1. Association between substance abuse and long-term outcome of schizophrenia – a meta-analysis Jouko Miettunen Professor of Clinical Epidemiology University of Oulu, Finland

2. Conflicts of interest: None

3. Alcohol and other substance use problems are common among individuals with schizophrenia. Many of the previous studies have focused on clinical comorbidity, not on longitudinal studies aiming to look for possible causal associations. Cannabis is a potential risk factor for schizophrenia We aimed to investigate if premorbid or early substance use predicts long-term clinical and social course in schizophrenia.

4. Koskinen J, Löhönen J, Koponen H, Isohanni M, Miettunen J. Rate of cannabis use disorders in clinical samples of patients with schizophrenia: a meta-analysis. Schizophr Bull 2010; 36: 1115-30. Approximately every fourth schizophrenia patient had a diagnosis of cannabis use disorders (35 studies). median current rate of cannabis use disorders was 16.0% and median lifetime rate was 27.1% higher in first-episode vs. long-term patients (current 28.6% vs. 22.0%) Approximately every fifth schizophrenia patient had a diagnosis of cannabis use disorders (60 studies). Koskinen J, Löhönen J, Koponen H, Isohanni M, Miettunen J. Prevalence of alcohol use disorders in schizophrenia - a systematic review and meta-analysis. Acta Psychiatr Scand 2009; 120: 85-96.

5. Prevalence of cannabis use disorder

6. A meta-analysis including nine mainly cross-sectional studies found that substance using patients have more positive, but less negative symptoms (Talamo et al. 2006). In depressive symptoms, Potvin et al. (2007) found that substance using schizophrenia patients have more depressive symptoms, although the difference was smaller than commonly assumed. Other outcomes, such as employment or social functioning, have not been studied in systematic reviews. Substance Abuse and Outcome Potvin S, et al. Austr NZ J Psychiatry 2007; 41: 792-9; Talamo A, et al. Schizophr Res. 2006;86:251–255.

7. A systematic review to identify potentially relevant studies was conducted. Only studies with a follow-up period of at least two years were included. We studied following outcomes: negative, positive and total symptoms clinical remission hospitalizations social functioning employment global outcome Current data search until January 2014 Substance Abuse and Outcome

8. The search identified 9582 unique potentially relevant articles of which 25 studies presenting results from 30 samples met our inclusion criteria. The meta-analysis included 5 to 13 studies in each outcome category. Identification of Studies

9. ReferenceSample (M/F)Outcome(s) Addington and Addington 1998 (Canada) 80 (54/26) positive, negative and total symptoms (PANSS) Arndt et al. 1992 (USA)131 (93/38) symptoms (SANS/SAPS), hospitalization, global outcome (GAS), social and overall functioning Blow et al. 1998 (USA)682 (660/22) hospitalization, symptoms (BPRS), functioning (GAF) Bodén et al. 2009 (Sweden)71 functioning (living independently, work/ studying 50%, and meeting friends) Bühler et al. 2002 (Germany)46employment Caspari 1999 (Germany)53 (41/12) global outcome (GAS), hospitalization, employment, positive and negative symptoms (BPRS, AMDP) Cleghorn et al. 1991 (Canada)27 (19/8)positive and negative symptoms Dubertret et al. 2006 (France)181 (~118/63)positive and negative symptoms Foti et al. 2010 (USA)162symptoms (SAPS, SANS), global (GAF) Haro et al. 2011 (worldwide: six areas) 11078clinical and functional (social) remission

10. ReferenceSample(M/F)Outcome(s) Hodgins et al. 2008 (UK)225 menreal life functioning Huguelet et al. 1996 (Switzerland)37 (18/19)hospitalization, relapse, functioning (GAF) Jockers-Scherübl et al. 2007 (Germany) 39 (23/16) positive and negative symptoms, hospitalization, global clinical outcome (CGI) Jordan et al. 2014 (Canada) 159 (108/51) social functioning Juola et al. 2013, Miettunen et al. 2007 (Finland) 105 (63/43)employment Kozaric-Kovacic et al. 1995 (Croatia) 312 (150/162)social functioning, hospitalization, course Manrique-Garcia et al. 2014357 (357/0)hospitalization Marwaha et al. 2009 (United Kingdom, France, Germany) 213 to 773employment (losing or getting job) Orlandi and Bersani 2001 (Italy)125 negative, positive, total symptoms, hospitalization Pencer et al. 2005 (Canada)49employment/ productivity Verdoux et al. 2010 (France)108 (72/36)employment Whitty et al. 2008 (United Kingdom) 97 (63/34) Strauss–Carpenter Scale outcome scale (total score) Yen et al. 2009 (Taiwan)118 (99/19)symptoms (PANSS)

11. Summary of results positive symptoms (n=7) negative symptoms (n=6) total psychotic symptoms (n=6) clinical remission (n=8) hospitalizations (n=7) social functioning (n=13) employment (n=7) global outcome (n=5) Study -0.00 (-0.08, 0.07) 0.09 (-0.02, 0.21) 0.03 (-0.09, 0.15) -0.01 (-0.05, 0.02) -0.05 (-0.18, 0.07) -0.00 (-0.06, 0.05) -0.06 (-0.16, 0.04) -0.05 (-0.13, 0.04) correlation (95% CI) -0.00 (-0.08, 0.07) 0.09 (-0.02, 0.21) 0.03 (-0.09, 0.15) -0.01 (-0.05, 0.02) -0.05 (-0.18, 0.07) -0.00 (-0.06, 0.05) -0.06 (-0.16, 0.04) -0.05 (-0.13, 0.04) 0-0.2-0.100.10.20.3 correlation outcomes

12. Odds Ratio < 1 indicates lower likelihood of achieving remission Haro JM, et al. Cross-national clinical and functional remission rates: Worldwide Schizophrenia Outpatient Health Outcomes (W-SOHO) study. Br J Psychiatry 2011; 199:194-201.

13. Mullin K, Gupta P, Compton MT, Nielssen O, Harris A, Large M. Does giving up substance use work for patients with psychosis? A systematic meta-analysis. Aust N Z J Psychiatry 2012; 46:826-39. See also: Large M et al. Aust N Z J Psychiatry 2014; 48:418-32; Gupta P et al. Aust N Z J Psychiatry 2013; 47:524-37

14. although comorbid substance use associates with poorer outcome in schizophrenia, the early substance use has only a modest effect as a predictor of long-term outcome changes in substance use? effect of medication? alcohol vs. cannabis ? covariates? milder disease?

15. Tiina-Mari Paaso, BMed, Katja Kasurinen, BMed, Antti Mustonen, BMed, Eetu Oinas, BMed, Juha Käkelä, BMed, Erika Jääskeläinen, Adjunct Professor, Jouko Miettunen, Professor Center for Life Course Epidemiology and Systems Medicine and Research Unit for Clinical Neuroscience, University of Oulu, Oulu, Finland Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland Noora Hirvonen, MA Information studies, Faculty of Humanities, University of Oulu Email: jouko.miettunen@oulu.fi Homepage: www.joukomiettunen.net