LIST REFERENCES LIST REFERENCES A) PARANOID DISORDERS 2308 J) SEROTONIN 32971 B) SCHIZOPHRENIA 26186 K) *SUM HIJ 37865 C) SCHIZOPHRENIA, CATA... 306 L) *ON G&K 600 D) SCHIZOPHRENIA, CHIL... 1073 M) ABSTRACT ONLINE 2679631 E) SCHIZOPHRENIA, DISO... 330 N) 1990...91 545948 F) SCHIZOPHRENIA, PARA... 1731 O) 1985...91 2261887 G) *SUM ABCDEF 31934 P) *ON L&M&O 62 H) SEROTONIN... 619 Q) FENFLURAMINE 1407 I) RECEPTORS, SEROTONIN 4275 R) *ON M&O&Q 200 *** *** *****AMERICAN JOURNAL OF PSYCHIATRY***** (REFERENCE 1 OF 35) 87125374 Kolakowska T Molyneux SG Platelet serotonin concentration in schizophrenic patients. Am J Psychiatry 1987 Feb;144(2):232-4 Platelet serotonin (5-HT) concentration did not significantly differ between control subjects (N = 45) and schizophrenic (N = 62) or chronic schizophrenic (N = 39) patients. No clinical feature was associated with hyperserotonemia, but the subgroup receiving benzodiazepines had a significantly higher 5-HT level than other patients. *****ARCHIVES OF GENERAL PSYCHIATRY***** (REFERENCE 2 OF 35) 88251238 Weinberger DR Berman KF Illowsky BP Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry 1988 Jul;45(7):609-15 We previously reported that compared with normals, patients with chronic schizophrenia have reduced regional cerebral blood flow (rCBF) in dorsolateral prefrontal cortex (DLPFC) during performance of the Wisconsin Card Sort Test (WCS), a DLPFC-related cognitive task, but not during nonprefrontal tasks, such as a simple number- matching (NM) test. We also found that unlike normals, patients failed to activate DLPFC during the WCS over their own baseline (NM) level. To explore the reproducibility of these findings, a new cohort of 16 medication-free patients underwent a series of xenon 133 inhalation rCBF studies under the following conditions: at rest, while performing the WCS, and while performing NM. The results confirmed our earlier findings. In addition, the concentrations in cerebrospinal fluid of homovanillic acid and 5-hydroxyindoleacetic acid correlated with prefrontal rCBF during the WCS but not during the NM test or at rest. The results show that behavior-specific hypofunction of DLPFC in schizophrenia is reproducible, and they implicate a monoaminergic mechanism. Institutional address: Clinical Brain Disorders Branch National Institute of Mental Health St Elizabeths Hospital Washington DC 20032. *** *** *****ACTA NEUROLOGICA BELGICA***** (REFERENCE 3 OF 35) 86264433 Maloteaux JM Drug and transmitter receptors in human brain. Characterization and localization of serotonin, dopamine and adrenergic receptors. Acta Neurol Belg 1986 Mar-Apr;86(2):61-129 The neuroreceptors in the brain are the targets of transmitters and drugs. Tritiated ligands - mostly selective antagonists - allowed to characterize the dopamine, serotonin and adrenergic receptors in human brain. Their properties were compared to those of rat brain receptors. Our results confirm the high affinity of several antagonist drugs for the corresponding binding sites in human brain. D2 dopamine receptors were identified in the striatum. S2 serotonergic receptors were located mainly in the cerebral cortex and their binding properties in solubilized form did not differ from those of the rat brain solubilized receptors. Adrenergic receptors were located either in cortical and subcortical areas. The subregional study indicates that wide variations could occur between adjacent areas of the cortex and between the different cortical layers. The subcellular distribution of several receptors revealed a main synaptosomal localization in human brain in contrast to other species. The S2 serotonergic receptors, the substance P peptide receptors and the benzodiazepine receptors were studied in the brain of Parkinsonian patients. The results were compared with those obtained in other neurological illnesses. A decrease in receptor number often corresponds to neuronal cell loss in degenerative diseases. *****ACTA PSYCHIATRICA SCANDINAVICA***** (REFERENCE 4 OF 35) 88306845 Traskman-Bendz L Stanley M Stanley B Matthews B Brown L N-acetylation and serotonergic measures in a group of psychiatric patients. Acta Psychiatr Scand 1988 Jun;77(6):736-40 Serotonin is N-acetylated to melatonin. The purpose of this study was to explore the possibility of N-acetylation of dapsone reflecting serotonergic activity. The ratio of monoacetyldapsone/dapsone (MAD/DDS) in plasma, 5-HIAA in CSF, and imipramine-binding to platelets were investigated in a group of psychiatric patients, diagnosed according to the DSM-III as affective disorders, schizophrenia, and personality disorders. There was no significant correlation between either of the serotonergic estimates and N- acetylation in the whole patient group or in diagnostic subgroups of patients. Sixty-four percent of the patients were slow N-acetylators (MAD/DDS less than 0.4), which is a ratio in line with several other studies of psychiatric patients. Among patients with affective disorders, all unipolar patients were slow N-acetylators, while five out of six bipolar patients were fast N-acetylators. The N- acetylation of patients with a history of suicide attempt did not differ from those without. The discrepancy in N-acetylation between uni- and bipolar patients might again address the issue of them representing two different biochemical and genetic disorders. Institutional address: University Hospital Department of Psychiatry I Lund Sweden. *****ACTA PSYCHIATRICA SCANDINAVICA. SUPPLEMENTUM***** (REFERENCE 5 OF 35) 91050701 Sedvall G Monoamines and schizophrenia. Acta Psychiatr Scand Suppl 1990;358:7-13 The hypothesis that central biogenic amines may play a role in the pathophysiology of schizophrenia was originally based upon the fact that hallucinogenic and antipsychotic drugs have profound effects on central transmitter pathways where dopamine, noradrenaline and serotonin are involved. The structural similarities between hallucinogenic drugs such as amphetamine and mescaline, and catecholamines on the one hand and lysergic acid diethylamide (LSD) and indolamines such as serotonin on the other hand have by direct experimentation been shown to explain their important effects on the transmitter systems. The marked effect of several classes of chemically different antipsychotic drugs on central dopamine receptor function formed the basis for the dopamine hypothesis regarding the mechanisms of action of these drugs and also for the hypothesis that dopamine D2 receptor function played a significant role in the pathophysiology of schizophrenia. Direct experimental analysis of aminergic functions in the brain of schizophrenic patients, both during life and post mortem, has been and will for the foreseeable future continue to be a rational approach to the further elucidation of the validity of these hypotheses. Analysis of metabolite levels in the cerebrospinal fluid and plasma of schizophrenic patients has shown great variation in the results with reports of both elevated and reduced release of amines in the brains of schizophrenic patients. Analysis of the aminergic receptor structures in the postmortem human brain has relatively consistently revealed an increased density of D2 receptors in the major basal ganglia of schizophrenic patients. Whether these alterations represent a primary feature of brain structure in schizophrenia or a drug-induced effect still remains to be shown. Positron emission tomographic (PET) scan studies of D2 receptors in schizophrenia have demonstrated both increased densities and absence of change in the characteristics of D2 receptors in the patients as compared to matched controls.(ABSTRACT TRUNCATED AT 250 WORDS) Institutional address: Department of Psychiatry and Psychology Karolinska Institute Stockholm Sweden. *****BIOLOGICAL PSYCHIATRY***** (REFERENCE 6 OF 35) 91002774 Lindstrom LH Wieselgren IM Klockhoff I Svedberg A Relationship between abnormal brainstem auditory-evoked potentials and subnormal CSF levels of HVA and 5-HIAA in first-episode schizophrenic patients. Biol Psychiatry 1990 Sep 1;28(5):435-42 Auditory brainstem-evoked responses (ABRs) were recorded and the CSF concentration of the amine metabolites homovanillic acid (HVA) and 5- hydroxyindoleacetic acid (5-HIAA) were measured in 39 drug-free schizophrenic patients. Twenty-four of the patients were first admissions and had never received antipsychotic medication. The ABRs were judged according to our normative data and the CSF concentrations of the amine metabolites were compared with those of 47 healthy volunteers. Clear-cut abnormal ABRs, identified as a lack of one or more peaks or abnormal peak latencies, were found in 15 patients. In controls and patients with normal ABRs, there was a significant positive correlation between the cerebrospinal fluid (CSF) levels of HVA and 5-HIAA; no such correlation was found in patients with abnormal ABRs. Schizophrenics with abnormal ABRs had significantly lower levels of HVA, but not 5-HIAA, in the CSF when compared with controls. Schizophrenic patients with normal ABRs (n = 24) did not differ from the controls with regard to the amine metabolites in CSF. A comparison of the CSF levels of HVA and 5-HIAA yielded no significant difference between patients with normal and those with abnormal ABRs. In contrast, when only first-episode, never- treated schizophrenics were considered, patients with abnormal ABRs (n = 10) had significantly lower levels of both HVA and 5-HIAA when compared with those having normal ABRs (n = 14). The results indicate an association between brainstem dysfunction and reduced central nervous dopaminergic and possibly also serotoninergic activity in schizophrenia. Institutional address: Psychiatric Research Center University of Uppsala Sweden. (REFERENCE 7 OF 35) 88107945 Muck-Seler D Jakovljevic M Deanovic Z Time course of schizophrenia and platelet 5-HT level. Biol Psychiatry 1988 Feb 1;23(3):243-51 The concentration of platelet serotonin (5-HT) and the simultaneous uptake of 5-HT into platelets have been investigated in schizophrenic patients with (A) intermittent time course of illness (complete remission), (B) chronic time course (partial remission and residual symptoms), and (C) intermittent-chronic time course (good remission at the beginning of illness with gradual progression to chronic stage). An increased platelet 5-HT concentration (i.e., hyperserotoninemia) of unknown etiology was observed, especially in the group with chronic time course of disease as compared to the normal controls. At the same time, kinetic constants Km and Vmax of 5- HT uptake into platelets were unchanged in all patients. Neuroleptic treatment did not produce any significant change either in platelet 5- HT level or in the uptake of 5-HT. These results provide further support for the possible 5-HT dysfunction in schizophrenia. Institutional address: Department of Experimental Biology and Medicine Rudjer Boskovic Institute Zagreb Yugoslavia. (REFERENCE 8 OF 35) 87076787 Mita T Hanada S Nishino N Kuno T Nakai H Yamadori T Mizoi Y Tanaka C Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics. Biol Psychiatry 1986 Dec;21(14):1407-14 Serotonin S2 and dopamine D2 receptors in the prefrontal cortex and caudate nucleus of postmortem brains of chronic schizophrenics were studied using 3H-ketanserin and 3H-spiperone, respectively. In the prefrontal cortex of schizophrenics, we found a significant decrease in the maximum number of 3H-ketanserin binding sites (Bmax), with no change in the dissociation constant (Kd). Conversely, both Bmax and Kd of 3H-spiperone binding to the caudate nucleus were significantly increased in the schizophrenic patients. There were no differences in receptor indices between patients who were taking neuroleptics until their death and those who had taken none for 2 months or more prior to death. These findings suggest that alterations in S2 receptors in the prefrontal cortex may reflect the disease process, per se, and that the increase in the number of D2 receptors in the caudate nucleus of schizophrenics is not due solely to neuroleptic medication. (REFERENCE 9 OF 35) 86000766 Stahl SM Uhr SB Berger PA Pilot study on the effects of fenfluramine on negative symptoms in twelve schizophrenic inpatients. Biol Psychiatry 1985 Oct;20(10):1098-102 We treated 12 chronic schizophrenic inpatients with fenfluramine, an anorexigenic drug that depletes serotonin, to test the hypothesis that the "negative" symptoms of schizophrenia might be related to brain serotonin activity. We measured change in both positive and negative symptoms in a double-blind, parallel-design trial of fenfluramine or placebo. Negative symptoms improved over time in some individuals within the active treatment group, but not in individuals within the placebo group. However, group comparisons of active treatment versus placebo were not significant. *****EUROPEAN ARCHIVES OF PSYCHIATRY AND NEUROLOGICAL SCIENCES***** (REFERENCE 10 OF 35) 89356755 Meltzer HY Bastani B Ramirez L Matsubara S Clozapine: new research on efficacy and mechanism of action. Eur Arch Psychiatry Neurol Sci 1989;238(5-6):332-9 Clozapine can produce greater clinical improvement in both positive and negative symptoms than typical antipsychotic drugs in neuroleptic- resistant schizophrenic patients. The clinical response may occur rapidly in some patients but is delayed in others. Clozapine has also been reported to produce fewer parkinsonian symptoms, to involve a lower risk of producing tardive dyskinesia, and to produce no serum prolactin elevations in man. It seems likely that these effects are the result of a common biological mechanism or related mechanisms, rather than unrelated effects. Other atypical antipsychotic drugs, such as melperone and fluperlapine, share at least some of these properties. A relatively low affinity for the D-2 dopamine (DA) receptor and high affinity for the 5-HT2 receptor, producing a high 5- HT2/D-2 ratio, best distinguishes atypical antipsychotics like clozapine from typical antipsychotic drugs. Through its weak antagonist action on D-2DA receptors and a potent inhibitory effect on 5-HT2 receptors, as well as its ability to increase DA and 5-HT2 release, clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions. The numerous advantages of clozapine over typical neuroleptics are consistent with the primary importance of DA to the pathophysiology of schizophrenia. The secondary but still significant role of 5-HT in the action of clozapine may either be direct or via the effect of 5-HT on dopaminergic mechanisms. Some aspects of schizophrenia could be due to a dysregulation of the interaction between serotonergic and dopaminergic neurotransmission. Institutional address: Department of Psychiatry Case Western Reserve University School of Medicine Cleveland OH 44106. *****HOSPITAL AND COMMUNITY PSYCHIATRY***** (REFERENCE 11 OF 35) 85129014 Brown RP Mann JJ A clinical perspective on the role of neurotransmitters in mental disorders. Hosp Community Psychiatry 1985 Feb;36(2):141-50 The authors first review the mechanisms of neural transmission. They then provide a detailed discussion of norepinephrine, dopamine, and serotonin--the three neurotransmitters that have been implicated most often in etiological studies of affective disorders and schizophrenia. After outlining the synthesis, location, and pharmacological response of these transmitters, the authors consider the role of neurotransmission in the theoretical models of depression and schizophrenia. *****JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY***** (REFERENCE 12 OF 35) 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 13 OF 35) 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. *****JOURNAL OF NEURAL TRANSMISSION. GENERAL SECTION***** (REFERENCE 14 OF 35) 91328962 Arora RC Meltzer HY Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J Neural Transm Gen Sect 1991;85(1):19-29 Serotonin2 (5-HT2) receptor binding was studied, using 3H-spiperone as the ligand, in post-mortem brain specimens obtained from schizophrenic patients (N = 11) and non-psychiatric controls (N = 11). The maximum number of binding sites (Bmax) was significantly decreased in schizophrenic patients as compared to normal controls. This difference did not appear to be due to neuroleptic treatment. No difference in Kd (an inverse measure of the affinity of 3H-spiperone to its binding sites) was observed between the two groups. However, studies with unmedicated schizophrenic patients are needed to draw any definite conclusion. The role of serotonergic processes in the psychobiology of schizophrenia is discussed. Institutional address: Department of Psychiatry School of Medicine Case Western Reserve University Cleveland OH. *****LAKARTIDNINGEN***** (REFERENCE 15 OF 35) 91041205 Carlsson A [Monoamine research--a productive field of particular importance in neuroscience] Monoaminforskningen--en aktiv forskning med sarstallning inom neurovetenskapen. Lakartidningen 1990 Nov 7;87(45):3764, 3767-9 (Published in Swedish) Modern monoamine research had its origin in work done in the 1950s and 1960s to elucidate the modes of action of the major groups of psychotropic drugs, since when it has played a spearhead role in neuroscience. For example, it has contributed much to the introduction of the chemicalneurotransmission concept in CNS- research. We are now about to reap the harvest of more than three decades of intensive and successful basic research, in the form of more efficacious and safer drugs for the treatment of certain important mental and neurological disorders, and the formulation of research strategies focused on prophylaxis. The paper reviews this development. Institutional address: Farmakologiska institutionen Goteborgs universitet. *****LIFE SCIENCES***** (REFERENCE 16 OF 35) 91117035 Hashimoto T Nishino N Nakai H Tanaka C Increase in serotonin 5-HT1A receptors in prefrontal and temporal cortices of brains from patients with chronic schizophrenia. Life Sci 1991;48(4):355-63 Binding studies with [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT), a specific serotonin1A (5-HT1A) receptor agonist, were done on the autopsied brains from control subjects and from patients with chronic schizophrenia. All the patients and controls were of the Japanese race. In the controls, representative Scatchard plots for the specific [3H]8-OH-DPAT bindings in the prefrontal cortex and hippocampus revealed a single component of high affinity binding site (Kd value = 5.7 and 5.9 nM, Bmax value = 80.1 and 101.0 fmol/mg protein, respectively). The [3H]8-OH-DPAT bindings to the prefrontal cortex and hippocampus were potently inhibited by serotonin (IC50 = 6.3 x 10(-9) M) and 5-HT1A agonists (IC50 = 5.0 x 10(-9) - 2.3 x 10(-7) M), while other neurotransmitters, 5-HT2 and 5- HT3 related compounds did not inhibit the binding (IC50 greater than 10(-5) M). The bindings were decreased in the presence of 0.1mM GTP and 0.1mM GppNHp but not in the presence of 0.1mM GMP. In the prefrontal and temporal cortices of schizophrenics, there was a significant increase in the specific [3H]8-OH-DPAT binding, by 40% and 60%, respectively, with no change in the hippocampus, amygdala, cingulum, motor cortex, parietal or occipital cortex, as compared to findings in the controls. Scatchard analysis showed that this increased binding reflects changes in the number of sites but not in the affinity. The effect of 0.1mM GppNHp on the binding to prefrontal cortex was observed in both controls and schizophrenic patients. The bindings were significantly greater in the schizophrenic patients than in controls, in the presence of 0.1mM GppNHp. Our findings suggest that there are GTP-sensitive 5-HT1A sites in the human brain and that selective increases in GTP-sensitive 5-HT1A sites in the prefrontal and temporal cortices of schizophrenics relate to the pathophysiology of schizophrenia. Institutional address: Department of Pharmacology Kobe University School of Medicine. (REFERENCE 17 OF 35) 89237711 Demeter E Tekes K Majorossy K Palkovits M Soos M Magyar K Somogyi E The asymmetry of 3H-imipramine binding may predict psychiatric illness. Life Sci 1989;44(19):1403-10 The Bmax and Kd values for 3H-imipramine binding were measured in post-mortem human brains from drug-free selected psychiatric subject homicide victims (n = 15) and normal controls (n = 15). The two groups were comparable in age and gender. The number of imipramine binding sites (Bmax) in the frontal cortices of psychiatric subjects had significantly higher Bmax values in the left hemisphere than in the right hemisphere. Inversely, the number of imipramine binding sites (Bmax) in the frontal cortices of normal controls were significantly higher in the right brain than in the left brain. It was postulated that the inhibiting effect of central serotonin (5-HT) has weakened in psychiatric cases, therefore the change of presynaptic serotonergic activity might be associated with psychiatric illness in the left hemisphere of human brain. Institutional address: Dept. of Forensic Medicine Semmelweis Medical University Budapest Hungary. *****MEDICAL HYPOTHESES***** (REFERENCE 18 OF 35) 90190449 van Woerkom AE The major hallucinogens and the central cytoskeleton: an association beyond coincidence? Towards sub-cellular mechanisms in schizophrenia. Med Hypotheses 1990 Jan;31(1):7-15 There appears to be a remarkably consistent structural and functional relationship between the phenylethylamine hallucinogens and the microtubule inhibitor colchicine. Such a relationship is not sustained in simple form through to the indoleamine hallucinogens and the indole based Vinca alkaloids. However, LSD and the more potent hallucinogens retain the full potential to disrupt the structure of the brain's cytoskeleton indirectly via serotonin and the raphe system. Serotonin appears to have a direct role in regulating and maintaining microtubules and microfilaments. It appears that a second receptor mediated action is required for full hallucinogenic activity. It is deduced that cytoskeletal restraints may have a role in governing central information processing. A theory for the cellular mechanisms of thought disorder and drug induced hallucinations is proposed. Schizophrenia may reflect a subtle disorder of central cytoskeletal function. Institutional address: University of Cambridge Clinical School Addenbrooke's Hospital UK. *****NEUROPSYCHOBIOLOGY***** (REFERENCE 19 OF 35) 89344364 Brambilla F Bondiolotti GP Maggioni M Sciascia A Grillo W Sanna F Latina A Picotti GB Vasopressin (DDAVP) therapy in chronic schizophrenia: effects on negative symptoms and memory. Neuropsychobiology 1989;20(3):113-9 Ten chronic undifferentiated schizophrenics, 6 men and 4 women, aged 28-63, with 6- to 31-year histories of the disease were given DDAVP to observe the effects of this neuropeptide on the prevalent negative symptoms of their illness. Patients were maintained on neuroleptic therapy and first given a 20-day course of placebo followed by 20 days of DDAVP i.m., 4 micrograms Andreasen Scale for assessment of negative symptoms, the Brief Psychiatric Rating Scale, the NOSIE Rating Scale and the Luria-Nebraska Rating Scale were administered to monitor negative symptomatology, behavior and memory before the study began, after placebo and after DDAVP administration. Patients were also given a growth hormone-clonidine test and in addition plasma basal concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5- hydroxyindoleacetic acid (5-HIAA) were measured at the same intervals. DDAVP therapy induced a significant improvement of negative symptomatology and a trend toward improvement of short- to medium-term memory. No changes in homovanillic acid, MHPG, 5-HIAA and DOPAC, nor of growth hormone response to clonidine stimulation were observed. Institutional address: Ospedale Psichiatrico Pini Milano Italia. *****PROGRESS IN NEURO-PSYCHOPHARMACOLOGY AND BIOLOGICAL PSYCHIATRY***** (REFERENCE 20 OF 35) 89129448 Sarai K Nakahara T Morioka S Yokota N Fukuchi H Tsukiai S Kitaura T Serum neuroleptic activities required to inhibit relapse in schizophrenic patients--a study by radioreceptor assay. Prog Neuropsychopharmacol Biol Psychiatry 1988;12(5):821-31 1. The serum levels of antidopaminergic (anti-D2), anti-alpha- adrenergic (anti-NA) and antiserotonergic (anti-5HT2) activities of neuroleptics were determined in schizophrenic patients on maintenance treatment. 2. The patients whose conditions remained stable had significantly higher serum levels of anti-D2 and anti-5HT2 activities than those who were considered to be in unstable conditions after a period of remission. 3. However, the serum levels of anti-5HT2 activity in patients whose conditions remained stable varied as much as those of anti-NA activities did, so it appeared that from a pharmacological viewpoint anti-D2 activity of neuroleptics was the most important in preventing a relapse in schizophrenic patient. 4. The serum levels of anti-D2 activity required to prevent relapses differed for each neuroleptic. 5. The frequency of side effects increased concordant with increasing serum levels of anti-D2, anti-NA and anti-5HT2 activities, and unfortunately even minimum effective serum levels of anti-D2 activity elicited slight side effects in the majority patients. Institutional address: Department of Neurology and Psychiatry Hiroshima University School of Medicine Japan. *****PSYCHIATRIC CLINICS OF NORTH AMERICA***** (REFERENCE 21 OF 35) 86177085 van Kammen DP Peters J van Kammen WB Cerebrospinal fluid studies of monoamine metabolism in schizophrenia. Psychiatr Clin North Am 1986 Mar;9(1):81-97 The authors review the studies of spinal fluid monoamines and their metabolites with and without probenecid and during drug-free and medicated conditions. Although technical knowhow and understanding of the variable that influence the actual levels measured has dramatically increased over the last 20 years, many questions still remain. Despite or rather because of advances such as CT, PET, and MRI, CSF studies still carry great promise for understanding the illness, predicting drug response, and behavioral change following drug withdrawal. (REFERENCE 22 OF 35) 86177074 Bracha HS Kleinman JE Postmortem neurochemistry in schizophrenia. Psychiatr Clin North Am 1986 Mar;9(1):133-41 The renaissance in postmortem studies in schizophrenia is in full bloom. Although there is no shortage of findings, there have been significant problems with replications and interpretations. Regardless, the postmortem approach remains a valid and promising one. Thus far, it has allowed for the testing of a number of hypotheses involving catecholamines, indoleamines, and neuropeptides in schizophrenia. It is hoped that new approaches, such as autoradiography and automated cell counting, will add new dimensions to postmortem studies of schizophrenia. If these studies can be coupled with premortem exams of patients, perhaps new inroads can be made in the understanding and treatment of the schizophrenic syndrome. *****PSYCHIATRY RESEARCH***** (REFERENCE 23 OF 35) 87092811 Arora RC Locascio JJ Meltzer HY 3H-imipramine binding in blood platelets of schizophrenic patients. Psychiatry Res 1986 Nov;19(3):215-24 3H-Imipramine binding was studied in the blood platelets of 51 unmedicated chronic schizophrenic patients. Univariate analyses of log-transformed data revealed that Bmax was significantly lower in schizophrenic patients than normal volunteers; Kd was nonsignificantly higher in the schizophrenics. A multivariate analysis of variance indicated the Kd and Bmax both differ significantly between normal controls and schizophrenic patients in the direction of increased Kd and decreased Bmax in the schizophrenics. These results indicate that decreased platelet imipramine binding is not specific for major depression. (REFERENCE 24 OF 35) 85216960 King R Faull KF Stahl SM Mefford IN Thiemann S Barchas JD Berger PA Serotonin and schizophrenia: correlations between serotonergic activity and schizophrenic motor behavior. Psychiatry Res 1985 Mar;14(3):235-40 Increased serotonergic activity in animals has been associated with a variety of stereotyped motor behaviors. In addition, serotonin facilitates brainstem, reticular, and spinal motor neuronal activity implicated in the expression of these behaviors. This report presents positive correlations between both peripheral (platelet serotonin levels) and central (cerebrospinal concentrations of 5-hydroxy- indoleacetic acid) measures of serotonin metabolism and the symptom of peculiar or unusual mannerisms and posturing in schizophrenic patients. The findings are discussed in light of the animal behavioral correlates of increased serotonergic activity and the stereotyped affectomotor behavior seen in some schizophrenic patients. *****PSYCHOPHARMACOLOGY***** (REFERENCE 25 OF 35) 90047426 Meltzer HY Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 1989;99 Suppl:S18-27 Clozapine administration to schizophrenic patients was found to produce dopamine2 (D-2) and serotonin2 (5-HT2) receptor blockade, as evidenced by the ability to block the increases in growth hormone and cortisol secretion produced by apomorphine and MK-212, respectively, direct acting dopamine (DA) and 5-HT2 agonists. Clozapine did not increase plasma prolactin (PRL) levels nor did it block the apomorphine-induced decrease in plasma PRL concentration, as would be expected from a D-2 receptor antagonist. These PRL results are consistent with the observation that clozapine may increase DA release. Clozapine also decreased plasma tryptophan, plasma homovanillac acid (HVA) and basal plasma cortisol levels. Rodent studies suggest clozapine also increases 5-HT release. We hypothesize that antagonism of D-2 and 5-HT2 receptors and enhancement of DA and 5-HT release are critical elements in the action of clozapine to minimize both positive and negative symptoms without producing significant extrapyramidal symptoms or plasma PRL increases. It is proposed that schizophrenia may also involve a dysregulation of 5-HT2- and D-2-mediated neurotransmission, and that a more normal balance in serotonergic and dopaminergic neurotransmission is at least partially restored by clozapine. Institutional address: Case Western Reserve University School of Medicine Cleveland OH 44106. (REFERENCE 26 OF 35) 85217037 Ceulemans DL Gelders YG Hoppenbrouwers ML Reyntjens AJ Janssen PA Effect of serotonin antagonism in schizophrenia: a pilot study with setoperone. Psychopharmacology (Berlin) 1985;85(3):329-32 The new antipsychotic drug setoperone is pharmacologically characterized by its potent serotonin and moderate dopamine receptor blocking properties. Forty chronic schizophrenic patients were included and 34 completed this pilot study. Following a drug-free period of 1 week the patients received setoperone 5 mg t.i.d. After 1 month of treatment, the psychotic symptoms, as measured by the BPRS, improved by approximately 50% (P less than 0.001) as compared with the condition under previous neuroleptic medication. Blockade of serotonin receptors may be related to improvement of autistic behaviour, dysphoria, and parkinson-like symptoms. In residual schizophrenic patients, the need for dopamine blockade, which is normally correlated with the therapeutic effect on positive symptoms, can be reduced substantially. *****SCHIZOPHRENIA BULLETIN***** (REFERENCE 27 OF 35) 91352568 Gerlach J New antipsychotics: classification, efficacy, and adverse effects. Schizophr Bull 1991;17(2):289-309 Compared to traditional neuroleptics, most of the new antipsychotics are characterized by a low extrapyramidal side effect (EPS) liability and varying antipsychotic efficacy. This topic is reviewed for four principal classes of new, established, and potential antipsychotics: (1) Antipsychotics such as sulpiride and remoxipride that block a subgroup of dopamine (DA) D2/D3 receptors produce a relatively low level of side effects, including EPS, and have an antipsychotic effect equal to or slightly weaker than traditional neuroleptics. D1 antagonists demonstrate a low level of EPS in primates and may prove to be a valuable new type of antipsychotic drug. (2) Theoretically, partial D2 agonists have the advantage of producing few or no EPS and a specific beneficial effect in negative symptoms, but as yet the expectations have not been fulfilled. (3) Nondopamine drugs such as serotonin (5HT1) agonists, 5HT2 antagonists, 5HT3 antagonists, and gamma-amino-butyric-acid-A (GABA-A) benzodiazepine agonists have anxiolytic, antidepressant, antiaggressive, and maybe antiparkinsonian effects and may play an adjunctive role in the treatment of schizophrenia. 5HT3 antagonists (e.g., ondansetron), partial benzodiazepine agonists, and partial glutamate agonists may prove to be effective antipsychotics. (4) Antipsychotics such as clozapine and risperidone, which affect D2/D3 receptors as well as 5HT, alpha 1, and/or D1 receptors appear to have the most pronounced antipsychotic effect. Institutional address: St. Hans Hospital Roskilde Denmark. (REFERENCE 28 OF 35) 89072614 Bleich A Brown SL Kahn R van Praag HM The role of serotonin in schizophrenia. Schizophr Bull 1988;14(2):297-315 Studies examining serotonin (5-hydroxytryptamine; 5HT) in schizophrenia show variable and inconsistent findings, which might reflect the heterogeneity of the disease. When these studies are reviewed in the light of Crow's "two-syndrome" paradigm of schizophrenia, a new trend emerges. It appears that 5HT findings may be related to certain features of Type II schizophrenia such as negative symptoms, degenerative brain changes, and chronicity in the following manner: (1) 5HT2 antagonists, which have recently become available, have been shown to have an antipsychotic effect, particularly on the negative symptom cluster. (2) Decreased levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid have been found to be correlated with cortical atrophy or ventricular enlargement in schizophrenic patients. (3) A subgroup of chronic schizophrenic patients has been shown to have elevated levels of platelet or whole blood 5HT. We propose, then, that 5HT dysfunction might be related to Type II, or negative syndrome, schizophrenia, and that the nature of this dysfunction might involve 5HT postsynaptic receptor hypersensitivity. We further suggest that the pharmacotherapy of schizophrenia should include a 5HT-blocking component, as well as a dopamine-blocking component, and we propose that future research should address the role of selective 5HT receptor hypersensitivity in schizophrenia. Institutional address: Department of Psychiatry Albert Einstein College of Medicine Bronx NY 10561. (REFERENCE 29 OF 35) 87263233 Meltzer HY Biological studies in schizophrenia. Schizophr Bull 1987;13(1):77-111 The question of whether schizophrenia is associated with structural or functional abnormalities of the nervous system, or both, has become the principal focus of biological studies of schizophrenia. Computed tomography studies have revealed ventricular enlargement and cortical atrophy in a subgroup of schizophrenic patients. While present from the early stages of the illness, they appear to be most severe in patients with negative symptoms and poor outcome. Quantitative neuropathological studies have tentatively demonstrated decreased volume of specific brain areas, neuronal loss, and other changes in the limbic system, basal ganglia, and frontal cortex. Dopamine (DA) remains the neurotransmitter most likely to be involved in schizophrenia, although there is also evidence for disturbances of serotonin and norepinephrine. Post-mortem and positron emission tomographic studies suggest an increased number of D2 DA receptors in some schizophrenics. Neuroendocrine studies reinforce the role of DA in schizophrenics. Viral infections and autoimmune disturbances may be responsible for some types of schizophrenia, but there is no firm experimental evidence to support either hypothesis. The possibility that mixtures of structural abnormalities and functional changes involving DA occur in the same patients rather than independently as part of two syndromes (Type I, II) seems attractive. Future studies should identify subtypes of schizophrenia based on biological criteria and contribute to identification of specific genetic abnormalities which increase vulnerability to manifest the schizophrenic phenotype. *****SCHIZOPHRENIA RESEARCH***** (REFERENCE 30 OF 35) 91248791 Deutch AY Moghaddam B Innis RB Krystal JH Aghajanian GK Bunney BS Charney DS Mechanisms of action of atypical antipsychotic drugs. Implications for novel therapeutic strategies for schizophrenia. Schizophr Res 1991 Mar-Apr;4(2):121-56 The mechanisms which contribute to the actions of atypical antipsychotic drugs, such as clozapine and the putative atypical agents remoxipride and raclopride, are reviewed. Examination of available preclinical and clinical data leads to two hypotheses concerning the mode of action of atypical antipsychotic drugs. The first hypothesis is that antagonism of the dopamine D2 receptor is both necessary and sufficient for the atypical profile, but that interaction with subtypes of the D2 receptor differentiates typical from atypical antipsychotic drugs. The second hypothesis has been previously advanced, and suggests that a relatively high ratio of serotonin 5-HT2:dopamine D2 receptor antagonism may subserve the atypical profile. It seems likely that the atypical antipsychotic drug profile may be achieved in more than one way. Institutional address: Department of Psychiatry Yale University School of Medicine New Haven CT 06510. (REFERENCE 31 OF 35) 91120442 Castelao JF Ferreira L Gelders YG Heylen SL The efficacy of the D2 and 5-HT2 antagonist risperidone (R 64,766) in the treatment of chronic psychosis. An open dose-finding study. Schizophr Res 1989 Jul-Oct;2(4-5):411-5 After a wash-out period of 1 week, 20 patients suffering from schizophrenia were treated for 4 weeks in an open dose-finding study with a new serotonin-dopamine antagonist risperidone. All patients completed the trial. The mean daily dose of risperidone was 4.6 mg (range 2-10 mg) at completion. Risperiodone had a rapid onset of action: a highly significant decrease of the total BPRS score (Brief Psychiatric Rating Scale) was already noticed at the end of the second week. This decrease was found in all BPRS factors after 4 weeks. In spite of the withdrawal of antiparkinson medication at selection, a clear decrease of EPS (extrapyramidal symptoms), assessed on the Simpson and Angus Scale, was observed. The Global Therapeutic Impression agreed to the BPRS scores, showing a highly significant improvement after 2 weeks of treatment. Risperidone was very well tolerated, only mild side effects were reported. Vital signs, electrocardiographic parameters and laboratory values remained normal during the trial. This study indicates that risperidone can be an effective and well-tolerated alternative in the treatment of chronic schizophrenia, combining an antipsychotic activity, a beneficial effect on anergia and anxiety depression and a low EPS- inducing profile. Institutional address: Casa de Saude do Telhal Lisboa Portugal. (REFERENCE 32 OF 35) 91151919 Lerer B Ran A Blacker M Silver H Weller MP Drummer D Ebstein B Calev A Neuroendocrine responses in chronic schizophrenia. Evidence for serotonergic dysfunction. Schizophr Res 1988 Nov-Dec;1(6):405-10 Neuroendocrine and mood responses to a 60 mg oral dose of the serotonin-releasing agent, fenfluramine, were assessed in ten neuroleptic-free, chronic schizophrenic patients and in age- and sex- matched normal control subjects. The prolactin (PRL) response to fenfluramine was significantly blunted in the schizophrenic subjects. Growth hormone and cortisol levels were not differentially affected by the challenge. There was no significant effect of fenfluramine on mood in either group. The blunted PRL response in the schizophrenic group suggests serotonergic dysfunction; possible mechanisms of this finding and implications for treatment are considered. Institutional address: Jerusalem Mental Health Center-Ezrath Nashim Hospital Israel. *****SEMINARS IN ARTHRITIS AND RHEUMATISM***** (REFERENCE 33 OF 35) 85300571 Malek-Ahmadi P Rheumatoid arthritis and schizophrenia: are they mutually exclusive? Semin Arthritis Rheum 1985 Aug;15(1):70-2 The relationship between schizophrenia and rheumatoid arthritis has been explored in a number of studies. It has been claimed that the two disorders are mutually exclusive. Review of the literature indicates that the two conditions seldom coexist. The underlying mechanisms responsible for the infrequent coexistence of schizophrenia and rheumatoid arthritis are far from clear. However, various hypotheses have been proposed to explain the negative correlation between the two diseases. *****SLEEP***** (REFERENCE 34 OF 35) 91327044 Benson KL Faull KF Zarcone VP Jr Evidence for the role of serotonin in the regulation of slow wave sleep in schizophrenia. Sleep 1991 Apr;14(2):133-9 Nocturnal sleep data and cerebrospinal fluid (CSF) concentrations of the biogenic amine metabolites were measured in 20 male schizophrenics. Consistent with other reports of a stage 4 sleep deficit in schizophrenia, measures of stage 4 sleep were low relative to normal reference data. Measures of stage 4 sleep in absolute amounts and corrected for total sleep were positively correlated with CSF concentrations of the serotonin metabolite, 5-hydroxyindole acetic acid (5-HIAA). CSF 5-HIAA was also correlated with measures of stage 3 sleep and total sleep time suggesting that serotonin may modulate the amount of slow wave sleep broadly defined and possibly sleep duration. Total stage 4 time was also correlated with the dopamine metabolite HVA; consequently, the specificity of the finding might be limited. Also, in this study, schizophrenia was used as a particular model for stage 4 deficits; however, the association of measures of stage 4 sleep with CSF levels of 5-HIAA is not thought to be specific to schizophrenia. Institutional address: Department of Psychiatry Veterans Administration Medical Center Palo Alto California 94304. *****ZENTRALBLATT FUR NEUROCHIRURGIE***** (REFERENCE 35 OF 35) 89205102 Kolarik J Nadvornik P Tabarka K Dvorak M Rozhold O Transplantation of human embryonic nerve tissue into a schizophrenic's brain. Zentralbl Neurochir 1988;49(3):147-50 Inspired by current knowledge of the possible participation of monoamines in the origin of schizophrenia and by experimental experience with embryonic nerve tissue transplantations, the authors ventured implantation of a human embryo's nervous tissue into a schizophrenic's brain. Six cubic millimeters of the transplant were placed in the septal area of both hemispheres. The substantial improvement of the clinical picture and, particularly, distinct improvement of memory abilities in the patient can more likely be attributed to the effect of the transplant rather than to the simultaneous mechanical intervention in the target structure of the recipient's brain. Institutional address: Research Institute of Higher Nervous Activity Palacky University Olomoue Czechoslovakia.