LIST REFERENCES LIST REFERENCES A) ANTIPSYCHOTIC... 851 H) *ON C&F&G 31 B) TRANQUILIZING AGENT... 6407 I) PSYCHOTIC DISORDERS 10391 C) *SUM AB 7258 J) SCHIZOPHRENIA 26008 D) DRUG RESISTANCE 11473 K) SCHIZOPHRENIC PSYCH... 8135 E) REFRACTORY 3815 L) *SUM IJK 44534 F) *SUM DE 15288 M) *ON F&G&L 58 G) ABSTRACT ONLINE 2640208 *** *** *****AMERICAN JOURNAL OF PSYCHIATRY***** (REFERENCE 1 OF 36) 91103349 Perry PJ Miller DD Arndt SV Cadoret RJ Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 1991 Feb;148(2):231-5 OBJECTIVE: Clozapine, an atypical antipsychotic, has been estimated to be effective in 30% of treatment-refractory schizophrenic patients. The authors hypothesized that if a dose-response relationship was obvious for this drug, the response rate could be significantly amplified. METHOD: Following an 8-24-day dose titration phase, 29 inpatients with treatment-resistant schizophrenia diagnosed according to DSM-III-R were given a clozapine dose of approximately 400 mg/day for 4 weeks; blood samples were obtained weekly during this period. RESULTS: A receiver operator curve demonstrated that the threshold clozapine plasma concentration for therapeutic response was 350 ng/ml. Sixty-four percent of the patients with clozapine plasma concentrations greater than 350 ng/ml responded, whereas only 22% of the patients with concentrations less than 350 ng/ml responded. CONCLUSIONS: Use of clozapine blood levels as a predictor for treatment response in treatment-refractory schizophrenic patients appears worthwhile, since the measurement's sensitivity for response was 64% and the specificity for nonresponse was 78%. Institutional address: Department of Psychiatry College of Medicine University of Iowa Iowa City. (REFERENCE 2 OF 36) 81279550 Lehmann CR Ereshefsky L Saklad SR Mings TE Very high dose loxapine in refractory schizophrenic patients. Am J Psychiatry 1981 Sep;138(9):1212-4 The authors report on three chronic, treatment-refractory schizophrenic patients who dramatically improved when placed on very high doses of loxapine (300-500 mg/day). Numbness transiently appeared in two patients at very high doses of loxapine; it may be a frequently occurring but unreported side effect. The relative lack of serious side effects to very high dose loxapine suggests that this may be a useful intervention in carefully selected refractory patients. The authors recommend that controlled studies be done to elucidate the benefit to risk ratio. (REFERENCE 3 OF 36) 76134031 Davis JM Recent developments in the drug treatment of schizophrenia. Am J Psychiatry 1976 Feb;133(2):208-14 The author reviews six topics relevant to the drug treatment of schizophrenia. The quantitative effectiveness of promazine is of interest with respect to the structural models of the phenothiazines and the dopamine theory of schizophrenia. The quantitative effectiveness of antipsychotic drugs is also important in evaluating new agents and therefore relevant to a discussion of two newly released neuroleptics, molindone and loxapine. The author's discussion of high-dose treatment of typical acute schizophrenics or treatment-resistant patients reviews the available data and calls attention to the fact that these areas of pharmacologic research have not received sufficient attention. (REFERENCE 4 OF 36) 88220555 Sramek J Herrera J Costa J Heh C Tran-Johnson T Simpson G A carbamazepine trial in chronic, treatment-refractory schizophrenia. Am J Psychiatry 1988 Jun;145(6):748-50 Carbamazepine was given to 12 chronic, treatment-refractory schizophrenic patients for 5 weeks. No overall change was found, but four patients significantly improved while eight worsened. Given the paucity of successful treatments for refractory schizophrenia, further study of carbamazepine appears warranted. Institutional address: Clinical Research Unit Metropolitan State Hospital Norwalk CA 90650. *****ARCHIVES OF GENERAL PSYCHIATRY***** (REFERENCE 5 OF 36) 76038904 Quitkin F Rifkin A Klein DF Very high dosage vs standard dosage fluphenazine in schizophrenia. A double-blind study of nonchronic treatment-refractory patients. Arch Gen Psychiatry 1975 Oct;32(10):1276-81 Previous work with chronic schizophrenic patients and a pilot study with nonchronic treatment-refractory schizophrenic patients indicated that very high doses of fluphenazine hydrochloride (1,200 mg/day) have a greater antipsychotic effect than do standard doses. Increased side-effects were not reported. In a double-blind six-week random assignment study, 18 nonchronic treatment-refractory patients received the very high dose and 13 the standard dose. The standard- dose treated patients had greater improvement on a variety of measures. Analysis of Inpatient Multidimensional Psychiatric Scale scores indicate that some patients taking very high doses had akinesia, and extrapyramidal side-effect that in part accounted for their inferior response. *****BRITISH JOURNAL OF PSYCHIATRY***** (REFERENCE 6 OF 36) 87077217 Roberts JE Edwards JG Checkley S Crammer JL Cutting JC Lader MH Murray RM A case of resistant schizophrenia. Br J Psychiatry 1986 Dec;149:789-93 In an era when it is generally believed that the acute symptoms of schizophrenia can be controlled pharmacologically, the case of a young man who has remained almost continuously floridly psychotic for 13 years, despite treatment, is disquieting. Conventional psychiatric treatment appears to be rendered impotent. It is in this context that it may be of interest to report a summary of the proceedings of a Special Problems Conference held at the Institute of Psychiatry on 18 February 1985 to discuss such a case. *****JOURNAL OF CLINICAL PSYCHIATRY***** (REFERENCE 7 OF 36) 84135622 Lindenmayer JP Smith D Katz I Radioreceptor assay of neuroleptics in refractory chronic schizophrenic patients. J Clin Psychiatry 1984 Mar;45(3):117-9 Radioreceptor assay, a promising new tool for studying serum levels of neuroleptics and their biologically active metabolites, was used to elucidate the role of neuroleptic plasma levels in 24 chronic schizophrenic patients with a poor clinical response to standard treatment. Most of these 24 patients attained serum levels reportedly associated with improvement in more acute patients, suggesting that their lack of response was not due to relative absence of drug in serum. Alternative reasons for lack of response despite adequate plasma levels are discussed. (REFERENCE 8 OF 36) 82030592 Stern SL Mendels J Drug combinations in the treatment of refractory depression: a review. J Clin Psychiatry 1981 Oct;42(10):368-73 The authors critically review several drug combinations that may be of promise in the management of depressions that do not respond to treatment with a single drug. These include the use of tricyclic antidepressants with monoamine oxidase inhibitors (MAOI's), L- triiodothyronine (T3), methylphenidate, lithium carbonate, L- tryptophan, reserpine, and neuroleptics; MAOI's with lithium and L- tryptophan; and L-tryptophan with allopurinol. The authors stress the need for further double-blind, controlled studies to evaluate the safety and efficacy of these combinations. (REFERENCE 9 OF 36) 90008831 Mattes JA Clozapine for refractory schizophrenia: an open study of 14 patients treated up to 2 years. J Clin Psychiatry 1989 Oct;50(10):389-91 Clozapine is a novel antipsychotic agent that selectively blocks mesolimbic--rather than nigrostriatal--dopamine receptors, causes fewer extrapyramidal symptoms than do other neuroleptics, and has superior antipsychotic efficacy in some patients. However, clozapine also causes agranulocytosis more frequently than do other neuroleptics. The evidence documenting the superior benefits obtained with clozapine has primarily involved short-term (4-6 weeks) trials, and the systematic evaluation of long-term clozapine use has been limited. In this study, 14 patients with refractory chronic schizophrenia were treated openly with clozapine up to 2 years; 8 did substantially better when given clozapine than they had when given other neuroleptics. That finding suggests that clozapine may provide a useful addition to the therapeutic armamentarium for the long-term treatment of schizophrenia, despite the increased risks and the need for frequent blood tests. Institutional address: Psychopharmacology Research Association Princeton NJ 08540. (REFERENCE 10 OF 36) 86250655 Vital-Herne J Gerbino L Kay SR Katz IR Opler LA Mesoridazine and thioridazine: clinical effects and blood levels in refractory schizophrenics. J Clin Psychiatry 1986 Jul;47(7):375-9 Seven schizophrenic (according to DSM-III criteria) inpatients completed a two-phase study; each phase had a 1-week drug-free period followed by 6 weeks of a drug trial. The first phase uniformly involved treatment with chlorpromazine, and in the second phase patients received either mesoridazine (N = 3) or thioridazine (N = 4). Clinical ratings (Brief Psychiatric Rating Scale and Clinical Global Impressions) and neuroleptic blood levels were obtained weekly throughout the study. Whereas patients failed to respond to chlorpromazine 1800 mg/day, response to mesoridazine 400 mg/day and to thioridazine 800 mg/day was established on all Brief Psychiatric Rating Scale factors except for anxiety-depression. A higher neuroleptic blood level was achieved with mesoridazine or thioridazine at less than half the reference chlorpromazine dosage. Correlations between neuroleptic blood level and clinical response were positive for mesoridazine, negative for chlorpromazine, and nonsignificant for thioridazine. These findings are consistent with earlier research. We conclude that drug-resistant schizophrenics seem to improve clinically with mesoridazine or thioridazine, unlike with chlorpromazine, and that for mesoridazine this difference may be a function of selective dopamine receptor blockade. *****JOURNAL OF NERVOUS AND MENTAL DISEASE***** (REFERENCE 11 OF 36) 91086928 Douglass AB Hays P Pazderka F Russell JM Florid refractory schizophrenias that turn out to be treatable variants of HLA-associated narcolepsy. J Nerv Ment Dis 1991 Jan;179(1):12-7; discussion 18 Narcolepsy in which the hallucinatory component is unusually prominent may lead to the development of an illness indistinguishable from the schizophrenic syndrome. Psychotic symptoms dominate the symptomatology, so that the primary illness is obscured. Five patients are described for whom conventional antipsychotic drugs were ineffectual, but for whom treatment with stimulants produced substantial improvement. The diagnosis of narcolepsy was confirmed by Human Leukocyte Antigen typing and sleep laboratory testing. These results support the "REM intrusion" hypothesis of the causation of schizophrenia in as many as 7% of a series of schizophrenic patients. Implications for diagnosis and treatment are discussed. Institutional address: Department of Psychiatry University of Alberta Edmonton Canada. (REFERENCE 12 OF 36) 75116033 Itil TM Marasa J Saletu B Davis S Mucciardi AN Computerized EEG: predictor of outcome in schizophrenia. J Nerv Ment Dis 1975 Mar;160(3):118-203 Based on a double blind cross-over study, it was determined that schizophrenic patient who have more high frequency fast activity and a lesser degree of alpha and slow waves in computerized EEG before the treatment have a better therapeutic outcome to the major tranquilizer (neuroleptic) treatment. The correlation between pretreatment high frequency computer EEG measurements and better therapeutic outcome reached the level of statistical significance. "Therapy resistant" schizophrenic patients were characterized by a lesser degree of very fast beta activity, more alpha waves and slow waves, higher amplitudes in computer EEG, and a lesser degree of acute (florid) psychotic symptomatology but more "negative" symptoms such as motor retardation and blunted affect. One of the most striking results of the study is the finding that schizophrenic patients with certain psychopathological profiles also have similar computer EEG profiles. *** *** *****ACTA PSYCHIATRICA BELGICA***** (REFERENCE 13 OF 36) 78231836 Wouters J A six-month follow-up of refractory chronic psychotics treated with Haldol-AID. Acta Psychiatr Belg 1978 Mar-Apr;78(2):399-406 Nine refractory chronic psychotics were switched to a lower dosage of, mostly, a long-acting diphenylbutylpiperidine after having been treated with high initial and maintenance doses of Haldol. This switch-over was rated as very good in three patients (allocation to nursing family) and good in two patients on fluspirilene (Imap); it was also rated as good in one patient on fluphenazine decanoate and one on pipamperone. One patient could discontinue neuroleptic treatment. One was rated as a failure. A switch-over is not always easy as it is a time of trial and error. A switch-over to a parenteral diphenylbutylpiperidine offers good prospectives. As a rule, further improvement is feasible after a period of Haldol medication. It seems that the advantages of a maintenance therapy with Imap are its lack of inconveniences for the patient (not sedative, only slightly hypokinetic) and its good antipsychotic and adequately prolonged activity 2 weeks). (REFERENCE 14 OF 36) 78057766 Nicodeme A Vranckx-Haenen J Wouters J A multicentre study on the efficacy and safety of individualized dosage of haloperidol (Haldol) in refractory chronic psychotics. Acta Psychiatr Belg 1977 Jul-Aug;77(4):516-29 This study was carried out on 38 chronic refractory psychotic patients who received partial multimodal treatment with individually adapted doses of Haldol. The study was based on: --Howard's experiences: more than half of his chronic psychotic patients were able to leave the State Hospital because of the multimodal treatment with high individualized doses of Haldol; -Paquay and Tanghe's experiences: one-fourth to more than one-half of their chronic refractory patients showed remarkable improvement with a partial multimodal treatment. This study shows that improvement is obtained in more than 2 out of 3 cases, thus proving that the best results are obtained when an adequate selection of the patients is made. As side- effects, above all, the extrapyramidal symptoms are possible. However, their frequency and intensity are not higher than those provoked by other incisive neuroleptics or conventional doses of Haldol. Special attention should be given to any pseudodepression or neurovegetative reactions. The individualization of the doses should be carefully done. *****ACTA PSYCHIATRICA SCANDINAVICA***** (REFERENCE 15 OF 36) 81203679 Dencker SJ Enoksson P Johansson R Lundin L Malm U Late (4-8 years) outcome of treatment with megadoses of fluphenazine enanthate in drug-refractory schizophrenics. Acta Psychiatr Scand 1981 Jan;63(1):1-12 Fourteen schizophrenics who did not respond to standard doses of neuroleptics have been treated with megadoses of fluphenazine enanthate during a period of 4-8 years. Repeated attempts have been made to reduce the dose to the standard dosage. Some of the patients have gradually been transferred to maintenance treatment with standard doses, with megadoses given only during psychotic relapse. The megadose treatment has led to substantial reduction in social disablement, enabling the patients, for instance, to leave the hospital or live in an open ward. These patients have been evaluated with rating scales for psychopathology and side effects, and subjected to EEG, ECG, chest X-ray, and examinations for skin and eye changes and local infiltrations. Laboratory tests, including anti-DNA examination, have also been performed. These patients, treated with high total doses of different oral neuroleptics and fluphenazine depot, showed some EEG and ECG abnormalities, eye changes, slight leucopenia, a low number of staff nuclei neutrophils and infiltrations at the injection site, but these reactions did not result in any practical handicaps. The rating scales showed dyskinetic movements, usually slight, in six out of the 14 patients studied. (REFERENCE 16 OF 36) 87237845 Ota T Maeshiro H Ishio H Shimizu Y Uchida R Toyoshima R Ohshima H Takazawa A Motomura H Noguchi T Treatment resistant chronic psychopathology and CT scans in schizophrenia. Acta Psychiatr Scand 1987 Apr;75(4):415-27 In order to examine the relationship between the neuroleptic resistant chronic psychopathology and CT findings in schizophrenia, 25 schizophrenics who had been treated well and were in a stable condition were assessed for positive and negative symptoms, CT findings, medication, and the clinical course of illness. Correlational analysis showed that there was a group of patients who had comparatively small ventricles and presented treatment resistant positive symptoms, and another group of patients who had larger ventricles and lacked positive symptoms. Negative symptoms showed a tendency toward positive correlation with atrophic CT changes of cortices. Literature on CT findings and symptomatology was critically reviewed. The importance of the more chronic positive symptoms correlating to CT findings in schizophrenia were discussed. *****CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE***** (REFERENCE 17 OF 36) 81258208 Brent R Kalman T Fluphenazine resistant psychosis. Can J Psychiatry 1981 Mar;26(2):118-9 A fifty year old female chronic schizophrenic was admitted to hospital following a relapse of her psychosis. She had previously responded well to treatment with trifluoperazine but because of her history of medication non-compliance, a trial of fluphenazine enanthate was instituted. Despite the close chemical similarity between trifluoperazine and fluphenazine the patient failed to respond to the latter in either its oral or depot intramuscular form. Although it is not unusual for a patient to respond to one antipsychotic and not to another, the above case of intra-class non- responsiveness is indeed rare and not readily explained. We present this unusual case and discuss some possible explanations. *****CLINICAL NEUROPHARMACOLOGY***** (REFERENCE 18 OF 36) 90335837 van Kammen DP Schooler N Are biochemical markers for treatment-resistant schizophrenia state dependent or traits? Clin Neuropharmacol 1990;13 Suppl 1:S16-28 With increased understanding of antipsychotic drug treatment, the emphasis in research and clinical practice is shifting toward patients who do not respond or who respond only in part. At present the clinician can determine only after the fact whether a schizophrenic patient will respond to drug treatment. Antipsychotic drug response is seen as state dependent and may be determined by the biochemical condition of the patient. The authors have reviewed studies of biochemical measures and antipsychotic drug response. It appears that psychotic patients with elevated catecholamine release are likely to respond rapidly to neuroleptic treatment, whereas psychotic patients with lower cerebrospinal fluid (CSF) or plasma catecholamine levels are most likely to be treatment nonresponders. A dysregulation of the locus ceruleus may affect the dopamine system's responsivity to pharmacological interventions. Institutional address: Highland Drive Veterans Administration Medical Center Pittsburgh PA 15206. (REFERENCE 19 OF 36) 90335835 Altamura AC Drug-resistance phenomena in major psychoses: their discrimination and causal mechanisms. Clin Neuropharmacol 1990;13 Suppl 1:S1-15 Drug-resistance phenomena are commonly encountered in psychiatric practice and are of particular concern in the treatment of major psychoses. Of paramount importance is the need to discriminate between drug-resistance problems due to pharmacodynamic factors (i.e., receptor sensitivity) or pharmacokinetic factors (inadequate plasma concentration of the drugs at receptor sites). To exclude the former, plasma level measurements of antidepressant and neuroleptic compounds are desirable. Actually, lack of or poor compliance is a peculiarity (often underestimated) when treating psychotic patients, and the use of the drug plasma level/dose ratio (L/D) approach is useful, particularly with outpatients. Another source of drug resistance stems from the inter-individual metabolic variability, as with haloperidol or anticholinergic drugs, which are used to counteract neuroleptic-induced extrapyramidal side effects. In general, plasma-level measurement is advisable whenever no or poor response is obtained during standard treatments with neuroleptic, antidepressant, or anticholinergic drugs. Finally, this author suggests a four-level discrimination process to determine drug resistance in major psychoses, which includes clinical, pharmacological, pharmacokinetic, and pharmacodynamic factors. Institutional address: Department of Clinical Psychiatry University of Milan Italy. *****ENCEPHALE***** (REFERENCE 20 OF 36) 83104909 Berrios GE Neuroleptic-refractory patients and their drug plasma levels. Encephale 1982;8(4):465-85 The clinical, pharmacological and technical aspects of estimations of plasma concentrations of neuroleptics are discussed in the context of the treatment of the neuroleptic-refractory schizophrenic patient. A flow diagramme is suggested for the clinical analysis of schizophrenic patients who do not respond to medication. It is concluded that, in spite of the sizeable amount of research carried out in this area, no evidence is yet available that drug plasma level concentrations correlate adequately with clinical response; hence no therapeutic window has yet emerged. The reasons for this failure are mentioned. Hence it might be premature for the ordinary mental hospital to develop costly laboratory facilities to cater for this experimental advance. (REFERENCE 21 OF 36) 90276297 Pere JJ Chaumet-Riffaud D [Clozapine and resistant schizophrenia] Clozapine et schizophrenie resistante. Encephale 1990 Mar-Apr;16(2):143-5 (Published in French) Clozapine is an atypical antipsychotic drug, with distinguishing features from neuroleptics which are believed to exert their therapeutic effect by blocking dopamine receptors in the limbic system. Clozapine is both chemically and pharmacologically distinct from neuroleptics such as chlorpromazine and haloperidol. This tricyclic dibenzodiazepine derivative is moderately active on the dopaminergic pathways, blocking D1 and D2 receptors to the same extent; and chronic treatment with clozapine does not lead to a compensatory increase in the number of striatal D2 receptors in rats. Pharmacological studies showed that clozapine produces psychomotor inhibition but without catalepsy and other typical effects of dopamine receptor blockade. The drug also has adrenergic (alpha 1), histamine (H1), and serotonin (5-HT2) blocking activity and is a potent muscarinic antagonist. The efficacy and side-effect profile of clozapine are unique. Treatment-resistant patients are much more likely to respond to clozapine than to haloperidol or chlorpromazine. In double-blind trials, clozapine has improved both positive and negative psychotic symptoms in schizophrenic patients who were refractory to conventional neuroleptics. Extrapyramidal side-effects are exceptional during therapy and tardive dyskinesia never demonstrated in relationship to clozapine. There is an increased risk of agranulocytosis with clozapine use estimated to be up to 20 cases of agranulocytosis per thousand patients treated during one year. Accordingly, a careful patient selection and regular blood monitoring are mandatory over the treatment period (blood testing to be performed weekly and immediately at the first sign of infection). Generally, this agranulocytosis is reversible with early detection and prompt drug discontinuation. Institutional address: Departement de Recherche Clinique Systeme Nerveux Central Rueil-Malmaison. *****INTERNATIONAL PHARMACOPSYCHIATRY***** (REFERENCE 22 OF 36) 82097496 Pi EH Simpson GM The treatment of refractory schizophrenia: pharmacotherapy and clinical implications of blood level measurement of neuroleptics. Int Pharmacopsychiatry 1981;16(3):154-61 The treatment of refractory schizophrenia requires careful definition. This is usually a statement based on clinical and/or intuitive experience. The definition can be extended and tightened if laboratory evidence is incorporated into this definition. Suggestions on how to accomplish this, e.g. measuring blood levels of antipsychotic agents, are made. Strategies for "trials of therapy' in nonresponsive patients and for decisions for changing to a new antipsychotic agent are presented. Clinical and laboratory difficulties in tackling this problem are also discussed. (REFERENCE 23 OF 36) 81214797 Psaras M Zissis NP Mouzakis D Lyketsos G Mobilization of refractory chronic schizophrenics with haloperidol. Int Pharmacopsychiatry 1980;15(3):180-5 Adequate high doses of haloperidol have been administered to 24 chronic, refractory to standard antipsychotic treatment, schizophrenics (16 male, 8 female, mean age 32.9 years) to investigate the possibility of mobilizing and releasing these patients from the hospital. Treatment was started with 20 mg haloperidol and optimal doses were determined for each patient. The median daily optimal dose at the end of the trial was 100mg. All patients were followed up for 16 weeks. Evaluating criteria were the BPRS, the Discharge Readiness Questionnaire, a side-effect rating scale, a CGI scale and the number of patients able to leave the hospital. 3 patients were evaluated as able to leave the hospital. 87.4% of the patients were subjectively evaluated as improved. High doses of haloperidol did not correlate with a higher incidence of unwanted effects. On the contrary antiparkinson treatment was discontinued or decreased in 14 patients. It is concluded that nonresponsive chronic schizophrenics can profit from adequate high doses of haloperidol. *****JOURNAL OF AFFECTIVE DISORDERS***** (REFERENCE 24 OF 36) 86086804 Shukla S Cook BL Miller MG Lithium-carbamazepine versus lithium-neuroleptic prophylaxis in bipolar illness. J Affective Disord 1985 Nov;9(3):219-22 Fourteen DSM-III diagnosed patients with lithium-resistant bipolar affective disorder treated with a combination of lithium and carbamazepine were followed in a lithium clinic for one year to study the prophylactic benefit and side effects of this drug regimen. Comparison data for the previous year on lithium and neuroleptics showed that for the 9 patients who completed the study, the lithium- carbamazepine regimen was superior to lithium-neuroleptics in decreasing the number of affective episodes and side effects. Carbamazepine blood levels appeared to be a possible contributing factor in the development of side effects. *****JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY***** (REFERENCE 25 OF 36) 90330739 Soper HV Elliott RO Jr Rejzer AA Marshall BD Jr Effects of fenfluramine on neuropsychological and communicative functioning in treatment-refractory schizophrenic patients. J Clin Psychopharmacol 1990 Jun;10(3):168-75 Reported behavioral improvement among autistic patients following feufluramine treatment and a high serotonin level among certain chronic schizophrenic patients suggested that fenfluramine treatment might be beneficial with such schizophrenic patients, especially within the realm of neuropsychological and communicative functioning. A brief neuropsychological battery was administered to eight chronic schizophrenic subjects before, during, and after fenfluramine treatment. Conversations in controlled settings were audiotaped before and during fenfluramine treatment for seven of these subjects and one additional subject. These language samples were analyzed for communicative competence and evidence of thought disorder. Overall, neuropsychological and communicative functioning was worse under the fenfluramine condition, even though blood serotonin levels were about half those at baseline conditions. The results suggest that it is not the higher levels of blood serotonin by themselves that are related to depressed neuropsychological, communicative, and other functioning. In fact, the higher levels of serotonin may well be related to adaptations for maximal level of functioning. These results suggest caution in the use of fenfluramine for other schizophrenic populations. Institutional address: Camarillo State Hospital and Developmental Center California. (REFERENCE 26 OF 36) 84112157 Kim DY Hollister LE Drug-refractory chronic schizophrenics: doses and plasma concentrations of thiothixene. J Clin Psychopharmacol 1984 Feb;4(1):32-5 Some treatment-resistant schizophrenics will respond to rather large doses of thiothixene, such as 120 to 400 mg/day. These patients also show higher plasma concentrations (24 to 57 ng/ml) of the drug than those who respond less well. Patients tolerated this intensive treatment equally well as more conservative programs. Chronic refractory schizophrenics may benefit from such intensive treatment in the short term, but one cannot yet be certain about long-term effects. (REFERENCE 27 OF 36) 89256079 Marshall BD Jr Glynn SM Midha KK Hubbard JW Bowen LL Banzett L Mintz J Liberman RP Adverse effects of fenfluramine in treatment refractory schizophrenia. J Clin Psychopharmacol 1989 Apr;9(2):110-5 Fenfluramine was administered to eight severely ill schizophrenic patients as an adjunct to neuroleptic drugs in a double-blind, multiple baseline design. A significant adverse effect of fenfluramine on psychopathology was detected through nurses' ratings, target symptom scales, the Brief Psychiatric Rating Scale, and time- sampled behavioral observations. Clinical deterioration was correlated with fenfluramine-induced reductions in blood serotonin levels and persisted beyond the point of discontinuation of fenfluramine. Institutional address: Department of Psychology University of California Los Angeles. (REFERENCE 28 OF 36) 86224721 Berlant JL Neuroleptics and reserpine in refractory psychoses. J Clin Psychopharmacol 1986 Jun;6(3):180-4 This retrospective review of the naturalistic use of reserpine in combination with neuroleptics for symptoms refractory to neuroleptics and lithium demonstrated a moderate to dramatic response rate in 50% of 36 chronically disabled psychotic patients. Observed improvement was in marked contrast to the baseline pattern of chronically persistent psychotic symptoms and poor functioning in these patients. Female patients and patients with schizoaffective or bipolar diagnoses responded best to treatment. Reserpine may be an underutilized adjunctive treatment for refractory psychotic states, and further investigation into its clinical applications is warranted. *****PROGRESS IN NEURO-PSYCHOPHARMACOLOGY AND BIOLOGICAL PSYCHIATRY***** (REFERENCE 29 OF 36) 87318703 Bloom DM Tourjman SV Nair NP Verapamil in refractory schizophrenia: a case report. Prog Neuropsychopharmacol Biol Psychiatry 1987;11(2-3):185-8 Verapamil, a papaverine calcium channel blocker, has been used effectively and safely in the treatment of angina pectoris and auricular arrhythmias, and more recently in the treatment of mania. Many antipsychotic drugs show calcium channel blocking effects similar to verapamil's. A 41 year old male schizophrenic, only partially responsive to haloperidol decanoate and oral haloperidol, was given increasing doses of verapamil concomitantly, and monitored clinically and by the BPRS, electrocardiogramme, and other laboratory measures. The patient's total BPRS score dropped from 79 to 41 and remained stable, after initial worsening at lower doses, at verapamil 80 mg po qid. Mild fatigue was the only side effect. Further investigation of verapamil in the treatment of schizophrenia is warranted. *****PSYCHOLOGICAL MEDICINE***** (REFERENCE 30 OF 36) 80212696 Kolakowska T Gelder MG Orr MW Drug-related and illness-related factors in the outcome of chlorpromazine treatment: testing a model. Psychol Med 1980 May;10(2):335-43 Patients who presented with acute psychoses and were treated with chlorpromazine were first divided into 2 groups with good (23) and poor (13) outcome. These outcome groups differed little in their initial clinical features and showed no difference in 2 indices of dopamine receptor blockade (extrapyramidal symptoms and plasma prolactin concentrations). The group which improved was then subdivided on the basis of evidence of dopaminergic blockade into 15 who had improved and also showed anti-dopamine effects ('responders') and 8 who had improved but showed no anti-dopamine effects ('remitters'). The remainder were eventually classified as 'resistant' to the effects of the drug. The group of 'remitters' contained no patients with nuclear schizophrenia; the 'responders' were mainly nuclear schizophrenics; and the 'resistant' patients were schizophrenic or schizo-affective. The 3 groups who were defined in this way also differed in their subsequent clinical course. It is suggested that this scheme for dividing patients may be useful in clinical work and could also assist research worker to identify the patients who can most appropriately be studied to determine mechanisms of drug action. *****PSYCHOPHARMACOLOGY***** (REFERENCE 31 OF 36) 84043335 Nestoros JN Nair NP Pulman JR Schwartz G Bloom D High doses of diazepam improve neuroleptic-resistant chronic schizophrenic patients. Psychopharmacology (Berlin) 1983;81(1):42-7 According to the two currently most popular biological hypotheses, schizophrenic symptoms result from a hyperactivity in dopaminergic neurotransmission or from a hypoactivity in GABAergic neurotransmission. Since diazepam is known to reduce dopamine release and to potentiate GABA, the possible beneficial effects of diazepam were tested in ten hospitalized chronic schizophrenic patients who were resistant to standard neuroleptic treatment. High doses of diazepam, up to 200 mg/day initially, but smaller maintenance doses (less than 55 mg/day diazepam in eight of the ten patients) were added to the previous neuroleptic medication of these patients. The diazepam dose was adjusted daily to avoid oversedation. The effects of diazepam treatment on the mental status were assessed weekly for 12 weeks by the Brief Psychiatric Rating Scale (BPRS), the physician's Clinical Global Impressions Scale (CGI), and the Psychotic Inpatient Profile Scale (PIP). For additional documentation, videotapes of mental status interviews were obtained at baseline and during diazepam treatment. These videotapes were rated blind by an independent psychiatrist. The addition of diazepam produced a marked improvement in three, a moderate improvement in four, a mild improvement in one and no change in two of the ten patients. Four of the ten patients were so much improved that they were discharged from the hospital. No side effects were noted, except for one patient who became confused and disoriented on 160mg diazepam/day.(ABSTRACT TRUNCATED AT 250 WORDS) (REFERENCE 32 OF 36) 90047440 Lindstrom LH A retrospective study on the long-term efficacy of clozapine in 96 schizophrenic and schizoaffective patients during a 13-year period. Psychopharmacology (Berl) 1989;99 Suppl:S84-6 The effect of long-term treatment with clozapine in schizophrenia and schizoaffective disorder was evaluated in a retrospective study comprising 96 patients treated with the drug during the period 1974- 1986 at the Psychiatric Research Center in Uppsala. All patients had previously been treated with different kinds of antipsychotic drugs but with insufficient clinical effect or distressing extrapyramidal side effects. When clozapine treatment was initiated, the mean duration of the illness was 8 years and 9 months. In 36% of the patients clozapine treatment was discontinued, the main reasons being lack of efficacy, poor compliance or temporary withdrawal from the market in 1975. Clinical evaluation of the effect revealed that 85% of the patients could be discharged from the hospital within a year and that 43% of the patients were significantly and 38% moderately improved compared to previous treatments. Of those patients who were still on clozapine 2 years after the treatment was initiated, 39% had employment compared to only 3% before clozapine. In ten patients a transient decrement in white blood cells (WBC) was noted but normalized during ongoing treatment. One patient developed leukopenia and one agranulocytosis, none with fatal outcome. Common side effects were sedation, hypersalivation, weight gain and obstipation. In one patient clozapine treatment was stopped because of grand mal seizures. No extrapyramidal side effects were observed or reported during clozapine treatment. It is concluded that clozapine offers particular advantages for many "therapy-resistant" schizophrenic patients when compared to classical neuroleptics. Institutional address: Psychiatric Research Center University of Uppsala Sweden. *****SCHIZOPHRENIA BULLETIN***** (REFERENCE 33 OF 36) 88145556 Berlant JL One more look at propranolol for the treatment of refractory schizophrenia. Schizophr Bull 1987;13(4):705-14 Propranolol, a beta-adrenergic blocking agent, has been proposed previously as potentially useful in the treatment of certain otherwise treatment-unresponsive psychotic patients. This article reviews the published clinical trials of the efficacy of propranolol in schizophrenia to characterize those patients in whom it might be helpful and for whom future clinical trials should be designed. Despite a large number of inconsistent reports, the evidence to date favors its potential value as an adjunct to neuroleptic therapy in neuroleptic-resistant chronic schizophrenic patients. Several recommendations are made to improve the methodology of future clinical trials with this agent for the treatment of schizophrenia. Institutional address: Fair Oaks Hospital Summit NJ 07901. *****SCHIZOPHRENIA RESEARCH***** (REFERENCE 34 OF 36) 91129142 Konig P Glatter-Gotz U Combined electroconvulsive and neuroleptic therapy in schizophrenia refractory to neuroleptics. Schizophr Res 1990 Oct-Dec;3(5-6):351-4 The results of treatment in 13 schizophrenic patients (nine males, four females) who underwent electroconvulsive therapy (ECT) because of varying degrees of therapy resistance to neuroleptics (therapy failures, renewed and in some cases catatonic exacerbation under neuroleptic therapy, neuroleptic intolerance) are reported. The single treatments, which were carried out on average 12 times (between six and 20 times), led from very good to good remission in a period of between 10 and 7 years in nine patients. Four patients did not respond adequately: the small improvement of psychopathology on discharge correlated with unfavorable outcome. In three of these patients, the asthenic syndrome was found on admission and persisted. In patients with good remission, neuroleptics could be reduced after ECT by over 70%, and over 50% in patients with poor remission. This result confirms corresponding literature data with regard to neuroleptics. The results in this highly selected group also confirm Bleuler's 'one third rule' of remissions, also the fact that global outcome does not correlate with response to neuroleptics, as well as confirming the relevance of the psychopathological state on discharge as an outcome predictor. Institutional address: Landes-Nervenkrankenhaus Valduna Department of Psychiatry I Rankweil Austria. *****ZHURNAL NEVROPATOLOGII I PSIKHIATRII IMENI S. S. KORSAKOVA***** (REFERENCE 35 OF 36) 91263534 Govorin NV [HLA immunogenetic markers in predicting therapeutic resistance in paranoid schizophrenia] Immunogeneticheskie markery HLA v prognozirovanii terapevticheskoi rezistentnosti pri paranoidnoi shizofrenii. Zh Nevropatol Psikhiatr 1991;91(3):90-3 (Published in Russian) A study was made of the incidence of HLA histocompatibility antigens of A, B and C loci in 100 male patients suffering from paranoid continuous schizophrenia associated with hallucinatory paranoid symptomatology during the formation in them of therapeutic resistance. In accordance with the clinico-pathogenetic philosophy, 2 groups of resistant patients were formed: an "endogenous" one (because of rapid progression) and a "pharmacogenous" one (secondary, formed by the mechanisms of "adaptation" to neuroleptics). In addition, a group of "nonresistant" patients (a reference one) was also distinguished. The data were compared to those obtained in normal subjects (50 men) and to those derived within the distinguished groups, employing mathematic computation of the risk coefficient. It has been shown that in contrast to the group of normal subjects, the general group of patients suffering from paranoid schizophrenia manifested the accumulation of the HLA antigens A2, A9, W7 and B15. The accumulation of the HLA antigens A2 and A11 was characteristic of the patients suffering from "endogenous" resistance, which distinguished those patients from normal subjects, from "nonresistant" patients and those with "pharmacogenous" resistance. The HLA phenotype A2,11 can be regarded as a potential marker of progression (risk grades 9.8). Besides, it has been demonstrated that the HLA antigens B7 may attest to risk of tolerance to psychopharmacotherapy and formation of "pharmacogenous" resistance (risk grades 4.3). (REFERENCE 36 OF 36) 86210872 Neduba AA [Typology of therapy-resistant states in schizophrenia] Tipologiia rezistentnykh k terapii sostoianii u bol'nykh shizofreniei. Zh Nevropatol Psikhiatr 1986;86(3):424-8 (Published in Russian) Clinical regularities in the formation of resistance to therapy in schizophrenic patients make it possible to identify 4 groups of therapy resistance: (1) resistance due to clinical factors (regularities of the process); (2) resistance due to both clinical and therapeutical factors (predicted insufficient cure); (3) resistance due to therapeutic factors in connection with adaptation to drugs and therapeutic errors (inadequate or insufficiently intensive treatment); (4) idiopathic resistance. This systematics of states resistant to therapy may contribute to differentiation of their treatment.