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Dieter Naber Department of Psychiatry and Psychotherapy

Treatment of Schizophrenia : Remission, Functioning , Quality of Life and the Patients ‘ Perspective. Dieter Naber Department of Psychiatry and Psychotherapy University Medical Center , Hamburg-Eppendorf Hamburg, Germany. Disclosures: Dieter Naber.

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Dieter Naber Department of Psychiatry and Psychotherapy

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  1. Treatment of Schizophrenia: Remission, Functioning, Quality of Life and thePatients‘ Perspective Dieter Naber Department of Psychiatry and Psychotherapy University Medical Center, Hamburg-Eppendorf Hamburg, Germany

  2. Disclosures: Dieter Naber • I have an interest in relation with one or more organisations that could be perceived as a possible conflict of interest in the context of this presentation. The relationships are summarised below:

  3. More ambitious treatment goals over the past 50 years • Reduction of (positive) psychotic symptoms • Long-term treatment • Negative symptoms • Neuropsychological deficits • Quality of life (QoL)/Subjective well-being (SW) • Early detection/delay of transition to psychosis • Remission/recovery (functional outcome) 1960 1980 1990 2000 2005

  4. Interest in quality of life in schizophrenia Number of publications from 1988 to 2014 http://www.ncbi.nlm.nih.gov/pubmed Data obtained March 2015 using the Medline, PubMed search: schizophrenia AND “quality of life” OR “subjective well being” OR “subjective wellbeing”

  5. Main reasons for neglectingQoL and subjective well-being (SW) in schizophrenia • Lack of agreement on definition, on essential components of QoL or SW and on rating scales1 • Self-rated judgment of QoL or SW is often disqualified as unreliable1 • Before availability of atypicals, only limited ways to consider patient’s complaints 1. Lambert et al. Pharmacopsychiatry 2003;36(Suppl3):181–190 QoL=quality of life; SW=subjective well-being

  6. HRQoL and SW in schizophrenia: Overview on definitions 1,2,3,4,5 • Health Related Quality of Life (HRQoL)1 Patient's self-reported bio-psychosocial perception of the disorder and of the health status including capacity to function physically, mentally and socially • Subjective well-being (SW) 2,3,4,5 All experiences in patients’ report, whether positive or negative, at the physical, emotional and cognitive levels under treatment with antipsychotic medication, causality (illness or drug effects) not questioned 1. Bullinger and Hasford. Control Clin Trials 1991;12(4 Suppl):91-105 2. Lambert M et al. Pharmacopsychiatry 2003; 36 Suppl 3:181-90. 3. Naber D. Int Clin Psychopharmacology 1995;10 (suppl 3):133-138. 4. De Haan et al. Psychopharmacology (Berl) 2002;162(1):24-8. 5. Singh MM. Dis Nerv Syst 1976;37:191-196.

  7. Quantifying Clinical Relevance in the Treatment of Schizophrenia (Corell et al, 2011) Increasing attention has been focused in recent years on the importance of patient-reported outcomes in informing research and clinical practice. Given the subjective nature of many aspects of psychopathology, it is particularly important in psychiatry to have this perspective. Yet, in schizophrenia there are concerns about insight, cognitive dysfunction, reality testing and communicative ability, which must be recognized in the acquisition and interpretation of such data.

  8. Are schizophrenic patients able to self-rate? • The wide majority of schizophrenia patients, if no more acutely psychotic and without severe cognitive deficits(and not living under socially deprived conditions), is able to reliably self-rate their quality of life /subjective well-being Naber et al, 1995; Voruganti et al, 1998; Khatri et al., 2001; de Haan et al., 2002; Voruganti et al., 2002; Liraud et al., 2004; Baumstarck et al., 2013; Hayhurst et al. 2014

  9. Do weassesswithsubjectiveQoLtheresult of an adaptationprocess? A theory of socialcomparisonprocesses(Festinger 1954) Personscomparethemselvestoothers in ordertoevaluatetheirownsituation. Lateral and downwardcomparisonsincreasesatisfaction, whileupwardcomparisonsdecreasesatisfaction

  10. Quality of Life and Duration of Hospitalization N = 266, PatientssufferingfromchronicSchizophrenia satisfied 6 5 Neither /nor 4 3 dissatisfied < 10 10-20 20-30 30-40 > 40 J. Duration of Hospitalization Franz et al. 1998, 1999, 2001

  11. Quality of life measurement in schizophrenia • Numerous scales are available (generic versus disease-specific, self- versus expert-rated). • Disease-specific scales seem to be more sensitive than generic scales, self-rated scales are less time consuming and might be more useful than interview-based scales. • Quality of Life scale (Heinrichs et al., 1984) is most widely used. 21-item semi-structured interview to access QOL in relation to deficit symptoms and impaired functioning. Total score and 4 subscores, 45 minutes.

  12. Subjective effects of antipsychotics • Many schizophrenic patients, particularly if treated with typical antipsychotics, report not only motor effects, but also emotional and affective restrictions – ‘I feel like a zombie’ • Complaints are well known (pharmacogenic depression, akinetic depression, pharmacogenic anhedonia, neuroleptic-induced deficit syndrome), but barely investigated • Symptoms are often difficult to differentiate from negative symptoms of schizophrenia • Clinical experience: when patients were switched from typical antipsychotics to clozapine, they reported major improvement

  13. Subjective well-being under neuroleptics (SWN) • The self-report of 20 items (10 positive, 10 negative, Likert scale) shows sufficient internal consistency (Cronbach‘s  .92) and good construct validity. • Most patients do not need more than 5-10 minutes to fill it out. • Thereare 5 subscores (emotional regulation, self-control, socialintegration, mental and physicalfunctioning). • SWN improvement is rather relevant for adherence (more than improvement of psychopathology) and also for the chance to reach remission.

  14. Self-report of well-being by schizophrenic patients • All statements refer to the past 7 days. • Total score, 5 subscores (e.g. physical functioning) Not at all A little Somewhat Noticeable Much Very much My body is a burden to me I feel very comfortable with my body I feel weak and exhausted My body feels familiar

  15. Improvements of Psychopathology and Subjective Well-Being under Atypical Neuroleptics are not strongly related • Relationship between individual changes of SWN and PANSS in 97 in-patients with schizophrenia treated with olanzapine (n=36), risperidone (n=28) or clozapine (n=36) for 30-58 days • r=-0.29, p<0.006 Naber D, et al. Schizophr Res. 2001;50(1-2):79-88.

  16. Double-blind Comparison of Olanzapine and Clozapine SWN Total Score D SWN - D PANSS, r = -.45, p=.003 Naber et al., Acta Psychiat Scand 2005

  17. Relationships among SWN and other outcome measures in schizophrenia (Chen et al. 2010) • Data of a randomised multi-centrestudy of chronicschizophreniapatients (n=628) wereexaminedtoinvestigatetherelationshipamongseveraloutcomemeasures, including PANSS, MADRS, SchizophreniaObjectiveFunctioning Instrument (SOFI), Quality of Life Scale (QLS), and the SWN. • Twoanalyticapproacheswereused: 1) pairs analysis and 2) factor analysis. • Findingssuggestsomeredundancy, particularlyamongtheclinician-ratedfunctional and quality of lifemeasures. Only a smallproportion of thevariance in SWN was explainedbytheclinician-ratedmeasures, suggestingthatthe SWN capturesuniqueinformation.

  18. Relationships between SW/QoL and expert-rated psychopathology high Negative Symptoms Negative subjective well-being Meltzer et al. (1990) r = -.3 bis -.4 (< 0.01) Browne et al. (1990) r = -.69 (< 0.01) Naber et al. (1994) r = -.3 bis -.4 (< 0.01) Gervin et al. (1999) r = -.5 (< 0.001) Bow-Thomas et al. (1999) r = -.45 (p<0.05) Naber et al. (2001) r = -.4 (< 0.01) Depressive Symptoms Carpiniello et al. (1997) r = -.3 bis -.4 (< 0.01) Dickerson et al. (1998) r = -.45 (< 0.01) Franz et al. (1997) r = -.35 (<0.01) Karow et al. (in press) = r = -.4 (<0.01) Meltzer et al. (1990) r = -.2 bis -.3 (ns) Browne et al. (1990) r = -.21 (ns) Naber et al. (1994) r = .1 bis -.2 (ns) Naber et al. (2001) r = -.1 (ns) Positive Symptoms less high 1. Lambert M et al., Pharmacopsychiatry 2003; 36 Suppl 3:181-90.

  19. The Neuroleptic Strategy Study (NeSSy): Randomized double-blind 6-months comparison of twofirstgenerationantipsychotics (Haloperidol, Flupentixole: conventionalstrategy) versus threesecondgenerationantipsychotics (Aripiprazole, Olanzapine, Quetiapine: „atypical“ strategy) Six substancepairs: Haloperidol/AripiprazoleFlupentixole/Aripiprazole Haloperidol/OlanzapineFlupentixole/Olanzapine Haloperidol/QuetiapineFlupentixole/Quetiapine Choice of both „the best“ typical or atypical,based on characterics of patient and substance Randomization: either the typical or the atypical antipsychotic

  20. Primary endpoint: CGI-I

  21. Primary endpoint: SF-36 Health Survey The doctors did not see a difference,but the patients did! Moreover, cognition improved under atypicals but worsened under typicals

  22. Impact of Side Effects on SWN • Under treatment with typical AP: EPS are most disturbing • Under atypical AP: sexual SE, weight gain and sedation 1. Putzhammer et al. Pharmacopsychiatry2005; 38: 132-8

  23. Prediction of 5-year Remission by early Improvement of SWN , but not of PANSS 1 • 110 patients with first episode of schizophrenia • Continuous symptomatic remission between month 6 and month 60 p=.095 Change of SWN-K and PANSS values in the first 6 weeks p=.0004 SWN-K PANSS 1. DeHaan et al. Pharmacopsychiatry, 2008

  24. Early detection of incomplete remission with the SWN-K 1 727 patients with SWN-K ≤ 60 at admission, treated with amisulpride for 12 weeks CGI-S SOFAS PANSS pos SWN-K response = increase ≥ 20% PANSS neg 1. Lambert et al. Acta Psychiatrica Scand, 2006.

  25. SWN-K as predictor of response 1 631 patients, 12 weeks follow-up PANSS pos & neg, CGI-S, SOFAS, and SWN-K were transformed into measures ranging from 0-100 and combined to total outcome Linear regression of baseline scores with OUT at 3 months 1. Karow et al. J Clin Psychiatry, in preparation.

  26. Animal data on affective changes with (typical) antipsychotics • Extensive animal data indicate the importance of mesocortical dopamine (mostly D2) systems in mediating reward behaviour • Several animal studies have demonstrated that antipsychotics strongly and negatively affect reward system(s) in a variety of models • Dopamine agonists (cocaine, crack) are abused, dopamine antagonists (antipsychotics) never! • Less inhibition of reward systems by some atypical antipsychotics (a.o.aripiprazole, olanzapine, and clozapine)

  27. High D2 receptor blockade results in reduced subjective well-being: a PET study in schizophrenia • In 12 patients, treated with 1 mg RIS (n=2), 4 mg RIS (n=3), 2.5 mg OLA (n=3), or 15 mg OLA (n=4) striatal and extrastriatal dopamine D2 occupancy (50–91%, 4–95% respectively) as well as PANSS, SWN and motor symptoms were assessed • SWN and PANSS positive symptom scores were not significantly correlated (r=0.11, p=0.78) but SWN and Simpson-Angus Rating Scale scores were (r=-0.71, p=0.047) • SWN and D2 occupancy were significantly correlated in the striatum (r=-0.66, p=0.01) as well as in the temporal lobe (r=-0.76, p=0.003) Mizrahi et al. Am J Psychiatry 2007;164(4):630–637 OLZ=olanzapine; PANSS=Positive and Negative Syndrome Scale; PET=positron emission tomography; RIS=risperidone; SWN=Subjective Well-being Under Neuroleptic Treatment Scale

  28. Relationships between SWN and Dopamin D2 Receptor Occupancy: Striatal r =-.66, p=.01, temporal, r =-.76, p=.003 (Mizrahi et al., 2007) 28

  29. Howto Balance Subjective Quality of Life and AntipsychoticEfficacy? Whatistherightantipsychoticdosage (dopaminergicblockade)? • PET studies indicate a „right“ dopaminergic blockade of 75-85% • Iftheblockadeistoo high: motorsideeffects and rewardinhibition • If the blockade is too low: insufficient antipsychotic efficacy • For most antipsychotics, particularly for typicals, the range is small • A good balance (broad range) of QoL vs. efficacy was found for atypical antipsychotics such as aripiprazole, clozapine, olanzapine and quetiapine- Clozapine! Low dopaminergicblockade ( 60%), but goodantipsychoticefficacy

  30. Non-Adherence is still the Major Problem in the Treatment of Schizophrenia • Reasons for Non-Adherence: a.o. lack of insight , side effects , cognitive problems, alcohol/substance abuse • Atypical/second generation antipsychotics have not markedly increased adherence • Most relevant factor to improve adherence: Quality of therapeutic alliance • How to increase adherence? - Psychoeducation, involvement of caregivers / relatives dopaminergic blockade as high as necessary - as low as possible - ”peer patients” - long-acting injection (LAI)

  31. Attitude towards antipsychotic medication1 228 patients with schizophrenia assessed with: • Psychopathology (PANSS) • Antipsychotic side effects (LUNSERS) • Attitude towards antipsychotic medication (DAI) • Knowledge about antipsychotics • Insight (Birchwood Insight scale, PANSS item G12) • Therapeutic alliance with clinicians (CALPAS, PEESS) • Experience during first admission (McArthur Admission Experience Survey) Attitudes towards antipsychotics and subsequent compliance were best predicted by the quality of the therapeutic alliance and a positive experience during first admission 1. Day et al. Arch Gen Psychiatry 2005;62:717–724 CALPAS=California Psychotherapy Alliance Scale; DAI=Drug Attitude Inventory; LUNSERS=Liverpool University Neuroleptic Side Effect Rating Scale; PANSS=Positive and Negative Syndrome Scale; PEESS=Perceived Expressed Emotion in Staff Scale

  32. What is special about LAI formulations of antipsychotics? • Immediate transparency of non-adherence and the chance of interventions (from calling the patient or his/her caregivers to home treatment) • Questions of carers and doctors “Have you taken your medication? ” is not necessary anymore • Improvement of the therapeutic alliance by regular contact with the therapeutic team (setting, what happens in addition to the injections?) • Surveys: Doctors: “My patients refuse the injection!” Patients: “My doctor never offered me this formulation!” • In the past: Negative image of LAIs (stigma, highly negatively selected patients, “control?”)

  33. Patients are willing to accept LAI antipsychotic when properly informed (despite their negative reputation!) • In a survey of psychiatrists: • Approximately 80% cited patient refusal as a primary reason for not prescribing LAI antipsychotics1 • In a survey of patients with/without LAI antipsychotic experience: • 79% of patients without LAI experience cited having never been informed about the option by their psychiatrist2 • 75% of psychiatrists felt that they informed the patient, but only 33% of patients felt informed2 • In a survey of patients with ≥3 months of LAI antipsychotic experience: • Injectable antipsychotics were the preferred formulation3 • 70% of patients felt better supported in their illness by virtue of regular contact with the doctor or nurse who administered their injection3 1. Heres et al. J Clin Psychiatry 2006;67(12):1948–1953; 2. Jaeger & Rossler. Psychiatry Res 2010;175(1–2):58–62; 3. Caroli et al. Patient Prefer Adherence 2011;5:165–171 LAI=long-acting injectable antipsychotic

  34. Efficacy of LAIs versus oral antipsychotics Randomised controlled trials • No differences in study-defined relapse/all-cause discontinuation between LAIs and oral antipsychotics1 Mirror image studies • LAIs reduce risk of hospitalisation compared with oral antipsychotics2 Cohort study • LAI antipsychotics significantly improve treatment outcomes (risk of discontinuation or rehospitalisation) in patients with schizophrenia3 1. Kishimoto et al. Schizophr Bull 2014;40(1):192–213; 2. Kishimoto et al. J Clin Psychiatry 2013;74(10):957–965; 3. Tiihonen et al. Am J Psychiatry 2011;168(6):603–609 LAI=long-acting injectable

  35. Real-world studies favour the use of LAI antipsychotics As study design shifts toward real-world populations, LAI formulations display significant advantages 2.2 Relapsea 2.0 Favoursoral Hospitalisationa 1.8 All-cause discontinuationa 1.6 Overalla 1.4 1.2 Adjusted risk ratio 1.0 0.8 FavoursLAI 0.6 RR=0.89 0.4 RR=0.62 0.2 RR=0.56 0 Randomisedclinical studies Prospectivestudies Retrospectivestudies RCT Real-world aRisk ratio of LAI to oral antipsychotic; LAI=long-acting injectable antipsychotic; RCT=randomised controlled trial; RR=risk ratio Kirson et al. J Clin Psychiatry2013;74(6):568–575

  36. LAI vs. OAP Mirror-Image Studies [Hospitalizatio Risk] 16 studies, 4066 patients Risk Ratio=0.43, 95%CI:0.35-0.53, p<0.0001 NNT=3 Kishimoto et al. Journal of Clinical Psychiatry 2013

  37. LAIs vs. OAPs CohortStudies [Hospitalization Risk] Kishimoto et al. Scz Bull in press

  38. LAI antipsychotics approved for the treatment of schizophrenia in the EU – the more the better, to individualise treatment LAI antipsychotics are designed to deliver a gradual release of active antipsychotic from a single deep-tissue injection1 1. Weiden et al. Psychiatr Ann 2011;41(5):271–278 All agents listed in the table may also have additional indications, and local variations may apply

  39. Effectiveness study – study design Oral aripiprazole5–30 mg/day(n=143) Aripiprazole-OM 400 mg Aripiprazole-OM 400/300 mg 5 injections R Oral paliperidone3–12 mg/day(n=143) Paliperidone IM injection Paliperidone IM injection Naber et. al. Schiz. Res. 2011 aPatients undergo screening for eligibility (7–14 days); patients stratified according to age >35 or ≤35 years with expected ratio of 1:2; IM=intramuscular; LAI=long-acting injectable; OM=once-monthly; PAL=paliperidone; PP=paliperidonepalmitate; R=randomisation

  40. QUALIFY Study: effectiveness endpoints Primary • Mean change from baseline to Week 28 in the Quality of Life Scale (QLS) total score Secondary • Mean change from baseline to Week 28 in: • Investigator Assessment Questionnaire (IAQ) total score • Clinical Global Impression-Severity of Illness (CGI-S) score • Subjective Well-being under Neuroleptics-short version (SWN-S) score • Tolerability and Quality of Life (TooL) score Other • Mean change from baseline to Week 28 in: • Readiness for Work Questionnaire (WoRQ) • Arizona Sexual Experience Scale (ASEX) • Clinical Global Impression-Improvement (CGI-I) score at Week 28 Naber et. al. Schiz. Res. 2011

  41. Quality of Life Scale (Heinrichs-Carpenter QLS) Heinrichs et al. Schizophr Bull 1984;10(3):388–398 aThe items within the ‘Intrapsychic foundations’ domain are considered to be the building blocks for interpersonal and instrumental role functioning

  42. QUALIFY Study: primary effectiveness variable – LS mean change from baseline in QLS total score (FAS) * * * LS mean difference at Week 28:4.67 (95% CI: 0.32, 9.02)p=0.036 Treatment week • LS mean change from baseline at endpoint for QLS total score was significantly greater with aripiprazole-OM compared with paliperidone IM injection Naber et. al. Schiz. Res. 2011 *p<0.05 versus paliperidone IM injection Based on MMRM, FAS; mean baseline QLS score (FAS): aripiprazole-OM (n=136) 66.1, paliperidone IM injection (n=132) 62.5; FAS=full analysis set; IM=intramuscular; LS=least squares; MMRM=mixed-model repeated measures; OM=once-monthly; QLS=Quality of Life Scale; SE=standard error

  43. QLS scores by age groups Significant improvements for aripiprazole-OM vs paliperidone-IM on QLS total scores in patients ≤35 years (FAS) * * Naber et. al. Schiz. Res. 2011 *p<0.05 vs paliperidone-IM patients ≤35 years; LSM changes from baseline are based on MMRM; in treated patients ≤35 years, baseline mean (±SD) QLS total scores were 67.5±21.6 for aripiprazole-OM and 64.1±24.6 for paliperidone-IM; in patients >35 years: 65.7±21.3 for aripiprazole-OM and 61.9±20.1 for paliperidone-IM; IM=intramuscular; LSM=least squares mean; MMRM=mixed-model repeated measures; OM=once-monthly; QLS=Heinrichs–Carpenter Quality of Life Scale; SE=standard error

  44. Effect of aripiprazole once-monthly on quality of life may be more pronounced in early schizophrenia ≤35 years >35 years * * * 1. Naber et al. Poster presented at 11th Annual NEI Congress. 2015; Orlando, FL. Poster 160 *p<0.05 vs PP; mixed model for repeated measures, full analysis set; mean baseline QLS domain scores for AOM 400 mg and PP, respectively: ≤35 years (AOM, n=41; PP, n=37): common objects and activities, 7.3 and 7.4; intrapsychic foundations, 23.7 and 23.1; interpersonal relations, 25.3 and 23.8; instrumental role, 11.0 and 10.3. >35 years (AOM, n=95; PP, n=95): common objects and activities, 7.7 and 7.5; intrapsychic foundations, 23.5 and 22.6; interpersonal relations, 23.4 and 22.7; instrumental role, 10.8 and 9.6; AOM=aripiprazole once-monthly, LS=least squares, PP=paliperidone palmitate, QLS=Quality of Life Scale, SE=standard error

  45. CGI-S scores by age groups Significant improvements for aripiprazole-OM vs paliperidone-IMon CGI-S scores in patients ≤35 years (FAS) * * * ** * * * Naber et. al. Schiz. Res. 2011 *p<0.05, **p<0.01 vs paliperidone-IM; LSM changes from baseline are based on MMRM; in treated patients ≤35 years: baseline CGI-S scores were 3.95±0.62 for aripiprazole-OM and 4.00±0.57 for paliperidone-IM; in patients >35 years: 4.01±0.67 for aripiprazole-OM and 3.96±0.68 for paliperidone-IM; CGI-S=Clinical Global Improvement – Severity; IM=intramuscular; LSM=least squares mean; MMRM=mixed-model repeated measures; OM=once-monthly; SE=standard error

  46. Other secondary endpoints – IAQ, SWN-S and TooL Significant or numerical improvements for aripiprazole-OM vs paliperidone-IMtreatment on IAQ, SWN-S, and TooL total scores (FAS) * Naber et al. Poster at ASCP; Miami, Florida, June 22–25, 2015 *p<0.05 vs paliperidone-IM; LSM changes from baseline are based on MMRM; IAQ=Investigator’s Assessment Questionnaire; IM=intramuscular; LSM=least squares mean; MMRM=mixed-model repeated measures; OM=once-monthly; SE=standard error; SWN-S=Subjective Well-Being under Neuroleptic Treatment – Short version; TooL=Tolerability and quality of life questionnaire

  47. Sexual dysfunction-change from baseline to week 28 AOM vs PP- Patients 18-35 years % * p=0,0036 Potkin SG Reduced sexual dysfunctionwitharipiprazoleonce-monthlyversuspaliperidonepalmitate: results from QUALIFY IntClinPsychpharmacol 2017 Mar 1. doi: 10.1097/YIC.0000000000000168

  48. Other secondary endpoints – WoRQ Significant improvements for aripiprazole-OM vs paliperidone-IM on WoRQ total and numbers of patients shifting in work readiness status from baseline to Week 28 (FAS) Shift in status on ‘Readiness for work’ (WoRQ Item 8) ** The odds at Week 28 of being rated ready for work were higher for aripiprazole-OM vs paliperidone-IM(adjusted odds ratio: 2.67, 95% CI: 1.39, 5.14; p=0.003) Naber et al. Poster at ASCP; Miami, Florida, June 22–25, 2015 **p<0.01 vs paliperidone-IM; LSM change from baseline based on MMRM; IM=intramuscular; LSM=least squares mean; MMRM=mixed-model repeated measures; OM=once-monthly; SE=standard error; WoRQ=Readiness to work questionnaire

  49. Correlationsbetween Outcomes

  50. Remission and Recovery:New Hopes- RealisticAims in the Treatment of Schizophrenia Providing hope : a difficultbalance ! • Toomuchoptimismmightleadto non-compliance and unrealisticexpectations, • Toomuchscepticismmightleadtorefusal of treatment and despair Regardingnecessity of antipsychoticlong-term treatment, manypatients, families and doctorshopethat in firstepisodepatients, psychosisis„onlydrug-induced“

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