Hostname: page-component-78c5997874-m6dg7 Total loading time: 0 Render date: 2024-11-19T02:17:31.622Z Has data issue: false hasContentIssue false
  • English
  • Français

Antipsychotic drugs v. barbiturates or benzodiazepines used as active placebos for schizophrenia: a systematic review and meta-analysis

Published online by Cambridge University Press:  18 October 2019

Spyridon Siafis Open the ORCID record for Spyridon Siafis [Opens in a new window] ,
Giacomo Deste ,
Anna Ceraso ,
Christian Mussoni ,
Antonio Vita ,
Senad Hasanagic ,
Johannes Schneider-Thoma Open the ORCID record for Johannes Schneider-Thoma [Opens in a new window] ,
Georgios Papazisis Open the ORCID record for Georgios Papazisis [Opens in a new window] ,
John M Davis  and
Stefan Leucht Open the ORCID record for Stefan Leucht [Opens in a new window]
Spyridon Siafis*
Affiliation:
Department of Psychiatry and Psychotherapy, School of Medicine, Technische Universität München, München, Germany
Giacomo Deste
Affiliation:
Department of Psychiatry, Spedali Civili Hospital, Brescia, Italy
Anna Ceraso
Affiliation:
Department of Psychiatry, Spedali Civili Hospital, Brescia, Italy
Christian Mussoni
Affiliation:
Department of Psychiatry, Spedali Civili Hospital, Brescia, Italy
Antonio Vita
Affiliation:
Department of Psychiatry, Spedali Civili Hospital, Brescia, Italy
Senad Hasanagic
Affiliation:
Medical Center of the University of Sarajevo, Sarajevo, Bosnia and Herzegovina
Johannes Schneider-Thoma
Affiliation:
Department of Psychiatry and Psychotherapy, School of Medicine, Technische Universität München, München, Germany
Georgios Papazisis
Affiliation:
Department of Clinical Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
John M Davis
Affiliation:
Department of Psychiatry, University of Illinois at Chicago, Chicago, USA Illinois and Maryland Psychiatric Research Center, Baltimore, Maryland, USA
Stefan Leucht
Affiliation:
Department of Psychiatry and Psychotherapy, School of Medicine, Technische Universität München, München, Germany
*
Author for correspondence: Spyridon Siafis, E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Comparisons of antipsychotics with placebo can be biased by unblinding due to side effects. Therefore, this meta-analysis compared the efficacy of antipsychotics for acute schizophrenia in trials using barbiturates or benzodiazepines as active placebos.

Methods

Randomized controlled trials (RCTs) in acute schizophrenia with at least 3 weeks duration and comparing any antipsychotic with barbiturates or benzodiazepines were eligible. ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, PubMed, WHO-ICTRP as well as previous reviews were searched up to 9 January 2018. Two separate meta-analyses, one for barbiturates and one for benzodiazepines, were conducted using random-effects models. The primary outcome was response to treatment, and mean values of schizophrenia rating scales and dropouts were analyzed as secondary outcomes. This study is registered with PROSPERO (CRD42018086263).

Results

Seven barbiturate-RCTs (number of participants n = 1736), and two benzodiazepine-RCTs (n = 76) were included in the analysis. The studies were published between 1960 and 1968 and involved mainly chronically ill patients. More patients on antipsychotics in comparison to barbiturates achieved a ‘good’ response (36.2% v. 16.8%; RR 2.15; 95% CI 1.36–3.41; I2 = 48.9) and ‘any’ response (57.4% v. 27.8%; RR 2.07; 95% CI 1.35–3.18; I2 = 68.2). In a single small trial (n = 60), there was no difference between antipsychotics and benzodiazepines on ‘any’ response (74.7% v. 65%; RR 1.15; 95% CI 0.82–1.62).

Conclusions

Antipsychotic drugs were more efficacious than barbiturates, based on a large sample size. Response ratios were similar to those observed in placebo-controlled trials. The results on benzodiazepines were inconclusive due to the small number of studies and participants.

Keywords

First-generationphenobarbitalphenothiazinesrandomizedresponse
Type
Original Articles
Information
Psychological Medicine , Volume 50 , Issue 15 , November 2020 , pp. 2622 - 2633
Check for updates
Copyright
Copyright © Cambridge University Press 2019

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

Adelson, D and Epstein, L (1962) A study of phenothiazines with male and female chronically ill schizophrenic patients. Journal of Nervous and Mental Disease 134, 543–554.CrossRefGoogle ScholarPubMed
Begg, C, Cho, M, Eastwood, S, Horton, R, Moher, D, Olkin, I, Pitkin, R, Rennie, D, Schulz, K, Simel, D and Stroup, D (1996) Improving the quality of reporting of randomized controlled trials. The CONSORT statement. Journal of the American Medical Association 276, 637–639.CrossRefGoogle ScholarPubMed
Bender, S, Olbrich, H, Fischer, W, Hornstein, C, Schoene, W, Falkai, P, Haarmann, C, Berger, M and Gastpar, M (2003) Antipsychotic efficacy of the antidepressant trimipramine: a randomized, double-blind comparison with the phenothiazine perazine. Pharmacopsychiatry 36, 61–69.CrossRefGoogle ScholarPubMed
Brunoni, AR, Tadini, L and Fregni, F (2010) Changes in clinical trials methodology over time: a systematic review of six decades of research in psychopharmacology. PLoS ONE 5, e9479.CrossRefGoogle ScholarPubMed
Carpenter, W and Davis, J (2012) Another view of the history of antipsychotic drug discovery and development. Molecular Psychiatry 17, 1168–1173.CrossRefGoogle ScholarPubMed
Casey, J, Bennett, I, Lindley, C, Hollister, L, Gordon, M and Springer, N (1960 a) Drug therapy in schizophrenia. A controlled study of the relative effectiveness of chlorpromazine, promazine, phenobarbital, and placebo. AMA Archives of General Psychiatry 2, 210–220.CrossRefGoogle ScholarPubMed
Casey, J, Lasky, J, Klett, C and Hollister, L (1960 b) Treatment of schizophrenic reactions with phenothiazine derivatives. American Journal of Psychiatry 117, 97–105.CrossRefGoogle ScholarPubMed
Clark, M, Ray, T, Paredes, A, Costiloe, J, Chappell, J, Hagans, J and Wold, S (1961) Chlorpromazine in chronic schizophrenic women: I. Experimental design and effects at maximum point of treatment. Psychopharmacologia 2, 107–136.CrossRefGoogle ScholarPubMed
Davis, J and Chen, N (2004) Dose response and dose equivalence of antipsychotics. Journal of Clinical Psychopharmacology 24, 192–208.CrossRefGoogle ScholarPubMed
Davis, J, Barter, J and Kane, J (1989) Antipsychotic drugs. In Baltimore, MWW (ed.), Comprehensive Textbook of Psychiatry. Baltimore: Williams & Wilkins Co. pp. 1591–1626.Google Scholar
DerSimonian, R and Laird, N (1986) Meta-analysis in clinical trials. Controlled Clinical Trials 7, 177–188.CrossRefGoogle ScholarPubMed
Dold, M, Li, C, Tardy, M, Khorsand, V, Gillies, D and Leucht, S (2012) Benzodiazepines for schizophrenia. The Cochrane Database of Systematic Reviews 11, Cd006391.Google Scholar
Egger, M, Smith, G, Schneider, M and Minder, C (1997) Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629.CrossRefGoogle ScholarPubMed
Elbourne, D, Altman, D, Higgins, J, Curtin, F, Worthington, H and Vail, A (2002) Meta-analyses involving cross-over trials: methodological issues. International Journal of Epidemiology 31, 140–149.CrossRefGoogle ScholarPubMed
Furukawa, T, Akechi, T, Wagenpfeil, S and Leucht, S (2011) Relative indices of treatment effect may be constant across different definitions of response in schizophrenia trials. Schizophrenia Research 126, 212–219.CrossRefGoogle ScholarPubMed
Gallant, D, Bishop, M, Nesselhof, W and Sprehe, D (1965) Further observations on trifluperidol: a butyrophenone derivative. Psychopharmacologia 7, 37–43.CrossRefGoogle ScholarPubMed
Gardner, D, Murphy, A, O'Donnell, H, Centorrino, F and Baldessarini, R (2010) International consensus study of antipsychotic dosing. American Journal of Psychiatry 167, 686–693.CrossRefGoogle ScholarPubMed
Guy, W, National Institute of Mental Health, Psychopharmacology Research Branch & Program ECDE (1976) ECDEU assessment manual for psychopharmacology. U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs: Rockville, Md.Google Scholar
Heiss, WD, Hoyer, J and Thalhammer, G (1976) Antipsychotic drugs and dopamine-mediated responses in Aplysia neurons. Journal of Neural Transmission 39, 187–208.CrossRefGoogle ScholarPubMed
Higgins, JPT and Green, S (2011) Cochrane Handbook for Systematic Reviews of Interventions. Chichester: Wiley and Sons, UK. (Version 5.1.0 [updated March 2011]).Google Scholar
Holden, J, Itil, T, Keskiner, A and Fixk, M (1968) Thioridazine and chlordiazepoxide, alone and combined, in the treatment of chronic schizophrenia. Comprehensive Psychiatry 9, 633–643.CrossRefGoogle ScholarPubMed
Hollister, L (1972) Clinical use of psychotherapeutic drugs. I. Antipsychotic and antimanic drugs. Drugs 4, 321–360.CrossRefGoogle ScholarPubMed
Hollister, L, Erickson, G and Motzentecker, F (1960) Trifluoperazine in chronic psychiatric patients. Journal of Clinical & Experimental Psychopathology & Quarterly Review of Psychiatry and Neurology 21, 15–23.Google ScholarPubMed
Huhn, M, Nikolakopoulou, A, Schneider-Thoma, J, Krause, M, Samara, M, Peter, N, Arndt, T, Backers, L, Rothe, P, Cipriani, A, Davis, J, Salanti, G and Leucht, S (2019) Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 394(10202): 939–951.CrossRefGoogle ScholarPubMed
Jensen, JS, Bielefeldt, AO and Hrobjartsson, A (2017) Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview. Journal of Clinical Epidemiology 87, 35–46.CrossRefGoogle ScholarPubMed
Klein, DF and Davis, JM (1969) Diagnosis and Drug Treatment of Psychiatric Disorders. Baltimore: Williams & Wilkins.Google Scholar
Kurland, A, Hanlon, T, Tatom, M, Ota, K and Simopoulos, A (1961 a) The comparative effectiveness of six phenothiazine compounds, phenobarbital and inert placebo in the treatment of acutely ill patients: global measures of severity of illness. Journal of Nervous and Mental Disease 133, 1–18.CrossRefGoogle ScholarPubMed
Kurland, A, Hanlon, T, Tatom, M and Simopoulos, A (1961 b) Comparative studies of the phenothiazine tranquilizers: methodological and logistical considerations. Journal of Nervous and Mental Disease 132, 61–74.CrossRefGoogle ScholarPubMed
Kurland, A, Michaux, M, Hanlon, T, Ota, K and Simopoulos, A (1962) The comparative effectiveness of six phenothiazine compounds, phenobarbital and inert placebo in the treatment of acutely ill patients: personality dimensions. Journal of Nervous and Mental Disease 134, 48–60.CrossRefGoogle ScholarPubMed
Leucht, S, Kane, JM, Kissling, W, Hamann, J, Etschel, E and Engel, R (2005) Clinical implications of Brief Psychiatric Rating Scale scores. British Journal of Psychiatry 187, 366–371.CrossRefGoogle ScholarPubMed
Leucht, S, Davis, J, Engel, R, Kane, J and Wagenpfeil, S (2007) Defining ‘response’ in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacology 32, 1903–1910.CrossRefGoogle ScholarPubMed
Leucht, S, Heres, S, Hamann, J and Kane, J (2008) Methodological issues in current antipsychotic drug trials. Schizophrenia Bulletin 34, 275–285.CrossRefGoogle ScholarPubMed
Leucht, S, Engel, R, Davis, J, Kissling, W, Meyer Zur Capellen, K, Schmauss, M and Messer, T (2012) Equipercentile linking of the Brief Psychiatric Rating Scale and the Clinical Global Impression Scale in a catchment area. European Neuropsychopharmacology 22, 501–505.CrossRefGoogle Scholar
Leucht, S, Cipriani, A, Spineli, L, Mavridis, D, Orey, D, Richter, F, Samara, M, Barbui, C, Engel, RR, Geddes, JR, Kissling, W, Stapf, MP, Lassig, B, Salanti, G and Davis, J (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382, 951–962.CrossRefGoogle ScholarPubMed
Leucht, S, Helfer, B and Hartung, B (2014) Perazine for schizophrenia. Cochrane Database of Systematic Reviews, (1), CD002832.Google Scholar
Leucht, S, Leucht, C, Huhn, M, Chaimani, A, Mavridis, D, Helfer, B, Samara, M, Rabaioli, M, Bacher, S, Cipriani, A, Geddes, JR, Salanti, G and Davis, J (2017) Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. American Journal of Psychiatry 174, 927–942.CrossRefGoogle ScholarPubMed
Levine, SZ, Rabinowitz, J, Engel, R, Etschel, E and Leucht, S (2008) Extrapolation between measures of symptom severity and change: an examination of the PANSS and CGI. Schizophrenia Research 98, 318–322.CrossRefGoogle ScholarPubMed
Liberati, A, Altman, D, Tetzlaff, J, Mulrow, C, Gotzsche, P, Ioannidis, J, Clarke, M, Devereaux, P, Kleijnen, J and Moher, D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. British Medical Journal 339, b2700.CrossRefGoogle ScholarPubMed
Lorr, M, Jenkins, R and Holsopple, J (1953) Multidimensional scale for rating psychiatric patients. Veterans Administration Technical Bulletin Volume VI, Series 10–507, 1–44.Google Scholar
Lorr O'Connor, J and Stafford, J (1960) The psychotic reaction profile. Journal of Clinical Psychology 16, 241–245.3.0.CO;2-F>CrossRefGoogle Scholar
Marshall, M, Lockwood, A, Bradley, C, Adams, C, Joy, C and Fenton, M (2000) Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. British Journal of Psychiatry 176, 249–252.CrossRefGoogle Scholar
McMahon, R, Kelly, D, Boggs, D, Li, L, Hu, Q, Davis, J and Carpenter, W (2008) Feasibility of reducing the duration of placebo-controlled trials in schizophrenia research. Schizophrenia Bulletin 34, 292–301.CrossRefGoogle ScholarPubMed
Merlis, S, Turner, WJ and Krumholz, W (1962) A double-blind comparison of diazepam, chlordiazepoxide and chlorpromazine in psychotic patients. Journal of Neuropsychiatry and Clinical Neurosciences 3(suppl. 1), S133–S138.Google ScholarPubMed
Moher, D, Liberati, A, Tetzlaff, J and Altman, D (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Medicine 6, e1000097.CrossRefGoogle ScholarPubMed
Moncrieff, J and Cohen, D (2005) Rethinking models of psychotropic drug action. Psychotherapy & Psychosomatics 74, 145–153.CrossRefGoogle ScholarPubMed
Moncrieff, J, Wessely, S and Hardy, R (2004) Active placebos versus antidepressants for depression. Cochrane Database of Systematic Reviews (1), Cd003012.Google ScholarPubMed
National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group (1964) Phenothiazine treatment in acute schizophrenia: effectiveness. Archives of General Psychiatry 10, 246–261.CrossRefGoogle Scholar
R Core Team (2018) R: a language and environment for statistical computing.Google Scholar
Rhodes, KM, Turner, RM and Higgins, JPT (2015) Predictive distributions were developed for the extent of heterogeneity in meta-analyses of continuous outcome data. Journal of Clinical Epidemiology 68, 52–60.CrossRefGoogle ScholarPubMed
Samara, M, Spineli, L, Furukawa, T, Engel, R, Davis, J, Salanti, G and Leucht, S (2013) Imputation of response rates from means and standard deviations in schizophrenia. Schizophrenia Research 151, 209–214.CrossRefGoogle Scholar
Samara, M, Cao, H, Helfer, B, Davis, J and Leucht, S (2014) Chlorpromazine versus every other antipsychotic for schizophrenia: a systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs. European Neuropsychopharmacology 24, 1046–1055.CrossRefGoogle ScholarPubMed
Schünemann, H, Brożek, J, Guyatt, G and Oxman, A (2013) GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. The GRADE Working Group. https://community.cochrane.org/style-manual/references/reference-types/cochrane-publications#handbook.Google Scholar
Schwarzer, G (2007) Meta: an R package for meta-analysis. R News 7, 40–45.Google Scholar
Shader, R, Cohler, J, Elashoff, R and Grinspoon, L (1964) Phenobarbital and atropine in combination, an active control substance for phenothiazine research. Journal of Psychiatric Research 2, 169–183.CrossRefGoogle ScholarPubMed
Shen, W (1999) A history of antipsychotic drug development. Comprehensive Psychiatry 40, 407–414.CrossRefGoogle ScholarPubMed
The Cochrane Collaboration (2014) Review Manager (RevMan). (ed. C. T. N. C. Centre).Google Scholar
Tiihonen, J, Suokas, JT, Suvisaari, JM, Haukka, J and Korhonen, P (2012) Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Archives of General Psychiatry 69, 476–483.CrossRefGoogle ScholarPubMed
TREC Collaborative Group (2003) Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. British Medical Journal 327, 708–713.CrossRefGoogle Scholar
Trikalinos, T, Churchill, R, Ferri, M, Leucht, S, Tuunainen, A, Wahlbeck, K and Ioannidis, J (2004) Effect sizes in cumulative meta-analyses of mental health randomized trials evolved over time. Journal of Clinical Epidemiology 57, 1124–1130.CrossRefGoogle ScholarPubMed
Vestre, N, Hall, W and Schiele, B (1962) A comparison of fluphenazine, triflupromazine, and phenobarbital in the treatment of chronic schizophrenic patients: a double-blind controlled study. Journal of Clinical & Experimental Psychopathology & Quarterly Review of Psychiatry and Neurology 23, 149–159.Google ScholarPubMed
Viechtbauer, W (2010) Conducting meta-analyses in R with the metafor package. Journal of Statistical Software 36, 1–48.CrossRefGoogle Scholar
Wahlbeck, K, Tuunainen, A, Ahokas, A and Leucht, S (2001) Dropout rates in randomised antipsychotic drug trials. Psychopharmacology 155, 230–233.CrossRefGoogle ScholarPubMed
Wolkowitz, O and Pickar, D (1991) Benzodiazepines in the treatment of schizophrenia: a review and reappraisal. American Journal of Psychiatry 148, 714–726.Google ScholarPubMed
Zhu, Y, Krause, M, Huhn, M, Rothe, P, Schneider-Thoma, J, Chaimani, A, Li, C, Davis, J and Leucht, S (2017 a) Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. The Lancet. Psychiatry 4, 694–705.CrossRefGoogle ScholarPubMed
Zhu, Y, Li, C, Huhn, M, Rothe, P, Krause, M, Bighelli, I, Schneider-Thoma, J and Leucht, S (2017 b) How well do patients with a first episode of schizophrenia respond to antipsychotics: a systematic review and meta-analysis. European Neuropsychopharmacology 27, 835–844.CrossRefGoogle ScholarPubMed
Supplementary material: PDF

Siafis et al. supplementary material

Siafis et al. supplementary material

Download Siafis et al. supplementary material(PDF)
PDF 2.4 MB