D.P. van Kammen

A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia

Sertindole is a novel antipsychotic agent with high selectivity for the mesolimbic dopaminergic pathway and nanomolar affinities for dopamine D2, serotonin 5-HT2, and norepinephrine NEα1 receptors. This 40-day randomized, placebo-controlled, dose-ranging multicenter study was designed to assess the effect of sertindole on previously neuroleptic-responsive, hospitalized schizophrenic patients (n=205). Sertindole doses began at 4 mg/day and were increased to 8, 12, or 20 mg/day, depending on randomization. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Extrapyramidal symptoms (EPS) were assessed by movement rating scales, EPS-related adverse events, and use of anti-EPS medications. A dose-related improvement was observed for PANSS, BPRS, and CGI, with statistically significant mean differences (P<0.05) between placebo and 20-mg/day sertindole (decreases from baseline of −5.8 versus −16.9 for PANSS, −4.8 versus −10.4 for BPRS, respectively). The differences in CGI final improvement score between placebo and 20-mg/day sertindole were 3.8 versus 2.9, respectively. EPS-related events were comparable in the placebo and sertindole groups. In conclusion, sertindole 20 mg/day was effective, well tolerated, and not associated with significant motor system abnormalities.

Amphetamine and negative symptoms of schizophrenia.

The purpose of this study was to assess further the effect of amphetamine on negative symptoms of schizophrenia. Thirty-seven schizophrenic males meeting DSM-III criteria were rated with the Brief Psychiatric Rating Scale, the Abrams and Taylor Scale, and the Abnormal Involuntary Movements Scale before and after double-blind administration of either amphetamine (n=26) or placebo (n=11). Our results indicated that amphetamine administration generally did not improve negative symptoms, even when accounting for changes in positive symptoms. However, greater baseline negative symptoms were associated with a modest diminution after amphetamine treatment. Therefore, amphetamine may modestly improve negative symptoms in those schizophrenics in whom this symptomatology is more severe.

Increased turnover of platelet phosphatidylinositol in schizophrenia

The potential role of receptor-stimulated phosphatidylinositol (PI) hydrolysis in a signal transduction mechanism has been increasingly recognized. Earlier studies have suggested a defect in alpha-adrenergic receptor function in the platelets of schizophrenic patients. Little is known, however, about the mechanisms for PI synthesis, breakdown, and regulation in schizophrenia. The present study was undertaken to investigate the metabolic turnover of inositol phospholipids and inositol phosphates by incorporation of [3H]myoinositol or [32P]orthophosphate into resting and activated platelets of normal controls and schizophrenic patients with and without neuroleptic treatment. After 5 h incubation at 37 degrees C, the majority of [3H]myoinositol was incorporated into platelet PI. Following thrombin-induced platelet activation, there was rapid formation of 3H-labeled inositol phosphates (IPs) with inositol monophosphate (IP1) being the most abundant product. The thrombin-induced formation of platelet IPs was found significantly higher in both haloperidol-stabilized and drug-free schizophrenics than in normal control subjects. When platelets were prelabeled with [32P]orthophosphates, thrombin-induced formation of phosphatidic acid (PA) was also significantly higher in haloperidol-stabilized schizophrenics than in normal controls. It is thought that thrombin-induced platelet activation is mediated through hydrolysis of polyphosphoinositides (poly-PI). The present data thus may reflect an increased signal transduction in schizophrenia, which is mediated through neuroleptic-regulated inositol phospholipid hydrolysis.

Effect of Pimozide on Positive and Negative Symptoms in Schizophrenic Patients: Are Negative Symptoms State Dependent?

In a double-blind, placebo-controlled trial of treatment with the neuroleptic pimozide, negative symptoms improved in schizophrenic patients who showed an antipsychotic response. Furthermore, there was a significant positive correlation between changes in positive and negative symptoms for the group as a whole, including both pimozide responders and nonresponders. In our patient sample, neuroleptic treatment did not exert a differential effect on the positive and negative symptoms of schizophrenia. It is conceivable that negative symptoms are state dependent and may become neuroleptic nonresponsive over time just as positive symptoms do in some chronic patients.

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.

Relationship between immune and behavioral measures in schizophrenia

Schizophrenia, which is a chronic but episodic disorder of unknown etiology, shares immunological features with organ specific autoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis and insulin-dependent diabetes mellitus. However, recent studies have raised the issue as to whether the reported immune disturbances in schizophrenia may be the result of a stress-induced dysregulation of CNS cytokine production, rather than a permanent immunological disorder, i.e., autoimmunity.

Concurrent Posttraumatic Stress Disorder in Psychogeriatric Patients

Despite the fact that there are over 11 million World War II veterans in the United States, recent research on combat-related trauma has focused primarily on symptoms of posttraumatic stress disorder (PTSD) in Vietnam veterans. Several studies have found that the majority of Vietnam veterans who meet the Diagnostic and Statistical Manual of Mental Disorders, ed 3 (DSM-III) criteria for PTSD have an additional major psychiatric diagnosis. This study explores the presence of the diagnosis of PTSD in an inpatient sample of 42 World War II veterans with an admission diagnosis other than PTSD. Following a structured diagnostic interview, a second examiner, blind to the patients combat history, interviewed the subjects to obtain information regarding the past and current impact of the most stressful experience of their lives. Subjects were instructed not to reveal the nature of the stressor until completion of the study. Fifty-four percent of the combat-exposed veterans (14 of 26) spontaneously listed combat as the most significant stressor in their life. Furthermore, 54% of the combat-exposed veterans met DSM-III criteria for past PTSD and 27% met criteria for current PTSD in addition to another axis I diagnosis. These preliminary findings underscore the need for clinicians to assess the long-term effects of combat trauma in psychogeriatric patients. (J Geriatr Psychiatry Neurol 1989;2:65-69).

Dopamine turnover in schizophrenia before and after haloperidol withdrawal : CSF, plasma, and urine studies

The dopamine hypotheses of schizophrenia and antipsychotic drug action suggest that the dopamine metabolite homovanillic acid (HVA) should change with drug withdrawal and change in clinical state. We designed a study of cerebrospinal fluid (CSF), plasma, and urinary HVA on and off haloperidol to examine the effects of drug withdrawal. CSF and plasma HVA samples were obtained in 72 healthy schizophrenic (DSM-III-R) males (age: 36 ± 7.4 years), before and after haloperidol withdrawal, which was after 6 weeks on placebo or sooner if they met specific criteria for relapse. We collected three 24-hour urine samples in 34 of these patients. In addition, CSF HVA was obtained in 24 well-screened age-matched male normal controls. HVA was measured with high-pressure liquid chromatography (HPLC). CSF HVA decreased significantly after drug withdrawal, particularly in those who met relapse criteria; drug-free CSF HVA levels were not significantly different from those of normals. Plasma HVA increased significantly after haloperidol withdrawal in relapsing patients, but not in clinically stable patients. Urinary HVA excretion decreased after withdrawal with decreased HVA clearance. We conclude that haloperidol withdrawal had a strong effect on dopamine turnover, whereas the patient’s clinical state had only a weak central effect, without affecting total body production of HVA. Conceivably, dopamine involvement in schizophrenia reflects the failure of the homeostatic mechanisms that allow for integration of different functional brain components as needed.

Incorporation of 3H-arachidonic acid into platelet phospholipids of patients with schizophrenia

Incorporation of 3H-arachidonic acid (AA) into resting platelets was carried out in normal control subjects as well as in schizophrenic patients before and after haloperidol (HD) withdrawal. Metabolic turnover of membrane phospholipids was subsequently evaluated in prelabelled platelets at various time intervals after thrombin activation. 3H-AA was mainly incorporated into phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidylserine (PS) of resting platelets. Very minute amounts of 3H-labelling were found in phosphatidic acid (PA). Following thrombin activation, however, substantial amounts of 3H-labelling were found in PA. Such an increase in thrombin-induced PA formation was not reduced in schizophrenic patients both receiving and not receiving HD treatment. Increased labelling has been found in platelet diacylglycerol (DAG) after thrombin activation. It is therefore not likely that a decreased DAG kinase activity contributes to the accumulation of DAG. However, the thrombin-induced PA production was temporally associated with a decreased 3H-labelling in PI, but not in PC, PS and PE. The present data taken together with our previous findings suggest that the increased production of second messengers (DAG, PA and inositol phosphates) in schizophrenia may result from an increased phospholipase C (PLC) activity in schizophrenia, because thrombin-induced platelet activation is mediated by polyphosphoinositide hydrolysis through the G-protein activation.

SLEEP DISTURBANCE AND COMPUTERIZED AXIAL TOMOGRAPHIC SCAN FINDINGS IN FORMER PRISONERS OF WAR

Ten drug-free former American prisoners of war (POWs), captured on Bataan and Corregidor by the Japanese in World War II, participated in a study of the relationship between structural brain abnormalities on computerized axial tomographic (CT) scans and sleep electroencephalographic (EEG) findings. All subjects had complaints of sleep disturbances and other posttraumatic stress disorder (PTSD)-related symptoms. Six of 10 subjects had no stage 4 sleep, and had significantly higher mean ventricular brain ratios (VBRs). Structural brain measures such as VBRs and global sulcal widening (GSW) correlated significantly with the number of awakenings; GSW also correlated significantly with time spent asleep. However, because data from normal age-matched controls are not available, it remains to be seen whether our findings are PTSD specific.