Optimizing Scripted Dialogues for an e-Health Intervention for Suicidal Veterans with Major Depression.

Suicide is a health concern among Veterans with depression. We had previously reported on scripted dialogues adapted for an e-health system that engages at-risk veterans with schizophrenia. Here we report a further adaptation of the dialogues for Veterans with depression. Usability was assessed with nine outpatients with a history of major depression and suicidality. We noted that participants preferred greater specificity in the wording of questions. Topics that elicited an emotional response dealt with questions on suicide, social isolation and family relationships. Based on feedback, dialogues were revised for patients with depression. We also compared responses between those with depression and those with schizophrenia who were previously tested. The two groups shared similar themes. Also, individuals with a history of major depression had less trouble with vocabulary comprehension but were less willing to answer more questions daily.

Development of telehealth dialogues for monitoring suicidal patients with schizophrenia: consumer feedback.

Suicide is a health concern among individuals with schizophrenia. A telehealth system for monitoring suicidal patients with schizophrenia was developed using the Health Buddy©. The existing dialogues were improved using an expert panel; the new dialogues were tested in 10 consumers with schizophrenia and a history of suicidal behavior. Using qualitative editing, several themes emerged: (1) Certain topics elicited strong emotional responses; (2) There were concerns with confidentiality; (3) Some content was too vague and (4) There were problems with vocabulary and wording. The process yielded information for improving the intervention and demonstrated that the approach is feasible in this population.

Development of a recovery manual for suicidal patients with schizophrenia: consumer feedback.

A recovery-oriented manual was developed for patients with schizophrenia and suicidality. It included psychoeducational information, vignettes, "workbook" sections and was reviewed by experts in suicidology, recovery, patient education, manual development and psychosocial interventions. The revised version was tested in 22 consumers with schizophrenia and a history of suicidality. Consumer-based focus groups yielded five key themes which were used to further refine the manual. A satisfaction survey indicated that 85% stated the manual was 'somewhat easy', 'easy' or 'very easy to read.' All stated it was 'very useful', 'useful' or 'somewhat useful. Thus, the manual appears to be acceptable and useful.

Behavioral vs biochemical prediction of clinical stability following haloperidol withdrawal in schizophrenia.

BACKGROUND: We sought to identify haloperidol-treated subjects who relapsed within 6 weeks of placebo replacement and those who did not, using multivariate analysis. METHODS: In the week prior to discontinuation of haloperidol treatment, global behavioral ratings and a lumbar puncture for cerebrospinal fluid monoamine metabolities were obtained in 88 patients with chronic schizophrenia. Logistic regression analyses were used to evaluate two competing models of relapse prediction. The models were then compared using receiver operating characteristic analysis and a final combined model was derived. RESULTS: The behavioral model was less variable in its prediction than the cerebrospinal fluid monoamine model. The final model consisted of increased psychosis, decreased anxiety, higher cerebrospinal fluid homovanillic acid levels, and lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels. CONCLUSIONS: Several monoamine systems are involved in psychotic relapse within 6 weeks of haloperidol withdrawal. Future studies of relapse prediction should include both clinical and biological measures to fully assess relapse risk.

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.

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.

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.

CSF dopamine beta-hydroxylase in schizophrenia: associations with premorbid functioning and brain computerized tomography scan measures.

OBJECTIVE: The authors attempted to replicate previous findings of relationships of CSF dopamine beta-hydroxylase with premorbid functioning and computerized tomography (CT) scan measures in a new cohort of schizophrenic patients. METHOD: Data on CSF dopamine beta-hydroxylase-like immunoreactivity and premorbid functioning, as well as CT scans, were obtained in 60 drug-free, male schizophrenic patients and two groups of normal comparison subjects. RESULTS: CSF dopamine beta-hydroxylase did not differ between the comparison subjects and schizophrenic patients. Lower CSF dopamine beta-hydroxylase was associated with better premorbid social functioning and with less prefrontal sulcal widening. Better premorbid school functioning and more years of education, however, were associated with higher CSF dopamine beta-hydroxylase. CONCLUSIONS: The association between low CSF dopamine beta-hydroxylase and premorbid functioning was confirmed for social functioning, while the opposite was observed for scholastic performance, suggesting that these are different dimensions. Dopamine beta-hydroxylase modulates the prognosis and potentially the course of schizophrenia without necessarily causing the disorder.

Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status.

OBJECTIVE: Interleukin-2, traditionally viewed as solely involved in immunological events, has recently been shown to exert profound effects on the development and regulation of the central nervous system. This study examined the relationships between interleukin-2 in the CSF and plasma of schizophrenic patients and clinical measures, including relapse and medication status. Plasma and CSF interleukin-1 alpha levels were also measured to ascertain the specificity of changes in cytokine levels. METHODS: Seventy-nine physically healthy male patients with schizophrenia (DSM-III-R) received diagnostic evaluation and behavioral ratings. Haloperidol treatment was withdrawn for up to 6 weeks and patients were evaluated for symptom recurrence. CSF and plasma were obtained by established procedures before haloperidol withdrawal (N = 79) and after (N = 64). RESULTS: CSF levels of interleukin-1 alpha decreased significantly after haloperidol withdrawal but showed no relation to clinical status. In contrast, levels of CSF interleukin-2 were associated with recurrence of psychotic symptoms. Relapse-prone patients, examined both while medicated and after drug withdrawal, had significantly higher levels of CSF interleukin-2 than patients who did not relapse. CSF interleukin-2 level during haloperidol treatment was a significant predictor of worsening in psychosis. CONCLUSIONS: Levels of interleukin-2, a molecule that plays both neurodevelopmental and neuroregulatory roles, may have a role in relapse in schizophrenia. Levels of CSF interleukin-2 appear to be affected by relapse mechanisms, while peripheral blood levels are not. These changes are specific to interleukin-2, since levels of interleukin-1 alpha were affected by medication withdrawal but not by change in clinical state.

Noradrenergic activity and prediction of psychotic relapse following haloperidol withdrawal in schizophrenia.

OBJECTIVE: The purpose of this study was to develop a model based on the authors' previous studies to identify which neuroleptic-treated schizophrenic patients are at risk of early relapse following drug withdrawal. METHOD: Clinical and CSF monoamine-related variables obtained for 50 male haloperidol-treated, schizophrenic patients were used in a logistic regression model to identify those who relapsed (N = 24) within 6 weeks after placebo substitution and those who did not (N = 26). RESULTS: The oral dose of haloperidol, weight, CSF norepinephrine, 3-methoxy-4-hydroxyphenylglycol and chromogranin A-like immunoreactivity, and the anxiety and paranoia subscale ratings of the Brief Psychiatric Rating Scale produced a model that correctly predicted 18 relapsers and 21 nonrelapsers. By including the interactions of paranoia subscale by CSF norepinephrine and anxiety by CSF norepinephrine, the model correctly identified 20 relapsers and 23 nonrelapsers with a sensitivity and specificity of 83% and 88%, respectively. CONCLUSIONS: Increased noradrenergic activity during chronic dopamine blockade may be an episode marker and may predict relapse within 6 weeks following haloperidol withdrawal in schizophrenia. Effective relapse prediction models have important practical implications for the treatment of schizophrenia and the understanding of the psychotic relapse process.

Predicting duration of clinical stability following haloperidol withdrawal in schizophrenic patients.

Although chronic maintenance antipsychotic drug treatment is the most effective way of preventing relapse in schizophrenic patients, it is not very successful. A considerable number of patients relapse on medication, and many others do not take their medications as prescribed after leaving the hospital. Unfortunately, clinicians are not able to identify how long patients will remain clinically stable after drug discontinuation. To develop a model consisting of behavioral and monoaminergic variables to identify the risk of symptom exacerbation, we obtained in the week prior to haloperidol discontinuation global behavioral ratings and cerebrospinal fluid (CSF) values for monoamine metabolites in a sample of 109 DSM-III-R schizophrenic patients. Patients were followed until specific criteria for increases in psychosis were met for up to 1 year and then returned to antipsychotic drug treatment. Cox regression analysis identified predictors of the survival function, or the probability of relapse at a given time drug free. The best model indicated that increased psychosis, decreased anxiety, an increased CSF homovanillic acid (HVA) to 5-hydroxyindoleacetic acid (5-HIAA) ratio, and decreased CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) prior to haloperidol withdrawal were associated with early increases in psychosis. Our study indicates that it is possible to identify those patients who are more likely to remain clinically stable without medication. When the model is validated, it will help clinicians assess the relapse risk over time, lower doses in treatment-resistant patients, and possibly determine the optimal time for aftercare visits following hospital discharge.

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.

Chronic haloperidol treatment does not affect structure of attention in schizophrenia.

Results of a number of investigations indicate attention is a multifactorial construct composed of four distinct cognitive factors including focus-execute, sustain, encode and shift abilities. While investigators have partially or fully replicated this attentional structure in a number of clinical and nonclinical populations, no study has adequately examined the structure of attention in patients with schizophrenia who are not treated with antipsychotics. In this study, we examined the four-factor theory of attention in patients with schizophrenia while they were stabilized on haloperidol (with no adjunctive antiparkinsonian/anticholinergic medications) and again when they were approximately 3 weeks drug free. Standard neuropsychological measures were used to assess attentional functions. Principal components analyses (varimax rotation) of neuropsychological test scores in medicated and drug-free conditions indicated that four factors accounted for 84.2 and 91.8 of total variance in medicated and unmedicated conditions, respectively. Based on these results, it appears that: (1) haloperidol does not appreciably affect structure of the attentional system in patients with schizophrenia; (2) unmedicated patients with schizophrenia exhibit a similar structure of attention as both medicated patients and controls, suggesting that attentional structure is 'normal' in schizophrenia; and (3) the four-factor attention theory is a useful and valid paradigm for evaluating attention in patients with schizophrenia, regardless of medication status.

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 Kaufman's 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, Ward's 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.

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.

Confirmation of a two-factor model of premorbid adjustment in males with schizophrenia.

Because schizophrenia is considered to be a neurodevelopmental disorder, premorbid adjustment is of particular interest. Premorbid adjustment is probably not a unitary construct but rather is expressed across a number of developmental domains. The current investigation examined the validity of a two-factor model that differentiated premorbid adjustment across social and academic domains and evaluated relationships between these premorbid adjustment domains and other variables of interest. Participants with schizophrenia (n = 141) underwent evaluation of premorbid adjustment (using the Premorbid Adjustment Scale), intellectual functioning, and psychiatric symptoms. Using confirmatory factor analysis, a two-factor model of premorbid adjustment was identified that included an academic domain and a social domain. The social domain was associated with symptom variables, while the academic domain was associated with measures of intelligence. Results provide evidence for at least two domains of premorbid adjustment in schizophrenia. Distinguishing between these two premorbid domains may be theoretically important because of potential differences in incidence rates and deterioration courses; some individuals with schizophrenia may exhibit adequate academic adjustment but poor social adjustment, while others may exhibit the opposite pattern.

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 chromogranin A-like immunoreactivity in schizophrenia: relationships with REM latency and slow wave sleep.

Chromogranin A (CgA) is a calcium binding protein and a precursor of modulatory peptides in the brain. We measured CgA-like immunoreactivity (CgA-LI) in cerebrospinal fluid (CSF) in 15 male schizophrenic patients (diagnosed by DSM-III-R criteria) after 3 nights of polysomnography. Patients had been drug free for at least 33 days. Our earlier report that CSF CgA-LI in schizophrenic patients correlated significantly with negative symptoms and ventricle-brain ratios, which have been related to slow wave sleep, raised the possibility that CgA-LI might relate to slow wave sleep. CSF CgA-LI was significantly correlated with stage 4 sleep and rapid eye movement latency. Whether these positive relationships between CSF CgA-LI and electroencephalographic sleep measures are specific for schizophrenia awaits further study.

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.