Hostname: page-component-745bb68f8f-l4dxg Total loading time: 0 Render date: 2025-01-10T18:05:52.780Z Has data issue: false hasContentIssue false
  • English
  • Français

Do negative symptoms of schizophrenia change over time? A meta-analysis of longitudinal data

Published online by Cambridge University Press:  26 November 2014

M. Savill ,
C. Banks ,
H. Khanom  and
S. Priebe
M. Savill*
Affiliation:
Unit for Social and Community Psychiatry, WHO collaborating Centre for Mental Health Service Development, Queen Mary University of London, London, UK
C. Banks
Affiliation:
Unit for Social and Community Psychiatry, WHO collaborating Centre for Mental Health Service Development, Queen Mary University of London, London, UK
H. Khanom
Affiliation:
Unit for Social and Community Psychiatry, WHO collaborating Centre for Mental Health Service Development, Queen Mary University of London, London, UK
S. Priebe
Affiliation:
Unit for Social and Community Psychiatry, WHO collaborating Centre for Mental Health Service Development, Queen Mary University of London, London, UK
*
* Address for correspondence: Mr M. Savill, Unit for Social and Community Psychiatry, WHO collaborating Centre for Mental Health Service Development, Queen Mary University of London, Newham Centre for Mental Health, London E13 8SP, UK. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Background.

Negative symptoms are a core component of schizophrenia which can severely impact quality of life and functional outcomes. These symptoms are understood to be highly stable but this has not been tested in a meta-analysis, despite the wealth of longitudinal data available.

Method.

A systematic review of the literature was conducted, with eligible studies pooled into a random-effects meta-analysis. Planned meta-regressions were conducted to evaluate the impact of factors known to induce secondary negative symptoms, in addition to other possible sources of heterogeneity.

Results.

The main analysis included 89 samples from 41 studies, totalling 5944 participants. Negative symptoms were found to significantly reduce in all treatment interventions, including in placebo and treatment as usual conditions, with a medium effect size (ES) present across all study conditions (ES = 0.66, 95% confidence interval 0.56–0.77, I2 = 94.0%). In a multivariate meta-regression, only the type of scale used was found to significantly influence negative symptom change. No difference in outcome was found between studies that excluded patients with a high level of positive or depressive symptoms, compared to those that did not.

Conclusions.

Negative symptoms were found to reduce in almost all schizophrenia outpatient samples. A reduction was found across all conditions, with effect sizes ranging from small to large depending upon the condition type. These findings challenge the convention that negative symptoms are highly stable and suggest that they may improve to a greater extent than what has previously been assumed.

Keywords

Longitudinal coursenegative symptomsschizophreniasymptom assessment
Type
Original Articles
Information
Psychological Medicine , Volume 45 , Issue 8 , June 2015 , pp. 1613 - 1627
Copyright
Copyright © Cambridge University Press 2014 

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

Adams, DH, Kinon, BJ, Baygani, S, Millen, BA, Velona, I, Kollack-Walker, S, Walling, DP (2013). A long- term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. BMC Psychiatry 13, 143.Google Scholar
Addington, J, Addington, DG (2000). Neurocognitive and social functioning in schizophrenia: a 2.5 year follow-up study. Schizophrenia Research 41, 47–56.CrossRefGoogle Scholar
Addington, J, Addington, DJ (1991). Positive and negative symptoms of schizophrenia. Their course and relationship over time. Schizophrenia Research 5, 51–59.Google Scholar
Aguglia, E, De Vanna, M, Onor, ML, Ferrara, DG (2002). Insight in persons with schizophrenia effects of switching from conventional neuroleptics to atypical antipsychotics. Progress in Neuro-Psychopharmacology and Biological Psychiatry 26, 1229–1233.Google Scholar
Alptekin, K, Erkoc, S, Gogus, AK, Kultur, S, Mete, L, Ucok, A, Yazici, KMG (2005). Disability in schizophrenia: clinical correlates and prediction over 1-year follow-up. Psychiatry Research 135, 103–111.CrossRefGoogle ScholarPubMed
Alvarez, E, Ciudad, A, Olivares, JM, Bousono, M, Gomez, JCG (2006). A randomized, 1-year follow-up study of olanzapine and risperidone in the treatment of negative symptoms in outpatients with schizophrenia. Journal of Clinical Psychopharmacology 26, 238–249.Google Scholar
Amell, R, Llandrich, JG (2008). Validity of a social skills training program for schizophrenic patients. Actas Espanolas de Psiquiatria 36, 123–132.Google Scholar
Andreasen, NC (1983). Scale for the Assessment of Negative Symptoms. University of Iowa: Iowa City.Google Scholar
Arango, C, Garibaldi, G, Marder, R (2013). Pharmacological approaches to treating negative symptoms: a review of clinical trials. Schizophrenia Research 150, 346–352.Google Scholar
Bales, A, Peterson, MJ, Ojha, S, Upadhaya, K, Adhikari, B, Barrett, BG (2009). Associations between betel nut (Areca catechu) and symptoms of schizophrenia among patients in Nepal: a longitudinal study. Psychiatry Research 169, 203–211.Google Scholar
Becker, BJ (1988). Synthesizing standardized mean-change measures. British Journal of Mathematical and Statistical Psychology 41, 257–278.Google Scholar
Behere, RV, Arasappa, R, Jagannathan, A, Varambally, S, Venkatasubramanian, G, Thirthalli, J, Subbakrishna, DK, Nagendra, HR, Gangadhar, BNG (2011). Effect of yoga therapy on facial emotion recognition deficits, symptoms and functioning in patients with schizophrenia. Acta Psychiatrica Scandinavica 123, 147–153.CrossRefGoogle ScholarPubMed
Bhowmick, S, Hazra, A, Ghosh, MG (2010). Amisulpride versus olanzapine in the treatment of schizophrenia in Indian patients: randomized controlled trial. Australian and New Zealand Journal of Psychiatry 44, 237–242.Google Scholar
Bio, DS, Gattaz, WFG (2011). Vocational rehabilitation improves cognition and negative symptoms in schizophrenia. Schizophrenia Research 126, 265–269.Google Scholar
Blanchard, JJ, Kring, AM, Horan, WP, Gur, R (2011). Toward the next generation of negative symptom assessments: the collaboration to advance negative symptom assessment in schizophrenia. Schizophrenia Bulletin 37, 291–299.CrossRefGoogle Scholar
Bleuler, E (1950). Dementia Praecox and the Group of Schizophrenias. New York: International Universities Press.Google Scholar
Bobes, J, Ciudad, A, Alvarez, E, San, L, Polavieja, P, Gilaberte, I (2009). Recovery from schizophrenia: results from a 1-year follow-up observational study of patients in symptomatic remission. Schizophr Research 115, 58–66.CrossRefGoogle ScholarPubMed
Bodkin, J, Siris, SG, Bermanzohn, PC, Hennen, J, Cole, JOG (2005). Double-blind, placebo-controlled, multicenter trial of selegiline augmentation of antipsychotic medication to treat negative symptoms in outpatients with schizophrenia. American Journal of Psychiatry 162, 388–390.Google Scholar
Buchanan, RW (2007). Persistent negative symptoms in schizophrenia: an overview. Schizophrenia Bulletin 33, 1013–1022.Google Scholar
Carpenter, WT, Heinrichs, DW, Alphs, LD (1985). Treatment of negative symptoms. Schizophrenia Bulletin 11, 440–452.Google Scholar
Chiolero, A, Paradis, G, Rich, B, Hanley, JA (2013). Assessing the relationship between the baseline value of a continuous variable and subsequent change over time. Frontiers in Pulblic Health 1 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854983/). Accessed 11 November 2014.Google Scholar
Chouinard, G, Annable, L, Serrano, M, Albert, JM, Charette, R (1975). Amitriptyline-perphenazine interaction in ambulatory schizophrenic patients. A controled study of drug interaction. Archives of General Psychiatry 32, 1295–1307.CrossRefGoogle ScholarPubMed
Crawford, MJ, Killaspy, H, Barnes, TR, Barrett, B, Byford, S, Clayton, K, Dinsmore, J, Floyd, S, Hoadley, A, Johnson, T, Kalaitzaki, E, King, M, Leurent, B, Maratos, A, O'neill, FA, Osborn, D, Patterson, S, Soteriou, T, Tyrer, P, Waller, D (2012). Group art therapy as an adjunctive treatment for people with schizophrenia: a randomised controlled trial (MATISSE). British Medical Journal 344 (http://www.bmj.com/content/344/bmj.e846).Google Scholar
Dersimonian, R, Laird, N (1986). Meta-analysis in clinical trials. Controlled Clinical Trials 7, 177–188.Google Scholar
Dollfus, S, Petit, MG (1995). Stability of positive and negative symptoms in schizophrenic patients: a 3-year follow-up study. European Psychiatry 10, 228–236.Google Scholar
Dossenbach, M, Erol, A, Kessaci, MEM, Shaheen, MO, Sunbol, MM, Boland, J, Hodge, A, O'Halloran, RA, Bitter, IG (2004). Effectiveness of antipsychotic treatments for schizophrenia: interim 6-month analysis from a prospective observational study (IC-SOHO) comparing olanzapine, quetiapine, risperidone, and haloperidol. Journal of Clinical Psychiatry 63, 312–321.Google Scholar
Eaton, WW, Thara, R, Federman, B, Melton, B, Liang, KYJ (1995). Structure and course of positive and negative symptoms in schizophrenia. Archives of General Psychiatry 52, 127–134.Google Scholar
Fenton, WS, McGlashan, THJ (1991). Natural history of schizophrenia subtypes. II. Positive and negative symptoms and long-term course. Archives of General Psychiatry 48, 978–986.CrossRefGoogle ScholarPubMed
Fleischhacker, WW, Eerdekens, M, Karcher, K, Remington, G, Llorca, PM, Chrzanowski, W, Martin, S, Gefvert, OJ (2003). Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. Journal of Clinical Psychiatry 64, 1250–1257.Google Scholar
Gaebel, W, Riesbeck, M, Wolwer, W, Klimke, A, Eickhoff, M, Von Wilmsdorff, M, Jockers-Scherubl, MC, Kuhn, KU, Lemke, M, Bechdolf, A, Bender, S, Degner, D, Schlosser, R, Schmidt, LG, Schmitt, A, Jager, M, Buchkremer, G, Falkai, P, Klingberg, S, Kopcke, W, Maier, W, Hafner, H, Ohmann, C, Salize, HJ, Schneider, F, Moller, HJG (2007). Maintenance treatment with risperidone or low-dose haloperidol in first-episode schizophrenia: 1-year results of a randomized controlled trial within the German research network on schizophrenia. Journal of Clinical Psychiatry 68, 1763–1774.CrossRefGoogle ScholarPubMed
Goff, DC, Herz, L, Posever, T, Shih, V, Tsai, G, Henderson, DC, Freudenreich, O, Evins, A, Yovel, I, Zhang, H, Schoenfeld, DG (2005). A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology 179, 144–150.Google Scholar
Gorna, K, Jaracz, K, Rybakowski, F, Rybakowski, J (2008). Determinants of objective and subjective quality of life in first-time-admission schizophrenic patients in Poland: a longitudinal study. Quality of Life Research 17, 237–247.CrossRefGoogle ScholarPubMed
Harrow, M, Jobe, TH (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multi follow-up study. Journal of Nervous and Mental Disease 195, 406–414.Google Scholar
Hayes, RL, Halford, WK, Varghese, FTJ (1995). Social skills training with chronic schizophrenic patients: effects on negative symptoms and community functioning. Behavior Therapy 26, 433–449.Google Scholar
Hecht, EM, Landy, C (2012). Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis. Schizophrenia Research 134, 202–206.Google Scholar
Higgins, JPT, Green, S (2011). Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. The Cochrane Collaboration (www.cochrane-handbook.org). Accessed 11 November 2014.Google Scholar
Hirsch, SR, Kissling, WB, Uml, J, Power, A, O'connor, RJ (2002). A 28-week comparison of ziprasidone and haloperidol in outpatients with stable schizophrenia. Journal of Clinical Psychiatry 63, 516–523.Google Scholar
Horan, WP, Kring, AM, Gur, RE, Reise, SP, Blanchard, JJ (2011). Development and psychometric validation of the Clinical Assessment Interview for Negative Symptoms (CAINS). Schizophrenia Research 132, 140–145.Google Scholar
Jääskeläinen, E, Juola, P, Hirvonen, N, McGrath, JJ, Saha, S, Isohanni, M, Veijola, J, Miettunen, J (2013). A systematic review and meta-analysis of recovery in schizophrenia. Schizophrenia Bulletin 39, 1296–1306.CrossRefGoogle ScholarPubMed
Jauhar, S, Mckenna, PJ, Radua, J, Fung, E, Salvador, R, Laws, KR (2014). Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. British Journal of Psychiatry 204, 20–29.CrossRefGoogle ScholarPubMed
Kane, JM, Mackle, M, Snow-Adami, L, Zhao, J, Szegedi, A, Panagides, JJ (2011). A randomized placebo-controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term treatment. Journal of Clinical Psychiatry 72, 349–355.Google Scholar
Kane, JM, Yang, R, Youakim, JM (2012). Adjunctive armodafinil for negative symptoms in adults with schizophrenia: a double-blind, placebo-controlled study. Schizophrenia Research 135, 116–122.CrossRefGoogle ScholarPubMed
Kaphzan, H, Ben-Shachar, D, Klein, E (2014). Entacapone augmentation of antipsychotic treatment in schizophrenic patients with negative symptoms; a double-blind placebo-controlled study. International Journal of Neuropsychopharmacology 17, 337–340.Google Scholar
Kasckow, JW, Twamley, E, Mulchahey, JJ, Carroll, B, Sabai, M, Strakowski, SM, Patterson, T, Jeste, DV (2001). Health-related quality of well-being in chronically hospitalized patients with schizophrenia: comparison with matched outpatients. Psychiatry Research 103, 69–78.CrossRefGoogle ScholarPubMed
Kay, SR, Flszbein, A, Opfer, LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261.CrossRefGoogle ScholarPubMed
Kinon, BJ, Potts, AJ, Watson, SB (2011). Placebo response in clinical trials with schizophrenia patients. Current Opinion in Psychiatry 24, 107–113.Google ScholarPubMed
Kirkpatrick, B, Fenton, WS, Carpenter, WT, Marder, SR (2006). The NIMH-MATRICS consensus statement on negative symptoms. Schizophrenia Bulletin 32, 214–219.Google Scholar
Klingberg, S, Wolwer, W, Engel, C, Wittorf, A, Herrlich, J, Meisner, C, Buchkremer, G, Wiedemann, GJ (2011). Negative symptoms of schizophrenia as primary target of cognitive behavioral therapy: results of the randomized clinical TONES study. Schizophrenia Bulletin 37, 98–110.CrossRefGoogle ScholarPubMed
Kraepelin, E (1971). Dementia Praecox and Paraphrenia (1919). Translated by Barclay, RM; edited by Robertson, GM. Robert E Krieger: New York.Google Scholar
Kurtz, MM, Mueser, KT (2008). A meta-analysis of controlled research on social skills training for schizophrenia. Journal of Consulting and Clinical Psychology 76, 491–504.Google Scholar
Kurtz, MM, Richardson, CL (2012). Social cognitive training for schizophrenia: a meta-analytic investigation of controlled research. Schizophrenia Bulletin 38, 1092–1104.Google Scholar
Lasser, A, Dirks, B, Nasrallah, H, Kirsch, C, Gao, J, Pucci, L, Knesevich, A, Lindenmayer, JP (2013). Adjunctive lisdexamfetamine dimesylate therapy in adult outpatients with predominant negative symptoms of schizophrenia: open-label and randomized-withdrawal phases. Neuropsychopharmacology 38, 2140–2149.CrossRefGoogle ScholarPubMed
Lecrubier, Y, Quintin, P, Bouhassira, M, Perrin, E, Lancrenon, SG (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 Psychiatrica Scandinavica 114, 319–327.Google Scholar
Leucht, S, Arbter, D, Engel, RR, Kissling, W, Davis, JM (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry 14, 429–447.CrossRefGoogle ScholarPubMed
Liberati, A, Altman, DG, Tetzlaff, J, Mulrow, C, Gotzsche, PC, Ioannidis, JP, Clarke, M, Devereaux, PJ, Kleijnen, J, Moher, D (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiology 62, e1–e34.CrossRefGoogle ScholarPubMed
Liberman, RP, Wallace, CJ, Blackwell, G, Kopelowicz, A, Vaccaro, JV, Mintz, J (1998). Skills training versus psychosocial occupational therapy for persons with persistent schizophrenia. American Journal of Psychiatry 155, 1087–1091.CrossRefGoogle ScholarPubMed
Lieberman, A, Dunbar, G, Segreti, C, Girgis, R, Seoane, F, Beaver, S, Duan, N, Hosford, A (2013). A randomized exploratory trial of an alpha-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia. Neuropsychopharmacology 38, 968–975.Google Scholar
Lieberman, JA, Stroup, TS, McEvoy, JP, Swartz, MS, Rosenheck, RA, Perkins, DO, Keefe, RS, Davis, SM, Davis, CE, Lebowitz, BD, Severe, J, Hsiao, JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 353, 1209–1223.Google Scholar
Liu, F, Guo, X, Wu, R, Ou, J, Zheng, Y, Zhang, B, Xie, L, Zhang, L, Yang, L, Yang, S, Yang, J, Ruan, Y, Zeng, Y, Xu, X, Zhao, J (2014). Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: a double blind, randomized, controlled trial. Schizophrenia Research 153, 169–176.CrossRefGoogle ScholarPubMed
Loebel, AD, Khanna, S, Rajadhyaksha, S, Siu, CO, Giller, E, Potkin, SGJ (2007). Ziprasidone in treatment-resistant schizophrenia: a 52-week, open-label continuation study. Journal of Clinical Psychiatry 68, 1333–1338.Google Scholar
Loo, H, Poirier-Littre, MF, Theron, M, Rein, W, Fleurot, OG (1997). Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. British Journal of Psychiatry 170, 18–22.Google Scholar
Lyne, JP, Kinsella, A, O'Donoghue, B (2012). Can we combine symptom scales for collaborative research projects? Journal of Psychiatric Research 46, 233–238.Google Scholar
Malhi, GS, Green, M, Fagiolini, A, Peselow, ED, Kumari, V (2008). Schizoaffective disorder: diagnostic issues and future recommendations. Bipolar Disorders 10, 215–230.Google Scholar
Marder, SR, Glynn, SM, Wirshing, WC, Wirshing, DA, Ross, D, Widmark, C, Mintz, J, Liberman, RP, Blair, KEJ (2003). Maintenance treatment of schizophrenia with risperidone or haloperidol: 2-year outcomes. American Journal of Psychiatry 160, 1405–1412.Google Scholar
Meltzer, HY, Bobo, WV, Lee, MA, Cola, P, Jayathilake, KG (2010). A randomized trial comparing clozapine and typical neuroleptic drugs in non-treatment-resistant schizophrenia. Psychiatry Research 177, 286–293.Google Scholar
Möller, HJ (2007). Clinical evaluation of negative symptoms in schizophrenia. European Psychiatry 22, 380–386.CrossRefGoogle ScholarPubMed
Morris, SB (2000). Distribution of the standardized mean change effect size for meta-analysis on repeated measures. British Journal of Mathamatical and Statistical Psychology 53, 17–29.Google Scholar
Morton, V, Torgerson, DJ (2003). Effect of regression to the mean on decision making in health care. British Medical Journal 326, 1083.Google Scholar
NCCMH (2010). Schizophrenia: The NICE Guideline on Core Interventions in the Treatment and Management of Schizophrenia in Adults in Primary and Secondary Care, updated edition. The British Psychological Society and the Royal College of Psychiatrists: London.Google Scholar
Norman, RM, Malla, AK, Mclean, T, Voruganti, LP, Cortese, L, Mcintosh, E, Cheng, S, Rickwood, A (2000). The relationship of symptoms and level of functioning in schizophrenia to general wellbeing and the Quality of Life Scale. Acta Psychiatrica Scandinavica 102, 303–309.Google Scholar
Olie, JP, Spina, E, Murray, S, Yang, RG (2006). Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study. International Clinical Psychopharmacology 21, 143–151.Google Scholar
Oshima, I, Yoshio, M, Yoshimasa, I (2003). Institutionalisation and schizophrenia in Japan: social environments and negative symptoms Nationwide survey of in-patients. British Journal of Psychiatry 183, 50–56.Google Scholar
Overall, JE, Gorham, DR (1962). The brief psychiatric rating scale. Psychological Reports 10, 799–812.Google Scholar
Pach, J, Finkbeiner, T, Glaser, T, Haug, J, Osterheider, M, Tegeler, JJ (1998). Positive and negative symptoms in chronic schizophrenic patients under maintenance therapy with flupenthixol decanoate for a twelve month perioid. Fortschritte der Neurologie Psychiatrie 66, 442–449.Google Scholar
Peet, M, Horrobin, DFG (2002). A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. Journal of Psychiatric Research 36, 7–18.Google Scholar
Pinto, R, Bannerjee, A, Ghosh, N (1979). A double-blind comparison of flupenthixol decanoate and fluphenazine decanoate in the treatment of chronic schizophrenia. Acta Psychiatrica Scandinavica 60, 313–322.Google Scholar
Pogue-Geile, MF, Harrow, MG (1985). Negative symptoms in Schizophrenia: their longitudinal course and prognostic importance. Schizophrenia Bulletin 11, 427–439.CrossRefGoogle ScholarPubMed
Priebe, S, Mccabe, R, Bullenkamp, J, Hansson, L, Lauber, C, Martinez-Leal, R, Rossler, W, Salize, H, Svensson, B, Torres-Gonzales, F, Van Den Brink, R, Wiersma, D, Wright, DJ (2007). Structured patient-clinician communication and 1-year outcome in community mental healthcare: cluster randomised controlled trial. British Journal of Psychiatry 191, 420–426.CrossRefGoogle ScholarPubMed
Purdon, SE, Jones, BD, Stip, E, Labelle, A, Addington, D, David, SR, Breier, A, Tollefson, GD (2000). Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Archives of General Psychiatry 57, 249–258.Google Scholar
Ravanic, DB, Dejanovic, SMD, Janjic, V, Jovic, SD, Milovanovic, DR, Jakovljevic, V, Pantovic, V, Ravanic, B, Pantovic, M, Pantovic, MMG (2009). Effectiveness of clozapine, haloperidol and chlorpromazine in schizophrenia during a five-year period. Arquivos de Neuro-Psiquiatria 67, 195–202.Google Scholar
Richardson, P, Jones, K, Evans, C, Stevens, P, Rowe, AG (2007). Exploratory RCT of art therapy as an adjunctive treatment in schizophrenia. Journal of Mental Health 16, 483–491.Google Scholar
Schoemaker, JH, Jansen, WT, Schipper, J, Szegedi, A (2014). The selective glycine uptake inhibitor org 25935 as an adjunctive treatment to atypical antipsychotics in predominant persistent negative symptoms of schizophrenia: results from the GIANT trial. Journal of Clinical Psychopharmacology 34, 190–198.Google Scholar
Semiz, UB, Cetin, M, Basoglu, C, Ebrinc, S, Uzun, O, Herken, H, Balibey, H, Algul, A, Ates, AG (2007). Clinical predictors of therapeutic response to clozapine in a sample of Turkish patients with treatment-resistant schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry 31, 1330–1336.Google Scholar
Singh, SP, Singh, V, Kar, N, Chan, K (2010). Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. British Journal of Psychiatry 197, 174–179.Google Scholar
Statacorp, L (2009). Stata: release 11, StataCorp LP.Google Scholar
Strauss, GP, Harrow, M, Grossman, LS, Rosen, CG (2010). Periods of recovery in deficit syndrome schizophrenia: a 20-year multi-follow-up longitudinal study. Schizophrenia Bulletin 36, 788–799.Google Scholar
Strauss, GP, Keller, WR, Buchanan, RW, Gold, JM, Fischer, BA, Mcmahon, RP, Catalano, LT, Culbreth, AJ, Carpenter, WT, Kirkpatrick, B (2012). Next-generation negative symptom assessment for clinical trials: validation of the brief negative symptom scale. Schizophrenia Research 142, 88–92.Google Scholar
Sumiyoshi, T, Park, S, Jayathilake, K, Roy, A, Ertugrul, A, Meltzer, HY (2007). Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophrenia Research 95, 158–168.Google Scholar
Taiminen, TJ, Syvalahti, E, Saarijarvi, S, Niemi, H, Lehto, H, Ahola, V, Salokangas, RKRG (1997). Citalopram as an adjuvant in schizophrenia: further evidence for a serotonergic dimension in schizophrenia. International Clinical Psychopharmacology 12, 31–35.Google Scholar
Tuominen, HJ, Tiihonen, J, Wahlbeck, K (2005). Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophrenia Research 72, 225–234.Google Scholar
Turkington, D, Sensky, T, Scott, J, Barnes, TRE, Nur, U, Siddle, R, Hammond, K, Samarasekara, N, Kingdon, DG (2008). A randomized controlled trial of cognitive-behavior therapy for persistent symptoms in schizophrenia: a five-year follow-up. Schizophrenia Research 98, 1–7.Google Scholar
Ucok, A, Serbest, S, Kandemir, PEG (2011). Remission after first-episode schizophrenia: results of a long-term follow-up. Psychiatry Research 189, 33–37.Google Scholar
Voruganti, LP, Awad, AG, Parker, G, Forrest, C, Usmani, Y, Fernando, ML, Senthilal, S (2007). Cognition, functioning and quality of life in schizophrenia treatment: results of a one-year randomized controlled trial of olanzapine and quetiapine. Schizophrenia Research 96, 146–155.Google Scholar
Wykes, T, Huddy, V, Cellard, C, Mcgurk, SR, Czobor, P (2011). A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. American Journal of Psychiatry 168, 472–485.Google Scholar
Xiang, Y, Weng, Y, Li, W, Gao, L, Chen, G, Xie, L, Chang, Y, Tang, WK, Ungvari, GSJ (2006). Training patients with schizophrenia with the community re-entry module: a controlled study. Social Psychiatry and Psychiatric Epidemiology 41, 464–469.Google Scholar
Zhang, Z, Xu, X, Ni, H (2013). Small studies may overestimate the effect sizes in critical care meta-analyses: a meta-epidemiological study. Critical Care 17, R2 (http://ccforum.com/content/17/1/R2). Accessed 11 November 2014.Google Scholar
Zoccali, R, Muscatello, MR, Bruno, A, Cambria, R, Mico, U, Spina, E, Meduri, MG (2007). The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophrenia Research 93, 109–116.Google Scholar