Impact of antipsychotics on long-term course of psychotic illness. Donald Goff, MD Nathan Kline Institute NYU School of Medicine

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1 Impact of antipsychotics on long-term course of psychotic illness Donald Goff, MD Nathan Kline Institute NYU School of Medicine

2 Disclosures Dr. Goff receives research support from NIMH, the Stanley Foundation and Avanir Pharmaceuticals. He has received no honoraria over the past 5 years.

3 Two stories 1989: tardive dyskinesia

4 Two stories 2016: Duration of untreated illness (DUP) determines outcome in the RAISE Study Kane et al, Am J Psychiatry 2016

5 Are antipsychotics neurotoxic? Are antipsychotics neuroprotective? What drives DUP?

6 Do antipsychotics worsen the course of illness? It seems paradoxical that drugs that ameliorate acute psychotic symptoms over the short term will increase the likelihood that a person so treated will fare poorly over the long term. But that disturbing fact showed up in the very first outcome studies, and has continued to show up ever since.

7 Does early antipsychotic treatment improve the course of illness?

8 The long-term effects of antipsychotic medication on clinical course in schizophrenia Donald C. Goff, MD Peter Falkai, MD, PhD W. Wolfgang Fleischhacker, MD Ragy R. Girgis, MD Rene M. Kahn, MD, PhD Hiroyuki Uchida, MD, PhD Jingping Zhao, MD, PhD Jeffrey A. Lieberman, MD

9 The argument against antipsychotics Models for antipsychotic adverse effects: D2 receptor supersensitivity Neurotoxicity Evidence Naturalistic longitudinal studies Wunderink drug discontinuation study Imaging studies of gray matter loss Animal studies

10 Meta-analyses of antipsychotic effectiveness Response: 41% vs 24% Relapse: 27% vs 64% Leucht et al, Mol Psychiatry 2009 Leucht et al, Lancet 2012

11 NIMH Collaborative Antipsychotic Trial Cole et al, Arch Gen Psychiatry 1964

12 NIMH Collaborative Antipsychotic Trial 29% of placebo group dropped due to nonresponse In the ITT sample, 16% of placebo group and 75% of antipsychotic group were much or very much improved Cole et al, Arch Gen Psychiatry 1964

13 Predictors of re-hospitalization & functioning in patients discharged from the NIMH Collaborative Antipsychotic Trial Schooler et al, AJP 1967

14 Predictors of re-hospitalization & functioning: NIMH Collaborative Antipsychotic Trial Schooler et al, AJP 1967

15 Rates of recovery in patients on & off antipsychotic medication Harrow et al, Psychol Med 2012

16 Reduced relapse & mortality associated with antipsychotics Tiihonen et al, BMJ 2008; Lancet 2009

17 Lack of evidence for antipsychotic withdrawal contributing to relapse Leucht et al, Lancet 2012

18 Relapse rates do not differ in first 3, 6 or 9 months Leucht et al, Lancet 2012

19 Rates of improvement with treatment Hegarty et al, Am J Psychiatry 1994

20 18 month relapse rates associated with guided medication discontinuation 131 remitted FEP patients randomized to med discontinuation vs med maintenance Wunderink et al, J Clin Psychiatry 2007

21 Seven-year follow-up of discontinuation/reduction versus maintenance treatment Wunderink et al, JAMA Psychiatry 2013

22 Mean antipsychotic doses during years 5-7 Wunderink et al, JAMA Psychiatry 2013

23 Rates of recovery & remission at 7 year follow-up Wunderink et al, Am J Psychiatry 2013

24 Meta-analysis: DUP associated with worse outcome Marshall et al, Arch Gen Psychiatry 2005

25 Early Treatment and Identification of Psychosis (TIPS) Study (n=281) Median DUP reduced to 5 weeks; 16 weeks in comparison catchment area Reduced negative symptoms at presentation Benefits persisted at 2 years Melle et al, Arch Gen Psychiatry 2008

26 Relationship between DUP & Objective Qualify of Life (n=50)

27 Decreasing gray matter volume with increasing antipsychotic dose (n=18,000) Haijma et al, Schiz Bull 2013

28 Change in gray matter volume (in ml/yr) in SZ pts offmeds (n=8), on meds (n=8) and healthy controls (n=20) Controls Off meds On meds

29 Brain weight in monkeys following sham, haloperidol & olanzapine treatment for mos Dorph-Petersen et al, Neuropsychopharmacology 2005

30 Loss of glia in monkey parietal lobe following treatment with olanzapine & haloperidol Konopaske et al, Neuropsychopharmacology 2006

31 Change in cortical volume over 8 weeks in rats Vernon et al, Biol Psychiatry 2010

32 Hippocampus Prominent volume loss in schizophrenia Correlates with clinical course Highly sensitive to hypoxia, inflammation, excitotoxicity & oxidative stress May be an early driver of psychosis & illness progression

33 Shanghai FEP Study Hippocampal measurement at baseline and after 8 weeks of treatment 24 medication naïve FEP patients & 24 matched healthy controls Collaborator: Jijun Wang, MD, PhD, Shanghai Mental Health Center

34 Hippocampus Volumetric Integrity (HI) HI = Parenchymal volume Total volume (parenchyma + CSF) Babak Ardekani, PhD

35 Test-Retest Reliability back-to-back scans in (64 subjects) ICC=0.9987

36 HI vs. FreeSurfer Hippocampus Volumes In Alzheimer s disease vs healthy controls Ardekani BA, Convit A, Bachman A Analysis of the MIRIAD Data Shows Sex Differences in Hippocampal Atrophy Progression, J. Alz Disease (in press)

37 Left hippocampal volume before and after 8 weeks of antipsychotic treatment (n=24) Healthy Control FEP Subjects weeks 0 8 Onset of psychosis Antipsychotic treatment weeks

38 Extension of left hippocampal volumes if equivalent between groups at start of psychosis Healthy Control FEP Subjects weeks 0 8 Onset of psychosis Antipsychotic treatment weeks

39 Annualized percent change in left hippocampal index

40 Relationship between DUP and left hippocampal volume loss R=-.61, p=.002

41 What mediates relationship between DUP & hippocampal volume loss? Baseline: Inflammation Baseline: Oxidative stress Genetic: Excitotoxity Hypothesis: Antipsychotic reduction of dopamine release & associated neurotoxicity may be a delayed effect

42 Summary Psychosis is disabling, distressing and dangerous Antipsychotics are highly effective for psychosis and prevention of relapse Delay of treatment is associated with a poorer course

43 Summary Evidence of a negative long-term effect of antipsychotics on outcomes is not compelling The relationship between progressive gray matter loss and antipsychotic treatment is not clear. Whether antipsychotics are neurotoxic or neuroprotective may depend upon context.

44 Summary Do not use antipsychotics unnecessarily and use the lowest effective dose.

45 Collaborators Shanghai Mental Health Center Jijun Wang MD, PhD Botao Zeng MD NYUMC Erica Diminich PhD Isaac Galatzer-Levy PhD NKI Babak Ardekani, PhD