First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver...
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First-episode psychosis and schizophrenia
Oliver Freudenreich, MD, FACLP
Co-Director,
MGH Schizophrenia Program
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Disclosures
I have the following relevant financial relationship with a commercial interest to disclose (recipient SELF; content SCHIZOPHRENIA):
• Alkermes – Consultant honoraria (Advisory Board)• Avanir – Research grant (to institution)• Janssen – Research grant (to institution), consultant honoraria (Advisory Board)• Neurocrine – Consultant honoraria (Advisory Board)• Novartis – Consultant honoraria• Otsuka – Research grant (to institution)• Roche – Consultant honoraria• Saladax – Research grant (to institution)• Elsevier – Honoraria (medical editing)• Global Medical Education – Honoraria (CME speaker and content developer)• Medscape – Honoraria (CME speaker)• Wolters-Kluwer – Royalties (content developer)• UpToDate – Royalties, honoraria (content developer and editor)
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Erich Lindemann Mental Health Center
Erich Lindemann1900-1974Chief of Psychiatry MGH 1955-1965
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Learning objectives
At the completion of this talk, participants will be able to
– Discuss which three broad treatment principles are critical for the optimal treatment of schizophrenia
– Give examples for stage-based treatment goals in schizophrenia– Select patients who should be offered long-acting injectable
antipsychotics
Erich Lindemann Mental Health Center
Erich Lindemann – Chief of Psychiatry at MGH 1955-1965
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Outline
A. Background: a brief history of psychiatryB. Broad treatment principles
• Recovery orientation• Prevention principles• High-quality medical care
C. New FDA drug approvalsD. New stage-based insights
• Prodromal phase• Acute psychosis• Post-psychotic/chronic phase
E. Summary: psychiatric jeopardy
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Fleishman M. Psychiatr Serv. 2003;54:142.
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Myth of “natural history”
• TB as social disease
• Holy grail of modern medicine: molecular basis of disease
• “Desocialization” of scientific inquiry
• “Structural violence”
– Structural – built-in
– Violence – causing injury
• Health disparities
Farmer PE et al., PLoS Medicine 2006;3(10):e449.
Social interventions have greater impact
on outcomes than molecular advances.
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Broad treatment principles
• Recovery orientation– Patient-centered care*– Patient/peer involvement in disease management– Holistic care (mens sana in corpore sano; no medical health
without psychiatric health)• Prevention orientation
– Timely care*– Staging– Medical prevention part of psychiatric care
• High-quality medical care– Effective care*– Safe care*– Integrated medical-psychiatric care
*Based on Institute of Medicine’s 6 Aims (2001)
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REVOVERYORIENTATION
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SOHO* – positive psychiatry
60.3
45.4
57
28.1
0 10 20 30 40 50 60 70
Symptoms
Function
Subjective Well-
being
Combined
remission
Percent
Lambert M et al., Acta Psychiatr Scand. 2008;118:220.MacBeth A et al. Early Interv Psychiatry. 2015;9:53.*Schennach R et al. Schizophr Res. 2019 [Epub ahead of print].**Dong M et al. Psychiatr Q. 2019 [Epub ahead of print]. [WHOQOL-BREF]
*N=392 never-treated patients
SOHO = Schizophrenia Outpatients Health Outcomes study
QoL**
Asymptomatic*18%
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RAISE trial
• Goal– Develop early-intervention system in real world of fragmented US
healthcare system
• NAVIGATE– Cluster randomization of 34 clinics in 21 states of NAVIGATE versus
community care (CC)– Core services: family education, resilience training, supported
employment/education, medications1
– N=404
• Results– Team-based, multi-component NAVIGATE improved primary outcome
variable (QoL) more than CC2
– Effects were better for those with shorter DUP (median 74 weeks)3
– Improved QOL if more perceived autonomy support4
1Mueser KT et al. Psychiatr Serv. 2015;66(7):680-90.2Kane JM et al. Am J Psychiatry. 2016;173(4):362-72.3Addington J et al. Psychiatr Serv. 2015;66(7):753-6.4Browne J et al. Psychiatr Serv. 2017;68(9):916-922.
RAISE = Recovery After an Initial Schizophrenia Episode
QoL = Quality of Life
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PREVENTIONPRINCIPLES
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Prevention in psychiatry
• Medical prevention in schizophrenia• Primary prevention
– Universal prevention• Whole population
– Selective prevention• More susceptible subgroup, still symptom free
• Secondary prevention – “early intervention”– Indicated prevention
• Already showing signs of illness
• Tertiary prevention – minimize disability– Relapse prevention
1Gates J et al. Lancet Psychiatry. 2015;2(8):726-42.
Mental healthstarts with
physical health1
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Omega-3 fatty acids for indicated prevention
STUDY DESIGN• Ultra-high risk patients• Intervention: omega-3 PUFA x 6
months• All participants received Cognitive
Behavioral Case ManagementRESULTS• N=304 randomized• ¼ lost to follow-up• 6-month transition rates (CAARMS):
– Placebo 5.1% (=15)– PUFA 6.7% (=17)
• 12-month transition rates:– Placebo 11.2%– PUFA 11.5%
• No effect of adherence (40%!)
NEURAPRO = ?
McGorry PD et al. JAMA Psychiatry. 2017;74(1):19-27.Editorial: Kane JM and Correll CU. JAMA Psychiatry. 2017;74(1):11-2.
1.4 g omega-3 FA (840 mg EPA/560 mg DHA
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Staging model of treatment
• Rational for staging– Avoid progression to disease stages where only
amelioration is possible– Better response to treatments in early stages– Earlier treatments are less aggressive
• Principles– Early intervention to treat patients as early as possible in
the disease course– Phase-specific care that tailors the interventions to the
patient’s needs– Stepped care that adjusts treatment intensity based on
response
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Clinical staging in psychiatry
STAGE Definition Clinical features
0 Asymptomatic subjects Not help seekingNo symptoms but risk
1a “Help-seeking” subjects with symptoms
Non-specific anxiety/depressionMild-to-moderate severity
1b “Attenuated syndromes” More specific syndromes incl. mixedAt least moderate severity
2 Discrete disorders Discrete depr/manic/psych/mixed syModerate-to-severe symptoms
3 Recurrent or persistent disorder
Incomplete remissionRecurrent episodes
4 Severe, persistent and unremitting illness
Chronic deterioratingNo remission for 2 years
Hickie IB et al. Early Interv Psychiatry 2013;7:31.
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HIGH-QUALITYMEDICAL CARE
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“However beautiful the strategy*, you should occasionally look at the results.**”
-Sir Winston Churchill
* = what your clinic does
** = how your patient is doing Haas LF. JNNP 1996;61:465.
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RAISE – baseline cardiovascular risk
• N= 394
• Age
– Mean age 24 (15 to 40)
• Diagnosis
– FES spectrum
• Treatment history
– Mean 46 days
48%
51%
57%
40%
10%
13%
15%
3%
Overweight
Smoking
Dyslipidemia
Prehypertension
Hypertension
Metabolic syndrome
Prediabetes*
Diabetes*
Prevalence
Prevalence
Correll CU et al. JAMA Psychiatry. 2014;71(12):1350-63.*HbA1c based
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Schizophrenia and diabetes
• Diabetes risk– Increased at illness onset1
– Risk increases once antipsychotics introduced2,3
– Insulin sensitivity decreases rapidly after second-generation antipsychotics are started4
– Subtype of schizophrenia5
• “Inherent” diabetes risk versus social determinants of health debate
• Maybe should focus on screening …6
1Pillinger T et al. JAMA Psychiatry. 2017;74(3):261-9. 2Rajkumar AP et al. Am J Psychiatry. 2017;174(7):686-94.3Andreassen OA. Am J Psychiatry. 2017;174(7):616-7. [Editorial] 4Nicole GE et al. JAMA Psychiatry. 2018;75(8):788-796.5Tomasik J et al. JAMA Psychiatry. 2019 [Epub ahead of print]. 6Mangurian C et al. JAMA Psychiatry. 2017;74(7);761-2. [Letter]
Diabetes is a disease that often shows itself in families in which insanity prevails.
- Sir Henry Maudsley, 1879
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Safe medical care: screening
Pringsheim T et al. J Can Acad Child Adolesc Psychiatry. 2011;20(3):218-33.Morrato EH et al. JAMA Psychiatry. 2016;73(7):721-30.Vanderlip ER et al. Am J Psychiatry 2016; 173(7):658-63.See Taking Issue: Mangurian C. Psych Serv. 2017;68(3):213.
PossibleBENCHMARK
80% glucose monitoring(40% lipid monitoring)
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New FDA drug approvals
• 2017: Valbenazine1
– Approved for tardive dyskinesia (TD)– VMAT-2 inhibitor
• 2017: Deutetrabenazine2
– Approved for Huntington’s disease and TD– VMAT-2 inhibitor
• 2017: Proteus sensor for aripiprazole• 2017: Aripiprazole lauroxil long-acting injectable
– 2-month dosage
• 2018: Aripiprazole lauroxil long-acting injectable– New initiation regimen
• 2018: SC risperidone long-acting injectable• 2019: NONE
– Perhaps lumateperone – PDUFA date September 27, 2019
1Freudenreich O and Remington G. Clin Schizophr Relat Psychoses. 2017;11(2):113-119.2Anderson KE et al. Lancet Psychiatry. 2017;4(8):595-604.
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Long-acting injectable antipsychotics
Drug Dose strengths Dose (IM) & Frequency Notes
Haloperidol decanoate[HALDOL DECANOATE]
Vials 50mg/mlVials 100mg/ml
50 - 200 mg monthlyOther dose intervals are possible
Initiation: overlap with oral antipsychoticLoading dose strategy possibleMaintenance dose equals 20 x oral dose
Fluphenazine decanoate[PROLIXIN DECANOATE]
Vials 25mg/ml 6.25 - 25 mg every 2 weeksOther dose intervals are possible
Initiation: overlap with oral antipsychotic
Risperidone microspheres[RISPERDAL CONSTA]
12.5mg, 25 mg, 37.5 mg, 50 mg
12.5-50 mg every 2 weeks Initiation: 3 week overlap with oral antipsychoticMain release of drug occurs 3 weeks after injection50 mg every two weeks corresponds to 4 mg/d oral (50 mg is highest IM dose]
Risperidone long-acting suspension[PERSERIS]
90 mg, 120 mg 90 or 120 mg monthlysubcutaneously
For subcuaneous use90 mg corresponds to 3 mg/d oral120 mg corresponds to 4 mg/d oral
Paliperidone palmitate[INVEGA SUSTENNA]
[INVEGA TRINZA]
39 mg, 78 mg, 117 mg, 156 mg, 234 mg
273 mg, 410 mg, 546 mg, 819 mg
39-234 mg monthly
273-819 mg every 3 months
Loading dose of 234 mg [deltoid!] to initiate (no oral overlap needed), 2nd
dose one week later, the monthly156 mg monthly corresponds to 9 mg/d oralEvery 3 months dose can be used after 4 months of monthly injections546 mg corresponds to 9 mg/d oral
Olanzapine pamoate[ZYPREXA RELVPEVV]
150 mg, 210 mg, 300 mg, 405 mg
150 or 300 mg every 2 weeks405 mg monthly
No overlap with oral antipsychotic (higher initiation doses)Monitor for 3 hours of observation for post-injection delirium/sedation syndrome (PDSS)*300 mg monthly corresponds to 10 mg/d oral
Aripiprazole monohydrate[ABILIFY MAINTENA]
Vials 200 mg/ml 160mg- 400mg monthly Initiation: 2 week overlap with oral antipsychotic300 mg corresponds to 10 mg/d oral; 400 mg to 15 mg/d
Aripiprazole lauroxil[ARISTADA]
441 mg, 662 mg, 882 mg, 1064 mg
441,662,882 mg every 4 weeks882 mg every 6 weeks1064 mg every 2 months
Initiation: 3 week overlap with oral antipsychotic or with initiation regimenInject rapidly due to non-Newtonian fluid characteristicsOnly lowest dose of 441 mg dose can be given in deltoid441 mg monthly corresponds to 10 mg/d oral 662 mg monthly or 1064 mg every two months corresponds to 15 mg/d oral882 mg monthly corresponds to 20 mg/d oral (highest IM dose)
Oral test dose required for all antipsychotic if patient has never been exposed to IM antipsychotic*See REMS website for olanzapine pamoate
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Prodrome
Pre-psychotic phase Critical phase Chronic phase
First episode
Stable disability
Partial recovery
Full recovery
Second episode
Sym
pto
ms,
fu
nct
ion
, dis
abili
ty
Typical course of schizophrenia
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New stage-based insights
GOALS KEY QUESTION
ProdromalPhase
Prevent psychosisPrevent schizophrenia?
Treat with antipsychotic?
AcutePsychosis
Keep DUP shortAchieve initial response and
early positive symptoms remission
Which antipsychotic?Problem: early non-response
(positive Sx)
Post-psychoticPhase
Achieve sustained remissionRecovery and QOLPrevent morbidity
Treat for how long?Problems: early relapse and residual Sx (adherence); risk-
benefit
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PRODROMAL PHASE
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Prodromal schizophrenia
• Prodrome can only be diagnosed in retrospect
• Transition risk for putatively prodromal patients not 100%1
• 18% after 6 months
• 22% after 1 year
• 29% after 2 years
• 36% after 3 years
• Majority will not convert (“false-positive”)
• “Probably at risk, but certainly ill”
• Help-seeking and not well2
1Fusar-Poli P. Arch Gen Psychiatry 2012;69:220.2Lin A et al. Am J Psychiatry 2015;172:249.
PLEIOTROPIC
REVIEWS:Klosterkoetter et al. Dtsch Arztebl Int 2008;105:532.Fusar-Poli et al. JAMA Psychiatry 2013;70:107.Fusar-Poli et al. Psychol Med. 2014;44:17.
BROAD SYNDROME OF MENTAL DISTRESS
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Transition risk prediction
• Challenge of identifying high-risk patients for selective or indicated prevention– Well-established in medicine (e.g., Framingham risk score)
• Two risk predictors:– NAPLS-2 sample1: http://riskcalc.org:3838/napls/
• Need neurocognitive data and data from SIPS interview
– South London and Maudsley NHS Foundation Trust2: http://www.psychosis-risk.net
• Limits of clinical approach in routine care– Low positive predictive value of positive symptoms (less then
2%)3
– Risk predictors are only for patients identified for being at risk– Risk predictors are not for routine screening
NAPLS = North American Prodrome Longitudinal Study1Cannon TR et al. Am J Psychiatry. 2016;173(10):980-8.2Fusar-Poli R et al. JAMA Psychiatry. 2017;74(5):493-500.3Livny A et al. Am J Psychiatry. 2018;175(4):351-358.
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Early intervention CHR guidance
• Assess and treat syndromes (anxiety, depression)• Benign interventions to delay conversion1,2
• CBT should be first-line treatment• Integrated psychological interventions (EDIPPP)3
• Omega-3 fatty acids ineffective;4 NAC?; minocycline?
• Use of antipsychotics• Low-dose second-generation antipsychotic• If severe symptomatology• Not long-term for primarily preventive purpose
• Note: do not treat for pseudo-ADD with stimulants5,6,7
IEPA=International Early Psychosis Association1
EPA = European Psychiatric Association2
1Br J Psychiatry Suppl. 2005 Aug;48:s120.2Schmidt SC et al. Eur Psychiatry 2015;30:388.3McFarlane et al. Schizophr Bull 2015;41:30.
4McGorry PD et al. JAMA Psychiatry. 2017;74(1):19-27.5Freudenreich O et al. Am J Psychiatry 2006;163:2019.6MacKenzie LA et al. Pediatrics 2016;137:1.7Moran LV et al. NEJM. 2019;380(12):1128-38.
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Cannabis guidance
• Clear down-sides– Component risk factor for 12% of schizophrenia1
– Increasingly potent THC products– Destabilizes early course schizophrenia via reduced
adherence2
– Effects on cognition
• CBD oil (brand name Epidiolex) (Schedule V)– 2018 FDA-approved for Lennox-Gastaut and Dravet
syndrome– Off-label prescribing– Minimal research regarding CBD
Pierre JM. Curr Psychiatry. 2019;18(5):13-20.Brunette MF et al. Psychiatr Serv. 2018;69(11):1181-3.1Di Forti M et al. Lancet Psychiatry. 2019;6(5):427-36.2Schoeler T et al. Lancet Psychiatry. 2017;4(8):627-33.
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“Der Ball ist rund und das Spiel dauert 90 Minuten.”
- Sepp Herberger
ACUTE PSYCHOSIS
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Suicide prevention
• Mortality risk in early course schizophrenia– 12-month mortality rate comparable to being age 701
– High-risk period for suicide– Substance-related deaths contribute significantly2
• Participation in early psychosis programs reduces risk of premature death from suicide– PEPP program in greater London, Ontario3
• 75% reduced mortality risk in those in program compared to those who are not
• Higher hospitalization rate for those in program
– EASY program in Hong Kong4
• Reduced suicide risk in 12-year follow-up for those in program
PEPP = Prevention and Early Intervention Program for PsychosesEASY = Early Assessment Service for Young People with Psychosis1Schoenbaum M et al. Schizophr Bull. 2017 Oct 21;43(6):1262-72.2Reininghaus U et al. Schizophr Bull. 2015 May; 41(3): 664–73. [AESOP cohort]3Anderson KK et al. Am J Psychiatry. 2018;175(5):443-52. 4Chan SKW et al. JAMA Psychiatry. 2018;75(5):458-64.
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Substance-induced psychosis
• Danish population-based registry study1,2
– 20-year follow-up– N=6,778– Majority alcohol, cannabis, amphetamines– 32.2% of patients converted to schizophrenia or bipolar disorder
• Substantial differences in conversion rates between substances– Almost 50% if cannabis-induced psychosis
• Half converted within 3 years to schizophrenia• The younger the patient, the higher the conversion risk
• Implications– 50% of cannabis induced psychosis will become schizophrenia– Longer-term follow-up and treatment needed to prevent
schizophrenia?– Are we looking at increased incidence rates of schizophrenia?
• “…drug-precipitated disorder in highly vulnerable individuals”3,4
1Starzer MSK et al. Am J Psychiatry. 2018;175(4):343-50.2Ghose S. Am J Psychiatry. 2018;175(4):303-4. [Editorial]3Kendler KS et al. Am J Psychiatry. 2019;176(9):711-9.4Tandon R and Shariff SM. Am J Psychiatry. 2019;176(9);683-4. [Editorial]
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Antipsychotic choice
• Efficacy1,2
– Antipsychotics not equivalent• Clozapine ES 0.88• Olanzapine ES 0.59• Risperidone ES 0.56
– Overall efficacy for rest• ES 0.33 to 0.50
• Avoid haloperidol in first-episode patients3
• Partial agonist antipsychotics– No higher risk for psychiatric hospitalization when
switching to aripiprazole4
1Smith RC et al. Psychopharmacology. 2019;236(2):545-59.2Leucht S et al. Lancet. 2013;382(9896):951-62.3Zhu Y et al. Lancet Psychiatry. 2017;4(9):649-705. [network meta-analysis]4Montastruc F et al. JAMA Psychiatry. 2019;76(4):409-17.
Choose wisely
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Should you switch antipsychotics?
• Good overall remission rate after 10 weeks of treatment
– 2/3 of patients
• 56% responded in four weeks to amisulpride
• No added benefit from switching to olanzapine
• Some benefit from switching to clozapine (25%) but not as good as responders
Amisulpride
Amisulpride
Clozapine
Olanzapine
Leucht, S et al. Schizophr Bull. 2015;41:549-58.Kahn RS et al. Lancet Psychiatry. 2018; 5(10):797-807.
DOUBLE BLIND
6 w
ks1
2 w
ks4
w
OPTiMiSE = Optimization of Treatment and Management of Schizophrenia in Europe
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Post-Psychotic PhaseChronic phase
Nach dem Spiel ist vor dem Spiel.- Sepp Herberger
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Premise
Schizophrenia is arelapsing-remitting illness
with accrued disability over time.
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Cost of relapse in schizophrenia
• Relapse has psychosocial toxicity– Loss of job– Derailed education– Criminal problems– Suicide– Loss of reputation
• Relapse might be biologically harmful1
– Emergent treatment non-response in 16%
• Sustained remission is basis for accrued treatment benefits over time
1Emsley R et al. J Clin Psychopharmacol. 2013;33(1):80-3.
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Prevention in psychiatry
• Primary prevention
• Secondary prevention – “early intervention”
• Tertiary prevention – minimize disability
Relapse prevention as key goalof schizophrenia care
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Rationale for treatment
Treatment asprevention
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Antipsychotic for relapse prevention
• 50 years of evidence1
• Meta-analysis of N=6493• Median follow-up 26 weeks
• Antipsychotics reduce 1-year relapse rate• Drug 27% versus placebo 64%• RR 0.40 [95% CI 0.33-0.49]• No effect of: number of episodes; length of stability; FGA
vs. SGA; abrupt vs. gradual withdrawal• Limitations
– Limited view of schizophrenia (recovery!)• Long-term cost-benefit (function)2
1Leucht S. Lancet. 2012;379(9831):2063.2Wunderink L et al. JAMA Psychiatry. 2013;70:913.See Goff DC et al. Am J Psychiatry. 2017;1;174(9):840-849.
“The benefit of maintenance drug
treatment is relapse prevention, not
comprehensive treatment of schizophrenia.”
-William Carpenter 2001
“It suggests the disquieting conclusion thatthe benefits of active neuroleptics in reducing relapse may exact a price in occupational terms.”
-Timothy Crow (1980s)
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Antipsychotic discontinuation
• Finish cohort study1,2
– N=8,719 first-episode patients, followed for 20 years – Three main findings
• Antipsychotics reduce relapse risk• Risk of relapse increases with increased treatment duration• Lowest risk of death in continuously treated patients compared to
untreated or minimally treated patients
– Conclusion• Patients stabilized on antipsychotics for several years have a high
relapse risk if antipsychotics are discontinued
• Unclear that diagnosis can be improved by discontinuing antipsychotics3
– Clear risks: higher mortality, reduced responsiveness after relapse
1Tiihonen J et al. Am J Psychiatry. 2018;175(8):765-773.2Kahn RS. Am J Psychiatry. 2018;175(8):712-713. [Editorial]3Sommer I et al. Curr Opin Psychiatry. 2019;32(3):147-156.
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Deprescribing
• Classic study1
– Eliminating a second antipsychotic often possible– Successful switch in 2/3 of patients
• Recent meta-analysis2
– All-cause discontinuation favors staying: RR = 2.28, 95% CI = 1.50-3.46, P < 0.001)
• Prioritize– TD risk: reduce cumulative antipsychotic dose and limit FGA use– Metabolic risk: eliminate high-risk antipsychotics– Cognition: anticholinergics– May want to keep clozapine plus aripiprazole3
– May want to keep antidepressant4
1Essock SM et al. Am J Psychiatry. 2011; 168(7):702-8. 2Matsui K et al. Schizophr Res. 2019 [Epub ahead of print].3Tiihonen J et al. JAMA Psychiatry. 2019 [Epub ahead of print].4Stroup TS et al. JAMA Psychiatry. 2019 [Epub ahead of print].See also behavioral economics (nudging): Sacarny A et al. JAMA Psychiatry. 2018; 75(10):1003-11.
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Long-acting injectable antipsychotic medications
• Relapse risk 20 to 30% lower for LAI compared to oral1
• Shared decision-making should be based on facts– LAI gives real-time, accurate information about adherence
• Greatest benefit if started in hospital on patients who have relapsed because of non-compliance
• A reasonable strategy for patients experiencing a first psychotic episode2
– Avoids family conflict
• Best if employed as part of comprehensive care program– Maintaining frequent clinical contact may be a valid psychosocial
relapse prevention treatment3
• Can be life-saving4
– 30% lower risk LAI compared to oral antipsychotic
• Breakthrough symptoms (hospitalization) still high: 30% incidence5
1Tiihonen J et al. JAMA Psychiatry. 2017 Jul 1;74(7):686-693. 2Subotnik KL et al. JAMA Psychiatry. 2015(8);72:822-9. 3Buckley PF et al. Psychiatr Serv. 2016(12);67:1370-72. 4Taipale H et al. Schizophr Res. 2017 [Epub ahead of print]. 5Rubio JM et al. Psychol Med. 2019 [Epub ahead of print].https://www.thenationalcouncil.org/topics/long-acting-medications/
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Not everyone gets better with first-line antipsychotics
• Move to clozapine1
– Refractoriness
– Aggression and self-injury
• Risks of not prescribing clozapine
– Accruing psychosocial toxicity
– “End-stage” brain disease with poor function
– Polypharmacy
– Higher mortality41Warnez S and Alessi-Severini S. BMC Psychiatry. 2014;14:102.2Demjaha A et al. Psychol Med. 2017;47(11):1981-9.3Tiihonen J et al. JAMA Psychiatry. 2017;74(7):686-93.4Tiihonen J et al. Lancet. 2009;374(9690):620-7.
Clozapine has real-world effectiveness for relapse prevention.3
Over 80% of refractory patients are refractory from the start.2
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TDM – Potential benefits
• Informed decision regarding root causes of treatment complications– Poor response to antipsychotics (25% of patients)
• Pseudo-refractoriness (non-adherence) vs. refractoriness*
– Poor tolerability of antipsychotics (15% of patients)• Slow elimination vs. high drug sensitivity
• Identifies patients at higher relapse risk1
• Indications– Non-response at therapeutic doses– Uncertain drug adherence– Suboptimal tolerability– Pharmacokinetic drug-drug interactions
Predmore Z et al. Psychiatr Serv. 2018;69:12-4.1Melkote R et al. Schizophr Res. 2018; 201:324-328. [CATIE sample]*McCutcheon R et al. Acta Psychiatr Scand. 2018;137(1): 39–46.
*1 in 5 TRS patientsmay have non-detectable drug level.
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Clozapine news
• Effectiveness– Excellent for relapse prevention1
– Clozapine augmentation strategies are limited2
– Clozapine plus aripiprazole prevents hospitalizations3
– Best clinical efficacy (cohort studies)4
• Safety– Diabetes, hyperlipidemia, intestinal obstruction,5 aspiration pneumonia– Safe for benign ethnic neutropenia6
– Feasible to continue during chemotherapy7
• Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program8
– Goal was to increase clozapine use– Replaces multiple registries– Absolute neutrophil count only– Different cut-offs for benign ethnic neutropenia
1Tiihonen J et al. JAMA Psychiatry. 2017;74(7):686-93. 2Correll CU et al. JAMA Psychiatry. 2017;74(7):675-84.3Tiihonen J et al. JAMA Psychiatry. 2019 [Epub ahead of print]. 4Masuda T et al. JAMA Psychiatry. 2019 [Epub ahead of print].5Stroup TS et al. Am J Psychiatry. 2016;173:166-73. 6Manu P et al. J Clin Psychiatry. 2016;77:e909.
7Graininger BT et al. Eur J Haematol. 2019 [Epub ahead of print]. [Review] 8https://www.clozapinerems.com/CpmgClozapineUI/home.u
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Clozapine underutilization
• Clozapine underused in London community settings1
– Point-prevalence of TRS: 56%
– Never received clozapine: 52%
• NASMHDP report: Clozapine underutilization: addressing the barriers2,3
NASMHDP = National Association of State Mental Health Program Directors1Back K et al. J Psychopharmacol. 2019 [Epub ahead of print].2http://www.nasmhpd.org/sites/default/files/Assessment%201_Clozapine%20Underutilization.pdf3Kelly DL et al. Psychiatr Serv. 2018;69(2):224-227.
www.mghcme.orgMarder SR. Am J Psychiatry 2016;173:103
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Treatment for negative symptoms
• SSRI antidepressant1
– Efficacy seen in DECIFER trial for citalopram2
– ES 0.32 (DUP <18 weeks) and 0.52 (DUP >18 weeks)
• Rasagiline3
– MAO-B inhibitor approved for Parkinson’s disease
– Small RTC with benefit for avolition
• CBT for negative symptoms4
• Cariprazine5
• L-methylfolate6 1Smith RC et al. Psychopharmacology. 2019;236(2):545-59.2Goff DC et al. Schizophr Res. 2019;208:331-337. 3Buchanan RW et al. Schizophr Bull. 2015;41(4):900-8.4Perivoliotis D and Cather C. J Clin Psychol. 2009:65(8):815-30.5Nemeth G et al. Lancet. 2017;389(10074):1103-13.6Roffman JL et al. Mol Psychiatry. 2018;23(2):316-22.
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Treatment for CIAS
• Avoid adding insult to injury– Reduce anticholinergic burden
• Short-term and long-term risks (10% of dementia cases)1
– Quit smoking!2
• Consider cognitive training if available3,4
• Psychopharmacology add-on strategies– Numerous pharmacological strategies including
enhancing glutamatergic activity, cholinesterase inhibitors, cannabidiol, alpha-7 nicotinic agonists have failed
– Missing: dopaminergic strategies (COMT inhibitors)5
1Coupland CAC et al. JAMA Intern Med. 2019 [Epub ahead of print]. 2Vermeulen JM et al. Am J Psychiatry. 2018;175(11):1121-8. 3Keshavan MS et al. Am J Psychiatry. 2014;171(5):510-22. Review4Best MW et al. Am J Psychiatry. 2019;176(4):297-306.5Sinkeviciute I et al. NPJ Schizophr. 2018;4:22.
CIAS = Cognitive Impairment Associated with Schizophrenia
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Beyond monitoring: need for action
• Physical health monitoring (screening) alone does not improve mortality
• Improving physical health through intervention1
– Psychiatric stability
– Dietary and exercise interventions
– Choice and duration of antipsychotic prescribing
– Pharmacological support for smoking cessation
– Screening for health conditions
• Correct (standard) medical treatment saves lives2
1Ilyas A et al. Br J Psychiatry. 2017;211:194-96.2Kugathasan P et al. JAMA Psychiatry. 2018;75:1234-40.Ward MC and Druss BG. JAMA Psychiatry. 2019;76(7):759-60. [JAMA Network Insights]
2018
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Keeping patients alive
• Iatrogenic morbidity1
• Example of med-psych integration RTC– HOME study2,3
– Improved quality of care (not clinical outcome…)
• Example of illness self-management RTC– TTIM study4
– Better diabetes control after 60-week intervention
• Example of screening– Screening, Testing, Immunization, Risk-Reduction, Integrated
Treatment (STIRR-IT)5
• Example of optimal cardiovascular care– Secondary prevention of myocardial infarction5
1Correll CU et al. World Psychiatry. 2015;14:119-136. 2Druss BG et al. Am J Psychiatry. 2017;174(3):246-55.3Chwastiak L and Fortney J. Am J Psychiatry. 2017;174(3):199-200. [editorial]4Sajatovic M et al. Psychiatr Serv. 2017 Sep 1;68(9):883-890. 5Arnold RM. Psychiatr Serv. 2018;69(11):1188-90.6Kugathasan P et al. JAMA Psychiatry. 2018; 75(12):1234-40.
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Exercise for schizophrenia patients
• The challenge– Cardiovascular morbidity and mortality in SMI patients– Sedentary life-style associated with poor cognition1
• The simple solution– Exercise is “neuroprotective”– Exercise has broad effects on well-being2
• Improves global cognition3
• Key pathways: inflammatory pathways, BDNF (hippocampus)
• Challenges– Implementation: supported exercise– Maintaining gains: sustaining exercise– Mobile interventions starting to show promise4
1Hamer M et al. Psychol Med. 2009;39:3-11.2Noordsy DL et al. Am J Psychiatry. 2018;175(3):209-214.3Firth J et al. Schizophr Bull. 2017;43:546-556.4Ben-Zeev D et al. Psychiatr Serv. 2018;69(9):978-985.
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Smoking cessation
• Prevalence remains high– 62% in a sample of research patients1
– Smoking affects, among other things, quality of life2
• Address smoking in schizophrenia– Cardiovascular and cancer mortality3
– Cognitive benefits from quitting4
• Improved processing speed (digit symbol coding)
• Smoking cessation principles5
• Varenicline– Efficacy: EAGLES trial6
– Safety: removal of black box warning7
1Dickerson F et al. Psychiatr Serv. 2018;69:147-153. 2Vermeulen J et al. Lancet Psychiatry. 2019;6(1)23-34.3Olfson M et al. JAMA Psychiatry 2015;72(12):1172-81.4Vermeulen JM et al. Am J Psychiatry. 2018;. 175(11):1121-8. 5Cather C et al. CNS Drugs. 2017;31(6):471-81.6Anthenelli RM et al. Lancet. 2016;387(10037):2507-20. [EAGLES trial]7www.fda.gov/downloads/Drugs/DrugSafety/UCM532262.pdf
NeededOpt-out stanceMaintenance treatment
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Acronym Jeopardy
Prodrome Cohorts Treatment
NAPLS SOHO OPTiMiSE
IEPA RAISE EAGLES
CHR GROUP DECIFER
Berkwits M. Ann Intern Med 2000;133(9):755-62.
Capture! Shock! Excite! Clinical trial acronyms and the "branding" of clinical research.
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How do we avoid poor outcomes?
• Poor outcomes so commonly observed in schizophrenia are likely best explained by:– Poor access to treatment– Late engagement in care– Poor engagement in ongoing care/poor adherence– Cumulative negative impact of substance abuse, medical/psychiatric
comorbidities, and multiple social determinants of health
• Antipsychotic adherence to prevent relapse is a critical part of treatment– Increasing role of digital medicine unavoidable*
• Deficits must be realistically assessed and supported• Medical prevention must be part of psychiatric treatment
• 2018 WHO Guidelines for Management of physical health conditions in adults with severe mental disorders**
Zipursky RB. J Clin Psychiatry. 2014;75 Suppl 2:20-24.Fusar-Poli P et al. World Psychiatry. 2017;16(3):251-64.*Buck B et al. Schizophr Res. 2019;208:167-172.**https://www.who.int/mental_health/evidence/guidelines_physical_health_and_severe_mental_disorders/en/
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Sequential antipsychotic trials
• Select• Lowest-risk choice• Patient preference
• LAI acceptable?• Early ancillary medical prevention
• Behavioral interventions• Adjunctive metformin*
• Monitor• Clinical response• Follow antipsychotic monitoring guidelines**
• Step-up• Switch antipsychotics
• Early use of clozapine for refractory patients• Clozapine over polypharmacy
• Add psychological treatments• Treat medical morbidities
**Perfect is the enemy of good.
*Gerken AT et al. Curr Psychiatry. 2016;15(11):e1-2.**Vanderlip ER et al. Psychiatr Serv. 2014;65(5):573-6.
It is not the critic who counts […]. The credit belongs to the
man who is actually in the arena […].
President Theodore Roosevelt (1910)
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Rudolf Virchow
„Die Medizin ist eine soziale Wissenschaft, und die Politik ist nichts weiter als Medizin im Großen.“
- Rudolf Virchow, 1821-1902
Waitzkin H. Social Medicine. 2006;1:5-10.
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John Umstead Hospital, Butner, NC, ca. 1995
Thank you!