Jeffrey L. Peters

Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial

BACKGROUND Enhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide. METHODS This study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events. RESULTS Ten baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinsons, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present. CONCLUSIONS This is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.

CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal

Thirty-two male DSM-III diagnosed schizophrenic patients received a lumbar puncture (LP) during chronic haloperidol treatment that was followed by replacement with placebo for up to 6 weeks. Fourteen patients relapsed on placebo within 6 weeks. Patients received a second LP at the time of relapse or at the end of 6 weeks if they had not relapsed. Bunney-Hamburg Global Psychosis Ratings of the day and the hours of sleep of the night before the LP were obtained, as were the Brief Psychiatric Ratings Scale (BPRS) ratings during the week of the LPs. CSF norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5 HIAA) concentrations were measured with high-pressure liquid chromatography (HPLC). Patients who relapsed had significantly higher CSF NE levels on and off haloperidol than patients who did not relapse. CSF MHPG was higher in the relapsers in the drug-free condition only, but CSF HVA and 5-HIAA were not significantly different in either condition. In the drug-free relapsed patients, CSF NE correlated significantly with the psychosis ratings of the day and hours of sleep the night prior to the LP. Our data indicate that elevated CSF NE levels during neuroleptic treatment may predict behavioral decompensation after discontinuing the medication.

The InterSePT scale for suicidal thinking reliability and validity

BACKGROUND The InterSePT Scale for Suicidal Thinking (ISST) is a 12-item instrument for the assessment of current suicidal ideation in patients with schizophrenia and schizoaffective disorders. We report the psychometric characteristics of this new scale based on two studies. METHOD In Study 1, 22 inpatients with schizophrenia and schizoaffective disorders, who had recently attempted suicide or engaged in suicidal ideation, were rated by three trained independent raters to examine interrater reliability. In Study 2, a total of 980 patients with schizophrenia or schizoaffective disorder with a history of suicidal ideation in the past 36 months were enrolled in a 2-year industry-sponsored suicide prevention study. At baseline, these patients were administered the ISST and the Clinical Global Impression Scale for Severity of Suicidality (CGI-SS) by the Principal Investigator (PI) and by a blinded rater (BR), who also administered the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDS), and the Scale of Functioning (SOF). Indices of internal reliability, construct and discriminant validity were examined. RESULTS The intraclass correlation coefficient (ICC) for the total ISST score for the 22 subjects in Study 1 was 0.90 and mean weighted item kappa coefficients ranged from 0.66 to 0.92. In Study 2, internal reliability (Cronbach alpha) was high, ranging from 0.86 to 0.89 for the individual items, and the overall Cronbach alpha coefficient for all items was 0.88. The ISST (PI) total score was highly correlated with the CGI-SS by the blind rater (r = 0.61, p < 0.0001). ISST total scores significantly differentiated the different levels of CGI-SS (F = 519.2; p < 0.0001). Results of construct and discriminant validity analyses are also presented. CONCLUSION The ISST is a reliable and valid instrument for the assessment of current suicidal thinking in patients with schizophrenia and schizoaffective disorder by both clinicians and researchers.

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.

Neuropeptide Y-like immunoreactivity in schizophrenia: Relationships with clinical measures

Abstract Neuropeptide Y-like immunoreactivity (NPY-li) was measured in CSF of 35 drug-free chronic schizophrenic patients. Compared to a group of drug-free controls, CSF NPY-li was significantly higher in these patients. CSF NPY-li decreased with age and longer duration of illness. Measures of structural brain abnormalities on CT scans were significantly associated with lower CSF NPY-li. Relationships between NPY-li and schizophrenic behavior, i.e. positive symptoms, were observed only in the clinically stable (nonrelapsed) drug-free patients. In 31 of the patients CSF was obtained before and after withdrawal from haloperidol maintenance treatment. This withdrawal from haloperidol treatment was associated with a significant increase in CSF NPY-li. There was no significant difference in CSF NPY-li between patients who did and those who did not relapse within 6 weeks following haloperidol withdrawal. The present findings suggest a relationship of CSF NPY-li with various aspects of 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.

Neuropeptide Y-like immunoreactivity in schizophrenia

Neuropeptide Y-like immunoreactivity (NPY-li) was measured in CSF of 35 drug-free chronic schizophrenic patients. Compared to a group of drug-free controls, CSF NPY-li was significantly higher in these patients. CSF NPY-li decreased with age and longer duration of illness. Measures of structural brain abnormalities on CT scans were significantly associated with lower CSF NPY-li. Relationships between NPY-li and schizophrenic behavior, i.e. positive symptoms, were observed only in the clinically stable (nonrelapsed) drug-free patients. In 31 of the patients CSF was obtained before and after withdrawal from haloperidol maintenance treatment. This withdrawal from haloperidol treatment was associated with a significant increase in CSF NPY-li. There was no significant difference in CSF NPY-li between patients who did and those who did not relapse within 6 weeks following haloperidol withdrawal. The present findings suggest a relationship of CSF NPY-li with various aspects of schizophrenia.

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.