John A. Gurklis

Elevated interleukin-6 in schizophrenia

Interleukin 6 (IL-6) levels have been shown to be increased in a number of autoimmune disorders and have recently been shown to be elevated in the serum of schizophrenic patients. Given the involvement of the CNS in schizophrenia, levels of interleukin-6 in the CSF are also of interest. Thus, we examined levels of both CSF and serum IL-6 concomitantly to determine if these levels were different from control values. In addition, we examined these measures in patients both on and off antipsychotic drugs to determine if any medication or exacerbation effects may account for the difference from controls. CSF IL-6 was measured by ELISA in 61 drug-free male schizophrenic (DSM-IIIR) patients and 25 well-screened healthy male control subjects. Serum IL-6 was measured in 43 of the 61 patients, and in 16 control subjects. Serum IL-6 was significantly higher in the schizophrenic patients compared to control subjects. CSF IL-6 was also higher in the patients, but the difference was not statistically significant. Paired data showed no medication or exacerbation effects on CSF IL-6, but plasma IL-6 significantly decreased in patients that experienced an exacerbation after medication withdrawal. The results indicate that IL-6 levels may be altered in schizophrenia. The relative decrease in exacerbated patients following haloperidol withdrawal may be indicative of a compensatory response of plasma IL-6 levels to relapse.

Further Studies of Elevated Cerebrospinal Fluid Neuronal Cell Adhesion Molecule in Schizophrenia

BACKGROUND The purposes of the present study were to attempt to replicate a previous finding of increased cerebrospinal fluid (CSF) neuronal cell adhesion molecule (N-CAM) in schizophrenia, and to assess whether the increases could be related to medication, clinical state effects, or brain structural measures. METHODS CSF N-CAM was measured by the Western blot technique in 45 DSM-III-R diagnosed male schizophrenic patients both on and off haloperidol treatment and in 20 healthy male control subjects. RESULTS CSF N-CAM was significantly increased in schizophrenic patients, with no overlap in the ranges, when compared to controls. There were no significant effects of medication or exacerbation on CSF N-CAM. No associations with measures of brain structure were found. CONCLUSIONS Because N-CAM levels were not shown to be different on and off treatment or in exacerbated versus nonexacerbated patients, the higher levels seen in schizophrenic patients may be inherent to the disorder and possibly related to neurodevelopment.

Electroencephalographic sleep in clinically stable schizophrenic patients: two-weeks versus six-weeks neuroleptic-free.

EEG sleep studies in schizophrenic patients are influenced by alterations in clinical state and medication status. The current study defines longitudinal alterations in electroencephalographic (EEG) sleep for 10 healthy men who were schizophrenic patients who remained relatively clinically stable during a double-blind neuroleptic withdrawal study. Clinical assessments and EEG sleep studies were performed at baseline on haloperidol, and then at 2-week and 6-week drug-free periods. Sleep continuity and rapid eye movement (REM) sleep measures declined not only between the haloperidol baseline and 2-week drug-free conditions, but continued to decline from 2-week to 6-weeks neuroleptic-free. Alterations in EEG sleep from the 2-week to 6-week haloperidol-free assessments did not correlate with changes in clinical symptoms suggesting effects related to drug-withdrawal or subclinical state changes. These results show that despite relative clinical stability over time, the EEG sleep of schizophrenic patients continues to change following withdrawal of a neuroleptic and is dependent on the duration of the drug-free interval.

Red blood cell membrane dynamics in schizophrenia. III. Correlation of fatty acid abnormalities with clinical measures

Fatty acid composition was quantitatively analyzed in RBC ghost membranes of 20 schizophrenic patients stabilized with haloperidol (5-20 mg/day) and of the same individuals after haloperdol (HD) withdrawal. The average days on medication and drug-free period were 52 and 40 days, respectively. No significant differences were demonstrated in levels (% or nmol/ml packed RBC) of polyunsaturated fatty acids (PUFAs) between HD-treated and drug-free patients. Similarly, no significant difference was found between relapsed and nonrelapsed schizophrenic patients, although the mean levels of 20:4 (n - 6), total PUFAs or fatty acid unsaturation index (FAUI) were consistently higher in nonrelapsers than in relapsers. On the other hand, the decreases in FAUI were significantly (r = -0.46, p = 0.04) correlated to the increases in psychosis rating which is consistent with our previous reported correlation between altered membrane fluidity and the severity of symptomatology. In addition, decreases in 18:2 (n - 6) but not 20:4 (n - 6) was significantly correlated to the increases in psychosis rating. The present results lend further support that decreased levels of RBC PUFAs in schizophrenic patients lie in an initial stage of PUFAs pathway, possibly a defective uptake of 18:2 (n - 6) into RBC membranes.

Confirmatory factor analysis of the WAIS-R in patients with schizophrenia

Although factor scores are commonly used to interpret the Weschsler Adult Intelligence Scale--Revised (WAIS-R), the WAIS-R factor structure has not been investigated in patients with schizophrenia. We used confirmatory factor analysis (CFA) to examine five latent construct models in 169 males with schizophrenia. The WAIS-R standardization sample (ages 35-44; n = 250) was used as a comparison group. For both groups, all model fit indexes used to determine model adequacy supported models composed of Verbal Comprehension (VC), Perceptual Organization (PO) and Freedom from Distractibility (FFD) factors. However, the Digit Symbol subtest loaded on both the PO and FFD factors for patients with schizophrenia but only on the FFD factor for the WAIS-R standardization sample. Patients with schizophrenia performed significantly worse on the FFD and PO factors compared to the VC factor, reflecting the well-characterized attention and problem solving deficits associated with schizophrenia. Also, patients with schizophrenia performed significantly worse than the WAIS-R sample on all factors. These results provide support for the validity of the WAIS-R factors in patients with schizophrenia.

Abnormal incorporation of arachidonic acid into platelets of drug-free patients with schizophrenia

Incorporation of [3H]arachidonic acid (AA) into resting platelets was studied in samples from schizophrenic patients before and after haloperidol withdrawal, and from normal subjects. Eicosanoid biosynthesis was subsequently evaluated in prelabeled platelets by sequential events of thrombin activation. The total incorporation of [3H]AA in drug-free patients was significantly lower than in the same individuals during haloperidol treatment as well as in normal volunteers. No significant difference of [3H]AA incorporation was demonstrated between relapsed and nonrelapsed drug-free patients. The majority of 3H-labeled lipids were found in platelet phospholipids, and < 10% of incorporated lipids were found in free AA, diacylglycerol (DAG), triacylglycerol, and hydroxyeicosatetraenoic acid (HETE) of normal resting platelets. After thrombin activation, however, there was an increased 3H-labeling in 12-HETE, 12-hydroxyheptadecatrienoic acid, and thromboxane B2. The thrombin-induced formation of eicosanoids was found to be significantly higher in haloperidol-treated patients than in normal volunteers. This increased formation of eicosanoids appeared to be normalized after haloperidol withdrawal. In addition, both haloperidol-treated and drug-free patients showed increased 3H-labeling in thrombin-induced DAG compared with normal volunteers. Such an increase in the second messenger formation may be due, at least in part, to an increased turnover of membrane phosphoinositides via phospholipase C reaction. The present data support our previous findings demonstrating altered membrane dynamics in schizophrenia.

Platelet Aggregation and Dense Granule Secretion in Schizophrenia

The functional state of platelets and their possible impairment in response to various stimuli were assessed in saline-diluted citrated blood samples of normal male control subjects (n = 27), and in schizophrenic patients with (n = 34) and without (n = 23) haloperidol treatment. In response to collagen, but not to arachidonic acid (AA) and adenosine diphosphate, platelet aggregation (as measured by changes in impedance) was significantly higher in both haloperidol-treated and drug-free schizophrenic patients than in normal control subjects. Comparison of the secretion traces, however, indicated that only AA-induced adenosine triphosphate (ATP) release was significantly lower in haloperidol-treated schizophrenic patients than in normal control subjects. In response to thrombin, collagen, and AA, the mean values of ATP release from drug-free patients were significantly higher than those from the same individuals when they were receiving haloperidol. Furthermore, there was a trend toward increased ATP release (in response to thrombin or collagen) in the nonrelapsed group of drug-free schizophrenic patients as compared with the relapsed group. The collagen-induced platelet aggregation or dense granule secretion in drug-free patients was correlated significantly and negatively with psychosis ratings. Such changes in platelet function of schizophrenic patients were not correlated significantly with daily haloperidol dose, plasma haloperidol levels, age of subjects, age of onset, or duration of illness.

CSF diazepam binding inhibitor and schizophrenia: Clinical and biochemical relationships

Diazepam-binding inhibitor (DBI) is a 9-kD neuropeptide that interacts with the benzodiazepine (BZD) binding sites of the neuronal gamma-aminobutyric acid type A (GABAA) receptor and with the glial mitochondrial BZD receptor (MBR). We explored the involvement of CSF DBI-LI in schizophrenia, based on the potential role of GABA in the negative symptoms associated with schizophrenia, the relationship of its receptors with dopamine and norepinephrine release, and the proposed therapeutic efficacy of BZDs in schizophrenia. Clinical data, CSF DBI-LI and CSF monoamine measures were obtained in 65 drug-free male chronic (DSM-IIIR) schizophrenic patients, 53 of whom were also tested prior to haloperidol withdrawal. Following haloperidol withdrawal, CSF DBI-LI increased significantly. Drug-free CSF DBI-LI did not correlate with CSF monoamines. CSF DBI-LI was significantly higher in paranoid compared to chronic undifferentiated schizophrenic patients. The data suggest that DBI may have a symptom modulatory rather than an etiological role in schizophrenia.

GABA and brain abnormalities in schizophrenia.

Some recent autopsy studies indicate that gamma-aminobutyric acid (GABA) function is decreased in brain areas that involve some of the well-described structural changes observed in schizophrenia. The current study examined the relationship between CSF and plasma GABA levels and brain structural measures in schizophrenia. Sixty-two drug-free, physically healthy male patients with schizophrenia (DSM-IIIR) were evaluated for plasma and CSF GABA, as well as brain structural measures on CT scans. Plasma levels of GABA were associated with prefrontal sulcal widening and VBRs, but not global sulcal widening in the schizophrenic patients. CSF GABA measures were not associated with brain structural measures, but were associated with age and age of onset. The significant relationship between plasma GABA, but not CSF GABA, and specific brain morphology measures in schizophrenic patients suggests that if GABA transmission is impaired in schizophrenia, it is a local, but not global, phenomenon.

Utility of WAIS-R short forms in schizophrenia.

Recently, short forms of the Wechsler Adult Intelligence Scale-Revised (Wechsler, 1981) have received increasing attention because of their ability to provide estimated IQ scores with substantial time savings (in some cases 85-90% savings). These short forms may have particular utility for individuals with schizophrenia because they require less time to administer and, as a result, are less taxing for these patients who often exhibit impaired attention and deficient motivation. In this study, we examine the psychometric properties of nine popular WAIS-R short forms in a group of 143 patients diagnosed with schizophrenia. Our results indicated that Kaufmans four subtest short form was the best overall estimator of Full Scale IQ (FSIQ) when a combination of administration time and psychometric properties were considered. However, Wards seven subtest short form provided the closest estimation of FSIQ and had the lowest misclassification rate, while also providing estimates of Verbal and Performance IQs and yielding 46.5-49.7% time savings. All short forms had substantial misclassification rates, indicating that caution is warranted when using these forms to classify individuals according to standard levels of intellectual functioning (e.g., Average, Low Average, High Average). Clearly, the main consideration in selecting a short form is whether time savings or accuracy have priority.