EPA guidance on treatment of negative symptoms in schizophrenia

S Galderisi, S Kaiser, I Bitter, M Nordentoft, A Mucci, M Sabé, G M Giordano, M Ø Nielsen, L B Glenthøj, P Pezzella, P Falkai, S Dollfus, W Gaebel, S Galderisi, S Kaiser, I Bitter, M Nordentoft, A Mucci, M Sabé, G M Giordano, M Ø Nielsen, L B Glenthøj, P Pezzella, P Falkai, S Dollfus, W Gaebel

Abstract

Negative symptoms of schizophrenia remain a major therapeutic challenge. The progress in the conceptualization and assessment is not yet fully reflected by treatment research. Nevertheless, there is a growing evidence base regarding the effects of biological and psychosocial interventions on negative symptoms. The importance of the distinction between primary and secondary negative symptoms for treatment selection might seem evident, but the currently available evidence remains limited. Good clinical practice is recommended for the treatment of secondary negative symptoms. Antipsychotic treatment should be optimized to avoid secondary negative symptoms due to side effects and due to positive symptoms. For most available interventions, further evidence is needed to formulate sound recommendations for primary, persistent, or predominant negative symptoms.However, based on currently available evidence recommendations for the treatment of undifferentiated negative symptoms (including both primary and secondary negative symptoms) are provided. Although it has proven difficult to formulate an evidence-based recommendation for the choice of an antipsychotic, a switch to a second-generation antipsychotic should be considered for patients who are treated with a first-generation antipsychotic. Antidepressant add-on to antipsychotic treatment is an option. Social skills training is recommended as well as cognitive remediation for patients who also show cognitive impairment. Exercise interventions also have shown promise. Finally, access to treatment and to psychosocial rehabilitation should be ensured for patients with negative symptoms. Overall, there is definitive progress in the field, but further research is clearly needed to develop specific treatments for negative symptoms.

Keywords: Negative symptoms; schizophrenia; treatment.

Conflict of interest statement

S. Galderisi has been a consultant and/or advisor to or has received honoraria or grants from Millennium Pharmaceuticals, Innova Pharma-Recordati Group, Janssen Pharmaceutica NV, Sunovion Pharmarmaceuticals, Janssen-Cilag Polska Sp. zo. o., Gedeon Richter-Recordati, Pierre Fabre, Otsuka, and Angelini.

A. Mucci received honoraria, advisory board, or consulting fees from the following companies: Amgen Dompé, Angelini-Acraf, Astra Zeneca, Bristol-Myers Squibb, Gedeon Richter Bulgaria, Innova-Pharma, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer, and Pierre Fabre.

S. Dollfus received honoraria as expert/consultant by Fabre, Gedeon, Roche, and Takeda; invited Conferences: Lundbeck, Otsuka, Janssen, and has contracts with Prophase MedAvances and NeuroCogTrials.

S. Kaiser has royalties for cognitive training software from Schuhfried and advisory board honoraria from Recordati and Lundbeck on an institutional account for education and research.

I. Bitter has received in the past 5 years honoraria or consultation fees from Angelini, Eli Lilly, Gedeon Richter, Janssen/Janssen Cilag, and Sun Pharma.

All other authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Preferred reporting items for systematic reviews and meta-analyses flowchart of studies retrieved in the systematic literature search. *11,905 duplicates; 1,826 studies other than meta-analysis, randomized controlled trial, review, cohort study, open study, descriptive study, expert opinion; 843 studies published in journal not indexed in Embase or Medline; 2,895 studies on pathophysiological mechanisms of negative symptoms; 5,813 articles not related to any topic; 1,792 articles related to the assessment of negative symptoms; 158 studies conducted in animals. **Outdated; concerns about quality of meta-analytic procedures or of the original studies; addressed population/intervention/outcome not usable for formulation of recommendations.

References

    1. Bleuler E. Dementia praecox or the group of schizophrenias. New York, NY: International Universities Press; 1950.
    1. Jackson JH. Selected writings of JH Jackson. London, UK: Hodder and Stoughton; 1931.
    1. Kraepelin E. Dementia praecox and paraphrenia. Chicago, IL: Chicago Medical Book Company; 1919.
    1. Galderisi S, Mucci A, Buchanan RW, Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry. 2018;5(8):664–677.
    1. Marder SR, Galderisi S. The current conceptualization of negative symptoms in schizophrenia. World Psychiatry. 2017;16(1):14–24.
    1. Dollfus S, Lyne J. Negative symptoms: History of the concept and their position in diagnosis of schizophrenia. Schizophr Res. 2017;186:3–7.
    1. Bucci P, Galderisi S. Categorizing and assessing negative symptoms. Curr Opin Psychiatry. 2017;30(3):201–208.
    1. Schooler NR, Buchanan RW, Laughren T, Leucht S, Nasrallah HA, Potkin SG, et al. Defining therapeutic benefit for people with schizophrenia: focus on negative symptoms. Schizophr Res. 2015;162(1–3):169–174.
    1. Galderisi S, Mucci A, Dollfus S, Nordentoft M, Falkai P, Kaiser S, et al. EPA guidance on assessment of negative symptoms. Eur Psychiatry. 2021; Feb 18:1–91. doi:10.1192/j.eurpsy.2021.11. Online ahead of print.
    1. Aleman A, Lincoln TM, Bruggeman R, Melle I, Arends J, Arango C, et al. Treatment of negative symptoms: where do we stand, and where do we go? Schizophr Res. 2017;186:55–62.
    1. Kirschner M, Aleman A, Kaiser S. Secondary negative symptoms—a review of mechanisms, assessment and treatment. Schizophr Res. 2017;186:29–38.
    1. Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, et al. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr Bull. 2015;41(4):892–899.
    1. Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, et al. 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. 2017;174(10):927–942.
    1. Czobor P, Bitter I. Pharmacologic treatment of negative symptoms: focus on efficacy. In: Bitter I, editor. Managing negative symptoms of schizophrenia. Oxford: Oxford University Press; 2020; p. 67–86.
    1. Savill M. The impact, assessment, and longitudinal course of negative symptoms of schizophrenia. London: Queen Mary University; 2016.
    1. Gaebel W, Becker T, Janssen B, Munk-Jorgensen P, Musalek M, Rossler W, et al. EPA guidance on the quality of mental health services. Eur Psychiatry. 2012;27(2):87–113.
    1. Gaebel W, Grossimlinghaus I, Heun R, Janssen B, Johnson B, Kurimay T, et al. European Psychiatric Association (EPA) guidance on quality assurance in mental healthcare. Eur Psychiatry. 2015;30(3):360–387.
    1. Heun R, Gaebel W, EPA Guidance Committee. The relevance of EPA guidance papers in the framework of the European Psychiatric Association. Eur Psychiatry. 2015;30(3):357–359.
    1. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–e34.
    1. Gaebel W, Moller HJ. European guidance: a project of the European Psychiatric Association. Eur Psychiatry. 2012;27(2):65–67.
    1. Gaebel W, Grossimlinghaus I, Mucic D, Maercker A, Zielasek J, Kerst A. EPA guidance on eMental health interventions in the treatment of Posttraumatic Stress Disorder (PTSD). Eur Psychiatry. 2017;41:140–152.
    1. Carpenter WT, Jr, Heinrichs DW, Alphs LD. Treatment of negative symptoms. Schizophr Bull. 1985;11(3):440–52.
    1. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31–41.
    1. Leucht S, Komossa K, Rummel-Kluge C, Corves C, Hunger H, Schmid F, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. 2009;166(2):152–163.
    1. Helfer B, Samara MT, Huhn M, Klupp E, Leucht C, Zhu Y, et al. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry. 2016;173(9):876–886.
    1. Gregory A, Mallikarjun P, Upthegrove R. Treatment of depression in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2017;211(4):198–204.
    1. Galling B, Vernon JA, Pagsberg AK, Wadhwa A, Grudnikoff E, Seidman AJ, et al. Efficacy and safety of antidepressant augmentation of continued antipsychotic treatment in patients with schizophrenia. Acta Psychiatr Scand. 2018;137(3):187–205.
    1. Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior therapy for schizophrenia: effect sizes, clinical models, and methodological rigor. Schizophr Bull. 2008;34(3):523–537.
    1. Opoka SM, Lincoln TM. The effect of cognitive behavioral interventions on depression and anxiety symptoms in patients with schizophrenia spectrum disorders: a systematic review. Psychiatr Clin North Am. 2017;40(4):641–659.
    1. Assessing the effects of atypical antipsychotics on negative symptoms. Collaborative Working Group on Clinical Trial Evaluations. J Clin Psychiatry. 1998;59(Suppl_12):28–34.
    1. Samara MT, Dold M, Gianatsi M, Nikolakopoulou A, Helfer B, Salanti G, et al. Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: a network meta-analysis. JAMA Psychiatry. 2016;73(3):199–210.
    1. Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209(5):385–392.
    1. Mizuno Y, McCutcheon RA, Brugger SP, Howes OD. Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis. Neuropsychopharmacol. 2020;45:622–631.
    1. Jauhar S, McKenna PJ, Radua J, Fung E, Salvador R, Laws KR. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. Br J Psychiatry. 2014;204(1):20–29.
    1. Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry. 2018;17(3):341–356.
    1. Young SL, Taylor M, Lawrie SM. “First do no harm.” A systematic review of the prevalence and management of antipsychotic adverse effects. J Psychopharmacol. 2015;29(4):353–362.
    1. Guideline on clinical investigation of medicinal products, including depot preparations in the treatment of schizophrenia. London: European Medicines Agency; 2012.
    1. Laughren T, Levin R. Food and Drug Administration commentary on methodological issues in negative symptom trials. Schizophr Bull. 2011;37(2):255–256.
    1. Krause M, Zhu Y, Huhn M, Schneider-Thoma J, Bighelli I, Nikolakopoulou A, et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci. 2018;268(7):625–639.
    1. Danion JM, Rein W, Fleurot O. Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group. Am J Psychiatry. 1999;156(4):610–616.
    1. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. 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 2019;394(10202):939–951.
    1. Nemeth G, Laszlovszky I, Czobor P, Szalai E, Szatmari B, Harsanyi J, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet (London, England). 2017;389(10074):1103–13.
    1. Tiihonen J, Taipale H, Mehtala J, Vattulainen P, Correll CU, Tanskanen A. Association of Antipsychotic Polypharmacy vs Monotherapy with Psychiatric Rehospitalization among adults with schizophrenia. JAMA Psychiatry. 2019;76(5):499–50.
    1. Galling B, Roldan A, Hagi K, Rietschel L, Walyzada F, Zheng W, et al. Antipsychotic augmentation vs monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry. 2017;16(1):77–89.
    1. Kane JM, Correll CU, Goff DC, Kirkpatrick B, Marder SR, Vester-Blokland E, et al. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry. 2009;70(10):1348–1357.
    1. Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174(3):216–229.
    1. Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A, et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry. 1994;151(1):20–26.
    1. Andrade C, Kisely S, Monteiro I, Rao S. 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.
    1. Sabe M, Kirschner M, Kaiser S. Prodopaminergic drugs for treating the negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials. J Clin Psychopharmacol. 2019;39(6):658–664.
    1. Kishi T, Matsuda Y, Iwata N. Memantine add-on to antipsychotic treatment for residual negative and cognitive symptoms of schizophrenia: a meta-analysis. Psychopharmacology (Berl). 2017;234(14):2113–2125.
    1. Zheng W, Li XH, Yang XH, Cai DB, Ungvari GS, Ng CH, et al. Adjunctive memantine for schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Psychol Med. 2018;48(1):72–81.
    1. Andrade C. Memantine as an augmentation treatment for schizophrenia: limitations of meta-analysis for evidence-based evaluation of research. J Clin Psychiatry. 2017;78(9):e1307–e1309.
    1. Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014;40(1):181–191.
    1. Deakin B, Suckling J, Barnes TRE, Byrne K, Chaudhry IB, Dazzan P, et al. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial. Lancet Psychiatry. 2018;5(11):885–894.
    1. Solmi M, Veronese N, Thapa N, Facchini S, Stubbs B, Fornaro M, et al. Systematic review and meta-analysis of the efficacy and safety of minocycline in schizophrenia. CNS Spectr. 2017;22(5):415–426.
    1. Williams DR, Burkner PC. Effects of intranasal oxytocin on symptoms of schizophrenia: a multivariate Bayesian meta-analysis. Psychoneuroendocrinology. 2017;75:141–151.
    1. Firth J, Stubbs B, Sarris J, Rosenbaum S, Teasdale S, Berk M, et al. The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychol Med. 2017;47(9):1515–1527.
    1. Aleman A, Enriquez-Geppert S, Knegtering H, Dlabac-de Lange JJ. Moderate effects of noninvasive brain stimulation of the frontal cortex for improving negative symptoms in schizophrenia: meta-analysis of controlled trials. Neurosci Biobehav Rev. 2018;89:111–118.
    1. Kennedy NI, Lee WH, Frangou S. Efficacy of non-invasive brain stimulation on the symptom dimensions of schizophrenia: a meta-analysis of randomized controlled trials. Eur Psychiatry. 2018;49:69–77.
    1. Osoegawa C, Gomes JS, Grigolon RB, Brietzke E, Gadelha A, Lacerda ALT, et al. Non-invasive brain stimulation for negative symptoms in schizophrenia: an updated systematic review and meta-analysis. Schizophr Res. 2018;197:34–44.
    1. Wobrock T, Guse B, Cordes J, Wolwer W, Winterer G, Gaebel W, et al. Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial. Biol Psychiatry. 2015;77(11):979–988.
    1. Boes AD, Kelly MS, Trapp NT, Stern AP, Press DZ, Pascual-Leone A. Noninvasive brain stimulation: challenges and opportunities for a new clinical specialty. J Neuropsychiatry Clin Neurosci. 2018;30(3):173–179.
    1. Zheng W, Cao XL, Ungvari GS, Xiang YQ, Guo T, Liu ZR, et al. Electroconvulsive therapy added to non-clozapine antipsychotic medication for treatment resistant schizophrenia: meta-analysis of randomized controlled trials. PloS One. 2016;11(6):e0156510.
    1. Sinclair DJM, Zhao S, Qi F, Nyakyoma K, Kwong JSW, Adams CE. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2019;3:CD011847.
    1. Lally J, Tully J, Robertson D, Stubbs B, Gaughran F, MacCabe JH. Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2016;171(1–3):215–224.
    1. 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(5):324–332.
    1. Velthorst E, Koeter M, van der Gaag M, Nieman DH, Fett AK, Smit F, et al. Adapted cognitive-behavioural therapy required for targeting negative symptoms in schizophrenia: meta-analysis and meta-regression. Psychol Med. 2015;45(3):453–465.
    1. Grant PM, Huh GA, Perivoliotis D, Stolar NM, Beck AT. Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with schizophrenia. Arch Gen Psychiatry. 2012;69(2):121–127.
    1. Favrod J, Nguyen A, Chaix J, Pellet J, Frobert L, Fankhauser C, et al. Improving pleasure and motivation in schizophrenia: a randomized controlled clinical trial. Psychother Psychosom. 2019;88(2):84–95.
    1. Priebe S, Savill M, Wykes T, Bentall RP, Reininghaus U, Lauber C, et al. Effectiveness of group body psychotherapy for negative symptoms of schizophrenia: multicentre randomised controlled trial. Br J Psychiatry. 2016;209(1):54–61.
    1. Sabe M, Sentissi O, Kaiser S. Meditation-based mind-body therapies for negative symptoms of schizophrenia: Systematic review of randomized controlled trials and meta-analysis. Schizophr Res. 2019;212:15–25.
    1. NICE. Psychosis and schizophrenia in adults: Prevention and management. London: National Institute for Health and Care Excellenece; 2014.
    1. Bastiampillai T, Allison S, Gupta A. NICE guidelines for schizophrenia: can art therapy be justified? Lancet Psychiatry. 2016;3:1016–1017.
    1. Attard A, Larkin M. Art therapy for people with psychosis: a narrative review of the literature. Lancet Psychiatry. 2016;3(11):1067–1078.
    1. Geretsegger M, Mossler KA, Bieleninik L, Chen XJ, Heldal TO, Gold C. Music therapy for people with schizophrenia and schizophrenia-like disorders. Cochrane Database Syst Rev. 2017;5:CD004025.
    1. Turner DT, McGlanaghy E, Cuijpers P, van der Gaag M, Karyotaki E, MacBeth A. A meta-analysis of social skills training and related interventions for psychosis. Schizophr Bull. 2018;44(3):475–491.
    1. Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry. 2011;168(5):472–485.
    1. Cella M, Preti A, Edwards C, Dow T, Wykes T. Cognitive remediation for negative symptoms of schizophrenia: A network meta-analysis. Clin Psychol Rev. 2017;52:43–51.
    1. Dauwan M, Begemann MJ, Heringa SM, Sommer IE. Exercise improves clinical symptoms, quality of life, global functioning, and depression in schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2016;42(3):588–599.
    1. Vogel JS, van der Gaag M, Slofstra C, Knegtering H, Bruins J, Castelein S. The effect of mind-body and aerobic exercise on negative symptoms in schizophrenia: a meta-analysis. Psychiatry Res. 2019;279:295–305.
    1. Sabe M, Kaiser S, Sentissi O. Physical exercise for negative symptoms of schizophrenia: systematic review of randomized controlled trials and meta-analysis. Gen Hosp Psychiatry. 2020;62:13–20.
    1. Stubbs B, Vancampfort D, Hallgren M, Firth J, Veronese N, Solmi M, et al. EPA guidance on physical activity as a treatment for severe mental illness: a meta-review of the evidence and Position Statement from the European Psychiatric Association (EPA), supported by the International Organization of Physical Therapists in Mental Health (IOPTMH). Eur Psychiatry. 2018;54:124–144.
    1. Dieterich M, Irving CB, Park B, Marshall M. Intensive case management for severe mental illness. Cochrane Database Syst Rev. 2010;6(10):CD007906.
    1. Suijkerbuijk YB, Schaafsma FG, van Mechelen JC, Ojajärvi A, Corbière M, Anema JR. Interventions for obtaining and maintaining employment in adults with severe mental illness, a network meta-analysis. Cochrane Database Syst Rev. 2017;9(9):CD011867.
    1. Aubry T, Goering P, Veldhuizen S, Adair CE, Bourque J, Distasio J, et al. A multiple-city RCT of housing first with assertive community treatment for homeless Canadians with serious mental illness. Psychiatr Serv. 2016;67(3):275–281.
    1. Thorup A, Petersen L, Jeppesen P, Ohlenschlaeger J, Christensen T, Krarup G, et al. Integrated treatment ameliorates negative symptoms in first episode psychosis—results from the Danish OPUS trial. Schizophr Res. 2005;79(1):95–105.
    1. Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P, Group C. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008;148(4):295–309.
    1. Devoe DJ, Peterson A, Addington J. Negative symptom interventions in youth at risk of psychosis: a systematic review and network meta-analysis. Schizophrenia Bull. 2018;44(4):807–823.
    1. Craig TK, Garety P, Power P, Rahaman N, Colbert S, Fornells-Ambrojo M, et al. The Lambeth Early Onset (LEO) Team: randomised controlled trial of the effectiveness of specialised care for early psychosis. BMJ. 2004;329(7474):1067.
    1. Petersen L, Jeppesen P, Thorup A, Abel MB, Ohlenschlaeger J, Christensen TO, et al. A randomised multicentre trial of integrated versus standard treatment for patients with a first episode of psychotic illness. BMJ. 2005;331(7517):602.
    1. Correll CU, Galling B, Pawar A, Krivko A, Bonetto C, Ruggeri M, et al. Comparison of early intervention services vs treatment as usual for early-phase psychosis: a systematic review, meta-analysis, and meta-regression. JAMA Psychiatry. 2018;75(6):555–565.
    1. Kane JM, Robinson DG, Schooler NR, Mueser KT, Penn DL, Rosenheck RA, et al. Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE early treatment program. Am J Psychiatry. 2016;173(4):362–372.
    1. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. World Federation of Societies of Biological Psychiatry (WFSBP) 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(5):318–378.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa