Hostname: page-component-586b7cd67f-dlnhk Total loading time: 0 Render date: 2024-12-01T00:27:21.753Z Has data issue: false hasContentIssue false
  • English
  • Français

Determinants for clinical activity of neuroleptic drugs: chemical substances, doses, assessment tools

Published online by Cambridge University Press:  28 April 2020

P. Boyer  and
A.J. Puech
P. Boyer
Affiliation:
INSERM, Clinique des Maladies Mentales et de l’Encéphale, 100, rue de la Santé, 75014Paris, France
A.J. Puech
Affiliation:
Département de Pharmacologie Clinique, Hôpital de la Salpêtrière, 47, bd de l'Hôpital 75013Paris, France
Get access

Summary

As emphasized by Lecrubier in 1980, the major finding of the last thirty years of classical neuroleptic use in schizophrenia is not that they are antischizophrenic or antipsychotic agents, but that they act on positive symptoms whatever the cause. There is now a widely accepted attribution of this kind of therapeutic property to the post-synaptic dopaminergic blockade induced by most of the neuroleptics when administered at high doses. On the other hand, during the last decade, various authors have reported clear evidence for a disinhibitory action of some neuroleptics when used at low doses. From a clinical point of view, the literature on the therapeutic action of low doses of neuroleptics seems quite controversial. In order to assess the exact determinants for clinical activity of neuroleptics (such as patient type, selected substances, administered doses) two series of independent controlled studies were conducted.

First series of studies: active drugs at low and high doses in schizophrenic patients

(Tables 1 to 6)

The first study was designed to assess the change of negative symptoms under low doses of neuroleptics. Sixty-two patients meeting the DSM III criteria of schizophrenia (subtypes: disorganized, catatonic or residual) were randomly assigned after a three-week washout period to six weeks’ treatment with either amisulpride (50 to 300 mg/day) or fluphenazine (2 to 12 mg/day), administered in keeping with a flexible dosage schedule. All patients had to meet the Andreasen criteria for negative symptoms (at least two of the following components had to be checked as present: anhedonia, alogia, affective flattening, avolition-apathy, attentional impairment). None of the patients presented one of the positive components to a marked degree: hallucinations, delusions, bizarre behavior, positive formal thought disorders. The evolution of symptomatology was assessed by means of the Brief Psychiatric Rating Scale (B.P.R.S.) and an ad hoc defective symptoms scale (D.S.A.S.), the sensitivity and reliability of which was previously tested in our department. The results show that the two groups (amisulpride versus fluphenazine) were initially highly comparable. Negative symptoms were severe, as evidenced by the D.S.A.S. scores, and by the presence of three items of the A6 criterion of the DSM III. The final global clinical assessment and the final D.S.A.S. scores both showed a significant improvement, with no statistically significant difference between the two treatments. Nevertheless, the scores of the “anergia” and “anxiety-depression” factors of the B.P.R.S. showed a significantly greater improvement in the amisulpride group.

The second study, complementary to the first, aimed to check the efficacy of high doses of amisulpride on the productive symptoms of schizophrenia. In this case, only the B.P.R.S. was used due to the good correlation of this scale with the global severity of the positive symptomatology. After three weeks of treatment, consisting either of amisulpride at a high, flexible dosage (800 to 1200 mg/day) or of haloperidol (20 to 30 mg/day), each of the two groups of twenty patients showed a significant improvement. In particular, the “thought disorders” factor of the B.P.R.S. (which unfortunately does not correspond exactly to the “formal thought disorder” component of the Andreasen positive symptoms scale - S.A.P.S.) was greatly improved in both groups. Evolution of the other symptoms was however identical in the two groups.

Second series of studies: active drugs versus placebo in schizophrenia

(Figures 1 to 6)

As we know, dopaminergic blocking agents are able to induce negative symptomatology. Consequently, to separate the secondary syndrome from the true deficit, a longer washout period than that previously described has to be imposed. On the other hand, the longitudinal course of schizophrenia must be taken into account for correct interpretation of changes in symptomatology; for example, patients with negative symptoms may abruptly present productive episodes, in particular during the neuroleptic withdrawal period. For optimal control of these two variables (natural history of the disease, the blunting effect of neuroleptics), 90 patients presenting either or both subtypes of schizophrenia were selected and included in a two-step, double-blind, controlled study. Patients with negative symptoms underwent a six-week washout period, after which they were treated either with low doses of amisulpride (100 or 300 mg/day) or a placebo. Patients with initial positive symptoms received mandatory high doses of amisulpride. According to the protocol, negative patients presenting productive symptoms during the washout period were to be systematically assigned to the highdose group. First results concerning 38 patients with a predominant negative symptomatology are presented here. A very clear improvement can be shown both for the SANS global mean score and for the sum of global ratings in the groups treated with low doses of amisulpride compared to the placebo group. The scores of the alogia, blunted affect and attentional impairment subscales decrease dramatically as well with the active drug.

Keywords

SchizophreniaNegative symptomsPositive symptomsNeurolepticsBenzamidesSchizophrénieSymptômes négatifsSymptômes positifsNeuroleptiquesBenzamides
Type
Research Article
Information
Psychiatry and Psychobiology , Volume 2 , Issue 4 , 1987 , pp. 296 - 305
Copyright
Copyright © European Psychiatric Association 1987

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References/Bibliographie

Alfredsson, G. - Effects of sulpiride and chlorpromazine on autistic and positive psychotic symptoms in schizophrenic patients; relationship to drug concentrations. Psychopharmacology 1985; 85: 8–13.CrossRefGoogle ScholarPubMed
Andreasen, N. - Positive vs negative schizophrenia: a critical evaluation. Schizophr Bull 1985; 11: 380–389.CrossRefGoogle ScholarPubMed
Andreasen, N. - Evaluation of positive and negative symptoms in schizophrenia. Psychiatry Psychobiol 1986; I, 2: 108–123.Google Scholar
Angrist, B., Rotrosen, J., Gershon, S. - Response to Apomorphine Amphetamine and Neuroleptics in Schizophrenic Subjects. Psychopharmacology 1980; 67: 31–38.CrossRefGoogle ScholarPubMed
Angrist, B., Rotrosen, S., Gerhson, S. - Differential Effects of Amphetamine and Neuroleptics on Negative vs Positive Symptoms in Schizophrenia. Psychopharmacology 1980; 72: 17–19.CrossRefGoogle Scholar
Angrist, B. - CNS stimulants as tools in the study of schizophrenia. Trends in Neurosci 1984; 7: 388–390.CrossRefGoogle Scholar
Asberg, M., Perris, C., Schalling, O., Sedvall, G. - The CPRS - Development and applications of a psychiatric rating scale. Acta Psychiatr Scand 1978; suppl 271.Google Scholar
Boyer, P. - Biochimie et pharmacologie des benzamides. Sem Hôp Paris 1983; 59: 831–835.Google Scholar
Boyer, P. - Etude de l’efficacité de faibles doses de neuroleptiques atypiques dans les états déficitaires. Ann Med Psychol 1986; 6: 593–599.Google Scholar
Carnoy, P., Ravard, S., Hervé, D., Tassin, J.P., Soubrie, P. - Apomorphine-induced operant deficits: a neuroleptic- sensitive but drug - and dose - dependent animal model of behavior Psychiatry Psychobiol 1987; II, 4: 266–275Google Scholar
Casey, J.F., Bennett, J.F., Lindley, C.J., Hollister, L.E., Gordon, M.H., Pringer, N.W. - Drug therapy in schizophrenia: a controlled study of the relative affectiveness of chlorpromazine, promazine, phenobarbital and placebo. Arch Gen Psychiatry 1980; 2: 210–220.CrossRefGoogle Scholar
Chouinard, G., Jones, B.D. - Evidence of brain dopamine deficiency with schizophrenia. Can J Psychiatry 1979; 24: 661–667.CrossRefGoogle ScholarPubMed
Cole, J.O., Klerman, G.L., Goldberg, S.C. - Phenotiazine treatment in acute schizophrenia. Arch Gen Psychiatry 1964; 10: 246–261.Google Scholar
Colonna, L., Petit, M. - L’effet stimulant des neuroleptiques. Mythe ou réalité ? Encéphale 1979; 5: 239–242.Google Scholar
Crow, T.J. - Positive and negative symptoms and the role of Dopamine. Br J Psychiatry 1981; 139: 251–254.CrossRefGoogle ScholarPubMed
Crow, T.J. - Molecular pathology of schizophrenia: more than one disease process? Br Med J 1980; 200: 66–68.CrossRefGoogle Scholar
Davis, K.L. - Plasma homovanillic acid concentration and the severity of schizophrenic illness. Science 1983; 227: 1601–1602.CrossRefGoogle Scholar
Deniker, P. - Encycl Méd Chir 1973; 37860-B20.Google Scholar
Goldberg, S.C. - Negative and deficit symptoms in schizophrenia do respond to neuroleptics. Schizophr Bull 1985; 11: 453–456.CrossRefGoogle ScholarPubMed
Guelfi, J.D., Pull, C.B., Guelfi, G., Ruschel, S., Dreyfus, J.-F. - CHESS - Utilisation dans la pathologie anxieuse et dépressive. Structure factorielle. Ann Med Psychol 1983; 3: 257–278.Google Scholar
Johnstone, E.C., Crow, T.J., Frith, C.D. - Cerebral ventricular size and cognitive impairment in chronic schizophrenia. The Lancet 1976; 30: 924–926.CrossRefGoogle Scholar
Johnstone, E.C., Crow, T.J., Frith, C.D. - The dementia of dementia precox. Acta Psychiatr Scand 1978; 57: 304–324.CrossRefGoogle Scholar
Kane, J.-M., Rifkin, A. et al. - High dose versus low dose strategies in the treatment of schizophrenia. Psychopharmacol Bull 1985; 21, 3: 533–537.Google Scholar
Karoum, F., Karson, C.N., Bigelow, L.B., Lawson, W.B., Wyatt, R.J. - Preliminary evidence of reduced combined output of dopamine and its metabolites in chronic schizophrenia. Arch Gen Psychiatry 1987; 44: 604–607.CrossRefGoogle ScholarPubMed
Kleinman, J.E., Bridge, P., Kamoun, F., Speciale, S. - Catecholamines and metabolites in the brains of psychotics and normals: post mortem studies, In: Udsin, E., Kopin, I.J. & Barchas, J.J. eds Catecholamines: Basic and Clinical Frontiers, 1845–1848, Pergamon Press, New York, 1979.CrossRefGoogle Scholar
Lapierre, Y.D., Lavallee, J. - Pimozide and the social behavior of schizophrenics. Curr Ther Res 1975; 18: 181–188.Google ScholarPubMed
Lecrubier, Y., Puech, A.J. - Schizophrénie : hyper ou hypofonctionnement dopaminergique : une hypothèse bipolaire. Psychologie Méd 1980; 12: 2431–2441.Google Scholar
Lecrubier, Y., Douillet, P. - Neuroleptics and the bipolar dopaminergic hypothesis of schizophrenia, In: Special aspects of psychopharmacology, 375–382, Exp. Sc. Fr. Ed. Paris 1983.Google Scholar
Liddle, - Dimensional classification of positive and negative symptoms in schizophrenia. Communication, 3rd Winter Conference on schizophrenia, Davos, 1983.Google Scholar
Lieberman, J.A., Kane, J.M., Aluir, J. - Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology 1987; 421–431.Google Scholar
Mackay, - Positive and negative schizophrenic symptoms and the role of dopamine. Br J Psychiatry 1980; 2: 213–219.Google Scholar
May, P.R. - Schizophrenia: a follow-up study of the results of five forms of treatment. Arch Gen Psychiatry 1981; 38: 776–784.CrossRefGoogle ScholarPubMed
Overall, J.E. - The Brief Psychiatric Rating Seule, E.C.D.E.U. Manual; 1971, 1978.Google Scholar
Petit, M., Zahn, M., Colonna, L. - Etude contrôlée de l’effet désinhibiteur de faibles doses de sulpiride dans les psychoses schizophréniques déficitaires. Encéphale 1984; 10: 557–559.Google Scholar
Puech, A.J., Lecrubier, Y., Laurille, C., Simon, P. - Pharmacological study for classification of benzamides. Abstract, XIIIth CINP Congress, 1982, Jerusalem, June 21-26.Google Scholar
Spitzer, R., Endicott, J. - Research Diagnostic Criteria: Rationale and Reliability. Arch Gen Psychiatry 1978; 35: 773–782.CrossRefGoogle ScholarPubMed
Wyatt, R.J. - The Dopamine Hypothesis: variations on a theme. Psychopharmacol Bull 1986; 223: 923–927.Google Scholar
Submit a response

Comments

No Comments have been published for this article.