Motoric neurological soft signs and psychopathological symptoms in schizophrenic psychoses

Psychiatry Research 142 (2006) 191 – 199 www.elsevier.com/locate/psychres

Motoric neurological soft signs and psychopathological symptoms in schizophrenic psychoses Thomas Jahn a,b,*, Werner Hubmann c, Marcus Karr d, Fritz Mohr c, Regine Schlenker b, Thomas Heidenreich b, Rudolf Cohen b, Johannes Schro¨der d a

Department of Psychiatry and Psychotherapy, Technical University Munich, Munich, Germany b Department of Psychology, University of Konstanz, Konstanz, Germany c Psychiatric Hospital, Haar, Germany d Section of Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany Received 20 December 2002; accepted 23 December 2002

Abstract Motoric neurological soft signs (NSS) were investigated by means of the Brief Motor Scale (BMS) in 82 inpatients with DSM-III-R schizophrenic psychoses. To address potential fluctuations of psychopathological symptoms and extrapyramidal side effects, patients were examined in the subacute state, twice at an interval of 14 days on the average. NSS were significantly correlated with severity of illness, lower social functioning, and negative symptoms. Modest, but significant correlations were found between NSS and extrapyramidal side effects as assessed on the Simpson-Angus Scale. Neither the neuroleptic dose prescribed to the patient, nor scores for tardive dyskinesia and akathisia were significantly correlated with NSS. Moreover, NSS scores did not significantly differ between patients receiving clozapine and conventional neuroleptics. Patients in whom psychopathological symptoms remained stable or improved over the clinical course showed a significant reduction of NSS scores. This finding did not apply to those patients in whom psychopathological symptoms deteriorated. Our findings demonstrate that NSS in schizophrenic psychoses are relatively independent of neuroleptic side effects, but they are associated with the severity and persistence of psychopathological symptoms and with poor social functioning. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Schizophrenia; Neurological soft signs; Motor coordination; Neuroleptic side effects

1. Introduction * Corresponding author. Clinical and Experimental Neuropsychology, Department of Psychiatry and Psychotherapy, Technical University Munich, Ismaninger Strahe 22, D-81675 Munich, Germany. Tel.: +49 89 4140 4278; fax: +49 89 4140 4837. E-mail address: [email protected] (T. Jahn).

Minor motor and sensory deficits or neurological soft signs (NSS) are present in a substantial proportion of patients with schizophrenia (for review, see Heinrichs and Buchanan, 1988; Jahn, 1999; Boks et al.,

0165-1781/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2002.12.003

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2000). NSS comprise a variety of deficits, such as subtle impairments in sensory integration, discrete motor incoordination and clumsiness, or even occurrence of primitive reflexes. NSS are significantly correlated with a poor premorbid adjustment, early onset of the disease, and poor prognosis (Quitkin et al., 1976; Torrey, 1980; Woods et al., 1986; Johnstone et al., 1990; Schro¨der et al., 1993; Gupta et al., 1995a). Increased NSS scores can also be found in the non-affected first degree relatives (especially in the offspring) of schizophrenic patients, with prevalence rates significantly exceeding those of the general population (Marcus et al., 1985; Kinney et al., 1986; Rossi et al., 1990; McNeil et al., 1993; Chen et al., 2000). Consequently, NSS in schizophrenia are generally considered as indicators of an underlying, probably genetically transmitted factor contributing to the vulnerability to the disease (e.g., Meehl, 1990; Fish et al., 1992). Despite the significance of NSS in schizophrenia, some aspects remained controversial. While the studies cited above indicate that NSS may represent a trait marker in individuals at risk for schizophrenia, others found NSS to be significantly correlated with psychopathological symptoms of the disease. Unfortunately, these findings appear somewhat inconsistent, showing associations with both negative (Manschreck et al., 1982; Buchanan et al., 1990; Merriam et al., 1990) and positive symptoms (Green and Walker, 1985). Significant correlations with both psychopathological domains were also reported (King et al., 1991; Schro¨der et al., 1993; Mohr et al., 1996), while others did not detect any association between NSS and psychopathological symptoms (Bartko´ et al., 1988; Buchanan et al., 1994). NSS have been shown to antedate the onset of the disease in some cases (Walker, 1994), but little is known on their course after the illness has manifested itself. Four studies (Tucker and Silberfarb, 1978; Schro¨der et al., 1992, 1996, 1998) showed a significant decrease of NSS scores with remission of psychopathological symptoms in the course of a single episode as well as over a 3-year period, while one study (Buchanan et al., 1994) demonstrated a remarkable stability of NSS in schizophrenic patients during a 10-week drug trial. Another controversy is the potential role of neuroleptic drug treatment. Although some investigators

have found significant correlations between NSS and doses of neuroleptic medication and/or extrapyramidal side effects (Quitkin et al., 1976; Youssef and Waddington, 1988; Merriam et al., 1990; King et al., 1991), the majority did not (Buchanan et al., 1994; Gupta et al., 1995b; for review, see Heinrichs and Buchanan, 1988). Moreover, increased NSS scores were also found in drug-naive patients with schizophrenia (Sanders et al., 1994; Schro¨der et al., 1992, 1998). Obviously, methodological differences may account for these discrepancies. NSS are heterogenous phenomena that may be defined and operationalized in various ways. This seems to be of primary importance with respect to the potential impact of neuroleptic treatment since motor NSS are apparently more vulnerable to extrapyramidal side effects as sensory NSS. The heterogeneity of schizophrenia itself has to be discussed as an additional potential confounding variable. The majority of studies investigated patients with repeated episodes; only some authors focused on first episode, drug-naive patients. Variability of psychopathological symptoms in the clinical course from acute exacerbation to remission of acute symptoms in the subacute state is likely to affect NSS scores in cross-sectional studies and should be carefully controlled for. To address these issues in a clinical study, we decided to focus on patients in subacute states in whom acute symptoms were at least partially remitted and restricted the investigation of NSS to pure motor signs. The aims of our study were: (1) to further clarify the relations between NSS and psychopathological symptoms in patients with schizophrenia or schizophreniform psychoses; and (2), to investigate the potential relation between NSS and neuroleptic drug treatment.

2. Methods 2.1. Subjects A total of 82 patients in the subacute state were recruited from three psychiatric hospitals (Research Unit of the University of Konstanz at the Psychiatric Hospital Reichenau; Department of Psychiatry/Heidelberg; Psychiatric State Hospital Haar/Munich)

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according to the following criteria: (1) age 18–50 years; (2) DSM-III-R (American Psychiatric Association, 1987) diagnosis of schizophrenia or schizophrenia spectrum psychosis in whom acute symptoms were at least partially remitted; (3) absence of any neurological or serious medical illness, mental retardation and history of substance abuse. Diagnoses were defined on the basis of the Structured Clinical Interview for DSM-III-R (SCID; German version by Wittchen et al., 1990). The majority of patients (n = 73) were inpatients at the time of testing; only nine were being treated as out-patients at the Reichenau Hospital. Twenty-two of the patients were hospitalized with their first episode. All but three patients received neuroleptics at the time of testing; 33 were treated with clozapine, and three patients were taking clozapine in combination with standard neuroleptics. Sample characteristics and subtype diagnoses are presented in Table 1. Subsamples did not differ with respect to age, marital status, age at onset, total duration of illness, current neuroleptic intake, and severity of illness (v 2tests and Kruskal–Wallis H-tests with subsequent pairwise Mann–Whitney U-tests), the latter being rated by means of the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) in the expanded 24-item version developed by Lukoff et al. (1986). Scoring of the items ranged from 1 (not present) to 7 (extreme severity). When compared with the Heidelberg subsample, patients recruited in Haar had undergone a larger number and longer duration of hospitalizations (U = 70.0; P b 0.005; and U = 219.0; P b 0.01, respectively). Comparisons between Konstanz and Heidelberg reached significance only for the total duration of hospitalizations (U = 122.5; P b 0.001). Global level of social functioning, as rated with the Global Assessment of Functioning Scale (GAF; Axis V of the DSM-IIIR), was lowest in the Heidelberg patients (H-test: v 2 = 4.75; P = 0.09), reaching the 5% level of significance only in comparison with the Haar patients (U = 164.0; P b 0.05). Comparisons between subsamples on the basis of BPRS subscores showed that the Heidelberg patients scored higher on subscores of Anxiety/Depression and Activation than the patients in the two other subsamples (U-tests; P b 0.005). None of the other measures obtained differed significantly between subsamples.

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2.2. Assessment and procedure NSS were investigated using the Brief Motor Scale (BMS, Jahn et al., 2006-this issue), which solely focuses on motor signs. Four of the six raters (two raters per center) showed adequate to excellent interrater reliabilities with motor tasks that were identical or very similar to those included in the BMS (see Schro¨der et al., 1992; Mohr et al., 1996, Table 1). One of these raters carefully trained the two new raters until complete convergence of scoring was obtained in at least three consecutive patients. Neuroleptic side effects were examined by means of the following instruments: the Rating Scale for Extrapyramidal Side Effects (EPS; Simpson and Angus, 1970), the Abnormal Involuntary Movement Scale (AIMS; Guy, 1976), and the Rating Scale for Drug-Induced Akathisia (Barnes, 1989). From the 82 patients, 78 were examined twice on these scales, with a time interval between the first and the second assessment of 14 days on the average. Psychopathological symptoms were rated on the BPRS. Intelligence level was assessed using a short, forced choice vocabulary test (Mehrfachwahl-Wortschatz-Intelligenztest/MWT-B; Lehrl, 1989). The Wisconsin Card Sorting Test (WCST) in the modified version (MCST) described by Nelson (1976) was applied to address signs indicating frontal lobe dysfunction. On the second examination, potential changes of the psychopathological state from the first test session were rated on the Clinical Global Impressions Scale (CGI; Guy, 1976). 2.3. Data analysis The BMS consists of 10 motor tasks, of which six are scored separately for each hand. Scoring of the items ranges from 0 (normal) to 2 (maximum deviation). Since the score for each bilateral item is the mean from the right and the left hand performances, the maximal total score of the scale is 20. In addition to the total score (TS) of the BMS, two empirically defined subscores were calculated as the sum of the respective items: subscale dMotor CoordinationT (MOCO: diadochokinesia, foot tapping, gaze impersistence, Oseretzki test, bilateral rhythm tapping), and subscale dMotor SequencingT (MOSE: fingerthumb-opposition, pronation–supination, fist-edge-

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palm test, fist-ring test, rhythm production) (see appendix in Jahn et al., 2006-this issue, for a detailed description). In case of the EPS, each item ranges from 0 (not present) to 4 (extreme severity). Following a suggestion by G. Simpson (personal communication), the items "salivation" and "glabella reflex" were excluded since they do not reflect muscle rigidity. Total EPS scores were calculated as the sum of the remaining eight items, of which seven assess different aspects of muscular rigiditiy and one item records tremor. From the Barnes Scale, only the global rating of akathisia was used. Because only 17 patients had scores N 0 (no akathisia), scores 1 (questionable akathisia) to 5 (severe akathisia) were recoded as one score, thus dichotomizing the akathisia rating into 0/1 (akathisia no/yes). On the basis of the CGI ratings at the end of the 2-week interval, the total patient sample was subdivided into three subgroups: patients who improved (CGI scores b 4; n = 27), patients who remained in a stable condition (CGI score 5; n = 44), and patients who got worse (CGI score N 6; n = 6). For further data analysis, nonparametric test statistics were employed: Comparisons between subsamples or subgroups were calculated by means of Kruskal–Wallis H-tests and/or Mann–Whitney Utests, results from first and second test sessions were compared using the Wilcoxon matched pairs signed ranks test, and correlational analyses were done with zero order and partial Spearman rankorder correlations. Joint distributions of nominal variables (contingency tables) were analyzed using the Pearson v 2-statistic.

3. Results At t 1, the median of the BMS total score (TS) in the combined schizophrenic sample was 5.50 (interquartile range 6.63). For the subscales, medians and interquartile ranges were: MOCO = 2.75 (4.00), MOSE = 2.00 (3.50). As shown elsewhere, these scores range far beyond the medians of a group of normal controls (see Jahn et al., 2006-this issue). When compared between the subsamples, patients recruited in Heidelberg were characterized by the highest total and subscale scores, but a trend toward statistical significance was obtained only for the subtest MOCO (H-test:

2.97 V v 2df=2 V 5.62; 0.06 V P V 0.23; subsequent Utests: 186.5 V U V 419.0; 0.015 V P V 0.843). No significant correlations emerged between the BMS total score or subscores and age, age at onset, duration of illness, number of previous hospitalizations, and total duration of hospitaliziation ( 0.07 Vr s V 0.13; n.s.). Level of social functioning (GAF score) was significantly related to motor signs: TS: r s = 0.40 (P = 0.000), MOCO: r s = 0.36 (P = 0.002),MOSE: r s = 0.38 ( P = 0.001). Thus, lower levels of functioning were associated with more motor impairments. BMS scores were significantly correlated with the severity of illness (BPRS total and subscale scores; see Table 2). Since psychopathological symptoms were also associated with EPS (0.14 V r s V 0.33), partial rank order correlations with EPS as the covariate were also calculated. However, this analysis revealed corresponding results. Among the measures of neuroleptic side effects, only EPS correlated significantly with motor impairments (Table 3). Partial rank-order correlations with the BPRS as the covariate yielded somewhat lower coefficients (BMS total score: r s = 0.30 with P = 0.007; MOCO: r s = 0.29 with P = 0.008; MOSE: r s = 0.18, n.s.; N = 78). To further investigate the effects of neuroleptic medication, the 33 patients on clozapine monotherapy were compared with the 43 patients receiving standard conventional neuroleptics. The BMS total score and the subscores were almost identical (0.42V P V 0.88; U-tests), although the clozapine patients displayed significantly fewer extrapyramidal symptoms (U = 403.0; P = 0.002; N = 75). No significant correlations arose between IQ level and motor performance, but the BMS total score was clearly associated with neuropsychological performance in the modified WCST (Table 4). At t 2, the median of the BMS total score was somewhat reduced in the total patient sample (N = 78), as were the medians of the subscores: TS = 4.00 (interquartile range 4.38), MOCO = 2.00 (3.00), MOSE = 1.50 (2.50). Mean differences between t1 and t2 are shown in Fig. 1. Improvement in motor behavior was significant for the total score and for both subcales. When the patient sample was subdivided into those in whom symptoms improved (n = 27), remained stable (n = 44), or deteriorated (n = 6) in the interval, only the latter showed no significant decrease of motor abnormalities (Fig. 1).

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Table 1 Sample and subsample characteristics Total, N = 82 Gender Age (years)

Level of education

Marital status

DSM-III-R diagnoses

Course of previous episodes

Age at onseta

Number of previous hospitalizationsb

Total duration of hospitalizations (weeks)c Total duration of illness (yrs)a

Global level of functioning (GAF)d

Pychopathology (BPRS total score)

Neuroleptic dosage (CPZ)a

a b c d

N = 79. N = 62. N = 80. N = 73.

Female Male Mean S.D. Range Low (8 years) Medium (10 years) High (13 years) Unmarried Married Widowed or divorced 295.1 Disorganized 295.2 Catatonic 295.3 Paranoid 295.4 Schizophreniform 295.6 Residual 295.7 Schizoaffective 295.9 Undifferentiated 298.9 Psychotic disorders Not elsewhere classified Completely remitted Partly remitted Chronic Not clear First manifestation Median Interquartile range Range Median Interquartile range Range Median Interquartile range Range Median Interquartile range Range Median Interquartile range Range Median Interquartile range Range Median Interquartile range Range

27 55 29.6 7.0 18–49 28 25 29 74 2 6 15 1 35 2 15 8 5 1 3 23 28 6 22 23.0 7.0 16–46 3 4.3 0–15 24.0 61.5 0–472 3.0 8.0 0–20 42.0 18.5 25–75 39.0 14.3 24–87 400 350 0–1400

Konstanz, n = 27

Haar, n = 32

Heidelberg, n = 23

7 20 29.1 6.4 19–42 12 7 8 26 – 1 8 – 15 2 – 2 – –

8 24 30.9 8.4 18–49 12 12 8 28 1 3 7 1 5 – 13 – 5 1

12 11 28.2 5.3 21–40 4 6 13 20 1 2 – – 15 – 2 6 – –

2 12 7 1 5 22.0 6.0 16–40 3.0 3.5 0–15 28.0 60.5 0–472 5.0 8.5 0–14 45.0 26.0 25–75 34.0 18.0 24–65 471 351 10–1400

– – 19 4 9 24.0 13.0 16–46 5.0 5.0 1–15 36.5 97.5 0–460 4.0 8.0 0–20 46.0 12.0 25–65 38.5 13.5 25–70 400 400 0–1200

1 11 2 1 8 25.0 5.0 19–36 1.5 2.0 0–8 6.0 24.0 0–78 3.0 5.0 0–14 38.0 12.0 25–65 42.0 6.0 29–87 400 340 114–1253

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Table 2 Spearman rank-order correlations between subtle motor signs (BMS) and psychopathology (BPRS) (N = 82). Partial rank-order correlations with medication side effects (EPS) as a covariate in parentheses (N = 78)

Table 4 Spearman rank-order correlations of subtle motor signs (BMS) with IQ level (N = 79) and performance on the modified WCST (N = 80) Total score and subscores of the BMS

Total score and subscores of the BMS

BPRS total score Anxiety/depression Anergia Thought disturbance Activation Hostility/suspiciousness

Total score

Motor coordination

Motor sequencing

0.46*** (0.42***) 0.26* (0.24*) 0.45*** (0.36***) 0.24* (0.21) 0.26* (0.20) 0.35*** (0.32**)

0.46*** (0.41**) 0.24* (0.21) 0.44*** (0.36***) 0.22* (0.18) 0.26* (0.20) 0.27* (0.23*)

0.36*** (0.33**) 0.22* (0.21) 0.34** (0.28*) 0.22* (0.20) 0.22* (0.19) 0.35*** (0.33**)

BMS: Brief Motor Scale. BPRS: Brief Psychiatric Rating Scale. EPS: Extrapyramidal Symptoms Scale. * P V 0.05. ** P V 0.01. *** P V 0.001.

No significant correlations between changes (difference scores t 2 t 1) in neuroleptic dose levels, extrapyramidal symptoms, tardive dyskinesia or akathisia and changes in any of the BMS scores arose.

4. Discussion The present study revealed two major findings: (1) evidence that NSS are significantly correlated with Table 3 Spearman rank-order and point-biserial correlations between subtle motor signs (BMS) and medication variables (79 V N V 81) Total score and subscores of the BMS

CPZa AIMSa EPSa Akathisiab

Total score

Motor coordination

0.15 0.05 0.38*** 0.14

0.18 0.15 0.37*** 0.10

Motor sequencing 0.07 0.06 0.26* 0.14

AIMS: Abnormal Involuntary Movement Scale. BMS: Brief Motor Scale. CPZ: Chlorpromazine dose equivalents. EPS: Extrapyramidal Symptoms Scale. a Spearman correlations. b Point-biserial correlations. *P V 0.05. **P V 0.01. ***P V 0.001.

MWT-B: IQ level MCST: categories MCST: total errors MCST: perserverations

Total score

Motor coordination

Motor sequencing

0.15 0.44*** 0.43*** 0.42***

0.04 0.33** 0.35** 0.27*

0.18 0.39*** 0.34** 0.40***

BMS: Brief Motor Scale. MWT-B: Mehrfachwahl-Wortschatz-Intelligenztest. MCST: Modified Card Sorting Test. * P V 0.05. ** P V 0.01. *** P V 0.001.

poor social functioning and psychopathological symptoms; and (2) an indication that neuroleptic side effects only partially contribute to NSS. Our results clearly indicate that subtle motor signs are substantially correlated with lower level of social functioning, severity of illness in general, and with negative symptoms in particular. Consistently, the degree of motor impairment varied over time to some extent, depending at least in part on variations in the clinical state of the patients. Similar findings were reported by Schro¨der et al. (1992, 1996), who investigated NSS in 50 and 36 patients with schizophrenia in the clinical course. Both studies revealed a significant decrease of NSS scores with remission of the acute illness under neuroleptic therapy. Despite these findings, it should be emphasized that in each of the subgroups reported here and at both time points, motor impairments were present to an extent that ranged – on the average – far beyond the level observed in healthy controls. With respect to neuroleptic side effects, only the degree of extrapyramidal symptoms showed medium correlations with motor signs. When symptom level was partialled out, these correlations decreased to some extent, while adjusting for the level of EPS when calculating correlations between psychopathology and motor signs had far smaller effects. In addition, BMS scores showed only minor, non-significant differences between patients on clozapine and those receiving standard conventional neuroleptics, although the former showed significantly fewer extrapyramidal side effects. These results are generally consistent with previous findings of our group (Schro¨der et al., 1992, 1998), and correspond to the observation that NSS

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Fig. 1. Mean difference scores (t 2 t 1) between the first and the second test session for BMS total and subscale scores in the combined patient sample (N = 78) and in three subgroups according to their clinical course (improved: n = 27; stable: n = 44; worsened: n = 6). Wilcoxon matchedpairs signed-ranks test: (*) P V.10, * P V.05, ** P V.01, *** P V.001.

decrease with remission of the acute symptoms under neuroleptic therapy. Although the findings presented here should be interpreted with caution because they have been calculated from the same patient sample that was used for standardization of the BMS (see Jahn et al., 2006-this issue), our data point to a closer association between subtle motor signs and psychopathology than between these signs and medication effects. In contrast, other studies (Quitkin et al., 1976; Youssef and Waddington, 1988; Merriam et al., 1990; King et al., 1991) reported substantial correlations between NSS and neuroleptic side effects, such as parkinsonian symptoms, akathisia, or tardive dyskinesia. Obviously, methodological differences may account for this discrepancy. In the studies cited above, both patients with remitting and chronic schizophrenia were included. This is of particular importance, since neuroleptic side effects and NSS are more pronounced in patients with a chronic than those with a remitting course of the disorder (Sachdev, 1995; Karr et al., 1996; Schro¨der et al., 1992). Hence in a cross-sectional study, significant correlations between the two parameters may occur. Follow-up studies of patients may be adequate to overcome these methodological limitation. A recent longitudinal study found a dissociation between

decreasing NSS but increasing scores for extrapyramidal side effects in drug-naive patients who received a standardized neuroleptic treatment. Moreover, up-regulation of striatal dopamine D2 receptors as revealed by single photon emission computed tomography (SPECT) was significantly correlated with scores for parkinsonian side effects but not with NSS (Schro¨der et al., 1998). This finding may be of particular importance since D2 dopamine receptor blockade in the basal ganglia is generally accepted to be among the most important factors in the pathogenesis of extrapyramidal side effects. That NSS do not relate to basal ganglia changes is further supported by Rubin et al. (1994). In contrast, NSS refer to changes in different cerebral sites, such as the sensorimotor cortices and the cerebellum (Gu¨nther et al., 1994; Schro¨der et al., 1995, 1999). In conclusion, the present study confirms a significant association between NSS and psychopathological symptoms in schizophrenia and schizophrenia spectrum disorders, and it demonstrates that NSS scores decrease with clinical stabilization even in the subacute state after remission of acute symptoms. While we focused on pure motor signs, only minor – although significant – correlations between NSS and parkinsonian side effects arose. To study further the significance

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