Differential treatment effects of amisulpride versus flupentixol on latent dimensions of depressive and negative symptoms in acute schizophrenia

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Methods: All patients who participated in clinical trials of new antipsychotics on a research ward in a long term hospital had their study books reviewed for the length of placebo wash out, arm of study, completion of study, chronicity and other basic demographics, and the total length of hospital admission. A control group matched on time of admission and time to start of study was formed. Correlation and regression analyses were conducted. Results: 111 patients participated in the clinical trials (age 36.7+8.7) with 15.2_+9.1 years duration of illness: 94 were male, 50 black, 36 hispanic and 24 white. The clinical trial patients had 704_+658 days of hospitalization. Patients on either placebo or standard drug arm were associated with discontinuation before the end of the double-blind (p=0.01). Longer placebo wash out predicted premature discontinuation of the double-blind phase ( p = 0.000) and longer hospitalization (p=0.05). Compared with a control group matched only on date of admission participants stayed longer in hospital. Analyses are continuing with the closer match described above. Conclusions: Participation in clinical trials may affect length of stay and this may vary with length of washout and arm of study.

NEGATIVE

SYMPTOMS

IMPROVED

BY CSF

FILTRATION IN A CASE OF RECENT ONSET SCHIZOPHRENIA K. Bechter, S. H e r z o g , V. Schreiner, K . - H . Wollinsky, R. Schtittler

ZUCLOPENTHIXOL PSYCHIATRIC FOR

EVIDENCE

ACETATE

EMERGENCIES: FROM

IN LOOKING

CLINICAL

TRIALS

E. C o u t i n h o , M. F e n t o n * , C.E. A d a m s , C. C a m p b e l l

*South Warwickshire Mental Health Services, St Michael's Ho,wital, Warwick, CV34 5QW, UK. Telephone." + 44 (0) 1926 406123. E- Mail." m./enton@mcmail, corn Background: Open studies have suggested the effectiveness of zuclopenthixol acetate for psychiatric emergencies and it is now recommended as part of management of acutely psychotic people by respected guidelines. This review investigates the evidence for these suggestions and recommendations. Methods: All randomised clinical trials that compared zuclopenthixol acetate with other 'standard' treatments for those with serious mental illnesses were identified and, if possible, summated. Results. Six trials, all with methodological problems, were identified. Data did not demonstrate that zuclopenthixol acetate was better than 'standard care' for altering behaviour, decreasing the need for supplementary medication, avoiding sideeffects, or postponing early self-discharge. One trial presented data which suggested an earlier, more intense level of sedation. Conclusions: Recommendations on the use of zuclopenthixol acetate in preference to 'standard" treatments for the management of psychiatric emergencies are not supported by evidence from randomised controlled trials.

PD Dr.med. K. Bechter, Department Psychiatry 11, Universi O' o1' Uhn, Ludwig-Heihn
AMISULPRIDE LATENT AND

TREATMENT VERSUS

DIMENSIONS

NEGATIVE

EFFECTS

FLUPENTIXOL

OF ON

OF DEPRESSIVE

SYMPTOMS

IN ACUTE

SCHIZOPHRENIA M.J. Mtiller, H. Wetzel, O. B e n k e r t

Department q['PaTch&tt T, Universi O, o[' Mainz, Untere Zahlbacher Strafle 8, D-55131 Mainz, Germany. Phone." +41 6131 172920, Fax: +41 6131 176690 Differential effects of amisulpride (600-1000 mg) and flupentixol (15 25 rag) on negative and depressive components of acute schizophrenic symptomatology were examined. Patients with acute schizophrenia (DSM-III-R) were treated for six weeks in a randomized double-blind study. Treatment differences on positive symptomatology (BPRS, SAPS) were not found. The latent structure of negative and depressive symptomatology was analyzed by Confirmatory Factor Analysis (CFA) using baseline data of 126 patients. The original five SANS subscores, three subscales of the BRMES as derived by first order CFA, and two BPRS subscales were subjected to a second order CFA. A three-factor solution of moderately correlated 'negative', "depressive" and 'anhedonia/apathy' dimensions was revealed showing sufficient fit (GFI=0.89,

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A G F I = 0 . 8 2 ) superior to competing models. The treatment effects on the CFA-dimensions were compared by means of ANCOVA using an intent-to-treat approach, adjusting for baseline values, dose, and emerging EPS. No substantial treatment differences were yielded with respect to "negative' and 'anhedonia/apathy' dimensions, whereas a significant difference emerged with respect to the "depressive' symptom component. The decrease in "depressive' symptoms was 51% for amisulpride and 26% for flupentixol (p=0.014). Furthermore, the 'depressive" factor improved in 93.8% of amisulpride patients and in 71.2% of flupentixol patients ( p = 0.018). Thus, analysis of latent structures of acute schizophrenic symptomatology indicated a specific beneficial effect of high dose amisulpride on the "depressive" dimension as compared to flupentixol independent of effects on positive, negative and extrapyramidal symptoms.

GLYCINE AND D-CYCLOSERINE A D J U V A N T P H A R M A C O T H E R A P Y FOR TREATMENT-RESISTANT SCHIZOPHRENIA U. H e r e s c o - L e v y , D.C. Javitt, M. Ermilov, C. M o r d e l Ezrath Nashim-Herzog Memor&l Hospital; Department q/' Psychiatry, Hadassah Medical School, Hebrew University. P. O. Box 35300, Jerusalem 91351, Israel Insufficient activation of the N-methyl-D-aspartate ( N M DA ) subtype of glutamate receptor has been proposed as a possible mechanism underlying schizophrenia symptoms. Glycine (GLY) and D-Cycloserine (DCS) act as obligatory co-agonist and partial agonist, respectively, at the GLY site associated with the NMDA receptor. Two double-blind, placebo controlled, six week crossover adjuvant treatment trials were conducted, in which treatment-resistant chronic schizophrenic patients received 0.8 g/kg/day GLY and 25 mg x 2/day DCS, respectively, in addition to their ongoing antipsychotic drug treatment. Both treatments were well-tolerated. GLY treatment resulted in increased GLY serum levels (p < 0.005) and induced a 30% (p < 0.001 ) reduction in negative symptoms as measured by the Positive and Negative Syndrome Scale (PANSS). This improvement was negatively correlated (p<0.001) with baseline GLY serum levels. Additional improvements were induced in depression and cognitive symptoms. Preliminary results indicate that DCS induced a 9% ( p < 0.05 ) reduction in negative symptoms that was also negatively correlated (p < 0.008) with baseline GLY serum levels. In seven patients who participated in both studies, the clinical improvements with GLY and DCS treatment were significantly correlated (p <0.05). These findings support the hypoglutamatergic hypothesis of schizophrenia and suggest an innovative strategy for the treatment of negative symptoms and neurocognitive deficits associated with this illness.

E I C O S A P E N T A E N O I C A C I D (EPA) AS A N A D J U N C T IN THE T R E A T M E N T OF SCHIZOPHRENIA S. S h a h * , G . K . V a n k a r , S.D. Telang, C.N. R a m c h a n d , M. Peet *SSG Ho.wital and Medical College, MS UniversiO, o/ Barodu 390002, h~dia Evidence that the metabolism and the composition of polyunsaturated fatty acids is abnormal in membrane phospholipids of schizophrenic patients has led to therapeutic trials of this fatty acids. Initial results from an open study and a small double blind study in the UK suggest that EPA leads to symptomatic improvement where given as an adjunct to existing antipsychotic medication. We are conducting similar studies in India. 10 of DSM IV diagnosed schizophrenic patients (7 males, 3 females, mean age of 35.8 years) who were still symptomatic despite conventional antipsychotic treatment, were given EPA as an adjunct to their regular medication, for 3 months. Symptoms were rated at the start and finish of the study on the positive and negative syndrome scale (PANSS). Mean total PANSS score fell from 75.3 ( S D = 11.68) to 46.5 ( S D = 12.33) (p < 0.01 ), positive symptoms from mean 19 (SD = 6.76 to 13.3 (SD=6.8) (p<0.05), negative symptoms from mean 20.8 (SD=8.16) to 10.5 (SD=3.6) (p<0.05). The most significant reduction was observed in hallucinatory behaviour and difficulty in abstract thinking. The study indicates that the benefits of EPA in Indian patients are similar to those previously reported in the UK. A double blind trial of EPA as sole treatment for schizophrenia is now in progress.

M U S C A R I N I C AGENTS: A N E W A P P R O A C H TO THE T R E A T M E N T OF PSYCHOSIS H.E. S h a n n o n , F.P. Bymaster, N.W. Bodick, W . W . Often, N.C. D e L a p p , K . W . Perry, K. R a s m u s s e n , J.S. W a r d , C.A. Whitesitt, A. F i n k - J e n s e n , P. Olesen, T. R a s m u s s e n , M. S h e a r d o w n , M. Swedberg, P. S a u e r b e r g Lilly Research Laboratories, Eli Lilly and Compa~o', hTdianapolis, IN and Novo Nordisk. Health Care Group, Pharmaceuticals Division, Malov, Denmark Clues to novel approaches for the treatment of psychosis have come from recent studies with the muscarinic agonist xanomeline which is currently in clinical development for Alzheimer"s disease. Psychotic symptoms occur in most patients with Alzheimer's disease at some time during the course of the illness. In the clinical trials with xanomeline, it was observed that it not only had positive effects on cognition, but also had profound effects on psychotic and other problematic behaviors in these patients. Most notably, xanomeline produced doserelated decreases in delusions, hallucinations and other