Multiple outcome assessment in a study of the cost-effectiveness of clozapine in the treatment of refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.

OBJECTIVE: To develop new methods for combining results from multiple outcome domains and to demonstrate their application in a study of the cost-effectiveness of clozapine in treating hospitalized patients with refractory schizophrenia. DATA SOURCES/STUDY SETTING: Interview assessments, and administrative utilization and cost data, concerning 423 patients with refractory schizophrenia who had been hospitalized for 30-364 days during the year before study entry, at 15 VA medical centers. STUDY DESIGN: A 12-month double-blind trial compared clozapine (n = 205) and haloperidol (n = 218) in the treatment of refractory schizophrenia. DATA COLLECTION/EXTRACTION METHODS: Data from standard assessment instruments, gathered at baseline and at 6 weeks, and at 3, 6, 9, and 12 months, were used to develop a Composite Health Index for Schizophrenia, a measure that addresses outcome in six domains, weighted by patient or provider preferences. Cumulative improvement was estimated by computing the area under the improvement curve. This measure was then combined with cost data, reflecting consumption of societal resources to estimate incremental cost-effectiveness ratios. PRINCIPAL FINDINGS: Clozapine was significantly more effective than haloperidol on measures of symptoms (p = .02) and side effects (p < .0001), with nonsignificant trends in the positive direction on community role functioning (p = .06), family relationships (p = .23), social relationships (p = .30), and daily activities (p = .20). Clozapine was also more effective than haloperidol on the one-year cumulative Composite Health Index for Schizophrenia (p < .0001 for all weighting schemes). After converting this measure to a 0-1 Worst Health-Good Health Scale analogous to Quality Adjusted Life Years, clozapine was found to yield a small improvement of .049 Worst Health-Good Health Units as compared to an improvement of only .027 Units for haloperidol (p < .0001). Average annual costs were $2,733 lower for clozapine (95% C.I. = -$9,220 to $3,754). Although clozapine was significantly more effective than haloperidol, the summary cost-effectiveness ratio had a wide 95 percent confidence interval ranging from -$431,585 to $177,352. CONCLUSIONS: Methods demonstrate an approach to using conventional disease-specific measures to evaluate the cumulative effectiveness of novel treatments for psychotic disorders and for expressing their economic effect as cost-effectiveness ratios. Among high hospital users with refractory schizophrenia, clozapine is more cost-effective than standard treatment, although the magnitude of its effect is small and there is considerable uncertainty about the cost estimates.

Change in plasma prolactin and clinical response to haloperidol in schizophrenia and schizoaffective disorder.

There has been a long-standing interest in plasma prolactin as a potential in vivo indicator of blockade of tuberoinfundibular D2 dopamine receptors. Potential relationships between prolactin response and neuroleptic treatment have been obscured by the use of high doses which have caused prolactin to plateau. With lower doses of neuroleptic now commonly in use, prolactin may be more valuable as a correlate of clinical response. In this study, 23 acutely exacerbated schizophrenic and schizoaffective patients were washed out for at least 6 days and were then treated with haloperidol to achieve fixed low to moderate plasma levels under double-blind conditions. Clinical response, plasma prolactin, and haloperidol plasma levels were measured weekly for 3 weeks. Clinical symptoms at endpoint were related to both prolactin change and final prolactin level during haloperidol treatment. Specifically, fewer symptoms at endpoint were associated with a greater increase in prolactin over time and a higher prolactin level at endpoint. Thus, prolactin increase caused by low to moderate doses of haloperidol may be a correlate of endpoint symptomatology. As lower doses of typical neuroleptics are now in use, prolactin response as a predictor of clinical response may have more clinical utility. Further study of prolactin and clinical response to typical neuroleptics should focus on low neuroleptic doses.

Subtle neurological deficits and psychopathological findings in substance-abusing homeless and non-homeless veterans.

This study evaluated the hypothesis that homeless individuals would display higher levels of neurological deficits than non-homeless individuals, particularly in frontal lobe or executive functions. Eighteen acutely homeless, 15 chronically homeless, and 20 non-homeless individuals admitted to an inpatient psychiatric service received a battery of neurological and psychosocial measures. In comparison to non-homeless subjects with comparable levels of psychopathology, homeless individuals showed higher levels of hostility, prior criminal activity, and family history of psychiatric illness, but lower levels of depression. A positive relationship between hostility and neurological soft signs was observed among chronically homeless subjects. These results suggest that a substantial subset of nonpsychotic homeless veterans suffers from "occult" neurological deficits.

HIV-1 proviral DNA load across neuroanatomic regions of individuals with evidence for HIV-1-associated dementia.

A definitive relation between HIV-1 load and the clinical diagnosis of HIV-1-associated dementia (HAD) has not yet been established. Knowledge of the neuroanatomic distribution of HIV-1 load in the brain of individuals with HAD and HIV-1 encephalitis may facilitate elucidation of this relation. Nine individuals with AIDS were analyzed postmortem by three independent methods with each assessment performed blinded to the others: 1) a neuropsychiatric review of clinical records for evidence of possible HAD, 2) HIV-1 DNA load determination by quantitative polymerase chain reaction (PCR) across several neuroanatomic regions, and 3) a pathologic examination for diagnosis of HIV-1 encephalitis by immunohistochemical techniques. Of eight AIDS cases with clinical records sufficient for neuropsychiatric review, seven were shown to have evidence for HAD. HIV-1 DNA was detected and quantified in specimens from all of the medial temporal lobe regions analyzed but was not detectable in the frontal lobe at the same level of sensitivity in two of these cases (<1 per 1000 cellular genomes). HIV-1 DNA load in the medial temporal lobe region was significantly larger than that in the frontal lobe. Only four of seven cases with evidence for HAD were also diagnosed with HIV-1 encephalitis.

Subtle neuropsychological impairment and minor cognitive-motor disorder in HIV-1 infection. Neuroradiological, neurophysiological, neuroimmunological, and virological correlates.

HIV-1 infection of brain may be associated with multiple treatment targets, only the most severe of which is represented by HAD. Focusing on earlier treatment targets such as MCMD and cognitive-motor impairment in the absence of any clinical disorder (as well as neuroprotection) may prove to be of greater clinical utility in the treatment and prevention of such impairment than a focus on later-stage cognitive-motor disease, when neuronal cell death is already extensive. This may be especially important now that improvements using the protease inhibitors in triple-drug combination regimens have reduced plasma viral load to unmeasurable levels, while these drugs do not penetrate the CSF well. Currently, peripheral blood markers do not appear to be highly sensitive for central nervous system impairment, and specific CSF laboratory markers have some limited value at present-while requiring a lumbar puncture to obtain. Hence, a role for noninvasive techniques using neuroimaging exists in the clinical management of HIV-1-infected patients. To date, structural imaging techniques have proven limited in value for HIV-1-specific impairment. Several functional techniques (PET, SPECT, and MR spectroscopy) have now provided promising results for the purposes of identifying clinically significant dysfunction, relating such dysfunction to clinical neuropsychiatric symptom status, and for treatment response monitoring. Further studies are needed to examine the extent to which such imaging modalities not only parallel clinically relevant aspects of HIV-1 disease progression, but also match specific types of neuropsychologic performance deficits with potential significance for neuroanatomical localization. It is particularly important to include neurophysiological, neuroimmunological, and virological measures in studies that examine clinical neuropsychiatric status with neuroimaging techniques. In addition, the inclusion of neuropathology data, where possible, is important because demonstration of HIV-1 encephalitis cannot be equated with clinical disorder and because specific HIV-1-associated pathological changes have not yet been proven to be assessed well with neuroimaging techniques (e.g., the extent of microglial cell and macrophage activation). Also, treatment response studies are needed in conjunction with primary antiretroviral therapy regimens specifically aimed at central nervous system penetration (e.g., GW1592, GW141, and nevirapine). The results of such work will provide the data required to determine whether these promising functional neuroimaging techniques will aid in meeting the expected, imminent increase in clinical burden of this frequent complication of HIV-1 infection.

Assessment of risk behaviors for HIV infection among psychiatric inpatients.

A 13-item questionnaire was constructed to assess risk factors for HIV infection among 476 patients newly admitted over a one-year period to a state psychiatric hospital in New York City. Because psychopathology can affect patients' self-reports, the validity of the instrument was established by HIV antibody tests in a subset of 352 patients. Results of the questionnaire indicated that the 352 patients were almost equally divided between the high-risk and low-risk categories. HIV seroprevalence was .6 percent among the low-risk patients, but 14.4 percent among the high-risk patients. The findings suggest that a screening program to detect HIV-positive patients should be undertaken in this population, that it should be focused on the high-risk subgroup, and that the questionnaire can be used to define that subgroup. However, results of the study may not generalize to other geographic areas.

HIV seroprevalence and risk behaviors in psychiatric inpatients.

The seroprevalence of the human immunodeficiency virus (HIV) in 515 patients consecutively admitted to a state psychiatric hospital in New York City was 8.9%. There were 365 patients whose results were individually traceable; the remaining 150 patients were tested anonymously. Risk factors including parenteral drug abuse, male homosexual behaviors, and other sexual behaviors were studied in the traceable patients. Logistic regressions indicated that parenteral drug abuse was the main risk factor in both males and females. In females, two additional factors were significant: sex with parenteral drug users or with partners who have the acquired immunodeficiency syndrome (AIDS), and sex with bisexual men. Females with bipolar disorders were particularly likely to report sex with parenteral drug users or with partners who have AIDS.

The effects of electroconvulsive shock on dopamine-1 and dopamine-2 receptor ligand binding activity in MPTP-treated mice.

To explore the possible therapeutic use of electric convulsive treatment in Parkinson's disease (PD), the authors examined the biochemical effects of electroconvulsive shock (ECS) on dopaminergic systems in a rodent model of PD, induced with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased dopamine turnover, as indicated by an increase in the ratio of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to dopamine. [3H]Spiperone binding to the D2 site increased after lesioning of striatal dopamine terminals. With ECS alone, no changes were found in monoamine levels, brain monoamine oxidase activity, or the D2-labeled sites measured 24 hours after the last treatment. [3H]SCH-23390 binding to the D1 site increased after ECS. In MPTP-treated mice, ECS also increased [3H]SCH-23390 binding to the D1 site, whereas [3H]spiperone binding to the D2 site was unchanged compared to control or to only ECS-treated animals, and decreased compared to the MPTP-treated group that did not receive ECS. ECS appears to selectively modify both the D1 and D2 sites when given after MPTP, increasing the binding of a D1 radioligand and decreasing the binding of a D2 radioligand.

Akathisia and violence.

Akathisia is a common side effect of neuroleptic drugs that may present with behavioral disturbances. There have been preliminary reports on the association between violence and akathisia. We report the first observational study of this relationship. Patients studied were from a special unit for violent patients. A closed-circuit television camera was installed in each of the corners in its dayroom. Incidents of assault plus the 5 minutes preceding each assault were recorded on videotape. Participants and bystanders were rated for the motor component of akathisia. For each of nine incidents, we compared the akathisia scores for participants and for bystanders. Both victims and assailants were akathisic before about half of all incidents; bystanders rarely were. The classification of the movements we rated and the implications for further studies are discussed.

ECT and Parkinson's disease revisited: a "naturalistic" study.

In an open study, seven patients with Parkinson's disease received ECT for major depression. Both the motor dysfunction and the mood impairment of these patients improved following an average of seven ECT sessions. Significant improvement in motor function occurred after only two treatments. All aspects of Parkinson's disease improved significantly after ECT. Older patients showed greater improvement in motor function. The authors conclude that the therapeutic utility of ECT in depressed and nondepressed patients with Parkinson's disease should be further evaluated.

Neuroleptic augmentation with alprazolam: clinical effects and pharmacokinetic correlates.

Alprazolam added to stable doses of neuroleptics in nine schizophrenic patients was associated with a 20%-30% mean reduction in positive and negative symptoms, although clinical response was variable and in some patients particularly brisk. The authors examined the possibilities of a pharmacokinetic effect of alprazolam on neuroleptic plasma levels and of a clinical effect of alprazolam. The modest increase in mean neuroleptic plasma levels did not correlate with clinical change, but those patients with the highest alprazolam plasma levels tended to show more robust clinical responses.