Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis

  • Marc Krause
  • Yikang Zhu
  • Maximilian Huhn
  • Johannes Schneider-Thoma
  • Irene Bighelli
  • Adriani Nikolakopoulou
  • Stefan LeuchtEmail author
Original Paper



Negative symptoms are the core of schizophrenia, but whether antipsychotics are efficacious for their treatment is unclear. Moreover, there is debate whether patients in relevant trials should have predominant negative symptoms or whether prominent negative symptoms are also acceptable.


We systematically reviewed randomised, blinded antipsychotic drug trials in patients with schizophrenia and either predominant or prominent negative symptoms (last search Dec 12, 2017). Separate pairwise meta-analyses were conducted in these two populations. The primary outcome was negative symptoms. Depressive, symptoms, positive symptoms, and extrapyramidal side-effects were analysed as causes of secondary negative symptoms.


We included 21 randomized-controlled trials with 3451 participants which revealed the following significant differences in the primary outcome: in patients with predominant negative symptoms amisulpride was superior to placebo (N = 4; n = 590, SMD 0.47, CI 0.23, 0.71), olanzapine was superior to haloperidol in a small trial (n = 35) and cariprazine outperformed risperidone (N = 1, n = 456, SMD − 0.29, CI − 0.48, − 0.11). In patients with prominent negative symptoms, olanzapine and quetiapine were superior to risperidone in single trials. Overall, studies in prominent negative symptoms were potentially more confounded by improvements of secondary negative symptoms.


Amisulpride is the only antipsychotic that outperformed placebo in the treatment of predominant negative symptoms, but there was a parallel reduction of depression. Cariprazine was better than risperidone in a large trial that was well-controlled for secondary negative symptoms, but the trial was sponsored by its manufacturer. Future trials should apply scientifically developed definitions such as the deficit syndrome and the persistent negative symptoms concept.


Deficit syndrome Deficit schizophrenia Persistent negative symptoms Depressive symptoms Positive symptoms Study design 



This work was supported by a grant from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF, Grant Number FKZ 01KG1508). The authors thank Georgia Salanti for the work on the original proposal, Samantha Roberts for help in the literature search and Leonie Reichelt, Hannah Röder, Susanne Bächer and Lio Bäckers for help in data extraction. Special thanks to Rolf Engel, who participated in the development of the project and supervised Marc Krause for his doctoral thesis of which this publication will be part. For full text acquisition and proofreading of the final manuscript, we thank Patricia Kratchowill. We thank all authors of the included studies, particularly those who sent us additional information about their trials.

Compliance with ethical standards

Conflict of interest

In the last 3 years, Stefan Leucht has received honoraria for consulting from LB Pharma, Lundbeck, Otsuka, Teva Pharmaceutical Industries Ltd, LTS Lohmann, Geodon Richter, Recordati, Boehringer Ingelheim, and for lectures from Janssen, Lilly, Lundbeck, Otsuka, SanofiAventis and Servier.

Supplementary material

406_2018_869_MOESM1_ESM.docx (1.3 mb)
Supplementary material 1 (DOCX 1345 KB)


  1. 1.
    Buchanan RW, Kirkpatrick B, Heinrichs DW et al (1990) Clinical correlates of the deficit syndrome of schizophrenia. Am J Psychiatry 147(3):290–294. CrossRefPubMedGoogle Scholar
  2. 2.
    Carpenter WT, Heinrichs JR, Wagman DW AM (1988) Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry 145(5):578–583. CrossRefPubMedGoogle Scholar
  3. 3.
    Crow TJ (1985) the two-syndrome concept: origins and current status. Schizophr Bull 11(3):471–488. CrossRefPubMedGoogle Scholar
  4. 4.
    Strauss JS, Carpenter WT, Bartko JR JJ (1974) The diagnosis and understanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull 11:61–69CrossRefGoogle Scholar
  5. 5.
    Andreasen NC, Olsen S (1982) Negative v positive schizophrenia. Definition and validation. Arch General Psychiatry 39(7):789–794CrossRefGoogle Scholar
  6. 6.
    Marder SR, Galderisi S (2017) The current conceptualization of negative symptoms in schizophrenia. World Psychiatry 16(1):14–24. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Buchanan RW (2007) Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull 33(4):1013–1022. CrossRefPubMedGoogle Scholar
  8. 8.
    Leucht S, Leucht C, Huhn M et al. (2017) Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review; bayesian meta-analysis; and meta-regression of efficacy predictors. Am J Psychiatry.
  9. 9.
    Leucht S, Arbter D, Engel RR et al (2009) How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14(4):429–447. CrossRefPubMedGoogle Scholar
  10. 10.
    Leucht S, Corves C, Arbter D, Engel R, Li C, Davis J (2009) Second-generation versus first-generation antipsychotic drugs for schizophrenia. A meta-analysis. Lancet 373:31–41.
  11. 11.
    Marder SR, Alphs L, Anghelescu I-G et al (2013) Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia. Schizophr Res 150(2–3):328–333. CrossRefPubMedGoogle Scholar
  12. 12.
    Leucht S, Huhn M, Rothe P et al (2016) Which are the most important first-generation antipsychotic drugs? Survey of international schizophrenia experts. Abstracts from the 5th Biennial SIRS Conference—Poster Abstracts. NPJ schizophrenia, p 25Google Scholar
  13. 13.
    Leucht S, Pitschel-Walz G, Engel RR et al (2002) Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 159(2):180–190. CrossRefPubMedGoogle Scholar
  14. 14.
    Fusar-Poli P, Papanastasiou E, Stahl D et al (2015) Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr Bull 41(4):892–899. CrossRefPubMedGoogle Scholar
  15. 15.
    Remington G, Foussias G, Fervaha G et al (2016) Treating negative symptoms in schizophrenia: an update. Curr Treat Options Psychiatry 3:133–150. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Elbourne DR, Altman DG, Higgins JPT et al (2002) Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol 31(1):140–149CrossRefPubMedGoogle Scholar
  17. 17.
    Divine GW, Brown JT, Frazier LM (1992) The unit of analysis error in studies about physicians’ patient care behavior. J General Intern Med 7(6):623–629CrossRefGoogle Scholar
  18. 18.
    Higgins JPTea (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. Wiley and Sons, ChichesterGoogle Scholar
  19. 19.
    Bian ZX, Li YP, Moher D et al. (2006) Improving the quality of randomized controlled trials in Chinese herbal medicine, part I: clinical trial design and methodology. Zhong xi yi jie he xue bao J Chin Integr Med 4(2):120–129CrossRefGoogle Scholar
  20. 20.
    Wu T, Li Y, Bian Z et al (2009) Randomized trials published in some Chinese journals: how many are randomized? Trials 10:46. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13(2):261–276CrossRefPubMedGoogle Scholar
  22. 22.
    Andreasen NC (1989) The scale for the assessment of negative symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl 155(7):49–58Google Scholar
  23. 23.
    Kirkpatrick B, Buchanan RW, McKenny PD et al (1989) The schedule for the deficit syndrome. An instrument for research in schizophrenia. Psychiatry Res 30(2):119–123. CrossRefPubMedGoogle Scholar
  24. 24.
    Leucht S, Cipriani A, Spineli L et al (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia. A multiple-treatments meta-analysis. Lancet 382(9896):951–962CrossRefPubMedGoogle Scholar
  25. 25.
    Furukawa TA, Barbui C, Cipriani A et al (2006) Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol 59(1):7–10. CrossRefPubMedGoogle Scholar
  26. 26.
    Higgins JPT, Jackson D, Barrett JK et al (2012) Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods 3(2):98–110. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    White IR, Barrett JK, Jackson D et al (2012) Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Res Synth Methods 3(2):111–125. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188. CrossRefPubMedGoogle Scholar
  29. 29.
    Chaimani A, Salanti G (2015) Visualizing assumptions and results in network meta-analysis: the network graphs package. Stata Journal 15(4):905–950Google Scholar
  30. 30.
    Review Manager (RevMan) (2014) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane CollaborationGoogle Scholar
  31. 31.
    Boyer P, Lecrubier Y, Puech AJ et al (1995) Treatment of negative symptoms in schizophrenia with amisulpride. Br J Psychiatry 166(1):68–72CrossRefPubMedGoogle Scholar
  32. 32.
    Buchanan RW, Panagides J, Zhao J et al (2012) Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia. J Clin Psychopharmacol 32(1):36–45. CrossRefPubMedGoogle Scholar
  33. 33.
    Danion JM, Rein W, Fleurot O (1999) Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group. Am J Psychiatry 156(4):610–616PubMedGoogle Scholar
  34. 34.
    Lecrubier Y, Quintin P, Bouhassira M et al (2006) The treatment of negative symptoms and deficit states of chronic schizophrenia. olanzapine compared to amisulpride and placebo in a 6-month double-blind controlled clinical trial. Acta Psychiatr Scand 114(5):319–327CrossRefPubMedGoogle Scholar
  35. 35.
    Lindenmayer JP, Khan A, Iskander A et al (2007) A randomized controlled trial of olanzapine versus haloperidol in the treatment of primary negative symptoms and neurocognitive deficits in schizophrenia. J Clin Psychiatry 68(3):368–379CrossRefPubMedGoogle Scholar
  36. 36.
    Loo H, Poirier-Littre MF, Theron M et al (1997) Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br J Psychiatry 170:18–22CrossRefPubMedGoogle Scholar
  37. 37.
    Moller HJ, Riedel M, Muller N et al (2004) Zotepine versus placebo in the treatment of schizophrenic patients with stable primary negative symptoms. a randomized double-blind multicenter trial. Pharmacopsychiatry 37(6):270–278CrossRefPubMedGoogle Scholar
  38. 38.
    Németh G, Laszlovszky I, Czobor P et al (2017) Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia. A randomised, double-blind, controlled trial. Lancet 389(10074):1103–1113. CrossRefPubMedGoogle Scholar
  39. 39.
    Alvarez E, Ciudad A, Olivares JM et al (2006) A randomized, 1-year follow-up study of olanzapine and risperidone in the treatment of negative symptoms in outpatients with schizophrenia. J Clin Psychopharmacol 26(3):238–249CrossRefPubMedGoogle Scholar
  40. 40.
    Barnas C, Stuppack CH, Miller C et al (1992) Zotepine in the treatment of schizophrenic patients with prevailingly negative symptoms. A double-blind trial vs. haloperidol. Int Clin Psychopharmacol 7(1):23–27CrossRefPubMedGoogle Scholar
  41. 41.
    Buchanan RW, Breier A, Kirkpatrick B et al (1998) Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry 155(6):751–760. PubMedCrossRefGoogle Scholar
  42. 42.
    Kinon BJ, Noordsy DL, Liu-Seifert H et al (2006) Randomized, double-blind 6-month comparison of olanzapine and quetiapine in patients with schizophrenia or schizoaffective disorder with prominent negative symptoms and poor functioning.[Erratum appears in J Clin Psychopharmacol 26(5) 2009 Apr. 169]. J Clin Psychopharmacol 29(2):453–461CrossRefGoogle Scholar
  43. 43.
    Pichot P, Boyer P (1989) Controlled double blind multi-centre trial of low dose amisulpride versus fluphenazine in the treatment of the negative syndrome of chronic schizophrenia expansion. Scientifique Francaise 125–137Google Scholar
  44. 44.
    Riedel M, Muller N, Strassnig M et al (2005) Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms. Eur Arch Psychiatry Clin Neurosci 255(6):432–437CrossRefPubMedGoogle Scholar
  45. 45.
    Ruhrmann S, Kissling W, Lesch OM et al (2007) Efficacy of flupentixol and risperidone in chronic schizophrenia with predominantly negative symptoms. Prog Neuropsychopharmacol Biol Psychiatry 31(5):1012–1022CrossRefPubMedGoogle Scholar
  46. 46.
    Saletu B, Kufferle B, Grunberger J et al (1994) Clinical, EEG mapping and psychometric studies in negative schizophrenia. comparative trials with amisulpride and fluphenazine. Neuropsychobiology 29(3):125–135CrossRefPubMedGoogle Scholar
  47. 47.
    Sirota P, Pannet I, Koren A et al (2006) Quetiapine versus olanzapine for the treatment of negative symptoms in patients with schizophrenia. Human 21(4):227–234Google Scholar
  48. 48.
    Speller JC, Barnes TR, Curson DA et al (1997) One-year, low-dose neuroleptic study of in-patients with chronic schizophrenia characterised by persistent negative symptoms. Amisulpride v. haloperidol. Br J Psychiatry 171:564–568CrossRefPubMedGoogle Scholar
  49. 49.
    Olie JP, Spina E, Murray S et al (2006) Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia. results of a 12-week, double-blind study. Int Clin Psychopharmacol 21(3):143–151CrossRefPubMedGoogle Scholar
  50. 50.
    Soni SD, Mallik A, Schiff AA (1990) Sulpiride in negative schizophrenia. A placebo-controlled double-blind assessment. Hum Psychopharmacol 5(3):233–238CrossRefGoogle Scholar
  51. 51.
    Asada S, Ishimaru T, Kubo S et al (1976) A double-blind study of sulpiride and perphenazine in 82 schizophrenics. Encephale 2(1):73–83PubMedGoogle Scholar
  52. 52.
    Cesarec Z, Eberhard G, Nordgren L (1974) A controlled study of the antipsychotic and sedative effects of neuroleptic drugs and amphetamine in chronic schizophrenics. A clinical and experimental-psychological study. Acta Psychiatr Scand Suppl 249:65–77CrossRefPubMedGoogle Scholar
  53. 53.
    Paillere-Martinot ML, Lecrubier Y, Martinot JL et al (1995) Improvement of some schizophrenic deficit symptoms with low doses of amisulpride. Am J Psychiatry 152(1):130–134CrossRefPubMedGoogle Scholar
  54. 54.
    Collins AD, Dundas J (1967) A double-blind trial of amitriptyline/perphenazine, perphenazine and placebo in chronic withdrawn inert schizophrenics. Br J Psychiatry 113(505):1425–1429CrossRefPubMedGoogle Scholar
  55. 55.
    Abbas AI, Hedlund PB, Huang X-P et al (2009) Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo. Psychopharmacology 205(1):119–128. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Boyer P, Lecrubier Y, Stalla-Bourdillon A et al (1999) Amisulpride versus amineptine and placebo for the treatment of dysthymia. Neuropsychobiology 39(1):25–32CrossRefPubMedGoogle Scholar
  57. 57.
    Kiss B, Horváth A, Némethy Z et al (2010) Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther 333(1):328–340. CrossRefPubMedGoogle Scholar
  58. 58.
    Jensen NH, Rodriguiz RM, Caron MG et al (2008) N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine’s antidepressant activity. Neuropsychopharmacology 33(10):2303–2312. CrossRefPubMedGoogle Scholar
  59. 59.
    Zohar J, Nutt DJ, Kupfer DJ et al (2014) A proposal for an updated neuropsychopharmacological nomenclature. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol 24(7):1005–1014. CrossRefGoogle Scholar
  60. 60.
    Sagud M, Mihaljevic-Peles A, Begic D et al (2011) Antipsychotics as antidepressants: what is the mechanism? Psychiatr Danub 23(3):302–307PubMedGoogle Scholar
  61. 61.
    Correll CU, Rubio JM, Inczedy-Farkas G et al (2017) Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 74(7):675–684. CrossRefPubMedGoogle Scholar
  62. 62.
    Helfer B, Samara MT, Huhn M et al (2016) Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry 173(9):876–886. CrossRefPubMedGoogle Scholar
  63. 63.
    Mao Y-M, Zhang M-D (2015) Augmentation with antidepressants in schizophrenia treatment: benefit or risk. Neuropsychiatr Dis Treat 11:701–713. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Cazorla P, Panagides J, Zhao J et al (2010) Long-term efficacy of asenapine in people with persistent negative symptoms of schizophrenia. Int J Neuropsychopharmcol 13:215. CrossRefGoogle Scholar
  65. 65.
    Kirkpatrick B, Fenton WS, Carpenter WT et al (2006) The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 32(2):214–219. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Levine SZ, Leucht S (2013) Identifying clinically meaningful symptom response cut-off values on the SANS in predominant negative symptoms. Schizophr Res 145(1–3):125–127. CrossRefPubMedGoogle Scholar
  67. 67.
    Mucci A, Merlotti E, Üçok A et al (2017) Primary and persistent negative symptoms: concepts, assessments and neurobiological bases. Schizophr Res 186:19–28. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Psychiatry and PsychotherapyTechnical University of MunichMunichGermany
  2. 2.Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao TongUniversity School of MedicineShanghaiChina
  3. 3.Institute of Social and Preventive Medicine (ISPM)Bern UniversityBernSwitzerland
  4. 4.Ludwig-Maximilians-Universität MünchenMunichGermany

Personalised recommendations