et al., 1984), have been found to predict a poor response to neuroleptic drugs. (3) Responses to laboratory tests (e.g., an increase in plasma homovanillic acid concentration after 4 days of treatment with haloperidol) have been related to a good response to neuroleptic treatment (Davila et al., 1988). (4) Biological indicators such as ventricular enlargement (Weinberger et al., 1980; Gattaz et al., 1988) and low levels of electrodermal activity (Schneider, 1982) have been linked to a poor response to neuroleptic medication. The association of poor response with low levels of electrodermal activity is not supported by two studies (Frith et al., 1979; Zahn et al, 1981) in which low levels of electrodermal activity were found to be prognostic of clinical improvement in schizophrenic patients selected for good premorbid adjustment (Zahn et al., 1981) or primarily positive symptoms (Frith et al., 1979). However, none of these studies examined clinical improvements primarily as an effect of medication. In fact, only a minority of patients in each study had received any neuroleptic treatment at all. Thus, the findings of these two studies that high levels of electrodermal activity were related to poor short-term symptomatic outcome have little bearing on the issue of electrodermal activity as a predictor of response to neuroleptic medication. Electrodermal activity, measured during repeated presentations of a moderately intense tone stimulus, appears to delineate two clinically important schizophrenic subgroups (ohman, 1981; ohman et al., 1989). In contrast to normal subjects, who show an electrodermal orienting response to the first tones and then habituate, as much as 40-50% of schizophrenic patients fail to respond at all (ohman, 198 1). Previous research has documented that electrodermal nonresponders tend to have primarily but not exclusively negative symptoms (Bernstein, 1987) third ventricular enlargement (Cannon et al., 1988; but see Schnur et al., 1989), cortical atrophy (Zahn et al., 1982) family history of schizophrenia (Alm et al., 1984) poor premorbid adjustment, and poor social outcome (ohman et al., 1989). In contrast to patients with low electrodermal levels who did not differ from normal control subjects, electrodermally responding schizophrenic patients showed deviantly low levels of dopamine metabolites in cerebrospinal fluid (ohlund et al., 1992). Finally, schizophrenic patients with low levels of electrodermal activity, including failure to respond to the first two stimuli, tended to be born in the season of excess risk for schizophrenia (January-April) (ohlund et al., 1990, 1991). Birth during that seasonal period, in turn, has been associated with many of the predictors of poor treatment response such as structural brain abnormalities (Zipursky and Schulz, 1987; Degreef et al., 1988), early onset of psychosis (Pulver et al., 1981) and negative symptomatology (Opler et al., 1984; ohlund et al,, 1990). Thus, electrodermal
147 activity appears to be consistently associated with a number of measures related to the response to neuroleptic treatment in schizophrenia. This conclusion suggests that low levels of electrodermal activity, including electrodermal nonresponding to orienting stimuli, could be a prognostic sign for poor response to neuroleptic medication. The present study examined three partially overlapping potential predictors of response to neuroleptic medication in schizophrenic patients: electrodermal activity, symptomatology, and premorbid adjustment. The purpose of the study was to evaluate the independent contributions of the various potential prognostic factors in predicting the overall treatment effect. Subjects were drawn from a group of patients who took part in a longitudinal study involving repeated assessments in multiple domains. Thus, patients were located who had been assessed for symptomatology and electrodermal activity in a drug-free state, and who were then put on a standard neuroleptic regime by their regular clinician for a minimal treatment duration. The response to neuroleptic drugs was systematically evaluated from hospital records for the following year.
Methods The total group included 29 acutely psychotic male inpatients, diagnosed as meeting DSM-III criteria for schizophrenia (American Psychiatric Association, 1980). Twenty-two of the cases were first-admission patients who had not been previously treated with neuroleptic drugs according to their medical records. Seven patients were relapsers, almost all of whom had received neuroleptic medication during at least one period after their first episodes of illness. Patients who had been on medication before the electrodermal test session had a washout period of at least, and typically more than, 14 days. Eight patients were excluded from further consideration. One was lost because he refused to take the prescribed medication. An additional seven patients were eliminated from the study because they did not receive traditional neuroleptic drugs for an adequate period (2 21 days) during the l-year followup period. Thus, the final study group comprised 21 acutely psychotic male inpatients with a mean age of 27.9 years (range 18-42 years). Subjects.
Background Factors. Age of first symptoms was determined by interviews both with the patients and at least one close relative or friend. Estimates of premorbid behavioral deviations were obtained from interviews with close relatives, typically one or both of the parents. The deviations were rated on a 5-point scale. For a rating of 1, no behavioral abnormality was observed before the psychotic symptoms appeared. For a rating of 2, slight but obvious deviations in behavior were apparent during adolescence, such as the patient’s having few friends and tendencies toward social isolation. For a rating of 3, clear-cut behavioral abnormalities were observed, such as the patient’s having no friends and being characterized by eccentricity and problems at school. For a rating of 4, a history was noted of previous contact with a psychiatric treatment facility for children and adolescents on an outpatient basis. For a rating of 5, inpatient treatment had been received for behavioral disturbances at a clinic for child and adolescent psychiatry. Before the data were analyzed, the 5-point scale was dichotomized. Those with a rating of I were a normal group with no behavioral abnormalities before the psychotic symptoms appeared, while those with ratings of 2-5 were considered a deviant group with premorbid abnormalities. Clinical
Psychotic and 17 observed
Assessment.
using 16 reported
symptoms displayed by the individual patients were rated items from the Comprehensive Psychopathological Rating
148
Scale (CPRS; Asberg et al., 1978). These ratings were based on a systematic interview made within a week of the psychophysiological testing session, by one of three ward psychiatrists or a psychologist, on 18 of the patients. Two of the studied individuals were interviewed and rated up to 4 weeks after the psychophysiological test. However, as they were unmedicated during that time, the clinical state for these two patients was considered to be the same both at the interview and at the test. Clinical ratings were not performed for one of the patients due to his lack of cooperation. None of the ratings were performed by the psychiatrist (E.L.) who evaluated treatment response from the hospital records. Raters at the clinic have been documented to show good agreement (2 83%) (Lindstrom et al., 1978; Sjostrom, 1990). Psychophysiological Experiment. All patients were unmedicated, acutely psychotic, and in need of inpatient treatment when they participated in the psychophysiological experiment. They were exposed to a series of I5 tones (1000 Hz, 80 dB, 2 second duration, with 50 msec on and off ramps to prevent startle). The intervals between the tones, offset to onset, varied between 30 and 60 seconds with a mean of 45 seconds. Skin conductance was recorded with a constant-voltage system by standard Beckman silver/silver chloride electrodes (8 mm in diameter), filled with electrolyte (0.05 molar NaCI) using Unibase as a medium (Fowles et al., 198 1). The electrodes were attached to the second phalanges of the first and second fingers of the subject’s left hand with standard adhesive collars that provided a controlled skin area for exposure to the electrodes. The instructions specified that tones would be presented through the earphones, but that they had no special significance. Skin conductance levels (SCL) were measured at the onset of each tone and averaged for the 15 tones. Spontaneous skin conductance fluctuations (SFs) were brief changes in conductance exceeding 0.05 microsiemens that were not correlated with the stimulus. The number of SFs was summed during the 20 seconds preceding each tone and transformed to a rate/minute format. Skin conductance responses (SCRs) that exceeded 0.05 microsiemens were preliminarily counted within a response window of l-5 seconds after the stimulus. The final data were, as recommended by Levinson and Edelberg (1985) derived from a more narrow window defined as the median latency f I second for each subject.
After the psychophysiological session, all patients received standard treatment with conventional neuroleptic drugs (i.e., dopamine-receptor blockers). Schizophrenic patients treated with atypical neuroleptic drugs such as clozapine were excluded. Treatment started with low doses to minimize the side effects that often prompt patients to discontinue the medication regime. Higher doses were prescribed after intervals of a few days. In some of the cases, because of a weak antipsychotic effect, or to avoid serious side effects, the administered neuroleptic compound was changed to another similar compound. Two of the patients were given antiparkinsonian, anticholinergic medication and one patient needed hypnotics. Neuroleptic doses were converted into chlorpromazine equivalents (CPEQ) according to Davis (I 974). The patients were followed for I year after the determination of electrodermal activity and the initiation of medication. Treatment response was rated as well as side effects (unpublished results). A minimum of 3 weeks (21 days) was set for the key treatment period. The key treatment period lasted 21-180 days, during which time neuroleptic drugs of different kinds were prescribed in varying doses. Five patients received haloperidol orally (CPEQ: 125-250 mg daily). Four patients received flupenthixol, either orally or as enanthate (CPEQ: 40-60 mg daily), and seven patients received perphenazine either orally or as enanthate (CPEQ: 90-106 mg daily). Two patients were treated with remoxipride orally (CPEQ: 90-300 mg), one with chlorpromazine (225 mg daily), one with pimozide (CPEQ: 200 mg daily) and one with zuclopentixole (CQEQ: 80 mg daily).
Treatment.
Response. Hospital records were evaluated by a psychiatrist (E.L.) who was unaware of the electrodermal findings, CPRS ratings, and premorbid adjustment ratings. The data evaluated were dosage, length of medication, clinical response to treatment, and side effects. Treatment response was rated on a 5-point scale as follows: -1 = deterioration; 0 = no Treatment
149 change; 1 = moderate improvement; 2 = significant improvement; and 3 = symptom free. The patients were divided into two groups on the basis of good (scores 2 or 3) and poor (scores < 2) treatment response. Fifteen of the original 29 hospital records were evaluated by an additional independent psychiatrist (L.L.), who was also unaware of the electrodermal findings and the ratings performed by the other psychiatrist; 13 of these 15 patients were included in the final sample of 21 patients. The interrater reliability for the judgment of good versus poor treatment response on the basis of hospital records was 1.0 (i.e., 100% agreement). Statistical Analysis. When data were continuous, t tests for independent samples and analyses of covariance (ANCOVAs) were performed using the T-TEST or GLM Procedures supplied by SAS Institute Inc. (1987). For categorical data, following the recommendation of Siegel (1956), x* tests with Yates’ correction for continuity were used when all expected frequencies were > 5. When the smallest expected frequency was < 5, Fisher’s exact probability test was used. The relationships between CPRS items and neuroleptic response groups were examined by @ coefficients and tested for significance by Yates’ corrected x2 test or, when appropriate, Fisher’s exact test. The low variance and anomalous distribution of the scores, which primarily were due to frequent zero ratings on many symptom items, dictated the use of @ coefficients. The data were dichotomized (Siegel, 1956) as those scores above and below the median. All tests were performed using the statistical package supplied by SAS Institute Inc. (1987). All tests were two-tailed.
Results Of the total sample of 21 young male schizophrenic patients studied, 10 (47.6%) showed significant improvement and 11 (52.4%) showed a poor response to neuroleptic treatment at the dosage used. Earlier results from this group (ohman et al., 1989; ohlund et al., 1990) have shown a more obvious relationship between electrodermal activity and other variables (e.g., social functioning and season of birth) in schizophrenic patients in their first episodes of illness than in previously treated individuals. Therefore, the following results are presented for both the total sample and the neuroleptic-naive subsample. Background Factors. Patients with good and poor responses to treatment with neuroleptic drugs did not differ in background characteristics such as the age of appearance of first symptoms, age of first admission, duration of symptoms, duration since first admission, or level of premorbid adjustment (see Table 1). The absence of differences held true both for the complete sample and the neurolepticnaive subsample. Medication. When patients with good and poor responses to treatment with neuroleptic medication were compared by dosage (in CPEQ), there was a tendency toward higher maximum dosage levels in patients who had a poor response to treatment. A more detailed analysis of the key treatment period revealed no significant difference between the two groups regarding dosage (low, mean, main), or for the duration during which the main dosage was given (see Table 1). Electrodermal Activity. As shown in Fig. 1 (right panel), patients who showed a good response to neuroleptic treatment had more SCRs than did patients with a poor response, and this relationship was particularly obvious for first episode patients. However, whereas this effect was statistically reliable for the neuroleptic-
I IScomputed
%
3.6
3.0
2.1
7.1
77.1
8.5
8.5
7.5
99.5
84.5
101.5
80.3
53.9
60.2
SD
1.8
1.9
1.3
0.6
0.6
0.4
0.6
0.2
1.3
1.1
2.0
1.2
1.3
0.9
1
NS
NS
%
6.0
5.1
3.3
1.4
44.0
5.2
5.2
2.3
59.4
56.7
59.4
17.6
65.6
66.2
SD
62.5 (n = 5)
37.5 (n = 3)
6.9
6.0
5.0
0.5
31.1
26.6
26.6
24.8
125.7
124.1
125.7
99.0
102.8
104.3
Mean
8)
Good (n=
0.05
0.03
skin conductance
50.0 (n = 3) fluctuation.
SCR = skin
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
p<
NS
8.7’
7.5’
9.3’
8.5’
12.0
12.0
12.0
5.4’
12.0
12.0
12.0
5.3’
12.0
12.0
df
66.7 (n = 4)
2.3
2.7
1.4
0.6
0.3
0.5
0.5
0.3
0.7
0.6
0.7
0.8
0.5
0.3
t
Fisher’s exact test
1.9
0.8
1.2
0.4
38.3
8.1
8.1
9.3
87.9
85.7
87.9
88.3
65.8
75.7
SD
Analysis
%
1.7
0.9
3.2
0.2
36.8
28.3
28.3
25.8
151.4
147.1
151.4
127.3
84.2
93.7
Mean
6)
Poor (n=
and Satterhwalte’s approximation for the degrees of freedom is used (SAS, 1987).
level. SF = Spontanous
0.08
0.08
NS
NS
NS
NS
NS
NS
NS
NS
0.07
NS
NS
NS
p<
Fisher’s exact test
19.0
19.0
19.0
9.7’
19.0
19.0
19.0
14.3’
19.0
19.0
19.0
12.3’
19.0
19.0
df
Analysis
activity. SCL = skin conductance
63.6 (n = 7)
54.5 (n = 6)
2.7
2.0
3.8
4.5
67.9
28.5
28.3
23.2
163.1
150.4
190.4
120.3
72.2
83.7
Mean
EDA = electrodermal
1. Because of unequal variances, the approximate
eqwalents.
70.0 (n = 7)
Note. CPEQ = chlorpromazine conductance response.
30.0 (n = 3)
adjustment
5.4
4.8
3.2
34.0
54.0
5.0
4.6
3.4
59.3
56.8
59.1
26.4
Deviant premorbid
%
64.1 64.3
Nonresponders
6.4
SCR
5.3
5.3
Electrodermal activity SCL (microsiemens)
SF (per min)
11.2
1st admission-EDA
49.0
27.2
EDA test
Duration (mo) 1st symptom-EDA
26.5
1 st admission
23.7
114.8
116.8
Mean
Main
Age (yr) 1st symptom
116.9
Highest
89.2
Main dose
Dose (CPEQ; mgiday) Lowest
109.0
106.9
Time (days) Key treatment
Mean
SD
Poor (A 11)
10)
(n=
Good
Table 1. Summary of findings in good and poor responders to neuroleptic drugs within the total group and the neuroleptic-naive subgroup Total group Neuroleptic-naivesubgroup 5
151
Fig. 1. Relationships between electrodermal activity and response to treatment with neuroleptic drugs SFs SCRs -15
0
150
0 0
0
lo-
l
-10
0 0 0
5-
0 00
,:
:
0’0 a
00
000~ 00
Poor
Good
Poor
Neuroleptic
Response
oGood
-
5
- 0
The left panel shows the distribution of spontaneous skin conductance fluctuations (SFs) and the right panel shows the drstribution of skin conductance responses (SCRs) to simple tone stimuli. Open circles represent neuroleptic-naive patients, and the closed circles represent patients who had previously been treated with neuroleptic drugs.
naive subsample, it was only marginally significant in the complete group (see Table 1). A clear difference between responders and nonresponders was also seen for SFs (i.e., spontaneous electrodermal responses in the interstimulus intervals) where a good treatment response was associated with a higher number of SFs (Fig. 1, left panel). This difference was clearly significant in the neuroleptic-naive patients where a five-fold difference between the groups was obtained, but once again the effect was only marginally significant in the total group (see Table 1). Findings for SCL showed a similar trend to that for SCR and SF, but no significant differences were obtained between good and poor responders (see Table 1). To control statistically for potential interfering factors in the relationship between treatment response and electrodermal activity, one-way ANCOVAs were tried with time, dose, age, and duration of illness as covariates. Only dose level (highest, mean, and main) provided a significant adjustment to the electrodermal variables in the total sample. When the effect of dose level was removed, the ANCOVA showed that all the three continuous electrodermal variables yielded significant differences between patients with good and poor responses to treatment. In the neuroleptic-naive subsample, duration since first admission provided a significant adjustment when rate of SFs was compared between the groups. However, the rate of SFs in good versus poor responders remained significantly different regardless of what variables were used as covariates. Clinical
As shown in Fig. 2, some positive symptoms were significantly with a good neuroleptic response, whereas some negative symptoms were with a poor response. There was a strong relationship (positive I#J between good treatment response and the CPRS item depersonalization total group and the neuroleptic-naive subgroup. In the total group, there
Picture.
associated associated coefficient) in both the
152 was also a relationship between good treatment response and the CPRS item derealization and a trend toward an association with the CPRS item flight of ideas. In addition, there was a significant relationship (negative $J coefficient) between poor treatment response and the CPRS item slowness of movement for the neuroleptic-naive subgroup and a trend in the total group. Finally, a correlational trend was observed in the neuroleptic-naive subgroup between poor treatment response and both hallucinatory behavior and apparent sadness. In the total group, a
Fig. 2. Relationship between degree of psychopathology and neuroleptic response in the total group and in the neuroleptic-naive subgroup Reported
items
Observed
items
Hypochondriosis Rituals Indecision Lassitude Oerealisation Depersonalisation Feeling controlled Disrupted thoughts Ideas of persecution ldeos of grandeur Delusional mood Other delusions Commenting voices Other auditory hallucinations Visual hallucinations Other hallucinations Reported items, total score
Apparent
sadness Hostility Labile emotional responses Lack of appropriate emotion Withdrawal Perplexity Blank spells Pressure of speech Reduced speech Flight of ideas Incoherent speech
5; ;
a
z
l
In 0 ; .
a t
Perseveration Overactivity Slowness of movement Agitation Mannerisms and postures Hallucinatory behaviour Observed items, total score
-0.8
-0.4
0.0
0.4
0.8
Phi coefficient The relationship, expressed as @ coefficients, IS shown between the degree of psychopathology, measured by the Comprehensive Psychopathological Rating Scale. and the response to neuroleptic treatment in the total gorup (filled bars) and in the neuroleptic-naive subgroup (unfilled bars). Positive correlation means that those with a good treatment response display that symptom to a higher degree than those with a poor treatment response. Consequently, a negative correlation means that those with a poor treatment response display that symptom to a higher degree than those with a good treatment response.
153 similar trend was observed reduced speech.
between
poor treatment
response
and the CPRS
item
Multivariate Analysis. To examine the independence of the contributions of the various predictors, the variables that showed significantly or marginally significant univariate associations with neuroleptic response were entered in a stepwise discriminant analysis with good and poor treatment response as the criterion groups. The variables entered in the analyses for the total group were two electrodermal variables (SF and SCR), and five items (derealization, depersonalization, reduced speech, flight of ideas, and slowness of movement) from the CPRS. Symptomatology (depersonalization and flight of ideas) turned out to be the best independent predictors in the total group (see Table 2). The variables entered in the analyses for the neuroleptic-naive subgroup were two electrodermal variables (SF and SCR), and four CPRS items (depersonalization, apparent sadness, slowness of movement, and hallucinatory behavior). In the drug-naive subgroup, both a positive symptom (depersonalization) and a negative symptom (slowness of movement) contributed independently to the prediction of neuroleptic response (see Table 2).
Table 2. Summary of stepwise discriminant analysis Canonical f2
Variable
F
df
D<
Total group
Depersonalization
0.407
12.4
1, 18
0.003
Flight of ideas
0.579
11.7
2, 17
0.0006
Depersonalization
0.536
12.7
1,11
0.005
Slowness
0.717
12.6
2, 10
0.002
Neuroleptic-naive subgroup of movement
Discussion The results from this study showed that electrodermal activity (number of SCRs and SFs) and symptomatology predicted the response to treatment with neuroleptic drugs in schizophrenic patients. Patients who showed low levels of electrodermal activity and predominantly negative symptoms had a poor response to treatment. However, the multivariate analysis suggested that the predictive relationship for the electrodermal variables overlapped with those for symptoms, because only the latter were retained in the model in the multivariate analysis. However, even though the multivariate findings suggested that the electrodermal variables, from a statistical perspective, were secondary to the symptom ratings in predicting outcome, their demonstrated relationship to neuroleptic response may nevertheless prove useful. The electrodermal variables provide information that is objective, reliable, and relatively easy to collect, whereas symptom ratings confront many methodological problems. The findings indicating associations between treatment response and factors such as symptomatology and electrodermal activity are consistent with the idea that the
154 diversity of response to neuroleptic drugs may provide a ground for the subclassifcation of schizophrenic patients (Brown and Herz, 1989). The reliable relationship obtained between symptomatology and neuroleptic response also appears to support the idea (Crow, 1980) that schizophrenic patients can be divided into distinct subgroups on the basis of their presenting symptoms. As in earlier studies (Csernansky et al., 1985), positive symptoms (depersonalization, derealization, and flight of ideas) were associated with a good response to treatment and negative symptoms (slowness of movement and reduced speech) were associated with a poor response to treatment. However, some of these associations were only marginally significant, probably due to the relatively small sample size. Nevertheless, the pattern was clear and, because of the large number of items, the pattern rather than single symptoms should provide the basis for interpretation. The present results show that the orienting response, as indicated by electrodermal activity, can be a predictor of the effect of neuroleptics in schizophrenic males. Thus, patients with many orienting responses to stimuli showed a better clinical response to neuroleptic drugs than did patients with few orienting responses. This finding is consistent with reports that electrodermal responding is associated with deviations in measures of dopaminergic activity in cerebrospinal fluid (ohlund et al., 1992) and with reports relating electrodermal nonresponding to negative symptoms (e.g., Bernstein, 1987) enlarged third ventricles (Cannon et al., 1988) winter births (ohlund et al., 1990, 1991) and poor social outcome (ijhman et al., 1989). Patients with a good effect of drug treatment also showed an elevation in tonic electrodermal activity, because they had significantly more spontaneous electrodermal fluctuations than patients with a poor treatment effect. This difference was most pronounced in the group of first-episode patients, who had not been treated with neuroleptic drugs before. Thus, the differences between the groups appeared to pertain to electrodermal responding in general instead of being restricted specifically to electrodermal orienting responses. However, the mean SCL did not discriminate between patients who had a good or poor effect of drug treatment, unless dose level was used as covariate. Thus, except for the failure to find differences in SCL, our results replicated those of Schneider (1982) in the sense that we found a prognostic relation between low levels of electrodermal activity and a poor effect of neuroleptic medication. This replication occurred despite the fact that we studied a young group of male schizophrenic patients, a majority of whom were first episode patients, whereas Schneider’s study group consisted of much older chronic male patients. Thus, even though in our study the relationship between electrodermal activity and neuroleptic response was most clear-cut in the neuroleptic-naive subgroup, there are reasons to believe that the relationship holds across groups of male patients with different degrees of chronicity. In conclusion, two of the four parameters of electrodermal activity that were used in the present study successfully predicted the effect of neuroleptic drugs in the schizophrenic patients studied. This finding alone is of sufficient interest to promote further studies of electrodermal variables as predictors of the outcome of neuroleptic treatment in larger samples of both male and female schizophrenic patients. If our findings were replicated in such studies, electrodermal activity would be a promising
155 tool for clinicians. Not only would it give clues to the likely social outcome for the patient (ohman et al., 1989), but it would also provide an inexpensive, simple, robust, and reliable prognostic marker for the effect of antipsychotic medication. This study failed to replicate earlier work (Klein and Rosen, 1973; Andreasen et al., 1990) demonstrating that poor premorbid adjustment and early onset of illness predicted poor response to neuroleptic treatment. A limited sample size and the problems associated with inaccurate reporting of retrospective data are two factors that may help to explain these discrepancies. Although electrodermal activity was measured before neuroleptic treatment began, the assessment of clinical improvement was retrospective, which dictates that the results be interpreted cautiously. However, there was a very high level of agreement between the two experienced psychiatrists, who showed 100% agreement when rating the degree of clinical improvement on the basis of careful university hospital records. This indicates that hospital records can be useful tools in retrospective longitudinal followup studies. Other examples of the fruitfulness of such an approach are provided by Keck et al. (1989) and Dening and Berrios (1989). Surprisingly few of our young patients responded to neuroleptic drugs. Thus, less than 50% of the total sample of young schizophrenic males showed a good response to neuroleptic treatment. Most followup evaluations have found that approximately 70% of schizophrenic patients have a favorable response to neuroleptic drugs (Davis et al., 1980). Our results cannot be explained by the fact that chronic, readmitted patients were included, since the number of patients who responded favorably to medication was similar in first-episode drug-naive patients and the relapsers. A possible explanation could be that only male patients were included in the study. It is well documented (Seeman, 1986; Goldstein, 1988) that schizophrenic males have a poorer prognosis and respond less well to neuroleptic drugs than do schizophrenic females. Yet another explanation could be that rather low doses of antipsychotic drugs were administered, and to a certain extent, higher doses of neuroleptics do appear to increase improvement rates (Baldessarini et al., 1988). In this study, however, we found that improved patients received lower doses of neuroleptic medication than did those who failed to improve. Still, it cannot be ruled out that we could have achieved symptomatic improvement in the currently nonimproved patients with further increases in dose levels, but perhaps at the cost of more side effects and less compliance with the medication regime. The exclusion of female subjects and the rather low doses of medication received by the patients will, of course, limit the generalizability of our findings. Thus, the relationship between therapeutic response to neuroleptic medication, on the one hand, and symptomatology and electrodermal activity, on the other, may be valid only for males receiving low doses of neuroleptics. Nevertheless, as Young and Meltzer (1980) have pointed out, given the risk of long-term side effects, it is particularly important to improve the possibility of accurately predicting which patients will respond to low doses of neuroleptic treatment. On the basis of our results, this appears to be exactly the information provided by electrodermal activity. Acknowledgments. The research reported in this article was supported by grants from the Swedish Medical Research Council awarded to Leif H. Lindstriim (no. 5095) and to Arne
156
Ghman (no. 7960). The authors thank Thomas Alm for his assistance in this study Margret Bywater-Ekenas for her helpful comments on an earlier version of this report.
and
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158 Seeman, M.V. Current outcome in schizophrenia: Women vs. men. Acta Psychiatrica Scandinavica, 73:609-617, 1986. Siegel, S. Nonparametric Statistics for the Behavioral Sciences. New York: McGraw-Hill, 1956. Sjostriim, R. Psykoterapi vid schizofreni-en prospektiv studie. Liikartidningen, 87:32793282, 1990. Weinberger, D.R.; Bigelow, L.B.; Kleinman, J.E.; Klein, S.T.; Rosenblatt, J.E.; and Wyatt, R.J. Cerebral ventricular enlargement in chronic schizophrenia. Archives of General Psychiatry, 37: I l-13, 1980. Young, M.A., and Meltzer, H.Y. The relationship of demographic, clinical and outcome variables to neuroleptic treatment requirements. Schizophrenia Bulletin, 6:88-101, 1980. Zahn, T.P.; Carpenter, W.T.; and McGlashan, T.H. Autonomic nervous system activity in acute schizophrenia: II. Relationships to short term prognosis and clinical state. Archives of General Psychiatry, 38:260-266, 198 I. Zahn, T.P.; van Kammen, D.P.; Schooler, C.; and Mann, L.S. Autonomic activity in schizophrenia: Relationships to cortical atrophy and symptomatology. (Abstract) Psychophysiology, 19:593, 1982. Zipursky, R.B., and Schulz, S.C. Seasonality of birth and CT findings in schizophrenia. Biological Psychiatry, 22: 1288-l 292, 1987.
Psychiatry Research, 42:145-158 Elsevier
Symptomatology of Neuroleptic Inpatients Eva M. Lindstrijm,
and Electrodermal Activity as Predictors Response in Young Male Schizophrenic
Lennart
S. bhlund,
Leif H. LindstrGm,
and Arne
ohman
Received July 16, 1991; revised version received Fehruar_ta20, 1992; accepted April 20, 1992. Abstract. This study examined whether the response to treatment with neuroleptic medication in 21 schizophrenic patients could be predicted from symptomatology, electrodermal activity, and premorbid adjustment. Positive symptoms and high levels of electrodermal activity were associated with a good response to conventional neuroleptic drugs. However, multivariate analysis indicated that symptomatology was the only independent predictor of treatment response. Key Words. Psychopharmacology, skin conductance.
autonomic
nervous system, positive symptoms,
discovery and continuing refinement of neuroleptic medications have contributed greatly to the relief of disturbing symptoms in patients with schizophrenia. However, only 60-70% of schizophrenic patients improve when medicated with neuroleptic drugs (e.g., Davis et al., 1980; Lewander et al., 1990). Thus, a large number of patients show little or no benefit from such treatment. This variability in treatment response depends on a number of factors such as gender (Seeman, 1986), chronicity (Clark et al., 1972), dosage (Baldessarini et al., 1988), length of treatment (Baldessarini et al., 1988), and the type of criteria used to assess treatment gains (Manchanda et al., 1988). A persistent problem with neuroleptic treatment regimes concerns the variety of side effects that occur in a significant proportion of patients, independent of whether they benefit from the treatment. Among the most acute disabilities are akathisia, akinesia, anxiety, dystonia, and dysphoria (Lingjaerde, 1988). Tardive dyskinesia is a particularly severe, sometimes irreversible, late side effect that strikes about 10-20’30 of treated patients (Hlggstram, 1984). Some reports suggest that side effects tend to be more severe in patients with a poor treatment response-for example, those with primarily negative symptoms (Montague et al., 1989). Thus, it is crucial to delineate The
Eva M. Lindstriim, M.D., is Psychiatrist, Department of Psychiatry, University of Uppsala, Sweden. Lennart S. ohlund, M.Sc., is Research Psychologist, Department of Clinical Psychology, University of Uppsala, Sweden. Leif H. LindstrGm, M.D., Ph.D., is Professor, University of Uppsala, Sweden, and Senior Psychiatrist, V&z& Hospital. Arne ijhman, Ph.D., is Professor, Department of Clinical Psychology, University of Uppsala, Sweden. (Reprint requests to Prof. A. ohman, Dept. of Clinical Psychology, University of Uppsala, P.O. Box 1225, S-75 I 42 Uppsala, Sweden.) 0165-1781/92/$05.00
@ 1992 El sevier Scientific
Publishers
Ireland
Ltd
146 prognostic indicators that could aid the clinician in deciding which patients should be given neuroleptic medication. At least four different factors have been suggested to predict treatment response: (1) Background factors such as poor premorbid adjustment (Klein et al., 1973) and an early age of onset of first symptoms (Andreasen et al., 1990) have been associated with poor neuroleptic response. (2) Clinical characteristics, such as predominantly negative symptoms as assessed by rating scales (Csernansky et al., 1985) or a poor information processing capacity as measured by the span of apprehension test (Marder et al., 1984), have been found to predict a poor response to neuroleptic drugs. (3) Responses to laboratory tests (e.g., an increase in plasma homovanillic acid concentration after 4 days of treatment with haloperidol) have been related to a good response to neuroleptic treatment (Davila et al., 1988). (4) Biological indicators such as ventricular enlargement (Weinberger et al., 1980; Gattaz et al., 1988) and low levels of electrodermal activity (Schneider, 1982) have been linked to a poor response to neuroleptic medication. The association of poor response with low levels of electrodermal activity is not supported by two studies (Frith et al., 1979; Zahn et al, 1981) in which low levels of electrodermal activity were found to be prognostic of clinical improvement in schizophrenic patients selected for good premorbid adjustment (Zahn et al., 1981) or primarily positive symptoms (Frith et al., 1979). However, none of these studies examined clinical improvements primarily as an effect of medication. In fact, only a minority of patients in each study had received any neuroleptic treatment at all. Thus, the findings of these two studies that high levels of electrodermal activity were related to poor short-term symptomatic outcome have little bearing on the issue of electrodermal activity as a predictor of response to neuroleptic medication. Electrodermal activity, measured during repeated presentations of a moderately intense tone stimulus, appears to delineate two clinically important schizophrenic subgroups (ohman, 1981; ohman et al., 1989). In contrast to normal subjects, who show an electrodermal orienting response to the first tones and then habituate, as much as 40-50% of schizophrenic patients fail to respond at all (ohman, 198 1). Previous research has documented that electrodermal nonresponders tend to have primarily but not exclusively negative symptoms (Bernstein, 1987) third ventricular enlargement (Cannon et al., 1988; but see Schnur et al., 1989), cortical atrophy (Zahn et al., 1982) family history of schizophrenia (Alm et al., 1984) poor premorbid adjustment, and poor social outcome (ohman et al., 1989). In contrast to patients with low electrodermal levels who did not differ from normal control subjects, electrodermally responding schizophrenic patients showed deviantly low levels of dopamine metabolites in cerebrospinal fluid (ohlund et al., 1992). Finally, schizophrenic patients with low levels of electrodermal activity, including failure to respond to the first two stimuli, tended to be born in the season of excess risk for schizophrenia (January-April) (ohlund et al., 1990, 1991). Birth during that seasonal period, in turn, has been associated with many of the predictors of poor treatment response such as structural brain abnormalities (Zipursky and Schulz, 1987; Degreef et al., 1988), early onset of psychosis (Pulver et al., 1981) and negative symptomatology (Opler et al., 1984; ohlund et al,, 1990). Thus, electrodermal
147 activity appears to be consistently associated with a number of measures related to the response to neuroleptic treatment in schizophrenia. This conclusion suggests that low levels of electrodermal activity, including electrodermal nonresponding to orienting stimuli, could be a prognostic sign for poor response to neuroleptic medication. The present study examined three partially overlapping potential predictors of response to neuroleptic medication in schizophrenic patients: electrodermal activity, symptomatology, and premorbid adjustment. The purpose of the study was to evaluate the independent contributions of the various potential prognostic factors in predicting the overall treatment effect. Subjects were drawn from a group of patients who took part in a longitudinal study involving repeated assessments in multiple domains. Thus, patients were located who had been assessed for symptomatology and electrodermal activity in a drug-free state, and who were then put on a standard neuroleptic regime by their regular clinician for a minimal treatment duration. The response to neuroleptic drugs was systematically evaluated from hospital records for the following year.
Methods The total group included 29 acutely psychotic male inpatients, diagnosed as meeting DSM-III criteria for schizophrenia (American Psychiatric Association, 1980). Twenty-two of the cases were first-admission patients who had not been previously treated with neuroleptic drugs according to their medical records. Seven patients were relapsers, almost all of whom had received neuroleptic medication during at least one period after their first episodes of illness. Patients who had been on medication before the electrodermal test session had a washout period of at least, and typically more than, 14 days. Eight patients were excluded from further consideration. One was lost because he refused to take the prescribed medication. An additional seven patients were eliminated from the study because they did not receive traditional neuroleptic drugs for an adequate period (2 21 days) during the l-year followup period. Thus, the final study group comprised 21 acutely psychotic male inpatients with a mean age of 27.9 years (range 18-42 years). Subjects.
Background Factors. Age of first symptoms was determined by interviews both with the patients and at least one close relative or friend. Estimates of premorbid behavioral deviations were obtained from interviews with close relatives, typically one or both of the parents. The deviations were rated on a 5-point scale. For a rating of 1, no behavioral abnormality was observed before the psychotic symptoms appeared. For a rating of 2, slight but obvious deviations in behavior were apparent during adolescence, such as the patient’s having few friends and tendencies toward social isolation. For a rating of 3, clear-cut behavioral abnormalities were observed, such as the patient’s having no friends and being characterized by eccentricity and problems at school. For a rating of 4, a history was noted of previous contact with a psychiatric treatment facility for children and adolescents on an outpatient basis. For a rating of 5, inpatient treatment had been received for behavioral disturbances at a clinic for child and adolescent psychiatry. Before the data were analyzed, the 5-point scale was dichotomized. Those with a rating of I were a normal group with no behavioral abnormalities before the psychotic symptoms appeared, while those with ratings of 2-5 were considered a deviant group with premorbid abnormalities. Clinical
Psychotic and 17 observed
Assessment.
using 16 reported
symptoms displayed by the individual patients were rated items from the Comprehensive Psychopathological Rating
148
Scale (CPRS; Asberg et al., 1978). These ratings were based on a systematic interview made within a week of the psychophysiological testing session, by one of three ward psychiatrists or a psychologist, on 18 of the patients. Two of the studied individuals were interviewed and rated up to 4 weeks after the psychophysiological test. However, as they were unmedicated during that time, the clinical state for these two patients was considered to be the same both at the interview and at the test. Clinical ratings were not performed for one of the patients due to his lack of cooperation. None of the ratings were performed by the psychiatrist (E.L.) who evaluated treatment response from the hospital records. Raters at the clinic have been documented to show good agreement (2 83%) (Lindstrom et al., 1978; Sjostrom, 1990). Psychophysiological Experiment. All patients were unmedicated, acutely psychotic, and in need of inpatient treatment when they participated in the psychophysiological experiment. They were exposed to a series of I5 tones (1000 Hz, 80 dB, 2 second duration, with 50 msec on and off ramps to prevent startle). The intervals between the tones, offset to onset, varied between 30 and 60 seconds with a mean of 45 seconds. Skin conductance was recorded with a constant-voltage system by standard Beckman silver/silver chloride electrodes (8 mm in diameter), filled with electrolyte (0.05 molar NaCI) using Unibase as a medium (Fowles et al., 198 1). The electrodes were attached to the second phalanges of the first and second fingers of the subject’s left hand with standard adhesive collars that provided a controlled skin area for exposure to the electrodes. The instructions specified that tones would be presented through the earphones, but that they had no special significance. Skin conductance levels (SCL) were measured at the onset of each tone and averaged for the 15 tones. Spontaneous skin conductance fluctuations (SFs) were brief changes in conductance exceeding 0.05 microsiemens that were not correlated with the stimulus. The number of SFs was summed during the 20 seconds preceding each tone and transformed to a rate/minute format. Skin conductance responses (SCRs) that exceeded 0.05 microsiemens were preliminarily counted within a response window of l-5 seconds after the stimulus. The final data were, as recommended by Levinson and Edelberg (1985) derived from a more narrow window defined as the median latency f I second for each subject.
After the psychophysiological session, all patients received standard treatment with conventional neuroleptic drugs (i.e., dopamine-receptor blockers). Schizophrenic patients treated with atypical neuroleptic drugs such as clozapine were excluded. Treatment started with low doses to minimize the side effects that often prompt patients to discontinue the medication regime. Higher doses were prescribed after intervals of a few days. In some of the cases, because of a weak antipsychotic effect, or to avoid serious side effects, the administered neuroleptic compound was changed to another similar compound. Two of the patients were given antiparkinsonian, anticholinergic medication and one patient needed hypnotics. Neuroleptic doses were converted into chlorpromazine equivalents (CPEQ) according to Davis (I 974). The patients were followed for I year after the determination of electrodermal activity and the initiation of medication. Treatment response was rated as well as side effects (unpublished results). A minimum of 3 weeks (21 days) was set for the key treatment period. The key treatment period lasted 21-180 days, during which time neuroleptic drugs of different kinds were prescribed in varying doses. Five patients received haloperidol orally (CPEQ: 125-250 mg daily). Four patients received flupenthixol, either orally or as enanthate (CPEQ: 40-60 mg daily), and seven patients received perphenazine either orally or as enanthate (CPEQ: 90-106 mg daily). Two patients were treated with remoxipride orally (CPEQ: 90-300 mg), one with chlorpromazine (225 mg daily), one with pimozide (CPEQ: 200 mg daily) and one with zuclopentixole (CQEQ: 80 mg daily).
Treatment.
Response. Hospital records were evaluated by a psychiatrist (E.L.) who was unaware of the electrodermal findings, CPRS ratings, and premorbid adjustment ratings. The data evaluated were dosage, length of medication, clinical response to treatment, and side effects. Treatment response was rated on a 5-point scale as follows: -1 = deterioration; 0 = no Treatment
149 change; 1 = moderate improvement; 2 = significant improvement; and 3 = symptom free. The patients were divided into two groups on the basis of good (scores 2 or 3) and poor (scores < 2) treatment response. Fifteen of the original 29 hospital records were evaluated by an additional independent psychiatrist (L.L.), who was also unaware of the electrodermal findings and the ratings performed by the other psychiatrist; 13 of these 15 patients were included in the final sample of 21 patients. The interrater reliability for the judgment of good versus poor treatment response on the basis of hospital records was 1.0 (i.e., 100% agreement). Statistical Analysis. When data were continuous, t tests for independent samples and analyses of covariance (ANCOVAs) were performed using the T-TEST or GLM Procedures supplied by SAS Institute Inc. (1987). For categorical data, following the recommendation of Siegel (1956), x* tests with Yates’ correction for continuity were used when all expected frequencies were > 5. When the smallest expected frequency was < 5, Fisher’s exact probability test was used. The relationships between CPRS items and neuroleptic response groups were examined by @ coefficients and tested for significance by Yates’ corrected x2 test or, when appropriate, Fisher’s exact test. The low variance and anomalous distribution of the scores, which primarily were due to frequent zero ratings on many symptom items, dictated the use of @ coefficients. The data were dichotomized (Siegel, 1956) as those scores above and below the median. All tests were performed using the statistical package supplied by SAS Institute Inc. (1987). All tests were two-tailed.
Results Of the total sample of 21 young male schizophrenic patients studied, 10 (47.6%) showed significant improvement and 11 (52.4%) showed a poor response to neuroleptic treatment at the dosage used. Earlier results from this group (ohman et al., 1989; ohlund et al., 1990) have shown a more obvious relationship between electrodermal activity and other variables (e.g., social functioning and season of birth) in schizophrenic patients in their first episodes of illness than in previously treated individuals. Therefore, the following results are presented for both the total sample and the neuroleptic-naive subsample. Background Factors. Patients with good and poor responses to treatment with neuroleptic drugs did not differ in background characteristics such as the age of appearance of first symptoms, age of first admission, duration of symptoms, duration since first admission, or level of premorbid adjustment (see Table 1). The absence of differences held true both for the complete sample and the neurolepticnaive subsample. Medication. When patients with good and poor responses to treatment with neuroleptic medication were compared by dosage (in CPEQ), there was a tendency toward higher maximum dosage levels in patients who had a poor response to treatment. A more detailed analysis of the key treatment period revealed no significant difference between the two groups regarding dosage (low, mean, main), or for the duration during which the main dosage was given (see Table 1). Electrodermal Activity. As shown in Fig. 1 (right panel), patients who showed a good response to neuroleptic treatment had more SCRs than did patients with a poor response, and this relationship was particularly obvious for first episode patients. However, whereas this effect was statistically reliable for the neuroleptic-
I IScomputed
%
3.6
3.0
2.1
7.1
77.1
8.5
8.5
7.5
99.5
84.5
101.5
80.3
53.9
60.2
SD
1.8
1.9
1.3
0.6
0.6
0.4
0.6
0.2
1.3
1.1
2.0
1.2
1.3
0.9
1
NS
NS
%
6.0
5.1
3.3
1.4
44.0
5.2
5.2
2.3
59.4
56.7
59.4
17.6
65.6
66.2
SD
62.5 (n = 5)
37.5 (n = 3)
6.9
6.0
5.0
0.5
31.1
26.6
26.6
24.8
125.7
124.1
125.7
99.0
102.8
104.3
Mean
8)
Good (n=
0.05
0.03
skin conductance
50.0 (n = 3) fluctuation.
SCR = skin
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
p<
NS
8.7’
7.5’
9.3’
8.5’
12.0
12.0
12.0
5.4’
12.0
12.0
12.0
5.3’
12.0
12.0
df
66.7 (n = 4)
2.3
2.7
1.4
0.6
0.3
0.5
0.5
0.3
0.7
0.6
0.7
0.8
0.5
0.3
t
Fisher’s exact test
1.9
0.8
1.2
0.4
38.3
8.1
8.1
9.3
87.9
85.7
87.9
88.3
65.8
75.7
SD
Analysis
%
1.7
0.9
3.2
0.2
36.8
28.3
28.3
25.8
151.4
147.1
151.4
127.3
84.2
93.7
Mean
6)
Poor (n=
and Satterhwalte’s approximation for the degrees of freedom is used (SAS, 1987).
level. SF = Spontanous
0.08
0.08
NS
NS
NS
NS
NS
NS
NS
NS
0.07
NS
NS
NS
p<
Fisher’s exact test
19.0
19.0
19.0
9.7’
19.0
19.0
19.0
14.3’
19.0
19.0
19.0
12.3’
19.0
19.0
df
Analysis
activity. SCL = skin conductance
63.6 (n = 7)
54.5 (n = 6)
2.7
2.0
3.8
4.5
67.9
28.5
28.3
23.2
163.1
150.4
190.4
120.3
72.2
83.7
Mean
EDA = electrodermal
1. Because of unequal variances, the approximate
eqwalents.
70.0 (n = 7)
Note. CPEQ = chlorpromazine conductance response.
30.0 (n = 3)
adjustment
5.4
4.8
3.2
34.0
54.0
5.0
4.6
3.4
59.3
56.8
59.1
26.4
Deviant premorbid
%
64.1 64.3
Nonresponders
6.4
SCR
5.3
5.3
Electrodermal activity SCL (microsiemens)
SF (per min)
11.2
1st admission-EDA
49.0
27.2
EDA test
Duration (mo) 1st symptom-EDA
26.5
1 st admission
23.7
114.8
116.8
Mean
Main
Age (yr) 1st symptom
116.9
Highest
89.2
Main dose
Dose (CPEQ; mgiday) Lowest
109.0
106.9
Time (days) Key treatment
Mean
SD
Poor (A 11)
10)
(n=
Good
Table 1. Summary of findings in good and poor responders to neuroleptic drugs within the total group and the neuroleptic-naive subgroup Total group Neuroleptic-naivesubgroup 5
151
Fig. 1. Relationships between electrodermal activity and response to treatment with neuroleptic drugs SFs SCRs -15
0
150
0 0
0
lo-
l
-10
0 0 0
5-
0 00
,:
:
0’0 a
00
000~ 00
Poor
Good
Poor
Neuroleptic
Response
oGood
-
5
- 0
The left panel shows the distribution of spontaneous skin conductance fluctuations (SFs) and the right panel shows the drstribution of skin conductance responses (SCRs) to simple tone stimuli. Open circles represent neuroleptic-naive patients, and the closed circles represent patients who had previously been treated with neuroleptic drugs.
naive subsample, it was only marginally significant in the complete group (see Table 1). A clear difference between responders and nonresponders was also seen for SFs (i.e., spontaneous electrodermal responses in the interstimulus intervals) where a good treatment response was associated with a higher number of SFs (Fig. 1, left panel). This difference was clearly significant in the neuroleptic-naive patients where a five-fold difference between the groups was obtained, but once again the effect was only marginally significant in the total group (see Table 1). Findings for SCL showed a similar trend to that for SCR and SF, but no significant differences were obtained between good and poor responders (see Table 1). To control statistically for potential interfering factors in the relationship between treatment response and electrodermal activity, one-way ANCOVAs were tried with time, dose, age, and duration of illness as covariates. Only dose level (highest, mean, and main) provided a significant adjustment to the electrodermal variables in the total sample. When the effect of dose level was removed, the ANCOVA showed that all the three continuous electrodermal variables yielded significant differences between patients with good and poor responses to treatment. In the neuroleptic-naive subsample, duration since first admission provided a significant adjustment when rate of SFs was compared between the groups. However, the rate of SFs in good versus poor responders remained significantly different regardless of what variables were used as covariates. Clinical
As shown in Fig. 2, some positive symptoms were significantly with a good neuroleptic response, whereas some negative symptoms were with a poor response. There was a strong relationship (positive I#J between good treatment response and the CPRS item depersonalization total group and the neuroleptic-naive subgroup. In the total group, there
Picture.
associated associated coefficient) in both the
152 was also a relationship between good treatment response and the CPRS item derealization and a trend toward an association with the CPRS item flight of ideas. In addition, there was a significant relationship (negative $J coefficient) between poor treatment response and the CPRS item slowness of movement for the neuroleptic-naive subgroup and a trend in the total group. Finally, a correlational trend was observed in the neuroleptic-naive subgroup between poor treatment response and both hallucinatory behavior and apparent sadness. In the total group, a
Fig. 2. Relationship between degree of psychopathology and neuroleptic response in the total group and in the neuroleptic-naive subgroup Reported
items
Observed
items
Hypochondriosis Rituals Indecision Lassitude Oerealisation Depersonalisation Feeling controlled Disrupted thoughts Ideas of persecution ldeos of grandeur Delusional mood Other delusions Commenting voices Other auditory hallucinations Visual hallucinations Other hallucinations Reported items, total score
Apparent
sadness Hostility Labile emotional responses Lack of appropriate emotion Withdrawal Perplexity Blank spells Pressure of speech Reduced speech Flight of ideas Incoherent speech
5; ;
a
z
l
In 0 ; .
a t
Perseveration Overactivity Slowness of movement Agitation Mannerisms and postures Hallucinatory behaviour Observed items, total score
-0.8
-0.4
0.0
0.4
0.8
Phi coefficient The relationship, expressed as @ coefficients, IS shown between the degree of psychopathology, measured by the Comprehensive Psychopathological Rating Scale. and the response to neuroleptic treatment in the total gorup (filled bars) and in the neuroleptic-naive subgroup (unfilled bars). Positive correlation means that those with a good treatment response display that symptom to a higher degree than those with a poor treatment response. Consequently, a negative correlation means that those with a poor treatment response display that symptom to a higher degree than those with a good treatment response.
153 similar trend was observed reduced speech.
between
poor treatment
response
and the CPRS
item
Multivariate Analysis. To examine the independence of the contributions of the various predictors, the variables that showed significantly or marginally significant univariate associations with neuroleptic response were entered in a stepwise discriminant analysis with good and poor treatment response as the criterion groups. The variables entered in the analyses for the total group were two electrodermal variables (SF and SCR), and five items (derealization, depersonalization, reduced speech, flight of ideas, and slowness of movement) from the CPRS. Symptomatology (depersonalization and flight of ideas) turned out to be the best independent predictors in the total group (see Table 2). The variables entered in the analyses for the neuroleptic-naive subgroup were two electrodermal variables (SF and SCR), and four CPRS items (depersonalization, apparent sadness, slowness of movement, and hallucinatory behavior). In the drug-naive subgroup, both a positive symptom (depersonalization) and a negative symptom (slowness of movement) contributed independently to the prediction of neuroleptic response (see Table 2).
Table 2. Summary of stepwise discriminant analysis Canonical f2
Variable
F
df
D<
Total group
Depersonalization
0.407
12.4
1, 18
0.003
Flight of ideas
0.579
11.7
2, 17
0.0006
Depersonalization
0.536
12.7
1,11
0.005
Slowness
0.717
12.6
2, 10
0.002
Neuroleptic-naive subgroup of movement
Discussion The results from this study showed that electrodermal activity (number of SCRs and SFs) and symptomatology predicted the response to treatment with neuroleptic drugs in schizophrenic patients. Patients who showed low levels of electrodermal activity and predominantly negative symptoms had a poor response to treatment. However, the multivariate analysis suggested that the predictive relationship for the electrodermal variables overlapped with those for symptoms, because only the latter were retained in the model in the multivariate analysis. However, even though the multivariate findings suggested that the electrodermal variables, from a statistical perspective, were secondary to the symptom ratings in predicting outcome, their demonstrated relationship to neuroleptic response may nevertheless prove useful. The electrodermal variables provide information that is objective, reliable, and relatively easy to collect, whereas symptom ratings confront many methodological problems. The findings indicating associations between treatment response and factors such as symptomatology and electrodermal activity are consistent with the idea that the
154 diversity of response to neuroleptic drugs may provide a ground for the subclassifcation of schizophrenic patients (Brown and Herz, 1989). The reliable relationship obtained between symptomatology and neuroleptic response also appears to support the idea (Crow, 1980) that schizophrenic patients can be divided into distinct subgroups on the basis of their presenting symptoms. As in earlier studies (Csernansky et al., 1985), positive symptoms (depersonalization, derealization, and flight of ideas) were associated with a good response to treatment and negative symptoms (slowness of movement and reduced speech) were associated with a poor response to treatment. However, some of these associations were only marginally significant, probably due to the relatively small sample size. Nevertheless, the pattern was clear and, because of the large number of items, the pattern rather than single symptoms should provide the basis for interpretation. The present results show that the orienting response, as indicated by electrodermal activity, can be a predictor of the effect of neuroleptics in schizophrenic males. Thus, patients with many orienting responses to stimuli showed a better clinical response to neuroleptic drugs than did patients with few orienting responses. This finding is consistent with reports that electrodermal responding is associated with deviations in measures of dopaminergic activity in cerebrospinal fluid (ohlund et al., 1992) and with reports relating electrodermal nonresponding to negative symptoms (e.g., Bernstein, 1987) enlarged third ventricles (Cannon et al., 1988) winter births (ohlund et al., 1990, 1991) and poor social outcome (ijhman et al., 1989). Patients with a good effect of drug treatment also showed an elevation in tonic electrodermal activity, because they had significantly more spontaneous electrodermal fluctuations than patients with a poor treatment effect. This difference was most pronounced in the group of first-episode patients, who had not been treated with neuroleptic drugs before. Thus, the differences between the groups appeared to pertain to electrodermal responding in general instead of being restricted specifically to electrodermal orienting responses. However, the mean SCL did not discriminate between patients who had a good or poor effect of drug treatment, unless dose level was used as covariate. Thus, except for the failure to find differences in SCL, our results replicated those of Schneider (1982) in the sense that we found a prognostic relation between low levels of electrodermal activity and a poor effect of neuroleptic medication. This replication occurred despite the fact that we studied a young group of male schizophrenic patients, a majority of whom were first episode patients, whereas Schneider’s study group consisted of much older chronic male patients. Thus, even though in our study the relationship between electrodermal activity and neuroleptic response was most clear-cut in the neuroleptic-naive subgroup, there are reasons to believe that the relationship holds across groups of male patients with different degrees of chronicity. In conclusion, two of the four parameters of electrodermal activity that were used in the present study successfully predicted the effect of neuroleptic drugs in the schizophrenic patients studied. This finding alone is of sufficient interest to promote further studies of electrodermal variables as predictors of the outcome of neuroleptic treatment in larger samples of both male and female schizophrenic patients. If our findings were replicated in such studies, electrodermal activity would be a promising
155 tool for clinicians. Not only would it give clues to the likely social outcome for the patient (ohman et al., 1989), but it would also provide an inexpensive, simple, robust, and reliable prognostic marker for the effect of antipsychotic medication. This study failed to replicate earlier work (Klein and Rosen, 1973; Andreasen et al., 1990) demonstrating that poor premorbid adjustment and early onset of illness predicted poor response to neuroleptic treatment. A limited sample size and the problems associated with inaccurate reporting of retrospective data are two factors that may help to explain these discrepancies. Although electrodermal activity was measured before neuroleptic treatment began, the assessment of clinical improvement was retrospective, which dictates that the results be interpreted cautiously. However, there was a very high level of agreement between the two experienced psychiatrists, who showed 100% agreement when rating the degree of clinical improvement on the basis of careful university hospital records. This indicates that hospital records can be useful tools in retrospective longitudinal followup studies. Other examples of the fruitfulness of such an approach are provided by Keck et al. (1989) and Dening and Berrios (1989). Surprisingly few of our young patients responded to neuroleptic drugs. Thus, less than 50% of the total sample of young schizophrenic males showed a good response to neuroleptic treatment. Most followup evaluations have found that approximately 70% of schizophrenic patients have a favorable response to neuroleptic drugs (Davis et al., 1980). Our results cannot be explained by the fact that chronic, readmitted patients were included, since the number of patients who responded favorably to medication was similar in first-episode drug-naive patients and the relapsers. A possible explanation could be that only male patients were included in the study. It is well documented (Seeman, 1986; Goldstein, 1988) that schizophrenic males have a poorer prognosis and respond less well to neuroleptic drugs than do schizophrenic females. Yet another explanation could be that rather low doses of antipsychotic drugs were administered, and to a certain extent, higher doses of neuroleptics do appear to increase improvement rates (Baldessarini et al., 1988). In this study, however, we found that improved patients received lower doses of neuroleptic medication than did those who failed to improve. Still, it cannot be ruled out that we could have achieved symptomatic improvement in the currently nonimproved patients with further increases in dose levels, but perhaps at the cost of more side effects and less compliance with the medication regime. The exclusion of female subjects and the rather low doses of medication received by the patients will, of course, limit the generalizability of our findings. Thus, the relationship between therapeutic response to neuroleptic medication, on the one hand, and symptomatology and electrodermal activity, on the other, may be valid only for males receiving low doses of neuroleptics. Nevertheless, as Young and Meltzer (1980) have pointed out, given the risk of long-term side effects, it is particularly important to improve the possibility of accurately predicting which patients will respond to low doses of neuroleptic treatment. On the basis of our results, this appears to be exactly the information provided by electrodermal activity. Acknowledgments. The research reported in this article was supported by grants from the Swedish Medical Research Council awarded to Leif H. Lindstriim (no. 5095) and to Arne
156
Ghman (no. 7960). The authors thank Thomas Alm for his assistance in this study Margret Bywater-Ekenas for her helpful comments on an earlier version of this report.
and
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