Overview Treatment Goals First Episode Optimizing Treatment in - - PDF document

Optimizing Treatment in Schizophrenia: An Update

Christoph U. Correll, MD

Professor of Psychiatry, Hofstra Northwell School of Medicine Hempstead, New York Medical Director, Recognition and Prevention Program The Zucker Hillside Hospital Glen Oaks, New York

Overview

• Treatment Goals
• First Episode
• Chronic Schizophrenia
• Maintenance Treatment
• Treatment Resistance
• Adverse Effects
• Medications in Development
• Conclusions

Exacerbation

Illness Severity

Response Recovery Acute Stabilization Relapse Maintenance Treatment Phase Resistance

18%–65% (FES: 40%–87%) 10%–45% (FES: 5%–10%) 13.5% [8%–20%]† (FES: 16.6%†) Any duration‡: 57.3% Any duration: 44% (7%–52%) (FES: 17%–81%)

Remission

Remission: 6 mo: 44% 12 mo: 52% 24 mo: 47% > 24 mo: 49%

FES = first-episode schizophrenia. †Median [interquartile range]; ‡In antipsychotic discontinuation studies. Carbon M, et al. Dialogues Clin Neurosci. 2014;16(4):505-524.

Illness Phases

Exacerbation

Illness Severity

Response Recovery Acute Stabilization Relapse Maintenance Treatment Phase Resistance

18%–65% (FES: 40%–87%) 10%–45% (FES: 5%–10%) 13.5% [8%–20%]† (FES: 16.6%†) Any duration‡: 57.3% Any duration: 44% (7%–52%) (FES: 17%–81%)

Remission

Relapse (placebo‡): ≤ 3 mo: 37% 4–6 mo: 50% 7–12 mo: 64% 13–36 mo: 79% Relapse (FES): 12 mo: 16% 24 mo: 54% 36 mo: 63% 48 mo: 75% 60 mo: 82%

FES = first-episode schizophrenia. †Median [interquartile range]; ‡In antipsychotic discontinuation studies. Carbon M, et al. Dialogues Clin Neurosci. 2014;16(4):505-524.

Illness Phases

First Episode

N = 13, n = 2509. CGI-S = Clinical Global Impression – Severity; FGA = first-generation antipsychotic; SGA = second-generation antipsychotic. Zhang JP, et al. Int J Neuropsychopharmacol. 2013;16(6):1205-1218.

Randomized Trials of SGAs vs FGAs in First-Episode Schizophrenia

A Randomized Comparison of Aripiprazole and Risperidone for the Acute Treatment of FES and Related Disorders: 3-Month Outcomes

ARI = aripiprazole; RIS = risperidone; LDL = low-density lipoprotein; NOS = not otherwise specified; RCT = randomized controlled trial. Robinson DG, et al. Schizophr Bull. 2015;41(6):1227-1236.

• First large scale, double-masked, randomized comparison of aripiprazole (5–30

mg/day) vs risperidone (1–6 mg/day) in FES

• 198 patients, 15–40 years old, with schizophrenia, schizophreniform disorder,

schizoaffective disorder, or psychosis NOS

• Antipsychotic treatment ≤ 2 weeks lifetime
• 12-week RCT yielded no difference in:

– Positive symptom response rate (ARI = 62.8% vs RIS = 56.8%, P = .61) – Time to response (8.0 vs 8.2 weeks) – Change in total (P = .32) or positive symptoms (P = .96) or CGI-S (P = .57) – Body weight gain

• Superiority of risperidone (mean dose: 3.2 mg/day) for

– Less akathisia (P = .03), but only early on in the trial (weeks 1–4)

• Superiority of aripiprazole (mean dose: 14.8 mg/day) for

– Negative symptoms: Avolition-apathy (P = .03) – Depressed mood (P = .02) – Total cholesterol (P = .003), LDL-cholesterol (P < .01), fasting glucose (P = .03) – Prolactin levels (P < .0001).

Recovery after an Initial Schizophrenia Episode– Early Treatment Program (RAISE-ETP)

Kane JM, et al. J Clin Psychiatry. 2015;76(3):240-246.

• N = 404 (394 with cardiometabolic data)
• Age: 15–40 years
• Diagnoses: Schizophreniform disorder, schizophrenia,

schizoaffective disorder, psychotic disorder NOS, acute psychotic disorder

• < 6 months antipsychotic treatment
• Cluster randomized assignment of 34 centers to

integrated care (NAVIGATE) or community care

• Treatment and follow-up for ≥ 2 years
• Primary outcome: Quality of life
• Secondary outcomes: Service utilization, cost,

subjective well-being, relapses, hospitalization, recovery, cardiometabolic health

NAVIGATE

Kane JM, et al. J Clin Psychiatry. 2015;76(3):240-246.

Team-based Shared decision making Strength and resiliency focus Psychoeducational teaching skills Motivational enhancement teaching skills Collaboration with natural supports 4 components

• 1. Psychopharmacology – COMPASS
• 2. Individual Resiliency Training (IRT)
• 3. Family psychoeducation
• 4. Supported employment/education

Demographics Adjusted for Cluster Design

Kane JM, et al. Am J Psychiatry. 2016;173(4):362-372.

NAVIGATE Community Care P value Age and Gender Age (mean) 23.5 23.2 Males (%) 77.6 66.2 .05 Race White (%) 65.9 49.9 African American (%) 25.4 44.1 Other (%) 8.7 6.0 Role Functioning In school (%) 14.9 25.5 .03 Working (%) 12.6 16.6 Prior Hospitalization (%) 76.2 81.6 .05

NAVIGATE Participants Stayed in Treatment Longer

Time to Last Mental Health Visit (P = .009)

Kane JM, et al. Am J Psychiatry. 2016;173(4):362-372.

Quality of Life Scale Fitted Model

DUP = duration of untreated psychosis; QLS = Quality of Life Scale. Kane JM, et al. Am J Psychiatry. 2016;173(4):362-372.

Group by Time Interaction (P = .015) DUP by Time Interaction (P = .003)

PANSS Total Score Change over 2 Years

Median DUP = 74 weeks. PANSS = Positive and Negative Syndrome Scale. Kane JM, et al. Am J Psychiatry. 2016;173(4):362-372.

Group by Time Interaction : P = .016 DUP by Time Interaction: P = .043

% With Any Work or School Days / Month

(Group by time interaction: P = .044)

Kane JM, et al. Am J Psychiatry. 2016;173(4):362-372.

Months

Time to First Psychiatric Hospitalization

(Difference between treatments, P = .75)

Kane JM, et al. Am J Psychiatry. 2016;173(4):362-372.

First-Episode Schizophrenia: Key Points

• First-episode patients are generally more treatment

responsive

• They require lower doses (~ 50%)
• They are more sensitive to side effects
• Relapse is very common
• While acute efficacy might be similar with FGAs and

SGAs, relapse and treatment discontinuation seem to be higher with FGAs

• Multidisciplinary interventions focusing on engagement,

treatment continuation, relapse prevention, physical health, and functional recovery are paramount

Multi-episode / Chronic Multiple Treatments Meta-Analysis

Leucht S, et al. Lancet. 2013;382(9896):951-962.

Aim

• Create hierarchy for 15 antipsychotic

drugs

• Efficacy and major side effects
• Direct and indirect comparisons
• Includes some treatments without a

European Union license for schizophrenia (sertindole, iloperidone, zotepine, ziprasidone, asenapine) Data set

• 212 RCTs
• Acute schizophrenia
• 43,049 participants
• Mean illness duration: 12.4 years
• Mean age: 38.4 years

Network of comparisons for efficacy

Forrest Plot: Efficacy of Antipsychotics vs Placebo

1, 2, or 3 asterisks: Significant separation from placebo; **Significant separation from agents with 1 asterisk; ***Significant separation from all other agents; a: Only superior to lurasidone and iloperidone; b: Only superior to iloperidone; SMD +/- 95% CIs. Leucht S, et al. Lancet. 2013;382(9896):951-962.

The differences in efficacy between non-clozapine, first- line antipsychotics were small: Standardized mean differences: 0.0–0.33, median = 0.11 Antipsychotics differed substantially in side effects: Standardized mean differences: 0.11– 1.52, median = 0.34 (body weight) and 0.49 (prolactin)

Magnitude PANSS Total Change on Placebo over Time in Trials of Acute Schizophrenia

Alphs L, et al. Int J Neuropsychopharmacol. 2012;15(7):1003-1014.

Maintenance

What is the Importance of Relapse Prevention?

• 1. Harrison G, et al. Br J Psychiatry. 2001;178:506-517. 2. Herings RM, et al. Pharmacoepidemiol Drug Saf.

12(5):423-424. 3. Lieberman JA, et al. Neuropsychopharmacology. 1996;14(Suppl 3):13S-21S. 4. Lieberman JA, et al. Psychiatr Serv. 2008;59(5):487-496. 5. Kane JM. J Clin Psychiatry. 2007;68 Suppl 14:27-30.

Clinical Predictors of Poor Outcomes in the Long-Term Course of FES*

*Based on longitudinal first-episode samples. Carbon M, et al. Dialogues Clin Neurosci. 2014;16(4):505-524.

Depot antipsychotics reduced relapse (RR 0.31, 95% CI 0.21–0.41) more than oral drugs (0.46, 0.37–0.57; P = .03). In a meta- regression, drug-placebo advantages decreased with study length. Leucht S, et al. Lancet. 2012;379(9831):2063-2071.

Antipsychotics vs Placebo for Relapse Prevention in Schizophrenia

Antipsychotics vs Placebo for Relapse Prevention in Schizophrenia

Depot antipsychotics reduced relapse (RR 0.31, 95% CI 0.21–0.41) more than oral drugs (0.46, 0.37–0.57; P = .03). In a meta- regression, drug-placebo advantages decreased with study length. Leucht S, et al. Lancet. 2012;379(9831):2063-2071.

Antipsychotics vs Placebo for Relapse Prevention in Schizophrenia

Depot antipsychotics reduced relapse (RR 0.31, 95% CI 0.21–0.41) more than oral drugs (0.46, 0.37–0.57; P = .03). In a meta-regression, drug-placebo advantages decreased with study length. Leucht S, et al. Lancet. 2012;379(9831):2063-2071.

Indirect Comparison: LAIs and Oral Antipsychotics Compared with Placebo for Relapse Prevention

LAI = long-acting injectable antipsychotic. Leucht S, et al. Lancet. 2012;379(9831):2063-2071.

Test for subgroup differences: P = .03, I2 = 77.9%

Characteristics of Selected FGA and SGA LAIs

Correll CU, et al. J Clin Psychiatry. 2016;77(suppl 3):1-24.

No Differences in Study-Defined Relapse/All-Cause Discontinuation between LAIs and Oral Antipsychotics

1966–2012; 21 RCTs, N = 5176; > 6 months follow-up, in- and outpatients. AP = antipsychotic. Kishimoto T, et al. Schizophr Bull. 2014;40(1):192-213.

0.01 0.10 1.00 10.00 Risk ratio (95% CI) N studies Total RR P value

Relapse

Fluphenazine 8 826 0.79 0.02 Haloperidol 1 25 0.99 0.97 Olanzapine LAI 2 1445 1.08 0.65 Risperidone LAI 9 2608 0.98 0.88 Zuclopenthixol 1 46 1.28 0.56 Total 21 4950 0.93 0.35

All-cause discontinuation

Fluphenazine 7 721 1.00 0.98 Haloperidol 1 29 0.79 0.52 Olanzapine LAI 2 1445 1.24 0.25 Risperidone LAI 9 2641 1.00 0.98 Zuclopenthixol 1 46 0.51 0.44 Total 20 4882 1.03 0.65

No difference in adherence between pooled LAIs and oral APs (only measured in 2 studies)

Favors LAI Favors oral APs

LAIs Were Not Superior to Oral Antipsychotics Regarding Adherence

Meta-analysis of 10 RCTs in schizophrenia followed for ≥ 6 months

Kishimoto T, et al. Schizophr Bull. 2014;40(1):192-213.

LAIs Reduce Risk of Hospitalization Compared with Oral Antipsychotics in Mirror Image Studies

1966–2012; 25 mirror-image studies; N = 5940; > 6 months follow-up Kishimoto T, et al. J Clin Psychiatry. 2013;74(10):957-965.

Study RR P value Girardi et al. 2010 0.024 0.009 Beauclair et al. 2005 0.092 <0.001 Arato & Erdos 1979 0.204 <0.001 Devito et al. 1978 0.281 <0.001 Denham & Adamson 1971 0.333 <0.001 Morritt 1974 0.343 <0.001 Lam et al. 2009 0.369 <0.001 Lindholm 1975 0.391 <0.001 Peng et al. 2011 0.452 <0.001 Gottfries & Green 1974 0.529 0.005 Rosa et al. 2012 0.529 0.094 Chang et al. 2012 0.557 <0.001 Johnson & Freeman 1972 0.570 <0.001 Crivera et al. 2011 0.597 <0.001 Ren et al. 2011 0.663 <0.001 Svestka et al. 1984 1.286 0.569

Total (16 studies) (n = 4066) 0.430 <0.001

Medication Possession Ratio Improved following Initiation of LAIs

*Patients ≥ 13 years old were identified using an ICD-9 diagnosis of schizophrenic disorders (295.xx)

• n administrative claims, which includes schizophrenia, schizophreniform disorder, and

schizoaffective disorder. MPR = medication possession ratio. Offord S, et al. J Med Econ. 2013;16(2):231-239.

MPR (%) MPR (%)

In an analysis of US databases, patients* who initiated LAI antipsychotics demonstrated an improvement in MPR

P < .001

Commercially Insured (n = 394)

P < .001

Medicare Insured (n = 147)

LAIs Significantly Improve Treatment Outcomes in Patients with Schizophrenia

2000–2007; nationwide register study; follow-up after first admission for schizophrenia. Tiihonen J, et al. Am J Psychiatry. 2011;168(6):603-609.

Risk of discontinuation or rehospitalization after a first hospitalization for schizophrenia, by antipsychotic treatment (n = 2588)

33% vs 5% Relapse in 86 FES Patients Randomized to Oral RIS vs RIS LAI

Excellent adherence: RIS = 33%, RIS LAI = 95%. Subotnik KL, et al. JAMA Psychiatry. 2015;72(8):822-829.

Treatment Resistance

Management of Treatment-Resistant Patients

Kane JM, et al. UptoDate. 2016. www.uptodate.com/contents/topic.do?topicKey=PSYCH/14808. Accessed June 5, 2017.

Network Meta-Analysis of Head-to-Head Trials of APs vs Clozapine in Treatment-Resistant Schizophrenia: Total Symptoms

Samara MT, et al. JAMA Psychiatry. 2016;73(3):199-210. Correll CU, et al. JAMA Psychiatry. 2017;[Epub ahead of print].

Psychopharmacologic Augmentation of Any AP: Total Symptoms

AMSTAR= A MeaSurement Tool to Assess systematic Reviews.

Shea BJ, et al. BMC Med Res Method. 2007;7:10. Correll CU, et al. JAMA Psychiatry. 2017;[Epub ahead of print].

AMSTAR-Plus Content Score Items

A. AMSTAR-Plus Content Score

• 1. Was the majority of all meta-analyzed

studies double-blind? □ Can’t answer/ Double-blind studies: < 84% of all included studies □ Double-blind studies: 85%–94% of all included studies □ Double-blind studies: 95%–100% of all included studies 0 Points 1 Point 2 Points

• 2. Was the total number of participants in the

meta-analysis sufficiently large? □ Can’t answer / Total n < 500 □ Total n = 500–999 □ Total n ≥ 1000 0 Points 1 Point 2 Points

• 3. Was the meta-analytically derived primary
• utcome result confirmed in at least 1 large

study with approximately 100 patients/arm? □ Can’t answer/Not confirmed in study with n ≥ 200 □ Confirmed in a 2-arm study with n ≥ 200 □ Confirmed in a 3-arm study with n ≥ 300 0 Points 1 Point 2 Points

• 4. Were studies with observed cases

analyses included in the meta-analysis? □ Can’t answer/ Yes □ No 0 Points 1 Point

• 5. Was the primary outcome result

heterogeneous? □ Can’t answer/Yes □ No (Q statistic = P > .05 and I2 < 50%) 0 Points 1 Point

• 6. Was there significant publication bias

regarding the primary outcome result? □ Can’t answer/Yes □ No (Egger’s test P > .05, symmetrical funnel plot) 0 Points 1 Point

Adverse Effects

Adverse Effects Considered by Patients’ Relatives to Have Most Negative Effects on Quality of Life

Angermeyer MC, et al. Psychiatr Prax. 1999;26(4):171-174.

5 10 15 20 25 50 45 30 35 40

Sedation Weight gain Parkinsonism Anticholinergic effects Acute dystonia Insomnia Hypersalivation Akathisia Sexual dysfunction Anxiety

Relatives Listing Adverse Effect (%) Written survey of relatives of patients with schizophrenia, N = 320

Adverse Events Considered by Patients to Have Most Negative Effect on Quality of Life

UNITE survey was an Internet-based multinational survey with 1155 respondents with schizophrenia and 1300 respondents with bipolar disorder from 11 countries. McIntyre RS. J Clin Psychiatry. 2009;70 Suppl 3:5-11. 38 29 24 20 16 10 20 30 40

Weight gain Somnolence/insomnia Concentration difficulties Memory loss Disorganized thoughts

Patients Reporting Adverse Event Prevalence (%)

Patients rated metabolic consequences of medication to contribute to morbidity, low quality of life, and low satisfaction with care

Relapse and Adverse Efffects Reduce Quality of Life in Patients with Schizophrenia

*The relevance of the different health states was assessed using a Time-Tradeoff instrument. Higher scores reflect better utility for the patient. EPS = extrapyramidal side effects. Briggs A, et al. Health Qual Life Outcomes. 2008;6:105. Stable Schizophrenia 0.92

Mean Utility-Score*

Stable Schizophrenia with Weight Gain Stable Schizophrenia with Hyperprolactinemia Stable Schizophrenia with Diabetes Stable Schizophrenia with EPS Relapse 0.83 0.82 0.77 0.72 0.60 Dyslipidemia: TG ≥ 150 mg/dL, LDL-C or non-HDL-C: ≥ 130 mg/dL; HDL-C for males < 40 mg/dL, for females < 50 mg/dL. TG = triglyceride; HDL = high-density lipoprotein. Correll CU, et al. JAMA Psychiatry. 2014;71(12):1350-1363.

RAISE: Smoking, Lipid Abnormalities, Hypertension, Diabetes, and Metabolic Syndrome with Related Drug Rx

Medical Risk Management Strategies of Antipsychotic-Treated Patients

Correll CU. CNS Spectr. 2007;12(10 Suppl 17):12-20, 35.

Treatment Initiation

• Healthy lifestyle counseling
• Healthy lifestyle intervention
• Start with lower-risk antipsychotic

PRIMARY

If Adverse Effect Is Present

• Healthy lifestyle counseling/intervention
• Consider changing to lower-risk antipsychotic
• Consider weight loss intervention

SECONDARY

If Adverse Effect Progresses/Serious

• Healthy lifestyle counseling/intervention
• Considering changing to lower-risk antipsychotic
• Add targeted treatment for pathological values
• Consider referral to specialist

TERTIARY

PREVENTION

Treatment Initiation

• Healthy lifestyle counseling
• Healthy lifestyle intervention
• Start with lower-risk antipsychotic

PRIMARY

If Adverse Effect is Present

• Healthy lifestyle counseling/intervention
• Consider changing to lower-risk antipsychotic
• Consider weight loss intervention

SECONDARY

If Adverse Effect Progresses/Serious

• Healthy lifestyle counseling/intervention
• Considering changing to lower-risk antipsychotic
• Add targeted treatment for pathological values
• Consider referral to specialist

TERTIARY

PREVENTION

Medications in Development

Köster LS, et al. Expert Opin Emerg Drugs. 2014;19(4):511-531.

Targets of Phase 2 and Phase 3 Agents for Schizophrenia

Targets of Phase 2 and Phase 3 Agents for Schizophrenia (cont’d)

Recently Approved and Active Phase 3 Agents Pursued by the Pharmaceutical Industry and Academia

Garay RP, et al. Expert Opin Pharmacother. 2016;17(7):921-936. SCZ Target

Schizophrenia Schizophrenia Schizophrenia

• Neg. SXS

Tardive dyskinesia Cannabis Use

• Neg. SXS, Cognition
• Neg. SXS, Cognition

Schizophrenia Weight Loss Schizophrenia Schizophrenia Schizophrenia Schizophrenia

• Neg. SXS

Schizophrenia

• Neg. SXS

N = 335 N = 450 N = 696

ITI-007 (Lumateperone) for Acute Schizophrenia

Vanover KE, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL.

ITI-007 (Lumateperone) for Acute Schizophrenia

Vanover KE, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL.

MIN-101 for Negative Symptoms

Davidson M, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL.

MIN-101 for Negative Symptoms

Davidson M, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL.

ALKS-3831 (Olanzapine + Samidorphan) (ALKS-33 – μ Opioid Antagonist) for Schizophrenia

Silverman B, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; June 22-25, 2015; Miami, FL.

ALKS-3831 (Olanzapine + Samidorphan) (ALKS-33 – μ Opioid Antagonist) for Schizophrenia

Silverman B, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; June 22-25, 2015; Miami, FL.

Vesicular Monoamine Transporter Type 2

https://lookfordiagnosis.com/mesh_info.php?term=Vesicular+Monoamine+Transport+Proteins&lang=1.

VMAT2 is a protein concentrated in the human brain that is primarily responsible for re-packaging and transporting monoamines (dopamine, norepinephrine, serotonin, and histamine) in pre-synaptic neurons

Deutetrabenazine vs Placebo

N = 117. *P = .007; †P = .019. AIMS = Abnormal Involuntary Movement Scale. Fernandez HH, et al. Neurology. 2017;88(21):2003-2010.

* †

Deutetrabenazine significantly improved AIMS scores from baseline to Week 12 compared with placebo (-3.0 vs -1.6 , P = .019)

KINECT 3: Change in AIMS total Score from Baseline

Hauser RA, et al. Am J Psychiatry. 2017;174(5):476-484.

Valbenazine for Tardive Dyskinesia: Phase 3 Trial (KINECT 3)

AIMS Scores by Study Visit in Extension Phase (ITT)

Grigoriadis D, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL.

Conclusions

• Schizophrenia is a severe disorder that often has a

chronic and debilitating course

• Early interventions are hoped to delay or prevent the
• nset of the disorder and to reduce morbidity
• Due to lack of reliable intra-individual response

predictors, antipsychotic choice needs to be tailored to patient characteristics and needs

• Broadly similar efficacies of antipsychotics (except for

clozapine) make optimization of safety and tolerability a significant goal in individualized drug selection

• Maintenance medication is essential to prevent

relapses—and nonadherence, often associated with adverse effects, is a leading cause of relapse

• Novel mechanisms, biomarkers, and personalized

medicine are needed