, Volume 77, Issue 13, pp 1423–1459 | Cite as

Treatment for Negative Symptoms in Schizophrenia: A Comprehensive Review

  • Selene R. T. VeermanEmail author
  • Peter F. J. Schulte
  • Lieuwe de Haan
Review Article


Negative symptoms (such as amotivation and diminished expression) associated with schizophrenia are a major health concern. Adequate treatment would mean important progress with respect to quality of life and participation in society. Distinguishing primary from secondary negative symptoms may inform treatment options. Primary negative symptoms are part of schizophrenia. Well-known sources of secondary negative symptoms are psychotic symptoms, disorganisation, anxiety, depression, chronic abuse of illicit drugs and alcohol, an overly high dosage of antipsychotic medication, social deprivation, lack of stimulation and hospitalisation. We present an overview of reviews and meta-analyses of double-blind, controlled randomised trials, in which the efficacy of pharmacological and non-pharmacological interventions for negative symptoms was assessed. Unfortunately, there have been very few clinical trials focusing on primary negative symptoms and selecting chronically ill patients with predominant persistent negative symptoms. An important limitation in many of these studies is the failure to adequately control for potential sources of secondary negative symptoms. At present, there is no convincing evidence regarding efficacy for any treatment of predominant persistent primary negative symptoms. However, for several interventions there is short-term evidence of efficacy for negative symptoms. This evidence has mainly been obtained from studies in chronically ill patients with residual symptoms and studies with a heterogeneous study population of patients in both the acute and chronic phase. Unfortunately, reliable information regarding the distinction between primary and secondary negative symptoms is lacking. Currently, early treatment of psychosis, add-on therapy with aripiprazole, antidepressants or topiramate, music therapy and exercise have been found to be useful for unspecified negative symptoms. These interventions can be considered carefully in a shared decision-making process with patients, and are promising enough to be examined in large, well-designed long-term studies focusing on primary negative symptoms. Future research should be aimed at potential therapeutic interventions for primary negative symptoms since there is a lack of research in this field.


Compliance with Ethical Standards

Conflicts of interest

S.R.T. Veerman reports no financial relationships with commercial interests. Dr. P.F.J. Schulte reports personal fees from H. Lundbeck A/S, outside the submitted work, and is a board member of the Dutch Clozapine Collaboration Group. Dr. L. de Haan has received investigator-led research grants or remuneration for presenting his research from Eli Lilly, Bristol-Myers Squibb, Janssen-Cilag and AstraZeneca, all more than 36 months ago.


No funding was received for the preparation of this manuscript.


  1. 1.
    McGrath JJ, Saha S, Al-Hamzawi AO, et al. Age of onset and lifetime projected risk of psychotic experiences: cross-national data from the World Mental Health Survey. Schizophr Bull. 2016;42:933–41.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Leucht S, Arbter D, Engel RR, et al. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry. 2009;4:429–47.Google Scholar
  3. 3.
    Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373:31–41.PubMedGoogle Scholar
  4. 4.
    Fusar-Poli P, Papanastasiou E, Stahl D, et al. Treatment of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr Bull. 2015;41:892–9.PubMedGoogle Scholar
  5. 5.
    Ventura J, Subotnik KL, Gitlin MJ, et al. Negative symptoms and functioning during the first year after a recent onset of schizophrenia and 8 years later. Schizophr Res. 2015;161:407–13.PubMedGoogle Scholar
  6. 6.
    Millan MJ, Fone K, Steckler T, et al. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur Neuropsychopharmacol. 2014;24:645–92.PubMedGoogle Scholar
  7. 7.
    Hartmann-Riemer MN, Hager OM, Kirschner M, et al. The association of neurocognitive impairment with diminished expression and apathy in schizophrenia. Schizophr Res. 2015;169:427–32.PubMedGoogle Scholar
  8. 8.
    Cohen AS, Saperstein AM, Gold JM, et al. Neuropsychology of the deficit syndrome: new data and meta-analysis of findings to date. Schizophr Bull. 2007;33:1201–12.PubMedGoogle Scholar
  9. 9.
    Roth RM, Koven NS, Pendergrass JC, et al. Apathy and the processing of novelty in schizophrenia. Schizophr Res. 2008;98:232–8.PubMedGoogle Scholar
  10. 10.
    Gold JM, Waltz JA, Matveeva TM, et al. Negative symptoms and the failure to represent the expected reward value of actions: behavioral and computational modeling evidence. Arch Gen Psychiatry. 2012;69:129–38.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Reddy LF, Horan WP, Green MF. Motivational deficits and negative symptoms in schizophrenia: concepts and assessments. Curr Topics Behav Neurosci. 2016;27:357–73.Google Scholar
  12. 12.
    Walther S, Strik W. Motor symptoms and schizophrenia. Neuropsychobiology. 2012;66:77–92.PubMedGoogle Scholar
  13. 13.
    Brébion G, Stephan-Otto C, Huerta-Ramos E, et al. Decreased processing speed might account for working memory span deficit in schizophrenia, and might mediate the associations between working memory span and clinical symptoms. Eur Psychiatry. 2014;29:473–8.PubMedGoogle Scholar
  14. 14.
    Pegoraro LF, Dantas CR, Banzato CE, et al. Correlation between insight dimensions and cognitive functions in patients with deficit and nondeficit schizophrenia. Schizophr Res. 2013;147:91–4.PubMedGoogle Scholar
  15. 15.
    Heilbronner U, Samara M, Leucht S, et al. The longitudinal course of schizophrenia cross the lifespan: clinical, cognitive, and neurobiological aspects. Harv Rev Psychiatry. 2016;24:118–28.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Savill M, Banks C, Khanom H, et al. Do negative symptoms of schizophrenia change over time? A meta-analysis of longitudinal data. Psychol Med. 2015;45:1613–27.PubMedGoogle Scholar
  17. 17.
    Goekoop R, Goekoop JG. A network view on psychiatric disorders: network clusters of symptoms as elementary syndromes of psychopathology. PLoS One. 2014;9:e112734.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Rovai L, Maremmani AG, Pacini M, et al. Negative dimension in psychiatry. Amotivational syndrome as a paradigm of negative symptoms in substance abuse. Riv Psichiatry. 2013;48:1–9.Google Scholar
  19. 19.
    Baker AL, Hides L, Lubman DI. Treatment of cannabis use among people with psychotic or depressive disorders: a systematic review. J Clin Psychiatry. 2010;71:247–54.PubMedGoogle Scholar
  20. 20.
    Smedslund G, Berg RC, Hammerstrøm KT, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev. 2011;11:CD008063.Google Scholar
  21. 21.
    Hunt GE, Siegfried N, Morley K, et al. Psychosocial interventions for people with both severe mental illness and substance misuse. Schizophr Bull. 2014;40:18–20.PubMedGoogle Scholar
  22. 22.
    Cooper K, Chatters R, Kaltenthaler E, et al. Psychological and psychosocial interventions for cannabis cessation in adults: a systematic review short report. Health Technol Assess. 2015;19:1–130.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Smeerdijk M, Keet R, Dekker N, et al. Motivational interviewing and interaction skills training for parents to change cannabis use in young adults with recent-onset schizophrenia: a randomized controlled trial. Psychol Med. 2012;42:1627–36.PubMedGoogle Scholar
  24. 24.
    Smeerdijk M, Keet R, van Raaij B, et al. Motivational interviewing and interaction skills training for parents of young adults with recent-onset schizophrenia and co-occurring cannabis use: 15-month follow-up. Psychol Med. 2015;45:2839–48.PubMedGoogle Scholar
  25. 25.
    Pawłowska B, Fijałkowska-Kiecka P, Potembska E, et al. Changes to psychosocial functioning as demonstrated by the patients diagnosed with schizophrenia covered by the psychiatric rehabilitation system. Psychiatr Pol. 2015;49:1191–202.PubMedGoogle Scholar
  26. 26.
    Aleman A, Lincoln TM, Bruggeman R, et al. Treatment of negative symptoms: where do we stand, and where do we go? Schizophr Res. 2016. doi: 10.1016/j.schres.2016.05.015.CrossRefPubMedGoogle Scholar
  27. 27.
    Dauwan M, Begemann MJ, Heringa SM, et al. Exercise improves clinical symptoms, quality of life, global functioning, and depression in schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2016;42:588–99.PubMedGoogle Scholar
  28. 28.
    de Haan L, Lavalaye J, Linszen D, et al. Subjective experience and striatal dopamine D(2) receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone. Am J Psychiatry. 2000;157:1019–20.PubMedGoogle Scholar
  29. 29.
    de Haan L, van Bruggen M, Lavalaye J, et al. Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized, double-blind study. Am J Psychiatry. 2003;160:303–9.PubMedGoogle Scholar
  30. 30.
    de Haan L, Lavalaye J, van Bruggen M, et al. Subjective experience and dopamine D2 receptor occupancy in patients treated with antipsychotics: clinical implications. Can J Psychiatry. 2004;49:290–6.PubMedGoogle Scholar
  31. 31.
    Mizrahi R, Rusjan P, Agid O, et al. Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors: a PET study in schizophrenia. Am J Psychiatry. 2007;164:630–7.PubMedGoogle Scholar
  32. 32.
    Janno S, Holi M, Tuisku K, et al. Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients. Am J Psychiatry. 2004;161:160–3.PubMedGoogle Scholar
  33. 33.
    Parksepp M, Ljubajev Ü, Täht K, et al. Prevalence of neuroleptic-induced movement disorders: an 8-year follow-up study in chronic schizophrenia inpatients. Nord J Psychiatry. 2016;70:498–502.PubMedGoogle Scholar
  34. 34.
    Cuesta MJ, Gil P, Artamendi M, et al. Premorbid personality and psychopathological dimensions in first-episode psychosis. Schizophr Res. 2002;58:273–80.PubMedGoogle Scholar
  35. 35.
    Sicras-Mainar A, Maurino J, Ruiz-Beato E, et al. Impact of negative symptoms on healthcare resource utilization and associated costs in adult outpatients with schizophrenia: a population-based study. BMC Psychiatry. 2014;14:225.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Buchanan RW. Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull. 2007;33:1013–22.PubMedGoogle Scholar
  37. 37.
    Weiner DM, Burstein ES, Nash N, et al. 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther. 2001;299:268–76.PubMedGoogle Scholar
  38. 38.
    Prus AJ, Wise LE, Pehrson AL, et al. Discriminative stimulus properties of 1.25mg/kg clozapine in rats: mediation by serotonin 5-HT2 and dopamine D4 receptors. Brain Res. 2016;1648:298–305.PubMedGoogle Scholar
  39. 39.
    Chiodo LA, Bunney BS. Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neurosci. 1983;3:1607–19.PubMedGoogle Scholar
  40. 40.
    Mortimer AM. Update on the management of symptoms in schizophrenia: focus on amisulpride. Neuropsychiatr Dis Treat. 2009;5:267–77.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Shea BJ, Grimshaw JM, Wells GA, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007;7:10.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Zeng X, Zhang Y, Kwong JS, et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med. 2015;8:2–10.PubMedGoogle Scholar
  43. 43.
    Sharif MO, Janjua-Sharif FN, Ali H, et al. Systematic reviews explained: AMSTAR-how to tell the good from the bad and the ugly. Oral Health Dent Manag. 2013;12:9–16.PubMedGoogle Scholar
  44. 44.
    Kao YC, Liu YP. Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. BMC Psychiatry. 2010;10:63.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Murru A, Carpiniello B. Duration of untreated illness as a key to early intervention in schizophrenia: a review. Neurosci Lett. 2016. doi: 10.1016/j.neulet.2016.10.003.CrossRefPubMedGoogle Scholar
  46. 46.
    Immonen J, Jääskeläinen E, Korpela H, et al. Age at onset and the outcomes of schizophrenia: a systematic review and meta-analysis. Early Interv Psychiatry. 2017. doi: 10.1111/eip.12412.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Boonstra N, Klaassen R, Sytema S, et al. Duration of untreated psychosis and negative symptoms: a systematic review and meta-analysis of individual patient data. Schizophr Res. 2012;142:12–9.PubMedGoogle Scholar
  48. 48.
    Perkins DO, Gu H, Boteva K, et al. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry. 2005;162:1785–804.PubMedGoogle Scholar
  49. 49.
    Penttilä M, Jääskeläinen E, Hirvonen N, et al. Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2014;205:88–94.PubMedGoogle Scholar
  50. 50.
    Souaiby L, Gaillard R, Krebs MO. Duration of untreated psychosis: a state-of-the-art review and critical analysis. Encephale. 2016;42:361–6.PubMedGoogle Scholar
  51. 51.
    Fusar-Poli P, De Micheli A, Cappucciati M et al. Diagnostic and prognostic significance of DSM-5 attenuated psychosis syndrome in services for individuals at ultra high risk for psychosis. Schizophr Bull. 2017. doi: 10.1093/schbul/sbx055.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Robustelli BL, Newberry RE, Whisman MA, et al. Social relationships in young adults at ultra high risk for psychosis. Psychiatry Res. 2017;247:345–51.PubMedGoogle Scholar
  53. 53.
    Fervaha G, Takeuchi H, Lee J, Foussias G, et al. Antipsychotics and amotivation. Neuropsychopharmacology. 2015;40:1539–48.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007;12:904–22.PubMedGoogle Scholar
  55. 55.
    Silver H, Einoch R, Youdim, et al. The role of GABA-A receptor in the synergism between SSRI and antipsychotic in schizophrenia; implications for antipsychotic modes of actions. Curr Med Chem. 2013;20:363–70.PubMedGoogle Scholar
  56. 56.
    Harvey RC, James AC, Shield GE. A systematic review and network meta-analysis to assess the relative efficacy of antipsychotics for the treatment of positive and negative symptoms in early-onset schizophrenia. CNS Drugs. 2016;30:27–39.PubMedGoogle Scholar
  57. 57.
    Pagsberg AK, Tarp S, Glintborg D, et al. Acute antipsychotic treatment of children and adolescents with schizophrenia-spectrum disorders: a systematic review and network meta-analysis. J Am Acad Child Adolesc Psychiatry. 2017;56:191–202.PubMedGoogle Scholar
  58. 58.
    Zhang JP, Gallego JA, Robinson DG, et al. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2013;16:1205–18.PubMedGoogle Scholar
  59. 59.
    Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. 2009;166:152–63.PubMedGoogle Scholar
  60. 60.
    Samara MT, Dold M, Gianatsi M, et al. Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: a network meta-analysis. JAMA Psychiatry. 2016;73:199–210.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Hasan A, Falkai P, Wobrock T, et al. WFSBP task force on treatment guidelines for schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. Guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13:318–87.PubMedGoogle Scholar
  62. 62.
    Leucht S, Heres S, Kissling W, et al. Pharmacological treatment of schizophrenia. Fortschr Neurol Psychiatr. 2013;81:e1–13.PubMedGoogle Scholar
  63. 63.
    Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951–62.PubMedGoogle Scholar
  64. 64.
    Essali A, Al-Haj Haasan N, Li C, et al. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009;1:CD000059.Google Scholar
  65. 65.
    Asenjo Lobos C, Komossa K, Rummel-Kluge C, et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;11:CD006633.Google Scholar
  66. 66.
    Barber S, Olotu U, Corsi M, et al. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2017;3:CD006324.PubMedGoogle Scholar
  67. 67.
    Souza JS, Kayo M, Tassell I, et al. Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses. CNS Spectr. 2013;18:82–9.PubMedGoogle Scholar
  68. 68.
    Siskind D, McCartney L, Goldschlager R, et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209:385–92.PubMedGoogle Scholar
  69. 69.
    Leucht S, Pitschel-Walz G, Engel RR, et al. Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry. 2002;159:180–90.PubMedGoogle Scholar
  70. 70.
    Fell MJ, McKinzie DL, Monn JA, et al. Group II metabotropic glutamate receptor agonists and positive allosteric modulators as novel treatments for schizophrenia. Neuropharmacology. 2012;62:1473–83.PubMedGoogle Scholar
  71. 71.
    Kinon BJ, Millen B, Zhang L, et al. Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia. Biol Psychiatry. 2015;78:754–62.PubMedGoogle Scholar
  72. 72.
    Nicoletti F, Bruno V, Ngomba RT, et al. Metabotropic glutamate receptors as drug targets: what’s new? Curr Opin Pharmacol. 2015;20:89–94.PubMedGoogle Scholar
  73. 73.
    Galling B, Roldán A, Hagi K, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry. 2017;16:77–89.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Veerman SR, Schulte PF, Begemann MJ, et al. Non-glutamatergic clozapine augmentation strategies: a review and meta-analysis. Pharmacopsychiatry. 2014;47:231–8.PubMedGoogle Scholar
  75. 75.
    Srisurapanont M, Suttajit S, Maneeton N, et al. Efficacy and safety of aripiprazole augmentation of clozapine in schizophrenia: a systematic review and meta-analysis of randomized-controlled trials. J Psychiatr Res. 2015;62:38–47.PubMedGoogle Scholar
  76. 76.
    Zheng W, Zheng YJ, Li XB, et al. Efficacy and safety of adjunctive aripiprazole in schizophrenia: meta-analysis of randomized controlled trials. J Clin Psychopharmacol. 2016;36:628–36.PubMedGoogle Scholar
  77. 77.
    Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA. 2009;301:1148–54.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Andrade C, Kisely S, Monteiro I, et al. Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials. J Psychiatr Res. 2015;60:14–21.PubMedGoogle Scholar
  79. 79.
    de Saint Hilaire Z, Orosco M, Rouch C, et al. Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport. 2001;12:3533–7.Google Scholar
  80. 80.
    Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology. 2008;33:1477–502.PubMedGoogle Scholar
  81. 81.
    Arbabi M, Bagheri M, Rezaei F, et al. A placebo-controlled study of the modafinil added to risperidone in chronic schizophrenia. Psychopharmacology (Berl). 2012;220:591–8.Google Scholar
  82. 82.
    Nolte S, Wong D, Lachford G. Amphetamines for schizophrenia. Cochrane Database Syst Rev. 2004;18(4):CD004964.Google Scholar
  83. 83.
    Lindenmayer JP, Nasrallah H, Pucci M, et al. A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: challenges and therapeutic opportunities. Schizophr Res. 2013;147:241–52.PubMedGoogle Scholar
  84. 84.
    Singh SP, Singh V, Kar N, et al. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry. 2010;197:172–9.Google Scholar
  85. 85.
    Helfer B, Samara MT, Huhn M, et al. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry. 2016;173:876–86.PubMedGoogle Scholar
  86. 86.
    Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther. 2007;113:296–320.PubMedGoogle Scholar
  87. 87.
    Kishi T, Mukai T, Matsuda Y, et al. Selective serotonin 3 receptor antagonist treatment for schizophrenia: meta-analysis and systematic review. Neuromol Med. 2014;16:61–9.Google Scholar
  88. 88.
    Millan MJ, Gobert A, Rivet JM, et al. Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur J Neurosci. 2000;12:1079–95.PubMedGoogle Scholar
  89. 89.
    Hecht EM, Landy DC. Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis. Schizophr Res. 2012;134:202–6.PubMedGoogle Scholar
  90. 90.
    Kishi T, Iwata N. Meta-analysis of noradrenergic and specific serotonergic antidepressant use in schizophrenia. Int J Neuropsychopharmacol. 2014;17:343–54.PubMedGoogle Scholar
  91. 91.
    Terevnikov V, Joffe G, Stenberg JH. Randomized controlled trials of add-on antidepressants in schizophrenia. Int J Neuropsychopharmacol. 2015;18:pyv049.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Yamamoto K, Hornykiewicz O. Proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:913–22.PubMedGoogle Scholar
  93. 93.
    Kishi T, Mukai T, Matsuda Y, et al. Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: a meta-analysis of double-blind randomized placebo-controlled trials. J Psychiatr Res. 2013;47:1557–63.PubMedGoogle Scholar
  94. 94.
    Kantrowitz JT, Javitt DC. N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull. 2010;83:108–21.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol Biochem Behav. 2012;100:665–77.PubMedGoogle Scholar
  96. 96.
    Stone JM, Morrison PD, Pilowsky LS. Glutamate and dopamine dysregulation in schizophrenia—a synthesis and selective review. J Psychopharmacol. 2007;21:440–52.PubMedGoogle Scholar
  97. 97.
    Veerman SR, Schulte PF, de Haan L. The glutamate hypothesis: a pathogenic pathway from which pharmacological interventions have emerged. Pharmacopsychiatry. 2014;47:121–30.PubMedGoogle Scholar
  98. 98.
    Sommer IE, Begemann MJ, Temmerman A, et al. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull. 2012;38:1003–11.PubMedGoogle Scholar
  99. 99.
    Veerman SR, Schulte PF, Begemann MJ, et al. Clozapine augmented with glutamate modulators in refractory schizophrenia: a review and metaanalysis. Pharmacopsychiatry. 2014;47:185–94.PubMedGoogle Scholar
  100. 100.
    Correll CU, Maayan L, Kane J, et al. Efficacy for psychopathology and body weight and safety of topiramate-antipsychotic cotreatment in patients with schizophrenia spectrum disorders: results from a meta-analysis of randomized controlled trials. J Clin Psychiatry. 2016;77:e746–56.PubMedGoogle Scholar
  101. 101.
    Okuyama Y, Oya K, Matsunaga S, et al. Efficacy and tolerability of topiramate-augmentation therapy for schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Neuropsychiatr Dis Treat. 2016;12:3221–36.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Zheng W, Xiang YT, Xiang YQ, et al. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2016;134:385–98.PubMedGoogle Scholar
  103. 103.
    Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109:10–4.PubMedGoogle Scholar
  104. 104.
    Kishi T, Iwata N. NMDA receptor antagonist interventions in schizophrenia: meta-analysis of randomized, placebo-controlled trials. J Psychiatr Res. 2013;47:1143–9.PubMedGoogle Scholar
  105. 105.
    Matsuda Y, Kishi T, Iwata N. Efficacy and safety of NMDA receptor antagonists’ augmentation therapy for schizophrenia: an updated meta-analysis of randomized placebo-controlled trials. J Psychiatr Res. 2013;47:2018–20.PubMedGoogle Scholar
  106. 106.
    Rezaei F, Mohammad-Karimi M, Seddighi S, et al. Memantine add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2013;33:336–42.PubMedGoogle Scholar
  107. 107.
    de Lucena D, Fernandes BS, Berk M, et al. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine add-on therapy to clozapine. J Clin Psychiatry. 2009;70:1416–23.PubMedGoogle Scholar
  108. 108.
    Veerman SR, Schulte PF, Smith JD, et al. Memantine augmentation in clozapine refractory schizophrenia: a randomised, double-blind, placebo-controlled crossover study. Psychol Med. 2016;46:1909–21.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Ossola B, Schendzielorz N, Chen SH, et al. Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GDNF in astroglia. Neuropharmacology. 2011;61:574–82.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Silver H, Goodman C, Isakov V, et al. A double-blind, cross-over comparison of the effects of amantadine or placebo on visuomotor and cognitive function in medicated schizophrenia patients. Int Clin Psychopharmacol. 2005;20:319–26.PubMedGoogle Scholar
  111. 111.
    Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive nmda receptor modulators in chronic schizophrenia. CNS Drugs. 2011;25:859–85.PubMedGoogle Scholar
  112. 112.
    Singer P, Dubroqua S, Yee BK. Inhibition of glycine transporter 1: the yellow brick road to new schizophrenia therapy? Curr Pharm Des. 2015;21:3771–87.PubMedGoogle Scholar
  113. 113.
    Raedler TJ, Bymaster FP, Tandon R, et al. Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry. 2007;12:232–46.PubMedGoogle Scholar
  114. 114.
    Friedman JI. Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists. Psychopharmacology (Berl). 2004;174:45–53.Google Scholar
  115. 115.
    Ribeiz SR, Bassitt DP, Arrais JA, et al. Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs. 2010;24:303–17.PubMedGoogle Scholar
  116. 116.
    Singh J, Kour K, Jayaram MB. Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database Syst Rev. 2012;1:007967.Google Scholar
  117. 117.
    Gray JA, Roth BL. Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr Bull. 2007;33:1100–19.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Muller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res. 2006;10:131–48.PubMedGoogle Scholar
  119. 119.
    Sommer IE, de Witte L, Begemann M, et al. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73:414–9.PubMedGoogle Scholar
  120. 120.
    Nitta M, Kishimoto T, Müller N, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013;39:1230–41.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Zheng W, Cai DB, Yang XH, et al. Adjunctive celecoxib for schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. J Psychiatr Res. 2017;92:139–46.PubMedGoogle Scholar
  122. 122.
    Marini S, De Berardis D, Vellante F, et al. Celecoxib adjunctive treatment to antipsychotics in schizophrenia: a review of randomized clinical add-on trials. Mediat Inflamm. 2016;2016:3476240.Google Scholar
  123. 123.
    Palacio JR, Markert UR, Martínez P. Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages. Inflamm Res. 2011;60:695–704.PubMedGoogle Scholar
  124. 124.
    Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294–321.PubMedGoogle Scholar
  125. 125.
    Berk M, Copolov D, Dean O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia: a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008;64:361–8.PubMedGoogle Scholar
  126. 126.
    Dean OM, Mancuso SG, Bush AI, et al. Benefits of adjunctive N-acetylcysteine in a sub-group of clozapine-treated individuals diagnosed with schizophrenia. Psychiatry Res. 2015;230:982–3.PubMedGoogle Scholar
  127. 127.
    Farokhnia M, Azarkolah A, Adinehfar F, et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 2013;36:185–92.PubMedGoogle Scholar
  128. 128.
    Hashimoto K. Abnormality of cerebral perfusion in the posterior cingulate gyrus of a refractory patient with schizophrenia and minocycline treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1132.PubMedGoogle Scholar
  129. 129.
    Oya K, Kishi T, Iwata N. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol. 2014;29:483–91.PubMedGoogle Scholar
  130. 130.
    Sirota P, Gavrieli R, Wolach B. Overproduction of neutrophil radical oxygen species correlates with negative symptoms in schizophrenic patients: parallel studies on neutrophil chemotaxis, superoxide production and bactericidal activity. Psychiatry Res. 2003;121:123–32.PubMedGoogle Scholar
  131. 131.
    Berger GE, Wood SJ, Wellard RM, et al. Ethyl-eicosapentaenoic acid in first-episode psychosis. A 1H-MRS study. Neuropsychopharmacology. 2008;33:2467–73.PubMedGoogle Scholar
  132. 132.
    Peet M, Brind J, Ramchand CN, et al. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res. 2001;49:243–51.PubMedGoogle Scholar
  133. 133.
    Fenton WS, Dickerson F, Boronow J, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry. 2001;158:2071–4.PubMedGoogle Scholar
  134. 134.
    Peet M, Horrobin DF, E-E Multicentre Study Group. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res. 2002;36:7–18.PubMedGoogle Scholar
  135. 135.
    Emsley R, Myburgh C, Oosthuizen P, et al. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry. 2002;159:1596–8.PubMedGoogle Scholar
  136. 136.
    Berger GE, Proffitt TM, McConchie M, et al. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. J Clin Psychiatry. 2007;68:1867–75.PubMedGoogle Scholar
  137. 137.
    Bastianetto S, Ramassamy C, Doré S, et al. The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci. 2000;12:1882–90.PubMedGoogle Scholar
  138. 138.
    Koltermann A, Hartkorn A, Koch E, et al. Ginkgo biloba extract EGb 761 increases endothelial nitric oxide production in vitro and in vivo. Cell Mol Life Sci. 2007;64:1715–22.PubMedGoogle Scholar
  139. 139.
    Singh V, Singh SP, Chan K. Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. Int J Neuropsychopharmacol. 2010;13:257–71.PubMedGoogle Scholar
  140. 140.
    Brondino N, De Silvestri A, Re S, et al. A systematic review and meta-analysis of ginkgo biloba in neuropsychiatric disorders: from ancient tradition to modern-day medicine. Evid Based Complement Alternat Med. 2013;2013:915691.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Chen X, Hong Y, Zheng P. Efficacy and safety of extract of Ginkgo biloba as an adjunct therapy in chronic schizophrenia: a systematic review of randomized, double-blind, placebo-controlled studies with meta-analysis. Psychiatry Res. 2015;228:121–7.PubMedGoogle Scholar
  142. 142.
    Gogos A, Sbisa AM, Sun J, et al. A role of estrogen in schizophrenia: clinical and preclinical findings. Int J Endocrinol. 2015;2015:615356.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Heringa SM, Begemann MJ, Goverde AJ, et al. Sex hormones and oxytocin augmentation strategies in schizophrenia: a quantitive review. Schizophr Res. 2015;168:603–13.PubMedGoogle Scholar
  144. 144.
    Weickert TW, Weinberg D, Lenroot R, et al. Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol Psychiatry. 2015;20:685–94.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Khodaie-Ardakani MR, Khosravi M, Zarinfard R, et al. A placebo-controlled study of raloxifene added to risperidone in men with chronic schizophrenia. Acta Med Iran. 2015;53:337–45.PubMedGoogle Scholar
  146. 146.
    Bratek A, Krysta K, Drzyzga K, et al. The role of selective estrogen receptor modulators in the treatment of schizophrenia. Psychiatr Danub. 2016;28(Suppl 1):45–8.PubMedGoogle Scholar
  147. 147.
    Williams-Brown MY, Salih SM, Xu X, et al. The effect of tamoxifen and raloxifene on estrogen metabolism and endometrial cancer risk. J Steroid Biochem Mol Biol. 2011;126:78–86.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Marjoribanks J, Farquhar C, Roberts H, et al. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2017;1:CD004143.PubMedGoogle Scholar
  149. 149.
    Elias A, Kumar A. Testosterone for schizophrenia. Cochrane Database Syst Rev. 2007;3:006197.Google Scholar
  150. 150.
    Ko YH, Lew YM, Jung SW, et al. Short-term testosterone augmentation in male schizophrenics: a randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2008;28:375–83.PubMedGoogle Scholar
  151. 151.
    Lakshman KM, Kaplan B, Travison TG, et al. The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men. J Clin Endocrinol Metab. 2010;95:3955–64.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Samyai Z, Kovács GL. Oxytocin in learning and addiction: from early discoveries to the present. Pharmacol Biochem Behav. 2014;119:3–9.Google Scholar
  153. 153.
    Gumley A, Braehler C, Macbeth A. A meta-analysis and theoretical critique of oxytocin and psychosis: prospects for attachment and compassion in promoting recovery. Br J Clin Psychol. 2014;53:42–61.PubMedGoogle Scholar
  154. 154.
    Oya K, Matsuda Y, Matsunaga S, et al. Efficacy and safety of oxytocin augmentation therapy for schizophrenia: an updated systematic review and meta-analysis of randomized, placebo-controlled trials. Eur Arch Psychiatry Clin Neurosci. 2016;266:439–50.PubMedGoogle Scholar
  155. 155.
    Williams DR, Bürkner PC. Effects of intranasal oxytocin on symptoms of schizophrenia: a multivariate Bayesian meta-analysis. Psychoneuroendocrinology. 2017;75:141–51.PubMedGoogle Scholar
  156. 156.
    Cramer H, Lauche R, Klose P, et al. Yoga for schizophrenia: a systematic review and meta-analysis. BMC Psychiatry. 2013;13:32.PubMedPubMedCentralGoogle Scholar
  157. 157.
    Pearsall R, Smith DJ, Pelosi A, et al. Exercise therapy in adults with serious mental illness: a systematic review and meta-analysis. BMC Psychiatry. 2014;14:117.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Broderick J, Knowles A, Chadwick J, et al. Yoga versus standard care for schizophrenia. Cochrane Database Syst Rev. 2015;10:CD010554.Google Scholar
  159. 159.
    Firth J, Cotter J, Elliott R, et al. A systematic review and meta-analysis of exercise interventions in schizophrenia patients. Psychol Med. 2015;45:1343–61.PubMedGoogle Scholar
  160. 160.
    Lutgens D, Gariepy G, Malla A. Psychological and psychosocial interventions for negative symptoms in psychosis: systematic review and meta-analysis. Br J Psychiatry. 2017;210:324–32.PubMedGoogle Scholar
  161. 161.
    Sarin F, Wallin L. Cognitive model and cognitive behavior therapy for schizophrenia: an overview. Nord J Psychiatry. 2014;68:145–53.PubMedGoogle Scholar
  162. 162.
    Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior therapy for schizophrenia: effect sizes, clinical models and methodological rigor. Schizophr Bull. 2008;34:523–37.PubMedGoogle Scholar
  163. 163.
    Lynch D, Laws KR, McKenna PJ. Cognitive behavioural therapy for major psychiatric disorder: does it really work? A meta-analytical review of well-controlled trials. Psychol Med. 2010;401:9–24.Google Scholar
  164. 164.
    Sarin F, Wallin L, Widerlöv B. Cognitive behavior therapy for schizophrenia: a meta-analytical review of randomized controlled trials. Nord J Psychiatry. 2011;65:162–74.PubMedGoogle Scholar
  165. 165.
    Jones C, Hacker D, Cormac I, et al. Cognitive behaviour therapy versus other psychosocial treatments for schizophrenia. Cochrane Database Syst Rev. 2012;4:CD008712.PubMedCentralGoogle Scholar
  166. 166.
    Jauhar S, McKenna PJ, Radua J, et al. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. Br J Psychiatry. 2014;204:20–9.PubMedGoogle Scholar
  167. 167.
    Velthorst E, Koeter M, van der Gaag M, et al. Adapted cognitive-behavioural therapy required for targeting negative symptoms in schizophrenia: meta-analysis and meta-regression. Psychol Med. 2015;45:453–65.PubMedGoogle Scholar
  168. 168.
    Cella M, Preti A, Edwards C, et al. Cognitive remediation for negative symptoms of schizophrenia: a network meta-analysis. Clin Psychol Rev. 2016;52:43–51.PubMedGoogle Scholar
  169. 169.
    Roder V, Mueller DR, Schmidt SJ. Effectiveness of integrated psychological therapy (IPT) for schizophrenia patients: a research update. Schizophr Bull. 2011;37(Suppl 2):S71–9.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Khoury B, Lecomte T, Gaudiano BA, et al. Mindfulness interventions for psychosis: a meta-analysis. Schizophr Res. 2013;150:176–84.PubMedGoogle Scholar
  171. 171.
    Mössler K, Chen X, Heldal TO, et al. Music therapy for people with schizophrenia and schizophrenia-like disorders. Cochrane Database Syst Rev. 2011;12:CD004025.Google Scholar
  172. 172.
    Tseng PT, Chen YW, Lin PY, et al. Significant treatment effect of adjunct music therapy to standard treatment on the positive, negative, and mood symptoms of schizophrenic patients: a meta-analysis. BMC Psychiatry. 2016;16:150.PubMedPubMedCentralGoogle Scholar
  173. 173.
    Blumberger DM, Fitzgerald PB, Mulsant BH, et al. Repetitive transcranial magnetic stimulation for refractory symptoms in schizophrenia. Curr Opin Psychiatry. 2010;23:85–90.PubMedGoogle Scholar
  174. 174.
    Freitas C, Fregni F, Pascual-Leone A. Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia. Schizophr Res. 2009;108:11–24.PubMedPubMedCentralGoogle Scholar
  175. 175.
    Dlabac-de Lange JJ, Knegtering R, Aleman A. Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: review and meta-analysis. J Clin Psychiatry. 2010;71:411–8.PubMedGoogle Scholar
  176. 176.
    Matheson SL, Green MJ, Loo C, et al. A change in the conclusions of a recent systematic meta-review: repetitive transcranial magnetic stimulation is effective for the negative symptoms of schizophrenia. Schizophr Res. 2010;122:276–7.PubMedGoogle Scholar
  177. 177.
    Shi C, Yu X, Cheung EF, et al. Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: a meta-analysis. Psychiatry Res. 2013;215:505–13.PubMedPubMedCentralGoogle Scholar
  178. 178.
    He H, Lu J, Yang L, et al. Repetitive transcranial magnetic stimulation for treating the symptoms of schizophrenia: a PRISMA compliant meta-analysis. Clin Neurophysiol. 2017;128:716–24.PubMedGoogle Scholar
  179. 179.
    Prikryl R, Kucerova HP. Can repetitive transcranial magnetic stimulation be considered effective treatment option for negative symptoms of schizophrenia? J ECT. 2013;29:67–74.PubMedGoogle Scholar
  180. 180.
    Murphy BP, Chung YC, Park TW, et al. Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res. 2006;88:5–25.PubMedGoogle Scholar
  181. 181.
    Jiawan VC, Arends J, Slooff CJ, et al. Pharmacological treatment of negative symptoms in schizophrenia; research and practice. Tijdschr Psychiatr. 2010;52:627–37.PubMedGoogle Scholar
  182. 182.
    Barnes TR, Paton C. Do antidepressants improve negative symptoms in schizophrenia? BMJ. 2011;342:d3371.PubMedGoogle Scholar
  183. 183.
    Möller HJ, Czobor P. Pharmacological treatment of negative symptoms in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2015;165:567–78.Google Scholar
  184. 184.
    Möller HJ. The relevance of negative symptoms in schizophrenia and how to treat them with psychopharmaceuticals? Psychiatr Danub. 2016;28:435–40.PubMedGoogle Scholar
  185. 185.
    Remington G, Foussias G, Fervaha G, et al. Treating negative symptoms in schizophrenia: an update. Curr Treat Options Psychiatry. 2016;3:133–50.PubMedPubMedCentralGoogle Scholar
  186. 186.
    Baandrup L, Østrup Rasmussen J, Klokker L, et al. Treatment of adult patients with schizophrenia and complex mental health needs—a national clinical guideline. Nord J Psychiatry. 2016;70:231–40.PubMedGoogle Scholar
  187. 187.
    Carpenter WT, Gold JM, Lahti A, et al. Decisional capacity for informed consent in schizophrenia research. Arch Gen Psychiatry. 2000;57:533–8.PubMedGoogle Scholar
  188. 188.
    Prentice KJ, Appelbaum PS, Conley RR, et al. Maintaining informed consent validity during lengthy research protocols. IRB. 2007;29:1–6.PubMedGoogle Scholar
  189. 189.
    Prentice KJ, Gold JM, Carpenter WT Jr. Optimistic bias in the perception of personal risk: patterns in schizophrenia. Am J Psychiatry. 2005;162:507–12.PubMedGoogle Scholar
  190. 190.
    Leichsenring F. Randomized controlled versus naturalistic studies: a new research agenda. Bull Menninger Clin. 2004;68:137–51.PubMedGoogle Scholar
  191. 191.
    Kahn RS, Sommer IE. The neurobiology and treatment of first-episode schizophrenia. Mol Psychiatry. 2015;20:84–97.PubMedGoogle Scholar
  192. 192.
    Lawrie SM, O’Donovan MC, Saks E, et al. Towards diagnostic markers for the psychoses. Lancet Psychiatry. 2016;3:375–85.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Mental Health Service Noord-Holland Noord, Community Mental Health Division, Flexible Assertive Community TreatmentAlkmaarThe Netherlands
  2. 2.Mental Health Service Noord-Holland Noord, Specialised Treatment Division, Treatment Centre for Bipolar DisordersAlkmaarThe Netherlands
  3. 3.Academic Medical Center, University of Amsterdam, Academic Psychiatric Centre, Early Psychosis Department, ArkinAmsterdamThe Netherlands

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