Optimizing Management of Schizophrenia (Rao)

11/6/20

OPTIMIZING MANAGEMENT OF SCHIZOPHRENIA

Sanjai Rao, MD Associate Clinical Professor Associate Residency Training Director UCSD Department of Psychiatry Site Director, Residency Training VA San Diego Healthcare System San Diego, CA

Disclosures

• Dr. Rao has been a consultant for and/or on the speaker’s bureau of: • Janssen • Alkermes • Otsuka • Sunovion • Neurocrine

Learning Objectives

• Summarize recent data on novel pharmacologic interventions that address nonadherence and treatment tolerability • Discuss factors that contribute to treatment nonresponse in patients with schizophrenia • Identify patients with treatment-resistant schizophrenia • Review strategies to integrate patient-centered care approaches for the management of patients with schizophrenia

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Medication Adherence & Relapse

• Medication discontinuation is Successive Episodes of Schizophrenia 1 common in schizophrenia Prolong Time to Remission3 • Discontinuation often leads to relapse, even after a single 1stEpisode psychotic episode2 2ndEpisode • Repeated relapses lead to • Prolonged time to remission3 3rd Episode • Treatment resistance/failure2 2 • Overall decline in functional status 0 5 10 15 20 25 30 Time to Re mission (wee ks)

1. Lieberman, et al. N Engl J Med 2005; 353:1209-1223 2. Emsley et al. BMC Psychiatry 2013, 13:50 3. Lieberman JA, et al. Neuropsychopharmacology. 1996; 14(3 suppl): 13S-21S 4

Why Do Patients Stop Meds?

Poor insight and denial of illness

Side Lack of Effects efficacy

Current Treatment Options for Schizophrenia

Improved Neurocognition nd 2 Generation • Working Memory Antipsychotics • Executive Functions • Secondary Verbal Memory • Vigilance, Attention

Anticholinergic Improved Functional Medications Psychotic Symptoms Outcome

+ Associations Strong Conventional Improved Moderate Antipsychotics Negative Symptoms Weak ‒ Associations Moderate Weak Adapted from: Green MF, et al. Schizophr Bull. 1999;25(2):309-319. 6

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Patients with Acute Schizophrenia Improving at Least ”Minimally” or “Much”

≥ 20% PANSS/BPRS Reduction ≥ 50% PANSS/BPRS Reduction or at Least Minimally Improved on CGI or at Least Much Improved on CGI (N=8918) (N=8403) 100 100

90 At least 90 At least “Minimal Response”: “Good Response”: 80 NNT: 5 80 NNT: 8 (95% Crl: 4–5) (95% Crl: 6–11) 70 70 51% 60 60

50 50 30% 40 40 23% 30 30 14% 20 20 Treatment Responders (%) Treatment Responders (%)

Weighted Average Percentage 10 Weighted Average Percentage 10

0 0 Antipsychotic Placebo Antipsychotic Placebo Error bars represent 95% credible intervals. BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression – Improvement; NNT = number needed to treat; PANSS = Positive and Negative Syndrome Scale. Leucht S, et al. Am J Psychiatry. 2017;174(10):927-942. 7

Adverse Events Lead to Nonadherence

Impact of AEs on Treatment Adherence Agitation Constipation Decreased interest in sex Difficult or painful menstrual periods Difficulty thinking or concentrating Dizziness Increased blood glucose levels Insomnia Male breast enlargement or secretions Nausea/vomiting Restlessness/feeling jittery Sedation Sexual dysfunction Sleepiness Tremors Weight gain

0 0.50 1.00 1.50 2.00 2.50 3.00 3.50 Adjusted odds ratios

AE=adverse event. Odds ratios based on multivariable logistic regression with adherence as dependent variable. Adherence defined as a score of zero on the Morisky Medication Adherence Scale. Side effect was reported as present and “somewhat,” “very,” or “extremely bothersome.” 95% confidence intervals are indicated. Dibonaventura M et al. BMC Psychiatry. 2012;12:20.

Odds ratios based on multivariable logistic regression with adherence as dependent variable. Dibonaventura M, et al. BMC Psychiatry. 2012;12:20. 8

Predictors of Nonresponse

• Lack of early antipsychotic response • Nonadherence to antipsychotics • Comorbidities (especially substance use)

Longer duration of untreated psychosis

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TREATMENT STRATEGIES

Antipsychotic Efficacy vs. Side Effects

• 1st vs. 2nd generation is not the way to think about relative efficacy • Some 2nd (and 1st) generation drugs are better than others • Drugs that treat overall and positive symptoms the best are also the best at treating negative symptoms (with some exceptions) • Some (but not all) 2nd generation drugs have more metabolic side effects • There is a real difference in EPS between 1st and 2nd generation drugs, but also some surprises

1st vs. 2nd Generation Antipsychotic Efficacy

Clozapine Olanzapine Risperidone Perphenazine Paliperidone

Haloperidol

Quetiapine Aripiprazole Ziprasidone Asenapine Lurasidone Pimavanserin Cariprazine Iloperidone Huhn M, et al. Lancet. 2019;394(10202):939-951. 12

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1st vs. 2nd Generation Antipsychotic EPS

Clozapine

Iloperidone Olanzapine Quetiapine

Paliperidone Aripiprazole Ziprasidone

Risperidone

Perphenazine Loxapine Haloperidol Lurasidone*

Huhn M, et al. Lancet. 2019;394(10202):939-951. 13

Antipsychotic Associated Weight Gain

Ziprasidone Lurasidone Aripiprazole Brexpiprazole Cariprazine Haloperidol

Clozapine Quetiapine Iloperidone Chlorpromazine Olanzapine

Huhn M, et al. Lancet. 2019;394(10202):939-951. 14

Initial Treatment Recommendations

• Start with lower metabolic risk agents (which also have low or modest EPS risk) • Aripiprazole, brexpiprazole, cariprazine (partial agonists) • Lurasidone, ziprasidone

• Transition to potentially higher efficacy (but also higher metabolic and/or EPS risk) agents • Risperidone à olanzapine

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Treatment Resistance Schizophrenia

Unlike treatment responsive patients, those with treatment resistant schizophrenia (TRS) tend to have: • Glutamatergic abnormalities • Lack of dopaminergic abnormalities • Significant decreases in prefrontal grey matter • Higher familial loading

Treatment Resistance – Clinical Definition

• Persistent significant schizophrenia symptoms, despite: • At least two antipsychotic trials of adequate dose, duration, and adherence • 6 weeks of treatment on adequate therapeutic dose • Recommended (but not required): at least one long acting injection trial x 4 months • Alternatively, use plasma levels to verify adherence

Advantages of Long Acting Injections

• If the patient takes the injection, adherence is assured • Stable plasma levels with less peak to trough fluctuation • Equal or increased efficacy • Sometimes fewer side effects than oral counterparts • Lack of adherence can be rapidly identified and acted upon • No immediate drop in drug levels

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LAI Options

• Risperidone/paliperidone • Risperidone microspheres (Consta) • Risperidone subcutanous (Perseris) • Paliperidone palmitate monthly (Sustenna) • Paliperidone palmitate 3-months (Trinza) • Aripiprazole • Aripiprazole monohydrate (Maintenna) • Aripiprazole lauroxil (Aristada) • Olanzapine • Olanzapine palmoate (Relprevv) • 1st Generation • Haloperidol decanoate (Haldol Dec) • Fluphenazine decanoate (Prolixin Dec)

Clozapine is Still the Gold Standard

Clozapine +/- another antipsychotic was better than almost all other options

Clozapine + aripiprazole performed better than other combinations

Next best options all involve a long-acting injection

Tiihonen J, et al. JAMA Psychiatry. 2019;76(5):499-507. 20

MANAGING SIDE EFFECTS

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Treatment of Acute/Subacute EPS

• Dystonia • Anticholinergic agents • Akathisia • Propranolol • Benzodiazepines • Mirtazapine • Parkinsonism • Amantadine • Anticholinergic agents

Tardive Dyskinesia

Short Answer: It still happens, and you can’t always fix it

Longer Answer: • Less common with 2nd generation antipsychotics • About 1%/year risk with risperidone, up to 4%/year with haloperidol • More common when antipsychotics are used in mood disorders

• Likely pathophysiology: D2 antagonism à compensatory response • More D2 receptors • Increased D2 receptor sensitivity • Increased presynaptic dopamine release • Oxidative cell damage à perhaps why some cases are irreversible

Tardive Dyskinesia Treatment

Classic Strategy: Lower D2 antagonism burden, hope for the best • Dose reduction • Switch from 1st generation to 2nd generation antipsychotic • Switch to 2nd generation antipsychotic with lower D2 potency • Switch to clozapine

Problem:

• Initially may get worse due to reduced D2 antagonism • Withdrawal dyskinesia • Sometimes won’t get better

Bhidayasiri R, et al. J Neurol Sci. 2018;389:67-75. Ricciardi L, et al. Can J Psychiatry. 2019;64(6):388-399. Caroff SN, et al. J Clin Psychiatry. 2020;81(2):19cs12983. 24

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Tardive Dyskinesia Treatment

New Strategy: Reduce pre-synaptic dopamine output with VMAT2 inhibitor • Tetrabenazine* was the prototype, but can cause depression, parkinsonism due to some active metabolites • Valbenazine: tetrabenazine metabolite, longer half-life, highly selective for VMAT2 • Deutetrabenazine: tetrabenazine with deuterium substitution à much longer half-life

Not as good, but cheaper: • Ginkgo biloba* (reduce oxidative damage?)

Bottom Line • Try classic strategy first, but now there are options if that doesn’t work

*Off-label; VMAT = vesicular monoamine transporter. Bhidayasiri R, et al. J Neurol Sci. 2018;389:67-75. Ricciardi L, et al. Can J Psychiatry. 2019;64(6):388-399. Caroff SN, et al. J Clin Psychiatry. 2020;81(2):19cs12983. 25

Prolactin Elevation

Short Answer: It’s all about D2 antagonism

Longer Answer: • Tuberoinfundibular pathway regulates prolactin • (hypothalamus à pituitary) • Inhibited by endogenous dopamine

• D2 antagonism increases prolactin output

Haloperidol Risperidone Paliperidone

Labad J, et al. Data Brief. 2020;31:105904. Huhn M, et al. Lancet. 2019;394(10202):939-951. 26

Prolactin Elevation

• Classic Strategy: Basically the same as TD à lower D2 burden • Dose reduction • Switch to drug with lower D2 potency • Switch to clozapine • Bromocriptine* (D2 agonist) has also been used, but risk of increased psychosis • New Strategy: Add low dose aripiprazole* • Multiple RCTs show reduction in prolactin • Typically only need 5 mg/day (range 2.5-10 mg) • Mechanism: aripiprazole binds D2 receptor with much higher affinity than any 1st/2nd generation D2 antagonist

*Off-label. Labad J, et al. Data Brief. 2020;31:105904. 27

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Antipsychotic Associated Weight Gain

Short Answer: Lots of reasonable approaches, no guarantees

Longer Answer:

• Mechanism unknown, but thought to be combination of 5-HT2C antagonism and H1 antagonism • Clozapine and olanzapine are inverse agonists • Risperidone doesn’t do much at either receptor • Aripiprazole, ziprasidone, lurasidone are partial agonists at 5-HT2C, very little H1 activity

Marteene W, et al. Expert Opin Drug Saf. 2019;18(12):1149-1160. 28

Antipsychotic Associated Weight Gain

Ziprasidone Lurasidone Aripiprazole Brexpiprazole Cariprazine Haloperidol

Clozapine Quetiapine Iloperidone Chlorpromazine Olanzapine

Huhn M, et al. Lancet. 2019;394(10202):939-951. 29

Antipsychotic Associated Weight Gain: Treatment

• Conventional Options: • Lifestyle: Can work, but many can’t follow it • Switch drug: Can work, but no guarantee of efficacy with second drug

• What about dose reduction? • Within FDA dose range, metabolic effects are mostly dose independent

• Adjunctive Treatment* • Metformin • Topiramate

*These medications are not FDA approved for antipsychotic associated weight gain.

Marteene W, et al. Expert Opin Drug Saf. 2019;18(12):1149-1160. 30

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Antipsychotic Associated Weight Gain

Bottom Line

Try to prevent it by using lower metabolic risk agents first, especially earlier in illness course

Strongly consider putting clozapine and olanzapine patients on adjunctive metformin

A FEW NEW OPTIONS

Lumateperone for Metabolic Symptoms

Switching from other antipsychotic to lumateperone led to • 60x higher affinity to 5-HT2A significantly improved metabolic, endocrine, and weight than D2 parameters at week 6, trending back within 2 weeks after • Presynaptic agonist and switching back to another antipsychotic Lumateperone 42 mg SOC 5 postsynaptic antagonist at D2 4 * Prolactin (ng/mL) • Presynaptic agonism à less 3 * Triglycerides (mg/dL) 2 Glucose (mg/dL) dopamine release 1 HDL cholesterol (mg/dL) 0 Weight (kg) -1 * Total cholesterol (mg/dL) • Placebo level effects on: * Insulin (mcIU/mL) -2 * LDL cholesterol (mg/dL) • EPS -3

Change -4 • Akathisia -5 -6 • Weight gain -7 -8 • Metabolic parameters -9 -10 • Prolactin levels Baseline Day 42 Day 56

Vanover K, et al. Long-Term S afety for Lumateperone (ITI-007) in the Treatment of Schizophrenia. Presented at: ACNP 57th Annual Meeting; December 9–13, 2018; Hollywood, Florida. 33

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Pimavanserin for Negative Symptoms

4 • Indicated for psychosis in Placebo PIM 20 mg PIM 34 mg Parkinson’s disease 2 0 At Week 26: -2 PIM 20 mg D=0.5 • Inverse agonist/antagonist -4 P=.6847 at 5-HT -6 2A ES=0.06 -8 -10

• No direct action at Score NSA Total -12 dopamine, adrenergic, Baseline from Change At Week 26: -14 PIM 34 mg histamine, serotonin, or -16 D=3.1 cholinergic receptors -18 P=.065 -20 ES=0.34 WeekWeek Week 8 Week 14 Week 20 Week 24 2 4 Baseline Study Visit

Data on file with Acadia Pharmaceuticals. ClinicalTrials.gov Identifier: NCT02970305. ClinicalTrials.gov Identifier: NCT03121586. 34

Olanzapine/Samidorphan for Weight Gain • Under investigation for prevention of weight gain from olanzapine • Samidorphan = μ-opioid antagonist • May reduce perceived reward from food intake • Similar (but lower magnitude) effect also observed with naltrexone

7 5

6 4 5 3 4

3 2

2 Olanzapine 1

1 Combined Olanzapine/Samidorphan Waist Circumference Waist Circumference Change from Baseline in Baseline from Change Change from Baseline in Baseline from Change 0 0 0 1 2 4 6 8 12 16 20 24 0 1 2 4 6 8 12 16 20 24 Study Week Study Week

Correll CU, et al. Am J Psychiatry. 2020 Aug 14 [OAP]. 35

PATIENT CENTERED CARE

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Models of Care

• Traditional medical • Clinician provides expert diagnosis and prescribes treatment • Patient follows this plan • Collaborative • Clinician tries to understand patient perspective on illness experience, past treatment experiences • Address beliefs about risks/benefits, try to correct misunderstandings about treatment • Patient ultimately chooses course of treatment

Collaborative Care and Adherence

• Cognitive behavior therapy, motivational interviewing • Engage family members, support network • Simplify medication regimen and/or dosing frequency • Monitor adherence to oral medication • Brief Adherence Rating Scale • Encourage the use of LAIs early in the treatment course!

Medication Adherence & Relapse

1. Lieberman, et al. N Engl J Med 2005; 353:1209-1223 2. Emsley et al. BMC Psychiatry 2013, 13:50 3. Lieberman JA, et al. Neuropsychopharmacology. 1996; 14(3 suppl): 13S-21S 39

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Mirror-Image LAI Studies Show Reduced Risk of Hospitalization vs. Orals

STUDY NAME RISK RATIO AND 95% CI RR P VALUE Girardi et al. 2010 0.024 0.0091 Beauclair et al. 2005 0.092 0.0000 LAIs showed Arató & Erdós 1979 0.204 0.0000 Devito et al. 1978 strong superiority 0.281 0.0000 Denham & Adamson 1971 over oral APs in 0.333 0.0000 preventing Morritt 1974 0.343 0.0000 hospitalization Lam et al. 2009 0.369 0.0000 Lindholm 1975 0.391 0.0004 Peng et al. 2011 0.452 0.0000 Gottfries & Green 1974 0.529 0.0046 Rosa et al. 2012 0.529 0.0944 Chang et al. 2012 0.557 0.0000 Johnson & Freeman 1972 0.570 0.0000 Crivera et al. 2011 0.597 0.0001 Ren et al. 2011 0.663 0.0000 Svestka et al. 1984 1.286 0.5694

Total (16 studies; n=4066) 0.430 0.0000 0.10 1.00 10.00 Favors LAI Favors oral APs Kishimoto T et al. J Clin Psychiatry. 2013 Oct;74(10):957-965. 40

60 Day Rehospitilization Risk Is Lower With LAI, Even After 1st Hospitalization

Adjusted Hazard Group 95% CI P Ratio

Any depot vs. equivalent oral 0.36 0.17–0.75 0.007

Haloperidol depot vs. 0.12 0.01–1.13 0.06 haloperidol oral

Risperidone depot vs. 0.57 0.30–1.08 0.09 risperidone oral

Tiihonen J et al. Am J Psychiatry. 2011 Jun;168(6):603-609. 41

Why Don’t We Use LAIs More Often?

• 90% of psychiatrists never/rarely recommend an LAI after first episode and only 50% recommend LAIs after multiple relapses1 • Historically, we have been trained that they are only for treatment resistant and non-adherent patients

APA suggests that patients receive treatment with a long-acting injectable antipsychotic medication if they prefer such treatment or if they have a history of poor or uncertain adherence.

1. Jaeger M, Rossler W. Psychiatry Res 2010;175(1-2):58-62.

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Will Patients Actually Take LAIs?

• Patient “preference” requires good patient education • There are negative, neutral, and positive ways of offering an LAI • In one study, 96% of patients were willing to try an LAI after a positive offer1

Negative Neutral Positive • “Since you’re not • “So… do you want to • “Would it be nicer for taking your meds, I take pills or get the you to take your think you should go shot?” medication once a on the shot.” month instead of every day?”

1. Weiden et al. J Clin Psychiatry. 2015 Jun;76(6):684-90. 43

SUMMARY

• Medication discontinuation is common in schizophrenia, and leads to relapse, treatment resistance, and poor outcomes • Individual antipsychotics have differences in efficacy and side effects that should be accounted for in initial treatment choice • Treatment resistant schizophrenia appears to be biologically distinct; gold standard treatment is clozapine • New treatment options and emerging medications can help us manage some antipsychotic related side effects

SUMMARY

• Patient centered care is collaborative, and involves therapeutic approaches, engaging the support network, and simplifying the medication regimen • LAIs have been demonstrated to reduce relapse rates and rehospitalization, and should be encouraged early in treatment • With good education, many patients will be willing to take an LAI

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THANK YOU!

QUESTIONS?