Psychiatry Research. 14, 235-240 Elsevier

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Serotonin and Schizophrenia: Correlations Between Serotonergic Activity and Schizophrenic Motor Behavior

Roy King, Kym F. Faull, Stephen M. Stahl, Ivan N. Mefford, Susan Thiemann, Jack D. Barchas, and Philip A. Berger

Received May 22, 1984; revised version received October 1, 1984; accepted October 22, 1984.

Abstract. Increased serotonergic activity in animals has been associated with a variety of stereotyped motor behaviors. In addition, serotonin facilitates brainstem. reticular, and spinal motor neuronal activity implicated in the expression of these behaviors. This report presents positive correlations between both peripheral (platelet serotonin levels) and central (cerebrospinal concentrations of Shydroxy- indoleacetic acid) measures of serotonin metabolism and the symptom of peculiar or unusual mannerisms and posturing in schizophrenic patients. The findings are discussed in light of the animal behavioral correlates of increased serotonergic activity and the stereotyped affectomotor behavior seen in some schizophrenic patients.

Key Words. Serotonin. stereotypy, schizophrenia.

Schizophrenia may represent a heterogeneous collection of separate diseases. One method of discriminating among subtypes of the disease is to use a variety of neurochemical measures and to correlate these biological parameters with specific psychotic symptoms. If an association is found, it may, along with other supporting evidence, lead to a valid method of subtyping the psychotic disorders.

Several recent experiments suggest that serotonin (5-hydroxytryptamine; 5HT) or its metabolites may be useful in distinguishing certain subtypes of schizophrenia. The work of Sedvall and his associates has suggested that the cerebrospinal fluid (CSF) concentrations of the 5HT metabolite 5-hydroxyindoleacetic acid (SHIAA) may identify a subtype of schizophrenia with a strong genetic predisposition. Schizophrenic patients with a family history of the disorder show elevated SHIAA concentrations (Sedvall and Wode-Helgodt, 1981). In another study, Sedvall et al. (1980) found that normal controls with a family history of schizophrenia also showed elevated CSF SHIAA.

Another approach for subtyping schizophrenia may be the measurement of platelet or blood 5HT concentrations. Early reports (Todrick et al., 1960) indicated that blood

Roy J. King, Jr., M.D.. Ph.D.. Kym F. Faull, Ph.D.. Stephen M. Stahl, M.D.. Ph.D., Susan Thiemann. M.S.. Jack D. Barchas. M.D.. and Philip A. Berger, M.D.. are in the Nancy PritTker Laboratory of Behavioral Neurochemistry and the Stanford-VA Mental Health Clinical Research Center, Department of Psychiatry and Behavioral Sciences. Stanford University School of Medicine, Stanford, CA. Ivan N. Mefford, Ph.D., is in the Department of Chemistry, Boston College. Chestnut Hill. MA. (Reprint requests to Dr. R.J. King. Dept. of Psychiatry and Behavioral Sciences. Stanford University School of Medicine, Stanford, CA 94305. USA.)

O/65-1781/85;$03.30 @ 1985 Elsevier Science Publishers B.V

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SHTconcentrations may be elevated in schizophrenia, and a number of recent studies have confirmed the elevation of platelet or blood 5HT levels in schizophrenic patients (Freedman et al., 1981; Stahl et al., 1983). Of relevance to the issue of subtyping, Freedman et al. (198 1) further observed that platelet 5HT concentrations were higher in chronic undifferentiated than in chronic paranoid schizophrenic patients.

Because 5HT has been implicated in dopamine-mediated behavioral stereotypy (Carter and Pycock, 1981) and has been associated with a specific stereotyped

behavioral syndrome (Jacobs and Klemfuss, 1975; Holman et al., I976), we have

carried out preliminary studies testing the relationship between behavioral indices of

stereotyped affectomotor activity and peripheral (platelet 5HT) and central (CSF

SHIAA) measures of serotonin metabolism in schizophrenia.

Methods

Patient Selection. Psychiatric subjects were male inpatients at the Palo Alto Veterans Administration Center. Diagnoses of schizoaffective disorder (SA) or schizophrenia (Sch) were made using Research Diagnostic Criteria (RDC) (Spitz.er et al., 1977). The RDC diagnosis was derived from a structured interview conducted by two trained diagnosticians who interviewed the patient on separate occasions. Based on the test-retest paradigm, the Kappa coefficient of reliability for the RDC diagnosis of schizophrenia is 0.68.

All subjects were rated by two independent interviewers during the weeks before the lumbar puncture or venipuncture with the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham. 1962). Because of the association between serotonergic activity and behavioral stereotypy, the symptom of peculiar or unusual mannerisms and posturing (M P) was selected from the BPRS to correlate with CSF SHIAA concentrations and platelet 5HT levels. For the group of subjects who received lumbar punctures. the BPRS MP-item showed strong stability (weekly test-retest reliability 0.83) and moderate interrater reliability (0.56 with the Spearman- Brown correction). To test the specificity of the serotonergic-behavioral correlations, the four factors of the BPRS (Overall et al., 1967) were correlated with CSF SHIAA and platelet 5HT concentrations. These four factors consisted of thinking disturbance (conceptual disorgani- zation, hallucinatory behavior, and unusual thought content), paranoid disturbance (suspiciousness, hostility, and uncooperativeness). withdrawal-retardation (emotional with- drawal, motor retardation, blunted affect), and anxiety-depression (anxiety, guilt feelings, depressed mood).

CSF Monoamine Metabolite Measurements. Measurements of CSF SHIAA levels were made on 2 I unmedicated patients (I 5 schizophrenic and 6 schizoaffective patients) with a mean age of 37.9 (SD I I. I) years. All patients were free of psychotropic medications for at least 2 weeks before lumbar puncture. Subjects fasted and remained in bed over night before the lumbar puncture, which was performed in the lateral decubitus position at approximately 8 a.m. CSF was collected without preservative and frozen immediately on dry ice and stored at -80” C until analysis. Measurement of SHIAA concentrations was done by gas chromatography: mass spectroscopy (GC: MS) (Faull et al.. 1979).

Platelet 5HT. Platelet 5HT measurements were made on samples from 25 RDC schizophrenic patients who were medication-free for 2 weeks before venipuncture. Their mean age was 36.0 (SD 11.0) years. Platelet 5HT levels were measured according to earlier published procedures (Stahl et al.. 1983). Thirty ml of blood was drawn between 8 and IO a.m. into EDTA-containing Vacutainer tubes using a 20-gauge needle. The platelets were immediately isolated by multiple centrifugations. Serotonin levels were assayed by high-performance liquid chromatography using electrochemical detection (Mefford and Barchas, 1980).

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Results

Because of the skewness of the CSF SHIAA data. log values were taken of the SHIAA concentrations. As shown in Fig. I, the BPRS mannerisms and posturing (M P) item correlated positively with log CSF SHIAA (r = 0.56, p < 0.01, two-tailed Pearson’s correlation coefficient). MP also correlated positively with platelet 5HT (r = 0.42, p < 0.05). The correlation of MP with log SHIAA was still significant when the sample was restricted to those individuals who satisfied RDC for schizophrenia (r = 0.54, p < 0.05, n q 15) (see Fig. 1). Neither log SHIAA nor platelet 5HT demonstrated a significant correlation with age or any of the four BPRS symptom clusters, with the exception of a negative correlation between platelet 5HT and the anxiety-depression factor (Table 1).

Discussion

This study presents preliminary evidence that both elevated CSF SHIAA concentrations and elevated platelet 5HT levels are associated with the schizophrenic symptom of mannerisms and posturing (MP). Since the correlation between CSF SHIAA and MP was done on a group that included patients with both RDC schizophrenia and RDC schizoaffective disorder, the specificity of the finding to schizophrenia could be

Fia. 1. Scattewlot of loa 5HIAA vs. BPRS-item mannerisms and posturing ior the schizbphrenic and schizoaffective subjects

2.5 - I I I I I

r = 0.56 0

p < 0.01

2.0 -

0.5 -

l SCHIZOAFFECTIVE 0 SCHIZOPHRENIC

O- I I I I I

0 1 2 3 4 5

MANNERISMS AND POSTURING

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questioned. However, the correlation still applied to the smaller sample of those satisfying RDC for schizophrenia. The subset of patients who had both CSF SHIAA and platelet 5HT levels measured was too small (n = 5) to permit conclusions about theirjoint correlations with M P. This issue requires a larger sample size for resolution.

Table 1. Correlations of CSF 5HlAA and 5HT with age, and the 4 BPRS symptom clusters

Platelet 5HT Log CSF 5HlAA Item correlations (n = 25) concentrations (n = 21)

Age -0.20 0.07

Mannerisms and posturing 0.421 0.562

Thinking disturbance -0.07 -0.04

Paranoid disturbance -0.06 -0.13

Withdrawal-retardation 0.22 0.00

Anxiety-depression -0.421 0.06

1 c 0.05 itwo-tailed Pearson’s p correlation coefficient 8. 2. < 0 01 (two-tailed Pearson’s p correlation coefficient

The lack of a significant correlation of CSF SHIAA with any of the other BPRS symptom clusters is important, and suggests that the categories of positive symptomatology (thinking disturbance), negative symptomatology (withdrawal- retardation), and paranoid schizophrenia may not reflect the possible aberration in serotonergic metabolism. The negative association of platelet 5HT levels with anxiety- depressive symptoms might reflect the presence of an atypical unipolar depressive syndrome among some of the schizophrenic patients, since unipolar depressive patients appear to have lower platelet 5HT concentrations than schizophrenic patients (Stahl et al., 1983).

Elevations in serotonin or its metabolites were found both for central (CSF SHIAA) and peripheral (platelet 5HT) measures, possibly suggesting a general alteration in serotonergic functioning. Because Sedvall and Wode-Helgodt (198 1) found that elevated CSF SHIAA was associated with a family history for schizophrenia and several researchers noted that hebephrenic schizophrenias seem to have an increased genetic loading compared to other subtypes (Kallmann, 1943; Kringlen, 1968) these results suggest that the triad of peculiar affectomotor behavior, elevated serotonin metabolism, and familial schizophrenia may cluster together. For the group of patients observed in this report, reliable family history data are lacking; however, future studies should consider the overlap between elevated SHIAA. unusual mannerisms, and family history of schizophrenia.

Since normal subjects with a family history of schizophrenia also tend to show elevated CSF SHIAA (Sedvall et al., 1980) such an increase in central serotonin metabolism might be a trait marker rather than a nonspecific correlate of psychosis. Multiple CSF SHIAA measures, as well as further repeated behavioral observations, will be necessary to assess the temporal stability of the finding.

In animal studies, increased serotonergic activity has been implicated in a specific stereotyped behavioral syndrome (Jacobs and Klemfuss, 1975) that has been attributed to a descending serotonergic facilitation of facial, oculomotor, and spinal

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motor neurons (McCall and Aghajanian, 1979). This hypothesized motor disinhibition

may explain many of the observed motor defects in schizophrenia, ranging from eye-tracking dysfunction (Holzman et al., 1974) to increased middle ear muscle activity bursts during sleep (Benson and Zarcone, 1982).

A central increase in serotonergic activity might also account for the hypofrontal metabolic activity, as measured by cerebral blood flow and glucose utilization, found in schizophrenia (Ingvar and Franzen, 1974; Buchsbaum et al., 1982). It has been reported that posttraumatic decreases in cerebral glucose utilization are mediated by serotonin (Pappius and Wolfe, 1983). These cerebral effects might, over a long period of time, impair cognitive-social and affective-learning skills.

One syndrome in which altered serotonergic functioning may be hypothesized to be involved is that described by Asperger in 1944. Asperger’s syndrome is seen in children who manifest pedantic, stereotyped speech, inappropriate affect and gestures, and poor social skills. Asperger felt that the syndrome was genetic (Wing, 1981). A recent followup study demonstrated the temporal stability of the syndrome, as well as a trend toward the development of schizophrenia in adulthood (Wolff and Chick, 1980).

Finally, this result adds weight to the view that there may be a subtype of schizophrenic patients with a serotonergic abnormality. If this hypothesis is borne out in future studies, the possibility exists that medications might be developed specifically for the subtype of patients with peculiar motor behavior.

Acknowledgments. The research reported was supported by MH-23861 and MH-30854 from the National Institute of Mental Health, a Schizophrenia Biological Research Center Grant from the Veterans Administration, and awards from the Scottish Rite Schizophrenia Program and the Robert Woods Johnson Foundation.

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